Nickel Background EU Risk Assessment Report March 2008 Final Draft
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Nickel Background EU Risk Assessment Report March 2008 Final Draft

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Nickel compounds are considered as human carcinogens based on epidemiological studies, mechanistic information and evidence from animal studies. The overall findings indicate that nickel ions ...

Nickel compounds are considered as human carcinogens based on epidemiological studies, mechanistic information and evidence from animal studies. The overall findings indicate that nickel ions generated in target cells are determinants for the carcinogenic process.

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Nickel Background EU Risk Assessment Report March 2008 Final Draft Nickel Background EU Risk Assessment Report March 2008 Final Draft Document Transcript

  • Nickel and nickel compounds Background Document in support of individual RISK ASSESSMENT REPORTS of nickel compounds prepared in relation to Council Regulation (EEC) 793/93 Final version March 2008Chapters 0, 1, 2, 4, 5, 6 and 7 – human health only. Danish Environmental Protection Agency
  • R_NickelBackground_0308_hh_chapter0124567.docInformation on the Rapporteur.The Danish Environmental Protection Agency is the Rapporteur for the risk assessment reports of metallicnickel, nickel sulphate, nickel chloride, nickel nitrate and nickel carbonate. The Rapporteur is responsible for thecontents of this report.Contact persons:Poul Bo Larsen & Henrik TyleChemicals DivisionDanish Environmental Protection AgencyStrandgade 29DK-1401 Copenhagen KDENMARKTel: +45 72 54 40 00E-mail: HTY@mst.dk / PBL@mst.dk / DEPA-ESR@mst.dkAcknowledgements.The scientific assessments included in this Background report have been prepared by the following organisationsby order of the Rapporteur: • Danish National Working Environment Authority (Occupational Exposure, Chapter 4) • Danish Technological Institute (Aquatic effects Assessment, Chapter 3) • Department of Toxicology and Risk Assessment, Danish Food and Veterinary Research, (Consumer and Indirect Exposure, Human health effects, Chapter 4) • National Environmental Research Institute, Denmark (Terrestrial effects Assessment, Chapter 3). • URS Corporation, London, UK (Chapter 3, UK environment exposure)The Rapporteur would also like to acknowledge the contributions from the following individuals: • Professor Aage Andersen and Dr. Tom K. Grimsrud of the Cancer Registry of Norway, Institute of Population-based Cancer Research, for their assistance in the preparation of the section on nickel carcinogenicity in Chapter 4, • Ivor Kirman, London, UK for general information about nickel, • Drs. Hudson Bates, Adriana Oller, Katherine Heim, Lisa Ortego, and Chris Schlekat, NiPERA, Durham, North Carolina, USA, for providing information on the health and environmental effects of nickel, • Jim Hart, Sherborne, Dorset, UK, for the preparation of Chapters 1, and 2, and sections of Chapters 4 and 7, • Professor Torkil Menné MD, Gentofte Hospital, Copenhagen, Denmark for his assistance in the preparation and critical review of the sections on the sensitising effects of nickel in Chapter 4, • Dr. Sally Pugh Williams, Inco, Wales, UK for general information on nickel. 2
  • R_NickelBackground_0308_hh_chapter0124567.doc Foreword to Draft Risk Assessment ReportsRisk assessment of priority substances is carried out in accordance with Council Regulation (EEC) 793/93 (EEC,1993b) on the evaluation and control of the risks of “existing” substances. Regulation 793/93 provides asystematic framework for the evaluation of the risks to human health and the environment of these substances ifthey are produced or imported into the Community in volumes above 10 tonnes per year.There are four overall stages in the Regulation for reducing the risks: data collection, priority setting, riskassessment and risk reduction. Data provided by Industry are used by Member States and the Commissionservices to determine the priority of the substances which need to be assessed. For each substance on a prioritylist, a Member State volunteers to act as “Rapporteur”, undertaking the in-depth Risk Assessment and ifnecessary, recommending a strategy to limit the risks of exposure to the substance.Denmark is Rapporteur for five nickel substances: nickel metal, nickel sulphate, nickel chloride, nickel nitrateand nickel carbonate. This Background Report has been prepared by the Rapporteur for a number of reasons.Firstly, this Background report includes general information about nickel that is common to all the individualreports. This is particularly relevant for information about the release of nickel into the environment, and manyof the environmental properties of nickel. This background report also provides information about other nickelcompounds for which separate reports are not being prepared, but where information on their properties is usefulfor drawing conclusions on the hazards and risks of the five specific substances under review. Finally, this reportprovides a brief review of the other nickel compounds on the EU market to provide a starting point for furtherassessment of their hazards and risks.Draft Risk Assessment Reports on nickel metal and other nickel compounds are currently under discussion in theCompetent Group of Member State experts with the aim of reaching consensus. During the course of thesediscussions, the scientific interpretation of the underlying scientific information may change, more informationmay be included and even the conclusions reached in this draft may change. The Competent Group of MemberState experts seek as wide a distribution of these drafts as possible, in order to assure as complete and accuratean information basis as possible. The information contained in these Draft Risk Assessment Reports do not,therefore, necessarily provide a sufficient basis for decision making regarding the hazards, exposures or the risksassociated with the priority substances under consideration.This Draft Background Risk Assessment Report is the responsibility of the Member State rapporteur. In order toavoid possible misinterpretations or misuse of the findings in this draft, anyone wishing to cite or quote thisreport is advised to contact the Member State rapporteur beforehand. 3
  • R_NickelBackground_0308_hh_chapter0124567.docCONTENTS0. OVERALL RESULTS OF THE RISK ASSESSMENT........................... 91. GENERAL SUBSTANCE INFORMATION ......................................... 10 1.1 NICKEL AND NICKEL COMPOUNDS 10 1.2 PHYSICO-CHEMICAL PROPERTIES OF SELECTED NICKEL COMPOUNDS. 10 Solubility of nickel compounds................................................................................................ 12 1.2.1 Summary....................................................................................................................................... 13 1.2.2 1.3 CLASSIFICATION. 14 1.3.1 Current classification ................................................................................................................ 14 1.3.1.1 UN Transport labelling. 14 1.3.1.2 Classification according to Directive 67/548/EEC. 15 1.3.2 Proposed classification ............................................................................................................. 22 1.3.2.1 UN Transport labelling. 22 1.3.2.2 Classification according to Directive 67/548/EEC. 222. GENERAL INFORMATION ON EXPOSURE TO NICKEL AND NICKEL COMPOUNDS......................................................................... 24 2.1 SOURCES OF NICKEL. 24 2.1.1 Industrial production and use of nickel and nickel compounds...................................................... 24 2.1.1.1 Production. 24 2.1.1.1.1 Mining .............................................................................................................................. 24 2.1.1.1.2 Beneficiation and smelting ............................................................................................... 26 2.1.1.1.3 Refining............................................................................................................................ 26 2.1.1.1.4 Nickel chemicals production. ........................................................................................... 26 2.1.1.1.4.1 High production volume nickel containing chemicals. 26 2.1.1.1.4.2 Low production volume nickel containing chemicals. 28 2.1.1.1.4.3 Other low production volume nickel containing chemicals. 30 2.1.1.2 Nickel Use. 31 2.1.1.2.1 Uses of nickel and nickel compounds .............................................................................. 32 2.1.1.2.1.1 High production volume nickel-containing chemicals. 32 2.1.1.2.1.2 Low production volume nickel-containing chemicals. 33 2.1.1.2.1.3 Other low production volume nickel-containing chemicals. 34 2.1.1.2.2 Uses of nickel containing products................................................................................... 35 2.1.1.3 Disposal. 35 2.1.1.4 Nickel emissions from production and use of nickel and nickel-containing chemicals and products. 35 2.1.2 Other anthropogenic sources of nickel........................................................................................... 36 2.1.2.1 Non-ferrous metals production. 36 2.1.2.2 Combustion processes. 36 2.1.2.3 Other Industrial Processes. 37 2.1.2.4 Emission to soil. 38 2.1.3 Natural sources of nickel................................................................................................................ 38 2.1.3.1 Nickel emissions from natural sources. 39 2.1.4 Summary of nickel exposure information. ...................................................................................... 40 2.1.4.1 Trends in nickel emissions. 40 2.1.5 Nickel Lifecycle. ............................................................................................................................. 40 2.2 LEGISLATIVE CONTROLS. 41 2.2.1 General Measures. ......................................................................................................................... 41 2.2.1.1 Directive 67/548/EEC on dangerous substances. 41 2.2.1.2 Directive 1999/45/EC on dangerous preparations. 41 2.2.1.3 Other EU legislation. 41 2.2.1.4 National Initiatives. 42 2.2.2 Protection of workers. .................................................................................................................... 42 2.2.3 Protection of consumers. ................................................................................................................ 44 4
  • R_NickelBackground_0308_hh_chapter0124567.doc 2.2.3.1 Directive 98/83/EC on the quality of water intended for human consumption 45 2.2.3.2 Food contact materials, Food supplements, additives and contaminants. 45 2.2.3.3 Council Directive 90/385/EEC on active implantable Medical Devices, Council Directive 93/42/EEC on Medical Devices and Council Directive 98/79/EEC on in vitro-diagnostic Medical Devices 45 2.2.3.4 Council Directive 88/378/EEC on the Safety of Toys 46 2.2.3.5 Council Directive 89/106/EEC on Construction Products 46 2.2.3.6 Directive 2001/95/EC on general product safety 46 2.2.4 Emissions to water.......................................................................................................................... 46 2.2.4.1 Directive 96/61/EC concerning integrated pollution prevention and control (IPPC) 46 2.2.4.2 Directive 76/464/EEC on pollution of the aquatic environment by certain dangerous substances. 47 2.2.4.3 Directive 2000/60/EC establishing a framework for Community action in the field of water policy. 47 2.2.4.4 Directive 80/68/EEC on the protection of groundwater against pollution caused by certain dangerous substances 47 2.2.4.5 Directive 2000/76/EC on the incineration of waste. 48 2.2.4.6 National Legislation. 48 2.2.5 Emissions to air .............................................................................................................................. 49 2.2.5.1 Directive 96/61/EC concerning integrated pollution prevention and control (IPPC) 49 2.2.5.2 Directive 96/62/EC on ambient air quality assessment and management. 49 2.2.5.3 Directive 2000/76/EC on the incineration of waste. 50 2.2.5.4 Directive 2001/80/EC on Large Combustion Plant Directive. 50 2.2.5.5 UN ECE Protocol on heavy metals. 50 2.2.5.6 National Legislation. 50 2.2.5.7 Other measures. 50 2.2.6 Soil.................................................................................................................................................. 51 2.2.6.1 Directive 86/278/EEC on Sludge in Agriculture. 51 2.2.6.2 National Legislation. 51 2.2.7 Waste management......................................................................................................................... 52 2.2.7.1 Directive 96/61/EC concerning integrated pollution prevention and control 52 2.2.7.2 Council Directive 91/689/EEC of 12 December 1991 on hazardous waste 523. ENVIRONMENT .................................................................................... 534. HUMAN HEALTH ................................................................................. 54 4.1 HUMAN HEALTH (TOXICITY) 54 4.1.1 Exposure assessment. ..................................................................................................................... 54 4.1.1.1 General 54 4.1.1.2 Occupational exposure. 54 4.1.1.3 Consumer exposure. 54 4.1.1.3.1 Exposure to nickel in food................................................................................................ 54 4.1.1.3.2 Exposure to nickel in water .............................................................................................. 57 4.1.1.3.3 Combined exposure to nickel from food and drinking water. .......................................... 58 4.1.1.3.4 Exposure to nickel from smoking..................................................................................... 59 4.1.1.4 Indirect exposure via the environment 59 4.1.2 Human health effects assessment.................................................................................................... 59 4.1.2.1 Toxico-kinetics, metabolism and distribution 60 4.1.2.1.1 Absorption ........................................................................................................................ 60 4.1.2.1.1.1 Inhalation 60 4.1.2.1.1.1.1 Discussion and conclusion, absorption following inhalation ................................................ 62 4.1.2.1.1.2 Oral 64 4.1.2.1.1.2.1 Discussion and conclusion, absorption following oral administration .................................. 66 4.1.2.1.1.3 Dermal 67 4.1.2.1.1.3.1 Discussion and conclusion, absorption following dermal contact......................................... 68 4.1.2.1.1.4 Other routes 68 4.1.2.1.2 Distribution and elimination............................................................................................. 69 4.1.2.1.2.1 Transport 69 4.1.2.1.2.2 Distribution 69 4.1.2.1.2.3 Transplacental transfer 70 5
  • R_NickelBackground_0308_hh_chapter0124567.doc 4.1.2.1.2.4 Cellular uptake 71 4.1.2.1.2.5 Elimination 72 4.1.2.1.2.6 Transfer to the milk 73 4.1.2.1.3 Conclusions ...................................................................................................................... 744.1.2.2 Acute toxicity 75 4.1.2.2.1 Animal studies.................................................................................................................. 75 4.1.2.2.1.1 Inhalation 75 4.1.2.2.1.2 Oral 76 4.1.2.2.1.3 Dermal 76 4.1.2.2.1.4 Other routes 76 4.1.2.2.2 Human studies .................................................................................................................. 76 4.1.2.2.3 Discussion and conclusion ............................................................................................... 77 4.1.2.2.3.1 Inhalation 77 4.1.2.2.3.2 Oral 77 4.1.2.2.3.3 Dermal 774.1.2.3 Irritation /corrosivity 78 4.1.2.3.1 Animal studies.................................................................................................................. 78 4.1.2.3.1.1 Skin and eye irritation 78 4.1.2.3.1.2 Respiratory irritation 79 4.1.2.3.2 Human data....................................................................................................................... 79 4.1.2.3.2.1 Skin irritation 79 4.1.2.3.2.2 Respiratory irritation 80 4.1.2.3.2.3 Conclusion 804.1.2.4 Sensitisation 81 4.1.2.4.1 Skin sensitisation.............................................................................................................. 81 4.1.2.4.1.1 Animal studies 81 4.1.2.4.1.2 Human data 82 4.1.2.4.1.2.1 Nickel allergy........................................................................................................................ 82 4.1.2.4.1.2.2 Mechanism for the development of nickel allergy. ............................................................... 83 4.1.2.4.1.2.3 Immunological tolerance....................................................................................................... 83 4.1.2.4.1.2.4 Occurrence of nickel allergy ................................................................................................. 83 4.1.2.4.1.2.5 Hand eczema......................................................................................................................... 86 4.1.2.4.1.2.6 Experimental sensitisation .................................................................................................... 86 4.1.2.4.1.2.7 The ability of nickel salts, nickel and nickel alloys to elicit nickel allergy ........................... 86 4.1.2.4.1.2.7.1 Skin contact ................................................................................................................... 86 4.1.2.4.1.2.7.2 Oral challenge................................................................................................................ 89 4.1.2.4.1.2.7.3 Hyposensitisation .......................................................................................................... 90 4.1.2.4.1.2.8 Occupational nickel allergy .................................................................................................. 90 4.1.2.4.1.3 Conclusion on skin sensitisation 91 4.1.2.4.1.3.1 Thresholds for elicitation ...................................................................................................... 92 4.1.2.4.1.3.1.1 Skin................................................................................................................................ 92 4.1.2.4.1.3.1.2 Oral................................................................................................................................ 92 4.1.2.4.2 Respiratory sensitisation................................................................................................... 92 4.1.2.4.2.1 Conclusion on respiratory sensitisation 92 4.1.2.4.3 Conclusion........................................................................................................................ 934.1.2.5 Repeated dose toxicity 93 4.1.2.5.1 Animal studies.................................................................................................................. 93 4.1.2.5.1.1 Inhalation 95 4.1.2.5.1.1.1 NTP studies of nickel sulphate hexahydrate, nickel subsulphide and nickel oxide............... 95 4.1.2.5.1.1.1.1 16-day rat studies........................................................................................................... 95 4.1.2.5.1.1.1.2 16-day mouse studies..................................................................................................... 96 4.1.2.5.1.1.1.3 13-week rat studies ........................................................................................................ 97 4.1.2.5.1.1.1.4 13-week mouse studies.................................................................................................. 98 4.1.2.5.1.1.1.5 2-year rat studies............................................................................................................ 99 4.1.2.5.1.1.1.6 2-year mouse studies ..................................................................................................... 99 4.1.2.5.1.1.2 Other inhalation studies ...................................................................................................... 100 4.1.2.5.1.1.3 Supporting mechanistic data for lung effects ...................................................................... 101 4.1.2.5.1.2 Oral 102 4.1.2.5.1.3 Dermal 102 4.1.2.5.2 Conclusion...................................................................................................................... 102 4.1.2.5.2.1 Inhalation 102 4.1.2.5.2.2 Oral 103 4.1.2.5.2.3 Dermal 1034.1.2.6 Mutagenicity 103 6
  • R_NickelBackground_0308_hh_chapter0124567.doc 4.1.2.6.1 Summary of mutagenicity test results for the five selected nickel compounds. ............. 103 4.1.2.6.1.1 Summary of mutagenicity test results in vitro. 103 4.1.2.6.1.1.1 DNA damage and repair. .................................................................................................... 103 4.1.2.6.1.1.2 Gene mutation..................................................................................................................... 104 4.1.2.6.1.1.3 Chromosomal effects. ......................................................................................................... 105 4.1.2.6.1.1.4 Cell transformation. ............................................................................................................ 106 4.1.2.6.1.2 Summary of mutagenicity test results in vivo. 106 4.1.2.6.1.2.1 DNA damage and repair. .................................................................................................... 106 4.1.2.6.1.2.2 Gene mutations. .................................................................................................................. 107 4.1.2.6.1.2.3 Chromosomal effects. ......................................................................................................... 107 4.1.2.6.2 Genotoxicity of other nickel compounds........................................................................ 108 4.1.2.6.2.1 Other soluble nickel compounds. 108 4.1.2.6.2.2 Insoluble compounds. 108 4.1.2.6.3 Conclusions on the mutagenicity of the five selected nickel compounds....................... 1104.1.2.7 Carcinogenicity 112 4.1.2.7.1 Animal data .................................................................................................................... 112 4.1.2.7.1.1 Inhalation 112 4.1.2.7.1.1.1 Nickel sulphate ................................................................................................................... 112 4.1.2.7.1.1.2 Nickel metal........................................................................................................................ 112 4.1.2.7.1.1.3 Nickel chloride, nickel nitrate, and nickel carbonate .......................................................... 114 4.1.2.7.1.1.4 Nickel oxide........................................................................................................................ 114 4.1.2.7.1.1.5 Nickel subsulphide.............................................................................................................. 114 4.1.2.7.1.2 Oral 114 4.1.2.7.1.2.1 Nickel sulphate ................................................................................................................... 114 4.1.2.7.1.2.2 Nickel chloride, nickel nitrate, nickel carbonate, and nickel metal ..................................... 115 4.1.2.7.1.2.3 Nickel acetate...................................................................................................................... 115 4.1.2.7.1.3 Dermal 115 4.1.2.7.1.3.1 Nickel sulphate, nickel chloride, nickel nitrate, nickel carbonate, and nickel metal ........... 115 4.1.2.7.1.3.2 Other nickel compounds ..................................................................................................... 115 4.1.2.7.1.4 Other routes of administration 115 4.1.2.7.1.4.1 Nickel sulphate ................................................................................................................... 115 4.1.2.7.1.4.2 Nickel chloride.................................................................................................................... 116 4.1.2.7.1.4.3 Nickel nitrate....................................................................................................................... 117 4.1.2.7.1.4.4 Nickel carbonate ................................................................................................................. 117 4.1.2.7.1.4.5 Nickel metal........................................................................................................................ 117 4.1.2.7.1.4.6 Other nickel compounds ..................................................................................................... 118 4.1.2.7.1.5 Initiator-Promoter studies 118 4.1.2.7.1.5.1 Nickel sulphate ................................................................................................................... 118 4.1.2.7.1.5.2 Nickel chloride.................................................................................................................... 119 4.1.2.7.1.5.3 Nickel metal........................................................................................................................ 120 4.1.2.7.1.5.4 Nickel nitrate, nickel carbonate........................................................................................... 120 4.1.2.7.1.5.5 Other nickel compounds ..................................................................................................... 120 4.1.2.7.1.6 Discussion and conclusions, carcinogenicity in experimental animals 121 4.1.2.7.1.6.1 Inhalation ............................................................................................................................ 121 4.1.2.7.1.6.2 Oral ..................................................................................................................................... 123 4.1.2.7.1.6.3 Dermal ................................................................................................................................ 123 4.1.2.7.1.6.4 Other routes of administration ............................................................................................ 123 4.1.2.7.1.6.5 Initiator-Promoter studies ................................................................................................... 124 4.1.2.7.1.6.6 Conclusions in reviews on nickel compounds..................................................................... 125 4.1.2.7.1.6.6.1 CSTEE (2001) ............................................................................................................. 125 4.1.2.7.1.6.6.2 TERA (1999) ............................................................................................................... 125 4.1.2.7.1.6.6.3 IARC (1999)................................................................................................................ 125 4.1.2.7.1.6.6.4 NiPERA (1996) ........................................................................................................... 125 4.1.2.7.1.6.6.5 IPCS (1991) ................................................................................................................. 125 4.1.2.7.1.6.6.6 IARC (1990)................................................................................................................ 125 4.1.2.7.1.7 Conclusion, carcinogenicity in experimental animals 126 4.1.2.7.2 Human data..................................................................................................................... 126 4.1.2.7.2.1 Epidemiology 126 4.1.2.7.2.2 Exposures 127 4.1.2.7.3 Discussion ...................................................................................................................... 128 4.1.2.7.4 Overall Conclusion for carcinogenicity.......................................................................... 1304.1.2.8 Toxicity for reproduction 131 4.1.2.8.1 Effects on fertility........................................................................................................... 131 4.1.2.8.1.1 Animal studies 131 4.1.2.8.1.2 Human data 132 7
  • R_NickelBackground_0308_hh_chapter0124567.doc 4.1.2.8.2 Developmental toxicity .................................................................................................. 132 4.1.2.8.2.1 Animal studies 132 4.1.2.8.2.1.1 Oral exposure...................................................................................................................... 132 4.1.2.8.2.1.2 Inhalation ............................................................................................................................ 132 4.1.2.8.2.1.3 Other routes ........................................................................................................................ 133 4.1.2.8.2.2 Human data 133 4.1.2.8.3 Conclusions .................................................................................................................... 133 4.1.3 Risk characterisation.................................................................................................................... 134 4.2 HUMAN HEALTH (PHYSICO-CHEMICAL PROPERTIES) 134 4.2.1 Exposure assessment .................................................................................................................... 134 4.2.2 Effects assessment: ....................................................................................................................... 134 4.2.2.1 Explosivity 134 4.2.2.2 Flammability 134 4.2.2.3 Oxidising potential 134 4.2.3 Risk characterisation.................................................................................................................... 1345. CONCLUSIONS/RESULTS ................................................................. 1356. REFERENCES ...................................................................................... 1367. APPENDICES ....................................................................................... 154 7.1 WATER SOLUBILITY OF SELECTED NICKEL COMPOUNDS. 154 7.2 NICKEL AND NICKEL COMPOUNDS IN EINECS 155 7.2.1 Nickel, nickel compounds, and complex substances containing nickel included in EINECS. ...... 155 7.2.2 Nickel compounds included in Elincs ........................................................................................... 164 7.2.3 Additional Nickel compounds included in TSCA (through 08/2000) but not included in EINECS. ...................................................................................................................................................... 165 7.2.4 Additional Nickel compounds listed in ECICS (European Customs Inventory of chemical substances), but not included in EINECS or the TSCA Inventory. ............................................... 166 7.2.5 Additional Nickel compounds in Annex I to Directive 67/548/EEC but not in EINECS or TSCA.166 7.2.6 Additional nickel compound found in the course of compiling the inventory of nickel compounds ...................................................................................................................................................... 166 7.2.7 Additional nickel hydroxycarbonate compounds not included in the lists above ......................... 167 7.2.8 Nickel containing minerals (from IARC, 1990 and NiPERA, 1996)............................................. 167 7.3 NICKEL CONTENT IN FOOD. 168 8
  • R_NickelBackground_0308_hh_chapter0124567.doc0. OVERALL RESULTS OF THE RISK ASSESSMENTThe risk assessment of the production and use of metallic nickel, nickel sulphate, nickel chloride, nickelcarbonate and nickel nitrate is described in the individual risk assessment reports on these substances.A full risk assessment of the production and use of the other nickel compounds described in this report has notbeen attempted by the Rapporteur, as these other nickel compounds are not included in a priority list under theExisting Substances Regulation. However, the Rapporteur considers that the approach used in the riskassessments of the five nickel compounds listed above may prove helpful to others when preparing a riskassessment for specific nickel compounds.Risk characterisations of scenarios not directly related to the production and use of nickel and nickel compounds(e.g. combustion processes) where exposure to nickel occurs is outside the scope of these risk assessments. 9
  • R_NickelBackground_0308_hh_chapter0124567.doc1. GENERAL SUBSTANCE INFORMATION1.1 NICKEL AND NICKEL COMPOUNDSNickel can be found in a variety of oxidation states ranging from 0 to IV. However, Ni (II) is the only oxidationstate occurring in ordinary chemistry. Ni (III) and Ni (IV) occur in certain complexes and in specific oxidesystems, the higher oxidation states, however, being considerably less stable than Ni (II). Ni (0) and Ni (I)compounds are scarce (Cotton & Wilkinson, 1968, quoted from Carlsen, 2001a).Ni (II) forms a wide variety of compounds ranging from simple inorganic complexes (salts) to complexes withvarious organic ligands. Ni can be found in various oxides. It appears that in the aqueous chemistry Ni (II) is theonly oxidation state that has to be considered. In the absence of strong complexing agents Ni (II) appears inaqueous solution as the green hexaquonickel (II) ion Ni (H2O)62+ (Cotton & Wilkinson, 1968, quoted fromCarlsen, 2001a).There are over three hundred entries in EINECS for nickel and nickel compounds and other, often complex,substances containing nickel. These are shown in Appendix 7.2.1. It should be noted that the EINECS reportingrules (CEC, 1982) implicitly include hydrates of the anhydrous salts listed in EINECS. Hence the numbers ofsubstances (and the numbers of CAS numbers) implicitly included in EINECS is much greater than this figure.Three nickel compounds are included in Einecs (Appendix 7.2.2).An additional 40 nickel containing compounds not listed in EINECS but included in the US EPA TSCAinventory are shown in Appendix 7.2.3.A number of nickel compounds are included in the European Customs Inventory of Chemical Substances(ECICS, 1997). ECICS includes a numerical list showing correlations between the CAS number and the EUCUS number (a five-digit number). Appendix 7.2.1 also includes the CUS numbers where relevant. It can beseen that whilst most HPVC nickel compounds have individual CUS numbers, there are several LPVC chemicalsthat do not. Similarly, there are many nickel compounds that have individual CUS numbers, although accordingto the information in IUCLID, they do not appear to be marketed in significant quantities. Additional compoundslisted in ECICS (the European Customs inventory of chemical substances) not included in either EINECS orTSCA are shown in Appendix 7.2.4.Substances in the ECICS are included in the European Community’s Combined Nomenclature (eight digit CNcode). The CN is based on the “Harmonized Commodity Description and Coding System” emanating fromWCO, in use throughout the world. Nickel metal, nickel sulphate and nickel chloride have CN numbers thatidentify these substances individually. Nickel oxides and hydroxides are identified under a separate CN No.(2825 40 00). However, other nickel compounds are included in CN numbers that also include varying numbersof other non-nickel-containing compounds.Appendix 7.2.5 shows additional substances included as part of group entries in Annex I to Directive67/548/EEC but not included in the previous lists. Finally, other nickel containing compounds (includingminerals and other nickel compounds listed in IARC) not included in any of the lists above are shown inAppendices 7.2.6, 7.2.7 and 7.2.8.1.2 PHYSICO-CHEMICAL PROPERTIES OF SELECTED NICKEL COMPOUNDS.Table 1.2.A shows the physical-chemical properties of some nickel compounds shown in order of decreasingwater solubility. Data for the four high volume nickel compounds for which individual reports have beenprepared are included for comparison. This data has been compiled from a number of reviews of nickel andnickel compounds. A more detailed discussion of the water solubility of nickel and nickel compounds is given inthe following section.Table 1.2.A: Summary of physical properties of selected nickel compounds (compiled from UKHSE, 1987, IARC, 1990, NiPERA, 1996, TERA, 1999)Nickel Atomic Physical Melting Boiling Density Oxidation Watercompound: weight State Point (°C) Point (g/cm3) state Solubility (°C) 3) 10
  • R_NickelBackground_0308_hh_chapter0124567.docnickel chloride 237.70 solid - - 1.92 +2 2540 g/l at(hexahydrate) 20°C.nickel nitrate 290.79 solid 56.7 136.7 1) 2.05 +2 2385 g/l at(hexahydrate) 0°C.nickel sulphate 280.85 solid 99 - 1.95 +2 756 g/l at(heptahydrate) 20°C.nickel chloride 129.60 solid 973 2) 1001 3.55 +2 642 g/l at(anhydrous) 20°C.nickel sulphate 262.84 solid 53.3 - 2.07 +2 625 g/l at(hexahydrate) 20°C. 1)nickel 286.88 - +2 300 g/l atammonium 20°C.sulphate(anhydrous)nickel sulphate 154.75 solid 848 1) - 3.68 +2 293 g/l at(anhydrous) 20°C. 1)nickel acetate 176.78 solid 16.6 1.80 +2 166 g/l at(anhydrous) 20°C. 1)nickel acetate 248.84 solid 16 +2 160 g/l at(tetrahydrate) 20°C.nickel 394.94 - - 1.92 +2 104 g/l atammonium 20°C.sulphate(hexahydrate)nickel fluoride 96.69 solid +2 40 g/l at 25°C 1)nickel 340.42 solid 2.14 Solublefluoroborate(hexahydrate)nickel formate 184.76 solid 2.15 +2 soluble 1)nickel 322.95 solid 200 +2 Solublesulphamate(tetrahydrate)nickel 170.73 liquid - 25 43 1.32 0 0.18 g/l atcarbonyl 9.8°Cnickel 92.7 solid 230 1) - 4.15 +2 0.13 g/lhydroxide 1)nickel 118.70 solid - 5.822 +2 0.0093 g/lcarbonate at 25°C.nickel sulphide 90.75 solid 797 - 5.5 +2 0.003618(amorphous) g/lnickel 74.69 solid 1990 - 4.83 / +2 0.0011 g/lmonoxide 6.67 at 20°C. 1)basic nickel 376.17 solid 2.6 +2 Insolublecarbonate 1)nickel 587.67 solid - 2.6 +2 Insolublehydroxy-carbonatenickel 174.71 solid - - 5.82 +2 Insoluble inchromate waterNickelocene 188.88 solid 171-173 - +2 Insoluble 1)nickel titantate 154.57 solid 1000 - +2 Insoluble 11
  • R_NickelBackground_0308_hh_chapter0124567.docnickel 180.44 solid 1158 1400 1) NS 4) Insolubleantimonidenickel arsenide 133.61 solid 968 - 7.17 NS 4) Insoluble(NiAs)nickel selenide 137.65 solid red heat - NS 4) Insolublenickel 333.99 solid - - Insolublesubselenidenickel 240.19 solid 790 - 5.82 NS 4) Insoluble insubsulphide cold waternickel telluride 186.29 solid 600 – 900 1) - NS 4) Insoluble1) 2) 3) Decomposes. Sublimes Further details are given in the following section.4) NS: Not Specified; mixed formal oxidation states of nickel and/or complex coordination in the solid form.1.2.1 Solubility of nickel compounds.In the Table above, the water solubility of many of these compounds are described as either “soluble” or“insoluble”. Many substances commonly considered as “insoluble” are however sufficiently soluble undercertain conditions to give rise to effects of concern. This simple distinction is not always helpful.The available literature of the solubility of inorganic (Carlsen, 2001a) and organic (Carlsen, 2001b) Ni (II)species has been reviewed. This review was carried out in order to provide a systematic basis on which to groupin particular inorganic nickel compounds on the basis of their solubility in water.For inorganic nickel compounds, a grouping of inorganically based nickel species has been suggested. Nickelmetal and nickel metal compounds (see Appendix 7.1.1) can all be considered as insoluble. Nickel oxides andmixed metal oxides are also very similar in terms of their solubility (Carlsen, 2001a).In Table 1.2.B a grouping of the nickel ligands with Group 13, 14, 15, 16 and 17 ligands is suggested. The term‘insoluble’ means that the solubility of the species is less that 10-4 mol/l, ‘slightly soluble’ covers the solubilityrange 10-4 - 10-2 mol/l, ‘soluble’ the range 10-2 - 5·10-1 mol/l and ‘very soluble’ refers to solubility above 5·10-1mol/l (Carlsen, 2001a).The grouping made in Table 1.2.B is based exclusively on water as the medium. Thus, the apparent increasedsolubility of otherwise slightly - or even insoluble - nickel species observed in biological fluids (Maximilien,1989) is not covered in the grouping made below (Carlsen, 2001a).A few species, i.e., NiXN and NiTeO4 are not included in Table 1.2.B. No indications concerning the solubilityof these species have been retrieved (Carlsen, 2001a).Table 1.2.B: Grouping of nickel species based on inorganic ligands in water (Carlsen, 2001a). Group 13 Group 14 Group 15 Group 16 Group 17 Misc.Insoluble NiXBa NiXSia NiXPYa NiXSY Ni2Fe(CN)6 a NiXAs NiXSe NiXSbYa NiXTe Ni2P2O7 Ni3(AsO3)2a Ni3(AsO4)2 Ni(AsO3)2aSlightly Ni(CO)4 Ni3(PO4)2 NiSO3a Ni(IO3)2 Ni2Fe(CN)5NObsoluble Ni(CN)2 Ni[NiP2O7] NiSeO3 NiCO3 Ni(HCO3)2 12
  • R_NickelBackground_0308_hh_chapter0124567.docSoluble NiK2(SO4)2 NiF2Very NiB6O10 Ni(SCN)2 Ni(NO3)2 NiSO4 NiCl2soluble Ni(BF4)2 NiSiF6 Ni(H2PO2)2 Ni(SO3NH2)2a Ni(ClO3)2 NiSeO4 Ni(ClO4)2 NiBr2 Ni(BrO3)2 NiI2a No quantitative data have been retrievedb Placed due to the possible higher solubility as discussed by Linke (1965).It is noted that the solubility in general follows the ‘rules of thumb’ for inorganic salts. Thus, halides are easilysoluble, apart from the fluoride, nitrates are easily soluble, carbonates and phosphates are typically only slightlysoluble, hydroxides of non-alkali metals are often very slightly soluble, etc. (Carlsen, 2001a).In the study by Carlsen (2001a) the focus is on the concentration of the free nickel (II) ion, Ni(H2O)62+ asresponsible for biological effects of nickel compounds. However, the free ligands and/or the intact nickelcomplexes may also give rise to biological effects. It should be emphasized that the grouping in Table 1.2.B ismade without taking into account the possible lowering of the concentration of the free nickel ions due tocomplex formation. For hazard and risk assessment purposes this corresponds to a conservative approach to thepossible maximum concentration of Ni(H2O)62+ (Carlsen, 2001a).No comparable grouping of organic ligands has yet been carried out (Carlsen, 2001b). In contrast to theinorganic nickel compounds it is not obvious how to group the organically based species based on solubilityalone. Aqueous solubility is, not unexpectedly, seen to decrease with increasing molecular weight and increasingcarbon content of the ligand. On the other hand, the introduction of hydrophilic and/or polar functional groups,such as OH, C=O, COO-, NH, SH and SO3- cause increased solubility. Further it should be emphasized that thesolubility of the complexes cannot immediately be related to the solubility of the single ligands (Carlsen 2001b).Hence, it seems more appropriate to group organically based nickel complexes based on the stability of thecomplexes. As a first attempt, grouping the individual complexes based on the nature of the ligand appears as anobvious choice, even though significant variations in stability may prevail within the single groups.Monocarboxylic acids serve as an example to illustrate the applicability of this concept. It appears that thestability constant for the first complex typically is found in the range around 1 and the second in the range of 1-2.Significant outliers are the sulphur-containing acids thiolactic acid and (phenylthio)acetic acid. Apart from thesulphur-containing acids, it would seem appropriate to treat nickel monocarboxylate complexes as a singlegroup, based on the salts of formic and acetic acid. Both these salts are highly soluble: thus, the approach wouldbe conservative. In order to evaluate the possible concentration of free nickel ions, as well as other nickelcontaining species in solution, it is important to take the actual acidity of the solution into consideration (Carlsen,2001b).1.2.2 SummaryThe availability of physical chemical data for the nickel compounds in Appendix 7.1 is very variable. However,there is data available for the water solubility of many inorganic nickel (II) compounds, although there are manycomplex nickel-containing substances with no solubility data. Grouping many of the conventional inorganicnickel (II) compounds on the basis of their water solubility is fairly straightforward. Grouping the much largernumbers of organic complexes is a more complicated process.Many legislative controls group all nickel compounds together (see Chapter 2.2). In other cases, nickelcompounds are divided into groups on the basis of their water solubility (e.g. TERA, 1999). This grouping ofcompounds reflects the assumption that the biological effects of nickel reflect the activity of the nickel ion,Ni(H2O)62+. NiPERA (1996) groups nickel compounds into five main classes: metallic nickel, nickel carbonyl,oxidic nickel (e.g. nickel oxides, hydroxide, silicates, carbonates, complex nickel oxides), sulphidic nickel (e.g.nickel sulphide, nickel subsulphide), and water-soluble nickel compounds (e.g. nickel sulphate hexahydrate,nickel chloride hexahydrate). The group of “oxidic nickel” includes substances with a range of different watersolubility, from compounds of very low solubility (e.g. nickel oxide) to compounds with a water solubility ahundred times greater (e.g. nickel hydroxide). There is little difference in the water solubility of sulphidic nickeland that of nickel oxides. Whilst these groupings reflect the substances encountered in nickel metal production,they do not reflect well the wider range of HPVC and LPC substances seen in practice (see Chapter 2). 13
  • R_NickelBackground_0308_hh_chapter0124567.docHowever, it is important to be able to recognise similarities and differences in biological behaviour across groupsof chemically related compounds. Derogation statements by Industry for not carrying out testing for particularendpoints is based on the recognition of similarities in effects between nickel-containing compounds where datais available, and other related compounds where experimental data is not available. Assumptions are made in therisk assessment reports of the individual compounds reviewed by the Rapporteur about the possibility toextrapolate data between these compounds. The data reviewed for the five individual substances can also be usedas a basis for similar extrapolations to other related nickel compounds.1.3 CLASSIFICATION.1.3.1 Current classification1.3.1.1 UN Transport labelling.Four nickel compounds are included as specific entries in the UN Recommendations on the Transport ofDangerous Goods (UN, 2001) and ADR (UN ECE 2001b). UN Number Class Subsidiary Packaging risk GroupNickel carbonyl (nickel tetracarbonyl) 1259 6.1 3 INickel cyanide (Nickel (II) cyanide) 1653 6.1 IINickel nitrate (Nickel (II) nitrate, nickelous nitrate) 2725 5.1 IIINickel nitrite (Nickel (II) nitrite, nickelous nitrite) 2726 5.1 IIINone of these four entries are included in Annex B.2 – Appendix 4 of the ADN (UN ECE, 2001a).According to information supplied by Industry to the Rapporteur, nickel containing compounds and products areclassified under the following n.o.s. entries: UN Name UN Number Class Subsidiary Packaging risk Groupnickel carbonate Environmentally UN 3077 9 M7 III hazardous substance, solid, n.o.snickel chloride (solid) Toxic solid, inorganic. UN 3288 6.1 T5 III n.o.s.nickel chloride (liquid) Toxic liquid, inorganic. UN 3287 6.1 T4 III n.o.s.Lithium nickel Lithium batteries. UN 3091 9, M4 IIbatteriesnickel catalyst, dry, metal catalyst, dry, UN 2881 4.2 I / IInickel catalyst, spent flammable solid, organic UN 1325 4.1 III n.o.s.nickel metal powder metal powder, UN 3089 4.1 IIwith very fine particle flammable, n.o.s.size (e.g. INCO 210)nickel powder less Environmentally UN 3077 9 M7 III.than 100 microns hazardous substance, solid n.o.snickel sulphate Environmentally UN 3077 9 M7 III hazardous substance solid n.o.s.The Rapporteur has no information on the Transport classification used for other nickel compounds 14
  • R_NickelBackground_0308_hh_chapter0124567.doc1.3.1.2 Classification according to Directive 67/548/EEC.Thirteen nickel compounds are included in Annex I to Directive 67/548/EEC (EEC, 1992a) as separate entries.Three of these are notified substances. The classification of all these entries (including substances reviewed inthe individual risk assessment reports are shown below. In some cases, a number of different compounds havethe same classification.Individual entries are classified as follows:Nickel carbonyl: 028-001-00-1 (EC No.: 236-669-2, CAS No.: 13463-39-3) (25th ATP, EC 1998b) ClassificationF; R11 Carc. Cat. 3; R40 Repr. Cat. 2; R61 T+; R26 N; R50-53 LabellingSymbols F; T+; NR Phrases 61-11-26-40-50/53 (Nota E)S-Phrases 53-45-60-61Nickel: 028-002-00-7 (EC No.: 231-111-4, CAS No.: 7440-02-0) (19th ATP, EEC, 1993d 1) ClassificationCarc. Cat. 3; R40 R43 LabellingSymbols XnR Phrases 40-43S-Phrases (2-)22-36Nickel monoxide: 028-003-00-2 (EC No.: 215-215-7, CAS No.: 1313-99-1) (28th ATP, EC 2001e)Nickel dioxide: 028-004-00-6 (EC No.: 234-823-3, CAS No.: 12035-36-8) (28th ATP, EC 2001e)Nickel trioxide: 028-005-00-3 (EC No.: 215-217-8, CAS No.: 1314-06-3) (28th ATP, EC 2001e) 2 ClassificationCarc. Cat. 1; R49 R43 R53 LabellingSymbols TR Phrases 49-43-53S-Phrases 53-45-611 This entry has been revised in the 30th ATP which was adopted by a Technical Progress Committee inFebruary 2007, but not yet adopted by the Commission or published in the Official Journal. The revised entry isclassified as: Carc. Cat. 3; R40; T; R48/23 and R43. An additional entry for particle size < 1 mm includingcalssification as R52-53 has been agreed by the TC C&L and included in a draft 31 ATP sent for comment inJuly 2007.2 Changes to these entries have been agreed by the TC C&L and included in a draft 31 ATP sent for comment inJuly 2007. The revised entries are classified as: Carc. Cat. 1; R49; T; R48/23, R43 and R53. 15
  • R_NickelBackground_0308_hh_chapter0124567.docNickel sulphide: 028-006-00-9 (EC No.: 240-841-2, CAS No.: 16812-54-7) (28th ATP, EC 2001e) 3 ClassificationCarc. Cat. 1; R49 R43 N; R50-53 LabellingSymbols T; NR Phrases 49-43-50/53S-Phrases 53-45-60-61Nickel subsulphide 1: 028-007-00-4 (EC No.: 234-829-6, CAS No.: 12035-72-2) (28th ATP, EC 2001e) 3 ClassificationCarc. Cat. 1; R49 R43 N; R51-53 LabellingSymbols T; NR Phrases 49-43-51/53S-Phrases 53-45-611) Heazlewoodite given as a synonym by NiPERA (1996).Nickel dihydroxide: 028-008-00-X (EC No.: 235-008-5, CAS No.: 12054-48-7) (28th ATP, EC 2001e) 4 ClassificationCarc. Cat. 3; R40 Xn; R20/22 R43 N; R50-53 LabellingSymbols Xn; NR Phrases 20/22-40-43-50/53S-Phrases (2-)22-36-60-61Nickel sulphate: 028-009-00-5 (EC No.: 232-104-9, CAS No.: 7786-81-4) (25th ATP, EC 1998b) 5 ClassificationCarc. Cat. 3; R40 Xn; R22 R42/43 N; R50-53 LabellingSymbols Xn; NR Phrases 22-40-42/43-50/53S-Phrases (2-)22-36/37-60-613 Changes to this entry has been agreed by the TC C&L and included in a draft 31 ATP sent for comment in July2007. The revised entry is classified as: Carc. Cat. 1; R49; Muta. Cat. 3; R68; T; R48/23, R43 and N; R50-53.4 Changes to this entry has been agreed by the TC C&L and included in a draft 31 ATP sent for comment in July2007. The revised entry is classified as: Carc. Cat. 1; R49; Repr. Cat. 2; R61; Muta. Cat. 3; R68; Xn; R20/22; T;R48/23, Xi; R38; R42/43 and N; R50-53.5 This entry has been revised in the 30th ATP. The revised entry is classified as: Carc. Cat. 1; R49; Repr. Cat. 2;R61; Muta. Cat. 3; R68; Xn; R20/22; T; R48/23; (SCL of 1%); Xi; R38; (SCL of 20%); R42; R43 (SCL of0.01%) and N; R50-53. 16
  • R_NickelBackground_0308_hh_chapter0124567.docNickel carbonate 1: 028-010-00-0 (EC No.: 222-068-2, CAS No.: 3333-67-3) (25th ATP, EC 1998b) 6 ClassificationCarc. Cat. 3; R40 Xn; R22 R43 N; R50-53 LabellingSymbols Xn; NR Phrases 22-40-43-50/53S-Phrases (2-)22-36/37-60-611): NiPERA (1996) also lists two other substances, not mentioned in Annex I as included in the same Annex Ientry (028-010-00-0). These are the 1:2 nickel hydroxycarbonate, with the EINECS name: [carbonato(2-)]tetrahydroxytrinickel), CAS and EC Nos. 12607-70-4 and 235-715-9, and 2NiCO3.3Ni(OH)2.4H2O shown withCAS No. 12122-15-5 and EC No. 235-715-9 (for comments on these CAS & EC Nos. see risk assessment reporton nickel carbonate).Tetrasodium (c-(3-(1-(3-(e-6-dichloro-5-cyanopyrimidin-f-yl(methyl)amino)propyl)-1,6-dihydro-2-hydroxy-4-methyl-6-oxo-3-pyridylazo)-4-sulfonatophenylsulfamoyl)phtalocyanine-a,b,d-trisulfonato(6-))nickelato II, wherea is 1 or 2 or 3 or 4,b is 8 or 9 or 10 or 11, c is 15 or 16 or 17 or 18, d is 22 or 23 or 24 or 25 and where e and ftogether are 2 and 4 or 4 and 2 respectively: 607-288-00-2 (EC No.: 410-160-7, CAS No.: 148732-74-5) (26thATP, EC 2000a; repeated in 28th. ATP, EC 2001e) ClassificationXi; R36 R43 R52-53 LabellingSymbols XiR Phrases 36-43-52/53S-Phrases (2-)22-26-36/37-61Trisodium (1-(3-carboxylato-2-oxido-5-sulfonatophenylazo)-5-hydroxy-7-sulfonatophthalen-2-amido)nickel(II):611-103-00-0 (EC No.: 407-110-1, CAS No.: -) (29th ATP, EC 2004a) ClassificationXi; R41 R43 N; R51-53 LabellingSymbols Xi; NR Phrases 41-43-51/53S-Phrases (2-)24-26-37/39-61Hexasodium (di(N-(3-(4-[5-(5-amino-3-methyl-1-phenylpyrazol-4-yl-azo)-2,4-disulfo-anilino]-6-chloro-1,3,5-triazin-2-ylamino)phenyl)-sulfamoyl](disulfo)-phthalocyaninato)nickel: 611-122-00-2 (EC No.: 417-250-5, CASNo.: 151436-99-6) (29th ATP, EC 2004a) ClassificationXi; R41 LabellingSymbols XiR Phrases 41S-Phrases (2-)26-396 This entry has been revised in the 30th ATP. The revised entry is classified as: Carc. Cat. 1; R49; Repr. Cat. 2;R61; Muta. Cat. 3; R68; Xn; R20/22; T; R48/23; Xi; R38; R42; R43 and N; R50-53. 17
  • R_NickelBackground_0308_hh_chapter0124567.docIn addition, 25 other nickel compounds are included in Annex I to Directive 67/548/EEC as part of groupentries 7. The classification of these entries reflects the hazards of the main functional group forming the basis ofthe group entry, and is not based on hazards related to nickel.Nickel compounds in EINECS are included in group entries in Annex I to Directive 67/548/EEC for salts ofhydrogen cyanide (006-007-00-5), fluorosilicates (009-013-00-6), chromium (VI) compounds (024-017-00-8),arsenic compounds (033-002-00-5), salts of arsenic acid (033-005-00-1), selenium compounds (034-002-00-8),antimony compounds (051-003-00-9), barium compounds (056-002-00-7), lead compounds (082-001-00-6),uranium compounds (092-002-00-3) salts of oxalic acid (607-007-00-3) and metal salts of thiocyanic acid (615-032-00-6).EINECS name Annex I entry EC No. CAS No. Classificationnickel (II) 006-007-00-5 209-160-8 557-19-7 T+; R26/27/28 R32 N; R50-53cyanide (1)nickel(2+), 006-007-00-5 273-379-5 68958-89-4 T+; R26/27/28 R32 N; R50-53bis(1,2-ethanediamine-N,N)-,bis[bis(cyano-C)aurate(1-)]Copper(2+), 006-007-00-5 264-136-4 63427-32-7 T+; R26/27/28 R32 N; R50-53bis(1,2-ethanediamine-N,N)-, (SP-4-1)-tetrakis(cyano-C)nickelate(2-)(1:1)Nickelate(2-), 006-007-00-5 237-877-6 14038-85-8 T+; R26/27/28 R32 N; R50-53tetrakis(cyano-C)-, disodium,(SP-4-1)-silicate(2-), 009-013-00-6 247-430-7 26043-11-8 Xn; R22hexafluoro-,nickel(2+) (1:1)(1)nickel chromate 024-017-00-8 238-766-5 14721-18-7 Carc. Cat. 2; R49 R43 N: R50-53(1)nickel dichromate 024-017-00-8 239-646-5 15586-38-6 Carc. Cat. 2; R49 R43 N: R50-53(1)nickel diarsenide 033-002-00-5 235-103-1 12068-61-0 T; R23/25 N; R50-53(1)nickel arsenide 033-002-00-5 248-169-1 27016-75-7 T; R23/25 N; R50-53(1)nickel (II) 033-005-00-1 236-771-7 13477-70-8 Carc. Cat. 1; R45 T; R23/25 N; R50-53arsenate (1)Nickel selenide 034-002-00-8 215-216-2 1314-05-2 T; R23/25 R33 N; R50-53(NiSe) (1)selenious acid, 034-002-00-8 233-263-7 10101-96-9 T; R23/25 R33 N; R50-53nickel(2+) salt(1:1) (1)selenic acid, 034-002-00-8 239-125-2 15060-62-5 T; R23/25 R33 N; R50-53nickel(2+) salt(1:1) (1)antimony, compd. 051-003-00-9 234-827-5 12035-52-8 Xn; R20/22 N; R51-53with nickel (1:1)7 Two nickel acrylates and two nickel methacrylates were excluded from the Annex I group entries for thesecompounds in the 28th. ATP (EC 2001e) when the nomenclature was changed to specify monoalkyl or monoarylor monoalkylaryl esters only. 18
  • R_NickelBackground_0308_hh_chapter0124567.docantimony, compd. 051-003-00-9 235-676-8 12503-49-0 Xn; R20/22 N; R51-53with nickel (1:3)C.I. Pigment 051-003-00-9 232-353-3 8007-18-9 Xn; R20/22 N; R51-53Yellow 53,(Antimony nickeltitanium oxideyellow,) (2)antimony oxide 051-003-00-9 277-627-3 73892-02-1 Xn; R20/22 N; R51-53(Sb203), solidsoln. with nickeloxide (NiO) andtitanium oxidePriderite, nickel 056-002-00-7 271-853-6 68610-24-2 Xn; R20/22(1)Speiss, lead, 082-001-00-6 308-765-5 98246-91-4 Repr. Cat. 1; R61; Xn; N; R50-53nickel-contg. Repr. Cat. 3; R62 R20/22; R33Residues, copper- 082-001-00-6 310-050-8 102110-49-6 Repr. Cat. 1; R61; Xn; N; R50-53iron-lead-nickel Repr. Cat. 3; R62 R20/22;matte, sulfuric R33acid-insol.uranate(2-), 092-002-00-3 275-994-4 71767-12-9 T+; R26/28 R33 N; R51-53tetrakis(acetato-O)dioxo-,nickel(2+)(1:1),(OC-6-11)-uranic acid 092-002-00-3 239-876-6 15780-33-3 T+; R26/28 R33 N; R51-53(H2U3O10),nickel(2+) salt(1:1) (1)ethandioic acid, 607-007-00-3 243-867-2 20543-06-0 Xn; R21/22nickel salt (1)ethandioic acid, 607-007-00-3 208-933-7 547-67-1 Xn; R21/22nickel(2+) salt(1:1) (1)thiocyanic acid, 615-032-00-6 237-205-1 13689-92-4 Xn; R20/21/22 R32 N; R50-53nickel(2+) salt (1)1) Chemical included in draft 31st ATP2) Low production volume chemical. See chapter 2.1.1.1.4. Classification discussed in preparation of draft 31stATP (Hart, 2007).For nickel compounds not included in Annex I, Industry is required to evaluate the available data to assess thehazard, and to apply a provisional classification.Information is available from Industry for the provisional classifications of the HPVC nickel compoundsreviewed by the Rapporteur: 8Com- Classification ReferencepoundNickel T; R25 Xn; R40/20 Xi; R36/37 R42/43 N; R50 Eramet, 2002chlorideNickel O; R8 Xn; R22 R43 HEDSET8 These two compounds have now been included in the 30th ATP. Nickel dichloride is classified as: Carc. Cat. 1;R49; Repr. Cat. 2; R61; Muta. Cat. 3; R68; T; R23/25; T; R48/23; (SCL of 1%); Xi; R38; (SCL of 20%); R42;R43 (SCL of 0.01%) and N; R50-53. Nickel dinitrate is classified as: O; R8; Carc. Cat. 1; R49; Repr. Cat. 2;R61; Muta. Cat. 3; R68; Xn; R20/22; T; R48/23; (SCL of 1%). Xi; R38 (SCL of 20%); Xi; R41; R42; R43 (SCLof 0.01%) and N; R50-53 19
  • R_NickelBackground_0308_hh_chapter0124567.docnitrate (2002a) Carc. Cat. 1; R45 T; R23/24/25 C; R34 IUCLID, 2001 O; R8 Carc. Cat. 3; R40 Xn; R22 C; R34 R42/43 HEDSET (2002b) O; R8 Carc. Cat. 1; R45 Xn; R22 R43 HEDSET (1) (2003a) O; R8 Carc. Cat. 3; R40 Xn; R22 C; R34 R43 N; R50/53 IUCLID (2003b) O; R8 Carc. Cat. 3; R40 Xn; R22 R42/43 N; R50/53 IUCLID (2) (2003b) O; R8 Xn; R22 Xi; R38/41 HEDSET (2003b)1) The classification category is not shown. Category 1 is assumed on the basis of the IARC conclusion and thelack of any animal data.2) R42 is applied when the nickel solution is used as an aerosol (IUCLID, 2003b).Only one of the HPVC nickel compounds not specifically reviewed by the Rapporteur (see Table 2.1.1.C) isincluded in Annex I. This is nickel oxide (Annex I entry 028-003-00-2).None of the remaining 14 substances includes a provisional classification in the IUCLID database at the ECB(IUCLID 2002). Several of the files include the remark that “UVCB-Stoffe sind zum größten teil nichteingestuft” (UVCB substances are not normally classified). There is no derogation from the requirement forprovisional classification for complex UVCB substances in the Directive, and guidance on the classification ofthese substances is given in section 1.7.2.1. of Annex VI (EC, 2001e).However, some information is available. Section C.5 of the IUCLID file for “ferronickel manufacturing slags”(EC No. 273-729-7) considers the substance fulfils the criteria for classification as Carc. Cat 3; R40 and R43.Section 1.15. 5 of the IUCLID file for “nickel matte” (EC No. 273-746-9) recognises that the main component isnickel subsulphide which is classified as Carc. Cat. 1 in Annex I (Annex I entry 028-007-00-4). It states that thedust is irritating for the respiratory tract and that it may also be a respiratory sensitiser.A comment in the IUCLID file for “Frits, chemicals” (EC No. 266-047-6) notes that classification depends onthe composition of an individual product.One manufacturer’s IUCLID file for “Leach residues, zinc ore-calcine, cadmium-copper ppt.” (EC No. 293-311-8) includes a provisional classification as Xn; R20 (harmful by inhalation) (IUCLID, 1996). This provisionalclassification is not included in the main IUCLID file. (IUCLID 2002).One manufacturer’s IUCLID file for “Leach residues, zinc ore-calcine, iron contg.,” (EC No. 293-312-3)includes a classification with R45, R46 and R61 (May cause cancer, may cause heritable genetic damage, maycause harm to the unborn child). It also includes a classification as T; R23/25 (Toxic by inhalation and ifswallowed), Xn; R20/21/22) (Harmful by inhalation, in contact with skin and if swallowed); and R33 (danger ofcumulative effects). This evaluation is based on the classification of the main components, lead, cadmium andarsenic. (IUCLID, 1995). This provisional classification is not included in the main IUCLID file. This doeshowever include a comment under section 1.15 from another manufacturer noting a composite classificationbased on the properties of lead and arsenic (IUCLID 2002).These “classifications” are shown in the table below.Compound Classification ReferenceSlags, ferronickel- Carc. Cat. 3; R40 R43 C.5 in IUCLIDmanufg. (2002) (1)nickel matte Carc. Cat. 1; R45 Xi; R37 R42 from section 1.15.5 in IUCLID (2002)Leach residues, Xn; R20 IUCLID (1996)zinc ore-calcine,cadmium-copperpptLeach residues, Carc. Cat. 1; R45 T; R23/25 Xn; R21 R33 IUCLID (1995)zinc ore-calcine, Muta. Cat. 2; R46iron contg. Repr. Cat. 1; R61 20
  • R_NickelBackground_0308_hh_chapter0124567.doc Carc. Cat. 1; R45 Xn; R33 from section 1.15 in Repr. Cat. 1; R61 R20/22 IUCLID (2002)1 ) Chemical included in draft 31st ATPThere is no assessment of “Slimes and Sludges, copper electrolyte refining, decopperised, Ni sulfate”, EC No.295-859-3, in the IUCLID file (IUCLID, 2002), even though the EINECS description of the substance indicatesnickel sulphate which is included in Annex I (028-009-00-5) as a main component.Some HPVCs, such as Ceramic materials and wares, chemicals (EC No. 266-340-9) are regarded as non-hazardous. For others, e.g. Slags, copper smelting EC No. 266-968-3 the substance is not classified due a lack ofinformation on the effects of the substance.The nickel-containing LPVCs are listed in Table 2.1.1.D.Nickel hydroxide (028-008-00-X) and nickel sulphide (028-006-00-9) are both included in Annex I. C.I. PigmentYellow (EC No. 232-353-3) is an antimony compound and, as such is included in the group entry (051-003-00-9). Nickel, [carbonato(2-)]tetrahydoxytri- (EC No. 235-715-9) is regarded by NiPERA as included in the nickelcarbonate entry (028-010-00-0) although it is not actually listed as part of the entry.The IUCLID data sets are not available for LPVCs in ESIS (IUCLID, 2002). The 37 IUCLID data sets submittedby the producers of the 22 LPVCs not included in Annex I with specific entries have been supplied by the ECBto the Danish Rapporteur. The Table below summarises the classifications shown in these files.Compound Classification Reference.Nickel, [carbonato(2- Carc. Cat. 3; R40 Xn; R22 R43 IUCLID, 2003a (1))]tetrahydroxytri-Nickel fluoride (NiF2) Carc. Cat. 3; R40 Xn; R22 Xi; R36 R42/43 IUCLID, 2003a (2,3) Carc. Cat. 3; R40 R43Nickel bromide (NiBr2) no data available IUCLID, 2003a for classificationSulfamic acid, nickel(2+) Carc. Cat. 3; R40 Xn; R22 Xi; R36/38 R42/43 IUCLID, 2003a (2)salt (2:1) Carc. Cat. 3; R40 Xn; R22 R42/43Acetic acid, nickel(2+) salt Carc. Cat. 3; R40 R43 IUCLID, 2003aAcetic acid, nickel salt Carc. Cat. 3; R40 Xn; R22 R42/43 IUCLID, 2003aOctanoic acid, nickel(2+) Carc. Cat. 3; R40 Xn; C; R35 R42/43 IUCLID, 2003asalt R20/21/22Nickel, Xi; R39 Xi; R36 IUCLID, 2003a (2, 4, 5)bis(dibutylcarbamodithioato-S,S’)-, (SP-4-1)- no dangerous propertiesNickel, bis(3-amino-4,5,6,7- no dangerous IUCLID, 2003a (5)tetrachloro-1H-isoindol-1- propertiesone oximato-N(2)-,O(1))-Nickel, bis[2,3- no dangerous IUCLID, 2003a (5)bis(hydroxyimino)-N- propertiesphenylbutanamidato-N(2)-,N(3)-]-Nickel, bis[2,3- no dangerous IUCLID, 2003a (5)bis(hydroxyimino)-N-(2- propertiesmethoxyphenyl)butanamidato]-Nickel, [29H,31H- no data available IUCLID, 2003aphthalocyaninato(2-)-N(29)- for classification,N(30)-,N(31)-,N(32)-]-,(SP-4-1)-Nickel, (1- R52/53 IUCLID, 2003a (2) 21
  • R_NickelBackground_0308_hh_chapter0124567.docbutanamine)[[2,2’-thiobis[4- Xn; R20 R52/53(1,1,3,3-tetramethylbutyl)phenolato]](2-)-O,O’,S]-Nickel, 5,5’-azobis- no dangerous IUCLID, 2003a (5)2,4,6(1H,3H,5H)- propertiespyrimidinetrione complexesNickel, acetate carbonate Carc. Cat. 3; R40 Xn; R22 R42/43 IUCLID, 2003aC8-C10-branched fattyacids C9-C11-neofatty acidscomplexesAntimony-nickel-titanium- no dangerous IUCLID, 2003a (2, 5, 6, 7)oxide-yellow-, C.I. Pigment propertiesYellow 53Cobalt-nickel-gray- no dangerous IUCLID, 2003a (2, 3, 5,7)periclase-, C.I. Pigment propertiesBlack 25.Nickel-ferrite-brown-spinel- no dangerous IUCLID, 2003a (5, 7), C.I. Pigment Brown 34 propertiesNickel-iron-chromite-black- no dangerous IUCLID, 2003a (2, 5, 7)spinel-, C.I. Pigment Black properties30Lead alloy, base, dross not applicable as IUCLID, 2003a this is an UVCBAshes (residues), heavy fuel no data available IUCLID, 2003aoil fly for classificationSlimes and Sludges, copper Carc. Cat. 3; R40 T; R23/25 R42/43 R33 IUCLID, 2003a (3, 8)electrolyte refining, (R61 included ondecopperised the label)1) As for nickel carbonate in Annex I but without the classification for the environment. Now included togetherwith other nickel hydroxycarbonates in 30th ATP2) Different provisional classifications from different IUCLID data sets.3) Included in draft 31st ATP.4) R39 is associated with the symbol “T+” or “T” and not “Xn”. In addition Annex VI to Directive 67/548/EEC(EC, 2001e) requires the route of administration to be included in the classification.5) The file contains no experimental data to support the claim that there are no dangerous effects.6) There are five producers of this substance. As an antimony compound, the group entry in Annex I requires thesubstance to be classified as Xn; R20/22, N; R51-53.7) The substance is a complex nickel oxide. Nickel oxide is classified as a Category 1 carcinogen in Annex I.8) Based on a composite classification of components: arsenic, lead compounds, nickel sulphate.1.3.2 Proposed classification1.3.2.1 UN Transport labelling.The International Council of Chemical Associations (ICCA) (UN CETDG, 2002) has made a proposal for aschematic classification of organometallic substances (which would include many of the nickel compoundsshown in the Appendix) to the Committee of Experts on the Transport of Dangerous Goods (UN CETDG) andon the Globally Harmonised System of classification and labelling of chemicals1.3.2.2 Classification according to Directive 67/548/EEC.Nickel chloride is problematic for Norway under the EEA Treaty. Norway has made a proposal to the EuropeanCommission (European Commission, 1995a) to classify nickel chloride as:Carc. Cat. 1; R45, Muta. Cat. 3; R40 T; R25 R42/43 N; R50-53 (1)1) The environmental classification proposal was added later. 22
  • R_NickelBackground_0308_hh_chapter0124567.docA further proposal for the classification of this substance was made by Denmark as a result of the findings of therisk assessment. Nickel dichloride, together with nickel dinitrate has been included in Annex I to Directive67/548/EEC as part of the 30th. ATP (see 1.3.1.2 above).Proposals from Denmark for the revision of a number of the other current entries for nickel compounds in AnnexI have also been discussed in the TC C&L and recommended for inclusion in the draft 31st ATP. These entriesinclude the entries for the nickel oxides (028-003-00-2, 028-004-00-6 and 028-005-003), for the sulfidic nickelcompounds (028-006-00-9 and 028-007-00-4) and for nickel dihydroxide (028-008-00X) (see 1.3.1.2 above).In addition, Norway has made a proposal to the European Commission for a group classification of inorganicnickel compounds in EINECS, not covered by individual entries in Annex I to Directive 67/548/EEC (EuropeanCommission, 1995b). The document included a list of inorganic nickel compounds in EINECS coveringapproximately 125 nickel substances. This list is similar to but not identical with the inorganic and diverse nickelcompounds shown in Annex 7.2.1. The classification proposed for the group entry is:Carc. Cat. 1; R49, R42/43 N; R50-53More recently, Sweden has made a proposal for the environmental classification of metals which includes anentry for “Inorganic compounds of nickel” not covered by individual entries in Annex VI (ECBI/89/04). Theclassification proposal covers only environmental effects and is also N; R50-53.The Rapporteur has also prepared a proposal for group classification of many of the nickel compounds listed inAppendix 7.2 (ECBI/96/04 – Add. 2). This proposal has been discussed in the TC C&L, and entries for a numberof additional nickel compounds (including many of the compounds for which self-classification is shown insection 1.3.1.2) have been recommended for inclusion in the draft 31st ATP. These proposals and the discussionin the EU Technical Committees have been described by Hart (2007). 23
  • R_NickelBackground_0308_hh_chapter0124567.doc2. GENERAL INFORMATION ON EXPOSURE TO NICKEL AND NICKEL COMPOUNDS.There are three broad source types which lead to exposure of man and the environment to nickel and nickelcompounds. Exposure due to the deliberate industrial production and use of nickel and nickel compounds is themain concern of Risk assessment reports prepared under Existing Chemicals Regulation (EEC) 793/93 (EEC,1993b). This use is described in detail for the five nickel compounds currently under review by the Rapporteur.Nickel has also a significant presence in fossil fuels and hence all combustion processes generally emit nickel tothe environment. And as a naturally occurring chemical, nickel is present in all compartments of the environment(including organisms) due to natural processes (URS, 2001).As a result, ‘ambient’ nickel concentrations observed in the environment (URS, 2001) result from a combinationof: ‘anthropogenic’ nickel arising from the ‘nickel industry’ i.e. the production and use of nickel metal, nickel alloys and nickel-containing compounds. This includes nickel extracted through mining, then processed into a variety of end products, resulting in environmental emissions at each stage in the life cycle. These emissions may also contribute to nickel levels in sewage and sewage sludge due to corrosion of domestic and industrial products. ‘anthropogenic’ nickel arising from combustion of fossil fuels, as well as waste incineration and wood combustion; this component of ambient nickel may also be deemed to include significant diffuse sources, particularly road transport and the agricultural application of fertiliser, manure and sewage sludge. ‘natural background’: natural sources of atmospheric nickel include wind-blown dusts, derived from weathering of rocks and soil, and volcanic emissions; natural sources of aqueous nickel derive from biogenic cycles and solubilisation of nickel compounds from soils.2.1 SOURCES OF NICKEL.2.1.1 Industrial production and use of nickel and nickel compounds.The industrial production and use of nickel metal, nickel sulphate, nickel chloride, nickel nitrate and nickelcarbonate are described in the individual risk assessment reports. The following section summarises briefly theinformation in these reports, and includes a brief description of the uses of other nickel compounds not describedin the individual reports.2.1.1.1 Production.2.1.1.1.1 MiningThe most important nickel-containing minerals occurring in nickel deposits are listed in Table 2.1.1.A below.This Table is taken from Kerfoot (1991).Table 2.1.1.A: Nickel-containing minerals (modified from Boldt & Queneau, 1967, quoted fromKerfoot, 1991).Name CAS Number 1) Chemical Nickel content % compositionSulphidesPentlandite 53809-86-2, 12174-14-0 2 (Fe,Ni)9S8 2 34.22Millerite 1314-04-1 NiS 64.67Heazlewoodite 12035-71-1 Ni3S2 73.30Polydymite Ni3S4 57.86Siegenite (Co,Ni)3S4 28.89Violarite Ni2FeS4 38.94ArsenidesNiccolite, nickeline 1303-13-5 NiAs 43.92 24
  • R_NickelBackground_0308_hh_chapter0124567.docRammelsbergite NiAs2 28.15Gersdorffite 12255-11-7 NiAsS 35.42AntimonidesBreithauptite 12125-61-0 NiSb 32.53Silicates and oxidesGarnierite (Ni, Mg)SiO3.nH2O < 47Nickeliferous limonite (Fe,Ni)O(OH).nH2O low1) The CAS numbers of these minerals have been added to the Table (see also Appendix 7.2.5).2) CAS No. 53809-86-2 corresponds to Fe9Ni9S16; CAS No. 12174-14-0 corresponds to (Fe0.4-0.6Ni0.4-0.6)9S8(NiPERA, 1996).Some of the minerals shown above are relatively uncommon, and only pentlandite, garnierite and nickeliferouslimonite are of economic importance (Kerfoot, 1991).Garnierite is commonly used as a generic name for a series of mixed nickeliferous silicates with a wide range ofnickel contents, and can include colloidal mixtures of silica and nickel hydroxide (Kerfoot, 1991). Garnierite is afieldname normally used for laterite ores found in New Caledonia, and named after the discovery, Jules Garnier.An alternative name is sarpolite (EniG, 2003). Nickeliferous limonite is the term used to describe poorlycrystalline nickel-bearing ferric oxide of which the main constituent is goethite (α-FeO.OH) (Kerfoot, 1991).These ores are known as laterite ores (see risk assessment report for nickel metal).Additional sulphidic ores include nickeliferous pyrrhotite (see below) and two ores containing copper as well asnickel. These ores are chalcopyrite (CuFeS2) and cubanite (CuFe2S3) (Kerfoot, 1991).An additional arsenide mineral, maucherite, Ni11As8, CAS No. 12044-65-4 (not included in EINECS), is given inNiPERA (1996).A list of nickel-containing minerals is also included by IARC (1990). This list, taken from Grandjean (1986)includes many of the ores are shown in Table 2.1.1.A above, and also includes a number of additional nickel-containing minerals shown in Table 2.1.1.B.Table 2.1.1.B: Additional nickel-containing minerals (modified from Grandjean, 1986, quoted fromIARC, 1990.).Name CAS Number 1) Chemical compositionVaesite 12035-50-6 NiS2Pyrrhotite, nickeliferous (Fe,Ni)1-xSZaratite (basic nickel carbonate, tetrahydrate) 39430-27-8 NiCO3.2Ni(OH)2.4H2OBunsenite 34492-97-2 NiOMorenosite (nickel sulphate heptahydrate) NiSO4.7H2O1) The CAS numbers of these minerals have been added to the Table shown in IARC (see also Appendix 7.2.5).Pyrrhotite (CAS No. 1317-37-9) was not included in the minerals shown in Table 2.1.1.A. because it is an ironsulphide, and nickel is not essential to its composition. Small amounts of nickel may substitute for the iron,making some pyrrhotite nickeliferous (Kerfoot, 1991). In addition, basic nickel carbonate, nickel oxide andnickel sulphate (heptahydrate) occur as minerals (Zaratite, Bunsenite and Morenosite respectively).Nickel is mined in significant quantities in 21 countries (Eurométaux, 1998).Ores used for the production of nickel are mined in Europe. The main EU deposit of sulphidic ores for theproduction of metallic nickel is located in Finland. The main EU deposit of oxidic laterite ore for the productionof ferronickel, used as a source of nickel in steel production, is in Greece. In addition, nickel is obtained fromores mined for their content of other metals (e.g. chalcopyrite containing copper), and the nickel recovered fromthese ores in the form of nickel salts (see risk assessment report for nickel sulphate). 25
  • R_NickelBackground_0308_hh_chapter0124567.doc2.1.1.1.2 Beneficiation and smeltingNickel matte and ferronickel are obtained by further processes including beneficiation and smelting of the ores.Following the removal of nickel ore from waste rock, the nickel ore is treated by beneficiation. Sulphidic oresare crushed, ground and concentrated and oxidic ores are homogenised. These processes normally take placeclose to the site where the ore is mined.Further refinement takes place at smelters. The intermediary product of the smelting (and converting) process ofsulphidic ores is nickel matte, and the intermediate product of the smelting process for oxidic ores is ferro-nickel.Melting processes are also used in the recovery of metal from secondary materials. Melting processes canproduce a matte similar to that produced from nickel ore.Nickel matte is used in the production of both nickel metal and of nickel salts (e.g. nickel chloride, nickelsulphate). Ferronickel is used in the production of stainless steel.2.1.1.1.3 Refining.Nickel refining processes uses nickel derived from ores produced in the EU as well as imported material. Nickelrefining processes lead to the production of pure nickel metal in a variety of forms (sheets or other formsproduced from nickel cathodes, pellets, briquettes, powder) as well as the nickel salts (sulphate, chloride)associated with the electrowinning processes.2.1.1.1.4 Nickel chemicals production.In some cases, nickel chemicals production is closely linked to the processes involved in the production of nickelmetal (see processes described above). In other cases, it occurs as a separate activity.2.1.1.1.4.1 High production volume nickel containing chemicals.There are a substantial number of nickel compounds and nickel-containing substances that are produced in highvolumes (> 1000 t/y). The Existing Substances Regulation (EEC, 1993b) places a duty on producers andimporters of chemicals to provide information on substances. This information is included in IUCLID. Lists ofsubstances included in this database have been prepared by the European Chemicals Bureau in Ispra (EuropeanCommission, 2000a, 2000b).The four nickel compounds, nickel sulphate, nickel chloride, nickel nitrate and nickel carbonate, are all highproduction volume chemicals (HPVCs). Production methods for these four substances are described in theindividual risk assessment reports. Production methods for other HPVC nickel compounds are described brieflybelow.Other HPVC nickel compounds than the five nickel substances currently under review are shown in Table2.1.1.C (European Commission, 2000a).Table 2.1.1.C: Other High production volume nickel compounds (European Commission, 2000a)EC No CAS No. EINECS name215-215-7 1313-99-1 Nickel oxide (NiO)273-729-7 69012-29-9 Slags, ferronickel-manufg.273-749-6 69012-50-6 Matte, nickel266-046-0 65997-17-3 Glass, oxide, chemicals266-047-6 65997-18-4 Frits, chemicals266-340-9 66402-68-4 Ceramic materials and wares, chemicals232-490-9 8052-42-4 Asphalt266-967-8 67711-91-5 Matte, copper266-968-3 67711-92-6 Slags, copper smelting268-627-4 68131-74-8 Ashes, residues273-701-4 69011-60-5 Lead alloy, base, Pb, Sn, dross 26
  • R_NickelBackground_0308_hh_chapter0124567.doc273-720-8 69012-20-0 Waste solids, copper electrolyte purifn. cathodes293-311-8 91053-46-2 Leach residues, zinc ore-calcine, cadmium-copper ppt.293-312-3 91053-47-3 Leach residues, zinc ore-calcine, iron contg.295-859-3 92129-57-2 Slimes and Sludges, copper electrolyte refining, decopperised, Ni sulfateThe CAS number 1313-99-1 (EC 215-215-7) relates to nickel (mon)oxide. The synonyms given by IARC (1990)for this CAS number include both black nickel oxide and green nickel oxide. Green nickel oxide, a finelydivided relatively pure form of nickel monoxide, is produced by firing a mixture of nickel powder and water inair at 1000 °C. Black nickel oxide, a finely divided, pure nickel monoxide, is produced by calcining nickelhydroxycarbonate or nickel nitrate at 600 °C (Antonsen, 1981, quoted from IARC, 1990). According toChemical Information Services Ltd. (1988, quoted from IARC, 1990), green nickel oxide is produced by twocompanies in the UK and one in Germany and black nickel oxide is produced by one company in the UK.Outside the EU, green nickel oxide is produced by two companies in the USA, and six in Japan, and black nickeloxide is produced by one company each in Argentina, Brazil, Canada, Japan, Mexico, and the US (ChemicalInformation Services Ltd. 1988, quoted from IARC, 1990).Nickel oxide sinter (a coarse, somewhat impure form of nickel monoxide) is manufactured by roasting a semipure nickel subsulfide (produced from nickel matte) at or above 1000 °C or by decomposing nickelhydroxycarbonate. These sinters contain either 76% nickel or, in partly reduced form, 90% nickel. Nickel oxidesinter is produced in Australia, Canada and Cuba (Sibley, 1985, quoted from IARC, 1990). The IUCLID data setfor nickel oxide (EC No. 215-215-7) includes nickel oxide sinter (or nickel oxide sinter 75) as a synonym for thissubstance. Two companies also include “catalyst” or “nickel oxide catalyst” as synonyms (IUCLID, 2002).The production of nickel matte and of ferro-nickel slags are described in the risk assessment report for nickelmetal. (It should be noted that ferronickel and slags from nickel matte production are not included in EINECS,and so are not included in this list, even though the quantities involved are also likely to qualify them asHPVCs.)The EINECS entries for “Glass, oxide”, “and “Ceramic materials and wares” list the various chemicalsmanufactured in the production of inorganic glasses and in the production of ceramics. The elements listed inthese EINECS entries are principally present as components of oxide systems, but some may be present in otherforms (EEC, 1990a).The EINECS entries for “Frits, chemicals”, describes the production of frits as a mixture of chemicals substancesproduced by rapidly quenching a molten, complex combination of materials, confining the chemical substancesthus manufactured as non-migratory components of glassy solid flakes or granules. This category includes all ofthe chemical substances specified in the entry (EINECS includes a list of 35 elements, including nickel) whenthey are intentionally manufactured in the production of frit. The primary members of this category are oxides ofsome or all the listed elements. Fluorides of these elements may also be included in combination with theseprimary substances (EEC, 1990a). The production of nickel containing frits from nickel oxide and nickelhydroxide has been described by Eurocolour (2002), an umbrella organisation under CEFIC.Asphalt is obtained as the non-volatile residue from distillation of crude oil or by separation as the raffinate froma residual oil in a deasphalting or decarbonisation process (EEC, 1990a). Asphalt is a very complex combinationof high molecular weight organic compounds containing a relatively high proportion of hydrocarbons havingcarbon numbers predominantly greater than C25 with high carbon-to-hydrogen ratios. Asphalt also contains smallamounts of various metals such as nickel, iron or vanadium (EEC, 1990a). The nickel content in asphalt reflectsthe nickel content in many fossil fuels, and, as such, is related to the anthropogenic emissions described inchapter 2.1.2.Copper matte is defined in EINECS as “the product of smelting roaster calcines concentrates or cement copperwith flux in reverberatory or electric furnaces. The matte is composed primarily of copper and copper, iron andlead sulphides with minor sulphides of other metals” (EEC, 1990a). Copper matte is produced from primary rawmaterials (ores/concentrates) by flash smelting at four sites in the EU, or by smelting roasted concentrates inelectric furnaces at one site in the EU (Laine, 2003). Copper matte produced from nickel-containing copper orescan contain some nickel sulphide. The production process for copper matte is similar to the production of nickelmatte described in the risk assessment report for metallic nickel. 27
  • R_NickelBackground_0308_hh_chapter0124567.docCopper smelting slags are slags resulting from the smelting of a heterogeneous mixture of copper and preciousmetals from primary and secondary sources and plant reverts. Major constituents are iron-calcium-aluminiumsilicates, with minor amounts of copper, lead, nickel and various non-ferrous metals and oxides (EEC, 1990a).The production process for copper smelting slag is similar to the production of the slags described in the riskassessment report for metallic nickel.The remaining six HPVC nickel containing complex substances are all secondary products from other industrialprocesses.Ashes (residues) are the residues from the burning of a combination of carbonaceous materials. The followingelements may be present as oxides: aluminium, calcium, iron, magnesium, nickel, phosphorous, potassium,silicon, sulfur, titanium and vanadium (EEC, 1990a).Lead alloy, base, Pb, Sn, dross are the oxides formed during melting, refining, and casting of solders. Majorconstituents are oxides of tin, lead and antimony; minor constituents are iron, nickel, sulfur, arsenic, copper andsilver (EEC, 1990a).Waste solids, copper electrolyte purifn. cathodes are impure copper cathodes formed during the electrolyticdemetallizing of spent copper refining electrolyte. They consist primarily of copper with varying levels ofantimony, arsenic, bismuth, lead and nickel (EEC, 1990a).Leach residues, zinc ore-calcine, cadmium-copper ppt. is an insoluble material precipitated by hydrolysis duringhydrometallurgical treatment of crude zinc sulfate solution. It consists primarily of cadmium, cobalt, copper,lead, manganese, nickel, thallium, tin and zinc (EEC, 1990a).Leach residues, zinc ore-calcine, iron-contg. is an insoluble material precipitated by hydrolysis duringhydrometallurgical treatment of crude zinc sulfate solution. It consists primarily of ferric oxide and, asimpurities, arsenic, cadmium, cobalt, copper, lead, nickel, thallium, tin and zinc (EEC, 1990a).Slimes and Sludges, copper electrolyte refining, decopperised, Ni sulfate is a product obtained from recycling ofthe end electrolyte of copper refining electrolysis followed by evaporation to separate the residual sulphuric acid.It consists primarily of nickel and iron sulfates with small amounts of the sulphates of zinc, alkali earths andalkali metals (EEC, 1990a).The first three substances will normally contain well-defined amounts of nickel. The amounts present in theremaining substances may vary considerably. Slimes and Sludges, copper electrolyte refining, decopperised, Nisulfate contains a high proportion of nickel (mainly as nickel sulphate). In most of the remaining substances,nickel is present either as a minor component or as an impurity.2.1.1.1.4.2 Low production volume nickel containing chemicals.Table 2.1.1.D: Low production volume nickel compounds (European Commission, 2000b).EC No CAS No. EINECS name235-715-9 12607-70-4 Nickel, [carbonato(2-)]tetrahydroxytri-235-008-5 12054-48-7 Nickel hydroxide (Ni(OH)2)240-841-2 16812-54-7 Nickel sulfide (NiS)233-071-3 10028-18-9 Nickel fluoride (NiF2)236-665-0 13462-88-9 Nickel bromide (NiBr2)237-396-1 13770-89-3 Sulfamic acid, nickel(2+) salt (2:1)206-761-7 373-02-4 Acetic acid, nickel(2+) salt239-086-1 14998-37-9 Acetic acid, nickel salt225-656-7 4995-91-9 Octanoic acid, nickel(2+) salt237-696-2 13927-77-0 Nickel, bis(dibutylcarbamodithioato-S,S’)-, (SP-4-1)-274-916-6 70833-37-3 Nickel, bis(3-amino-4,5,6,7-tetrachloro-1H-isoindol-1-one oximato-N(2)- ,O(1))- 28
  • R_NickelBackground_0308_hh_chapter0124567.doc249-503-9 29204-84-0 Nickel, bis[2,3-bis(hydroxyimino)-N-phenylbutanamidato-N(2)-,N(3)-]-255-924-9 42739-61-7 Nickel, bis[2,3-bis(hydroxyimino)-N-(2-methoxyphenyl)butanamidato]-237-893-3 14055-02-8 Nickel, [29H,31H-phthalocyaninato(2-)-N(29)-,N(30)-,N(31)-,N(32)-]-, (SP-4-1)-238-523-3 14516-71-3 Nickel, (1-butanamine)[[2,2’-thiobis[4-(1,1,3,3- tetramethylbutyl)phenolato]](2-)-O,O’,S]-270-944-8 68511-62-6 Nickel, 5,5’-azobis-2,4,6(1H,3H,5H)-pyrimidinetrione complexes291-673-1 90459-30-6 Nickel, acetate carbonate C8-C10-branched fatty acids C9-C11-neofatty acids complexes232-353-3 8007-18-9 Antimony nickel titanium oxide yellow, C.I. Pigment Yellow 53269-051-6 68186-89-0 Cobalt nickel gray periclase, C.I. Pigment Black 25; C.I. No. 77332.269-071-5 68187-10-0 Nickel ferrite brown spinel, C.I. Pigment Brown 34; C.I. No. 77497275-738-1 71631-15-7 Nickel iron chromite black spinel, C.I. Pigment Black 30273-700-9 69011-59-2 Lead alloy, base, dross297-402-3 93571-76-7 Ashes (residues), heavy fuel oil fly305-433-1 94551-87-8 Slimes and Sludges, copper electrolyte refining, decopperisedThe term used by the European Commission in reporting substances with production volumes from 10 to 1000t/year is “Low Production Volume Chemicals”, LPVCs. Other nickel-containing substances that are not includedin the lists prepared by the European Chemicals Bureau are discussed in a later section.Nickel, [carbonato(2-)]tetrahydroxytri- is produced as the tetrahydrate (CAS No. 29863-10-3) by precipitationfrom a nickel solution, usually the sulphate, with sodium carbonate. The exact composition depends on thetemperature and the concentrations of the components in solution (Lascelles et al., 1991). The production ofnickel carbonate is described in the risk assessment report for this substance.Nickel hydroxide (CAS No. 12054-48-7) is prepared by treating a nickel sulphate solution with sodiumhydroxide to yield a gelatinous nickel hydroxide which forms a fine precipitate when neutralised. Alternatively,nickel hydroxide is prepared by electrodeposition at an inert cathode using metallic nickel as the anode andnickel nitrate as the electrolyte or by extraction with hot alcohol of the gelatinous precipitate formed by nickelnitrate solution and potassium hydroxide (Antonsen, 1981, quoted from IARC, 1990). According to ChemicalInformation Services Ltd. (1988, quoted from IARC, 1990) nickel hydroxide is produced by one company inGermany and one in the UK. Nickel hydroxide is also produced outside the EU by four companies in Japan andthree in the US (Chemical Information Services Ltd. 1988, quoted from IARC, 1990).Purified nickel sulphide can be prepared by fusion of nickel powder with molten sulphur or by precipitationusing hydrogen sulphide treatment of a buffered solution of a nickel(II) salt (Antonsen, 1981, quoted fromIARC, 1990). Nickel sulphide (CAS No. 1314-04-1, not included in EINECS) also occurs naturally as millerite(Antonsen, 1996). Nickel sulphide and nickel subsulphide are produced as intermediates in processing sulphidicand silicate-oxidic ores and are traded in bulk for further processing (IARC, 1990). The CAS No. 16812-54-7which is associated with the EINECS No. 240-841-2 is used to describe the nickel sulphide catalyst used whenhigh concentrations of sulphur are present in the hydrogenation of petroleum distillates (Antonsen, 1996).Nickel fluoride (NiF2) is prepared as the tetrahydrate (CAS No. 13940-83-5) by the reaction of hydrofluoric acidon nickel carbonate. Nickel bromide (NiBr2) is prepared as the hexahydrate (CAS No. 18721-96-5) by thereaction of black nickel oxide and HBr (Antonsen, 1996). The anhydrous halides can be made by direct reactionof the elements at high temperature or in non-aqueous solution, although the fluoride is better made indirectly.They are also formed by dehydration of the hydrates in a stream of the hydrogen halide gas to prevent formationof nickel oxide (Lascelles et al., 1991)Sulfamic acid, nickel(2+) salt (2:1) is prepared as the tetrahydrate (CAS No. 13770-89-3) by dissolving nickelpowder in a hot solution of sulphamic acid. Soluble nickel oxide, hydroxide or carbonate can be used as well.Short reaction times are need for the preparation because sulphamic acid hydrolyses readily to form sulphuricacid. The substance is commercially available not as a solid but as a solution containing about 11% nickel(Lascelles et al., 1996). 29
  • R_NickelBackground_0308_hh_chapter0124567.docNickel acetate is listed in EINECS under two entries: Acetic acid, nickel(2+) salt (EC 306-761-7) and Aceticacid, nickel salt (EC 239-086-1). Both are listed as LPVCs. Nickel acetate is produced by heating nickelhydroxide with acetic acid in the presence of metallic nickel (Sax & Lewis, 1987, quoted from IARC, 1990). Thetetrahydrate (CAS No. 6018-89-9) is prepared when solutions of nickel(II) hydroxide or carbonate in acetic acidare evaporated at room temperature (Lascelles et al. 1991).No specific description of octanoic acid, nickel(2+) salt preparation is given in Antonsen (1996) or Lascelles etal. (1991). Nickel salts of simple organic acids can be prepared by reaction of the organic acid and nickelcarbonate or hydroxide; reaction of the acid and a water solution of a simple nickel salt; and, in some cases, bythe reaction of the acid and fine nickel powder or black nickel oxide (Antonsen, 1996).No specific description of the preparation of the next eight complex nickel substances shown in Table 2.1.1.D. isgiven in Antonsen (1996) or Lascelles et al. (1991). One of these substances, nickel, bis[2,3-bis(hydroxyimino)-N-phenylbutanamidato-N(2)-,N(3)-]-, is a pigment (CI Pigment Yellow 153) produced by Eurocolour (2002).The starting materials for this colorant, like the other nickel-containing colorant listed below, are nickel oxideand nickel hydroxide (Fischer, 2002).C.I. Pigments Yellow 53, Black 25, Brown 34 and Black 30 are all nickel-containing colorants. Their productionfrom nickel oxide and nickel hydroxide has been described by Eurocolour (2002). Colorants are produced inclosed facilities by mixing raw materials and subsequent calcination at temperatures above 1000° C. Theproducts produced are insoluble in water (Eurocolour, 2002). According to Eurocolour (2002), three of thesesubstances are identical to other EINECS entries. C.I. Pigment Yellow 53 (EC No. 232-353-3) is identical withAntimony oxide (Sb2O3), solid soln. with nickel oxide (NiO) and titanium oxide (TiO2) (EC No. 277-627-3); C.I.Pigment Brown 34 (EC No. 269-071-5) is identical with Iron nickel oxide (Fe2NiO4) (EC No. 235-335-3) andC.I. Pigment Black 30 (EC No. 269-051-6) is identical with Cobalt nickel oxide (CoNiO2) (EC No. 261-346-8).The remaining three LPVC nickel containing complex substances are all secondary products from otherindustrial processes.Lead alloy, base, dross is a scum formed on the surface of molten lead-base alloys. It includes those cases inwhich aluminium is used to remove arsenic, nickel and antimony (EEC, 1990a).Ashes (residues), heavy fuel oil fly are ashes from the flue gas collection of a steam generator fired with heavyheating oil. It consists predominantly of oxides and sulfates of aluminium, calcium, iron, nickel, sodium andvanadium among others. It is used as a raw material, for obtaining primarily V2O5 (EEC, 1990a).Slimes and Sludges, copper electrolyte refining, decopperised is a substance obtained as a powdery cathodicprecipitate during the electrolytic decoppering stage of copper refining electrolysis. It consists primarily ofcopper with antimony, arsenic, lead and nickel in metallic form as well as oxides and sulfates (EEC, 1990a).No information on the nickel concentration in these last three LPVC substances is available in IUCLID.2.1.1.1.4.3 Other low production volume nickel containing chemicals.Nickel trioxide, Ni2O3, (CAS number 1314-06-3) is also listed by IARC (1990) with black nickel oxide as asynonym (the same for the monoxide). According to NiPERA (1996), black nickel oxide is occasionally soldlabelled incorrectly as “nickel(III) oxide, Ni2O3”. The trioxide is included in EINECS (EC 215-217-8), and inAnnex I to Directive 67/548/EEC with the same classification as the monoxide (see Chapter 1.3.1.2). Lascelleset al. (1991) note that higher oxides such as Ni2O3, “have been proposed, but there is little evidence for theirexistence free of water”.A number of complex inorganic nickel-containing pigments are produced as colorants by Eurocolour companies(Eurocolour, 2002). These include CI Pigment Yellow 161 (EC No. 271-892-9), Nickel icosatitaniumpentatriacontaoxide diwolframate (NiO47Ti2W2) (EC No. 273-686-4), and C.I. Pigment Green 50 (EC No. 269-047-4).Nickel ammonium sulphate is prepared by reacting nickel sulphate with ammonium sulphate and crystallisingthe salt from a water solution (Antonsen, 1981, Sax & Lewis, 1987 quoted from IARC 1990).Reaction of nickel carbonate with hydriodic acid is used to prepare nickel iodide (NiI2) as the hexahydrate (CASNo. 7790-34-3), with phosphoric acid to form nickel phosphate (Ni3(PO4)2) as the heptahydrate (CAS No. 30
  • R_NickelBackground_0308_hh_chapter0124567.doc14396-43-1), with a water solution of arsenic anhydride to form nickel arsenate (Ni3(AsO4)2 as the octahydrate(CAS No. 7784-48-7), and with fluoroboric acid to prepare nickel fluoroborate (Ni(BF4)2) as the hexahydrate(CAS no. 14708-14-6) (Antonsen 1996).Nickel cyanide (Ni(CN)2) is made by the reaction of potassium cyanide and nickel sulphate (Antonsen, 1996).Nickel carbonyl can be prepared by the carbonyl process described in the risk assessment report for metallicnickel. In the US, nickel carbonyl was prepared commercially by the reaction of carbon monoxide with nickelsulphate solution (Antonsen, 1981, quoted from IARC, 1990).Nickelocene (CAS No. 1271-28-9) is formed by the reaction of nickel halides with sodium cyclopentadienide(Antonsen, 1981, quoted from IARC, 1990).An organic nickel colorant manufactured by Eurocolour companies is C.I. Solvent Brown 53 (Nickel, [2,3-bis[[(2-hydroxyphenyl)methylene]amino]-2-butenedinitrilato(2-)-N(2)-,N(3)-,O(2)-,O(3)-]-, (SP-4-2), EC No.265-022-7). The production from nickel oxide and nickel hydroxide is similar to that of C.I. Pigment Yellow 153described above (Eurocolour 2002). Another organic nickel compound is listed in Einecs with a C.I. Indexnumber (nickel, 3-[(4-chlorophenyl)azo]-4-hydroxy-2(1H)-quinolinone complex; C.I. 12775, EC No. 262-934-7)(EC 2002b).Antonsen (1996) and Lascelles et al. (1991) include details of production methods for a range of organo-nickelcomplexes.2.1.1.2 Nickel Use.The following figure shows the estimated distribution of nickel by end use.Figure 2.1.1.A: Estimated distribution of nickel by end-use in 1996 (NiPERA, 1997). B u ild in g & O th e r c o n s tru c tio n m a te ria ls in d u s tria l 22% N ic k e l c h e m ic a ls 1% 1% A u to m o tiv e 15% P e tro le u m in d u s try 1% R a ilw a y P o w e r g e n e ra tio n 2% 2% O th e r p ro c e s s A e ro s p a c e e q u ip m e n t 4% 11% M a rin e 2% O th e r tra n s p o rt C h e m ic a l 1% 8% C o n s u m e r p ro d u c ts O th e r c o m m e rc ia l E le c tro n ic s 18% 1% 8% B a tte rie s 3%Nickel statistics are complicated by the fact that much of the use of nickel metal, nickel-containing alloys andnickel salts are interrelated. Nickel chloride and nickel sulphate are used in nickel metal production, recyclednickel alloys are used to produce a matte that is used to produce nickel sulphate. As a result, strict specificationof nickel use for each individual nickel substance is not always easy or even useful. The Table above shows theuse of nickel in its various forms rather than the use of metallic nickel alone. 31
  • R_NickelBackground_0308_hh_chapter0124567.doc2.1.1.2.1 Uses of nickel and nickel compoundsThe use of nickel as metal and in alloys is described in detail in the risk assessment of metallic nickel. As thefigure above shows, this accounts for by far the largest proportion of nickel use.In 1994 the annual worldwide use and price of nickel compounds is given in Antonsen (1996).Table 2.1.1.E: Annual worldwide use of nickel compounds (Antonsen, 1996) Compound Structure Use: t x 103 Price: $/kg. nickel oxide sinter NiO 100 4.00 nickel sulphate hexahydrate NiSO4.6H2O 15 2.50 green nickel oxide NiO 10 4.50 nickel nitrate Ni(NO3)2.6H2O 8 3.50 black nickel oxide NiO 6 6.00 nickel carbonate NiCO3.6H2O 5 4.00 nickel chloride NiCl2.6H2O 3 4.00 others (including nickel acetate) 5 5.002.1.1.2.1.1 High production volume nickel-containing chemicals.For details of the uses of metallic nickel, nickel sulphate, nickel chloride, nickel nitrate and nickel carbonate, seeindividual reports on nickel metal and the individual nickel salts.Nickel oxide sinters, either in the form of rondelles containing partially reduced nickel oxide, compactscontaining about 90% Ni or compacts of nickel oxide sinter containing about 75% Ni sinters are important ClassII nickel products (see Chapter 1.2 of the risk assessment report for nickel metal). These sinters are the feedstockfor the nickel carbonyl refinery process at Inco, Clydach, UK (See Chapter 2.1 of the risk assessment report fornickel metal), and are used in the manufacture of alloys, steels and stainless steels (Antonsen, 1981, quoted fromIARC, 1990).Information from ECMA, the European Catalysts Manufacturers Association confirms the use of nickel oxide incatalyst production (ECMA, 2002). Nickel oxide is used in the production of colorants, glazes and frits(Eurocolour, 2002). In speciality ceramics, it is added to frit compositions used for porcelain enamelling of steel;in the manufacture of magnetic nickel-zinc ferrites used in electric motors, antennas and television tube yokes;and as a colorant in glass and ceramic stains used in ceramic tiles, dishes, pottery and sanitary ware (Antonsen,1981, quoted from IARC, 1990).Black nickel oxide is used in the manufacture of nickel salts and speciality ceramics. It is also used to enhancethe activity of three-way catalysts containing rhodium, platinum and palladium used in automobile exhaustcontrol. Like green nickel oxide, black nickel oxide is used for nickel catalyst manufacture and in the ceramicsindustry (Antonsen, 1981, quoted in IARC, 1990).Information from the Swedish Product Register lists nickel oxide as used for “Catalysts”, “Process regulators”,“Insulating materials, electricity”, “Absorbents and adsorbents” and “Other Uses” (Kemi, 2002).The use of nickel matte and of ferro-nickel slags are described in the risk assessment report for nickel metal.No further information on the use of nickel-containing “Glass, oxide”, “and “Ceramic materials and wares” isavailable.Eurocolour (2002) has estimated the European market for frits as about 5000 t/year. Frits are used for steelenamel (Eurocolour, 2002).The remaining seven substances on this list contain varying amounts of nickel. No further information on theuses of these substances is available. 32
  • R_NickelBackground_0308_hh_chapter0124567.doc2.1.1.2.1.2 Low production volume nickel-containing chemicals.Nickel, [carbonato(2-)]tetrahydroxytri-, is a basic nickel carbonate. The uses of nickel carbonate are described inthe risk assessment report for nickel carbonate.Nickel hydroxide is used in the production of nickel-cadmium batteries. It is also used as a catalyst intermediate(Antonsen, 1981, quoted in IARC, 1990). From the information available to the Rapporteur, nickel hydroxide ispresent in the production process for both batteries and catalysts (see appropriate sections in nickel metal riskassessment report). It is not clear however, whether this use reflects the deliberate use of the substance (i.e.following purchase of nickel hydroxide produced in a separate process), or whether nickel hydroxide occurs as anon-isolated intermediate in the production process. Nickel hydroxide is used in the production of colorants,glazes and frits (Eurocolour, 2002)Nickel sulphide is used as a catalyst in petrochemical hydrogenation when high concentrations of sulphur arepresent in the distillates (IARC, 1990).Antonsen (1996) reports a limited used of nickel bromide in plating. Information on nickel electroplatingsupplied by Eramet (2001) in the description of electroplating included in the Annex to the risk assessmentreport on nickel metal does not include any description of the use of nickel bromide as a component of theplating baths described. The reaction of nickel bromide (like nickel chloride) with dimethoxyethane yields ether-soluble NiX2.2C2H4(OCH3)2 compounds which are useful as nickel-containing reagents for a variety of reactionsused to form coordination compounds of nickel (Antonsen, 1996). Nickel fluoride is used for cold sealing ofanodic coatings on aluminium (Antonsen, 1996). According to Lascelles et al. (1991), the use of nickel halidessuch as nickel fluoride or nickel bromide is “minor”.Nickel sulphamate is used as a component in certain electroplating bath solutions (Eramet, 2001).Production volumes for nickel acetate have been reported under two separate EC numbers: 206-761-7 and 239-086-1, suggesting that similar chemicals are marketed under two different EC numbers. Nickel acetate is used asa catalyst intermediate, as an intermediate in the formation of other nickel compounds, as a dye mordant, as asealer for anodised aluminium and in nickel electroplating (Antonsen, 1981, quoted in IARC, 1990). Noinformation has been received from the catalyst industry that suggests that nickel acetate is used as a feedstock innickel catalyst production (ECMA, 2002). Information on nickel electroplating supplied by Eramet (2001) doesnot include any description of the use of acetate as a component of the plating baths described.One of the organic nickel-containing substances in Table 2.1.1.D is a colorant, also known as C.I. PigmentYellow 153 (EC No. 249-503-9). The last four substances in Table 2.1.1.D above are also colorants. Colorantsare widely used for the colouration of articles. Technical literature distinguishes between pigments and dyes.Pigments are mainly used for the colouration of plastics, paints and ceramics; dyes are mainly used for thecolouration of textiles, leather and paper (Eurocolour, 2002).The estimate for the size of the European market for colorants other than frits produced by Eurocolourcompanies is roughly 3400 t/y, of which CI Pigment Yellow 53 is by far the largest individual substance with amarket of about 2500 t/year (Eurocolour, 2002). 46% of the total use of these colorants is for plastics, 17% forpaints and 36% for ceramics. Details are shown in Table 2.1.1.F below.Table 2.1.1.F: Use of nickel colorants (other than frits) (Eurocolour, 2002). Name. EC Number Estimated % application 2 in use (t/year) 1 Plastics Paints Ceramics C.I. Pigment Yellow 53 232-353-3 3 2500 50 20 30 4 C.I. Pigment Green 50 269-047-4 300 90 10 C.I. Pigment Black 30 275-738-1 200 20 80 4 C.I. Pigment Yellow 161 271-892-9 100 100 4 Nickel titanium oxide tungstate 273-686-4 100 100 C.I. Pigment Black 25 269-051-6 100 100 C.I. Pigment Yellow 153 249-503-9 50 100 33
  • R_NickelBackground_0308_hh_chapter0124567.doc C.I. Pigment Brown 34 269-071-5 10 100 C.I. Solvent Brown 53 265-022-7 not available1 ) Estimate of European market for nickel containing colorants carried out by Eurocolour2 ) Estimate of use in different sectors carried out by Eurocolour3 ) European Commission shows this as LPVC (i.e. production volume less than 1000 t/year) (EuropeanCommission, 2000b).4 ) European Commission does not include this in the list of LPVCs (i.e. production volumes between 10 and1000 t/year) reported to the European Chemicals Bureau (European Commission, 2000b).Nickel, bis(dibutylcarbamodithioato-S,S)-, (SP-4-1)- (EC 237-696-2), (dibutyldithiocarbamate nickel), is usedas an additive in plastics as a uv-quencher in polyolefins (Antonsen, 1996).There is no additional information available to the Rapporteur about the uses of the other nickel-containingsubstances in Table 2.1.1.D.2.1.1.2.1.3 Other low production volume nickel-containing chemicals.Nickel carbonyl is produced as an intermediate in the Mond carbonyl refining process in the production of nickelmetal (Antonsen, 1991, quoted in IARC, 1990). For further details of this production process, see Riskassessment report on metallic nickel. Other uses of nickel carbonyl are in chemical synthesis as a catalyst, as areactant in carbonylation reactions such as the synthesis of acrylic and methacrylic esters from acetylene andalcohols, in the vapour plating of nickel, and in the fabrication of nickel and nickel alloy components and shapes(Antonsen, 1981, quoted in IARC, 1990). Whilst produced in large volumes as an intermediate in nickel metalproduction, nickel carbonyl is not included on either of the European Commission list of HPVCs or LPVCs(European Commission, 2001a, 2001b).The use of nickel ammonium sulphate is described in IARC (1990) as limited use as a dye mordant, in metal-finishing compositions and as an electrolyte for electroplating (Sax & Lewis, 1987, quoted in IARC, 1990). Itsuse as a component of electroplating bath solutions is described by Eramet (2001). This substance does nothowever appear on either the list of high or low production chemicals (European Commission, 2000a, 2000b).Additional organic nickel colorants are described by Antonsen (1996). These include the nickel disazomethinecomplex (CAS No. 61312-95-6, not included in EINECS or the TSCA inventories), Nickel Azo Yellow (EC No.257-521-3) which is a commercially important pigment with excellent light fastness and good heat stability andbleed resistance, and other nickel azo pigments including Nickel Azo Gold and Nickel Azo Red (Antonsen,1996).A number of other complex inorganic nickel-containing pigments are included in EINECS. According to Fischer(2002), information supplied during the compilation of EINECS included entries which are no longermanufactured. The substances listed in the Table 2.1.1.G below are not currently used entries (Fischer, 2002).Table 2.1.1.G: Other complex inorganic nickel-containing pigments (Eurocolour, 2002). marketed EINECS name Other name product EC No. 234-825-4 Nickel titanium oxide (NiTiO3) Nickel titanate 235-752-0 Nickel-titanium-oxide- 234-636-7 Chromium nickel oxide (Cr2-NiO4) 274-755-1 Nickel zirconium oxide (NiZrO3) 306-902-3 Iron nickel zinc oxide (Fe2-NiZnO4) 271-112-7 Olivine, nickel green CI Pigment Green 271-853-6 Nickel barium titanium primrose priderite 305-835-7 Spinels, cobalt nickel zinc grey 309-018-6 Cassiterite, cobalt manganese nickel grey 34
  • R_NickelBackground_0308_hh_chapter0124567.docNickel compounds are used as catalysts. This includes nickel silicide (EC No. 235-379-3) which, upon causticleaching, activates a nickel surface (Antonsen, 1996). Nickel boride (EC No. 234-493-0) when activated withcaustic is a reactive hydrogenation catalyst (Antonsen, 1996).Nickel compounds are used as plastics additives. The most important application is as uv-quenchers inpolyolefins. These include the dibutyldithiocarbamate compound included in Table 2.1.1.1.D as well as nickelthiobisphenolates, and nickel amide complexes of bisphenol sulphides (Antonsen, 1996). Nickel compoundshave been used as light stabilisers in high density polyethylene (HDPE) and ABS polymers, but are notcommercially important for use with PVC because of objectionable colouring of the plastic (Antonsen, 1996).Nickel compounds have been claimed for use as agricultural chemicals. Nickel chemicals afford little moreefficacy than the non-nickel containing derivatives (Antonsen, 1996).A number of the substances given as examples for a variety of uses in Antonsen (1996) with CAS numbers arenot included in either EINECS or the TSCA inventory. These include nickel niobium, NiNb, (CAS No. 59913-35-8), although NiNb is included in EINECS as EC No. 234-807-6. Nickel dibutyldithiocarbamate (CAS No.56377-13-0) is used as an oxidation inhibitor in synthetic elastomers, but is not in EINECS, althoughdibutyldithiocarbamate nickel (EC No. 237-696-2) (see above for use as a uv-quencher) is included. A numberof silicides, Ni3Si (CAS No. 12059-22-2), Ni5Si2 (CAS No. 12059-27-7) and NiSi (CAS No. 39467-10-2) usedas electroconductive materials are not in EINECS, although Ni2Si (EC No. 235-033-1) (see above) is used.Other substances given as examples which are not included in EINECS or the TSCA Inventory are nickelaluminide (CAS No. 12003-81-5), a high strength, light, ductile material, the nickel disazomethine complexpigment (CAS No. 61312-95-6), nickel bis-(3,5 di-tert-butylsalicylate) (CAS No. 68569-24-4) used for colourstabilisation of colour copy paper and nickel (2-hydroxy-4-methoxybenzophenone-5-sulphate) (CAS No.130543-71-4) used to reduce ultraviolet photofading of certain dyes (Antonsen, 1996).2.1.1.2.2 Uses of nickel containing products.Use of nickel-containing batteries, welding rods and catalysts have been described in the risk assessment reportfor metallic nickel.Information on production and use of colorants has been supplied by Eurocolour (2002). Ceramic frits and glazesare used to give colour and protection to ceramic surfaces. Final products as tableware, floor and wall tiles,artistic ceramic and steel enamelled parts do not release nickel in considerable amounts (Eurocolour, 2002).The fate of ceramic articles is normally landfill. In the case of plastics and paints only a small part of the wasteends up in landfill, where as the major part ends up in thermal waste treatment. The nickel containing pigmentswithstand firing temperatures above 1000° C without alteration and can be found in the ash (Eurocolour, 2002).2.1.1.3 Disposal.The recycling of the metallic nickel products has been described in the report of the risk assessment of nickelmetal. As this section shows, nickel is extensively recycled at many stages of the life cycle. The recyclingprocess can often involve the production of specific nickel compounds (e.g. nickel sulphate) which in turn arefrequently used in the production of other nickel-containing products. The life cycles of the different nickelcompounds are therefore closely linked.2.1.1.4 Nickel emissions from production and use of nickel and nickel-containing chemicals and products.Nickel is released to the atmosphere from emissions from nickel mining and refinery operations, from the use ofmetals in industrial processes and from incineration of wastes (Sunderman, 1986a, US EPA, 1986, quoted fromIARC, 1990).Estimates of nickel emission to the global atmosphere are reported in IARC (1990), based on Bennett (1984).The anthropogenic emissions are from the mid-1970s.Table 2.1.1.H: Anthropogenic emissions of nickel related to nickel production and use (Bennett, 1984,quoted from IARC, 1990)Source Emission rate (106 kg/year) 35
  • R_NickelBackground_0308_hh_chapter0124567.docNickel mining and refining 7.2Steel production 1.2Industrial applications 1.0Waste incineration 5.1Total 14.5The two categories “Industrial applications” and “waste incineration” may include emissions related to othersources of nickel than deliberate nickel production and use (see section 2.1.2.3 below).Nriagu (1989) gives totals for nickel emission from nickel mining and Cu/Ni production as 8.4 . 106 kg/year, ironand steel manufacture 3.7 . 106 kg/year and refuse incineration as 0.4 . 106 kg/year. His total for anthropogenicemissions directly related to intentional nickel production and use are 12.5 . 106 kg/year . This total is similar tothe total quoted in Table 2.1.1.H above.The Ambient Air Pollution Position paper (European Commission, 2000) gives a similar estimate for nickelemissions associated with intentional industrial use of nickel. The contribution of non-ferrous metal production(9.6 x 106 kg/y) and waste incineration (3.4 x 106 kg/y) gives a total contribution of 13 x 106 kg/y. The figuresquoted in the Position paper are taken from a diagram showing the atmospheric portion of the global nickel cyclefrom Nriagu (1980).2.1.2 Other anthropogenic sources of nickel.The section above describes the emissions associated with primary nickel production and use. This is mainlyrelated to nickel and nickel alloy production and to the production of nickel containing chemicals. This sectiondescribes other industrial activities that lead to nickel release.2.1.2.1 Non-ferrous metals production.Mining for other metals than nickel may involve release of nickel present as a minor component of the ore.Nickel is an important by-product of copper production (see risk assessment report for nickel sulphate). Anambient air quality level of 10 ng/m3 is unlikely to be achievable for all sites of copper or lead production (Entec,2001). Nickel release from zinc production is lower (Entec, 2001).2.1.2.2 Combustion processes.Nickel is released to air from combustion of fossil fuels in stationary and mobile power sources (Sunderman,1986a, US EPA 1986, quoted from IARC, 1990, European Commission, 2000).Stationary sources include power generation from coal- and oil-fired plants. Mobile sources include road, railand air transport. They also include emissions from ships burning bunker fuel (Entec, 2001)Table 2.1.2.A: Anthropogenic emissions of nickel related to fuel combustion (Bennett, 1984, quotedfrom IARC, 1990).Source Emission rate (106 kg/year)Residual and fuel oil combustion 27Gasoline and diesel fuel combustion 0.9Coal combustion 0.7Total 28.6In addition to coal and oil combustion, wood combustion also contributes to emissions to the atmosphere (URS,2001).The Ambient Air Pollution Position paper (European Commission, 2000) gives an estimate for nickel emissionsfrom fossil fuel combustion of 28.0 x 106 kg/y and “Others” of 6.0 x 106 kg/y. The figures quoted in the Positionpaper are taken from a diagram showing the atmospheric portion of the global nickel cycle from Nriagu (1980).The figures for nickel emission from coal and oil combustion given by Nriagu (1989) are substantially higher, at41 x 106 kg/year. Fuel wood combustion gives an additional 1.2 x 106 kg/year. Other anthropogenic sources of 36
  • R_NickelBackground_0308_hh_chapter0124567.docnickel emission are lead production (0.33 x 106 kg/year), phosphate fertilisers (0.41 x 106 kg/year) and cementproduction (0.49 . 106 kg/year). Niagu (1989) gives a total of 43.4 x 106 kg/year for anthropogenic emissions notdirectly related to the intentional production and use of nickel.The most significant emission source for nickel is found in the branch “stationary combustion” (Berdowski et al.1997, quoted from European Commission, 2000) Traces of nickel are found in fossil fuels like lignite (browncoal), hard coal and heating oil. Emission of heavy metals such as nickel is only relevant for fuels burning with asignificant ash residue. Combustion of natural gas and extra light heating oil is not a significant source ofemission of nickel (dust content < 0.1 mg/m3). Nickel concentrations vary not only between different fuelcategories, but also within the same category. The nickel emitted is not only due to the nickel content in the fuel,but also combustion conditions and temperatures and secondary abatement systems play an important role(European Commission, 2000).The role of stationary combustion compared to other sources of anthropogenic nickel emissions has beenestimated by TNO for the 15 EU Member States in 1990 (Van der Most, 1992, quoted in European Commission,2000). The contribution from stationary sources is roughly 60%, with an additional 30% from “Other mobilesources and machinery”. “Production processes” and “Road transport” comprise less than 10% of theanthropogenic emissions. Figures from Germany in 1995 and France and the UK in 1996 show figures of > 90%from stationary sources. Only in Germany was emission from production processes significant (10%) (EuropeanCommission, 2000).The source of emissions in the transport sector has changed considerably in the last 30 years in the UK (Entec,2001). In 1970 5.7 tonnes of nickel derived from rail, sea and air transport compared to 0.7 tonnes from roadtransport. In 1995 the comparable figures are 0.1 and 1.3 tonnes (data from UK DETR, 1997 quoted by Entec,2002).2.1.2.3 Other Industrial Processes.The three processes considered by Entec (2001) are petroleum refining, cement manufacture, incineration andglass production.The amounts estimated by Bennett (1984) for “Industrial applications” and “waste disposal” are shown in Table2.1.2.A above. It is not clear whether these emissions result from industrial processes strictly linked with nickelproduction and use or whether they are, at least in part, related to the processes described below.Nickel is the key metal of interest for the petroleum refining sector. Vanadium and nickel are present insignificantly greater quantities than arsenic, cadmium or mercury in those process streams which result inemissions to air from petroleum refining (Entec, 2001). Petroleum refining is not included as a specific source ofnickel emissions by Bennett (1984) or by the Position paper (European Commission, 2000).Table 2.1.2.B: Heavy Metals in Crude Oils (Jones, 1988, quoted from Entec, 2001)Metal as element Typical range in crude Lowest value reported, Highest value reported, oils, ppm ppm ppmArsenic <0.01 –0.1/0.2 Nil 2.3 <0.01 – 0.037, - - average 0.014 (1) <0.0002 – 26.2 (2)Cadmium Not detected - - 0.0004 – 0.0053, 0.0016 0.0004 (limit of - average (1) detection) <0.0001 – 0.50, typical - - values 0.0024, 0.050 (2)Mercury <0.05 0.01 29 (3) 0.0014-0.007 (4) - -Nickel 3 – 25 0.01 150Nickel in crudes run by 3.6 (non weighted 0.0 32.0surveyed petroleum average)refineries in Western 37
  • R_NickelBackground_0308_hh_chapter0124567.docEurope (5)Brent blend, North Sea 0.8 (6)Nigerian 7 (6)Iranian light 15 (6)Kuwait 9 (6)1) Data from measurements of eight crude oils (80% of The Netherlands consumption), Stigter, 2000.2) Data from literature cited by Stigter, 2000; includes some references cited by Jones, 1988.3) This is the atypical Cymric field, California, which was sited within a deposit of mercury ore.4) Liang, 2000; analyses of limited number of crude oils5) Concawe, 2000 (analyses of various crude oils also quoted)6) Data from Table 8.1 in Entec (2001).Nickel ambient air concentrations associated with nickel refineries quoted by Entec (2001) range from 1 ng/m3(UK Texaco Pembroke refinery) to 16 ng/m3 at Schiedam, Rotterdam, the Netherlands. Petroleum refinerycombustion emissions are estimated as 67.37 t/year in the UK, with the largest emission from a single refinerybeing 453 kg/year (Entec, 2001).Cement manufacturing is regarded as a minor source of atmospheric emissions of nickel from high temperatureprocesses. During cement manufacturing, nickel is emitted either as a component of the clays, limestones, andshales (raw materials) or as an oxide formed in high-temperature process kilns (European Commission, 2000).Incineration of waste and sewage sludge is shown as a source of nickel emissions (IPCS, 1991).Bennett (1984, quoted from IARC, 1990) estimates an emission rate of 5.1 x 106 kg/year (see Table 2.1.1.Habove).The glass industry contributes to a small extent of less than 1 % to the European nickel emissions (EuropeanCommission, 2000). Following consultation with the International Crystal Federation, Entec (2001) considersthat the contribution of this sector to emissions of nickel does not warrant further analysis.2.1.2.4 Emission to soil.In addition to atmospheric deposition, other sources of emission to soil include fertiliser, manure and sewagesludge (URS, 2001).Atmospheric deposition of nickel to the soil and inputs by waste disposal and through the application offertilizers are estimated to be 5.5 x 10-4 kg/a and 1.4 x 10-4 kg/a respectively (IPCS, 1991).2.1.3 Natural sources of nickelNickel is the fifth most abundant element by weight after iron, oxygen, magnesium, and silicon, and the 24thmost abundant element in the earths crust, with an average concentration estimated to be about 75-80 mg/kg(Mance & Yates, 1984; UK EGVM, 1999; IPCS, 1991, quoted from URS, 2001).Eisler (1998) has published an inventory of nickel in various global environmental compartments. This is shownin Table 2.1.3.A.Table 2.1.3.A: Inventory of nickel in various global environmental compartments (from Eisler, 1998). Compartment Mean concentration (mg/kg) Nickel in compartment (metric tons) Lithosphere, down to 45 km 75 4,300,000,000,000,000 Sedimentary rocks 48 120,000,000,000,000 Soils, to 100 cm 16 5,300,000,000,000 Oil shale deposits 30 1,400,000,000,000 Dissolved organic 0.0006 840,000,000 Nickel ore reserves > 2,000 160,000,000 Coal deposits 15 150,000,000 38
  • R_NickelBackground_0308_hh_chapter0124567.doc Terrestrial litter 15 33,000,000 Terrestrial plants 6 14,000,000 Suspended oceanic 95 6,600,000 particulates Crude oil 10 2,300,000 Terrestrial animals 2.5 50,000 Swamps and marshes 7 42,000 Lakes and rivers, total 0.001 34,000 Consumers/reducers 3.5 11,000 (biological) Atmosphere 0.3 1,500 Oceanic plants 2.5 500 Lakes and rivers, plankton 4 2302.1.3.1 Nickel emissions from natural sources.Nickel and its compounds are naturally present in the earth’s crust, and releases to the atmosphere occur fromnatural processes such as windblown dust and volcanic eruption, as well as from anthropogenic activities. Theselatter releases are mainly in the form of aerosols (US ATSDR, 1997).Table 2.1.3.B: Natural emissions of nickel to the atmosphere (Bennett, 1984, quoted from IARC,1990).Source Emission rate (106 kg/year)Wind-blown dusts 4.8Volcanoes 2.5Vegetation 0.8Forest fires 0.2Meteoric dusts 0.2Sea Spray 0.009Total 8.5Estimates by Nriagu for natural emissions are much higher. Table 2.1.3.C below shows considerably higherestimates for emissions from windblown soil particles, volcanoes, sea salt spray, and wild forest fires. Nriagudoes not include meteoric dusts in his estimates. The estimate of total median nickel release is 26 - 30 x 106 kg/y;between 3 and 4 times higher than the figures quoted above.Table 2.1.3.C: Natural emission rates of nickel in 106 kg/y (Pacyna, 1986, Nriagu, 1989).Source Pacyna, (1986), Nriagu (1989), quoted by European quoted by Mukherjee (1998) Commission (2000)Wind-blown dusts 20 (0.2 – 44) (1) 11.3 (1)Volcanoes 3.8 (2.4 – 82) 14 (1)Biogenic processes (Vegetation) 1.6 (1.6 –21) 0.8 (1)Forest fires 0.6 (0.05 – 3.3) 2.3 (1)Sea Spray 0.04 (0.01 – 0.05) 1.3Total emission (median value) 26 30 39
  • R_NickelBackground_0308_hh_chapter0124567.doc1) The Table shows Nriagu (1979) as the source of nickel data.. The values in brackets give the range of theemissions estimated by different authors. The main figure is the most acceptable value according to Pacyna. Thesource of the other estimates shown in the brackets is not clear from the Table.A figure some 60 times higher has recently been calculated by Richardson et al. (2000). This gives a mean figurefor nickel of 1.8 x 109 kg/y for nickel metal flux. The 5th percentile is 2.2 x 108, the 50th percentile 1.3 x 109 andthe 95th percentile 4.9 x 109 kg/y. The difference is mainly attributed to underestimates of the contribution frombiogenic sources.2.1.4 Summary of nickel exposure information.The Tables shown above give the emissions to the atmosphere from intentional industrial production and use ofnickel as 14. 5 x 106 kg/year (Table 2.1.1.H). This is more than the natural emissions (8.5 x 106 kg/year, Table2.1.3.B) but substantially less than the emissions from fuel combustion (28.6x 106 kg/year, Table 2.1.2.A). Eisler(1998) quotes a figure of 16% of the atmospheric nickel burden due to natural sources, and 84% due toanthropogenic sources, which agrees with the figures from these Tables shown above. The US ATSDR (1997)and CONCAWE (1999) assessments also use these figures as an estimate of the balance between natural nickelemission and the different forms of anthropogenic emission. These estimates are based on data that is nearly 30years old, and it is not clear how well these figures represent current emissions.The figures given for emissions of nickel to the atmosphere due to intentional production and use of nickel areall fairly similar at around 13 x 106 kg Ni/y. There are larger differences in the estimates for the contributionfrom other anthropogenic sources. These range from 28.6 x 106 kg Ni/y (Bennett, 1984) to gives a total of 43.4 .106 kg/year (Niagu, 1989). This difference is however very small compared to the range of estimates foremissions from natural sources which range from 8.5 x 106 kg/year (Bennett, 1984) to 1800 x 106 kg/year(Richardson et al. 2001). The uncertainties in the estimates of nickel emissions from processes not related tointentional nickel production suggests that the relative contribution of nickel emission associated with intentionalnickel production and use may have been overestimated in earlier reviews.Chemical and physical degradation of rocks and soils, atmospheric deposition of nickel-containing particulates,and discharges of industrial and municipal waste release nickel into ambient waters (US EPA, 1986, quoted fromEisler, 1998). The main anthropogenic sources of nickel in water are primary nickel production, metallurgicalprocesses, combustion and incineration of fossil fuels, and chemical and catalyst production (US EPA, 1986,quoted from Eisler, 1998). These are the same sources that contribute to emissions to the atmosphere.The primary anthropogenic sources of nickel to soils are emissions from smelting and refining operations anddisposal of sewage sludge or application of sludge as a fertiliser. Secondary sources include automobileemissions from electric power utilities (US EPA 1986 quoted from Eisler 1998). Weathering and erosion ofgeological materials also release nickel into soils (Eisler, 1998).2.1.4.1 Trends in nickel emissions.Emissions of nickel to the atmosphere are falling. Annual emissions of nickel in the UK have fallen fromroughly 1200 t/y in 1970 to roughly 300 t/y in 1996 (from Fig.1.11a, European Commission, 2000). Much of thisfall is due to changes in the types of fuels used in power generation. Nickel emissions in Germany have fallen toa third in the decade from 1985 to 1995 (from Table 1.8, European Commission, 2000). This fall is attributed toreductions mainly in the production sector in the former German Democratic Republic. Emissions at Harjavaltain Finland have fallen from 3.1 t Ni in 1990 to 1.7 t Ni in 1998. Estimates for 1999 are 0.87 t Ni (EuropeanCommission, 2000).The fall in emissions has been accompanied by a fall in ambient air levels. A reduction of 65% was seen in theRhine-Ruhr area of Germany between 1982 and 1990. A smaller decrease has been seen in other lessindustrialised regions of Germany. Only a small decrease in ambient air concentrations has been seen in the UK(European Commission, 2000).2.1.5 Nickel Lifecycle.No figures showing the total lifecycle for nickel are included here. Diagrams showing the lifecycle of theindividual substances and of some of the products such as catalysts and batteries, plated nickel and nickel alloyproduction are included in the individual risk assessment reports. 40
  • R_NickelBackground_0308_hh_chapter0124567.doc2.2 LEGISLATIVE CONTROLS.The following section follows the description of risk reduction measures described in the Nordic Risk Reductionreport (NMR, 2002) and the TGD for risk reduction (European Commission, 1998)2.2.1 General Measures.2.2.1.1 Directive 67/548/EEC on dangerous substances.Eleven nickel compounds are included in Annex I to Directive 67/548/EEC (EEC 1992a) with separateharmonised classifications. The entries for the ten existing chemicals were first introduced in the 15th. ATP(EEC, 1991b). Most of these entries have subsequently been revised to include the classification for dangers tothe environment in either the 25th. (EC, 1998b) or the 28th. ATP (EC, 2001e). An additional 18 substances areincluded in the Annex as part of group entries. For details of these classifications, see Chapter 1.3.The manufacturer or importer of substances not included in the Annex is required to evaluate available data andto apply a provisional classification. Some of the provisional classifications given by Industry are shown inChapter 1.3. Additional information on provisional classifications for substances not included in Annex I shouldbe available in the IUCLID database.Nickel compounds in EINECS are listed in Appendix 7.1.1. For many of these compounds there is little data,and, as a result, it would appear likely that only a limited number of the nickel compounds shown in Appendix7.1.1. are classified as hazardous. Harmonised classifications for many of these substances have been agreed bythe TC C&L (see Chapter 1.3).Professional users of users of hazardous substances have to be provided with a Safety data sheet by themanufacturer or supplier. The format for Safety data sheets is described in a separate Directive, EC (2001d).2.2.1.2 Directive 1999/45/EC on dangerous preparations.This Directive (EC, 1999) should be implemented into national law by the Member States by 30th. July 2002. Itreplaces Directive 88/379/EEC (EEC, 1988).Classification of hazards of preparations containing nickel compounds follows the general rules set out in theDirective. Where health or environment hazards are based on a calculation method, the general concentrationlimits set out in the Directive apply. None of the current nickel entries in Annex I to Directive 67/548/EECinclude specific concentration limits. Hence, for preparations containing nickel, current classification based onthe calculation method will be based on the general limits included in the Directive. It should be noted thatspecific concentration limits for some of the nickel entries have been introduced in the 30th ATP, together with anote on the classification of nickel-containing alloys on the basis of nickel release rather than on nickel content.2.2.1.3 Other EU legislation.Some uses of nickel metal are specifically controlled by Directive 76/769/EEC on restrictions on the marketingand use of certain dangerous substances and preparations (see Risk Assessment report on metallic nickel).Some nickel oxides and sulphides are classified in Annex I as Category 1 carcinogens. In addition, nickelchromate and dichromate are classified as Category 2 carcinogens as part of the group entry on chrome(VI)compounds, and nickel arsenate is classified as a Category 1 carcinogen as part of the entry on salts of arsenicacid. The 14th. Amendment of Directive 76/769/EEC (EC 1994b) introduced a general restriction on the sale ofcarcinogenic substances and preparations in categories 1 and 2 for consumer use. The Directive also introduces alabelling requirement for these substances and preparations in addition to the requirements in Directive67/548/EEC. The sentence: “Restricted to professional users” is also required. Exemptions are made formedicinal, veterinary, and cosmetic products, motor fuels and artists paints.Regulation (EC) No. 304/2003 (EC 2003a) of 28 January 2003 on the export and import of dangerous chemicalsdoes not include nickel in the Annex on the basis of the restrictions on marketing and use in Directive76/769/EEC. This regulation replaces Regulation (EEC) No 2455/92 (EEC, 1992c)There are a number of nickel compounds that fall within the scope of Community major accident legislationDirective 2003/105/EC (EC, 2003b) on the control of major-accident hazards involving dangerous substances onthe basis of their classification for inhalational toxicity. These include four substances (nickel carbonyl; nickel(II) cyanide; uranate(2-), tetrakis(acetato-O)dioxo-, nickel (2+)(1:1), (OC-6-11) and uranic acid (H2U3O10), 41
  • R_NickelBackground_0308_hh_chapter0124567.docnickel (2+) salt (1:1)), classified as very toxic by inhalation (T+; R26) and two further substances (seleniousacid, nickel (2+) salt (1:1) and selenic acid nickel(2+) salt, (1:1)), classified as toxic by inhalation (T; R23). Theclassifications of most other nickel compounds do not include hazards that bring them within the scope of thisDirective.In the Netherlands, a Safety report and emergency plan is required for installations where > 1 t of inhalablenickel compounds (nickel monoxide, dinickeltrioxide, nickel dioxide, nickel sulfide, trinickel sulphide) inpowder form are stored (Netherlands, 1999.)2.2.1.4 National Initiatives.The Danish list of undesirable substances (Danish EPA, 2000) includes nickel and nickel compounds.2.2.2 Protection of workers.The occupational use of hazardous chemicals is covered by the provisions of Directive 98/24/EC on theprotection of the health and safety of workers from the risks related to chemical agents at work (EC, 1998a).The Directive (Article 3) provides a framework for setting occupational exposure limit values and biologicallimit values. The Directive requires that risks arising from chemical agents are identified by employers throughrisk assessment (Article 4) and reduced by application of a set of general principles (Articles 5 and 6), whichinclude substitution, prevention, protection and control. In those instances where a national OEL is exceeded, theemployer is to remedy the situation through preventative and protective measures.The OELs at present in force generally group the nickel compounds for which OELs apply as either waterinsoluble inorganic nickel compounds or as water soluble nickel species. There are also specific limits for nickelcarbonyl.Table 2.2.A: Occupational Exposure Limits (OEL) 1 for nickel compounds in force in variouscountries (NIPERA, 1996 with updates).Country/Body mg/m3 Comments (as Ni)Austria 0. 05 nickel metal and alloys, nickel sulphide, sulphidic ores, oxidic nickel and nickel carbonates in inhalable dust, as well as any nickel compound in the form of inhalable droplets. 0.05 soluble Ni compounds 0.05 nickel carbonylBelgium 1.0 insoluble Ni compounds 0.1 soluble Ni compounds 0.12 nickel carbonylDenmark 0.05 metallic nickel; Arbejdstilsynet (2000). 0.05 insoluble nickel compounds; Arbejdstilsynet (2000). 0.01 soluble Ni compounds , Arbejdstilsynet (2000)France 1.0 nickel carbonate, nickel dihydroxide, nickel subsulphide, nickel monoxide, nickel sulphide, nickel trioxide, and for other chemical forms not otherwise specified such as “insoluble nickel compounds” and nickel sulphide roasting fume and dust. VME (Valeur Moyenne d’exposition). 0.1 soluble Ni compounds, VME (Valeur Moyenne d’exposition)Finland 1.0 metallic nickel; 0.1 nickel oxide, nickel carbonate compounds 0.1 soluble nickel compounds 0.12 (15 min) nickel carbonyl 0.007Germany 0.5 metallic nickel, nickel carbonate. TRK (Technische Richtkonzentrationen) (2) (TRGS 900, 2000) 42
  • R_NickelBackground_0308_hh_chapter0124567.doc 0.5 nickel dioxide, nickel sulphide and sulphidic ores. TRK (Technische Richtkonzentrationen) (2) (TRGS 900, 2000). 0.05 nickel compounds as inhalable droplets (e.g. nickel sulphate, nickel chloride, nickel acetate). TRK (Technische Richtkonzentrationen) (2, 3) (TRGS 900, 2000)Greece not available not availableIreland 1.0 insoluble Ni compounds 0.1 soluble Ni compounds 0.12 nickel carbonylItaly 1.0 insoluble Ni compounds 0.1 soluble Ni compounds 0.12 nickel carbonylLuxembourg 1.0 insoluble Ni compounds 0.1 soluble Ni compounds 0.12 nickel carbonylThe 1.0 metallic nickelNetherlands 0.1 nickel oxide, nickel carbonate 0.1 soluble nickel compounds 0.12 nickel carbonylPortugal 1.0 insoluble Ni compounds 0.1 soluble Ni compounds 0.12 nickel carbonylSpain 1.0 insoluble Ni compounds 0.1 soluble Ni compounds 0.12 nickel carbonylSweden 0.5 metallic nickel. LLV (Level Limit Value); occupational exposure limit for exposure during one working day. 0.1 nickel oxide, nickel carbonate 0.01 nickel subsulphide 0.1 soluble nickel compounds 0.01 nickel carbonylUnited 0.5 metallic nickel and insoluble Ni compounds. MEL (Maximum ExposureKingdom Limit) based on ’total inhalable’ aerosol as measured with the seven-hole sampler (UK HSE, 2000). 0.1 soluble Ni compounds . MEL (Maximum Exposure Limit).’total inhalable’ aerosol as measured with the seven-hole sampler (UK HSE, 2000). 0.24 (OES) nickel carbonylEU (proposed) [1.0] metallic nickel. NiPERA (1996) proposal under discussion in SCOEL. [0.5] oxidic nickel. NiPERA (1996) proposal under discussion in SCOEL. [0.1] sulphidic nickel. NiPERA (1996) proposal under discussion in SCOEL. [0.1] soluble nickel species. NiPERA (1996) proposal under discussion in SCOEL. [0.24 (OES)] nickel carbonyl. NiPERA (1996) proposal under discussion in SCOEL.Norway 0.05 nickel and nickel compounds 43
  • R_NickelBackground_0308_hh_chapter0124567.docUSA (OSHA) 1.0 insoluble Ni compounds. Soluble nickel compounds PEL (Permissible exposure limit) 1.0 soluble nickel compounds PEL (Permissible exposure limit) 0.007 nickel carbonyl PEL (Permissible exposure limit)1): 8-hour TWA (Time-Weighted Average) unless otherwise noted.2): In Germany, nickel metal and nickel compounds are classified by MAK as Carc. Cat. 1 if they occur inrespirable form as dusts or aerosols, and therefore MAK values cannot be fixed for these substances. The MAKlist also notes the risk of sensitisation of the skin and respiratory tract caused by nickel and nickel compounds(BAuA, 2003).3) According to German national regulations, soluble nickel compounds, nickel chloride, nickel sulphate andnickel acetate are classified as Carc. Cat. 1 (TRGS 905, 2002, in connection with EU Regulations) (BAuA,2003)ACGIH (1998) has the following inhalable Threshold Limit Values (TLVs) for nickel and nickel compounds:1.5 mg Ni/m3 for metallic nickel, 0.2 mg Ni/m3 for insoluble nickel, 0.1 mg Ni/m3 for nickel subsulfide and 0.1mg Ni/m3 for soluble nickel.Some nickel oxides and sulphides are classified in Annex I to Directive 67/548/EEC as Category 1 carcinogens.In addition, nickel chromate and dichromate are classified as Category 2 carcinogens as part of the group entryon chrome(VI) compounds, and nickel arsenate is classified as a Category 1 carcinogen as part of the entry onsalts of arsenic acid. These substances are covered by the provisions of Directive 90/394/EEC on the protectionof workers from the risks related to exposure to carcinogens at work (EEC, 1990c). Changes to the classificationagreed by the TC C&L when included in Annex I will bring more nickel compounds into the scope of thisDirective.A number of nickel compounds are covered by the provisions of Directive 92/85/EEC on the introduction ofmeasures to encourage improvements in the safety and health at work of pregnant workers and workers whohave recently given birth and are breastfeeding (EEC, 1992d). As well as the Category 1 & 2 carcinogens listedabove, the category 3 carcinogens in Annex I to Directive 67/548/EEC are also covered. These are nickelcarbonyl, nickel metal, nickel dihydroxide, nickel sulphate and nickel carbonate. For such workers, this Directiverequires that the employer shall assess the nature, degree and duration of exposure in the undertaking and/orestablishment concerned, of pregnant workers, workers who have recently given birth and workers who arebreast feeding in all activities liable to involve a specific risk of exposure to the agents. Changes to theclassification agreed by the TC C&L when included in Annex I will bring more nickel compounds into the scopeof this Directive as well.The possibility for young people to work with nickel compounds and preparations containing nickel compoundsthat are classified as harmful under Directive 88/379/EEC is covered by the provisions of Directive 94/33/EC(EC, 1994a) on the protection of young people at work. This Directive prohibits the employment of youngpeople for work involving exposure to such harmful agents.The use of personal protective equipment at the workplace is regulated by Directive 89/656/EEC (EEC, 1989b).The labelling required by Directive 67/548/EEC will often include Safety advice phrases such as: S22 (Do notbreath dust), S36 (Wear suitable protective clothing) and S37 (Wear suitable gloves).2.2.3 Protection of consumers.Consumer exposure to nickel comes mainly from contact with metallic nickel and nickel-containing alloys. Thislegislation is described in detail in the risk assessment report for nickel metal. With the exception of the use ofnickel sulphate and nickel chloride as a source of nickel in food supplements, there would appear to be little orno consumer exposure to nickel sulphate, nickel chloride, nickel nitrate or nickel carbonate (see individual riskassessment reports).Information on consumer exposure to the other nickel compounds described in this Background report is limited.Whilst many do not appear to have direct consumer uses, compounds such as those used as plastic additives maygive rise to exposure from food contact materials or from toys, whilst nickel in pigments may give rise toexposure from other articles. Eramet (2002) has provided information on the use of nickel chloride to producepigments used in both textiles and wallpaper. Some of the legislative controls provided in consumer protectionlegislation may therefore be relevant for certain nickel-containing compounds. 44
  • R_NickelBackground_0308_hh_chapter0124567.doc2.2.3.1 Directive 98/83/EC on the quality of water intended for human consumptionDirective 98/83/EC (EC, 1998d) sets a limit for nickel in drinking water of 20 μg/l. The EC Drinking waterstandard set in Directive 98/83/EC is lower than the previous limit of 50 μg/l set in Directive 80/778/EEC (EEC,1980b) which it replaced in December 2003, and is the same as the provisional drinking water guideline set bythe World Health Organisation in 1993 (WHO, 1993). It should be noted that this limit applies to nickel ion indrinking water rather than to nickel derived from any specific nickel compound.2.2.3.2 Food contact materials, Food supplements, additives and contaminants.The general requirements in article 2 of Directive 89/109/EEC on materials and articles intended to come intocontact with foodstuffs (EEC, 1989c) should be taken into account when evaluating the safe use of materials incontact with food. The requirements for nickel and nickel alloys have been described in the Risk Assessmentreport for nickel metal. However, a number of nickel compounds are used as additives to plastics (see section2.1.1.2.1 above). It is not clear to what extent materials containing these nickel-containing additives are used asfood contact materials.The Council of Europe has published a policy statement concerning materials and articles intended to come intocontact with foodstuffs (Council of Europe, 2001). Appendix II contains data indicating that the mean intake ofnickel via food is 2.8 mg/week, which is greater than 100% of the PTWI (Provisional Tolerated Weekly Intake)estimated as 2.1 mg/week.Finland has set limits for the release of nickel from food contact materials of 2.0 mg per dm2 (Finland, 1992).The UK and Germany have a number of standards for certain food contact materials (for references see Councilof Europe, 2001).Nickel or nickel compounds are not permitted as food supplements in Directive 2002/46/EC of the EuropeanParliament and the Council on food supplements in foodstuffs for human consumption (EC, 2002c) or in CouncilDirective 70/524/EEC concerning additives in feedingstuffs for animal nutrition (EEC, 1970). It should be notedthat the validity of Directive 2002/46/EC has been challenged at the European Court of Justice, and that theopinion of the Advocate General is that the Directive is invalid (European Court, 2005). The case is expected tobe decided before the end of July 2005.Nickel compounds are not included in the list of additives for specific nutritional purposes in foods for particularnutritional uses (Commission Directive 2001/15/EC of 15 February 2001, EC 2001c). There are no limits set fornickel as a contaminant in food (Council Regulation (EEC) No 315/93, EEC 1993a). There are limits set fornickel in the specific criteria of purity concerning certain polyolen sweeteners for use in foodstuffs (EEC, 1995and amendments). A limit of 2 mg/kg nickel expressed as dry weight is set for E420 sorbitol, E421 mannitol,E953 isomalt, E965 malitol, E966 latitol and E967 xylitol.Scientific advice was previously provided by the Commission Scientific Committee on Food (SCF) and theCommission Scientific Committee on Animal Nutrition (SCAN). Since the establishment of the European FoodSafety Authority, the relevant committees are the Panel on food additives, flavourings, processing aids andmaterials in contact with food (AFC), the Panel on dietetic products, nutrition and allergies (NDA), the Panel oncontaminants in the food chain (CONTAM) and the Panel on additives and products or substances used inanimal feed (FEEDAP).The Scientific Panel on Dietetic Products, Nutrition and Allergies has prepared an opinion on the tolerable upperlimit of nickel in response to a request from the Commission (NDA, 2005). During the decision making processfor the adoption of Directive 2002/46/EC on Food Supplements, the Parliament requested that nickel should beallowed to be used in food supplements. This opinion is a supplement to the previous opinions on individualvitamins and minerals evaluated by the SCF. The NDA was unable to establish a tolerable upper intake level fornickel due to the absence of adequate dose-response data.2.2.3.3 Council Directive 90/385/EEC on active implantable Medical Devices, Council Directive 93/42/EEC on Medical Devices and Council Directive 98/79/EEC on in vitro-diagnostic Medical DevicesCommunity legislation to regulate implantable medical devices was introduced in 1990 (EEC, 1990b), and thisDirective was amended in 1993 (EEC, 1993c) to cover a much wider range of medical devices. The latterinclude non-active implantable, medical devices (e.g. bone screws) as well as a wide range on non-implantdevices (e.g. scalpels, forceps and much dental instruments). Directive 98/79/EC (EC, 1998c) covers in vitro 45
  • R_NickelBackground_0308_hh_chapter0124567.docdiagnostic medical devices. These legislative controls required by these Directives are described in the RiskAssessment report for metallic nickel.Scientific advice on medical devices is provided by the Commission Scientific Committee on MedicinalProducts and Medical Devices.2.2.3.4 Council Directive 88/378/EEC on the Safety of ToysDirective 88/378/EEC on the safety of toys (EEC, 1988a) makes no specific mention to nickel; however, toysmust conform to the essential requirements of the Directive. Discussions on a revision of the Directive are takingplace.Scientific advice is provided by the Commission Scientific Committee on Health and Environmental Risks(SCHER).2.2.3.5 Council Directive 89/106/EEC on Construction ProductsCouncil Directive 89/106/EEC on the approximation of laws, regulations and administrative provisions of theMember States relating to construction products (EEC, 1989a) is described in the Risk Assessment report formetallic nickel.2.2.3.6 Directive 2001/95/EC on general product safetyDirective 92/59/EEC (EEC, 1992b) has recently been replaced by Directive 2001/95/EC of the EuropeanParliament and of the Council of 3 December 2001 on general product safety (EC, 2001h). The purpose of theDirective is to ensure that products are safe (Art. 1, 1). The Directive places a general obligation on the importersand manufacturers of products intended for consumer use to ensure that their products are safe based oncompliance with European and national standards (Art. 3). The manufacturer is also required to provideconsumers with the relevant information to enable them to assess the risk inherent in a product under normal andreasonably foreseeable conditions of use, and to take precautions against those risks (Art. 5).2.2.4 Emissions to water2.2.4.1 Directive 96/61/EC concerning integrated pollution prevention and control (IPPC)The aim of the Directive (EC, 1996a) is to lay down measures designed to prevent or control emissions in orderto achieve a high level of protection of the environment as a whole. It integrates provisions and measures dealingwith emissions to air, water and land, including measures concerning wastes.The directive covers medium-sized and large industrial installations, and waste management installations (AnnexI) (NMR, 2002).Annex I includes many of the processes described earlier in this Chapter. These include:2. Production and processing of metals2.1. Metal ore (including sulphide ore) roasting or sintering installations……..2.5. Installations (a) for the production of non-ferrous crude metals from ore, concentrates or secondary raw materials by metallurgical, chemical or electrolytic processes (b) for the smelting, including the alloyage, of non-ferrous metals, including recovered products, (refining, foundry casting, etc.) with a melting capacity exceeding 4 tonnes per day for lead and cadmium or 20 tonnes per day for all other metals2.6. Installations for surface treatment of metals and plastic materials using an electrolytic or chemical processwhere the volume of the treatment vats exceeds 30 m³4. Chemical industryProduction within the meaning of the categories of activities contained in this section means the production onan industrial scale by chemical processing of substances or groups of substances listed in Sections 4.1 to 4.6…….4.2. Chemical installations for the production of basic inorganic chemicals, such as:……. 46
  • R_NickelBackground_0308_hh_chapter0124567.doc(d) salts, such as ammonium chloride, potassium chlorate, potassium carbonate, sodium carbonate, perborate,silver nitrate(e) non-metals, metal oxides or other inorganic compounds such as calcium carbide, silicon, silicon carbide.Installations listed in Annex I have to have a permit. New installations have to have a permit in accordance withthe IPPC directive before they are put into operation. Existing installations (in operation before October 2000)have to have a permit in accordance with this directive at the latest 2007. (Art. 4 and 5). An application for apermit has to include inter alia descriptions of raw and auxiliary materials, nature and quantities of foreseeableemissions, proposed technology or other techniques for preventing or reducing emissions, and measures plannedto monitor emissions. (Art. 6). The permit shall include emission limit values for pollutants likely to be emittedfrom the installations in significant quantities. Annex III includes an indicative list of main polluting substancesto be taken into account when considering emission limits (Art 9.3) (NMR, 2002). Annex III includes “Metalsand their Compounds” for emissions to both air and to water.Emission limit values shall be based on best available techniques. (Art 9.4) Annex IV includes issues to be takeninto account when determining best available techniques. For instance the use of less hazardous substances(point 2), the nature, effects and volume of the emissions concerned (point 6), and the consumption and nature ofraw materials (point 9) have to be considered. The Commission shall organise an exchange of informationbetween Member States and the industries on best available techniques. (Art. 16) The results of this informationexchange are published as IPPC BAT Reference Documents (BREFs). The BREFs aim at providing referenceinformation for the permitting authority to be taken into account when determining emission limit values (NMR,2002). The Commission has published eight BREFs on Best Available techniques in a number of industries (EC,2002).The permit shall contain suitable release monitoring requirements. (Art 9.5). Permit conditions have to bereconsidered and updated periodically. (Art 13). The Council can set common emission limit values for thecategories of installations listed in Annex I and for the substances referred to in Annex III. (Art 18) (NMR,2002).2.2.4.2 Directive 76/464/EEC on pollution of the aquatic environment by certain dangerous substances.Nickel is included in List II of families and groups of substances covered by the Directive (EEC, 1976).List II contains • substances belonging to the families and groups of substances in List I for which the limit values referred to in Article 6 of the Directive have not been determined, and • certain individual substances and categories of substances belonging to the families and groups of substances listed below, and which have a deleterious effect on the aquatic environment, which can, however, be confined to a given area and which depend on the characteristics and location of the water into which they are discharged.Nickel is one of the families and groups of metalloids and metals and their compounds referred to in the secondindent.Under this legislation, pollution from List II substances has to be reduced by pollution control measures. A basicrequirement is that discharges of these substances require authorisation.Scientific advice is provided by the Commission Scientific Committee Health and Environmental Risks(SCHER).2.2.4.3 Directive 2000/60/EC establishing a framework for Community action in the field of water policy.Nickel and nickel compounds are specifically listed in the Decision (EC, 2001g) establishing the list of prioritysubstances in the field of water policy and amending Directive 2000/60/EC (EC, 2000b).According to the Directive, the Commission shall submit proposals for environmental quality standards (EQSs)applicable to concentrations of the priority substances in surface water, sediments or biota.2.2.4.4 Directive 80/68/EEC on the protection of groundwater against pollution caused by certain dangerous substancesNickel is included in List II of families and groups of substances covered by the Directive (EEC, 1980a). 47
  • R_NickelBackground_0308_hh_chapter0124567.docThe purpose of the Groundwater Directive is to prevent the pollution of groundwater by groups of substances inlists I and II in the Annex and as far as possible to check or eliminate the consequences of pollution which havealready occurred. The Directive obliges the Member States to limit the introduction of substances in list II so asto avoid pollution.According to the Water Policy Framework Directive (EC, 2000b) the Groundwater Directive will be repealedwith effect from 13 years after the data of entry into force of the Directive, that is 22.12.2013.2.2.4.5 Directive 2000/76/EC on the incineration of waste.The aim of the Directive (EC, 2000c) is to prevent or to limit as far as practicable negative effects on theenvironment, in particular pollution by emission into air, soil, surface water and ground water, and the resultingrisk to human health, from the incineration and co-incineration of waste.Annex III sets emission limit values for discharges of waste water from the cleaning of exhaust gases for nickeland its compounds, expressed as nickel (Ni): 0.5 mg/l.2.2.4.6 National Legislation.In Finland, the IPPC Directive is implemented by the Environmental Protection Act (2000/86) (Finland, 2000).In addition to installations listed in Annex I of the IPPC Directive, several other activity categories and activitiesnot exceeding capacity thresholds set in the IPPC Directive require a permit according to the Finnish Act.Concerning nickel emissions, the most important difference is that all surface treatment installations usingelectrolytic or chemical process require a permit regardless of the capacity. So far permit conditions for nickelhave been included in permits issued for the following sectors: mines, smelters, metal refiners, primary andsecondary steel production, electrolytic and chemical metal plating (including aluminium anodising) and wastehandling (Heiskanen, 2003).The Netherlands has a number of regulations concerning nickel in water. There is a general prohibition ondischarge of nickel to surface water (Netherlands, 1974). The concentration of nickel (individual) in purifiedgroundwater to inject in a provision for collection and transport of wastewater should be < 500 μg/l (Netherlands2001a). This legislation is part of an implementation of Council Directive 91/689/EEC on hazardous waste(EEC, 1991c, see 2.2.7.2 below) and Council Directive 91/271/EEC on urban wastewater treatment (EEC,1991a). The same limit value applies to polluted ground water discharges to surface water during soilremediation (Netherlands, 1997a).The limit value for water to be infiltrated into soil is 15 g/l (Netherlands, 1993).The Netherlands environmental quality standards for fresh surface water and for groundwater are shown inTables 2.2.4.A and 2.2.4.B.Table 2.2.4.A: Environmental Quality Standards for fresh surface water in the Netherlands (NLChemical Substances Bureau, 2002) Dissolved (µg/l) Total (µg/l)Background Target Maximal Background Target MaximalConcentration Value Permissible Concentration Value Permissible Concentration Concentration3.3 3.3 5.1 4.1 4.1 6.3Target Value (TV) and Maximal Permissible Concentration (MPC) figures include Background Concentration(BC).The values for water (total) are derived for water containing 30 mg/L of suspended solids (that contains 20% oforganic matter and 40% of clay). The Kp-value for nickel that is used for suspended solids-water is 8,000 L/kg,and for soil-water or sediment-water is 5,300 L/kg.Table 2.2.4.B: Environmental Quality Standards for nickel dissolved in groundwater in theNetherlands (NL Chemical Substances Bureau, 2002) Deep (>10m) (µg/l) Superficial (<10m) (µg/l) Dissolved (µg/l) 48
  • R_NickelBackground_0308_hh_chapter0124567.docBackground Target Value Background Target Value Intervention valueConcentration Concentration2.1 2.1 15 15 75Target Value (TV) includes Background Concentration (BC).The intervention value is a trigger for high concern, when a concentration exceeds this value, immediate researchmust be carried out to determine the urgency of sanitation. The value is based on ecotoxicological and humantoxicological data, and in addition on generic exposure scenarios.A number of environmental quality standards (EQSs) apply in the UK for protection of aquatic life in surfacewaters (URS, 2001). For freshwater, the current EQS ranges from 50 to 200 μg/l dependent on water hardness,although a lower range of 8-40 μg/l has been proposed in R&D work funded by the UK Department ofEnvironment Transport and the Regions 9 (Hunt & Hedgecott, 1992). The EQS in legislation for marine waters is30 μg/l (DoE, 1989), although again a lower 15 μg/l limit has been proposed (Hunt & Hedgecott, 1992).Table 2.2.4.C: Freshwater environmental quality standards for nickel in UK inland waters (URS2001).Total hardness EQS (μg/l) Proposed EQS (μg/l)(mg CaCO3/l) (DoE Circular 7/89) (Hunt & Hedgecott, 1992)0-50 50 850-100 100 20100-150 150 20150-200 150 40>200 200 402.2.5 Emissions to air2.2.5.1 Directive 96/61/EC concerning integrated pollution prevention and control (IPPC)See Chapter 2.2.5.1 above.Annex III includes an indicative list of the main polluting substances to be taken into account if they are relevantor fixing emission values. Metals and their compounds are included as item 5 in the list for emissions to air.2.2.5.2 Directive 96/62/EC on ambient air quality assessment and management.This Directive sets levels for a number of air pollutants which are to be taken into account in the assessment andmanagement of ambient air quality. Annex I part II includes nickel among such pollutants.A Directive on ambient air quality for nickel, cadmium, arsenic, mercury and polycyclic aromatic hydrocarbons(EC 2004b) identifies nickel as a genotoxic carcinogen and sets a target value of 20 ng Ni/m3. Measures toachieve this target value involve the use of Best Available Technology (BAT). The reference method for themeasurement of nickel concentrations in ambient air is currently being standardised by CEN and shall be basedon manual PM10 sampling equivalent to EN 12341, followed by digestion of the samples and analysis by AtomicAbsorption Spectrometry or ICP Mass Spectrometry.Before making proposals for this Directive, the Commission prepared a Position paper on ambient air pollutionby nickel compounds (European Commission, 2000). This paper has been reviewed by the CSTEE (CSTEE,2001). For non-cancer effects, the CSTEE found that a limit value of 20 ng/m3 was supported by the data. Forcancer effects, the CSTEE supported the recommendation from WHO (1999) of a unit risk of 3.8 x 10-4 (μgNi/m3)-1. This corresponds to concentrations of 25 ng Ni/m3 and 2.5 ng Ni/m3 for increased lifetime risks of1:100 000 and 1: 1 000 000 respectively. In view of the fact that these estimates are conservative in nature, theCSTEE concluded that the limit value of 20 ng/m3 is likely to provide reasonable protection of the generalpopulation to both the carcinogenic and non-carcinogenic effects of nickel compounds in ambient air (CSTEE,2001).9 The UK DoE, DETR and MAFF are now the Department of Environment, Food and Rural Affairs (DEFRA). 49
  • R_NickelBackground_0308_hh_chapter0124567.doc2.2.5.3 Directive 2000/76/EC on the incineration of waste.The Directive (EC, 2000c) sets air emission limit values for nickel and its compounds, expressed as nickel (Ni)of either a total of 0.5 mg/m3 or 1 mg/m3 (all average values over the sample period of a minimum of 30 minutesand a maximum of 8 hours) depending on when the plant was granted its permit to operate.2.2.5.4 Directive 2001/80/EC on Large Combustion Plant Directive.This Directive is expected to have implications on heavy metal emissions from existing coal and oil fired plantsas it will set limit values to total dust emissions. It will apply to new plants licensed after 1987 while older plantshave to comply from 2008 on. More substantial impacts on heavy metal emissions could result from the reviewdue in 2004.2.2.5.5 UN ECE Protocol on heavy metals.The 1998 Aarhus Protocol on Heavy Metals is a Protocol under the UN ECE convention on Long-rangetransport of atmospheric pollutants. Whilst this protocol is primarily directed at limiting the release of cadmium,lead and mercury, many of the installations that can be affected by the Protocol also emit nickel. The Protocolhas been signed by all Member States and the European Commission, and ratified or approved by Denmark,Finland, France, Luxembourg, the Netherlands and Sweden. Norway has also ratified the Protocol. The protocolhas been ratified or approved by Canada, the Czech Republic, the Republic of Moldova, Switzerland, the US andthe European Community.2.2.5.6 National Legislation.In Finland, the IPPC Directive is implemented by the Environmental Protection Act (2000/86) (Finland, 2000).See Chapter 2.2.4.6 above.Emissions of nickel and its compounds are regulated in Germany by TA Luft (2002) under section 5.2.2(inorganic dusts) in hazard class II, with emission limits expressed as nickel of 2.5 g/h or 0.5 mg/m3. Nickel andits compounds (with the exception of nickel metal, nickel alloys, nickel carbonate, nickel hydroxide and nickeltetracarbonyl) are also included in section 5.2.7.1.1. (Carcinogens) with emission limits expressed as nickel of1.5 g/h or 0.5 mg/m3.The Netherlands Emissions Guidelines for air (NeR) regard nickel and nickel compounds as category C.2carcinogens. C2 carcinogens are carcinogens without a threshold value and compulsory minimisation ofemissions is required. Specifically, in the case of an untreated mass flow of 5.0 grams per hour or more, anemission standard of 1.0 mg/mo3 (calculated as nickel) applies (Netherlands, 2001b). From 1. April, 2003, nickeland nickel compounds are regarded as carcinogens for which compulsory minimisation applies. For an untreatedmass flow of 0.15 g/hr, an emission standard of 0.05 mg/m3 applies. An immission assessment must be carriedout once every five years. (InfoMil, 2003)CEPN (Centre d’étude sur l’évaluation de la protection dans le domaine nucléaire) performed a risk assessmentbased on the respiratory cancer effects in animals and humans. This report did not recommend an actual airquality standard, but suggested that an exposure range between 0.01 and 0.03 μg Ni/m3 (10 – 30 ng Ni/m3)would be protective of public health (Lepicard et al., 1997, quoted in CONCAWE, 1999).The Netherlands is the only EU country with an ambient air quality standard in national legislation (EuropeanCommission, 2000). The Netherlands target value for nickel in air (yearly average) is 0.0025 μg/m3 with aMaximum Permissible concentration of 0.25 μg/m3.In Denmark airborne emissions of nickel from industrial sources should be reduced to be well below 0.01mg/normal m3 by filtering the air through an absolute (HEPA-) filter. An air concentration at ground level of0.0001 mg Ni/m3 for the surrounding neighbourhood should also be observed (Danish EPA, 2002).Belgium (Flanders) uses a non-legally binding target value of 5 ng/m3 (annual means) to assess theconcentrations of nickel (European Commission, 2000).2.2.5.7 Other measures.CONCAWE (1999) has recommended an Air quality standard for soluble nickel compounds of 0.6 μg/m3 (60 ngNi/m3) and 6 μg Ni/m3 (600 ng Ni/m3) for less soluble nickel compounds based on cancer epidemiology. 50
  • R_NickelBackground_0308_hh_chapter0124567.docCONCAWE (1999) quotes acceptable nickel ambient air concentration regulations and recommended exposurelimits from the US and Canada. The annual average recommended ambient limit ranges from 0.0002 μg/m3 (fornickel subsulphide, set by New York State Department of Health in 1989) to 3.37 μg/m3 (for metallic andinsoluble nickel compounds, set by New York State Department of Environmental Conservation in 1988).2.2.6 Soil2.2.6.1 Directive 86/278/EEC on Sludge in Agriculture.The EC Sludge in Agriculture Directive, Council Directive 86/278/EEC, (EEC, 1986) stipulates a maximumpermissible addition of 3 kg/ha/y of nickel in sewage sludge to agricultural land, not to result in a concentrationhigher than 30-75 mg/kg dry weight in soil at pH 6-7. The limit value for nickel in sewage sludge has been set at300-400 mg/kg dry weight.2.2.6.2 National Legislation.Immissions of nickel and its inorganic compounds are regulated in Germany by TA Luft (2002) under section4.5.1 (Immission values for the deposition of harmful substances). The immission limits expressed as nickel are15 μg/m2/d, measured as the mean value for 1 year. The bagatelle limit for the immission of these substances is0.025 kg/h.In the Netherlands, the standard for clean soil is < 35 mg/kg dry weight (Netherlands, 1995, see also below).There is a general prohibition against discharge of liquids containing nickel into soil, although exceptions arepossible (Netherlands, 1997b).The environmental quality standards used for sediment and soil in the Netherlands are shown in the Table below.Table 2.2.6.A Environmental Quality Standards for sediment and soil in the Netherlands (NLChemical Substances Bureau, 2002). Sediment & Soil (mg/kg s.b.) Sediment (mg/kg s.b.) Sediment & Soil (mg/kg s.b.)Background Target Value Maximal Permissible Intervention valueConcentration Concentration – sediment35 35 44 210Maximal Permissible Concentration (MPC) for sediment includes Background Concentration (BC)s.b.: standard soil or sediment, based on dry weight; (Dutch) standard soil or sediment contains 10% organicmatter and 25% lutum (clay).The intervention value is a trigger for high concern, when a concentration exceeds this value, immediate researchmust be carried out to determine the urgency of sanitation. The value is based on ecotoxicological and humantoxicological data, and in addition on generic exposure scenarios.The standards for a particular soil type (Nb) can be related to the standard for standard soil (Ns) by the followingformula:Nb = Ns x A + (B x % lutum) + (C x % organic substance) A + (B x 25) + (C x 10)For nickel, A = 10, B = 1 and C = 0.In addition there are standards for a number of products. The limit value for dredging sludge is 35 mg/kg d.w..The standards for sewage sludge are 30 mg/kg d.w., for compost: 20 mg/kg d.w. and for very clean compost: 10mg/kg d.w..The UK Ministry for Agriculture, Fisheries and Food (MAFF 10) has also set limits for metals in agricultural soilsreceiving sewage sludge (see Table 2.2.6.B) (URS, 2001). The 75 mg Ni/kg limit for agricultural soils at pH 6.0-7.0 is exceeded in relatively few places in England and Wales (McGrath & Loveland, 1992). These locations areoften in areas of mineralisation of rocks and soil, e.g. over carboniferous limestone in Derbyshire and serpentinein south Cornwall (URS, 2001).10 The UK DoE, DETR and MAFF are now the Department of Environment, Food and Rural Affairs (DEFRA). 51
  • R_NickelBackground_0308_hh_chapter0124567.docTable 2.2.6.B: Maximum permissible and advisable concentrations of potentially toxic elements(PTEs) in soil after application of sewage sludge to agricultural land (UK MAFF, 1988, from URS,2001). Maximum permissible concentrations of PTE1 at Maximum permissible average various pH values over a 10-year period (kg/ha)PH 5.0 –5.5 5.5-6.0 6.0-7.0 >7.0 -Nickel (mg/kg) 50 60 75 110 3 kg/ha1 PTE – Potentially Toxic ElementsThe UK Environment Agency use an environmental assessment level (EAL) of 50 mg/kg nickel in soil for thepurposes of monitoring releases under IPPC. In addition to this soil value, a maximum rate of deposition to soilof 0.11 mg nickel/m2/d is also specified (URS, 2001).The UK Inter-departmental Committee on the Redevelopment of Contaminated Land (ICRCL) has set athreshold concentration of 70 mg/kg nickel above which soil may be toxic to plants. Guideline Values (GVs) forthe assessment of soil contamination from a human health protection perspective are under development by UKDEFRA but have yet to be published (URS, 2001).In Denmark a health based soil quality criteria of 30 mg Ni/ kg soil has been set for the use of soil/area forsensitive uses e.g. kindergartens and domestic gardens (Danish EPA 2001).In Sweden, the nickel content of sludge for agricultural use should not exceed 50 mg/kg dry weight (Kemi,2003).2.2.7 Waste management.2.2.7.1 Directive 96/61/EC concerning integrated pollution prevention and controlSee Chapter 2.4.4.1 above.2.2.7.2 Council Directive 91/689/EEC of 12 December 1991 on hazardous wasteAnnex II of the Directive (EEC, 1991c) includes C5 nickel compounds as constituents of wastes in Annex IBwhich render them hazardous when they have the properties described in Annex III of the Directive.Lists of hazardous wastes of hazardous wastes have been published as two Commission Decisions (EC, 2001a,2001b). Decision 2001/118/EC (EC, 2001a) divides wastes into different chapters. These include a number ofcategories relevant to the production and use of nickel and nickel compounds:01 Wastes resulting from exploration, mining, quarrying, physical and chemical treatment of minerals04: Wastes from the leather, fur and textiles industries.06 Wastes from inorganic chemical processes08: Wastes from the manufacture, formulation, supply and use (MFSU) of coatings (paints, varnishes andvitreous enamels), adhesives, sealants and printing inks.10 Wastes from thermal processes11 Wastes from chemical surface treatment and coating of metals and other materials; non-ferroushydro-metallurgy12 Wastes from shaping and physical and mechanical surface treatment of metals and plasticsSpent batteries and catalysts are included in Chapter 16: Wastes not otherwise specified in the list.In general, wastes are classified as hazardous if they fulfil the same classification criteria for dangeroussubstances and preparations given in Directives 67/548/EEC and 88/379/EEC. 52
  • R_NickelBackground_0308_hh_chapter0124567.doc3. ENVIRONMENTPlease consult separate document. 53
  • R_NickelBackground_0308_hh_chapter0124567.doc4. HUMAN HEALTH4.1 HUMAN HEALTH (TOXICITY)4.1.1 Exposure assessment.4.1.1.1 GeneralThe human population may be exposed to nickel at the workplace, as a consumer or indirectly via theenvironment.4.1.1.2 Occupational exposure.Occupational exposure in the production and use of metallic nickel, nickel sulphate, nickel chloride, nickelcarbonate and nickel nitrate is described in the individual risk assessment reports on these substances.Occupational exposure in the production and use of other nickel compounds described in Chapter 2.1.1 is notcovered here. The approach used in the risk assessments of the five nickel compounds listed above may provehelpful in preparing occupational exposure assessments for specific compounds.Occupational exposure in other scenarios described in Chapter 2.1.2 not involving the production and use ofnickel compounds (e.g. combustion processes) where exposure to nickel occurs is outside the scope of these riskassessments.4.1.1.3 Consumer exposure.Consumer exposure to metallic nickel and nickel sulphate is described in the individual risk assessment reportson these substances.Consumers are also exposed to nickel in food, water and by tobacco smoking.4.1.1.3.1 Exposure to nickel in foodNickel in foodstuffs is measured as total nickel and thus does not give any information as to the content ordietary intake of individual nickel species in foodstuffs. It is generally assumed that nickel in food occurs in theform of complex bound organic nickel, which has different physico-chemical and possibly also differentbiological properties than inorganic nickel.Nickel from both natural and anthropogenic sources is contained in foodstuffs such as cocoa products (9.8mg/kg), soy beans (5.2 mg/kg), nuts (1.9 mg/kg), other dried legumes (1.7 mg/kg), oatmeal (1.2 mg/kg), seeds(0.8 μg/kg) and other cereals (0.6 mg/kg), (Danish Veterinary and Food Administration, 2000, Ellen et al., 1978,Flyvholm et al., 1984). Spinach and mushrooms can also contain levels above 1 mg/kg (Grandjean, 1984). Thesefigures are similar to other values found in Denmark, Germany and the UK (Veien & Andersen, 1986, Smart &Sherlock, 1987, Scheller et al., 1988, quoted from IARC, 1990).Beverages, such as tea and vegetable juices, also contain amounts of nickel that could significantly contribute todaily intake.Human milk contains from 20 – 500 μg/l whilst cows’ milk contains < 100 μg nickel/l (Clemente et al., 1980,quoted from Grandjean 1984). Casey & Neville (1987, quoted from California, 2001) monitored nickel levels inmilk of 13 women between delivery and 38 days postpartum. They reported that nickel concentrations in humanmilk did not change over that period of time; the overall average in the 46 milk samples analysed was 1.2±0.4µg/l. Camara & Kirkbright (1982 as cited in Casey & Neville, 1987) analysed 179 milk samples from severaldifferent countries and found a range of 3-50 µg/l (quoted from California, 2001).Nickel concentrations of 100 μg/l have been found in wine; average levels of about 30 mg/l were measured inbeer (Grandjean, 1984). In mineral water levels of a few micrograms per litre have been found (Grandjean,1984). In Germany, the mean concentration of nickel in mineral waters was 10 μg/l with a maximal value of 31μg/l (Scheller et al., 1988, quoted from IARC, 1990). Detailed figures for individual products are shown inGrandjean et al., (1989, quoted in IARC, 1990) and in Council of Europe (2001). These figures are shown inAppendix 7.3. 54
  • R_NickelBackground_0308_hh_chapter0124567.docThe nickel content in food has been investigated in Denmark for many years. The results of individual fooditems analysis have been combined with food consumption data in order to estimate the Danes’ dietary intake oftrace elements. The highest nickel intake comes from dairy products, grains and beverages (especially tea andcoffee). (Danish Veterinary and Food Administration, 2000).Figure 4.1.1.3: Nickel Intake in foods, μg/day 1993 – 1997. (Danish Veterinary and FoodAdministration, 2000) Milk Cheeses Miscellaneous Cereals Vegetables Fruits Meat products Fish Poultry Eggs Oils and fats Sugars and Preserves Beverages 0 10 20 30 40 50 60 Nickel Intake, µg/dayA similar investigation from the United Kingdom (UK EGVM, 2002) indicates results in good agreement withthe Danish investigations. The Total Diet Study shows that the food groups with the highest concentrations ofnickel are nuts, sugar and preserves and canned vegetables. The main contributors to dietary intake of nickel aresugars & preserves, beverages, bread, miscellaneous cereals and canned vegetables (UK EGVM, 2002).Table 4.1.1.3.A: Concentrations of Nickel in 1997 Total Diet samples and estimated average intake(UK EGVM, 2002).Food group (TDS) Mean nickel concentrations (1) Intake of nickel: μg/day (2) (mg/kg fresh weight)Bread 0.13 14Miscellaneous cereals 0.177 18Carcase meat 0.115 3Offal 0.016 0.02Meat products 0.08 4Poultry 0.024 0.5Fish 0.116 2 55
  • R_NickelBackground_0308_hh_chapter0124567.docOils & fats 0.04 1Eggs 0.017 0.24Sugars & preserves 0.42 26Green vegetables 0.088 3Potatoes 0.062 8Other vegetables 0.078 6Canned vegetables 0.313 10Fresh fruit 0.038 3Fruit products 0.048 2Beverages 0.025 23Milk 0.005 1Dairy produce 0.039 2Nuts 1.77 4Total intake (mg/day) 0.13 mg/day1) upper-bound means across the 20 TDS towns, i.e. concentrations below limit of detection taken as the limit ofdetection2) upper-bound intake, i.e. concentrations below limit of detection taken as the limit of detectionThe Total Diet Study is a model of the average domestic diet in the UK. A total of 119 categories of food anddrink are specified for inclusion in the Total Diet. These are assigned to one of twenty broad food groups. Thequantities and relative proportions of each food that make up the Total Diet are largely based on data from theNational Food Survey (NFS) and are updated annually. The population average intake of a particular foodconstituent can be estimated from its concentration in each food group and consumption of each group asdetermined by the NFS (UK EGVM, 2002).However, it should be noted that Total Diet Studies and estimates of dietary exposure from different countriesare not directly comparable because of differences in study design and dietary habits.Table 4.1.1.3.B: Dietary nickel exposure in mg/day Dietary Exposure (mg/day)Mean 95th %ile 97.5th %ile Reference.0.139 0.231 Larsen et al, (2002) (1).0.130 0.210 Gillian et al, (1999) (1, 2).0.120 0.210 UK EGVM (2002) (3)1) numerical values derived from a 60 kg person2) Result of the UK 1997 Total Diet Study (TDS) . The population average intake of nickel is 0.13 mg/day. Thisvalue is unchanged from that obtained from the analysis of samples from the 1994 Total Diet Study (from UKEGVM, 2002).3) Mean and upper level (97.5 percentile) nickel intake for adults has been estimated using the 1997 TDSconcentrations combined with consumption data from the 1986/87 Dietary and Nutritional Survey of BritishAdults. These figures are also unchanged from the 1994 TDS. This estimate should be used with caution due tothe differences between the Total Diet Study and Adults Survey food groups (UK EGVM, 2002).The UK EGVM (2002) report includes data on dietary nickel intakes. This includes data from Sweden(Solomons et al., 1982, quoted from UK EGVM, 2002) showing a mean intake of 0.75 mg/day with a rangefrom 0.2 to 4.460 mg/day and from Italy showing a daily intake of 0.3 mg/day.Other investigations confirm an average daily intake of nickel between 0.1 and 0.7 mg/day (UK MAFF, 1985,Codex Alimentarius Commission, 1995). 56
  • R_NickelBackground_0308_hh_chapter0124567.docA report on the impact of nickel on a contaminated site in Ontario includes estimates for the daily intake ofnickel from supermarket food for different age groups (Table A4-4 quoted from Ontario, 2002)Table 4.1.1.3.C: Estimated daily dietary intake of nickel in various countries in μg/day (Ontario,2002)Age Age range Nickel intake μg / day (range)Group CEPA (1994) Dabeka (1989), US FDA TDS UK TDS 1997 Dabeka & 95th %ile 95th %ile McKensie (1995) IOM (2001) Ysart et al., (2000)Infant 0 – 6 months 154 109.2 (1) 9 39 (72.2 – 146.2) (37, recalculated) (68, calculated)Toddler 1 – 4 year 208 190 81 68 (153, recalculated) (120, calculated)Child 5 – 11 year 270 251 107 105 (199, recalculated) (184, reported)Teen 12 – 19 year 325 313 125 120 (250, recalculated) (210, reported)Adult > 19 year 308 307 119 102 (233, recalculated) (178, calculated)1) Diet A assumes that the infant only consumes breast milk for the first six months; Diet B assumes that theinfant only consumes formula for the first six months; Diet C assumes that the infant consumes breast milk orformula for the first three months, and this diet is then supplemented by vegetables, cereal and bread, ands fruitand fruit juices.The CEPA results and the two Dabeka studies both reflect Canadian intake. The report recognises that the levelsin these Canadian studies are higher than the levels seen in the US (IOM, 2001) or the UK (Ysart et al., 2000).The values in the Table above have in some cases been recalculated to match the Canadian age class groups.These figures do however provide a basis on which to estimate the effects of oral intake of nickel in different agegroups.In general, nickel intake via foodstuffs does not cause hazards for the majority of consumers (CodexAlimentarius Commission, 1995).The figures shown above relate to concentrations of nickel in food. The nickel present may be due to naturalconcentrations in the soil or to environmental or soil contamination (see section on Indirect exposure via theenvironment). These figures do not include release of nickel to food during processing, storage or cooking.Release of nickel from nickel-containing food contact materials and kitchen utensils is described in chapter4.1.1.3.2.1 of the risk assessment report for metallic nickel.See further data in the common MvE RAR for the nickel substances (nickel; nickel carbonate; nickelchloride; nickel dinitrate and nickel sulphate): “Humans exposed indirectly via the environment andcombined exposure - exposure assessment and risk characterisation”4.1.1.3.2 Exposure to nickel in waterNickel concentration in drinking water in European countries were reported to range in general from 2-13 μg/l(mean, 6 μg/l) (Amavis et al., 1976, quoted from IARC, 1990). Other studies suggested low background levelsin drinking water, e.g. in Finland an average of about 1 μg/l (Punsar et al., 1975, quoted from IARC, 1990) andin Italy mostly below 10 μg/l (Clemente et al., 1980, quoted from Grandjean, 1984). Drinking water fromgroundwater in Germany (GDR) showed an average level of 10 μg/l, slightly below the amount present insurface water (Schuhmann, 1980, quoted from Grandjean, 1984). The mean concentration of drinking water inthe BRD was 9 μg/l with a maximal value of 34 μg/l (Scheller et al., 1988, quoted from IARC, 1990).The nickel content of groundwater is normally below 20 μg/l (US EPA, 1986, quoted from IARC, 1990), and thelevels appear to be similar in raw, treated and distributed municipal water. In US drinking water, 97% of allsamples contained < 20 μg/l, while about 90% had < 10 μg/l (US National Research Council, 1975, quoted fromIARC, 1990). 57
  • R_NickelBackground_0308_hh_chapter0124567.docThe WHO has established a TDI (Tolerable daily intake) of 0.005 mg/kg bodyweight for the intake of nickelfrom drinking water. This results in a Guideline level for nickel in drinking water of 20 μg/litre (WHO, 1996).Ingestion of water is often taken as 2 litres/day for an adult. Assuming a concentration of 20 μg/l, the WHO(1996) Guideline level for nickel in drinking water would result in a daily intake of 40 μg/day.A report on the impact of nickel on a contaminated site in Ontario includes estimates for the daily intake ofnickel from supermarket food for different age groups (Table A3-2 quoted from Ontario, 2002)Table 4.1.1.3.D: Estimated daily intake of nickel from drinking water (Ontario, 2002)Age group Age range (1) Metal Ingestion rate of Nickel Intake from concentration in drinking water drinking water drinking water (l/day) (μg/day) (μg/l) (2)Infant 0 – 6 month 1.3 0.3 0.39Toddler 7 months - < 5 years 1.3 0.6 0.78Child 5 - < 12 years 1.3 0.8 1.0Teen 13 - < 20 years 1.3 1.0 1.3Adult 20 + years 1.3 1.5 2.01) Note there are differences in the age ranges for the different groups compared to Table 4.1.1.3.C.The concentration of nickel in drinking water is the actual concentration at the site under evaluation. This figureof 1.3 μg/l is at the bottom end of the range of figures reported for EU drinking water. Using a figure of 10 μg/lfor mean nickel concentration in drinking water (cf. the figures for Germany shown above) the figures wouldrang from 3 to 15 μg/day.Intake of nickel from drinking water therefore represents very roughly 10% of the estimated intake from food.The figures shown above relate to concentrations of nickel in drinking water. The nickel present may be due tonatural concentrations in the soil or to environmental or soil contamination (see section on Indirect exposure viathe environment). The figures do not include release of nickel to drinking water from pipes or taps used tosupply the drinking water or from kettles or other heating devices. Release of nickel from taps and pipes isdescribed in chapter 4.1.1.3.2.3 and release of nickel from kettles and immersion heaters is described in section4.1.1.3.2.2 of the risk assessment report for metallic nickel.See further data in the common MvE RAR for the nickel substances (nickel; nickel carbonate; nickelchloride; nickel dinitrate and nickel sulphate): “Humans exposed indirectly via the environment andcombined exposure - exposure assessment and risk characterisation”4.1.1.3.3 Combined exposure to nickel from food and drinking water.The total amounts of nickel intake from dietary food and water have been estimated by Council of Europe (2001)and UK EGVM (2003).The UK EGVM have calculated the daily intake from food and water as 0.21 mg/day for the food intake (the95.5th %ile of the UK EGVM, 2002, figures - see Table 4.1.1.3.B) and the water intake as 0.04 mg/day,calculated on the basis of a nickel concentration of 20 μg/l and a drinking water intake of 2 litres/day. This givesa total intake of 0.25 mg/day.The Council of Europe figure is 0.4 mg/day (Council of Europe, 2001).Estimates for children are very much more uncertain. The figures from Table 4.1.1.3.C suggest that the intakefrom food for the child age group is very similar to the adult (105 μg/day vs. 102 μg/day, for the UK 1997 TDSfigures). The main difference in water intake is the slightly lower daily water intake estimated for children. Thetotal intake in children is therefore expected to be similar to the estimated adult intake. The average weight for a3 – 12 year old boy or girl is 28 kg and for an adult is 72 kg (US EPA, 1997). This would mean that the nickelintake from food and water expressed as mg/kg for a child would be roughly twice that of an adult. 58
  • R_NickelBackground_0308_hh_chapter0124567.docThe Scientific Panel on Dietetic products, Nutrition and Allergies (NDA, 2005) was unable to establish atolerable upper intake level for nickel due to the absence of adequate dose-response data.See further data in the common MvE RAR for the nickel substances (nickel; nickel carbonate; nickelchloride; nickel dinitrate and nickel sulphate): “Humans exposed indirectly via the environment andcombined exposure - exposure assessment and risk characterisation”4.1.1.3.4 Exposure to nickel from smokingNickel is present in tobacco and is present in tobacco smoke.Sunderman & Sunderman (1961) and Szadkowski et al. (1969) found average nickel contents of 2.2 and 2.3μg/cigarette with a range of 1.1 – 3.1 (quoted from IARC, 1990). The same range is given in Sunderman (1986,quoted in US ATSDR, 1997). Pipe tobacco, cigars and snuff have been reported to contain nickel at levels of thesame magnitude (2 – 3 μg/g tobacco) (National Research Council, 1975, quoted from IARC, 1990).Szadkowski et al. (1969) also showed that 10-20% of the nickel in cigarettes is released in mainstream smoke;most of the nickel was in the gaseous phase (quoted from IARC, 1990). The nickel content of mainstream smokeranges from 0.005 to 0.08 μg/cigarette (Klus & Kuhn, 1982, quoted from IARC, 1990).Mainstream smoke produced by five samples each of five brands of Canadian cigarettes contained from 0.25 to0.58 µg Ni (mean = 0.43 µg Ni) per cigarette. Levels of nickel present in side-stream smoke were similar,ranging from 0.25 to 0.53 µg (mean = 0.37 µg) per cigarette (Labstat Incorporated, 1991, quoted from Canada,1994).Cigarette smoking may contribute rather more than ambient air to daily absorption of nickel by inhalation ifabout 0.2 μg Ni is inhaled from each cigarette. Smoking one pack per day could cause a daily absorption ofabout 1 μg Ni (Grandjean, 1984). US ATSDR (1997) gives a higher estimate of 2-12 µg Ni inhaled for eachpack of cigarettes.See further data in the common MvE RAR for the nickel substances (nickel; nickel carbonate; nickelchloride; nickel dinitrate and nickel sulphate): “Humans exposed indirectly via the environment andcombined exposure - exposure assessment and risk characterisation”4.1.1.4 Indirect exposure via the environmentFor data on local and regional indirect human exposure see the common MvE RAR for the nickel substances(nickel; nickel carbonate; nickel chloride; nickel dinitrate and nickel sulphate): “Humans exposed indirectlyvia the environment and combined exposure - exposure assessment and risk characterisation”4.1.2 Human health effects assessmentIndividual nickel compounds now under review under EU Regulation 793/93 are nickel metal, nickel sulphate,nickel chloride, nickel nitrate, and nickel carbonate. The results of studies carried out on these nickel compoundsare described in the individual reports for each substance. This section includes a summary review of thesestudies. However, studies performed with other nickel compounds can also be relevant for the assessment of thefive specific nickel substances, and this document includes these studies where considered relevant.Information on nickel and nickel compounds has been provided by industry in the context of EU Regulation793/93. Much additional data on nickel and nickel compounds have been published. Much of these data havebeen reviewed in good quality reviews including UK HSE (1987), IARC (1990), IPCS (1991, 1996), USATSDR (1997) and a Nordic Expert Group (Aitio, 1995). The effects of nickel on the skin have also beenreviewed (Maibach & Menné, Eds. 1989). NiPERA in collaboration with Eurométaux have also produced acriteria document for nickel and nickel compounds for the European Commission (NiPERA 1996). ToxicologyExcellence for Risk Assessment (TERA) has prepared a toxicological review of soluble nickel salts for MetalFinishing Association of Southern California Inc., US-EPA and Health Canada (TERA1999). 59
  • R_NickelBackground_0308_hh_chapter0124567.docThese reviews plus (where considered relevant) the primary literature, have been used widely in this riskassessment report as it is felt that much of the essential data to establish possible hazards and risks of nickel forhuman health has already been adequately evaluated. This implies that not all the studies cited in this riskassessment report have been checked and studies have often been described in a summary form. Wheninformation is cited from reviews, the primary source is given with the notation “quoted from”.Whilst there is extensive data on the health effects of some of the substances under review, for others there ismuch more limited data. Where data is lacking for a particular endpoint, the effects have been evaluated usingdata from other relevant nickel compounds. It is assumed that the nickel cation is the determining factor forsystemic toxicity. Ideally, the actual or bioavailable concentration, which is important for the systemic toxicityshould form the basis for the effect assessment in both experimental animals and in humans. Nickel exists indifferent forms, some of which are more bioavailable than others. The bioavailability depends on variouscharacteristics of the individual nickel compounds of which solubility is considered as being particularlyimportant for the release of nickel ion and thus the systemic bioavailability of the nickel ion. Ideally, data on thesolubility of the nickel compounds in biological fluids are preferable; however, no data are available regardingthe solubility of any of the five prioritised nickel compounds in biological fluids. For the purpose of riskcharacterisation the water solubility will be used as a prediction of the solubility in biological fluids althoughrealising that such a prediction might not be correct as some data indicate that compounds insoluble or slightlysoluble in water might be more soluble in biological fluids.With respect to local effects, the nickel ion may not be responsible for the toxic effects in all situations.Therefore, use of data on other nickel compounds in evaluations of local effects of an individual nickelcompound is considered on a case-by-case basis.When expressing results, the term “significant” is used only if the result is statistically significant at a p-levellower than 0.05.4.1.2.1 Toxico-kinetics, metabolism and distribution4.1.2.1.1 AbsorptionNickel and its inorganic compounds can be absorbed in humans and in animals via the gastrointestinal tract aswell as the respiratory passages. Percutaneous absorption is negligible quantitatively. The relative amounts ofnickel absorbed are determined, not only by the quantities administered, but also by the physical and chemicalcharacteristics of the nickel compound. Solubility is an important factor in all routes of absorption. Solublenickel compounds dissociate readily in the aqueous environment of biological membranes, thus facilitating theirtransport as metal ions. Conversely, insoluble nickel compounds are relatively poorly absorbed. It is possible thatother factors, such as host, nutritional and physiological status, or stage of development, also play a role, butthese have not been studied. (IPCS 1991).4.1.2.1.1.1 InhalationExposure to nickel compounds by inhalation may be in the form of aerosols (dusts) or attached to particles.Whether particles are inhaled depends on the particle size (aerodynamic diameter) and particles withaerodynamic diameters below 100 µm have the potential to be inhaled (inhalable fraction) and deposited in therespiratory tract. The deposition patterns in the respiratory tract also depend on the particle size as well as on theshape, density, hygroscopicity, and electric charge the respiratory dynamics of the individual (breathing patternand thus, the respiratory minute volume). In humans, particles with aerodynamic diameters of 5-30 µm aremainly deposited in the upper airways, the nasopharyngeal region. Particles with aerodynamic diameters of 1-5µm pass through the nasopharyngeal region and enter the tracheobronchial region where they are deposited.Particles with aerodynamic diameters in the lower end of this size fractions and smaller enter the alveolar regionof the lungs where they are deposited.The fate and uptake of deposited particles depend on the clearance mechanism present in the different parts ofthe airways. In the nasopharyngeal region, most material will be cleared rapidly, either by expulsion (not thecase for oral breathers) or by translocation to the gastrointestinal tract; a small fraction will be subjected to moreprolonged retention, which can result in absorption from this region. From the tracheobronchial region, thelargest part of the deposited material will be cleared to the pharynx mainly by mucociliary clearance andsubsequently be swallowed into the gastrointestinal tract; only a small fraction will be retained and may result inabsorption from this region. Higher absorption may occur from the pulmonary region than from thenasopharyngeal and tracheobronchial regions. 60
  • R_NickelBackground_0308_hh_chapter0124567.docSolids must dissolve into the fluids lining the airways before absorption can occur and the solubility of the nickelcompound is thus an important factor for absorption. Absorption from the respiratory tract may therefore belimited by the solubility of nickel compounds in biological fluids. Consequently, soluble nickel compounds, suchas nickel chloride, nickel sulphate, and nickel nitrate, are expected to be absorbed readily from the pulmonaryregion, whereas poorly soluble nickel compounds, such as nickel metal, nickel oxide and nickel subsulphide, areexpected to be retained in the lung tissue and accumulate thereby having a long half-life.The data on absorption of nickel in particulate form are limited and generally, the absorbed fraction of inhalednickel has not been quantified. Furthermore, there are no data available on nickel compounds to estimate the partthat is cleared to the gastrointestinal tract either by translocation from the nasopharyngeal region or bymucociliary clearance from the tracheobronchial region. Once translocated into the gastrointestinal tract,absorption will be in accordance with oral absorption kinetics. Below, the available data regarding the fiveprioritised nickel compounds (nickel sulphate, nickel chloride, nickel nitrate, nickel carbonate, and nickel metal)are summarised; for further details, the reader is referred to the individual risk assessment reports. Data on othernickel compounds are also summarised below when considered relevant for the conclusion on the absorbedfraction of nickel following inhalation of the five prioritised nickel compounds.No studies providing specific information about the absorbed fraction of nickel following inhalation orintratracheal instillation of nickel sulphate have been located. However, studies in experimental animals providesome information in relation to absorption of nickel sulphate. No human data are available.An inhalation study by Benson et al. (1995) showed that clearance of nickel sulphate (nickel sulphatehexahydrate aerosol, mean mass median aerodynamic diameters (MMADs) ranging from 2.0 to 2.4 µm) from thelungs of rats and mice is extensive with 99% of inhaled nickel sulphate being cleared with a half-time of 2 to 3days in rats and with 80-90% being cleared with a half-time of less than one day in mice. Repeated inhalation ofnickel sulphate hexahydrate aerosol did not result in accumulation of nickel in the lungs of either rats or miceand did not affect the clearance of 63NiSO4 inhaled after either 2 or 6 months of nickel sulphate hexahydrateexposure. No nickel sulphate particles were observed histologically in the lungs of nickel sulphate exposedanimals. Nickel levels in blood and urine were not measured, so this study does not provide evidence for whetherclearance was via absorption from the lungs into the blood stream or by clearance from the respiratory tract viathe mucociliary mechanisms.An intratracheal instillation study by Medinsky et al. (1987) showed that nickel sulphate (administered as asolution in isotonic saline) is rapidly absorbed from the lungs into the blood in a dose dependent manner as theurinary excretion of nickel increased with increasing dose levels (50% at the two lower dose levels and 80% atthe high dose level).Inhalation studies in rats (Benson et al. 1988, NTP 1996a) indicate that lung nickel burdens increase withincreasing concentrations of nickel sulphate (at least up to around 0.8 mg Ni/m3) in the inhaled air as well aswith duration of exposure. A third study (Dunnick et al. 1989) found similar concentrations of nickel in the lungsof rats and mice after 4, 9, and 13 weeks of inhalation to nickel sulphate (0.02 to 0.4 mg Ni/m3). Of nickelremaining in the body after 96 hours following a single dose of nickel sulphate administered by intratrachealadministration, over 50% was in the lungs (Medinsky et al. 1987).No studies providing specific information about the absorbed fraction of nickel following inhalation orintratracheal instillation of nickel chloride have been located.Three studies in experimental animals indicate that absorption from the respiratory tract does occur as lowretention of nickel in the lungs and extensive excretion in the urine have been observed following intratrachealinstillation of nickel chloride in rats. The absorption from the respiratory tract might be extensive in rats asindicated by a urinary elimination of 96.5% of the initial body burden at day 21 post-instillation in the study byCarvalho & Ziemer (1982), an average of 70% of the instilled nickel being excreted by the third day afterinstillation in the study by English et al. (1981), and 90% of the instilled nickel being excreted, mainly in theurine (75%) by 72 hours after instillation in the study by Clary (1975). However, the experimental design inthese studies could not distinguish between nickel absorbed from the lungs and nickel cleared from the lungs,swallowed, and absorbed from the gastrointestinal tract. No human data are available.For metallic nickel exposure of rats to nickel powder at 1, 4 and 8 mg/m3 for a period of 13 weeks resulted inaccumulation of nickel particles in the lung and increased nickel blood levels (WIL Research Laboratories2003). From this study and using kinetic data on clearance rates an absorbed fraction of approximately 6 % as anupper estimate of the inhaled fraction was calculated by the rapporteur.No studies regarding absorption and retention of nickel in humans or experimental animals following inhalationor intratracheal instillation of nickel nitrate or nickel carbonate have been located. 61
  • R_NickelBackground_0308_hh_chapter0124567.docAccording to TERA (1999), several human studies indicate that exposure of electroplating workers to solublenickel salts results in nickel absorption. In studies on electroplating workers (workroom air concentrationsranging from 0.03-0.16 mg Ni/m3), the urinary and plasma nickel concentrations were higher in post-shiftsamples than in pre-shift ones, and a close positive correlation was found between the air nickel concentrationsand the urine and plasma nickel concentrations (Tola et al. 1979, Bernacki et al. 1980, Ghezzi et al. 1989). Whenthe nickel concentration in electroplating workers’ urine was measured before, in the middle, and at the end ofthe work shift, urinary nickel concentration increased over the course of a regular working day (Bernacki et al.1980).Workers in nickel roasting/smelting are exposed to less-soluble nickel compounds (such as nickel subsulphideand nickel oxide). These compounds are also absorbed after inhalation as evidenced by elevated nickelconcentrations in the plasma and urine of exposed workers. These less-soluble compounds were absorbed lessefficiently than the soluble nickel salts, since workers exposed to nickel subsulphide and nickel oxide had lowerplasma and urinary nickel concentrations than workers exposed to lower concentrations of soluble nickel. Highernickel concentrations in nasal mucosa resulted from exposure to nickel subsulphide and nickel oxide than fromexposure to soluble nickel, indicating that the lower plasma levels result from reduced clearance from the lung,rather than from reduced deposition. (Torjussen & Anderson 1979 – quoted from TERA 1999).No other quantitative human data on the amount and rate of absorption are available (TERA 1999).In a study by Benson et al. (1995), experimental animals (rats and mice) were exposed (whole-body, 6hours/day, 5 days/week for up to 6 months) to nickel oxide by inhalation (aerosol, mean mass medianaerodynamic diameters (MMADs) ranging from 2.1 to 2.3 µm, concentrations of 0.62 or 2.5 mg NiO/m3 for ratsand of 1.25 or 5.0 mg NiO/m3 for mice). Nickel accumulated in the lungs of both rats and mice, but to a greaterextent in lungs of rats. During 4 months after the end of exposure, some clearance of the accumulated nickelburden occurred from the lungs of rats and mice exposed to the lower, but not to the higher nickel oxideexposure concentrations.When Syrian golden hamsters were exposed to nickel oxide (not specified) particles (mass mean aerodynamicdiameters (MMADs) of 1.0-2.5 µm) by inhalation for 2 days (7 hours/day) at a concentration of 10-290 mg/m3,absorption seemed to be negligible. At 45 days after exposure, approximately 50% of the total amount inhaledstill remained in the lungs. (Wehner & Craig 1972 – quoted from IPCS 1991, US ATSDR 1995).Benson et al. have also evaluated the absorption and clearance of inhaled nickel subsulphide in experimentalanimals (Benson et al. 1994 – quoted from TERA 1999). They found that inhaled nickel subsulphide had arelatively rapid clearance half-time of 4 days, which, according to the citation in TERA (1999) in interpreted asalthough nickel subsulphide is nearly insoluble in water, it is dissolved rapidly in the lung, and behaves like arelatively soluble particle. (TERA 1999).When nickel subsulphide (63Ni3S2) was administered intratracheally to mice (11.7 µg/animal), the total lungburden at 4 hours after instillation was 85% of the administered dose. Thirty-five days after instillation, 10% ofthe administered dose was still retained by the lung. (Valentine & Fisher 1984 – quoted from IPCS 1991).4.1.2.1.1.1.1 Discussion and conclusion, absorption following inhalationThe data on absorption of nickel in particulate form are limited and based on the available data for various nickelcompounds and from a single inhalation study with metallic nickel exposure. Furthermore, there are no dataavailable on nickel compounds to estimate the part that is cleared to the gastrointestinal tract either bytranslocation from the nasopharyngeal region or by mucociliary clearance from the tracheobronchial region.Once translocated into the gastrointestinal tract, absorption will be in accordance with oral absorption kinetics.The deposition pattern of dust particles in the respiratory tract is related to the particle size (aerodynamicdiameter) as well as to other characteristics of the particles (shape, density, hygroscopicity, and electric charge)and the respiratory dynamics of the individual. Therefore, precise deposition patterns for dusts cannot bepredicted. As a rough guide, particles with aerodynamic diameters below 100 µm have the potential to beinhaled. Particles with aerodynamic diameters of above 1-5 µm have the greatest probability of settling in thenasopharyngeal region (non-respirable particles) whereas particles with aerodynamic diameters below 1-5 µmare most likely to settle in the tracheobronchial or pulmonary regions (respirable particles). Deposited non-respirable particles will predominantly be cleared from the respiratory tract by mucociliary action andtranslocated into the gastrointestinal tract whereas deposited respirable particles may either be absorbed from thelung or remain deposited in the lung tissues depending on the solubility in biological fluids of the nickelcompound. In order to evaluate whether clearance of nickel particulate from the respiratory tract might be due toabsorption, deposition or mucociliary action, one essential characteristic is thus the particle size. For the purposeof risk characterisation of the five prioritised nickel compounds, it is assumed that nickel particulates withaerodynamic diameters above 5 µm predominantly will be cleared from the respiratory tract by mucociliary 62
  • R_NickelBackground_0308_hh_chapter0124567.docaction and subsequently be translocated into the gastrointestinal tract and absorbed. For nickel particulates withaerodynamic diameters below 5 µm, it is assumed that clearance from the respiratory tract is due to eitherabsorption from the lung or deposition in the lung tissues.Solids must dissolve into the fluids lining the airways before absorption can occur and the solubility of the nickelcompound is thus an important factor for absorption. Absorption from the respiratory tract may therefore belimited by the solubility in biological fluids of the nickel compound. No data are available regarding thesolubility of the five prioritised nickel compounds in biological fluids. For the purpose of risk characterisation ofthese five compounds, the water solubility is used as a prediction of the solubility in biological fluids. It shouldbe noted that such a prediction might not be correct as data on nickel subsulphide indicate, according to TERA(1999), that this compound, which is nearly insoluble in water, is dissolved rapidly in the lung, and thus behaveslike a relatively soluble particle; however, based on the citation in TERA (1999) it is not clear whether clearanceof inhaled nickel subsulphide was due to absorption, deposition or by mucociliary clearance. As the absorptionof nickel from the respiratory tract into the blood stream depends on the solubility of the nickel compoundinhaled, different conclusions on the absorbed fraction of nickel following inhalation of soluble or insoluble andslightly soluble nickel compounds for the purpose of risk characterisation are taken.Most of the studies in experimental animals of soluble nickel compounds (nickel sulphate and nickel chloride)have used intratracheal instillation of the compound in solution. According to TERA (1999), the absorptionkinetics following inhalation exposure would be expected to be similar to the kinetics of intratracheally instillednickel. For the purpose of risk characterisation of the five prioritised nickel compounds, it is assumed that theabsorbed fraction of inhaled nickel is comparable to that following intratracheal instillation. It should be born inmind that this assumption may not be correct as the solubility of a given compound may depend on the solventused for the intratracheal instillation.Soluble nickel compounds, such as nickel sulphate, nickel chloride, and nickel nitrate, are expected to beabsorbed from the respiratory tract following inhalation exposure. This is supported by data from one study ofnickel sulphate in rats (Medinsky et al. 1987) using intratracheal instillation of nickel sulphate (as a solution insaline), which showed that 50 to 80% of a dose (dependent on the dose) of nickel sulphate can be absorbed fromthe respiratory tract. Studies in rats using intratracheal instillation of nickel chloride (Carvalho & Ziemer 1982,English et al. 1981, Clary 1975) showed that up to approximately 97% of a dose of nickel chloride can beabsorbed from the respiratory tract. By assuming that the absorption of nickel following inhalation exposure tonickel chloride is similar to absorption following intratracheal instillation, the absorption of nickel from therespiratory tract following inhalation of nickel chloride might be as high as about 97%. Furthermore, theinhalation study on nickel sulphate (Benson et al. 1995) showed that clearance of nickel sulphate from the lungsof rats and mice is rapid and extensive (up to 99% with a half-time of 2-3 days in rats; 80 to 90% with a half-time of less than one day in mice). By assuming that the clearance of nickel sulphate particles (respirableparticles, MMADs ranging from 2.0 to 2.4 µm) from the lungs in the inhalation study (Benson et al. 1995) is dueto absorption rather than to deposition or by mucociliary action, the absorption of nickel from the lungsfollowing inhalation of nickel sulphate might be as high as up to 99% (at concentrations up to 0.11 mg Ni/m3 inrats and up to 0.22 mg Ni/m3 in mice). Other inhalation studies in rats (Benson et al. 1988, NTP 1996a) indicatethat lung nickel burdens increase with increasing concentrations of nickel sulphate (at least up to about 0.8 mgNi/m3) in the inhaled air as well as with duration of exposure. No data are available regarding the absorption ofnickel following exposure by inhalation to nickel nitrate. As nickel nitrate, like nickel sulphate and nickelchloride, is very soluble in water, it is considered that the absorption of nickel following inhalation of nickelnitrate is comparable to that following inhalation of nickel sulphate and nickel chloride.In conclusion, the available data on nickel sulphate and nickel chloride indicate that the absorption of nickelfollowing inhalation of the soluble nickel compounds (nickel sulphate, nickel chloride and nickel nitrate) mightbe as high as up to 97-99%; it should be noted that the fraction absorbed apparently depends on the concentrationof the nickel compound in the inhaled air as well as on the duration of exposure. For the purpose of riskcharacterisation, a value of 100% is taken forward to the risk characterisation for the absorbed fraction of nickelfrom the respiratory tract following exposure by inhalation of the prioritised soluble nickel compounds (nickelsulphate, nickel chloride and nickel nitrate) for particulates with an aerodynamic diameter below 5 µm(respirable fraction). For nickel particulates with aerodynamic diameters above 5 µm (non-respirable fraction),the absorption of nickel from the respiratory tract is considered to be negligible as these particles predominantlywill be cleared from the respiratory tract by mucociliary action and translocated into the gastrointestinal tract andabsorbed. Hence, for the non-respirable fraction, 100% clearance from the respiratory tract by mucociliary actionand translocation into the gastrointestinal tract is assumed and the oral absorption figures can be taken.Insoluble and slightly soluble nickel compounds, such as nickel metal, nickel carbonate, nickel oxides andnickel sulphides, are expected to be absorbed from the respiratory tract following inhalation exposure to a morelimited extent compared to the soluble compounds. 63
  • R_NickelBackground_0308_hh_chapter0124567.docDepending on the particle size, insoluble and slightly soluble particles are expected to be retained in differentregions of the airways and to be removed to some extent by the mucociliary action and translocated into thegastrointestinal tract. It should be noted that data on nickel subsulphide indicate, according to TERA (1999), thatthis compound, which is nearly insoluble in water, is dissolved rapidly in the lung, and thus behaves like arelatively soluble particle. Also data on workers in nickel roasting/smelting, which are exposed to less-solublenickel compounds (such as nickel subsulphide and nickel oxide) indicate, according to TERA (1999), that thesecompounds are absorbed after inhalation as evidenced by elevated nickel concentrations in the plasma and urineof exposed workers. However, based on the citations in TERA (1999) it is not clear whether clearance of inhalednickel subsulphide or nickel oxide was due to absorption or by mucociliary action and subsequent absorptionfrom the gastrointestinal tract. Data from one study of nickel oxide in Syrian hamsters (Wehner & Craig 1972 –quoted from IPCS 1991, US ATSDR 1995) indicate that absorption seems to be negligible after inhalation andthat approximately 50% of the total amount inhaled still remained in the lungs at 45 days after exposure. Anotherstudy of nickel oxide (Benson et al. 1995) showed that nickel accumulated in the lungs of rats and micefollowing repeated inhalation. Furthermore, one study of nickel subsulphide in mice (Valentine & Fisher 1984 –quoted from IPCS 1991) using intratracheal instillation showed that 35 days after instillation, 10% of theadministered dose was still retained by the lung. No data are available regarding the absorption of nickelfollowing exposure by inhalation to nickel carbonate.For metallic nickel exposure of rats to nickel powder at 1, 4 and 8 mg/m3 for a period of 13 weeks resulted inaccumulation of nickel particles in the lung and increased nickel blood levels (WIL Research Laboratories2003). Increased nickel blood levels for up to 90 day after exposure has stopped indicated that the accumulatednickel particles continuously were dissolved and absorbed into the blood. From this study and using kinetic dataon clearance rates an absorbed fraction of approximately 6 % (as an upper estimate) of the inhaled fraction wascalculated by the rapporteur.In conclusion, the available data on nickel oxide indicate that the absorption of nickel from the respiratory tractfollowing inhalation is very limited. However, data on metallic nickel indicate an absorbed fraction of up toapproximately 6% after inhalation (i.e. both absorption from respiratory tract and the gastrointestinal tract). . Forthe purpose of risk characterisation, an overall absorbed fraction of 6% is used in relation to inhalation ofmetallic nickel.4.1.2.1.1.2 OralAbsorption of nickel from the gastrointestinal tract occurs after ingestion of various nickel compounds in food,beverages, or drinking water. In the occupational environment, an appreciable amount of nickel dust may beswallowed via the mucociliary clearance mechanisms. The rate of nickel absorption from the gastrointestinaltract is dependent on the chemical form and thus, the solubility. Furthermore, absorption may be suppressed bybinding or chelating substances, competitive inhibitors, or redox reagents. On the other hand absorption is oftenenhanced by substances that increase pH, solubility, or oxidation, or by chelating agents that are activelyabsorbed. While soluble nickel compounds are better absorbed than relatively insoluble ones, the contribution ofthe poorly soluble compounds to the total nickel absorption may be more significant, since they are more solublein the acidic gastric fluids. (IPCS 1991).Below, the available data regarding the five prioritised nickel compounds (nickel sulphate, nickel chloride,nickel nitrate, nickel carbonate, and nickel metal) are summarised; for further details, the reader is referred to theindividual risk assessment reports. Data on other nickel compounds are also summarised below when consideredrelevant for the conclusion on absorption of nickel following oral administration.Absorption of nickel following oral ingestion of nickel sulphate has been evaluated in a number of humanstudies; however, it is impossible to give a general estimate for the fraction of nickel absorbed after oraladministration of nickel sulphate. The available studies indicate that the extent of absorption is influenced bywhether nickel sulphate is administered in drinking water, to fasting subjects, or together with food. One study inhuman volunteers (Sunderman et al. 1989) showed that 27% of a dose was absorbed when nickel sulphate wasadministered in drinking water to fasting subjects compared with around 1% when administered together withfood to fasting subjects. Another study (Christensen & Lagesson 1981 – quoted from IARC 1990) supports anabsorption of about 1 to 5% when nickel sulphate was administered in lactose. A higher absorption fraction of 4to 20% was observed after ingestion of nickel sulphate during fasting (Cronin et al. 1980 – quoted from IARC1990). In addition, absorption of nickel was apparently slower when administered together with food comparedwith water. One study in rats (Ishimatsu et al. 1995) showed an absorption of 11% when nickel sulphate wasadministered in a 5% starch saline solution. 64
  • R_NickelBackground_0308_hh_chapter0124567.docAbsorption of nickel following oral ingestion of nickel chloride has been evaluated in a few studies inexperimental animals; no human data have been located. When non-fasting rats were dosed by gavage withnickel chloride, 3 to 6% of the nickel was absorbed regardless of the administered dose (Ho & Furst 1973 -quoted from TERA 1999 and IPCS 1991). Another study in rats (Ishimatsu et al. 1995) showed an absorption of9.8% when nickel chloride was administered in a 5% starch saline solution. In mice, the intestinal absorptionwas estimated to be 1.7 to 10% when nickel chloride was administered orally by gastric intubation (Nielsen et al.1993).Absorption of nickel following oral ingestion of nickel nitrate has been evaluated in one study in rats (Ishimatsuet al. 1995), which showed an absorption of 34% when nickel nitrate was administered in a 5% starch salinesolution. No human data have been located.No studies providing specific information about the absorbed fraction of nickel in humans or experimentalanimals following oral administration of nickel carbonate have been located. However, there is evidence thatnickel carbonate is absorbed after oral administration. Metabolic data from nickel-balance studies carried out byPhatak & Padwardhan (1950 - quoted from IPCS 1991) demonstrated that appreciable quantities of nickel fromthe nickel-containing diets were retained and tissue accumulation was significant. According to the authors, thiswas attributed to ready solubility of the compound in the stomach and the easier absorption from the intestine.Another study in calves (O’Dell et al. 1971 – quoted from IPCS 1991) showed pronounced increases in nickellevels in the pancreas, testes, and bone at the highest dietary level (1000 mg/kg bw/day).No specific studies regarding absorption and retention of nickel following oral administration of nickel metalhave been located neither in humans nor in experimental animals. As water-insoluble compounds may be moresoluble in the acidic gastric fluids, absorption from the gastrointestinal tract may take place. This is supported byone study in rats (Hayman et al. 1984 – quoted from NiPERA 1996) showing peak nickel concentrations inblood about 6 hours following dosing with insoluble Raney nickel suspended in polyethylene glycol 200.Another study in rats (Ishimatsu et al. 1995) showed an absorption of 0.09% when nickel metal wasadministered in a 5% starch saline solution.Nielsen et al. (1999) have examined the influence of fasting and food intake on the absorption and retention ofnickel added to drinking water. Eight non-allergic male volunteers received nickel (compound not specified) indrinking water (12 µg Ni/kg bw) and, at different time intervals, a standardised 1400 kJ portion of scrambledeggs. Before each nickel intake, the volunteers fasted for 12 hours (overnight). When nickel was ingested inwater 30 minutes or one hour prior to the meal, peak nickel concentrations in serum occurred one hour after thewater intake, and the peak was 13-fold higher than the one seen one hour after simultaneous intake of nickel-containing water and scrambled eggs. In the latter case, a smaller, delayed peak occurred 3 hours after the meal.Within 3 days, the amount of nickel excreted in the urine corresponded to 2.5% of the nickel ingested when itwas mixed into the scrambled eggs. Increasing amounts were excreted as the interval between the water and themeal increased, with 25.8% of the administered dose being excreted when the eggs were served 4 hours prior tothe nickel-containing drinking water.In a second experiment (Nielsen et al. 1999), a stable nickel isotope (61Ni, compound not specified) wasadministered in the drinking water (12 µg Ni/kg bw) to 20 nickel-sensitised women and 20 age-matchedcontrols, both groups having vesicular hand eczema. The course of nickel absorption and excretion in the allergicgroups did not differ and was similar to the pattern seen in the first study, although the absorption in the womenwas less (nickel-sensitised: 10.8%; control: 11.2% - at 72 hours after administration of the dose).Nickel balance studies have been performed on 10 male volunteers (aged 17 years), who ingested a mean of 289± 23 mg Ni/day (range 251-309 mg, compound not specified). Faecal elimination of nickel averaged around 89%(258 ± 23 mg Ni/day). (Nodiya 1972 – quoted from IPCS 1991).Diamond et al. (1998) have used a biokinetic model to estimate nickel absorption, based on experimental datafrom various studies. The results showed that estimated nickel absorption ranged from 12-27% of the dose whennickel was ingested after a fast, to 1-6% when nickel was administered either in food, in water, or in a capsuleduring (or in close proximity to) a meal.Ishimatsu et al. (1995) administered 8 different nickel compounds (10 mg Ni) orally to male Wistar rats bygavage in 5% starch saline solution. The nickel compounds used were nickel metal, nickel oxide (green), nickeloxide (black), nickel subsulphide, nickel sulphide, nickel sulphate, nickel chloride, and nickel nitrate. Nickeloxides and nickel metal were considered to be insoluble with a solubility in saline and in distilled water of lessthan 5 mg/l. The solubility of nickel sulphide was about 2000 mg/l and of nickel subsulphide about 500 mg/l.The solubility of these compounds in saline solution was greater than in distilled water. The absorbed fraction ofnickel at 24 hours after administration was 0.01% for nickel oxide (green), 0.04% for nickel oxide (black),0.09% for nickel metal, 0.47% for nickel subsulphide, 2.12% for nickel sulphide, 9.8% for nickel chloride, 65
  • R_NickelBackground_0308_hh_chapter0124567.doc11.12% for nickel sulphate, and 33.8% for nickel nitrate; the estimated absorbed fraction increased with theincrease of the solubility.4.1.2.1.1.2.1 Discussion and conclusion, absorption following oral administrationBased on the available studies, it is impossible to give a general estimate for the fraction of nickel absorbed afteroral administration of the five prioritised nickel compounds (nickel sulphate, nickel chloride, nickel nitrate,nickel carbonate, and nickel metal). As the absorption of nickel from the gastrointestinal tract into the bloodstream depends on the solubility of the nickel compound ingested, the absorbed fraction of nickel followingingestion of soluble or insoluble and slightly soluble nickel compounds is expected to be different. However,some insoluble and slightly soluble nickel compounds may be more soluble in the acidic gastric fluid than inwater thus facilitating the absorption from the gastrointestinal tract; however, no data are available elucidatingthis aspect. The extent of absorption from the gastrointestinal tract is influenced by whether the nickel compoundis administered in drinking water, to fasting subjects, or together with food. For the purpose of riskcharacterisation, different conclusions on the absorbed fraction of nickel for fasting and non-fasting individualsare drawn.Soluble nickel compounds, such as nickel sulphate, nickel chloride, and nickel nitrate, are expected to beabsorbed from the gastrointestinal tract following oral intake. Absorption of nickel following oral ingestion ofnickel sulphate has been evaluated in a number of human studies; no human data are available for the otherprioritised soluble compounds (nickel chloride and nickel nitrate). One study (Sunderman et al. 1989) has shownthat absorption of nickel can be as high as 27% when nickel sulphate was administered in drinking water tofasting individuals compared with about 1%, when administered together with food to fasting individuals.Another human study on volunteers (Nielsen et al. 1999), in which the nickel compound administered was notspecified, showed similar results with 25.8% of the administered dose being excreted in the urine followingadministration of nickel in drinking water to fasting individuals compared with 2.5% when nickel was mixedinto a meal. Based on experimental data from various human studies, Diamond et al. (1998) used a biokineticmodel to estimate nickel absorption; the results showed that estimated nickel absorption ranged from 12-27% ofthe dose when nickel was ingested after a fast, to 1-6% when nickel was administered either in food, in water, orin a capsule during (or in close proximity to) a meal. One study in rats (Ishimatsu et al. 1995) showed anabsorption of 11% for nickel sulphate, of 9.8% for nickel chloride, and of 34% for nickel nitrate when thecompound was administered in a 5% starch saline solution. Other studies of nickel chloride in experimentalanimals have shown an absorption of 3-6% in rats (non-fasting, gavage in 0.1N hydrochloric acid) and of 1.7-10% in mice (gavage).Insoluble and slightly soluble nickel compounds, such as nickel metal, nickel carbonate, nickel oxides and nickelsulphides, are expected to be absorbed from the gastrointestinal tract following oral exposure to a limited extent.However, some insoluble and slightly soluble nickel compounds may be more soluble in the acidic gastric fluidthan in water thus facilitating absorption from the gastrointestinal tract. No human data are available regardingabsorption of insoluble and slightly soluble nickel compounds. One study in rats (Phatak & Padwardhan 1950 -quoted from IPCS 1991) has demonstrated that appreciable quantities of nickel from diets containing nickelcarbonate were retained and tissue accumulation was significant; according to the authors, this was attributed toready solubility of the compound in the stomach and the easier absorption from the intestine. Another study inrats (Hayman et al. 1984 – quoted from NiPERA 1996) has shown peak nickel concentrations in blood about 6hours following dosing with insoluble Raney nickel suspended in polyethylene glycol 200. In rats (Ishimatsu etal. 1995), an absorption of 0.09% was observed when nickel metal was administered in a 5% starch salinesolution; the absorbed fraction was 0.01% for nickel oxide (green), 0.04% for nickel oxide (black), 0.47% fornickel subsulphide, and 2.12% for nickel sulphide.In conclusion, the available data on the soluble nickel compounds (nickel sulphate, nickel chloride and nickelnitrate) indicate that the absorption of nickel following administration in the drinking water to fasting individualsmight be as high as up to about 25-27% and about 1-6% when administered to non-fasting individuals and/ortogether with (or in close proximity to) a meal. The available data on insoluble and slightly soluble nickelcompounds (nickel metal, nickel carbonate, nickel oxides and nickel sulphides) indicate that absorption of nickelfrom the gastrointestinal tract may occur following oral exposure; however, the data are too limited for anevaluation of the absorbed fraction of nickel. For the purpose of risk characterisation, a value of 30% is takenforward to the risk characterisation for the absorbed fraction of nickel from the gastrointestinal tract followingoral exposure to nickel sulphate, nickel chloride and nickel nitrate in the exposure scenarios where fastingindividuals might be exposed to these nickel compounds based on the data for soluble nickel compounds. Thesame figure is also used for nickel carbonate, since there is evidence of oral absorption of this compound. In allthe other exposure scenarios, a value of 5% is used for the absorbed fraction of nickel from the gastrointestinaltract. 66
  • R_NickelBackground_0308_hh_chapter0124567.docBased on the study in rats by Ishimatsu et al. (1995), which indicates, by direct comparisons of the absorbedfractions, a 100-fold lower absorption of nickel following administration of nickel metal than for soluble nickelcompounds, values of 0.05% and 0.3% are taken forward to the risk characterisation for the absorbed fraction ofnickel from the gastrointestinal tract following oral exposure to nickel metal for non-fasting and for fastingindividuals, respectively.4.1.2.1.1.3 DermalDermal absorption is a complex process. The extent to which a compound is absorbed across the skin isinfluenced by many factors, e.g., physico-chemical properties of the compound, vehicle, occlusion,concentration, exposure pattern, skin site of the body, etc. In order to cross the skin, a substance must firstpenetrate into the dead stratum corneum and may subsequently reach the viable epidermis, the dermis and thevascular network. The stratum corneum provides its greatest barrier function against hydrophilic compounds,whereas the viable epidermis is most resistant to penetration by highly lipophilic compounds. When consideringdermal absorption, a distinction should therefore be made between penetration of a compound into skin andpercutaneous transport, where the compound is transported through the skin and into the blood stream.Studies in humans and experimental animals indicate that nickel can penetrate the skin following dermal contactto various nickel compounds. Below, the available data regarding the five prioritised nickel compounds (nickelsulphate, nickel chloride, nickel nitrate, nickel carbonate, and nickel metal) are summarised; for further details,the reader is referred to the individual risk assessment reports. Data on other nickel compounds are alsosummarised below when considered relevant for the conclusion on absorption of nickel following dermalcontact.In a recent human in vivo study of nickel sulphate (Hostýnek et al. 2001a), a large part of the administered doseremained on the surface of the skin after 24 hours or, according to the authors, was adsorbed in the uppermostlayers of the stratum corneum. In an in vitro study (Tanojo et al. 2001) using human skin (stratum corneum fromcadaver leg skin), about 97% of the dose was recovered in the donor solution after 96 hours, with about 1% inthe receptor fluid and 0.6% in the stratum corneum. Limited data obtained from other in vitro studies usinghuman skin (Fullerton et al. 1986, Samitz & Katz 1976 – quoted from IPCS 1991) indicate that absorptionfollowing dermal contact may have a significant lag time. Studies in experimental animals indicate that nickelcan be absorbed through the skin of rats (Mathur et al. 1977 – quoted from IPCS 1991) and guinea-pigs andrabbits (Norgaard 1957 – quoted from IPCS 1991). Another study in guinea pigs (Lindberg et al. 1989 – quotedfrom NiPERA 1996) showed that nickel only penetrated into the stratum corneum.No human in vivo studies providing information about the absorbed fraction of nickel following dermal contactto nickel chloride have been located. One study in guinea pigs (Lloyd 1980 - quoted from IPCS 1991) indicatethat nickel chloride can be absorbed following dermal contact, but only to a very limited extent (indicated by lowlevels in blood plasma and in urine up to 24 hours of exposure). In an in vitro study (Tanojo et al. 2001) usinghuman skin (stratum corneum from cadaver leg skin), 98.7% of the dose was recovered in the donor solutionafter 96 hours, with about 0.7% in the receptor fluid and 0.2% in the stratum corneum. Limited data obtainedfrom in vitro studies using human skin (Fullerton et al. 1986, Spruit et al. 1965 - quoted from IPCS 1991)indicate that absorption following dermal contact may have a significant lag time; the study by Spruit et al.(1965 - quoted from IPCS 1991) also showed that nickel was bound by the dermis.No in vivo studies providing specific information about the absorbed fraction of nickel in humans orexperimental animals following dermal contact to nickel nitrate have been located. In an in vitro study (Tanojoet al. 2001) using human skin (stratum corneum from cadaver leg skin), about 82.5% of the dose was recoveredin the donor solution after 96 hours, with about 0.5% in the receptor fluid and 1% in the stratum corneum.No in vivo or in vitro studies providing information about the absorbed fraction of nickel in humans orexperimental animals following dermal contact to nickel carbonate have been located.In a recent human in vivo study of nickel metal as powder (Hostýnek et al. 2001b), a large part of theadministered dose remained on the surface of the skin after 96 hours with a minor part (about 0.2%) havingpenetrated into the stratum corneum. No studies in experimental animals have been located. Nickel can bereleased from nickel alloys by solutions of artificial sweat (Katz et al. 1975 – quoted from NiPERA 1996). It hasalso been shown that artificial sweat is capable of releasing nickel ions from a pure nickel surface (Hemingway& Molokhia 1987 – quoted from NiPERA 1996). The process where nickel metal gives rise to nickel ion is to alarge extent described in the section on General exposure considerations concerning the mechanism forcorrosion. 67
  • R_NickelBackground_0308_hh_chapter0124567.docIn a study in humans employing a sensitive x-ray micro-analysis detection system, it was impossible to detectstratum corneum penetration of nickel (soluble compound, not specified) under patch test despite the occurrenceof clinical allergic reactions. The authors concluded that biologically significant amounts of nickel werepenetrating rapidly, although identifiable physical penetration was minimal. (Kalimo et al. 1985 – quoted fromNiPERA 1996).Percutaneous absorption of nickel is of negligible significance, quantitatively, but is clinically important in thepathogenesis of contact dermatitis (IPCS 1991).The stratum corneum has a considerable capacity to trap nickel and absorption is likely to be mainly limited tothe sweat ducts and hair follicles (Wells et al. 1991 – quoted from NiPERA 1996). Kolpakov (1963 - quotedfrom IPCS 1991), using skin from humans, found that the Malphigian layer of the epidermis, the dermis, and thehypodermis were readily permeable to nickel. In a study performed on guinea-pigs, it was found that theradioactive nickel accumulated within one hour in the highly keratinised areas, the stratum corneum, and hairshafts, showing a route of entry via the hair follicles and sweat glands (Lloyd 1980 - quoted from IPCS 1991).4.1.2.1.1.3.1 Discussion and conclusion, absorption following dermal contactThe data on dermal uptake of nickel following dermal contact to nickel compounds are limited and based on theavailable studies, it is impossible to give a general estimate for the fraction of nickel absorbed after dermalcontact to the five prioritised nickel compounds (nickel sulphate, nickel chloride, nickel nitrate, nickel carbonate,and nickel metal).Dermal absorption is a complex process and the extent to which a compound is absorbed across the skin isinfluenced by many factors, e.g., physico-chemical properties of the compound, vehicle, occlusion,concentration, exposure pattern, skin site of the body, etc. Furthermore, skin injury or increased water content ofthe stratum corneum may significantly increase absorption through the skin as well as some solvents anddetergents also may increase percutaneous absorption. When considering dermal absorption, it should also beborn in mind that a distinction should be made between penetration of nickel into the skin and percutaneoustransport (absorption), where nickel is transported across the skin and into the blood stream.Recent human in vivo studies of nickel sulphate and nickel metal (Hostýnek et al. 2001a,b) has shown that alarge part of the administered dose remained on the surface of the skin after 24 hours or had penetrated into thestratum corneum. No human in vivo studies have been located regarding the other prioritised nickel compounds(nickel chloride, nickel nitrate, and nickel carbonate). In vitro studies using human skin support the findings inthe human in vivo studies as most of the dose remained in the donor solution and only minor amounts werefound in the receptor fluid; the in vitro studies also indicate that absorption following dermal contact may have asignificant lag time. Some in vivo studies (Mathur et al. 1977 – quoted from IPCS 1991, Norgaard 1957 – quotedfrom IPCS 1991, Lloyd 1980 - quoted from IPCS 1991) in experimental animals (rats, guinea pigs and rabbits)indicate that nickel can be absorbed through the skin following dermal contact. The data indicate thatexperimental animals absorb nickel to a greater extent following dermal contact than humans do, which is inaccordance with the general understanding that the permeability of human skin is often lower than that of animalskin.In conclusion, the available data indicate that absorption of nickel following dermal contact to various nickelcompounds can take place, but to a limited extent with a large part of the applied dose remaining on the skinsurface or in the stratum corneum. The data are too limited for an evaluation of the absorbed fraction of nickelfollowing dermal contact to the five prioritised nickel compounds. The in vitro study of soluble nickelcompounds (nickel sulphate, nickel chloride, nickel nitrate, and nickel acetate) using human skin (Tanojo et al.2001) showed about 98% of the dose remained in the donor solution, whereas 1% or less was found in thereceptor fluid and less than 1% was retained in the stratum corneum. According to the revised TGD, the amountabsorbed into the skin, but not passed into the receptor fluid, should also be included in the estimate of dermalabsorption. For the purpose of risk characterisation, a value of 2% is taken forward to the risk characterisationfor the absorbed fraction of nickel following dermal contact to nickel sulphate, nickel chloride, nickel nitrate,and nickel carbonate. It is likely that this figure is an overestimate for nickel carbonate, as the compound is muchless water-soluble than other three nickel salts under evaluation. For nickel metal, a value of 0.2% is takenforward to the risk characterisation based on the data from the in vivo study in humans (Hostýnek et al. 2001).4.1.2.1.1.4 Other routesIn humans, absorption of nickel may occur from a variety of implanted nickel-containing medications, metallicdevices, and prostheses, which release nickel by leaching, i.e. absorption via iatrogenic exposures. This considerationis supported by some studies in experimental animals. For further details, the reader is referred to the riskassessment report for nickel metal. 68
  • R_NickelBackground_0308_hh_chapter0124567.docOther routes of exposure than inhalation, oral intake and dermal contact are not considered as being relevant for therisk characterisation of the other prioritised nickel compounds (nickel sulphate, nickel nitrate, nickel carbonate,nickel chloride).4.1.2.1.2 Distribution and elimination4.1.2.1.2.1 TransportUpon entry into the bloodstream, the nickel ion is bound to specific serum components and rapidly distributedthroughout the body. In serum, nickel is present in three forms: 1) as a complex associated with albumin; 2) as acomplex associated with a nickel-metalloprotein (nickeloplasmin); and 3) as ultrafiltrable material. The mostimportant nickel-binding protein in serum is albumin, which has a high binding capacity for nickel in most speciestested, including humans, rats, rabbits, and cows, while the nickel-binding capacity of albumin from dogs and pigs ismuch lower. The high-molecular weight nickeloplasmin serum protein has been identified as a macroglobulin and ithas been shown that purified nickeloplasmin is an α-2-macroglobulin in rabbit serum and a 9.5S α-glycoprotein inhuman serum. The predominant low molecular weight form of nickel in serum, including human serum, is a complexof nickel with the amino acid L-histidine, which play an important role in extracellular transport and in theelimination of nickel in urine. In human serum, 40% of the nickel is present as ultrafiltrable material, 34% isassociated with albumin, and 26% is associated with nickeloplasmin. (TERA 1999, IPCS 1991).In vitro, L-histidine had a greater affinity for nickel than serum albumin and nickel binding to human albuminbecame evident only when no more L-histidine was available. In vivo, the concentration of albumin was much higherthan the concentration of L-histidine and most of the nickel was associated with albumin. The equilibrium betweenL-histidine-nickel and serum-albumin-nickel may be biologically significant. The L-histidine nickel complex, whichhas a much smaller molecular size than the albumin-nickel complex, may mediate the transport through a biologicalmembrane by virtue of the equilibrium between these two molecular species of nickel. Nickel can exchange betweenalbumin and free L-histidine via a ternary complex that binds the nickel ion very tightly. The amount of nickel ineach compartment varies from species to species and this may be due, in part, to species variation in the affinity ofalbumin for nickel. (TERA 1999, IPCS 1991).The predominant intracellular form of nickel has been observed to vary among tissues. In the lung and liver of mice,nickel was bound predominantly to a high-molecular-weight protein; in the kidney, it was bound mainly to low-molecular-weight ultrafiltrable ligands. (TERA 1999).4.1.2.1.2.2 DistributionBelow, the available data on distribution for the five prioritised nickel compounds (nickel sulphate, nickelchloride, nickel nitrate, nickel carbonate, and nickel metal) are summarised; for further details, the reader isreferred to the individual risk assessment reports. Relevant information from reviews is also included.Two inhalation studies in rats (Benson et al. 1988, NTP 1996a) indicate that lung nickel burdens increase withincreasing concentrations of nickel sulphate (at least up to around 0.8 mg Ni/m3) in the inhaled air as well aswith duration of exposure. The study by Benson et al. (1988) indicates that the lung nickel burden may rise to asteady state level as the lung nickel burdens were almost similar in rats exposed to 15 or 30 mg/m3. A third study(Dunnick et al. 1989) found similar concentrations of nickel in the lungs of rats and mice after 4, 9, and 13weeks of inhalation to nickel sulphate (0.02 to 0.4 mg Ni/m3). Of nickel remaining in the body after 96 hoursfollowing a single dose of nickel sulphate administered by intratracheal administration, over 50% was in thelungs. The deposition of nickel in the lungs of rats is apparently greater than in the lungs of mice. Followingintratracheal instillation to rats, the highest concentrations of nickel at 96 hours after instillation were found inthe lung, trachea, larynx, kidney, urinary bladder, adrenals, blood, large intestine, and thyroid (Medinsky et al.1987). No human data have been located.Two drinking water studies in rats have reported some differences in tissue distribution. Followingadministration to rats in the drinking water (100 mg Ni/l) for 6 months, the highest concentrations of nickel werefound in the liver followed by the kidney (Severa et al. 1995). In the other drinking water study (13 weeks, about45-225 mg Ni/l) in male rats, the concentration in different organs was increased with increasing concentrationsof nickel in the drinking water; the relative order of bioaccumulation of nickel (at 225 mg Ni/l) was kidneys >testes > lung = brain > spleen > heart = liver (Obone et al. 1999). In mice, nickel levels were higher in kidneythan in liver (Dieter et al. 1988 – quoted from NiPERA 1996). No human data have been located. 69
  • R_NickelBackground_0308_hh_chapter0124567.docFollowing intratracheal instillation of nickel chloride to rats (English et al. 1981, Carvalho & Ziemer 1982,Clary 1975) or oral administration by gavage to mice (Nielsen et al. 1993), the highest concentrations of nickelwere found in the lungs, kidneys, and liver. No human data have been located.No studies regarding distribution of nickel in humans or in experimental animals following exposure to nickelnitrate have been located.Nickel from diets containing nickel carbonate has been reported to accumulate in tissues of rats (bones > heart >kidney > blood > spleen > intestine > testes > skin > liver at 100 mg nickel carbonate per 100 g diet for 9 weeks)(Phatak & Padwardhan 1950 - quoted from IPCS 1991) and of calves (serum > kidney > vitreous humour > lung >testis > bile > tongue > pancreas > rib > spleen > brain > liver > heart at 1000 mg nickel carbonate per kg dietarysupplementation for 8 weeks) (O’Dell et al. 1971 – quoted from IPCS 1991). No data regarding distribution ofnickel carbonate following inhalation in experimental animals and no data in humans have been located.In a 13 week inhalation study where rats were exposed to nickel powder distribution of nickel to the blood fromaccumulated nickel particles in the lung tissue was observed (WIL Research Laboratories 2003).Metabolic data from nickel-balance studies carried out by Phatak & Padwardhan (1950 - quoted from IPCS1991) who fed rats nickel metal catalyst (250, 500, or 1000 mg/kg in the diet for 2 months) demonstrated thattissue accumulation of nickel from the nickel-containing diets was not significant.Limited information exists on nickel tissue distribution in humans after inhalation. Animal studies show that inhaledsoluble nickel salts primarily distribute to the lung and kidney, with some distribution to the liver and other tissues.(TERA 1999).Very limited information exists on the human tissue distribution of nickel after oral exposure. Animal studies showthat after the ingestion of soluble nickel salts, the highest nickel level is observed in the kidney. In studies, where thelung was examined, the second highest nickel concentration was observed in this tissue. (TERA 1999).Workers occupationally exposed to nickel have higher lung burdens of nickel than the general population. Nickelcontent of the lungs at autopsy has been reported to be 330 ± 380 µg/g dry weight in roasting and smelting workersexposed to less soluble compounds, 34 ± 48 µg/g dry weight in electrolysis workers exposed to soluble nickelcompounds, and 0.76 ± 0.39 µg/g dry weight in unexposed controls. Nickel levels in the nasal mucosa have also beenreported to be higher in workers exposed to insoluble, relative to soluble, nickel compounds. Higher serum nickellevels have been found in occupationally exposed individuals compared to non-exposed controls and levels werefound to be higher in workers exposed to soluble nickel compounds compared to workers exposed to insoluble nickelcompounds. Nickel sensitised individuals had similar nickel levels in blood, urine and hair relative to non-sensitisedindividuals. An autopsy study of individuals not occupationally exposed to nickel have shown the highestconcentrations in the lungs, followed by the thyroid, adrenals, kidney, heart, liver, brain, spleen, and pancreas. (USATSDR 1995).There are few data on human tissue concentrations of nickel; the data indicate that the retained nickel is widelydistributed in very low concentrations in the body (IPCS 1991).In conclusion, nickel tends to deposit in the lungs of workers occupationally exposed to nickel and inexperimental animals following inhalation or intratracheal instillation of nickel compounds. Upon entry into thebloodstream, the nickel ion is bound to specific serum components and rapidly distributed throughout the body. Inserum, nickel is present in three forms: 1) as a complex associated with albumin; 2) as a complex associated with anickel-metalloprotein (nickeloplasmin); and 3) as ultrafiltrable material. In human serum, 40% of the nickel ispresent as ultrafiltrable material, 34% is associated with albumin, and 26% is associated with nickeloplasmin. Thetissue distribution of nickel in experimental animals does not appear to depend significantly on the route ofexposure (inhalation/intratracheal instillation or oral administration) although some differences have beenobserved. Low levels of accumulation in tissues are observed (generally below 1 ppm). A primary site of elevatedtissue levels is the kidney. In addition, elevated concentrations of nickel are often found in the lung, also after oraldosing, and in the liver. Elevated nickel levels are less often found in other tissues. Limited information exists ontissue distribution in humans.4.1.2.1.2.3 Transplacental transferTransplacental transfer provides an initial body burden that will be augmented by later exposures. For thisreason, and in view of the possible adverse effects associated with the exposure of pregnant women to nickelduring early pregnancy, transplacental transfer is important. Placental transfer is influenced by gestational ageand the availability of nickel in the maternal blood. Species differences in placental structure and implantation,which may possibly influence nickel transfer, must also be considered. (IPCS 1991). 70
  • R_NickelBackground_0308_hh_chapter0124567.docNickel has been shown to cross the human placenta. It has been found in both the foetal tissue (Schroeder et al.1962 – quoted in IPCS 1991) and the umbilical cord serum, where the average concentration from 12 new-bornbabies was 3 ± 1.2 µg/l (range 1.7-4.9 µg/l) and was identical with that in the mother’s serum, immediately afterdelivery (McNeely et al. 1971 – quoted in IPCS 1991). Measurable concentrations have been found in variousfoetal tissues with concentrations in liver, kidney, brain, heart, lung, skeletal muscle, and bone being similar tothose in adults ranging from 0.24-0.69 mg/kg dry matter. (IPCS 1991).Several reports indicate that transplacental transfer of nickel occurs in experimental animals: The newbornoffspring of rats fed nickel carbonate or nickel metal catalyst in the diet showed whole-body levels of 12-17 or22-30 mg Ni/kg bw, when dams received 500 or 1000 mg Ni/kg diet, respectively (Phatak & Padwardhan 1950 -quoted from IPCS 1991).Following intraperitoneal injection (on day 16 of gestation) of nickel chloride to pregnant mice, theconcentrations of nickel in the maternal blood and the placenta were found to be at a maximum 2 hours afterinjection; the maximum concentration in foetal tissues was reached 8 hours after injection, and only a slight andgradual decrease in concentration was observed up to 24 hours (Lu et al. 1981 – quoted from IPCS 1991). Inanother study by Lu et al. (1979 – quoted from IPCS 1991), the concentration of nickel retained in embryonictissues was 800 times higher in the exposed animals than in controls when pregnant mice were given anintraperitoneal injection of nickel chloride on day 8 of gestation. When pregnant mice were given a singleintraperitoneal injection (on day 18 of gestation) of nickel chloride, passage of nickel from mother to foetus wasrapid and concentrations in foetal tissues were generally higher than those in the dam (Jacobsen et al. 1978 –quoted from IPCS 1991).Sunderman et al. (1978 – quoted from IPCS 1991) administered nickel (compound not specified)intramuscularly to pregnant rats on days 8 or 18 of gestation and determined maternal and foetal tissueconcentrations by autoradiography. The mean nickel concentration in the foetuses of dams injected on day 8 ofgestation was equivalent to that in the maternal animals whereas in dams injected on day 18 of gestation, nickelwas localised in the placenta, in the yolk sacs and foetuses; the foetal organ with the highest concentration wasthe urinary bladder. When nickel (compound not specified) was administered to rats in the drinking water for 7months before, and during, pregnancy, the nickel content increased in the placentas, but not in the foetuses(Nadeenko et al. 1979 – quoted from IPCS 1991).In conclusion, nickel has been shown to cross the human placenta. Transplacental transfer has also beendemonstrated in rats administered nickel carbonate or nickel metal catalyst in the diet, in mice followingadministration of nickel chloride by intraperitoneal injection, and in rats following administration of nickel byintramuscular injection.4.1.2.1.2.4 Cellular uptakeNickel can enter animal cells by three different mechanisms: uptake via metal ion transport systems, diffusion oflipophilic nickel complexes through the membrane, and phagocytosis. Differences in cellular uptake of soluble andinsoluble forms of nickel compounds play an essential role in the observed differences in the toxicity among thesecompounds. Several reviews have been published regarding the different mechanisms by which cells uptake differentnickel compounds; the data are summarised below according to TERA (1999).A number of studies have shown that cellular uptake of the insoluble nickel compounds, nickel subsulphide andnickel sulphide particles, occurs via phagocytosis. Small amounts of nickel subsulphide may also dissolve outside thecell, and enter the cell as soluble nickel. In a comparison of a number of insoluble nickel compounds (similar particlesizes), transformation activity in Syrian hamster embryo (SHE) cells correlated with the phagocytic activity of thecompound. Soluble nickel chloride had lower transforming activity than the well-phagocytised compounds, which isattributed to more efficient uptake and better retention of insoluble nickel entering via phagocytosis compared tosoluble nickel entering via diffusion or transport. (TERA 1999).The process by which soluble nickel enters the cell is less clearly understood. Uptake of soluble nickel into cells mayoccur as a result of transport or diffusion of nickel complexes through the cell membrane. (TERA 1999).In enteric cells, nickel interacts with cell membranes in a manner similar to the interactions of cadmium and otherheavy metals, i.e., via passive diffusion, without the need for assuming specific transport systems. Similar passivediffusion mechanisms may exist in lung cells. Passive diffusion of nickel across cell membranes is markedly reducedunder normal physiological conditions, when nickel is bound to proteins or amino acid ligands, forming hydrophiliccomplexes. In vitro studies have shown that serum inhibits the uptake of nickel into cells and that metal-bindingamino acids such as cysteine and histidine appear to account for the majority of the inhibitory activity of serum. Bycontrast, packaging soluble nickel compounds in liposomes increases nickel transport by this mechanism. (TERA1999). 71
  • R_NickelBackground_0308_hh_chapter0124567.docUptake of nickel via ion transport systems, particularly via the magnesium transport system, has been reported as amajor route in microbial cells; the same mechanism may also exist in mammalian cells. Results from studies inanimals are consistent with the hypothesis that the magnesium ion transport system is responsible for the uptake ofsoluble nickel salts into cells, although this process has not been directly demonstrated in mammalian cells. Uptakeof nickel via the magnesium transport mechanism is also less efficient than phagocytosis as magnesiumconcentrations inside and outside the cell are in the millimolar range, so nickel would not compete effectively withmagnesium for uptake under normal exposure conditions, which would result in nickel concentrations well below themillimolar range. (TERA 1999).The differences between the processes by which soluble and insoluble nickel enter the cell are reflected in differencesin disposition once the nickel is inside the cell. Soluble nickel directly enters the cytoplasm, where it binds to cellularproteins thereby decreasing the bioavailability of soluble nickel to enter the nucleus and interact with DNA. Smallamounts of nickel subsulphide may also be dissolved in the extracellular fluid and be taken up by cells via thispathway. The presence of nickel ion in the cytoplasm increases the potential for cytotoxicity. By contrast,phagocytosed (insoluble) nickel particles are retained in vacuoles thereby decreasing the opportunity for insolublenickel to interact with cytosolic macromolecules and thus decreasing the potential for cytotoxicity or for interactionsthat render the nickel unavailable for interacting with DNA. The vacuoles migrate to the region near the nucleuswhere they interact with lysosomes. This interaction decreases the pH of the vacuole and thereby increasing the rateof dissolution of nickel ion in close proximity to the nuclear membrane, where they can interact with DNA. The netresult of these differences is that exposure to insoluble nickel compounds results in much higher nuclear nickelconcentrations and higher DNA binding than exposure to similar levels of soluble nickel compounds. (TERA 1999).In conclusion, the cellular uptake of soluble and insoluble nickel compounds are different as insoluble nickelcompounds enter the cell via phagocytosis, while soluble nickel compounds are not phagocytised, but enter the cellvia metal ion transport systems (particularly the magnesium transport system or through membrane diffusion. Thelatter two processes are much less efficient implicating that the same extracellular levels of soluble and insolublenickel compounds lead to lower intracellular nickel levels for soluble nickel compounds. Soluble forms of nickelinteract with the cell in a way that maximises cytotoxicity and minimises nickel delivery to the nucleus, whileinsoluble forms of nickel interact with cells in a way that decreases the cytotoxic potential while increasing thedelivery of nickel to the nucleus.4.1.2.1.2.5 EliminationBelow, the available data on elimination for the five prioritised nickel compounds (nickel sulphate, nickelchloride, nickel nitrate, nickel carbonate, and nickel metal) are summarised; for further details, the reader isreferred to the individual risk assessment reports. Relevant information from reviews is also included.The major route of excretion of nickel in rats following a single dose of nickel sulphate administered byintratracheal instillation was in urine; the extent of excretion increased and the half-time decreased withincreasing dose (Medinsky et al. 1987). No data on excretion of nickel sulphate in experimental animalsfollowing other exposure routes have been located.In humans, absorbed nickel is predominantly excreted in the urine following oral intake of nickel sulphate with20 to 30% of a dose being excreted in the urine when nickel sulphate is administered in drinking water to fastingsubjects or to fasting subjects compared with around 1 to 5% when administered together with food (Sundermanet al. 1989, Cronin et al. 1980 – quoted from IARC 1990). From biological monitoring in small groups ofelectroplaters exposed to nickel sulphate and nickel chloride, the half-life for urinary elimination of nickel hasbeen estimated to range from 17 to 39 hours (Sunderman et al. 1988 – quoted from TERA 1999, US ATSDR1995).The major route of excretion of nickel in rats following intratracheal instillation of nickel chloride was in urinewith 70 to 80% of a dose being eliminated via the urine within 3 days following instillation and approximately97% by 21 days after instillation (Carvalho & Ziemer 1982, Clary 1975). No data on excretion of nickel chloridein experimental animals following other exposure routes have been located. From biological monitoring in smallgroups of electroplaters exposed to nickel sulphate and nickel chloride, the half-life for urinary elimination ofnickel has been estimated to range from 17 to 39 hours (Sunderman et al. 1988 – quoted from TERA 1999, USATSDR 1995).No studies regarding elimination in humans or in experimental animals following exposure to nickel nitratehave been located. 72
  • R_NickelBackground_0308_hh_chapter0124567.docOne study in mice indicates that most of the nickel was eliminated 12 days after intratracheal instillation of nickelcarbonate (Furst & Al-Mahrouq 1981 - quoted from IPCS 1991). No data regarding elimination of nickelcarbonate following oral administration to experimental animals and no data in humans have been located.After 13 weeks exposure to metallic nickel powder, elimination of the accumulated particles in the lung tookplace with a half life of 30 to 60 days. The increased nickel blood levels during the elimination period indicatedthat the elimination was dependent on dissolution of the nickel particles in the lung and the following uptake andelimination from the blood stream (WIL Research Laboratories 2003).When soluble nickel salts are inhaled or injected intratracheally, most of the nickel is absorbed and then excretedthrough the urinary route, although appreciable faecal excretion has also been observed. Animal data indicate that therate of urinary nickel excretion increases at higher, when compare to lower, intratracheal doses. The half-life ofnickel in the lungs after exposure to soluble nickel salts varied with the solubility of the nickel species indicating thatclearance is related to nickel solubility. The half-life of nickel in the lungs of rats administered nickel sulphate wasabout 21-36 hours, while the half-life was 4 days and 120 days for nickel subsulphide and nickel oxide, respectively.In humans, most ingested nickel salts are not absorbed but are excreted in the faeces; absorbed nickel is excretedprimarily through the urinary route with the maximal excretion in the first 8-9 hours after ingestion. The half-life forurinary excretion in humans is about 20-30 hours. About 23-26% of the dose is excreted in the urine followingadministration of soluble nickel in water to fasting individuals, but only 2-3% if nickel is administered with a meal. Asimilar pattern of nickel excretion has been observed in experimental animals. In addition to excretion through theurinary route, small amounts of absorbed nickel can also be excreted through other routes, such as via sweat, bile,and milk. (TERA 1999).Absorbed nickel is excreted in the urine, regardless of the route of exposure. In nickel workers, an increase in urinaryexcretion was found from the beginning to the end of the shift and also as the workweek progressed. Nickel is alsoexcreted in the faeces of nickel workers, but this is most likely resulting from mucociliary clearance of nickel fromthe respiratory system to the gastrointestinal tract. Higher nickel levels were found in the urine of workers exposed tosoluble nickel compounds as compared to workers exposed to insoluble nickel compounds. In humans, most ingestednickel is excreted in the faeces; however, the nickel that is absorbed from the gastrointestinal tract is excreted in theurine. Similar patterns of nickel excretion have been observed in experimental animals. (US ATSDR 1995).The elimination routes for nickel in humans and animals depend, in part, on the chemical form of the nickelcompound and on the exposure route. Following oral exposure, the elimination of nickel is primarily in the faecesdue to the relatively low gastrointestinal absorption. Urinary excretion is usually the major clearance route forabsorbed nickel. Other routes of elimination, which are of minor importance, include hair, saliva, sweat, tears, andmilk. (IPCS 1991).In conclusion, absorbed nickel is excreted in the urine, regardless of the route of exposure; the half-life for urinaryexcretion in humans has been reported to be about 20-30 hours. Most ingested nickel is excreted via faeces due tothe relatively low gastrointestinal absorption. In humans, nickel excreted in the urine following oral intake ofsoluble nickel compounds accounts for 20-30% of a dose when the nickel compound is administered in drinkingwater to fasting subjects or to fasting subjects compared with 1-5% when administered together with food or inclose proximity to a meal. Small amounts of absorbed nickel can also be excreted through other routes, include hair,saliva, sweat, tears, and milk. Inhaled nickel particles that are deposited in the respiratory tract can be eliminatedfrom the airway by absorption from the lung or by removal via the mucociliary action. This latter fraction maysubsequently be swallowed and enter into the gastrointestinal tract..4.1.2.1.2.6 Transfer to the milkAppreciable amounts of nickel have been found in breast milk of women (IPCS 1991).The nickel concentration in milk specimens obtained from 102 American mothers averaged 17 ± 2 and 14 ± 1µg/kg at 4-7 days postpartum and at 30-45 days postpartum, respectively (Feeley et al. 1983 – quoted fromTERA 1999).Dostal et al. (1989 – quoted from IPCS 1991 and TERA 1999) studied the effects of nickel on lactating rats,their suckling pups, and the transfer of nickel via the milk. Dose-dependent increases were observed in theconcentrations of nickel in the milk and plasma, 4 hours after a single subcutaneous injection of nickel chlorideto lactating dams giving a milk/plasma nickel ratio of 0.02. Peak plasma nickel concentrations in the damsoccurred 4 hours after the injection, while the peak concentration in the milk was observed at 12 hours andremained elevated at 24 hours. Daily subcutaneous injections of dams for 4 days increased the milk/plasmanickel ratio to 0.10. Significant alterations in milk composition included increased solids and lipids (42 and 73
  • R_NickelBackground_0308_hh_chapter0124567.doc110%, respectively) and decreased milk protein and lactose (29 and 62%, respectively). In multiple dose studies(subcutaneous injection once daily, on days 12-15 of lactation), the plasma-nickel concentrations in sucklingwere 24-48 µg/litre dependent on the dose administered.No data regarding transfer of nickel to milk following exposure to nickel sulphate, nickel nitrate, nickel carbonate,nickel metal as well as to other nickel compounds have been located.In conclusion, nickel has been found in breast milk of women and in milk from lactating rats administerednickel chloride by subcutaneous injection.4.1.2.1.3 ConclusionsThe available data on nickel sulphate and nickel chloride indicate that the absorption of nickel followinginhalation of the soluble nickel compounds (nickel sulphate, nickel chloride and nickel nitrate) might be ashigh as up to 97-99%; it should be noted that the fraction absorbed apparently depends on the concentration ofthe nickel compound in the inhaled air as well as on the duration of exposure. For the purpose of riskcharacterisation, a value of 100% is taken forward to the risk characterisation for the absorbed fraction of nickelfrom the respiratory tract following exposure by inhalation of the prioritised soluble nickel compounds (nickelsulphate, nickel chloride and nickel nitrate) for particulates with an aerodynamic diameter below 5 µm(respirable fraction). For nickel particulates with aerodynamic diameters above 5 µm (non-respirable fraction),the absorption of nickel from the respiratory tract is considered to be negligible as these particles predominantlywill be cleared from the respiratory tract by mucociliary action and translocated into the gastrointestinal tract andabsorbed. Hence, for the non-respirable fraction, 100% clearance from the respiratory tract by mucociliary actionand translocation into the gastrointestinal tract is assumed and the oral absorption figures can be taken.The available data on nickel oxide indicate that the absorption of nickel from the respiratory tract followinginhalation is very limited. However, data on metallic nickel indicate an absorbed fraction of up to approximately6% after inhalation (i.e. both absorption from respiratory tract and the gastrointestinal tract).The available data on the soluble nickel compounds (nickel sulphate, nickel chloride and nickel nitrate) indicatethat the absorption of nickel following oral administration in the drinking water to fasting individuals might beas high as up to about 25-27% and about 1-6% when administered to non-fasting individuals and/or togetherwith (or in close proximity to) a meal. The available data on insoluble and slightly soluble nickel compounds(nickel metal, nickel carbonate, nickel oxides and nickel sulphides) indicate that absorption of nickel from thegastrointestinal tract may occur following oral exposure; however, the data are too limited for an evaluation ofthe absorbed fraction of nickel. For the purpose of risk characterisation, a value of 30% is taken forward to therisk characterisation for the absorbed fraction of nickel from the gastrointestinal tract following oral exposure tonickel sulphate, nickel chloride, nickel nitrate, and nickel carbonate in the exposure scenarios where fastingindividuals might be exposed to nickel compounds. In all the other exposure scenarios, a value of 5% is used forthe absorbed fraction of nickel from the gastrointestinal tract. Values of 0.05% and 0.3% are taken forward to therisk characterisation for the absorbed fraction of nickel from the gastrointestinal tract following oral exposure tonickel metal for non-fasting and for fasting individuals, respectively.The available data indicate that absorption of nickel following dermal contact to various nickel compounds cantake place, but to a limited extent with a large part of the applied dose remaining on the skin surface or in thestratum corneum. The data are too limited for an evaluation of the absorbed fraction of nickel following dermalcontact to the five prioritised nickel compounds. For the purpose of risk characterisation, a value of 2% is takenforward to the risk characterisation for the absorbed fraction of nickel following dermal contact to nickelsulphate, nickel chloride, nickel nitrate, and nickel carbonate. For nickel metal, a value of 0.2% is taken forwardto the risk characterisation.Nickel tends to deposit in the lungs of workers occupationally exposed to nickel and in experimental animalsfollowing inhalation or intratracheal instillation of nickel compounds. Upon entry into the bloodstream, the nickelion is bound to specific serum components and rapidly distributed throughout the body. In serum, nickel is present inthree forms: 1) as a complex associated with albumin; 2) as a complex associated with a nickel-metalloprotein(nickeloplasmin); and 3) as ultrafiltrable material. In human serum, 40% of the nickel is present as ultrafiltrablematerial, 34% is associated with albumin, and 26% is associated with nickeloplasmin.The tissue distribution of nickel in experimental animals does not appear to depend significantly on the route ofexposure (inhalation/intratracheal instillation or oral administration) although some differences have beenobserved. Low levels of accumulation in tissues are observed (generally below 1 ppm). A primary site of elevatedtissue levels is the kidney. In addition, elevated concentrations of nickel are often found in the lung, also after oral 74
  • R_NickelBackground_0308_hh_chapter0124567.docdosing, and in the liver. Elevated nickel levels are less often found in other tissues. Limited information exists ontissue distribution in humans.Nickel has been shown to cross the human placenta. Transplacental transfer has also been demonstrated in ratsadministered nickel carbonate or nickel metal catalyst in the diet, in mice following administration of nickelchloride by intraperitoneal injection, and in rats following administration of nickel by intramuscular injection.The cellular uptake of soluble and insoluble nickel compounds are different as insoluble nickel compounds enter thecell via phagocytosis, while soluble nickel compounds are not phagocytised, but enter the cell via metal ion transportsystems (particularly the magnesium transport system or through membrane diffusion. The latter two processes aremuch less efficient implicating that the same extracellular levels of soluble and insoluble nickel compounds lead tolower nickel levels intracellularly for soluble nickel compounds. Soluble forms of nickel interact with the cell in away that maximises cytotoxicity and minimises nickel delivery to the nucleus, while insoluble forms of nickelinteract with cells in a way that decreases the cytotoxic potential while increasing the delivery of nickel to thenucleus.Absorbed nickel is excreted in the urine, regardless of the route of exposure; the half-life for urinary excretion inhumans has been reported to be about 20-30 hours. Most ingested nickel is excreted via faeces due to therelatively low gastrointestinal absorption. In humans, nickel excreted in the urine following oral intake of solublenickel compounds accounts for 20-30% of a dose when the nickel compound is administered in drinking water tofasting subjects or to fasting subjects compared with 1-5% when administered together with food or in closeproximity to a meal. Small amounts of absorbed nickel can also be excreted through other routes, include hair,saliva, sweat, tears, and milk. Inhaled nickel particles that are deposited in the respiratory tract can be eliminatedfrom the airway by absorption from the lung or by removal via the mucociliary action. This latter fraction maysubsequently be swallowed and enter into the gastrointestinal tract. An elimination half life of 30-60 days hasbeen estimated for metallic nickel particles accumulated in lung tissue. The elimination is dependent ondissolution of the accumulated nickel particles followed by absorption and elimination of nickel from the blood.4.1.2.2 Acute toxicity4.1.2.2.1 Animal studies4.1.2.2.1.1 InhalationData on the inhalation toxicity of nickel and different nickel compounds comes from studies of nickel metal,nickel carbonyl and nickel chloride. None of the studies on nickel metal or nickel chloride are sufficient andnone of them allow the determination of a lethal concentration. A one-hour nickel metal powder dust aerosolexposure at the nominal concentration of 10.2 mg Ni/l did not cause mortality or signs of toxicity (FDRL, 1985).Nickel carbonyl appears to be exceptionally toxic by inhalation as evidenced by a number of human poisoningaccidents (NIPERA, 1996). In the rat, a 30-minute LC50 of 0.24 mg/l has been reported, presumably the dose isreported as nickel carbonyl (Kincaid et al., 1953, Sunderman et al., 1959; both quoted from UK HSE, 1987).Data is available for some nickel compounds following intratracheal administration (see UK HSE, 1987), but is notdiscussed further here because the relevance of this method of administration for the inhalation route is not known.It is not considered possible to predict an LC50 by extrapolation from oral acute toxicity data, as the toxico-kineticsand type of effect are expected to differ greatly between the two routes.Data for repeated dose inhalation studies are available, which allow the determination of concentrations, which arenot associated with lethality (please see the section on repeated dose toxicity for further study details).For metallic nickel (representing insoluble nickel compounds), concentrations up to 24 mg Ni/m3 (whole-bodyexposure) 6h/day, 5d/week for 4 weeks were not associated with mortality (WIL Research Laboratories, 2002).Two other insoluble nickel compounds, nickel oxide and nickel subsulphide, were tested by NTP (1996b, 1996c)in 16-day studies in mice and rats. Nickel oxide did not cause mortality in the tested concentrations up to andincluding 23.6 mg Ni/m3. Nickel subsulphide, however, appeared more toxic, especially in mice. The highestconcentration of nickel subsulphide which did not cause excess mortality was equivalent to 3.65 mg Ni/m3. TheLOAEC of this study was 7.33 mg Ni/m3.For soluble nickel compounds, a NOAEC/LOAEC (lethality) from the 16-day repeated dose toxicity study ofnickel sulphate hexahydrate by NTP (1996a) can be used (LOAEC of 0.7 mg Ni/m3 (3.7 mg/m3 NiSO4.6H2O) forreduced body weight and adverse effects in the respiratory tract (atrophy and inflammation). 75
  • R_NickelBackground_0308_hh_chapter0124567.doc4.1.2.2.1.2 OralA number of studies on the acute oral toxicity of nickel and different nickel compounds have been carried out.These studies are summarised in Table 4.1.2.2A which is based on the review by UK HSE (1987).Table 4.1.2.2.A: Summary of acute oral toxicity studies in rats. (quoted from UK HSE, 1987). solubility Sex LD50, mg/kg reference (all quoted in water (mg Ni/kg) from UK HSE, 1987)Nickel chloride male 430 (105) Itskova et al. (1969) very female 529 (130) soluble male 210 (51) FDRL (1983a) test substance NiCl2.6H2O female 175 (43)Nickel nitrate very 1620 (330) Smyth et al. (1969) solubleNickel sulphate 500 (190) Kosova (1979) very male 325 (73) FDRL (1983b) soluble female 275 (61) test substance NiSO4.6H2ONickel acetate soluble male 350 (119) Haro et al, 1968 female 360 (116)Nickel carbonate slightly male 1305 (625) FDRL (1983c) soluble female 840 (402)nickel hydroxide very male 1500 (915) FDRL (1983d) slightly soluble female 1700 (1037)nickel trioxide insoluble male, > 5000 (> 3548) FDRL (1983e) femalenickel oxide insoluble male, > 5000 (> 3930) FDRL (1983f) femalenickel subsulphide insoluble male, > 5000 (> 3663) FDRL (1983g)(crystalline) femalenickel subsulphide insoluble male, > 5000 (> 2620) FDRL (1983h)(amorphous) femaleiron nickel powder insoluble male, > 5000 (> 1475) FDRL (1983i) female1) Figures in brackets are mg Ni/kg4.1.2.2.1.3 DermalThere are no relevant data available on the acute toxicity of soluble or insoluble nickel compounds followingcutaneous administration. Absorption via this route is expected to be negligible, and further testing is not consideredrelevant.4.1.2.2.1.4 Other routesData for effects following intraperitoneal or intramuscular administration is available for some nickel compounds(see UK HSE, 1987), but these routes of administration are not discussed further here, because these routes are notconsidered relevant for the human exposure situation.4.1.2.2.2 Human studiesIn the 19th century, nickel salts were used medicinally, and 325 mg nickel sulphate in solution or in pill formproduced nausea and giddiness (Da Costa, 1883, quoted in UK HSE 1987). According to NIPERA, 1996, severetoxic effects of inhalation exposure to nickel carbonyl have been recognized for many years. The initial stage ofpoisoning involves headache, chest pain, weakness, dizziness, nausea, irritability, and a metallic taste in themouth. A general remission of 8-24 hours’ duration then occurs, followed by a second phase of chemical 76
  • R_NickelBackground_0308_hh_chapter0124567.docpneumonitis, with evidence of cerebral poisoning in severe cases. Common signs in severe cases includetachypnoea, cyanosis, tachycardia, and hyperaemia of the throat, and radiological signs of pulmonary oedema orpneumonitis.4.1.2.2.3 Discussion and conclusion4.1.2.2.3.1 InhalationThere is no data for acute inhalational toxicity from properly conducted Annex V inhalation tests for any of thenickel compounds.In the absence of such data, data from repeated dose inhalation studies is used for the risk characterisation. Thesedata do not indicate a solubility-related difference in toxicity. The use of results from these repeated dose studiesis considered to be a conservative approach, since greater toxicity is expected from repeated exposure comparedto a single 4h exposure as in the Annex V test.Data from repeated dose studies are not directly useful for classification, since greater toxicity is expected fromrepeated exposure (12 exposures during 16 days) compared to a single 4h exposure as in the Annex V test.However, there is evidence for acute oral toxicity for the soluble as well as the less soluble compounds (but notinsoluble or metallic nickel) (see below); absorption via inhalation is considerably greater than via the oral route,and the NTP 16 day repeated dose toxicity study (NTP, 1996a) showed mortality in rats at a level roughly 30times lower than the lower cut-off for classification for T; R23 and 100% of the female and 40% of the male ratsdied at the highest dose before the end of the study. The TC C&L has agreed to classify nickel chloride with T;R23 and nickel sulphate, nickel nitrate and the nickel carbonates with Xn; R20. These classifications areincluded in the 30th ATP. It should be noted that nickel hydroxide (which has a solubility similar to that of thenickel hydroxycarbonates) is already classified in Annex I with Xn; R20.4.1.2.2.3.2 OralA number of nickel compounds of varying solubility have been tested in acute oral toxicity tests. Although someof the variability in results is probably explained by differences in laboratory procedures etc., the results showthat soluble nickel compounds are more toxic by the oral route than the insoluble salts.The oral LD50 levels for the three soluble nickel salts, nickel sulphate, nickel chloride and nickel nitrate, tested ashydrates in the rat, ranged from 175 to 1620 mg compound/kg. The corresponding figures expressed as mg Ni/kgwere 43 –330. Since all three compounds are very soluble, these studies could be considered as estimates of thetoxicity of the nickel ion. However, the very soluble nickel nitrate appears to be less toxic than the other two solublenickel compounds, with a LD50 comparable to that for the sparingly soluble salts. The nickel nitrate LD50 study wasreported in 1969 and may not be comparable to more recent studies, as the study was carried out in non-fastedanimals and is probably an underestimate of the acute toxicity. However, a more recent toxic class method study(Pycher 2003a) showed no mortality or signs of toxic symptoms at 200 mg nickel nitrate hexahydrate/kg.The less soluble carbonate and hydroxide showed values of from 840 – 1700 mg compound/kg (402-1037 mgNi/kg). This is consistent with the evidence of oral absorption seen for nickel carbonate described above (see4.1.2.1.1.2). The insoluble oxides and sulphides showed LD50 values over 5000 mg compound/kg.For the risk characterisation, different values are used based on the solubility of the substance in question. Fornickel sulphate, nickel chloride and nickel nitrate, an oral LD50 value of 43 mg Ni/kg is used based on resultsfrom nickel chloride (FDRL, 1983a). For nickel carbonate, an oral LD50 value of 402 mg Ni/kg based on resultsfor the substance (FDRL, 1983c) is used. For nickel metal, the LD50 is in excess of 5000 mg/kg.The TC C&L has agreed to classify nickel chloride with T; R25 and nickel sulphate, nickel nitrate and the nickelcarbonates with Xn; R22. These classifications are included in the 30th ATP . It should be noted that nickelhydroxide is already classified for this effect in Annex I with Xn; R22.The insoluble compounds and the metal should not be classified for acute oral toxicity.4.1.2.2.3.3 DermalThere is no data on toxicity following cutaneous administration. Dermal absorption is expected to be verylimited. Therefore, this endpoint is not considered in the risk characterisation, and no classification for acutetoxicity via the dermal route is proposed. 77
  • R_NickelBackground_0308_hh_chapter0124567.doc4.1.2.3 Irritation /corrosivityInformation on the pH of nickel sulphate, nickel chloride and nickel (hydroxy)carbonate solutions is availablefrom the main EU producers. The pH of a 100g sample of nickel (hydroxy)carbonate added to 1 litre of watervaried between 7.8 and 8.9. The pH of a nickel chloride solution is 3.7 + 0.4, and that of a nickel sulphatesolution is between 3 and 3.5.Commercially available nickel nitrate may contain nitric acid, either as an impurity from the production processat concentrations from 0 – 4%, or as an additive at a concentration of up to ca. 10%. These nickel nitrateproducts are normally classified as C; R34, based either on the nitric acid content or on the basis of extreme pH(pH < 2).4.1.2.3.1 Animal studies4.1.2.3.1.1 Skin and eye irritationNeither the NIPERA (1997), the US ATSDR (1997) nor the TERA (1999) reviews discuss skin or eye irritationof soluble or insoluble nickel compounds. In the UK HSE (1987) review it is mentioned that no data were foundon the skin and eye irritancy of insoluble nickel compounds. Data for nickel metal and the soluble nickelsulphate and nickel nitrate have been found (table 4.1.2.3.A).Nickel metal did not cause skin irritation in an Annex V skin irritation test. Nickel sulphate gave slight irritation(erythema) in an Annex V skin irritation test. In two other studies, the application was repeated for 30 days, andresulted in adverse effects on the skin. Nickel nitrate hexahydrate was irritant in an Annex V test (as well as asecond sample and a solution).Nickel sulphate gave slight eye irritation (slight degree of conjunctival redness and oedema, and iris lesions) inan Annex V eye irritation test. Nickel nitrate hexahydrate is a severe eye irritant in an Annex V test, as irritationpersists at the end of a 21-day observation period.Table 4.1.2.3.A: Summary of skin and eye irritation studies Nickel Species Result Grading Method Reference compound (irritation scores) Skin Metal rabbit not irritant 0.5 (erythema) Annex V SLI 1999a 0.00 (oedema) Sulphate rabbit not irritant 0.42 (erythema) Annex V SLI 1999b 0.00 (oedema) Sulphate rabbit pustules seen on 50% aqueous solution Wahlberg & wounded skin but not Maibach intact skin 1981 Sulphate rat skin atrophy, acanthosis 40 – 100 mg Ni/kg Mathur et al. and hyperkeratinisation 1977 repeated application for 30 days Sulphate rat erythema, eschar 50% aqueous solution Kosova (1979 daily for 30 days - quoted from UK HSE 1987) Nitrate rabbit irritant 3.1 (erythema) Annex V Phycher 2003b 1.1 (oedema) Eye 78
  • R_NickelBackground_0308_hh_chapter0124567.doc Nickel Species Result Grading Method Reference compound (irritation scores) Sulphate rabbit not irritant 0. 00 (corneal Annex V SLI 1999c opacity) 0.33 (iris lesion) 0.67 (conjunctival redness) 0.44 (conjunctival oedema) Nitrate rabbit severe eye irritant as 1.0 (corneal Annex V Phycher effects persist to end of opacity) 2003c observation period 1.0 (iris lesion) 2.0 (conjunctival redness) 2.7 (conjunctival oedema)4.1.2.3.1.2 Respiratory irritationNo studies examining the respiratory irritation caused by a single exposure to nickel or nickel compounds havebeen found. Several studies have shown lung inflammation and degeneration of the olfactory epitheliumfollowing relatively short periods of exposure to the very soluble nickel sulphate (Benson et al. 1988 (aerosolinhalation 12 days), Dunnick et al. 1989 (inhalation – 13 weeks), Benson et al. 1989 (aerosol inhalation 13weeks) - all quoted from NiPERA 1996). Nickel sulphate induced atrophy of the olfactory epithelium and lunginflammation in mice and rats after only 16 days inhalation exposure (NTP 1996a). The lowest dose tested wasequivalent to 0.7 mg Ni/m3 and this was a LOAEC. In similar 16-day studies, the insoluble nickel compoundsnickel oxide and nickel subsulphide were also shown to cause respiratory effects (NTP 1996b, 1996c). Nickelsubsulphide was more potent than oxide, and caused lung inflammation and atrophy of the nasal olfactoryepithelium in all exposed groups with a LOAEC of 0.44 mg Ni/m3. Based on these data it is not possible to relatethe type or severity of respiratory effect to solubility characteristics of the nickel compounds.4.1.2.3.2 Human data4.1.2.3.2.1 Skin irritationIn a study performed to develop a new test for skin irritancy, nickel sulphate was included as one of the testagents (Frosch & Kligman, 1976). A volume of 0.1 ml of nickel sulphate in various concentrations was pipettedon to a disc of two thicknesses of non-woven cotton cloth. The disc was mounted in a chamber designed for usein tests of contact sensitisation, which was sealed to the skin with non-occlusive tape or Dermicel®. Theadvantage of the chamber compared with the use of patches was that there was no loss of test material anduniform contact with the skin. The test subjects were groups of 5-10 light-skinned, young Caucasians. The testmaterial was applied on the mid-volar forearm once daily for 3 days with readings made at 72h, 30 min afterremoval. The test was conducted on both intact and scarified skin. The reactions were graded on a five-pointscale from 0 to 4 (1:erythema, 2: increased erythema, 3: severe erythema with partial confluency with or withoutother lesions, 4: confluent severe erythema sometimes associated with oedema, necrosis or bulla formation). Onscarified skin nickel sulphate gave a dose-dependent response in the test, ranging from a score of 1 at aconcentration of 0.13% to 4 at 1%. The dose-response plot is very steep for nickel sulphate. The authors describetheir results as “a marginal irritant” at 0.13% but “a ferocious one at 1%”.The sensitivity of the assay on scarified skin was compared with the sensitivity on normal skin. No details of theresults on normal skin are shown. The threshold concentration to produce “just an irritation reaction in 3 days”on normal skin was 20.0% while on scarified skin it was 0.13%. The ratio of threshold concentration on normalskin and threshold concentration on scarified skin was 154. This was the highest ratio among the substancestested, which included surfactants, inorganic salts, antimicrobials, and acids (Frosch & Kligman, 1976). 79
  • R_NickelBackground_0308_hh_chapter0124567.docSkin irritancy of nickel chloride and nickel sulphate has also been reported in studies primarily concerned withskin sensitisation.Vandenberg & Epstein (1963) reported that irritancy was directly proportional to concentration and duration ofapplication. They concluded that a 10% nickel chloride solution causes too much irritation to have value as apredictive patch test, whilst a 5% solution ordinarily will not be a primary irritant. 5% nickel chloride causedirritation under occlusion.Kalimo & Lammintausta (1984) tested nickel chloride and nickel sulphate in patch tests with 24 and 48 hexposures. A 5% nickel chloride solution also caused irritation under occlusion, whilst a 2.5% solution could beused for patch testing. The standard patch test material for nickel sulphate (assumed to be 5%) was also irritantafter occlusion.Fullerton et al. (1989) tested various concentrations of nickel chloride hexahydrate in a hydrogel as a possiblealternative to the standard patch test material of 5% nickel sulphate pet. A 5% standard nickel sulphate patch, aswell as the 0.5% - 2% nickel chloride hydrogels caused some irritation.Storrs et al. (1989) recorded 8 cases of irritancy in 1123 subjects patch tested with 2.5% nickel sulphate inpetrolatum.Wahlberg (1990) reported that nickel chloride is more irritating than nickel sulphate when applied in equimolarconcentrations.Twenty-five healthy volunteers with no previous history of eczema underwent 5 patch tests with nickel sulphatein concentrations of 5, 10, and 20%, and 2 control areas. It was concluded that in non-nickel-sensitive subjectsaqueous solutions of nickel sulphate between 5 and 20 % did not evoke irritation on the skin (Seidenari et al.1996b).4.1.2.3.2.2 Respiratory irritationA number of case reports describe the relation between nickel sulphate and occupational asthma. Please seesection 4.1.2.4.2.No information on non-allergic respiratory irritation in relation to short-term exposure has been found.4.1.2.3.2.3 ConclusionThe available data for skin irritation produced by the soluble nickel salts indicates that they are skin irritants,although the data are not entirely consistent. Nickel sulphate causes only a slight degree of skin irritation in anAnnex V study, whilst irritation is seen in humans. Nickel chloride is also irritant in humans, and is moreirritating than nickel sulphate at equimolar concentrations. Nickel nitrate is a skin irritant in an Annex V study.The presence of nitric acid (either as an impurity or as an additive) can give rise to sufficiently extreme pH tojustify classification with C; R35. The insoluble nickel metal did not cause skin irritation in an Annex V study.The pH of nickel (hydroxy)carbonate does not lead to classification for this effect on the basis of extreme pH.The TC C&L has agreed to classify nickel sulphate, nickel chloride, nickel nitrate and the nickel carbonates asskin irritants: Xi; R38. These classifications are included in the 30th ATP. The TC C&L has also agreed toclassify nickel hydroxide with Xi; R38.The more limited data for eye irritation produced by the soluble nickel salts is not consistent. Nickel sulphatecauses only a slight degree of eye irritation in an Annex V study, whilst nickel nitrate is a severe eye irritant inan Annex V study as irritation persists at the end of the observation period. There is no data on the eye irritationcaused by insoluble nickel metal, but industry have expressed a concern for mechanical irritation from metalpowders. A similar concern (leading to a provisional classification as Xi; R36) has been expressed by oneproducer of nickel chloride.The TC C&L has agreed to classify nickel nitrate as a severe eye irritant: Xi; R41 on the basis of theexperimental data 11, whilst no classification is suggested for the other nickel compounds.In should be noted that for these local effects, the nickel ion alone may not be entirely responsible for the effects,as the counter-ion may itself show irritant properties.Short-term repeated inhalation of very soluble as well as insoluble nickel compounds is associated with lesions in theolfactory and lung epithelium. No data have been found regarding respiratory irritation following a single inhalationexposure. Respiratory irritation will not be taken forward as a separate endpoint for risk characterisation, but will bedealt with in relation to repeated dose inhalation toxicity.11 This classification is included in the 30th ATP. 80
  • R_NickelBackground_0308_hh_chapter0124567.doc4.1.2.4 Sensitisation4.1.2.4.1 Skin sensitisationNickel is well known as a skin sensitiser, and is one of the most frequent skin sensitisers in man. The Ni2+ ion isconsidered exclusively responsible for the immunological effects of nickel (Menné 1994).Most cases of primary nickel sensitisation are caused by skin contact with metallic items such as ear ornaments,ear stickers, jewellery, jeans buttons, and other nickel releasing items (European Environmental ContactDermatitis Group, 1990). Solutions of soluble nickel salts may also induce sensitisation e.g. nickel sulphate inthe nickel-plating industry.Nickel sensitisation is diagnosed by patch testing with 5% nickel sulphate in petrolatum in Europe and severalother countries, while some countries (including North America) use 2.5% nickel sulphate. The patch is placedunder occlusion in 48 hours to enhance skin penetration. A positive patch test shows that the patient is allergic tonickel ions. The patch test result does not indicate the source of nickel ions responsible for the primarysensitisation.There is an abundance of reports on human sensitisation with nickel. The following is based mainly on reviews.4.1.2.4.1.1 Animal studiesA number of studies on skin sensitisation in guinea pigs have been performed with nickel sulphate. Some ofthese studies are summarised in Table 4.1.2.4.1.A. Studies with nickel chloride are summarised in Table4.1.2.4.1.BTable 4.1.2.4.1.A: Skin sensitisation studies with nickel sulphate in animals Species Result Method Reference Guinea pig 11/22*, 4/7 Skin painting Lammintausta et al. (1985, 1986) Guinea pig 20/20, 7/20, 12/20 Optimization test Maurer et al. (1979) Guinea pig 13/14 Intradermal 1%, challenge 2% Bezian et al. (1965) Guinea pig 21/30, 27/30 Open adm. + SLS + potassium alun Zissu et al. (1987) injections Guinea pig Maximum response 40% GPMT Rohold et al. positive after 3% i.d. I.d. induction 0.01%-3% aqueous (1991) induction Topical induction 0.25%-10% pet Challenge 1% pet Guinea pig 1% lanolin: 57-93% pos. Open epicutaneous Nielsen et al. pretreatment SLS (1992) 3% lanolin: 60-100% pos. 0.3%-3% in lanolin or 0.3%-3% in 1% hydroxypropyl hydroxypropyl cellulose cellulose: 67-75% pos. i.d. injections of adjuvant* Number of positive animals/animals testedTable 4.1.2.4.1.B: Skin sensitisation studies with nickel chloride in animals Species Result Method Reference Guinea pig 1/10* GPMT Goodwin et al. Induction : Intradermal injection (1981) 0.25% Patch 2% Challenge: Patch 0.1% 81
  • R_NickelBackground_0308_hh_chapter0124567.doc Species Result Method Reference Guinea pig 0/10 SIAT (single injection adjuvant test) Goodwin et al. Induction: Intradermal injection (1981) 0.1% Challenge: Patch 0.15% Guinea pig 0/10 Modified Draize test Goodwin et al. Induction: Injection 0.375% (1981) Challenge: Injection 0.15% Application 10% Guinea pig 8/12 GPMT Hicks et al. (1979) Induction: Intradermal injection 1% Challenge: Patch 2.5% Guinea pig 0/10 Split adjuvant Induction Hicks et al. (1979) Injection 0.5% + 0.05% Challenge: Injection 2% Application 0.5% Guinea pig Intradermal 4/8 Method of Polak Hicks et al. (1979) Induction: 0.2% + FCA Application 2/8 intramuscularly Challenge: Intradermal injection Application + occlusion Guinea pig 0/8 Method of Gross Hicks et al. (1979) Induction: 0.2% + FCA subcutaneously Challenge: Intradermal injection 0.05%* Number of positive animals/animals testedNo animal data on sensitisation with nickel metal, nickel nitrate or nickel carbonate have been found.4.1.2.4.1.2 Human data4.1.2.4.1.2.1 Nickel allergyNickel allergy is a Type IV allergic reaction. Characteristic for this type of reaction is that it is cell mediated(mediated by T-lymphocytes) and delayed (the reaction appears 24-72 hours after exposure).Nickel allergy manifests itself as allergic contact dermatitis, which is an inflammatory reaction in the upper partof the skin (epidermis) with erythema, infiltrations, and vesicles. Dermatologists use the terms allergy andsensitisation synonymously, as well as eczema is used as a synonym for dermatitis. Menné (1992) describes thatinitially in 1889 nickel dermatitis was recognised as “Das Galvanizierekzem”. In 1925 patch testing provednickel allergy to be the cause of dermatitis in the electroplating industry. Occupational nickel dermatitis wascommon in the 1920’s and 1930’s while consumer nickel dermatitis first appeared in the early 1930’s. In 1992,five decades after the recognition of nickel dermatitis as a common disease in workers, it is still very common,now as a disease in the general population. Nickel dermatitis in consumers appears to have increased in thesefive decades (Menné, 1982, Peltonen, 1979), although the prevalence now seems to have stabilised (Menné1998).Nickel related sensitisation is normally diagnosed by patch testing with 5% nickel sulphate in petrolatum appliedto the back of the person tested under occlusion for 2 days. The reaction to the patch test is not immediate, andfor this reason the result is read after 2 days, at which time a positive effect is clearly visible.Individuals sensitised to nickel fall into three groups:• those with previous eczema present under nickel-releasing objects in direct and prolonged contact with the skin. They do not show signs of eczema, as they avoid contact with nickel objects.• those with current eczema, because they are currently exposed to nickel released from items in direct and prolonged contact with the skin• those suffering from chronic vesicular hand eczema 82
  • R_NickelBackground_0308_hh_chapter0124567.docIn Denmark, legislation limiting the use of nickel-releasing objects in close and prolonged contact with the skinwas introduced in 1991 (Danish EPA, 1991). As a result of this, exposure to nickel-releasing (>0.5 μgNi/cm2/week) objects in direct and prolonged contact with the skin has been prevented, and at the same time,patients with current eczema, because they are currently exposed to nickel released from items in direct andprolonged contact with the skin has nearly disappeared in Denmark (Menné 1998). The Danish legislation isbased on the use of the dimethylglyoxime test. This test is rather less sensitive than the draft EN 1811 described(Haudrechy et al. 1993).The nickel release rate of 0.5 μg/cm2/week which is specified in the nickel Directive (EC, 1994b) measured bythe EN 1811 reference method adopted in 1998 (CEN, 1998) is a cut-off value intended to both preventsensitisation in individuals that have not been previously sensitised to nickel and elicitation of symptoms inpreviously sensitised individuals. There may however be individuals that react to release levels lower than thiscut-off value (Andersen et al. 1993, Uter et al. 1995).4.1.2.4.1.2.2 Mechanism for the development of nickel allergy.The mechanism for development of nickel allergy has been reviewed by Menné (1996). Development of nickelallergy includes two steps, induction (also called sensitisation) and elicitation. Nickel allergy is induced by directand prolonged skin exposure to elemental nickel, which is corroded (release of ions) by contact with sweat (see4.1.1.1), or by skin exposure to other nickel compounds where Ni ions penetrate into the skin. In order to inducean allergic response, the nickel ion as a hapten must react with a protein in the skin to form a complete allergen,which is then taken up by a macrophage for antigen presentation to a T-lymphocyte. The Langerhans cells of theskin are believed to be responsible for transporting the allergen to the T-lymphocytes in the peripheral lymphnode, where antigen presentation takes place. Here, the nickel will be presented to naive T-lymphocytes, and asensitisation specific to nickel will take place, resulting in clones of specific sensitive memory- and effector-T-cells. This process lasts about 14 days. The next time the individual is exposed to nickel, the specific sensitisedT-lymphocytes will elicit an inflammatory response in the epidermis (elicitation) at the site of exposure andpossibly elsewhere.4.1.2.4.1.2.3 Immunological toleranceSystemic exposure to nickel orally or by inhalation in individuals without contact allergy to nickel does notresult in sensitisation but may result in immunological tolerance, meaning that the individual is unable todevelop contact allergy to nickel at subsequent exposures. Evidence suggesting that previous exposure mayprevent sensitisation was recently obtained in two epidemiological studies. The frequency of sensitisation wasremarkably low in a group of junior nurses who had oral contact with this allergen through orthodontic dentaltreatments (van der Burg et al., 1986). In a second investigation among dermatological patients, a reducedfrequency of sensitisation to nickel was observed in patients who have had oral contact with nickel releasingappliances (dental braces) at an early age, but only if this took place prior to ear piercing (van Hoogstraten et al.,1991). A study by Kerosuo et al., (1996) found that in individuals where orthodontic treatment preceded earpiercing, nickel sensitisation was prevented completely (0% prevalence). This mechanism is confirmed by thefact that earlier, in guinea pigs, the induction of immunological tolerance to nickel by oral administration beforeattempted sensitisation was demonstrated (Vreeburg et al., 1984). Further, in mouse models with other allergens,intravenously and orally induced tolerance have been demonstrated to depend on suppresser cell action (Gautam& Battisto, 1985, Knop et al., 1981, Asherson et al., 1985).4.1.2.4.1.2.4 Occurrence of nickel allergyIn order to quantify the problem, two methods can be used. Clinical patch test studies can be used which involvecollection of data from consecutively patch tested patients at dermatological centres. Secondly, epidemiologicalinvestigations of different populations, the general population included can also be used. The first method is arelative inexpensive method for monitoring the sensitisation pattern in a given population, whereas the lattermethod is necessary in order to measure the frequency of sensitised individuals in the general population, eventhough the technique is much more expensive.Table 4.1.2.4.1.C below is modified from Menné et al. (1989) and shows the results of clinical patch test studies:Table 4.1.2.4.1.C: Results of clinical patch test studies (modified from Menné et al. 1989)Study Country Number of patients tested Percentage positive to nickel Male Female Total Male Female TotalFregert et al. (1969) Europe 2039 2786 4825 1.8 10.2 6.7 83
  • R_NickelBackground_0308_hh_chapter0124567.docOleffe et al. (1972) Belgium 184 116 300 3.8 18.1 9.3NACDG (1973) U.S. 509 691 1200 5.6 15.0 11.0Husain (1977) Scotland 603 709 1312 5.0 26.0 16.0Moriearty et al. (1978) Brazil 271 265 536 2.6 11.7 7.1Sugai et al. (1979) Japan 291 447 738 4.8 4.3 4.5Hammershøj (1980) Denmark 1451 1774 3225 - - 6.4Olumide (1985) Nigeria 230 223 453 11.0 12.4 11.7Angelini et al. (1986) Italy 3587 3483 7070 4.6 20.0 12.0Schubert et al. (1987) Eastern 913 1487 2400 2.1 10.5 7.3 EuropeTable 4.1.2.4.1.D below shows the results of other more recent clinical patch test studies:Table 4.1.2.4.1.D: Results of clinical patch test studiesStudy Country Year Number of patients tested Percentage positive to nickel Male Female Total Male Female TotalLunder (1988) Yugoslavia 1972-76 1945 6.7 1977-81 2082 6.3 1982-86 2373 9.1Enders et al. (1989) Germany 1977-83 11962 2.6 13.7 9.2 1987 1845 4.5 23.9 16.7Christophersen et al. (1989) Denmark 1985-86 696 1470 2166 5.1 20.7 15.6Storrs et al. (1989) North 1984-85 1123 9.7 AmericaNethercott & Holness (1990) Canada 1981-87 335 294 629 5.1 16.7 10.5Shehade et al. (1991) UK 4719 18.5Nethercott et al. (1991) North 1985-89 2170 2876 5046 10.5 AmericaLim et al. (1992) Singapore 1986-90 2634 2923 5557 17.7McDonagh et al. (1992) UK 248 364 612 4.4 32.7 21.2Schnuch et al. (1997) Germany 36720 4.8 18.3 12.9Marks et al. (1998) North 1994-96 3108 14.3 AmericaDawn et al. (2000) Scotland 1982 307 493 800 7 22 16 1997 191 669 860 7 26 22Johansen et al. (2000) Denmark 1985-86 397 835 4.2 18.3 1997-98 423 844 4.9 20.0Kanerva et al. (2001) Finland 1693 14.6Some results of epidemiological investigations of different populations, the general population included, aregiven in Table 4.1.2.4.1.E, which shows the prevalence of sensitisation. By the prevalence is meant: theproportion of sensitised persons in the total population at risk, at a given point in time.Table 4.1.2.4.1.E: Prevalence of nickel allergy in different populations 84
  • R_NickelBackground_0308_hh_chapter0124567.docReference Study population Number of persons Prevalence % investigated M F Total M F TotalMenné (1978) Female non-dermatological - 213 213 - 9.4 inpatientsPrystowsky et al. Paid adult volunteers 460 698 1158 0.9 9.0(1979)Peltonen (1979) General population 478 502 980 0.8 8.0Kieffer (1979) Veterinary students 247 168 415 2.8 9.8Magnusson & Möller Orthopaedic patients 106 168 274 1.0 10.0(1979)Menné et al. (1982)1) General population - 1976 1976 - 14.5Boss & Menné (1982) Hairdressers – school - 53 53 - 20Menné & Holm (1983) Female twins - 1546 1546 - 9.6Larsson-Stymme & Schoolgirls - 960 960 - 9.0Windström (1985)Schmiel (1985) Surgical inpatients and hospital 244 259 503 1.6 7.7 staffvon Hums (1986) Schoolchildren 135 131 266 - 7.0van der Burg et al. Nursing (school) 29 188 217 - 13(1986) Hairdressers (school) 12 74 86 17.0 27.0Widström & Erikssohn Young men (military service) 216 - 216 1.4(1987)Dotterud & Falk (1994) School children 223 201 424 8.5 21.9 14.9Meijer et al. (1995) Young men (military service) 520 - 520 1.9Mangelsdorf et al. Aged population (age 68-87) 35 47 82 6(1996)Mattila et al. (2000) University students 96 188 284 3.1 38.8 26.8Nielsen et al. (2001) Adult population 1990 290 2.2 16.9 Adult population 1998 469 2.1 17.21): In the investigation by Menné et al. (1982) the nickel allergy was diagnosed by history only.The outcome of the studies presented above are rather uniform, with a prevalence among females in the mostrecent studies above 15% which is much higher than the prevalence among men. The different studies must becompared with caution because the investigated groups are more or less selected and the age structure differsamong the studies. School children are included in three of the studies and exhibit the same high prevalence rateof nickel sensitisation as adults, possibly indicating that the problem will become worse with time. A Danishpopulation study found 11.1% of the females and 2.2% of the males sensitised to nickel. Among the 16 to 35year old females, 19.6% gave a positive patch test to nickel. (Nielsen & Menné 1992). Whilst the overallprevalence of nickel allergy was increasing earlier (Menné et al. 1982, Peltonen 1979), it now seems to havestabilised, although at a high level (Menné 1998, Nielsen et al. 2001). In the age group 0-18 years the prevalenceof nickel sensitisation has decreased from 24.8% in 1985-86 to 9.2% in 1997-98 (Johansen et al. 2000). Otherstudies have also demonstrated decreased prevalence to nickel allergy in the young population (Veien et al.2001, Nielsen et al. 2001, Jensen et al. 2002).In the young age groups, ear piercing is the main cause of nickel sensitisation. The major causes of sensitisationvary, depending on fashion and other factors which influence exposure. In the 1950’s most patients weresensitised from suspenders, with the mean age for sensitisation being 30 to 35 years (Calnan 1956, Wilson1956). The mean age for sensitisation has gradually declined in the last decades, and today most females developtheir contact sensitivity to nickel as teenagers. Besides ear piercing, jewellery, jeans buttons, and other nickel 85
  • R_NickelBackground_0308_hh_chapter0124567.doccontaining items may induce ACD to nickel. Allergic contact dermatitis is lifelong, and the most importantpreventive measure to avoid relapses of dermatitis in already sensitised persons is to avoid exposure.It is commonly accepted by dermatologists that sensitisation requires more intense exposure than provocation orelicitation of nickel dermatitis in already sensitised persons. Among already sensitised persons the degree ofreactivity to nickel varies. Many have been shown to react to 5% nickel sulphate in petrolatum which is theconcentration used in diagnostic patch testing. A minority can react at concentrations as low as 0.001% (Uter etal. 1995). The threshold for reactivity is lower when the area is occluded compared to when it is not occluded,and further the threshold is lower on irritated skin compared to normal non-irritated skin in the absence of anyform of occlusion (Menné & Calvin 1993) as well as on closed exposure (Allenby & Basketter 1993).4.1.2.4.1.2.5 Hand eczemaEczema under earrings or other jewellery, spectacle frames, watches, buttons, zippers etc. is often obvious to theaffected person. Such exposures, when recognised, may be avoided rather easily. A much larger problem relatedto nickel allergy is however the increased risk of hand eczema, which in the general population appears with aprevalence of 10%. In populations sensitised to nickel, up to 40% have been shown to develop hand eczema,indicating that nickel allergy is one of the most prominent risk factors for hand eczema (Menné et al. 1982,Meding & Swanbeck 1990). A study by, Wilkinson & Wilkinson (1989), examined both the prevalence of nickelsensitivity in patients with hand eczema as well as the prevalence of hand eczema in nickel-sensitive patients. Inthe former instance, they found that nickel sensitivity in hand eczema patients appeared to be in the range of 12to 17 percent; in the latter instance, the incidence of current hand eczema in nickel-sensitised patients appearedto lie between 17 to 24 percent. Hand eczema related to nickel allergy may result in chronic suffering, sickleave, change of jobs, early retirement, and large costs for the society (Menné & Bachman 1979).It should be underlined that even though nickel allergy is a risk factor for hand eczema, it is not understood howthese two diseases are connected mechanistically. Epidemiological studies demonstrate that there is a high riskof hand eczema in populations sensitised to nickel. In individual cases, interpretation is more difficult.4.1.2.4.1.2.6 Experimental sensitisationKligman (1966) established a human maximisation test with the purpose to test whether a given substance wasable to induce skin sensitisation. Further, the test was designed to yield allergenicity ratings depending on thefrequency of sensitisation in a group of 25 test persons. The test was carried out for nickel sulphate, where theinduction procedure consisted of 5 sequences of 48 hours treatment with 10% nickel sulphate. The treatmentswere performed on the same place on one extremity (forearm or calf of the leg) under occlusion. Whether thesubjects became sensitised or not were tested with the challenge concentration of 2.5% nickel sulphate. Twelveout of 25 attempts were successful, data, which the author interprets as categorising, nickel sulphate as amoderate human sensitiser.4.1.2.4.1.2.7 The ability of nickel salts, nickel and nickel alloys to elicit nickel allergy4.1.2.4.1.2.7.1 Skin contactElicitation of skin reactions can be provoked by patch testing with nickel salts or nickel alloys releasingsufficient nickel. In patch tests material is applied under occlusion for 48 hours in order to enhance thepenetration. The concentration of free nickel ion is decisive for frequency and severity of reactions (see table4.1.2.4.1.F, G and H).Table 4.1.2.4.1.F: Total/threshold reactions (modified after Uter et al., 1995) 86
  • R_NickelBackground_0308_hh_chapter0124567.docµg Ni++/ Of all reactions a) No. Ncm2 Ni conc +-+++/thresh (tested) %(+) %(++) %(+++)264.0 5% 36.7 50.0 13.3 39 462105.6 2% 42.2 47.1 10.7 1752.8 1% 49.4 42.5 8.1 37 37226.4 0.5% 60.7 31.4 7.9 705.3 0.1% 68.3 26.0 5.7 652.64 0.05% 68.9 24.6 6.5 30 3290.53 100 ppm 83.8 16.2 - 190.264 50 ppm 100 - - 50.053 10 ppm 100 - - 4 920.026 5 ppm - - - **)0 0 ppm - - - 462a) %s are calculated from all reactions to a given concentration ‘all reactions’ are equal to or more than thecumulative frequency of threshold reactions, as patients without a determinable threshold) are included here.Patients without a determinable threshold are those with a negative reaction (few) or a questionable reaction tothe next higher concentration.**) Uter (2003).In the study by Uter et al. (1995) 462 nickel allergic patients were patch tested with serial dilutions of nickelsulphate. 92 patients were tested with the low nickel doses. Patient reactions could be negative, questionable orpositive. The positive reactions are scored as +, ++ or +++. This is a diagnostic test where the one + reaction isconsidered positive. 5 patients reacted to 0.264µg/cm2 and 4 to 0.053µg/cm2 with a one + reaction. The 4positive patients correspond to 4.3% with a 95% confidence interval of [1.2 % - 10.8 %]. The 5 patientscorrespond to 5.4 % with a 95% confidence interval of [1.8 % - 12.2 %]. No patients reacted to 0.026µg/cm2, thelowest dose used. This gives 0.0% positive responses with a 95% confidence interval of [0.0 % - 3.9 %]. None ofthe 462 patients developed a positive reaction to petrolatum only (Uter, 2003).On the basis of the above figures from the Uter et al. study it is not possible to set a concentration limit were nonickel allergic patients will react after close and prolonged contact with Ni-ions.Andersen et al. (1993) tested 72 nickel-sensitive patients with a 10-step nickel sulphate dilution series (using theTRUE test) and two placebo patches. The position of the patches was rotated and the readings were performedblind. The results were analysed using a logistic dose-response model. A control group of 25 individuals withoutapparent skin disease, or history of metal sensitivity, was tested with the same panel to exclude irritation.Nine of the patients had positive readings to one of the two placebo patches. The authors explain these positiveplacebo reactions as possibly related to defective recordings of readings. The 25 control persons did not have anyplacebo reactions, which supports the ‘misreading story’. The data are used to calculate a dose-response curvewithout taking into account the positive placebo reactions. This opens the study for criticism, but it still can beused to illustrate dose-response relationships.Table 4.1.2.4.1.G: Inverse estimation of nickel doses (µg Ni2+/cm2) causing patch-test reactions atgiven frequencies of doubtful (+?) and positive (+, ++, +++) reactions among nickel-sensitivepatients (modified after Andersen et al. 1993). Patch-test reaction (1)Response frequency ≥ +? ≥+Positive %25 0.09 (0.07-0.13) 0.27 (0.18-0.40)33 0.18 (0.11-0.25) 0.51 (0.36-0.74)50 0.60 (0.42-0.83) 1.65 (1.18-2.32) 87
  • R_NickelBackground_0308_hh_chapter0124567.doc67 1.94 (1.34-2.90) 5.22 (3.64-7.98)75 3.72 (2.52-5.93) 9.88 (6.58-16.15)1) The 0.95 confidence limits are given in parenthesisTable 4.1.2.4.1.G shows the relationship between nickel patch test dose and estimated number of patch testpositive patients. It illustrates the difficulties of setting NOAEL’s and LOAEL’s based on patch test studies innickel sensitive patients. It also illustrates the shape of the dose-response curve. When the frequency of positiveresponders increase by a factor 2 (from 33% to 67%) the corresponding nickel dose is increased by a factor 10(0.18-1.94 or 0.51-5.22 µg Ni2+/cm2).Both in the Uter and the Andersen studies there are patients reacting to very low nickel doses representing thevery most sensitive persons in the population. The biological relevance of the results is supported by thereactivity in nickel sensitive patients to alloys with a very low nickel release rate (see also Table 4.1.2.4.1.I) . Onthe basis of the available data it is not possible to set a scientifically based threshold for elicitation (NOEL) innickel sensitised individuals. Data gathered after the Danish legislation limiting nickel release from consumeritems came into force suggest that the majority of the population are protected by a release rate of 0.5µgNi/cm2/week for items in close and prolonged contact with the skin.It is the experience that the Danish legislation has also prevented current eczema in nickel sensitive patients(Menné 1998). This suggests that this rate of release is sufficient to prevent elicitation of symptoms in asignificant proportion of nickel-sensitised individuals. It is possible that not all subjects with nickel allergy in allcircumstances of exposure will be protected by the 0.5 µg/cm2 limit as studies with nickel sulphate has shownthat the lowest concentration resulting in a positive patch test in nickel sensitive subjects corresponds to 0.05µgNi/cm2 (Uter et al., 1995). Exposure to nickel sulphate in a patch test lasting 48 hours can be considered as adirect and prolonged contact. Whilst it is not possible to equate this figure of 0.05µg Ni/cm2 with the release rateof 0.5 µg Ni/cm2/week, the result would suggest that a lower release rate would be needed to ensure thatsymptoms are prevented in all nickel sensitive patients in all circumstances. This is supported by the resultsshown in Table 4.1.2.4.1.F, which show a decrease in elicitation rates with decreasing nickel release rates.Alloys with a nickel release of ≤ 0.5 µg Ni/cm2/week elicit a positive skin reaction in < 30% of subjects withprior sensitisation (LGC, 2003).Table 4.1.2.4.1.H: Patch test results in patients already sensitised to nickel using nickel sulphate,chloride or nitrate as patch test material. Number of patients Percent patch test tested positive patientsNickel sulphate 253µg/cm2 (1) 151 100 2Nickel sulphate 94µg/cm 101 60 2Nickel chloride 94µg/cm 101 61 2Nickel nitrate 94µg/cm 101 58 2Nickel sulphate 24µg/cm 50 34Nickel chloride 24µg/cm2 50 46 2Nickel nitrate 24µg/cm 50 46 2+1) The concentration of nickel is given as Ni .Menné et al (1987) patch tested 173 nickel sensitive patients with discs of 15 different nickel alloys. The alloyswere also tested for release of nickel in synthetic sweat pH 6.5. The results can be seen in Table 4.1.2.4.1.I.Table 4.1.2.4.1.I: Reactivity to different alloys and nickel release in synthetic sweatAlloy Nickel release Nickel release % reactivity in nickel- (µg/cm2/week) 1) (µg/cm2/week) 2) sensitised patients with 5% confidence limitsSafe alloysStainless steel 0.04 0.01 3 (0-11) 88
  • R_NickelBackground_0308_hh_chapter0124567.docWhite gold 0.3 0.02 11 (4-25)Nickel tin 0.5 0.1 23 (14-33)Sensitising alloysNickel silver 40 20 81 (69-89)Nickel chemical (2) 20 32 56 (41-69)Nickel electrochemical 10 40 76 (62-87)Nickel chemical (1) 70 45 79 (67-87)Nickel iron 80 65 79 (65-90)1): Data for nickel release after 1 weeks exposure estimated from Fig 1 and 2 in Menné et al. (1987).2): Data for nickel release after 3 weeks exposureNickel chemical (1) (2). Nickel alloy with 92% Ni, 8% P. (Menné et al. 1987 in Menné, 1994).Repeated immersion in nickel solutions has also been studied. Immersion of the hands in 1 ppm Ni (0.0001%)2x10 min/day for one week where penetration was enhanced with the skin irritant sodium dodecyl sulphate didnot result in elicitation of allergic reaction in nickel sensitive subjects (Allenby & Basketter 1994). In a study of35 patients with hand eczema immersion of a finger in 10 ppm Ni as nickel chloride 10 min/day for one weekfollowed by immersion in 100 ppm Ni the next week resulted in statistically significant increase in eczemasymptoms (Nielsen et al. 1999).4.1.2.4.1.2.7.2 Oral challengeTable 4.1.2.4.1.J: Challenge studies in nickel-sensitive patients with an oral dose of nickel given assulphate (updated after Menné et al., 1994).Author Type of study Allergen dose Duration of Response (mg elemental nickel) exposure frequencyChristensen & Møller (1975) Double-blind 5.6 Single exposure 9/12Kaaber et al (1978) Double-blind 2.5 Single exposure 17/28Kaaber et al (1979) Double-blind 0.6 Single exposure 1/11 1.2 Single exposure 1/11 2.5 Single exposure 9/11Veien et al (1979) Open 4.0 Single exposure 4/7Jordan & King (1979) Double-blind 0.5 2 repeated days 1/10Cronin et al (1980) Open 0.6 Single exposure 1/5 1.25 Single exposure 4/5 2.5 Single exposure 5/5Burrows et al (1981) Double-blind 2.0 2 repeated days 9/22 4.0 2 repeated days 8/22Goitre et al (1981) Open 4.4 Single exposure 2/2Single-blind 2.8 Repeated dose 34/43 5.6Sertoli et al (1985) Open 2.2 Single exposure 13/20Gawkrodger et al (1986) Double-blind 0.4 2 repeated days 5/10 2.5 2 repeated days 5/10 5.6 Single exposure 6/6Veien et al. (1987) Double-blind 2.5 Single exposure 55/131 89
  • R_NickelBackground_0308_hh_chapter0124567.docSantucci et al. (1988) Open 2.2 Single exposure 18/25Nielsen et al. (1999) Single-blind 0.72 (12 µg/kg) Single exposure 9/20Hindsén et al. (2001) 1 Single exposure 2/10 3 Single exposure 9/9In order to investigate whether oral administration of nickel sulphate were able to worsen hand eczemaChristensen & Möller (1975) gave 5.6 mg nickel as nickel sulphate orally to nickel allergic patients with handeczema in a double-blind investigation and observed worsening of hand eczema. Flare up of contact dermatitisafter oral challenge has been studied in a variety of studies thereafter with varying results (see Table 4.1.2.4.1.J).The variability may be due to variation in study design, patient groups and challenge conditions. Two studieshave showed flare of dermatitis after a single oral dose of 0.6 mg nickel (Kaaber et al., 1979, Cronin et al., 1980)and one study after two weekly doses of 0.5 mg nickel (Jordan & King, 1979).In the study by Nielsen et al. (1999) 12 µg Ni /kg (equivalent to 720 µg/ 60 kg person) was given on an emptystomach to 20 nickel sensitised women and 20 age-matched controls, both groups having vesicular hand eczema.The same dermatologist, who was blinded with regard to nickel sensitisation, examined the patients. Nine of the20 nickel allergic patients had a worsening of their hand eczema after the nickel administration, and three alsodeveloped maculopapular exanthema. No exacerbation was seen in the control group.Foodstuffs such as drinks that are often consumed in large quantities are of particular interest, as they maycontribute a fairly large single dose of nickel, even though the concentration does not seem excessive. Moreover,nickel dissolved in water is more bioavailable than nickel in foods (Solomons et al. 1982, Sunderman et al.,1989). The bioavailability is highly influenced by ingestion of food. Nielsen et al. (1999) showed that whennickel was ingested in water, after an overnight fast, 30 min or 1 h prior to a meal of scrambled eggs, peak nickelconcentration in serum was 13-fold higher than the one seen when nickel containing water and scrambled eggswere ingested simultaneously. It is likely that nickel intake from water will be accumulated as the median nickelhalf-times found in the Nielsen study was 19.9-26.7 h.A considerable number of nickel-sensitive patients have dermatitis at sites other than those in direct contact withnickel-releasing items. A fraction of these patients will benefit from a nickel-restricted diet (Veien & Menné1990, Veien et al. 1993). Nickel is an ubiquitous element. In Denmark the mean daily dietary intake of nickel is167µg/day with a 95% percentile of 278µg/day. The main food sources of nickel are cereal products, inparticular bran, müesli and similar products, pulses, legumes and oilseeds, cocoa beans, and nuts (Larsen et al.2002). It is possible to reduce the diet to around 100µg nickel/day (Danish Veterinary and Food Administration1998).4.1.2.4.1.2.7.3 HyposensitisationSystemic exposure may also result in hyposensitisation. In one attempt, fifty-one patients presenting adermatological allergy (erythema, urticaria, angioedema, contact dermatitis) to nickel were treated over 3 yearswith oral doses of 0.1 ng nickel sulphate per day, following a low-nickel diet. Diagnostic tests comprised patchand oral provocation tests. Among the 30 cases that went through the whole follow-up, symptomatology totallydisappeared in 29 cases, and a partial alleviation was achieved in 1 case after 1 year of treatment. Oralprovocation tests with these 30 patients showed an overall increase of tolerance. Patch tests showed no variationin 20 cases, a diminution in 5, and were negative in 5. Although the study was not conducted double blind, theresults of this attempt to cure nickel allergy are statistically significant (Panzani et al. 1995). In another attempt,thirty-nine patients with nickel allergy as diagnosed by results of clinical history and intradermal testing withnickel sulphate were treated by sublingual hyposensitisation. Intradermal testing was accurate and titrationshowed the degree of sensitivity. The immunologic principle of oral tolerance was used in treatment. Eighty-fivepercent of the thirty-nine patients showed subjective improvement in their dermatitis and all showed objectiveevidence of decreased intradermal sensitivity. None of the patients conditions worsened (Morris 1998).4.1.2.4.1.2.8 Occupational nickel allergyIn Denmark occupational nickel dermatitis is the second most common dermatological disease giving rise tocompensation for occupational skin diseases. Irritant contact dermatitis is first, nickel second, and rubberdermatitis third. In most of the compensated occupational cases in Denmark, primary nickel sensitisation hasbeen caused by consumer items such as buttons, ear piercing etc. (European Environmental Contact DermatitisGroup, 1990). Lidén (1994) studied occupational nickel allergy among men. The most common occupationsamong the nickel-allergic male patients were plating, building, mechanical and electrical work andtransportation. The majority had hand eczema, and some had dermatitis on the face. There are unexpected 90
  • R_NickelBackground_0308_hh_chapter0124567.docexposures e.g. a black nickel-plated metal piece in an optical instrument and aluminium sheets that had been coldsealed with nickel. Lidén states that occupational nickel exposure is often overlooked both by the patient and thedermatologist and that more knowledge of the possible sensitisation by occupational exposure is needed.Evidence suggests that humid environments are more likely to favour the release of the nickel ion from metallicnickel and nickel alloys, whereas dry, clean operations with moderate or even intense contact to nickel objectswill seldom, alone, provoke dermatitis (Fisher, 1989). It should be borne in mind that in some occupations forwhich hand eczema has been reported in higher proportion than the general populace (e.g. cleaning, hairdressingand hospital wet work), the wet work is, in and of itself, irritating, and decreases the barrier function of the skin.Often it is the combination of irritant dermatitis and compromised skin barrier that produces the allergic reaction(Fisher, 1989).Table 4.1.2.4.1.K: Occupations with potential significant exposure to nickel and nickel compounds(Fischer, 1989)Auto mechanic (nickel alloys) Ink maker (nickel containing chemicals)Butcher (nickel alloys) Jeweller (nickel alloys)Carpenter (nickel alloys) Mechanic (nickel alloys)Cashier (nickel alloys) Metal worker and welder (nickel and nickel alloys)Ceramic Worker (nickel containing chemicals) Office worker (nickel alloys)Cleaner and hospital worker (nickel alloys) Painter (nickel containing chemicals)Dentist (nickel alloys) Plumber (nickel alloys)Dryer (nickel alloys) Printer (nickel containing chemicals)Electrician (nickel alloys) Radio and television electronic (nickel alloys)Electroplater (nickel containing chemicals) Repairmen (nickel alloys)Enamel worker (nickel containing chemicals) Rubber worker (nickel catalyst)Food manufacturer and restaurant personnel Shop assistant (nickel alloys)(nickel alloys)Hairdresser and barber (nickel alloys) Textile worker (nickel alloys)Household worker (nickel alloys) Veterinarian (nickel alloys)4.1.2.4.1.3 Conclusion on skin sensitisationNickel metal and nickel sulphate are skin sensitiser in humans and meets the criteria for classification with R43.The Ni2+ ion is considered exclusively responsible for the immunological effects of nickel. A wide range ofnickel compounds release sufficient nickel to cause skin sensitisation, and that even nickel compounds with verylow water solubility can release sufficient nickel to produce the effect. However, it has been shown that certainnickel-containing oxides with specific crystal structures (spinel and rutiles) lead to a very limited release ofnickel ions, and these compounds are not considered as sensitisers (see the report on the classification of a groupof nickel compounds (Hart, 2007). Hence, a wide range of nickel compounds should be classified with R43.4.1.2.4.1.3.1 Thresholds for sensitisationFor nickel metal there is evidence that the Danish legislation limiting the use of nickel in objects in direct andprolonged contact with the skin to a release less than 0.5 µg Ni/cm2/week as measured by the dimethylglyoximeassay has resulted in decreased prevalence of sensitisation in the younger population (Johansen et al, 2000,Nielsen et al, 2001, Veien et al 2001, Jensen et al. 2002.). This suggests that this rate of release contributes toprevention of new cases of nickel allergy.There are no data from skin exposure to nickel sulphate, chloride, carbonate or nitrate to allow an estimate of thedose of these salts that may cause skin sensitisation. The empirical elicitation threshold of 0.3 µg Ni/cm2 issuggested to be used as the best estimate of a threshold for sensitisation. As sensitisation is assumed to requirehigher doses than elicitation this estimate for sensitisation is more conservative than the estimate for elicitation. 91
  • R_NickelBackground_0308_hh_chapter0124567.doc4.1.2.4.1.3.2 Thresholds for elicitation4.1.2.4.1.3.2.1 SkinIt is the experience that the Danish legislation has also prevented current eczema in nickel sensitive patients(Menné 1998). This suggests that this rate of release is sufficient to prevent elicitation of symptoms in asignificant proportion of nickel-sensitised individuals. It is possible that not all subjects with nickel allergy in allcircumstances of exposure will be protected by the 0.5 µg/cm2 limit as studies with nickel sulphate has shownthat the lowest concentration resulting in a positive patch test in nickel sensitive subjects corresponds to 0.05µgNi/cm2 (Uter et al., 1995). Exposure to nickel sulphate in a patch test lasting 48 hours can be considered as adirect and prolonged contact. Whilst it is not possible to equate this figure of 0.05µg Ni/cm2 with the release rateof 0.5 µg Ni/cm2/week, the result would suggest that a lower release rate would be needed to ensure thatsymptoms are prevented in all nickel sensitive patients in all circumstances. This is supported by the resultsshown in Table 4.1.2.4.1.F, which show a decrease in elicitation rates with decreasing nickel release rates.Alloys with a nickel release of ≤ 0.5 µg Ni/cm2/week elicit a positive skin reaction in < 30% of subjects withprior sensitisation (LGC, 2003).Empirically a patch test concentration of 2.5 or 5% nickel sulphate (132 or 264µg Ni/cm2) induces a positivereaction in nickel allergic individuals. As can be seen from Table 4.1.2.4.1.H, patch test results with nickelsulphate, nickel chloride and nickel nitrate are comparable. Thus it is the concentration of nickel ion thatdetermines the outcome of the patch test. On the basis of the available data it is not possible to set a scientificallybased threshold for elicitation (NOEL) in nickel sensitised individuals. For use in the risk characterisation ofoccupational exposure an empirical threshold based on the data from Uter et al. (1995) may be estimated. In theUter study a significant number of patients react to a 48 hours patch with 0.5 µg Ni/cm2 (19/329). In the nextdose group 5/92 patients react to 0.26 µg Ni/cm2. These patients only react with a one plus reaction and must beconsidered to belong to the very most sensitive part of the population. As it is unlikely that an occupationalexposure will last for 48 hours and that workers in the nickel industry have extremely sensitive nickel allergies.an empirical threshold (NOEL) of 0.3 µg Ni/cm2 is suggested.4.1.2.4.1.3.2.2 OralIt is not possible to establish a NOAEL for oral challenge in patients with nickel dermatitis. The LOAELestablished after provocation of patients with empty stomach is 12µg/kg body weight (Nielsen et al. 1999). Thisfigure is not far from the dose found in the study by Hindsén et al (2001) where a total dose of 1 mg (17µg/kgbody weight) resulted in a flare up of dermatitis in an earlier patch test site in 2/10 nickel sensitive patients. Itshould be noted that the dose of 12µg/kg body weight is the acute LOAEL in fasting patients on a 48h diet withreduced nickel content. A LOAEL after repeated exposure may be lower and a LOAEL in non-fasting patients isprobably higher because of reduced absorption of nickel ions when mixed in food.4.1.2.4.2 Respiratory sensitisationThe Technical Guidance Document underscores that respiratory hypersensitivity is a term that is used to describeasthma and other related respiratory conditions, irrespective of the mechanism by which they are caused.Five single cases of work related asthma due to exposure to nickel sulphate in electro- or metal plating have beenreported (Block & Yeung, 1982, Malo et al., 1982, Malo et al., 1985, McConnell et al. 1973, Novey et al.,1983). In all five cases, the diagnosis was based on clinical picture and specific bronchial inhalation test withnickel sulphate. Nickel sulphate is already classified as a respiratory sensitiser, R42.There are a number of reports of occupational asthma associated with exposure to metallic nickel (Block &Yeung, 1982, Estlander et al. 1993, Shirakawa et al. 1990). Whilst there is no proper epidemiologic study thathas specifically looked at incidence of asthma, there are many studies that have looked at mortality from non-malignant respiratory diseases (including asthma) among nickel workers with metallic nickel exposures. Thesestudies support the contention that the number of reported cases of nickel induced asthma is insufficient towarrant a classification compared to the large population exposed. The TC C&L does not consider that thesereports provide adequate evidence for classification for this effect.For nickel chloride, nickel nitrate and nickel carbonate no data regarding respiratory sensitisation in humanshave been located. As the soluble salt nickel sulphate induces respiratory sensitisation, and given the potentialfor respiratory sensitisation shown by the metal, it must be assumed that nickel carbonate, nickel nitrate andnickel chloride have also the potential to induce respiratory sensitisation.4.1.2.4.2.1 Conclusion on respiratory sensitisationNickel sulphate is a respiratory sensitiser in humans and meets the criteria for R42. 92
  • R_NickelBackground_0308_hh_chapter0124567.docThe Ni2+ ion is considered exclusively responsible for the immunological effects of nickel. As the soluble saltnickel sulphate induces respiratory sensitisation it must be assumed that nickel chloride, nickel nitrate and nickelcarbonate have also the potential to induce respiratory sensitisation and have been classified with R42 in the 30thATP. Metallic nickel has also been reported to cause respiratory sensitisation, but the effect is not sufficient tojustify classification with R42.It is not possible to set a threshold for sensitisation or elicitation.4.1.2.4.3 ConclusionNickel metal is a skin sensitiser in humans and should be classified as R43. Metallic nickel has also beenreported to cause respiratory sensitisation, but the effect is not sufficient to justify classification with R42.It is considered necessary to include a proposal for setting a specific release limit for the classification of alloyscontaining nickel for skin sensitisation. It is recognised that the limits for expressing this threshold is related notto the concentration of nickel in the metal or alloy but rather to the rate of nickel release expressed as µgNi/cm2/week from the material. A specific concentration limit based on a new Note relating to the labelling ofpreparations in the Foreword to Annex I has been included in the 30th ATP. The draft note reads: “Alloyscontaining nickel are classified for skin sensitisation when the release rate of 0.5 μg Ni/cm2/week as measured bythe European Standard reference test method, EN 1811 is exceeded.”The suggested level to prevent sensitisation after direct and prolonged contact with nickel releasing alloys in asubstantial proportion of a non-sensitised population is 0.5µg Ni/cm2/week. The suggested level to preventelicitation in nickel allergic patients is 0.5µg Ni/cm2/week. Complete protection for the most sensitive sensitisedpersons may only be achieved at lower levels. Alloys with a nickel release of ≤ 0.5 µg Ni/cm2/week elicit apositive skin reaction in < 30% of subjects with prior sensitisation (LGC, 2003). It is not possible to setthresholds for sensitisation and elicitation after intermittent and semi-direct exposures.Nickel sulphate is already classified as a skin and respiratory sensitiser (R42/43). The TC C&L has agreed thatnickel chloride, nickel nitrate and the nickel carbonates should also be classified as skin and respiratorysensitisers (R42/43). A specific concentration limit of 0.01% for R43 has also been agreed for nickel sulphate,nickel chloride and nickel nitrate 12.It is not possible to set a scientifically based threshold for skin elicitation and sensitisation caused by nickel saltsafter direct and prolonged exposure. For use in the risk characterisation of occupational exposure an empiricalthreshold of 0.3 µg Ni/cm2 is suggested.It is not possible to set a threshold for respiratory sensitisation or elicitation.An acute LOAEL for oral challenge of 0.012 mg Ni/kg is used in the risk assessment.4.1.2.5 Repeated dose toxicity4.1.2.5.1 Animal studiesData from the risk assessments of nickel metal, nickel carbonate, nickel sulphate, nickel chloride and nickelnitrate are shown in Table 4.1.2.5.A. In addition, the table contains data for two other nickel compounds, nickeloxide and subsulphide, where relevant studies of good quality have been performed. A more detailed descriptionis given in sections 4.1.2.5.2 to 4.1.2.5.4.Table 4.1.2.5.A: Summary of repeated dose toxicity studies for nickel compounds. Inhalation Oral Dermal Compound-specific conclusionNickel metal 28-day rat study (WIL No studies found No studies found Inhalation LOAEC 1 Research Laboratories, mg Ni/ m3 (lung(insoluble) 2002). inflammation, WIL Research Laboratories, 13-week rat study 2003). (WIL Research Laboratories,12 These classifications and specific concentration limits are included in the 30th ATP. 93
  • R_NickelBackground_0308_hh_chapter0124567.doc 2003).Five studies (Hueper 1958, Hueper & Payne 1962) no oral, no dermal conclusionNickel No studies found calves 8 weeks dietary No studies found Available data(hydroxy)carbonate (O’Dell et al., 1970) insufficient for conclusion(slightly soluble) monkeys 4 months dietary (Phatak & Patwardham, 1950, quoted from UK HSE, 1987)Nickel chloride No studies on systemic rats 25 weeks drinking No studies found Inhalation LOAEC 0.2 effects found. water (Kurokawa et mg Ni/m3 (effects in(very soluble) al., 1985) lung macrophages, A number of studies of Johansson et al., 1980, effects on lung 1986, 1987 and 1988; macrophages in rabbits Berghem et al., 1987; (Johansson et al., 1980, rats 91 days gavage Lundborg & Camner, 1986, 1987 and 1988; (American Biogenics 1981-82,1984; Camner Berghem et al., 1987; Corporation, 1988) et al., 1984) Lundborg & Camner, 1981-82,1984; Camner oral LOAEL of 5 mg et al., 1984). rats 77 days dietary Ni/kg bw/day (Nation et al., 1985) (mortality, American Biogenics Corporation, 1988) rats 28 days drinking water (Weischer et al., 1980) no dermal conclusionNickel sulphate 2-year studies, 13 rats 90-day oral gavage rats 15 or 30 days No NOAEC identified weeks studies (NTP, study (SLI, draft not (Mathur et al.,(very soluble) 1996a); Benson et al. , dated, submitted 2002) 1977) LOAEC of 0.056 mg 1989,1992, 1995; Ni/m3 (inflammation Kosova, 1979 – quoted and fibrosis), (NTP, from UK HSE 1987) 1996a). rats drinking water ad libitum for 13 weeks (Obone et al. 1999) oral LOAEL of 6.7 mg rats 2-year feeding Ni/kg bw/day study (Ambrose et al. (decreased survival rate 1976) (females), reduced body weight gain (both sexes)) and NOAEL of 2.2 mg Ni/kg bw/day rats gavage 7 months (however, associated (Itskova et al. 1969 – with a slight decrease in quoted from UK HSE body weight gain (both 1987) sexes) and survival in females (CRL 2005) available dermal data dogs dietary 2 years insufficient for (Ambrose et al. 1976) conclusion rats drinking water for 6 months (Vyskocil et al. 1994) mice drinking water 180 days (Dieter et al. 1988) mice dietary 4 weeks (Schiffer et al. 1991, quoted from TERA, 1999) 94
  • R_NickelBackground_0308_hh_chapter0124567.doc rats (gavage) for 2 years (CRL 2005)Nickel nitrate No studies found No studies found No studies found Available data insufficient for(very soluble) conclusionOther nickel compoundsNickel subsulphide 6 studies: 16 days, Inhalation LOAEC of 13 weeks, 2 years in 0.15 mg Ni/m3 (chronic(insoluble) rats and mice (NTP lung inflammation and 1996c) fibrosis in 2-year rat study, NTP, 1996c) 78 weeks (Ottolenghi et al. 1975, quoted from UK HSE, 1987)Nickel oxide 6 studies: 16 days, Inhalation LOAEC of 13 weeks, 2 years in 0.5 mg Ni/m3 (chronic(insoluble) rats and mice (NTP lung inflammation in 2- 1996b), a number of year rat study, NTP, 1996b) studies referred in UK HSE (1987)4.1.2.5.1.1 InhalationData for inhalation toxicity have been found for nickel sulphate hexahydrate, nickel subsulphide, nickel oxide,nickel chloride, and metallic nickel.The principal effects following inhalation of nickel compounds are found in the respiratory tract. Atrophy ofolfactory epithelium and chronic active lung inflammation with fibrosis are typical findings. Accumulation ofmacrophages has in some studies been found to occur at lower concentrations than other lesions, and it has beendebated whether the reaction should be interpreted as an adaptive repair response, or as an adverse event in asequence leading ultimately to fibrosis. A definitive conclusion regarding the biological significance ofmacrophage accumulation is not possible according to the TERA review (1999).4.1.2.5.1.1.1 NTP studies of nickel sulphate hexahydrate, nickel subsulphide and nickel oxide.The United States National Toxicology Program has carried out a series of inhalation studies in rats and micewith three nickel compounds (NTP 1996a, 1996b, 1996c). The three nickel compounds were the soluble nickelsulphate hexahydrate, and the insoluble compounds nickel subsulphide and nickel oxide. The present sectiongives a review of the studies and focuses on a comparison of the results. The data on nickel sulphate hexahydratehave already been described in the Risk Assessment Report for this substance, but are included here for the sakeof comparison.Nickel sulphate hexahydrate: Male and female F344/N rats and B6C3F1 mice were exposed to nickel sulphatehexahydrate (mass mean diameter 1.8-3.1 micrometer ± 1.6-2.9; greater than 98% pure) by inhalation for 16days, 13 weeks, or 2 years.Nickel oxide: Male and female F344/N rats and B6C3F1 mice were exposed to nickel oxide (high temperature,green nickel oxide; mass median diameter 2.2 ± 2.6 micrometer; at least 99% pure) by inhalation for 16 days, 13weeks, or 2 years.Nickel subsulphide. Male and female F334/N rats and B6C3F1 mice were exposed to nickel subsulphide (at least97% pure; the mean value for the mass median aerodynamic diameter at each exposure concentration rangedfrom 2.0 to 2.2 micrometer) by inhalation 6 hours per day, 5 days per week, for 16 days, 13 weeks, or 2 years.4.1.2.5.1.1.1.1 16-day rat studiesAll three studies used inhalation exposure for 6 h/day, 5 d/week for a total of 12 exposure days during a 16-dayperiod (core studies). The group size was 5 males and 5 females. Additional groups of five male and five femalerats were exposed for tissue burden studies, these studies are not described in the present section. 95
  • R_NickelBackground_0308_hh_chapter0124567.docA comparison of the results of the three compounds studied shows similar types of effects, including atrophy ofolfactory epithelium, lung tissue inflammation, and increased relative and absolute lung weights, however to avarying degree of incidence and severity depending on the compound and dose. The following order of toxicity,based on mg nickel/m3, is indicated: Nickel sulphate hexahydrate>nickel subsulphide>nickel oxide.Table 4.1.2.5.B: 16-day rat studiesNickel sulphate hexahydrate Nickel oxide Nickel subsulphide0, 3.5, 7, 15, 30, or 60 mg nickel 0, 1.2, 2.5, 5, 10, or 30 mg nickel 0, 0.6, 1.2, 2.5, 5, or 10 mg nickelsulphate hexahydrate/m3 (equivalent oxide/m3 (equivalent to 0, 0.9, 2.0, 3.9, subsulphide/m3 (equivalent to 0, 0.44, 0.88, 3to 0, 0.7, 1.4, 3.1, 6.1, or 12.2 mg 7.9, or 23.6 mg nickel/m ) 1.83, 3.65, and 7.33 mg nickel/m3)nickel/m3).In the core study, two 60 mg/m3 All core study rats survived until the One male exposed to 10 mg nickelmales, one 30 mg/m3 female, and all end of the study, final mean body subsulphide/m3 in the core study died on day60 mg/m3 females died before the end weights of exposed male and female 14; all other rats survived until the end of theof the study. Final mean body weights rats were similar to those of the study. Final mean body weights and meanof all exposed groups of males and controls, and there were no clinical body weight gains of males exposed to 5 orfemales were significantly lower than findings related to nickel oxide 10 mg nickel subsulphide/m3 and femalesthose of the controls, as were mean exposure. Absolute and relative lung exposed to 2.5, 5, or 10 mg/m3 werebody weight gains of male rats. weights of male and female rats significantly lower than those of theClinical findings included increased exposed to 10 or 30 mg/m3 were controls. Clinical findings of toxicity on dayrates of respiration and reduced significantly greater than those of the 5 of the study included laboured respirationactivity levels in rats in all exposure controls. Pigment particles in alveolar in 10 mg/m3 males and 5 and 10 mg/m3groups, except those exposed to 3.5 macrophages or within the alveolar females and dehydration in 5 and 10 mg/m3mg/m3. Absolute lung weights of 60 spaces were observed in the lungs of females. Absolute and relative lung weightsmg/m3 males and of all exposed exposed groups of males and females. of 2.5, 5, and 10 mg/m3 males and allgroups of females were significantly Chronic-active inflammation and exposed groups of females weregreater than those of the controls, as accumulation of macrophages in significantly greater than those of thewere the relative lung weights of all alveolar spaces of the lungs and controls, as was the absolute lung weight ofexposed groups of males and females. hyperplasia in the respiratory tract 1.2 mg/m3 males. Inflammation of the lungInflammation (including degeneration lymph nodes were most severe in 10 and atrophy of the nasal olfactory epitheliumand necrosis of the bronchiolar and 30 mg/m3 males and females. occurred in all exposed groups.epithelium) occurred in the lungs of Hyperplasia of bronchial lymph nodesall exposed groups of males and occurred in 30 mg/m3 rats. Atrophy of The concentrations of nickel in the lungs offemales. Atrophy of the olfactory the olfactory epithelium was observed exposed groups of rats increased withepithelium occurred in the nasal in one male and one female exposed to exposure concentration (males, 7 to 67 µgpassages of all exposed groups of 30 mg/m3. nickel/g lung; females, 9 to 77 µg nickel/gmales (except 60 mg/m3) and in 15, lung).30, and 60 mg/m3 females. Lymphoid The concentrations of nickel oxide inhyperplasia in the bronchial or the lungs of exposed groups of ratsmediastinal lymph nodes was were greater than those in the lungs ofobserved in 30 mg/m3 males and in 60 control groups (males, 42 to 267 µgmg/m3 males and females. nickel/g lung; females, 54 to 340 µg nickel/g lung).The concentration of nickel in thelungs of all exposed groups of malesand females was greater than incontrol animals.4.1.2.5.1.1.1.2 16-day mouse studiesAll three studies used inhalation exposure for 6 h/day, 5 d/week for a total of 12 exposure days during a 16-dayperiod (core studies). The exposure concentrations were identical to the corresponding rat study, allowing adirect comparison between the two species. The group size was 5 males and 5 females. Additional groups of 5male and 5 female mice were exposed for tissue burden studies; these studies are not described in the presentsection.Similar types of toxic effects, and a similar order of toxicity to that of the rat, based on mg nickel/m3, areindicated: Nickel sulphate hexahydrate>nickel subsulphide>nickel oxide. The mouse was more sensitive than therat to the toxic effects of nickel sulphate.Table 4.1.2.5.C: 16-day mouse studiesNickel sulphate hexahydrate Nickel oxide Nickel subsulphide0, 3.5, 7, 15, 30, or 60 mg nickel 0, 1.2, 2.5, 5, 10, or 30 mg nickel 0, 0.6, 1.2, 2.5, 5, or 10 mg nickelsulphate hexahydrate/m3 (equivalent oxide/m3 (equivalent to 0, 0.9, 2.0, subsulphide/m3 (equivalent to 0, 0.44, 0.88,to 0, 0.7, 1.4, 3.1, 6.1, or 12.2 mg 3.9, 7.9, or 23.6 mg nickel/m3) 1.83, 3.65, and 7.33 mg nickel/m3)nickel/m3).All core study mice exposed to 7 No exposure-related deaths occurred All male and female mice exposed to 10 mgmg/m3 or greater died before the end among core study mice, and final mean nickel subsulphide/m3 in the core study diedof the study; all control and 3.5 body weights of exposed male and before the end of the study; the death of onemg/m3 mice survived to the end of the female mice were similar to those of female was accidental. One control male,study. Final mean body weights and the controls. There were no chemical- one control female, and one 1.2 mg/m3 male 96
  • R_NickelBackground_0308_hh_chapter0124567.docweight gains of 7, 15, 30, and 60 related clinical findings. Pigment also died before the end of the study. Finalmg/m3 males and females were particles were present in the lungs of mean body weights and mean body weightsignificantly less than those of the mice exposed to 2.5 mg/m3 or greater. gains of 5 mg/m3 males were significantlycontrols, and clinical findings in these Accumulation of macrophages in lower than those of the controls. Clinicalgroups included emaciation, lethargy, alveolar spaces was observed in the findings at day 5 included labouredand rapid respiration rates. Absolute lungs of 10 and 30 mg/m3 males and respiration in 10 mg/m3 males and females.and relative lung weights of male and females. The absolute lung weight of 5 mg/m3 males,female mice exposed to 7 mg/m3 or the absolute and relative lung weights of 10greater were significantly greater than mg/m3 males and 5 mg/m3 females, and thethose of the controls. Only tissues relative lung weight of 10 mg/m3 femalesfrom mice exposed to 0, 3.5, or 7 The concentrations of nickel oxide in were significantly greater than those of themg/m3 were examined the lungs of exposed groups of mice controls. Inflammation of the lung occurredhistopathologically. Inflammation were significantly greater than those in in 2.5, 5, and 10 mg/m3 male and femaleoccurred in the lungs of 3.5 and 7 the lungs of control animals (males, 32 mice, fibrosis of the lung occurred in 5mg/m3 males and females; necrosis of to 84 µg nickel/g lung; females, 31 to mg/m3 males and females, and lymphoidthe alveolar and bronchiolar 71 µg nickel/g lung). hyperplasia of the bronchial lymph nodesepithelium was a component of the and atrophy of the nasal olfactory epitheliuminflammation in 7 mg/m3 males and occurred in 1.2, 2.5, 5, and 10 mg/m3 malesfemales. In addition, atrophy of the and females.olfactory epithelium of the nasalpassages was observed in 3.5 mg/m3 Nickel concentrations in the lung of exposedmales and females. male and female mice were greater than those of the controls (males, 10 to 20 µgNickel concentrations in the lungs of nickel/g lung; females, 8 to 20 µg nickel/gmice exposed to 3.5 mg/m3 were lung).greater than those in the controls.4.1.2.5.1.1.1.3 13-week rat studiesGroup size 10 males and 10 females. Additional groups of rats were exposed for tissue burden studies; thesestudies are not described in the present section.The comparison of the three compounds shows effects similar to those identified in the 16-day studies, includingatrophy of olfactory epithelium, lung tissue inflammation, and increased relative and absolute lung weights.Again, nickel oxide appears less toxic than the other two compounds based on mg nickel/m3.Table 4.1.2.5.D: 13-week rat studiesNickel sulphate hexahydrate Nickel oxide Nickel subsulphide0, 0.12, 0.25, 0.5, 1, or 2 mg nickel 0, 0.6, 1.2, 2.5, 5, or 10 mg nickel 0, 0.15, 0.3, 0.6, 1.2, or 2.5 mg nickelsulphate hexahydrate (equivalent to 0, oxide/m3 (equivalent to 0, 0.4, 0.9, 2.0, subsulphide/m3 (equivalent to 0, 0.11, 0.22, 30.03, 0.06, 0.11, 0.22, or 0.44 mg 3.9, or 7.9 mg nickel/m ) 0.44, 0.88, and 1.83 mg nickel/m3)nickel/m3)In the core study, one 2 mg/m3 male No exposure-related deaths occurred All core study rats survived until the end ofrat died before the end of the study; among core study rats, final mean the study. Final mean body weights andall other males and all females body weights of exposed male and mean body weight gains of 2.5 mg/m3 malessurvived until the end of the study. female rats were similar to those of the were significantly lower than those of theFinal mean body weights and body controls, and no clinical findings in controls; final mean body weights of allweight gains of all exposed groups any group were related to nickel oxide other exposure groups were similar to thosewere similar to those of the controls. exposure. Lymphocyte, neutrophile, of the controls. Chemical-related clinicalThere were no significant clinical monocyte, and erythrocyte counts; findings included laboured respiration in 2.5findings noted during the study. haematocrit values; and haemoglobin mg/m3 males and females during weeks 2Exposure-related increases in and mean cell haemoglobin through 7. In general, neutrophile andneutrophile and lymphocyte numbers concentrations in exposed rats were erythrocyte counts, haematocrit values, andoccurred and were most pronounced minimally to mildly greater than those haemoglobin concentrations were minimallyin female rats. With the exception of of the controls; these differences were increased in exposed rats. Absolute and0.12 mg/m3 rats, absolute and relative most pronounced in females. Mean relative lung weights of all exposed groupslung weights of all exposed groups cell volumes in exposed rats were were significantly greater than those of thewere generally significantly greater generally less than those in the controls.than those of the controls. Exposure- controls. Absolute and relative lungrelated increases in the incidence and weights of exposed groups of males Increases in the number of alveolarseverity of inflammatory lesions and females were generally macrophages, interstitial infiltrates, or(alveolar macrophages, chronic significantly greater than those of incidences of chronic inflammation of theinflammation, and interstitial controls. lung occurred in all groups exposed to nickelinfiltration) occurred in the lungs of subsulphide concentrations of 0.3 mg/m3 orall exposed groups of males and Chemical-related non-neoplastic greater; the severity of these lesionsfemales. Lymphoid hyperplasia of the lesions were observed in the lungs of generally increased with increasing exposurebronchial and/or mediastinal lymph male and female rats exposed to concentration. Increases in the number of 3nodes occurred in males exposed to concentrations of 2.5 mg/m or higher, alveolar macrophages were observed in 0.150.5 mg/m3 or greater. Atrophy of the and the severity of these lesions mg/m3 males and females. Lymphoidolfactory epithelium occurred in generally increased with exposure hyperplasia of the bronchial and mediastinalmales and females exposed to 0.5, 1, concentration. Accumulation of lymph nodes was observed in rats exposed toand 2 mg/m3 and in 0.25 mg/m3 alveolar macrophages, many of which 0.3 mg/m3 or greater. Most 0.6, 1.2, and 2.5females. The concentration of nickel contained black, granular pigment, was mg/m3 males and females had atrophy of thein the lungs of 0.5 and 2 mg/m3 rats generally observed in all exposed nasal olfactory epithelium, and the severitywas greater than that in the lungs of groups of males and females, and generally increased with increasing exposurecontrol animals at 4, 9, and 13 weeks increased incidences of inflammation concentration. 97
  • R_NickelBackground_0308_hh_chapter0124567.docfor males and at 13 weeks for occurred in males and females exposed Nickel concentrations in the lung increasedfemales. to 2.5 mg/m3 or higher. In addition, with exposure concentration and were lymphoid hyperplasia and pigment greater than those in the controls in rats occurred in the bronchial and exposed for 13 weeks (males, 5 to 18 mg mediastinal lymph nodes of 2.5, 5, and nickel/g lung; females, 5 to 17 mg/g lung). 10 mg/m3 males and females. The concentration of nickel oxide in the lungs of 0.6, 2.5, and 10 mg/m3 males was greater than in the lungs of controls at 4, 9, and 13 weeks, and nickel continued to accumulate in the lung at the end of the 13-week exposures (4 weeks, 33 to 263 µg nickel/g lung; 9 weeks, 53 to 400 µg nickel/g lung; 13 weeks, 80 to 524 µg nickel/g lung).In a recent 13-week inhalation toxicity study, groups of Wistar rats were exposed (whole body exposure) tometallic nickel powder 6h/d, 5 d/w for 13 weeks at exposure levels of 0, 1, 4, and 8 mg/m3 (WIL ResearchLaboratories, 2003). The histological and/or toxicological most prominent and significant findings in the lungswere described as: black pigment (nickel dust), alveolar proteinosis and granulomatous inflammation in allgroups of nickel exposure; mucoid exudate, fibrosis and mononuclear infiltrate in the 4 and 8 mg/m3 groups;alveolar/bronchiolar hyperplasia at the highest dose levels in both sexes and at 4 mg/m3 in males. The lowestexposure level, 1 mg/ m3, was a LOAEC for changes in lung weight and relative lung weight, alveolarproteinosis and granulomatous inflammation, accumulation of nickel particles in the lung and increased nickelblood levels.4.1.2.5.1.1.1.4 13-week mouse studiesThe exposure concentrations were identical to the corresponding rat study, allowing a direct comparison betweenthe two species. Effects were similar to those identified in the 16-day studies, including atrophy of olfactoryepithelium, lung tissue inflammation, and increased relative and absolute lung weights.Table 4.1.2.5.E: 13-week mouse studiesNickel sulphate hexahydrate Nickel oxide Nickel subsulphide0, 0.12, 0.25, 0.5, 1, or 2 mg nickel 0, 0.6, 1.2, 2.5, 5, or 10 mg nickel 0, 0.15, 0.3, 0.6, 1.2, or 2.5 mg nickelsulphate hexahydrate/m3 (equivalent oxide/m3 (equivalent to 0, 0.4, 0.9, 2.0, subsulphide/m3 (equivalent to 0, 0.11, 0.22, 3to 0, 0.03, 0.06, 0.11, 0.22, or 0.44 3.9, or 7.9 mg nickel/m ) 0.44, 0.88, and 1.83 mg nickel/m3)mg nickel/m3)In the core study, four control males, No exposure-related deaths occurred Final mean body weights of all exposurethree control females, and one 0.12 among core study animals, final mean groups were similar to those of the controls.mg/m3 male died before the end of the body weights of exposed male and No chemical-related clinical findings werestudy; the deaths were not considered female mice were similar to those of observed. Lymphocyte counts in 1.2 and 2.5to be chemical related, and all other the controls, and no clinical findings in mg/m3 males were minimally greater thanmice survived to the end of the study. any group were related to nickel oxide that of the controls. HaemoglobinThe final mean body weights and exposure. Haematocrit values and concentrations and erythrocyte counts in 0.3,body weight gains of all exposed erythrocyte counts in 5 and 10 mg/m3 0.6, 1.2, and 2.5 mg/m3 females weregroups were similar to those of the females were minimally greater than minimally greater than those of the controls.controls. There were no chemical- those of the controls, as was the Absolute and relative lung weights of 1.2related clinical findings. Haematology haemoglobin concentration in 5 mg/m3 and 2.5 mg/m3 males and females werechanges similar to those reported in females. Absolute and relative lung significantly greater than those of thefemale rats occurred in female mice, weights of 10 mg/m3 males and controls. An increase in alveolarbut the mice were minimally affected. females were significantly greater than macrophages was present in mice from theThe absolute and relative lung those of controls, and absolute and 0.3 mg/m3 and higher exposure groups.weights of 1 mg/m3 males and 2 relative liver weights of 10 mg/m3 Chronic inflammation and fibrosis weremg/m3 males and females were males were significantly less than observed in the lung of 1.2 and 2.5 mg/m3significantly greater than those of the those of controls. males and females. Interstitial infiltrates ofcontrols. Increased numbers of lymphocytes were observed in mice exposedalveolar macrophages occurred in all Accumulation of alveolar to 0.6, 1.2, or 2.5 mg/m3. Lymphoidmales and females exposed to 0.5 macrophages, many of which hyperplasia of the bronchial lymph nodesmg/m3 or greater. Chronic active contained pigment particles, occurred was observed in groups exposed to 1.2 or 2.5inflammation and fibrosis occurred in in all groups of mice exposed to nickel mg/m3.1 and 2 mg/m3 males and females. oxide. Inflammation (chronic activeLymphoid hyperplasia of the perivascular infiltrates or Atrophy of the nasal olfactory epitheliumbronchial lymph node and atrophy of granulomatous) occurred in 2.5, 5, and occurred in 0.6, 1.2, and 2.5 mg/m3 malesthe olfactory epithelium in the nasal 10 mg/m3 males and females. In and females, and incidences and severitypassages were observed in 2 mg/m3 addition, lymphoid hyperplasia and generally increased with increasing exposuremales and females. pigment occurred in the bronchial concentration. lymph nodes of males and femalesNickel concentration in the lung of 2 exposed to 2.5 mg/m3 or higher. At 13 weeks, nickel concentrations in themg/m3 females was significantly lungs of exposed mice were greater than The concentration of nickel in the lung those of the controls (males, 3 to 17 µg 98
  • R_NickelBackground_0308_hh_chapter0124567.docgreater than in control animals. was greater than that of controls in 0.6, nickel/g lung; females, 6 to 23 µg nickel/g 2.5, and 10 mg/m3 males at 13 weeks lung) and these concentrations increased (42 to 736 µg nickel/g lung). with increasing exposure concentration.4.1.2.5.1.1.1.5 2-year rat studiesGroups of 63-65 male and 63-64 female F344/N rats were exposed by inhalation for 6h/day, 5d/week, for 104weeks. Effects included lung tissue inflammation, and increased relative and absolute lung weights. The solublesulphate and insoluble subsulphide both caused atrophy of the nasal epithelium.Table 4.1.2.5.F: 2-year rat studiesNickel sulphate hexahydrate Nickel oxide Nickel subsulphide 30, 0.12, 0.25, or 0.5 mg/m 0, 0.62, 1.25, or 2.5 mg nickel 0, 0.15, or 1 mg nickel subsulphide/m3(equivalent to 0, 0.03, 0.06, or 0.11 oxide/m3 (equivalent to 0, 0.5, 1.0, or (equivalent to 0, 0.11, or 0.73 mg nickel/m3)mg nickel/m3) 2.0 mg nickel/m3)The survival rates of all exposed Survival of exposed male and female Survival of exposed males and female ratsgroups of males and females were rats was similar to that of the controls. was similar to that of the controls. Meansimilar to those of the controls. Mean Mean body weights of 1.25 mg/m3 body weights of males and females exposedbody weights of 0.5 mg/m3 female females and 2.5 mg/m3 males and to 0.15 mg/m3 were similar to those of therats were slightly lower (6% to 9%) females were slightly lower than those controls. Mean body weights of rats exposedthan those of the controls throughout of the controls during the second year to 1 mg/m3 were lower than those of thethe second year of the study; final of the study. No chemical-related controls throughout the second year of themean body weights of all exposed clinical findings were observed in male study. Chemical-related clinical findingsgroups of males and 0.12 and 0.25 or female rats during the 2-year study. included rapid and shallow breathingmg/m3 females were similar to those No chemical-related differences in following exposure periods. Haematocritof the controls. There were no clinical haematology parameters were values and haemoglobin concentrations in 1findings or haematology differences observed in male or female rats at the mg/m3 males and females and thethat were considered to be related to 15-month interim evaluation. erythrocyte count in 1 mg/m3 males werenickel sulphate hexahydrate mildly greater than those in the controls.administration. Absolute and relative lung weights of 1.25 and 2.5 mg/m3 males and females In general, the absolute and relative lung were significantly greater than those of weights of exposed males and females were the controls at 7 and 15 months. significantly greater than those of theIncreased incidences of inflammatory Chronic inflammation of the lung was controls at 7 and 15 months. Non-neoplasticlung lesions were generally observed observed in most exposed rats at 7 and lung lesions generally observed in exposedin all exposed groups of male and 15 months and at 2 years; the males and females included fibrosis; chronicfemale rats at the end of the study. incidences in exposed males and active inflammation; focal alveolar epithelialThe incidences of chronic active females at 2 years were significantly hyperplasia, macrophage hyperplasia, andinflammation, macrophage greater than those in the controls, and proteinosis; bronchial lymphoid hyperplasia;hyperplasia, alveolar proteinosis, and the severity of the inflammation and interstitial inflammation.fibrosis were markedly increased in increased in exposed groups. Themale and female rats exposed to 0.25 incidences of pigmentation in the At 2 years, the incidences of chronic active 3or 0.5 mg/m . Increased incidences of alveolus of exposed groups of males inflammation of the nose in 1 mg/m3 femaleslymphoid hyperplasia in the bronchial and females were significantly greater and of olfactory epithelial atrophy in 1lymph nodes occurred in 0.5 mg/m3 than those of the controls at 7 and 15 mg/m3 males and females were significantlymale and female rats at the end of the months and at 2 years. greater than those of the controls.2-year study. The incidences ofatrophy of the olfactory epithelium in Pigmentation in the bronchial lymph The incidences of lymphoid hyperplasia of0.5 mg/m3 males and females were nodes similar to that in the lungs was the bronchial lymph node in exposed malessignificantly greater than those in observed in all exposure groups with at 7 and 15 months and in exposed malescontrols at the end of the study. the exception of 0.62 mg/m3 males and and females at 2 years were significantly females at 7 months. Lymphoid greater than those of the controls. IncidencesLung nickel burdens in exposed male hyperplasia was observed in the of macrophage hyperplasia in the bronchialand female rats were greater than bronchial lymph nodes of 1.25 and 2.5 lymph node of exposed males at 15 monthsthose in the controls at the 7- and 15- mg/m3 males and females at 7 and 15 and exposed males and females at 2 yearsmonth interim evaluations, and lung months, and the incidence at 2 years were greater than those of the controls.nickel burdens values increased with generally increased with exposureincreasing exposure concentration. concentration. Nickel concentrations in the lungs of exposed rats were greater than those of the Nickel concentrations in the lung of controls at 7 months (males, 6 to 9 µg exposed rats were greater than those in nickel/g lung; females, 6 to 9 µg nickel/g the controls at 7 and 15 months (7 lung) and 15 months (males, 4 to 3 µg months, 173 to 713 µg nickel/g lung; nickel/g lung; females, 4 to 7 µg nickel/g 15 months, 262 to 1116 µg nickel/g lung). lung), and nickel concentrations increased with increasing exposure concentration and with time.4.1.2.5.1.1.1.6 2-year mouse studiesGroups of B6C3F1 mice were exposed by inhalation for 6h/day, 5d/week, for 104 weeks. For nickel sulphate andsubsulphide, the group size was 80, and for nickel oxide, the group size was 74-79. Effects included lung tissueinflammation, and increased relative and absolute lung weights.Table 4.1.2.5.G: 2-year mouse studies 99
  • R_NickelBackground_0308_hh_chapter0124567.docNickel sulphate hexahydrate Nickel oxide Nickel subsulphide 3 30, 0.25, 0.5, or 1 mg/m (equivalent to 0, 1.25, 2.5, or 5 mg nickel oxide/m 0, 0.6, or 1.2 mg nickel subsulphide/m30, 0.06, 0.11, or 0.22 mg nickel/m3). (equivalent to 0, 1.0, 2.0 or 4.0 mg (equivalent to 0, 0.44, or 0.88 mg nickel/m3) nickel/m3)The survival rates of all exposed Survival of exposed male and female Survival of exposed male and female micegroups of males and females were mice was similar to that of the was similar to that of the controls. Meansimilar to those of the controls. The controls. Mean body weights of 5 body weights of 0.6 and 1.2 mg/m3 malesmean body weights of 1 mg/m3 males mg/m3 females were slightly lower and females were less than those of theand of all exposed groups of females than those of the controls during the controls throughout the second year of thewere lower than those of the controls second year of the study. No chemical- study. Chemical-related clinical findings induring the second year of the study. related clinical findings were observed male and female mice included labouredThere were no clinical findings or in male or female mice during the 2- respiration following exposure periods. Thehaematology differences considered year study. No chemical-related haematocrit value and the segmentedto be related to chemical exposure. differences in haematology parameters neutrophile, monocyte, lymphocyte, andInflammatory lesions of the lung were observed in male or female mice total leukocyte counts in 1.2 mg/m3 femalesgenerally occurred in all exposed at the 15-month interim evaluation. were greater than those in the controls.groups of male and female mice at theend of the 2-year study. These lesions Generally, incidences of chronic Absolute and relative lung weights ofincluded macrophage hyperplasia, inflammation increased with exposure exposed males and females were generallychronic active inflammation, concentration in males and females at significantly greater than those of thebronchialization (alveolar epithelial 7 and 15 months. Bronchialization of controls at 7 and 15 months. In general, thehyperplasia), alveolar proteinosis, and minimal severity in exposed animals incidences of chronic active inflammation;infiltrating cells in the interstitium. and proteinosis were first observed at bronchialization (alveolar epithelialIncidences of macrophage hyperplasia 15 months. At 2 years, the incidences hyperplasia), macrophage hyperplasia andand/or lymphoid hyperplasia occurred of chronic inflammation, alveolar proteinosis; interstitial infiltration; andin the bronchial lymph nodes of most epithelial hyperplasia, and proteinosis fibrosis in exposed groups of males andof the 1 mg/m3 males and females and in exposed groups of males and females were greater than those of thein some 0.5 mg/m3 females at the end females were significantly greater than controls at 7 and 15 months and at 2 years.of the 2-year study. Atrophy of the those of the controls. The severity ofolfactory epithelium was observed in chronic inflammation increased with The incidences of atrophy of the nasal0.5 and 1 mg/m3 males and in all exposure concentration in females, and olfactory epithelium and inflammation of theexposed groups of females at the end proteinosis was most severe in 5 nose in exposed mice were also generallyof the 2-year study. mg/m3 males and females. Pigment greater than those of the controls. At 2 years, occurred in the lungs of nearly all the incidences of degeneration of olfactoryAt the 7- and 15-month interim exposed mice at 7 and 15 months and epithelium in exposed females wereevaluations, lung nickel burden at 2 years, and the severity increased significantly less than that of the controls.parameters measured in control and with exposure concentration.exposed groups were below the limit The incidences of lymphoid hyperplasia ofof detection. Absolute lung weights of Lymphoid hyperplasia occurred in two the bronchial lymph node in 1.2 mg/m30.5 and 1 mg/m3 lung burden study animals after 7 months; at 15 months, males at 15 months, in 0.6 and 1.2 mg/m3females were significantly greater lymphoid hyperplasia occurred in females at 15 months, and in 0.6 and 1.2than those of the controls at 15 males exposed to 2.5 and 5 mg/m3 and mg/m3 males and females at 2 years weremonths. in all exposed groups of females. At 2 significantly greater than those of the years, lymphoid hyperplasia occurred controls. The incidences of macrophage in some control animals, but this lesion hyperplasia in 1.2 mg/m3 males at 7 and 15 was still observed more often in months, in 0.6 and 1.2 mg/m3 females at 15 exposed males and females and the months, and in 0.6 and 1.2 mg/m3 males and incidence increased with exposure females at 2 years were significantly greater concentration. Pigmentation was than those of the controls. observed in the bronchial lymph nodes of exposed males and females at 7 and Nickel concentrations in the lungs of 15 months and in nearly all exposed exposed mice were greater than those of the animals at 2 years. controls at 7 months (males, 10 to 11 µg nickel/g lung; females, 10 to 14 µg nickel/g Nickel concentrations in the lungs of lung) and 15 months (males, 12 to 20 µg exposed mice were greater than those nickel/g lung; females, 15 to 26 µg nickel/g in the controls at 7 and 15 months (7 lung). months, 162 to 1034 µg nickel/g lung; 15 months, 331 to 2258 µg nickel/g lung), and nickel concentrations increased with increasing exposure concentration and with time.4.1.2.5.1.1.2 Other inhalation studiesA 78-week inhalation study of nickel subsulphide has been conducted in rats using groups of approximately 100animals of each sex. The concentration of nickel subsulphide was 0.71 mg Ni/m3. The exposure schedule was 6h/day, 5 d/week. Mortality was significantly higher, and body weight significantly lower in test animals.Inflammatory and hyperplastic responses due to inhalation of nickel subsulphide were seen in the lungs oftreated animals. There was also a higher incidence of adrenal medullary hyperplasia in treated animals.(Ottolenghi et al. 1975, quoted from UK HSE, 1987)A number of studies have examined local effects of nickel chloride inhalation in the lung. The effect ofinhalation for up to 8 months of low nickel chloride concentrations (0.2-0.6 mg Ni/m3) on lung macrophageshave been studied in rabbits (Johansson et al., 1980, 1986, 1987 and 1988; Berghem et al., 1987; Lundborg & 100
  • R_NickelBackground_0308_hh_chapter0124567.docCamner, 1981-82,1984; Camner et al., 1984). The effects included nodular accumulation of macrophages, whichappeared inactive, and decreased lysozyme content.Dunnick et al. (1989) investigated the relative toxicity of nickel oxide (NiO), nickel sulphate hexahydrate(NiSO4.6H2O), and nickel subsulphide (Ni3S2) in F344/N rats and B6C3F1 mice after inhalation exposure for 6hr/day, 5 days/week, for 13 weeks. Exposure concentrations used (as mg Ni/m3) were 0.4-7.9 for NiO, 0.02-0.4for NiSO4.6H2O, and 0.11-1.8 for Ni3S2. No exposure-related effects on mortality and only minor effects onbody weight gain were seen in rats or mice. The most sensitive parameter for nickel toxicity was histopathologicchange in the lungs of exposed animals were chronic active inflammation, fibrosis, and alveolar macrophagehyperplasia were associated with nickel exposure. There was an exposure-related increase in lung weight in ratsand mice. Equilibrium levels of nickel in the lung were reached by 13 weeks of nickel sulphate and nickelsubsulphide exposure, whereas lung levels of nickel continued to increase throughout exposure to nickel oxide.Additional exposure-related histopathological lesions in treated animals included atrophy of the olfactoryepithelium after nickel sulphate and nickel subsulphide exposure. No nasal lesions were seen after nickel oxideexposure. Lymphoid hyperplasia of the bronchial lymph nodes developed in animals exposed to all three nickelcompounds. The order of toxicity corresponded to the water solubility of the nickel compounds, with nickelsulphate being most toxic, followed by nickel subsulphide and nickel oxide (Dunnick et al. 1989).Dunnick et al. (1988) studied the relative toxicity of nickel oxide (NiO), nickel sulphate hexahydrate.(NiSO4.6H2O), and nickel subsulphide (Ni3S2) was studied in F344/N rats and B6C3F1 mice after exposure byinhalation for 6 h/day, 5 days/week for 12 exposure days. Exposure concentrations used (as mg Ni/m3) were 0.9-23.6 for NiO; 0.8-13.3 for NiSO4.6H2O, and 0.4-7.3 for Ni3S2. For each compound there were 5 exposure groupsplus a control group. NiSO4.6H2O was the most toxic compound with exposure related mortality seen atexposure concentrations of 13.3 mg/m3 in rats and 1.6 mg/m3 and above in mice. For Ni3S2, mortality was seenin mice (but not in rats) at the highest exposure concentration (7.3 mg/m3). No mortality was seen after NiOexposure. Lesions of the lung and nasal cavity were seen in both rats and mice after exposure to NiSO4.6H2Oand Ni3S2 at the 4 highest exposure concentrations. Lesions of the lung were seen primarily at the highestexposure concentrations after NiO exposure. The amount of nickel in the lungs at the end of exposure varied inrelation to the water solubility of the compounds. Based on these 2-week studies, the toxicity ranking wasNiSO4.6H2O > Ni3S2 > NiO.Haley et al. (1990) studied the immunotoxicity of three nickel compounds following 13-week inhalationexposure in the mouse. Groups of B6C3F1 mice were exposed to aerosols of nickel subsulphide (Ni3S2), nickeloxide (NiO), or nickel sulphate hexahydrate (NiSO4.6H2O) 6 hr/day, 5 days per week for 65 days to determinethe immunotoxicity of these compounds. Exposure concentrations were 0.11, 0.45, and 1.8 mg Ni/m3 for Ni3S2,0.47, 2.0, and 7.9 mg Ni/m3 for NiO; and 0.027, 0.11, and 0.45 mg Ni/m3 for NiSO4. Thymic weights weredecreased only in mice exposed to 1.8 mg Ni/m3 Ni3S2. Increased numbers of lung-associated lymph nodes(LALN), but not spleen nucleated cells, were seen with all compounds. Nucleated cells in lavage samples wereincreased in mice exposed to the highest concentrations of NiSO4 and NiO and to 0.45 and 1.8 mg Ni/m3 Ni3S2.Increased antibody-forming cells (AFC) were seen in LALN of mice exposed to 2.0 and 7.9 mg Ni/m3 NiO and1.8 mg Ni/m3 Ni3S2. Decreased AFC/10(6) spleen cells were observed in mice exposed to NiO, and decreasedAFC/spleen were seen for mice exposed to 1.8 mg Ni/m3 Ni3S2. Only mice exposed to 1.8 mg Ni/m3 Ni3S2 had adecrease in mixed lymphocyte response. All concentrations of NiO resulted in decreases in alveolar macrophagephagocytic activity, as did 0.45 and 1.8 mg Ni/m3 Ni3S2. None of the nickel compounds affected the phagocyticactivity of peritoneal macrophages. Only 1.8 mg Ni/m3 Ni3S2 caused a decrease in spleen natural killer cellactivity. The results indicate that inhalation exposure of mice to nickel can result in varying effects on theimmune system, depending on dose and physicochemical form of the nickel compound. These nickel-inducedchanges may contribute to significant immunodysfunction.4.1.2.5.1.1.3 Supporting mechanistic data for lung effectsIn order to compare the in vitro cytotoxicity of different nickel compounds Benson et al. (1992) studied thecytotoxicity of different nickel compounds, among these nickel sulphate, nickel subsulphide and nickel oxide toalveolar macrophages (AMs) and rat lung epithelial cells (LECs) in-vitro. Species differences in AM sensitivitywere studied as MAs from F344/N-rats, B6C3F1-mice, beagle-dogs, as well as from monkeys were used in thestudy. Generally ranking of species sensitivity of AM to nickel compounds was dog > rat > mouse, with someevidence suggesting that the sensitivity of monkey AMs lies between those of the dog and rat. Ranking of thenickel compounds of interest, in decreasing order of cytotoxicity to AMs was Ni3S2 > NiSO4 > NiO. Similarlythe ranking of the same nickel compounds with regard to cytotoxicity to LECs was Ni3S2 > NiSO4 > NiO. Inanother publication Benson et al. (1986) compared the cytotoxicity of the four nickel compounds nickelsubsulphide (Ni3S2), nickel sulphate (NiSO4), nickel chloride (NiCl2), and nickel oxide (NiO). These compoundswere tested in vitro for their relative toxicity to beagle dog and F344/Crl rat alveolar macrophages. Dog alveolar 101
  • R_NickelBackground_0308_hh_chapter0124567.docmacrophages were at least 10 times more sensitive to the effects of each of the four nickel compounds than wererat alveolar macrophages. Toxicity ranking of the four nickel compounds to macrophages from both species wasNi3S2 greater than NiCl2 which were approximately the same as NiSO4 , which again was greater than NiO.Benson et al. (1989) evaluated the biochemical responses of lungs of rats and mice exposed for 13 weeks tooccupationally relevant aerosol concentrations of nickel subsulphide, nickel sulphate or nickel oxide.Biochemical responses were measured in bronchoalveolar lavage fluid (BALF) recovered from lungs of exposedanimals. Parameters evaluated in BALF were lactate dehydrogenase (LDH), beta-glucuronidase (BG), and totalprotein (TP). Total and differential cell counts were performed on cells recovered in BALF. All compoundsproduced an increase in LDH, BG, TP, and total nucleated cells, and an influx of neutrophiles, indicating thepresence of a cytotoxic and inflammatory response in the lungs of exposed rats and mice. Increases in BG weregreater than increases in LDH and TP for both rats and mice. Chronic active inflammation, macrophagehyperplasia, and interstitial phagocytic cell infiltrates were observed histologically in rats and mice exposed toall compounds. Statistically significant increases in BG, TP, neutrophiles, and macrophages correlated well withthe degree of chronic active inflammation. Results indicated a toxicity ranking of NiSO4 which was greater thanNi3S2 and greater than NiO, based on toxicities of the compounds at equivalent mg Ni/m3 exposureconcentrations.4.1.2.5.1.2 OralData for effects following oral exposure have been found for nickel sulphate, nickel acetate, nickel chloride, andnickel carbonate.For nickel sulphate, long-term studies of toxicity following oral exposure have been conducted in rats, mice anddogs. Mainly non-specific indications of toxicity, such as decreased body weight, have been observed. Inaddition, reduced survival, increased urinary albumin (indicator of diminished kidney function), mild tubularnephrosis, as well as immuno-suppressive effects have been observed. An oral LOAEL of 6.7 mg Ni/kg bw/daybased on reduced body weight and increased mortality and a NOAEL of 2.2 mg Ni/kg bw/day has beenidentified in a 2 year gavage study CRL, 2005), although uncertainties remain whether this actually should beconsidered as a NOAEL as reduced body weight gain (both sexes) and increased mortality (females) occurred toa statistically non-significant extent..Data from 3 drinking water studies with Ni-acetate in rats and mice have been found. The concentration was 0 or5 ppm (for rats equivalent to 0.17 mg Ni/kg bw/day assuming a water intake of 100 ml/kg/day) and the studyduration was lifetime. Effects in rats included a 10-13% reduction in body weight and a 13% increased incidenceof myocardial fibrosis. In mice only body weigh reduction was found. The studies were limited in the number ofanimals and parameters examined. (Schroeder et al., 1964; Schroeder & Mitchener 1975; quoted from TERA1999)Although several studies of repeated dose oral toxicity of nickel chloride have been found, none are consideredadequate for the determination of a NOAEL. A LOAEL of 5 mg Ni/kg bw/day based on mortality was identifiedin a 91-day gavage study by American Biogenics Corporation, 1988.In the reviews by UK HSE (1987), NIPERA (1997) and TERA (1999), repeated dose toxicity of nickel nitrateare not discussed. No data have been found.Inadequate oral studies of nickel carbonate in calves and monkeys have been found (see Risk Assessment Reporton nickel carbonate).4.1.2.5.1.3 DermalNo relevant studies of repeated dose toxicity of nickel compounds via the dermal route have been found.4.1.2.5.2 Conclusion4.1.2.5.2.1 InhalationInhalation of the insoluble nickel compounds (metal, subsulphide, and oxide) results in lung inflammation andfibrosis. Inhalation of the soluble nickel sulphate and chloride also affects the lungs. For nickel sulphate lunginflammation and fibrosis has been found, while for chloride apparently less severe effects were seen. Thus, itappears that the effects following inhalation exposure to nickel compounds do not depend on the solubilitycharacteristics. Chronic lung inflammation and lung fibrosis are serious and potentially irreversible effects.Classification as T; R48/23 is included in the 30th ATP for nickel sulphate, nickel chloride, nickel nitrate and 102
  • R_NickelBackground_0308_hh_chapter0124567.docnickel carbonate, with a specific concentration limit of > 1% for T; R28/23 and > 0.1% for Xn; R48/20 for thethree soluble nickel salts.Since the two soluble nickel compounds (nickel sulphate and chloride) have not been tested in a parallel mannerit is not possible to carry out a direct comparison of the potency. For the three compounds tested by NTP in asimilar protocol, the following order of toxic potency, based on mg nickel/m3, could be determined: Nickelsulphate hexahydrate>nickel subsulphide>nickel oxide. For the two insoluble compounds inflammatory lunglesions were observed at all concentration levels in two-year studies. For the soluble nickel sulphate hexahydratea LOAEC for chronic lung inflammation and fibrosis could be determined at 0.056 mg Ni/m3. A definitiveNOAEC for these effects could not be defined from the data.In the absence of NOAECs for the other soluble and sparingly soluble nickel compounds, the LOAEC for nickelsulphate hexahydrate (LOAEC of 0.056 mg Ni/m3, lung inflammation and fibrosis in 2-year rat study, NTP,1996a) is taken forward to the risk characterisation for repeated dose toxicity via inhalation for nickel chloride,nickel nitrate and nickel (hydroxy)carbonate.For metallic nickel, a LOAEC of 1 mg/m3 from the 13 week inhalation study with rats (WIL Research Laboratories,2003) is taken forward to risk characterisation for repeated dose toxicity.4.1.2.5.2.2 OralSufficient oral repeated dose toxicity data are only available for the soluble nickel sulphate and nickel chloride.Nickel sulphate ingestion via feed or drinking water was associated with weight loss, and increased urinaryalbumin. In a 2 year gavage study with rats, decreased survival and reduced body weight gain was found.Reduced survival was also found with gavage administration of nickel chloride. However, when nickel chloridewas administered in feed or drinking water at comparable doses no effects were found. There are no data oneffects following repeated oral exposure with insoluble nickel compounds.In the absence of data for the insoluble nickel compounds, the values for nickel sulphate (oral LOAEL of 6.7 mgNi/kg bw/day based on reduced body weight and increased mortality and NOAEL of 2.2 mg Ni/kg bw/day) istaken forward to the risk characterisation for repeated dose oral toxicity for soluble as well as insoluble nickelcompounds, although uncertainties remain whether this actually should be considered as a NOAEL as reducedbody weight gain (both sexes) and increased mortality (females) occurred to a statistically non-significant extent.4.1.2.5.2.3 DermalDermal repeated dose toxicity data are lacking for soluble as well as insoluble nickel compounds. Dermalabsorption is expected to be very limited. Therefore, this endpoint is not considered in the risk characterisation.4.1.2.6 MutagenicityThe genotoxicity of nickel and nickel compounds have been reviewed by several organisations including IPCS(1991), IARC (1990), UK HSE (1987), ECETOC (1989), US ATSDR (1997), NiPERA 13 (1996) and TERA(1999). This section contains a summary of the data for the five individual nickel substances (nickel metal,nickel sulphate, nickel chloride, nickel nitrate and nickel carbonate) reviewed in the individual risk assessmentreports. This section also describes aspects of the mutagenicity and genotoxicity of some other nickelcompounds.4.1.2.6.1 Summary of mutagenicity test results for the five selected nickel compounds.The tables below show in summary (and in some cases, simplified) form the data presented in the five individualreports. The reader is referred to the individual reports for more detailed assessments of the five individual nickelsubstances. Absence of an entry indicates that the individual reports do not contain data for these endpoints.4.1.2.6.1.1 Summary of mutagenicity test results in vitro.4.1.2.6.1.1.1 DNA damage and repair.Most of the data in the five risk assessment reports comes from studies with nickel chloride. There are somestudies in bacteria showing differential toxicity between repair deficient and normal strains. There are positivestudies of gene conversion in yeast, and a series of studies showing induction of DNA single strand breaks in13 NiPERA has pointed out that this review was produced by independent scientists for NiPERA and that theconclusions of the report do not necessarily reflect the current position of NiPERA. 103
  • R_NickelBackground_0308_hh_chapter0124567.docmammalian cells. There is also evidence of DNA synthesis inhibition, disturbance of DNA damage recognitionand inhibition of DNA repair. Human cells appear to be more resistant to nickel induced strand breakage thanhamster cells (quoted from NiPERA, 1996).Whilst there is very little data in the five reports on other than nickel chloride and nickel sulphate, the NiPERA(1996) review indicates that similar effects are seen with both soluble nickel compounds such as the sulphate andchloride and with other, less soluble compounds. The S-phase inhibition seen in CHO cells with metal dust isconsistent with this.There is evidence indicating that nickel ions bind to DNA. Nickel ion also binds to chromatin more strongly thanto naked DNA. There is evidence of nickel catalysed oxidative damage to DNA. (Quoted from NiPERA, 1996).Table 4.1.2.6.1.1.A: Summary of results of in vitro tests for DNA damage and repair with five nickelcompounds. nickel nickel nickel nickel nickel sulphate chloride nitrate carbonate metalProkaryotesE. coli, differential toxicity in repair positive negativedeficient strainFungiYeast, gene conversion positive positiveMammalian cellsrat liver epithelial cells (inhibition of DNA positivesynthesis)Hamster CHO cells (DNA damage) positive positiveSHE (Strand breaks) positiveHuman bronchial epithelial cells (inhibition positiveof DNA synthesis)Human diploid fibroblasts (DNA damage) negative negativeHuman gastric mucosal cells (DNA negativedamage)Human peripheral lymphocytes (DNA equivocalstrand breaks)Human lung cells (inhibition of DNA positiverepair)4.1.2.6.1.1.2 Gene mutation.Nickel chloride has been tested extensively in bacteria, and most of the available data in the five risk assessmentreports comes from studies with this nickel compound. In general, the nickel compounds tested gave negativeresults in bacterial assays with S. typhimurium and E. coli. It has been shown with other metallic ions likecobalt(II) that the results in bacteria are greatly influenced by the choice of the tester strain and the testconditions used (Arlauskas 1985; Pagano & Zeiger 1992; Beyersmann 1994; Binderup 1999). In two studies, itwas shown that cobalt(II) was only genotoxic in the Salmonella strain TA97 and considerable more genotoxic inthe preincubation assay than in the standard plate assay (Pagano & Zeiger 1992; Binderup 1999). Both nickelchloride and nickel nitrate were tested in this strain with negative results. The overall evidence indicates thatnickel compounds are not mutagenic in bacteria.Both nickel sulphate and nickel chloride have been tested in gene mutation studies with mammalian cell lines.Many of these studies showed positive results, although these were often weakly positive. In some cases, onlycertain loci were affected (e.g. a positive result at the tkslow locus, but not at the tknormal or hprt loci, Skopek,1995). Whilst these results may indicate gene mutation, the positive results in at least some of these assays couldpossibly be due to other genetic events (chromosomal aberrations and DNA methylation) than point mutations.For instance, it has been shown that the increases in mutant frequency seen at the gpt gene of v79 cells (Christieet al., 1992) were due to changes in DNA methylation (Klein, 1994). DNA methylation seems to be related tothe inhibition of tumour suppression genes (Costa & Klein, 1999). 104
  • R_NickelBackground_0308_hh_chapter0124567.docTable 4.1.2.6.1.1.B: Summary of results of in vitro tests for gene mutations with five nickelcompounds. nickel nickel nickel nickel nickel sulphate chloride nitrate carbonate metalProkaryotesS. typhimurium negative negative (4) negativeE. coli negative negativeCorynebacterium positiveHost mediated assaySalmonella in NMRI mice negativeSerratia marcescens in NMRI mice negativeFungiS. cerevisiae negative positiveMammalian cellsCHO cells equivocal (1)Mouse lymphoma cells (TK+/-) positive positive (2)SHE cells negativeV79 cells positive (1) positiveRat NRK cells positiveRat 6m2 murine sarcoma virus infected cells positiveRat liver epithelial cells positive (3)Human lymphoblasts positive positive (3)1) weakly positive 2) co-mutagenic with benzo(a)pyrene3) for the tkslow locus only. 4) a fluctuation test gave a positive result4.1.2.6.1.1.3 Chromosomal effects.This effect has been extensively studied with both nickel chloride and nickel sulphate. There are slightly morestudies of chromosomal aberrations (CA) with nickel chloride than with nickel sulphate; the reverse is true forstudies of sister chromatid exchange (SCE).Positive results were seen in almost all studies of CA and SCE. Positive effects have also been seen with nickelcarbonate. Effects have also been seen on spindle function, suggesting that numerical changes might occur.Table 4.1.2.6.1.1.C: Summary of results of in vitro tests for chromosomal effects with five nickelcompounds. nickel nickel nickel nickel nickel sulphate chloride nitrate carbonate metalChromosomal aberrationsPisum positivemouse mammary carcinoma cells (FM3A positivecells )Rat lung epithelial cells positiveCHO cells positive positiveSHE cells positiveHuman lymphocytes positiveHuman bronchial epithelial cells positive negative 105
  • R_NickelBackground_0308_hh_chapter0124567.docSister chromatid exchangesmouse mammary carcinoma cells (FM3A positive positivecells )CHO cells positive positive positiveSHE cells positiveHuman lymphocytes positive positiveSpindle disturbancerat embryo cells positivehuman peripheral lymphocytes positiveMicronucleus test (kinetochore stained)Human diploid fibroblasts weak weak positive positive4.1.2.6.1.1.4 Cell transformation.Most of the data on cell transformation comes from studies on nickel sulphate, although there are additionalstudies with nickel chloride and nickel metal. Many of these studies indicate an effect on cell transformation,anchorage independence and loss of cell communication.The significance of these effects is largely related to the ability of modelling carcinogenic pathways in vitro.Table 4.1.2.6.1.1.D: Summary of results of in vitro tests for cell transformation and other effects withfive nickel compounds. nickel nickel nickel nickel nickel metal sulphate chloride nitrate carbonateBHK 21 cells positiveSHE cells positive positive positivemouse embryonic fibroblasts negative negativeRat embryo cells positiveHamster V79, loss of cell communication positive positiveHuman foreskin cells (anchorage positiveindependence)4.1.2.6.1.2 Summary of mutagenicity test results in vivo.4.1.2.6.1.2.1 DNA damage and repair.There is evidence that both soluble and insoluble nickel compounds can give rise to both DNA breaks and DNA-protein crosslinks in vivo (quoted from NiPERA, 1996). Recent studies by Benson et al. (2002) have shownDNA-strand breaks in the lung after high doses of nickel sulphate and nickel subsulphide (see 4.1.2.6.2) given byinhalation, and Danadevi et al. (2004) have shown that nickel chloride induced single and double stranded DNAbreaks as measured by the Comet assay in leucocytes in mice after oral administration.Table 4.1.2.6.1.2.A.: Summary of results of in vivo tests for DNA damage and repair with five nickelcompounds. nickel nickel nickel nickel nickel sulphate chloride nitrate carbonate metalRat, mouse, DNA strand breakage positive positive positiveMouse, inhibition of DNA synthesis:kidney epithelium negativeliver epithelium positive 106
  • R_NickelBackground_0308_hh_chapter0124567.docHamster, suppression of DNA synthesis positive4.1.2.6.1.2.2 Gene mutations.The only in vivo studies for gene mutations with soluble nickel compounds have been carried out in Drosophila.Weakly positive effects have been seen in one study. This is consistent with the data seen in vitro. Nickelsubsulphide has been studied in a transgenic rodent mutation assay (see 4.1.2.6.2).Table 4.1.2.6.1.2.B: Summary of results of in vivo tests for gene mutations with five nickel compounds. nickel nickel nickel nickel nickel sulphate chloride nitrate carbonate metalDrosophilasomatic eye colour test negative negative (1)wing spot mutation positiveMutation negative equivocal1) weakly positive4.1.2.6.1.2.3 Chromosomal effects.Data for the evaluation of chromosomal effects in vivo is mainly available for nickel sulphate, chloride andnitrate. It should be noted that in most cases, the same authors have studied more than one of the substances:concordance in the results is therefore not surprising.Chromosomal aberrations have been seen in vivo in a number of studies (Chorvatiovicova, 1983; Mohanty,1987: Sharma et al., 1987; Dhir et al., 1991). This effect has been seen with the three soluble substances tested.The authors of a much older study in bone marrow and spermatogonial cells (Mathur et al, 1978) claim anegative effect, but without reporting any data in support of this conclusion. The review of the mutagenicity datacarried out by NiPERA (2003a) concludes that the Dhir et al. (1991) and the Chorvatovicova (1983) studies arepositive. There is also evidence, sometimes with mixed exposure, to show that this effect is also seen in humans,although NiPERA (2003a) does not consider that these studies can be used as evidence.The data from micronucleus tests is conflicting, and these studies are discussed in more detail in the individualrisk assessment reports. One of the studies was carried out as part of an international collaborative study (Moritaet al., 1997). This study found a negative result for both nickel sulphate and nickel chloride. A micronucleusstudy of nickel sulphate in rats after oral administration using the Annex V B12 (OECD 474) protocol was alsonegative (Covance 2003). Deknudt & Léonard (1982) also found no effect on micronucleus induction. A numberof largely Indian studies (Dhir et al., 1991, Sharma et al. 1987, Sobti & Gill, 1989,) have all shown positiveresults. NiPERA (2003a) agrees that the Dhir et al. (1991) intraperitoneal study is positive, but considers the oralstudies (Sharma et al. 1987, Sobti & Gill, 1989) equivocal.The data from dominant lethal tests (Deknudt & Léonard, 1982, Saichenko, 1985) suggests that there is nosignificant dominant lethal effect, although the soluble nickel compounds tested may reduce fertilisation rateafter intraperitoneal administration. The study by Sobti & Gill (1989) showed a significant increase in spermhead anomalies.There is therefore in vivo data confirming the clastogenicity seen in vitro.Table 4.1.2.6.1.2.C: Summary of results of in vivo tests for chromosomal effects with five nickelcompounds. nickel nickel nickel nickel nickel sulphate chloride nitrate carbonate metalPlantsVicia faba (mitotic effects) positiveInsectsDrosophila positiveMammals – Chromosomal aberrations 107
  • R_NickelBackground_0308_hh_chapter0124567.docMouse positive (1) positive (1) positive (1)Rat negative ?Hamster positive (2)Human positive positive (2)Mammals – Sister chromatid exchangesMouseRat ?Human negativeMammals – MicronucleusMouse conflicting conflicting conflicting data data dataRat negative positiveMammals – Dominant lethal testMouse negative negativeRat negativeFor a detailed discussion of the results, see individual reports.1) regarded as equivocal by NiPERA (2003a)2) NiPERA (2003a) considers that these studies cannot be used as evidence that nickel exposure caused theeffects seen.4.1.2.6.2 Genotoxicity of other nickel compounds.4.1.2.6.2.1 Other soluble nickel compounds.The only other soluble nickel compound studied significantly is nickel acetate. The IARC (1990) review lists anumber of in vitro endpoints. Most of these studies (De Flora et al. 1984, Umeda & Nishimura 1979, Nishimura& Umeda, 1979, Beidermann & Landolph, 1987) are already included in the risk assessment reports for nickelsulphate or nickel chloride. The Umeda & Nishimura (1979) and Nishimura & Umeda (1979) studies both showchromosome aberrations in transformed cells in vitro.Nickel acetate induces DNA-strand breaks and DNA-protein crosslinks in the kidney in vivo (Misra et al., 1993,quoted from NiPERA, 1996). The Rapporteur has not carried out any specific search for additional in vivomutagenicity studies, and no additional information on in vivo studies with other soluble nickel compounds hasbeen supplied by NiPERA.4.1.2.6.2.2 Insoluble compounds.The data for insoluble compounds has been reviewed by IARC (1990) and NiPERA (1996). In some cases,insoluble compounds include nickel (hydroxy)carbonate under “oxidic” nickel. The data for this substance istreated separately above. Most of the studies on insoluble nickel compounds (oxides and (sub)sulphides) in thesereviews are in vitro studies.NiPERA (1996) in reviewing both soluble and less soluble nickel compounds finds no evidence of qualitativedifferences between the different types of nickel compounds. For instance, in the studies on the tk locus referredto in 4.1.2.6.1.1.2 above (Skopek, 1995), nickel sulphate, nickel sulphide (Ni2S3), nickel hydroxide (Ni(OH)2),nickel oxide (NiO, green) and nickel metal all gave positive results for the tkslow locus. Positive results with testsfor CA have been seen with nickel oxides and sulphides, as well as other soluble nickel compounds (nickelacetate). The NiPERA (1996) review concludes that “both soluble and insoluble nickel compounds areclastogenic in mammalian and human cells in culture”.More recent information is also available. Schwerdtle et al. (2002) studied the effects of nickel chloride(included in 4.1.2.6.1.1.1 above) and the largely water-insoluble black nickel oxide. A difference was seenbetween the two compounds in their ability to inhibit BPDE (benzo[a]pyrene-7,8-diol 9,10-epoxide) inducedadducts. With respect to adduct formation, nickel oxide but not nickel chloride reduced the generation of DNAlesions by about 30%. Both nickel chloride and nickel oxide reduced the removal of the adducts in a dose- 108
  • R_NickelBackground_0308_hh_chapter0124567.docdependant manner. The authors consider that the results show that the nucleotide excision repair pathway isaffected in general by both insoluble and water soluble nickel compounds, and provides further evidence thatDNA repair inhibition is a mechanism in nickel-induced carcinogenicity.The information on in vivo genotoxicity of insoluble nickel compounds is even more limited than for solublenickel compounds.The only in vivo animal study with either nickel oxides or sulphides included in IARC (1990) is a study whereheterocyclic abnormalities were seen in early-passage cultures of cells from crystalline nickel sulphide-induced,mouse rhabdomyosarcomas (Christie et al., 1988, quoted from IARC, 1990).The evidence for in vivo chromosome aberrations for oxidic and sulphidic compounds in the NiPERA (1996)review comes from human studies. These studies are either carried out in refinery workers (Boysen et al. 1980,Waksvik & Boysen. 1982) or retired refinery workers (Waksvik et al. 1984). There is also evidence fromexposure to nickel oxide at a chemical plant (Senft et al., 1992). These studies have been described in the nickelsulphate and nickel chloride reports. IARC (1990) regards the Waksvik studies as “other relevant information” intheir summary, whilst NiPERA (2003a) does not consider that either the Waksik or the Senft studies can be usedas evidence that nickel exposure caused the effects seen.Two studies on in vivo micronucleus formation by Arrouijal et al., (1990, 1992) for nickel sulphides are shownas positive in NiPERA (1996). From the description of the study in NiPERA (1996) one of these studies(Arrouijal et al., 1992) appears to be in vitro. Treatment with α- Ni subsulphide (2.2 – 73 mg Ni/l) increased thenumber of micronuclei in lymphocytes from Ni-hypersensitised and unsensitised individuals (Arrouijal et al.,1992, quoted from NiPERA, 1996). Positive induction of micronuclei (2 to 3 fold) has been seen in OF1 miceexposed intraperitoneally to α-Ni subsulphide (183 mg Ni/kg) (Arrouijal et al., 1990, quoted from NiPERA,1996).More recent information is also available.As well as the nickel chloride and nickel sulphate study reported above, Morita et al., (1997) also includes astudy on nickel oxide tested by a different group (M. Takeuchi et al., at Yoshitomi Pharmaceutical Co. Ltd.).Nickel oxide was dissolved in 0.5% HPMC (hydroxypropylmethyl cellulose) before intraperitonealadministration to CD-1 mice (ddY mice were used for the study with the soluble nickel salts). The study wascarried out using the same dose and sampling protocol as used for the studies with the soluble salts. The studyconcluded that “a negative response was also observed in CD-1 mouse bone marrow cells 24 hr after a secondintraperitoneal treatment with nickel oxide at 18.1, 36.3, 72.5 and 145 mg/kg bw/day although the ratio ofpolychromatic erythrocytes to total erythrocytes decreased markedly and dose-dependently”.The study by Mayer et al. (1998) into the genotoxic potential of nickel subsulphide included in vitro and in vivocomet assays and transgenic rat and mouse mutation tests. The study clearly indicates that nickel subsulphideinduces DNA damage as shown by the Comet assay in mouse lung and nasal mucosa cells in vitro. Following invivo exposure of male CD2F1 mice and F344 rats high doses of nickel subsulphide for 2 hr (up to 95 mg Ni3S2 /m3 for mice and up to 63 mg Ni3S2 / m3 for rates) increases in the incidence of DNA damage as measured by theComet assay was seen in the nasal mucosa, and to a lesser extent in the lung. The effect occurred at lower dosesin mice than in rats, and was less in rats than in mice. This study provides some evidence that nickel subsulphideis able to produce pre-mutagenic damage in target cells for carcinogenesis. No significant increase in mutationfrequency was evident in the nasal mucosa or lung cells of transgenic LacZ CD2F1 mice or lacI F344 ratsfollowing in vivo inhalational exposure for two hours to Ni3S2 at dose levels close to the MTD. The lack of effecton mutations in vivo is expected from the short exposure time, as this model needs 4-6 weeks of exposure formaximal expression of mutations. The results do not support any conclusion regarding the ability of nickelsubsulphide to induce mutations in vivo.Benson et al. (2002) have performed a comprehensive in vivo study in rats in order to throw some light on thedifferences and similarities in the mechanism of cancer induction by insoluble and soluble nickel compounds inthe lung, which is the target organ for cancer development after inhalation. Several endpoints were investigatedafter inhalation of insoluble nickel subsulphide and soluble nickel sulphate hexahydrate. The most importantendpoints for the evaluation of genotoxicity / carcinogenicity are DNA damage measured as DNA strand breaksand oxidative DNA damage in the comet assay, DNA degradation, DNA methylation and cell proliferation.Both compounds induce DNA strand breaks in the comet assay at the highest exposure levels (0.22 mg Ni /m3for nickel sulphate and 0.44 mg Ni /m3 for the subsulphide,). In this assay there were no indication of oxidativeDNA damage. DNA strand breaks were induced earlier and at lower concentrations with nickel subsulphide than 109
  • R_NickelBackground_0308_hh_chapter0124567.docwith nickel sulphate and persisted after a 13 weeks recovery period. These findings are in accordance with invitro studies of nickel and other metals, and are presumably due to higher intercellular concentrations ofinsoluble than soluble metals due to phagocytosis. Irregular shaped black particles were observed inmacrophages after nickel subsulphide inhalation only. DNA damage was also measured as DNAdegradation/fragmentation and there was a modest degradation of DNA after nickel subsulphide exposure after 3weeks to the highest concentrations. After 13 weeks the DNA degradation increased. However, large DNAfractions were still present in the samples. At the highest nickel sulphate concentration primarily small DNAfragments were found, which might have influenced the comet assay results. Inflammation was evident at thesame exposures where DNA strand breaks were observed. This might lead to confounding of the comet assay byapoptosis. However, there seems to be only a few seriously damaged cells, since the median scores were all wellbelow 800 at all exposure levels. Moreover, there was no indication that oxidative damage caused the strandbreaks as would be expected if they were secondary to inflammation. The genotoxic damage is therefore mostlikely unrelated to inflammation or apoptosis. In addition, DNA degradation reported in the study was notmeasured in the cells used for the comet assay but in whole lung tissue homogenate, and therefore a correlationbetween DNA strand breaks in the comet assay and the DNA degradation cannot be made.Overall there were few differences between the effects of the two compounds studied. The most pronounceddifference was the ability of nickel subsulphide but not nickel sulphate to induce cell proliferation and asomewhat higher genotoxicity of nickel subsulphide.The Benson et al. (2002) study is in accordance with the earlier reviewed studies in the nickel risk assessmentreports showing that both soluble and insoluble nickel compounds primarily induce structural DNA damage,which in other studies are mainly expressed as chromosomal aberrations. In this in vivo study the most relevantexposure pathway (inhalation) and target organ (the lung) were studied at a reasonable range of exposureconcentrations. The study gives a fair explanation of the differences in carcinogenic potency of nickelsubsulphide and nickel sulphate but underlines the genotoxic potential of both compounds in the target organ.The human studies by Waksvik and co-workers reported in the nickel sulphate and nickel chloride riskassessments were carried out on workers exposed to roasting and smelting operations as well as to workers in theelectrolysis plants. The exposure of roasting / smelting workers is primarily to insoluble (oxidic or sulphidic)nickel. These studies are regarded by IARC as relevant data. NiPERA (2003a) does not believe the Waksvikstudies can be used as evidence that nickel exposure induces chromosomal aberrations in the exposed workersstudied.The studies reviewed above suggest that qualitatively similar effects are seen with both insoluble nickelcompounds and the soluble salts described above, although solubility may well affect the potency of theseeffects.4.1.2.6.3 Conclusions on the mutagenicity of the five selected nickel compounds.There is considerable evidence for the in vitro genotoxicity of nickel compounds. Positive effects are generallyseen in studies of chromosomal effects (chromosomal aberrations, sister chromatid exchanges), celltransformation tests and tests for DNA damage and repair. Whilst there are positive results for gene mutations,particularly with nickel chloride, the positive results in at least some of these assays could possibly be due togenetic events other than point mutations.Interpretation of the results of in vivo studies is more complicated. Most of the studies reviewed in these reportshave been carried out with the three soluble nickel compounds under review: nickel chloride, nickel sulphate andnickel nitrate. There is little in vivo data on other soluble compounds, and data on sparingly soluble nickelcompounds such as nickel carbonate, insoluble compounds such as nickel oxide and nickel sulphides as well asnickel metal is also very limited.Of the individual compounds reviewed here, the genotoxicity of nickel chloride has been the most extensivelystudied following intraperitoneal and oral administration. There is data from studies on DNA damage,chromosomal aberration studies as well as micronucleus tests. Whilst NiPERA (1996) and TERA (1999)consider that the studies reviewed by them showed in general a positive effect in vivo, NiPERA (2003a)considers the evidence from many of these studies as equivocal. There is a recent collaborative study (Morita etal., 1997) which shows a negative micronucleus test after intraperitoneal administration. However, the positiveresults for chromosomal aberrations seen after intraperitoneal administration (Dhir et al., 1991 andChorvatovicova, 1983) are not disputed. The recent study by Danadevi et al. (2004) also shows positive resultsin vivo using the Comet assay with DNA damage in leucocytes after oral administration of nickel chloride. Inaddition, there is supporting evidence from studies of workers exposed by inhalation (Waksvik & co-workers 110
  • R_NickelBackground_0308_hh_chapter0124567.docand other studies) which is regarded by IARC (1990) as relevant, but which NiPERA (2003a) does not considercan be used in evidence.The data on intraperitoneal and oral exposure of nickel sulphate is rather more limited than for nickel chloride.Again, there is data from chromosomal aberration studies as well as from micronucleus tests. The positiveevidence in these studies is less clear-cut. Nickel sulphate was also tested in the recent collaborative study(Morita et al., 1997) after intraperitoneal administration and in a study commissioned by NiPERA (Covance,2003) after oral administration. Both these studies were negative. The evidence from human studies is alsorelevant to the evaluation of nickel sulphate, as the studies by Waksvik & co-workers, (see above) involvedexposure to both nickel sulphate and nickel chloride. There is also human evidence from workers exposed in achemicals plant (Senft et al., 1992). Nickel sulphate has been studied by Benson et al. (2002) after inhalationalexposure, and this study is the most comprehensive part of the database on in vivo genotoxicity of Nicompounds. The study has been criticized because it cannot discriminate direct induction of DNA damage fromindirect damage secondary to inflammation or apoptosis. The nickel compounds tested seem to induceinflammation and genotoxicity at approximately the same concentrations and further testing is not likely toovercome this dilemma unless more sensitive techniques can show that one of the effects is elicited by evenlower exposure levels.The evidence for nickel nitrate is even more limited, and adds little new information, as many of the studiesinclude either nickel sulphate and/or nickel chloride, and are the same as the studies discussed above.The data for nickel carbonate from both in vitro and in vivo studies is very limited. NiPERA (2003a) considersthat the mutagenicity assessment for nickel carbonate could be derogated to the overall mutagenicity assessmentfor either soluble or insoluble nickel compounds.As for nickel carbonate, the data for metallic nickel from both in vitro and in vivo studies is very limited. In thiscase, there is little or no agreement on whether it is appropriate to extrapolate from the results from other nickelcompounds.In addition to the evidence from the soluble salts, there is however evidence to regard both nickel carbonate andmetallic nickel as being of concern for genotoxicity.There are no definitive tests of nickel compounds on the germ cells and evidence for a possible effect is limited.There is evidence that the nickel ion reaches the testis, so a possible effect cannot be excluded. There are twonegative dominant lethal tests (Deknudt & Léonard, 1982, Saichenko, 1985), as well as a number of other studieswhich are relevant to an evaluation of the effects on germ cells. Whilst some effects are seen in males (e.g.sperm abnormalities) there is little evidence for inheritable effects on the germ cells.The opinion of the Specialised Experts has been sought at their meeting in April, 2004. The Specialised Expertsconcluded that nickel sulphate, nickel chloride and nickel nitrate should be classified as Muta. Cat. 3; R68. Thisconclusion is based on evidence of in vivo genotoxicity in somatic cells, after systemic exposure. Hence thepossibility that the germ cells are affected cannot be excluded (European Commission, 2004).Concerning the nickel carbonate, the Specialised Experts concluded that there was insufficient evidence forclassification (European Commission, 2004). However, classification as Muta. Cat. 3; R68 is justified on thebasis of the Industry derogation statement. In addition, the evidence for significant absorption of nickelcarbonate after oral administration (see 4.1.2.1.1.2), and the acute toxicity (see 4.1.2.2.3.2) also indicates that thepossibility that the germ cells are affected cannot be excluded.The TC C&L has agreed to classify nickel sulphate, nickel chloride, nickel nitrate and the nickel carbonates asMuta. Cat. 3; R68 and these classifications are included in the 30th ATP.The Specialised Experts did not consider that further testing of effects on germ cells was practicable (EuropeanCommission, 2004).Further testing in an in vivo comet assay in lung cells after inhalational exposure is also considered to beunnecessary for the purposes of risk characterisation. A positive result would not alter the conclusions for theclassification as a mutagen, and a negative result would not be regarded as sufficient evidence to justify the useof a threshold approach in the carcinogenicity risk characterisation. Hence, further testing for this effect wouldnot produce additional information that would significantly change the outcome of this risk assessment. 111
  • R_NickelBackground_0308_hh_chapter0124567.doc4.1.2.7 Carcinogenicity4.1.2.7.1 Animal data4.1.2.7.1.1 InhalationThe data on the carcinogenicity of nickel compounds in experimental animals following exposure by inhalationare limited. Below, the available data regarding carcinogenicity of the five prioritised nickel compounds (nickelsulphate, nickel chloride, nickel nitrate, nickel carbonate, and nickel metal) following inhalation exposure orintratracheal instillation are summarised; for further details, the reader is referred to the individual riskassessment reports. Data on other nickel compounds are also summarised below when considered relevant forthe conclusion on the carcinogenicity of nickel in experimental animals following inhalation of the fiveprioritised nickel compounds.4.1.2.7.1.1.1 Nickel sulphateThe National Toxicology Program (NTP) has performed a comprehensive investigation of the toxic effects inrats and mice after chronic inhalation of nickel sulphate hexahydrate (NTP 1996a). The data concerning thecarcinogenic effects of nickel sulphate hexahydrate are summarised in Table 4.1.2.7.1.A. The results asconcluded in the study seem reliable, i.e. neither rats (F344/N) nor mice (B6C3F1) developed exposure relatedneoplasms after being exposed to nickel sulphate hexahydrate (mass median aerodynamic diameter of 1.8-3.1 +1.6-2.9 μm) by inhalation at concentrations up to 0.11 mg Ni/m3 or 0.22 mg Ni/m3, respectively.Table 4.1.2.7.1.A: Summary of inhalation carcinogenicity studies of nickel sulphate hexahydrate inexperimental animals. Route of Species, group Concentration, Results References administration size and sex exposure duration Inhalation F344/N rats 0, 0.03, 0,06 or 0.11 mg Ni/m3 No exposure related NTP (1996a) neoplasms observed 63-65 males, 6 hours/day, 5 days/week, 63-64 females per group 2 years Inhalation B6C3F1 mice 0, 0,06, 0.11 or 0.22 mg Ni/m3 No exposure related NTP (1996a) 80 males, neoplasms observed 6 hours/day, 5 days/week, 80 females per group 2 years4.1.2.7.1.1.2 Nickel metalA number of animal studies on the carcinogenicity of nickel metal following inhalation or intratrachealinstillation have been performed; these studies are summarised in Table 4.1.2.7.1.B. Local neoplasms wereobserved in most of the studies; however, all the studies suffer from inadequacies and are consideredinappropriate for the risk assessment of the carcinogenic potential of nickel metal following exposure byinhalation.According to information provided by the Industry (NiPERA (2002b)), “a two-year inhalation cancer bioassaywith elemental nickel powder in male and female Wistar rats is currently underway and will be completed in2004. NiPERA is overseeing the conduct of this study. An OECD-compliant protocol is being used in the study,with supplemental lung burden analyses to assure absence of impaired lung clearance. “ NiPERA (2003b) hassubsequently pointed out that “the inhalation cancer bioassay in Wistar rats is expected to be completed in 2006.This is a 30-month exposure study that has not yet begun”.Table 4.1.2.7.1.B: Summary of carcinogenicity studies of nickel metal by inhalation and intratrachealinstillation in experimental animals.Route of Species, group Concentration/ Results References Remarksadministration size and sex dose, exposure durationInhalation Wistar rats 15 mg/m3, Numerous multicentric, Hueper (1958 No control group, adenomatoid alveolar – quoted from short duration, 50 animals of 6 hours/day, lesions and bronchial IARC 1990, each sex proliferations that were NiPERA one exposure level 112
  • R_NickelBackground_0308_hh_chapter0124567.docRoute of Species, group Concentration/ Results References Remarksadministration size and sex dose, exposure durationNickel metal 4-5 days/week considered (by the 1996)powder, particle 21 months author) as being benignsize ≤ 4µm Bethesda black Observed up to neoplasms rats 84 weeks 60 femalesInhalation C57B1 mouse 15 mg/m3, No neoplasms observed Hueper (1958 High mortality, – quoted from 20 females 6 hours/day, IARC 1990, no control group, NiPERA only one sex,Nickel metal 4-5 days/weekpowder, particle 1996) short duration,size ≤ 4µm 21 months one exposure level 3Inhalation Strain 13 15 mg/m , Almost all exposed Hueper (1958 High mortality, guinea-pigs animals developed – quoted from short duration, 6 hours/day, adenomatoid alveolar IARC 1990, 32 males, 10 lesions and terminal NiPERA one exposure levelNickel metal females 4-5 days/weekpowder (particle 21 months bronchiolar 1996)size not stated) 9 controls proliferations. (gender not One exposed animal specified) had an anaplastic intra- alveolar carcinoma; another an apparent adenocarcinoma metastasis in an adrenal node.Inhalation Wistar rats 3.1 mg/m3, 2 exposed rats and 1 Kim et al. Short duration, control rat developed (1969 – 77 males 6 hours/day, lung tumours of a quoted from one exposure level, carcinoid pattern IPCS 1990) one sex onlyMetallic nickel control group 5 days/weekdust, 98% of includedparticles less 21 monthsthan 2 µm indiameterIntratracheal Wistar rats 10 weekly Lung tumour incidence: Pott et al. One sex only,instillation females (group instillations of 8/32, 10/39 and 0/40 (1987 – size not stated) 0.9 mg, (controls), respectively. quoted from short duration, IARC 1990, few dose levels 40 saline-treated or 20 weekly Tumours: one adenoma, NiPERANickel metal controls injections of 0.3 four adenocarcinomas, 1996)powder mg in saline 12 squamous-cell carcinomas, one mixed Observed for tumour. almost 2.5 yearsIntratracheal Syrian golden Single Intrathoracic malignant Ivankovic et Reported in aninstillation hamsters instillation of neoplasms al. (1987 – abstract only, 10, 20, 40 mg, (fibrosarcomas, quoted from 100 animals per or four mesotheliomas, IARC 1990) short duration, group (sex not instillations of rhabdomyosarcomas) atMetallic nickel specified) few dose levelspowder (particle 20 mg every six up to 12% in the highestdiameter 3-8 µm) months single dose group and about 10% in the Vehicle control repeated dose group groupIntratracheal Syrian golden 12 instillations One adenocarcinoma in Muhle et al. No lung tumoursinstillation hamsters (Cpb- of 0.8 mg at lung of treated group (1990 – in positive control ShGa 51) two-week quoted from group, intervals IARC 1990) 60 males, Median lifespan one dose levelMetallic nickel females Vehicle 90-130 weekspowder (particle control group, 113
  • R_NickelBackground_0308_hh_chapter0124567.docRoute of Species, group Concentration/ Results References Remarksadministration size and sex dose, exposure durationsize 3.1 µm) positive control group4.1.2.7.1.1.3 Nickel chloride, nickel nitrate, and nickel carbonateNo studies regarding carcinogenicity of nickel chloride, nickel nitrate, and nickel carbonate following inhalationexposure or intratracheal instillation in experimental animals have been located.4.1.2.7.1.1.4 Nickel oxideF344/N rats were exposed to nickel oxide (CAS No: 1313-99-1) (high temperature, green nickel oxide, massmedian diameter 2.2 ± 2.6 µm, at least 99% pure) at concentrations of 0, 0.62, 1.25, or 2.5 mg/m3 (equivalent to0, 0.5, 1.0, or 2.0 mg Ni/m3) and B6C3F1 mice at concentrations of 0, 1.25, 2.5, or 5 mg/m3 (equivalent to 0, 1.0,2.0, or 3.9 mg Ni/m3) by inhalation for 6 hours per day, 5 days per week for 104 weeks. Survival of exposedanimals was similar to that of the controls. At 2 years, tumours were observed in the lungs of rats (males:alveolar/bronchiolar adenoma or carcinoma or squamous cell carcinoma (combined) 1/54, 1/53, 6/53, 4/52;females: alveolar/bronchiolar adenoma or carcinoma (combined) 1/53, 0/53, 6/53, 5/54) and female mice(alveolar/bronchiolar adenoma or carcinoma (combined) 6/64, 15/66, 12/63, 8/64) and in the adrenal medulla ofrats (males: benign or malignant pheochromocytoma (combined) 27/54, 24/52, 27/53, 35/52; females: benignpheochromocytoma 4/51, 7/52, 6/53, 18/53). It was concluded that there was some evidence of carcinogenicactivity of nickel oxide in rats based on the increased incidences of tumours in the lungs and of the adrenalmedulla. There was equivocal evidence of carcinogenic activity of nickel oxide in female mice based onmarginally increased incidences of lung tumours in the mid- and high-dose groups. There was no evidence ofcarcinogenic activity in male mice. (NTP 1996b).4.1.2.7.1.1.5 Nickel subsulphideF344/N rats were exposed to nickel subsulphide (CAS No: 12035-72-2) (mean value for the mass medianaerodynamic diameter 2.0-2.2 µm, at least 97% pure) at concentrations of 0, 0.15, or 1.0 mg/m3 (equivalent to 0,0.11, or 0.73 mg Ni/m3) and B6C3F1 mice at concentrations of 0, 0.6 or 1.2 mg/m3 (equivalent to 0, 0.44, or 0.88mg Ni/m3) by inhalation for 6 hours per day, 5 days per week for 104 weeks. Survival of exposed animals wassimilar to that of the controls. At 2 years, tumours were observed in the lungs of rats (males: alveolar/bronchiolaradenoma or carcinoma (combined) 0/53, 6/53, 11/53; females: alveolar/bronchiolar adenoma or carcinoma orsquamous cell carcinoma (combined) 2/53, 6/53, 9/53) and in the adrenal medulla of rats (males: benign ormalignant pheochromocytoma (combined) 14/53, 30/52, 38/53; females: benign pheochromocytoma 2/53, 7/53,36/53). No tumours were observed in mice. It was concluded that there was clear evidence of carcinogenicactivity of nickel subsulphide in rats based on the increased incidences of tumours in the lungs and of the adrenalmedulla. There was no evidence of carcinogenic activity in mice. (NTP 1996c).When F344 rats were exposed to nickel subsulphide (0.97 mg Ni/m3, 70% particles smaller than 1 µm) byhalation for 6 hours a day, 5 days per week for 78 weeks, the overall incidence of lung tumours in treatedanimals was 14% (15 adenomas, 10 adenocarcinomas, 3 squamous-cell carcinomas, 1 fibrosarcoma) comparedto 1% (1 adenoma and 1 adenocarcinoma) in control animals (241 animals) (Ottolenghi et al. 1974 – quotedfrom NiPERA 1996, IPCS 1991 and IARC 1990).4.1.2.7.1.2 OralWith the exception of nickel sulphate, the data on the carcinogenicity of nickel compounds in experimentalanimals following exposure by oral administration are very limited. Below, the available data regardingcarcinogenicity of the five prioritised nickel compounds (nickel sulphate, nickel chloride, nickel nitrate, nickelcarbonate, and nickel metal) following oral administration are summarised; for further details, the reader isreferred to the individual risk assessment reports. Data on other nickel compounds are also summarised belowwhen considered relevant for the conclusion on the carcinogenicity of nickel in experimental animals followingoral administration of the five prioritised nickel compounds.4.1.2.7.1.2.1 Nickel sulphateThe carcinogenicity of nickel sulphate following oral administration has been studied in rats and dogs; thesestudies are summarised in Table 4.1.2.7.1.C. An oral (gavage) OECD 451 carcinogenicity study in rats did notshow any treatment related increase in tumours related to the exposure (CRL 2005). Furthermore, no neoplasmswere revealed in either rats or dogs in the older studies; however, these studies are limited because of the low 114
  • R_NickelBackground_0308_hh_chapter0124567.docnumber of animals (rats and dogs), the high mortality in all groups of rats (causes of death not reported) resultingin only a small number of animals being exposed for the total period of 2 years and being available for sacrificeand histopathology, and the limited reporting of the study design and results.Table 4.1.2.7.1.C: Summary of oral carcinogenicity studies of nickel sulphate hexahydrate inexperimental animals. Route of Species, group Concentration, Results Reference administration size and sex exposure duration Oral, dietary Wistar rats 0, 100, 1000 or 2500 ppm Ni in feed No treatment related Ambrose et neoplasms observed al. (1976) 25 males and 2 years females per group Oral, dietary Beagle dogs 0, 100, 1000 or 2500 ppm Ni in feed No treatment related Ambrose et neoplasms observed al. (1976) 3 males and 2 years females per group Oral, gavage Fischer rats 0, 2.2, 6.7, 11 mg Ni/kg bw/day No treatment related CRL (2005) neoplasms observed 60 males and 2 years females per group4.1.2.7.1.2.2 Nickel chloride, nickel nitrate, nickel carbonate, and nickel metalNo data regarding carcinogenicity of nickel chloride, nickel nitrate, nickel carbonate, and nickel metal followingoral administration in experimental animals have been located.4.1.2.7.1.2.3 Nickel acetateThe carcinogenicity of nickel acetate has been tested in three drinking water studies with rats and mice(Schroeder et al. 1964, 1974, Schroeder & Mitchener 1975 – all three quoted in TERA 1999) receiving 0 or 5mg/l Ni as nickel acetate (hydration state not reported) from the time of weaning until natural death. Histologicalexaminations were limited to the lungs, heart, liver, kidneys, and spleen. No exposure-related neoplasms wasobserved in either rats or mice. According to TERA, the findings are not conclusively negative due to limitationsin the design of the studies (single dose level, unclear if a maximum tolerated dose was achieved, less than halfof the mice were necropsied and even fewer were sectioned).4.1.2.7.1.3 Dermal4.1.2.7.1.3.1 Nickel sulphate, nickel chloride, nickel nitrate, nickel carbonate, and nickel metalNo data regarding carcinogenicity following dermal contact to nickel sulphate, nickel chloride, nickel nitrate,nickel carbonate, and nickel metal in experimental animals have been located.4.1.2.7.1.3.2 Other nickel compoundsWhen male golden Syrian hamsters were painted on the mucosa of the buccal pouches with 1 or 2 mg α-nickelsubsulphide in 0.1 ml glycerol three times a week for 18 weeks (6-7 animals; total doses 54 and 108 mg nickelsubsulphide) or with 5 or 10 mg three times a week for 36 weeks (13-15 animals; total doses 540 and 1080 mgnickel subsulphide) and observed for more than 19 months, no tumours developed in the buccal pouch, oralcavity, or intestinal tract in the treated or control groups (Sunderman 1983 – quoted from IARC 1990).4.1.2.7.1.4 Other routes of administrationSeveral studies have investigated the carcinogenicity of nickel compounds in experimental animals followingexposure by other routes of administration than inhalation, oral administration, and dermal contact. Below, theavailable data regarding carcinogenicity of the five prioritised nickel compounds (nickel sulphate, nickelchloride, nickel nitrate, nickel carbonate, and nickel metal) following other routes of administration aresummarised; for further details, the reader is referred to the individual risk assessment reports. Data on othernickel compounds are also summarised below when considered relevant for the conclusion on thecarcinogenicity of the five prioritised nickel compounds in experimental animals following exposure by otherroutes of administration.4.1.2.7.1.4.1 Nickel sulphate 115
  • R_NickelBackground_0308_hh_chapter0124567.docStudies on the carcinogenicity of nickel sulphate following intramuscular injections or implants, orintraperitoneal injections have been performed in rats; these studies are summarised in Table 4.1.2.7.1.D.Tumours were observed following administration by intraperitoneal injections and by intramuscular implants,but not by intramuscular injections.Table 4.1.2.7.1.D: Summary of carcinogenicity studies of nickel sulphate in experimental animals byother routes of administration than inhalation, oral administration, and dermal contact. Route of Species, group Concentration, Results Reference administration size and sex exposure duration Intramuscular Wistar rats, Single dose of 5 mg of No local tumours at Gilman (1962 – injections to one nickel sulphate the injection sites, no quoted from IARC or both thigh 32 males and hexahydrate other treatment-related 1990, TERA 1999) muscles females tumours Observation for 603 days No control group Intramuscular NIH black rats, 35 3 implants (interval Implantation-site Payne (1964 – implants (in animals per group unspecified) of 7 mg of sarcomas in 1/35 quoted from IARC sheep fat pellets) nickel sulphate (hydration 1990, TERA not stated) 1999). Reported as Vehicle controls No tumours in an abstract. controls (0/35) Observation for 18 months Intramuscular Wistar rats 15 injections of 0.26 mg No injection site Kasprzak et al. injections of nickel as nickel tumours in treated (1983 – quoted 20 males sulphate (hydration not animals or in negative from IARC 1990, stated) every second day controls TERA 1999) during one month Positive (nickel subsulphide) and Local sarcomas in negative (sodium Observation for 2 years positive controls sulphate) controls (16/20) Intraperitoneal Wistar rats 50 injections of 1 mg Abdominal tumours in Pott et al. injections nickel as nickel sulphate 6/30 (p<0.05) 30 females heptahydrate twice (1989, 1992) weekly (1 mesothelioma, 5 sarcomas) (Pott et al. 1992 is cited in IARC and TERA 1999 as Controls: Observation for 132 Pott et al. 1990) weeks 1/33 (sarcoma) 1 ml saline x 3 0/34 1 ml saline x 50 3/66 (1 mesothelioma, 2 ml saline x 4 3 sarcomas)4.1.2.7.1.4.2 Nickel chlorideStudies on the carcinogenicity of nickel chloride following intramuscular implants or intraperitoneal injectionshave been performed in rats; these studies are summarised in Table 4.1.2.7.1.E. Tumours were observedfollowing administration by intraperitoneal injections but not by intramuscular implants.Table 4.1.2.7.1.E: Summary of carcinogenicity studies of nickel chloride in experimental animals byother routes of administration than inhalation, oral administration, and dermal contact. Route of Species, group Concentration, Results Reference administration size and sex exposure duration Intramuscular NIH black rats, 35 3 implants (interval No implantation-site Payne (1964 – implants (in animals per group unspecified) of 7 mg of tumours quoted from IARC sheep fat pellets) nickel chloride (hydration 1990, TERA not stated) 1999). Reported as Vehicle controls No tumours in an abstract. 116
  • R_NickelBackground_0308_hh_chapter0124567.doc Route of Species, group Concentration, Results Reference administration size and sex exposure duration Observation for 18 controls (0/35) months Intraperitoneal Wistar rats 50 injections of 1 mg Abdominal tumours in Pott et al. (1989, injections nickel as nickel chloride 4/32 (p<0.05) 1992) 32 females hexahydrate twice weekly (1 mesothelioma, 3 (Pott et al. 1992 is sarcomas) cited in IARC, 1990 and TERA Observation for 132 1999 as Pott et al. Controls: weeks 1990) 1/33 (sarcoma) 1 ml saline x 3 0/34 1 ml saline x 50 3/66 (1 mesothelioma, 2 ml saline x 4 3 sarcomas)4.1.2.7.1.4.3 Nickel nitrateNo data regarding carcinogenicity following exposure by other routes of administration of nickel nitrate inexperimental animals have been located.4.1.2.7.1.4.4 Nickel carbonateStudies on the carcinogenicity of nickel carbonate following intramuscular implants or intraperitoneal injectionshave been performed in rats; these studies are summarised in Table 4.1.2.7.1.F. Tumours were observedfollowing both routes of administration.Table 4.1.2.7.1.F: Summary of carcinogenicity studies of nickel carbonate in experimental animals byother routes of administration than inhalation, oral administration, and dermal contact. Route of Species, group Concentration, Results Reference administration size and sex exposure duration Intramuscular NIH black rats, 35 3 implants (interval Implantation-site Payne (1964 – implants (in animals per group unspecified) of 7 mg of sarcomas in 6/35 rats quoted from IARC sheep fat pellets) nickel carbonate 1990, TERA 1999). Reported as Vehicle controls No tumours in an abstract. Observation for 18 controls (0/35) months Intraperitoneal Wistar rats 25 or 50 injections of 1 Abdominal tumours in Pott et al. (1989, injections mg nickel as nickel 1/35 1992) 35 females carbonate twice weekly (1 sarcoma) or 3/33 (2 (Pott et al. 1992 is mesothelioma, 1 cited in IARC and sarcomas) TERA 1999 as Observation for 132 Pott et al. 1990) weeks Controls: 1/33 (sarcoma) 1 ml saline x 3 0/34 1 ml saline x 50 3/66 (1 mesothelioma, 3 sarcomas) 2 ml saline x 44.1.2.7.1.4.5 Nickel metalOne study on the carcinogenicity of nickel metal following subcutaneous implantation has been performed.Wistar rats (5 animals of each sex received four subcutaneous implants of pellets of metallic nickel or nickel-gallium alloy (60% nickel) used for dental prostheses and were observed for 27 months. Local sarcomas werenoted in 5/10 rats that received the metallic nickel and in 9/10 rats that received the nickel-gallium alloy. Nolocal tumours occurred in 10 groups of animals that received similar implants of other dental materials (Mitchellet al. 1960 – quoted from IARC 1990). 117
  • R_NickelBackground_0308_hh_chapter0124567.docA number of studies have been performed in which nickel metal powder has been injected at various sites toexperimental animals. Several studies in rats and one study in hamsters have shown sarcomas at the injectionsites following intramuscular injection. Intravenous injection produced local sarcomas in rats, but not in miceand rabbits. Following injection into the femurs of rats and rabbits, local sarcomas were observed at the injectionsite. Intrathoracic injections produced mesotheliomas in rats. Following intraperitoneal injection to rats, tumourswere observed. (IPCS, 1991).4.1.2.7.1.4.6 Other nickel compoundsDose-effect relationships could be demonstrated for nickel subsulphide in rats following intramuscular andintrarenal injections and in hamsters following intramuscular and intratesticular injections. Followingintramuscular injection, local tumours were mostly rhabdomyosarcomas, fibrosarcomas, and undifferentiatedsarcomas; rats appeared more susceptible to the induction of sarcomas by nickel subsulphide than mice,hamsters, or rabbits. (IPCS, 1991, IARC, 1990).Nickel oxide produced local tumours (mainly rhabdomyosarcomas, fibrosarcomas, and undifferentiatedsarcomas) at high incidence following intrapleural, intramuscular, and intraperitoneal injections (IARC, 1990,IPCS, 1991). No renal tumours were seen following intrarenal injections (IARC, 1990).Following intramuscular implants of sheep fat pellets (repeated three times) containing 0 or 7 mg of variousnickel compounds and observation for up to 18 months following treatment, implantation-site sarcomasdeveloped in 1/35, 4/35, and 12/35 rats treated with nickel acetate, nickel(II) oxide, and nickel subsulphide,respectively. No tumours were observed following implantation of anhydrous nickel acetate, nickel ammoniumsulphate, or nickel(III) oxide. (Payne, 1964, abstract only, quoted from TERA, 1999, IARC, 1990).Nickel acetate injected subcutaneously once or twice a week for 5-8 weeks in Male F344 rats producedfibrosarcomas in 5/16 rats 22-66 weeks after injections. Controls treated with physiological saline showed notumour growth (Teraki & Uchiumi, 1992).Other studies with nickel acetate given intraperitoneally to mice cited by IARC (1990) and TERA (1999) (Stoneret al., 1976, Poirier et al., 1984) suggest that water-soluble nickel salts may produce tumours in animals by thisroute of administration.4.1.2.7.1.5 Initiator-Promoter studiesBelow, the available data regarding promoting effects of the five prioritised nickel compounds (nickel sulphate,nickel chloride, nickel nitrate, nickel carbonate, and nickel metal) are summarised; for further details, the readeris referred to the individual risk assessment reports. Data on other nickel compounds are also summarised belowwhen considered relevant.4.1.2.7.1.5.1 Nickel sulphateThree studies evaluating the promoting effect of nickel sulphate in experimental animals have been located;these studies are summarised in Table 4.1.2.7.1.G. The studies may indicate a promoter effect of nickel sulphateif applied locally to the nasopharynx or the oral cavity, or by the feed to pups from initiated dams; however, theindications are rather weak. Based on these studies, it is not possible to draw any conclusion regarding apromoting potential of nickel sulphate.Table 4.1.2.7.1.G: Summary of promoter studies of nickel sulphate in experimental animals. Route of Species, group Concentration, Results Reference administration size and sex exposure duration 1) Topical Rats Initiation: single s.c. Ou et al. (1980, insertion into the injection of 9 mg/ml quoted from IARC nasopharynx 12 animals dinitrosopiperazine 1990, TERA 1999, IPCS 1991) 2) In drinking Controls: 1) 0.02 ml 0.5% nickel 1) Two tumours in the water sulphate in 4% aqueous nasopharynx (one Initiated only or papilloma, one early nickel sulphate gelatin once a week (0.04 mg Ni/week), for 7 weeks carcinoma) only 2) Two tumours in the 118
  • R_NickelBackground_0308_hh_chapter0124567.doc Route of Species, group Concentration, Results Reference administration size and sex exposure duration 2) 1 ml of aqueous 1% nasopharynx (one nickel sulphate (3.8 mg squamous cell Ni/day) for 6 weeks carcinoma, one fibrosarcoma) No tumours in any of Observation for 371 days the controls 3) Topical Rats Initiation: single s.c. Liu et al. (1983, insertion in the injection of 9 mg/ml quoted from IARC oral cavity 22 animals dinitrosopiperazine 1990, TERA 1999, IPCS 1991). Controls: 3) 5/22 developed Reported in an 4) In drinking 3) 0.02 ml 0.5% nickel abstract. water sulphate in 4% aqueous carcinomas (2 in the Initiated only or nasopharynx, 2 in the nickel sulphate gelatin once a week (0.04 mg Ni/week), for 7 week nasal cavity, 1 of the only hard palate) 4) No tumour 4) 1 ml of aqueous 1% developed nickel sulphate (3.8 mg Ni/day) for 6 weeks No tumours in any of the controls Observation for 371 days Feed Rats Initiation: single s.c. Ou et al. (1983, injection of 9 mg/ml quoted from IARC 13 females dinitrosopiperazine on 1990, TERA 1999, day 18 of gestation IPCS 1991). Reported in an abstract. Pups of treated dams fed 5/21 pups (24%) 0.05 ml of 0.05% nickel developed carcinomas sulphate (9.5 µg Ni/day) of the nasal cavity daily for one month increasing every month with 0.1 ml (19 µg Ni/day) for further 5 months Controls: No tumours (0/13) Initiated dams 3/11 pups (27%) Untreated pups of treated developed tumours dams (one nasopharyngeal squamous-cell carcinoma, one neurofibrosarcoma of the peritoneal cavity, one granulosa-thecal- cell carcinoma of the ovary) Untreated pups of uninitiated dams No tumours4.1.2.7.1.5.2 Nickel chloride 119
  • R_NickelBackground_0308_hh_chapter0124567.docA study evaluating the promoting effect of nickel chloride in male rats is summarised in Table 4.1.2.7.1.H. Thestudy indicates a promoter effect of orally administered nickel chloride in renal carcinogenesis under theconditions of the study.Table 4.1.2.7.1.H: Summary of promoter studies of nickel chloride in experimental animals. Route of Species, group Concentration, Method Results Reference administration size and sex exposure duration Drinking water Rats F344 Initiation: 500 mg/l Kidneys were The number of DF Kurokawa N-ethyl-N- examined was 170. et al. (1985) 15 males hydroxyethyl- histologically for nitrosamine assessment of 12 RCT’s (EHEN) for 2 Dysplastic Foci (adenomas) Controls: weeks (DF) and Renal identified in 8 rats. Distilled water Cell Tumours for 25 weeks (RCT) 600 mg/l nickel Controls: The chloride number of DF was hexahydrate for 25 17; 2 rats with weeks totally 3 RCT’s identified.In a two-stage carcinogenesis assay, orally administered nickel chloride enhanced the renal carcinogenicity of N-ethyl-N-hydroxyethylnitrosamine in rats, but not the hepatocarcinogenicity in rats after initiation with N-nitrosodiethylamine, the gastric carcinogenicity in rats after initiation with of N-methyl-N-nitro-N-nitrosoguanidine, the pancreatic carcinogenicity in Syrian golden hamsters following initiation with N-nitrosobis(2-oxopropyl)amine, or the skin carcinogenicity in mice initiated with 7,12-dimethylbenzanthracene(Hayashi et al., 1984, Kurokawa et al., 1985, quoted from IARC, 1990, IPCS, 1991).4.1.2.7.1.5.3 Nickel metalWhen female Wistar rats received intratracheal instillations of 20-methylcholanthrene with metallic nickelpowder, nickel seemed to enhance the lung carcinogenicity of 20-methylcholanthrene (squamous-cellcarcinomas) (Mukubo 1978 – quoted from IARC, 1990, IPCS, 1991).4.1.2.7.1.5.4 Nickel nitrate, nickel carbonateNo data regarding the promoting effect of nickel nitrate and nickel carbonate in experimental animals have beenlocated.4.1.2.7.1.5.5 Other nickel compoundsNo data regarding the promoting effect of other nickel compounds in experimental animals have been located.A two-stage carcinogenesis study has been performed in which nickel acetate (administered as the tetrahydrate,single intraperitoneal injection of 5.3 mg Ni/kg) was tested as a tumour initiator in male rats using sodiumbarbital (500 mg/l in the drinking water) as the promoter (Kasprzak et al. 1990). Incidences of renal corticaladenomas alone and combined adenomas and adenocarcinomas were significantly increased in theinitiated/promoted rats compared to those administered nickel without subsequent sodium barbital promotion.Nickel acetate by itself resulted in one renal cortical adenoma. Sodium barbital by itself resulted in six renalcortical adenomas and 13 renal pelvic tumours (12 papillomas and 1 carcinoma).A transplacental carcinogenicity study (Diwan et al. 1992) has been performed in pregnant rats administerednickel acetate by intraperitoneal injection. Offspring were either untreated or treated with sodium barbital in thedrinking water. The incidences of kidney tumours (adenomas or carcinomas) were significantly higher in maleoffspring that were treated with nickel acetate prenatally and sodium barbital postnatally than in control males.No kidney tumours developed in males given prenatal nickel acetate only, or in any of the female groups.Pituitary tumours (combined adenomas and carcinomas) were significantly increased in offspring of both sexesgiven nickel acetate prenatally compared to controls. Postnatal administration of sodium barbital had noinfluence on the development of the pituitary tumours. The authors conclude that “The results of this studyindicate that nickel acetate is a transplacental initiator of kidney tumours and a complete transplacentalcarcinogen for pituitary tumors”.TERA (1999) concludes that: “Nickel acetate also shows evidence of carcinogenicity in initiation-promotionstudies and demonstrates transplacental initiation (Diwan et al., 1992; Kasprazak et al., 1990; Tables 25 and 120
  • R_NickelBackground_0308_hh_chapter0124567.doc26) and of promotion of carcinogenesis (Kurokawa et al., 1985; Liu et al., 1980, 1983; Ou et al., 1980)(insoluble forms were not tested in the latter system)”.4.1.2.7.1.6 Discussion and conclusions, carcinogenicity in experimental animalsThe following plausible mechanisms leading to the carcinogenic effects of nickel have been presented by MAK(2006).A number of biochemical studies suggest that the release of nickel ions is responsible for the genotoxic andcarcinogenic effects of nickel compounds. Nickel ions from readily soluble nickel salts are slowly taken up intomammalian cells through plasma membrane ion channels. In contrast, nickel metal and the less soluble nickelsulphides and oxides are taken up by phagocytosis. Metallic nickel was phagocytized by alveolar macrophagesof exposed rats (Johansson et al. 1980) and also in vitro by CHO cells (Costa & Mollenhauer 1980). Nickelsubsulphide was also phagocytized by CHO cells (Lee et al. 1995). Inside mammalian cells, less soluble nickelcompounds and nickel metal result in the release of nickel ions.A much higher intracellular bioavailability of poorly soluble nickel compounds as compared to that of readilysoluble nickel salts may explain the higher potency of poorly soluble nickel salts. For example the concentrationof intracellular nickel ions was more than two orders of magnitude higher after phagocytosis of less solublenickel salts as compared to uptake of soluble nickel salts. And in CHO cells treated with a suspension of nickelsulphide (10 mg/l), binding of nickel ions to nucleic acids was 300 to 2 000 fold higher as compared toincubation with the same concentration of soluble nickel salts (Harnett et al. 1982). After the phagocytosis ofnickel subsulphide, very stable ternary protein-nickel-DNA complexes were formed in the nuclei of CHO cells(Lee et al. 1982) and intracellular nickel ion concentrations in the mmol/l range were calculated for poorlysoluble nickel compounds.4.1.2.7.1.6.1 InhalationInhalation studies of nickel sulphate hexahydrate (mass median aerodynamic diameter of 1.8-3.1 + 1.6-2.9 μm)have been performed in rats and mice (NTP 1996a); no exposure related neoplasms were observed in neither rats(F344/N) nor mice (B6C3F1) after exposure to nickel sulphate hexahydrate by inhalation in concentrations up to0.11 mg Ni/m3 or 0.22 mg Ni/m3, respectively for 2 years.A number of animal studies on the carcinogenicity of nickel metal following inhalation or intratrachealinstillation have been performed. Local neoplasms were observed in most of the studies; however, all the studiessuffer from inadequacies and are considered inappropriate for the risk assessment of the carcinogenic potential ofnickel metal following inhalation.No studies regarding carcinogenicity following inhalation exposure or intratracheal instillation of nickelchloride, nickel nitrate, and nickel carbonate in experimental animals have been located.NTP has also investigated the carcinogenic potential of nickel oxide and nickel subsulphide in 2-year inhalationstudies in rats (F344/N) and mice (B6C3F1).There was some evidence of carcinogenic activity of nickel oxide (high temperature, green nickel oxide, massmedian diameter 2.2 ± 2.6 µm) in rats (concentrations up to 2.0 mg Ni/m3) based on the increased incidences oftumours in the lungs and of the adrenal medulla. There was equivocal evidence of carcinogenic activity of nickeloxide in female mice (concentrations up to 3.9 mg Ni/m3) based on marginally increased incidences of lungtumours in the mid- and high-dose groups. There was no evidence of carcinogenic activity in male mice(concentrations up to 3.9 mg Ni/m3). (NTP 1996b).There was clear evidence of carcinogenic activity of nickel subsulphide (mean value for the mass medianaerodynamic diameter 2.0-2.2 µm) in rats (concentrations up to 0.73 mg Ni/m3) based on the increasedincidences of tumours in the lungs and of the adrenal medulla. There was no evidence of carcinogenic activity inmice (concentrations up to 0.88 mg Ni/m3). (NTP 1996c).In another inhalation study (78 weeks) of nickel subsulphide (0.97 mg Ni/m3, 70% particles smaller than 1 µm)in rats (F344/N), the incidence of lung tumours in treated animals was increased as well (Ottolenghi et al. 1974 –quoted from NiPERA 1996, IPCS 1991 and IARC 1990).According to TERA (1999), some arguments have been raised that the negative evidence from the NTP study(NTP 1996a) on nickel sulphate cannot be considered definitive. It has been questioned whether sufficiently highconcentrations were tested in the rat study on nickel sulphate based on the observation of a somewhat higherincidence of lung lesions in rats exposed to 0.11 mg Ni/m3 as nickel subsulphide than in rats exposed to the sameconcentration as nickel sulphate. According to TERA, the NTP review panel has noted that slightly higher 121
  • R_NickelBackground_0308_hh_chapter0124567.docconcentrations of nickel sulphate could have been tested, but overall the study was judged to be adequate.According to NTP (1996a), the high concentration (0.11 mg Ni/m3) in the nickel sulphate study was chosenbased on the observation of chronic active inflammation in the lungs of rat in the 13-week study and this lesionwas considered to be potentially life-threatening, because of the possibility of reduced lung function; the highnickel sulphate concentration in the 2-year rat study was just below the concentration at which mild chronicactive inflammation was seen in the 13-week study.Sanner & Dybing (1996) have analysed the sensitivity of the NTP-studies on nickel subsulphide, nickel oxideand nickel sulphate hexahydrate. In the sensitivity analysis, it was addressed and discussed whether the lack ofalveolar/bronchiolar neoplasms in rats exposed to nickel sulphate hexahydrate is related to the insignificantincreases in lung weights and nickel lung burden, especially after 7 months of treatment, when compared tofindings in the analogous studies performed on nickel subsulphide and nickel oxide, which induced lung tumoursin rats of both sexes (nickel subsulphide: clear evidence of carcinogenic activity; nickel oxide: some evidence ofcarcinogenic activity). Furthermore it was discussed whether nickel sulphate hexahydrate would have beenexpected to induce tumours if the tumour inducing potency of the sulphate was the same as that of thesubsulphide or oxide. According to the sensitivity analysis “the number of lung tumours in the three studiesincreased linearly with the observed increase in lung weight, which was assumed to be caused by inflammatoryprocesses in the lung. Moreover, the number of tumours found for nickel sulphate and nickel subsulphideincreased proportionally with the nickel lung burden.” It was concluded “that nickel sulphate may have thesame tumour inducing potency as nickel subsulphide and nickel oxide when using concentrations giving thesame increase in lung weight, and the same tumour inducing potency as nickel subsulphide when usingconcentrations giving the same nickel lung burden. Thus, it is likely that nickel sulphate would have showncarcinogenic activity if tested at a higher concentration.” Furthermore, “the members of the NTP TechnicalReport’s Review Subcommittee has noted that it could have been possible to use a higher exposure concentrationof nickel sulphate hexahydrate than those used.”A response from Industry (NiPERA 2002a) has pointed out that “when the lung weights of male and female ratsare compared after 15 months of exposure to the highest nickel sulphate concentration that was negative and thelowest nickel subsulphide and nickel oxide concentrations that were positive, similar values are found for allthree compounds, with lung weights differing by just 10% (males) or 30% (females). These results indicate thatalthough inflammatory processes may contribute to tumour induction they are not the primarily means by whichtumours are induced by exposure to nickel subsulphide or nickel oxide.” Furthermore, Industry pointed out that“if a two-fold higher concentration was tested in the NTP studies (i.e., 0.22 mg Ni/m3 for rats) without increasedmortality, the lung burdens of these animals would still be lower than those present in the nickel subsulphide-exposed animals based on curves for lung burdens as a function of nickel exposure levels. Nevertheless, the factthat nickel oxide was negative at 0.5 mg Ni/m3 with lung burdens much higher than those at which nickelsubsulphide was positive (0.11 and 0.73 mg Ni/m3) cast serious doubt on the relevance of nickel lung burdens topredict risk of lung tumours from nickel exposures.”According to TERA (1999), the lack of evidence (nickel sulphate, nickel subsulphide, nickel oxide in males) orequivocal evidence (nickel oxide in females) for carcinogenic activity in mice following inhalation has raised thequestion of how informative the mouse studies are. TERA states that there are “two interpretations to thenegative mouse data for nickel sulphate. One interpretation is that the mouse bioassay constitutes a valid test ina second species (in addition to the rat), and that the negative result in the mouse study (together with thenegative result in the rat bioassay) suggests that soluble nickel is not carcinogenic. A second interpretation isthat, based on the negative and equivocal results for nickel subsulphide and nickel oxide, respectively, in mice,the mouse is not a suitable species for studying nickel carcinogenesis. The mouse is, however, considered anappropriate model for inhalation carcinogenesis of metals.” The last statement is based on a search of the NTPbioassay results database, which found no tendency for mice to be less likely to develop lung tumours than rats,even when considering only inhalation studies or metals (cobalt sulphate, molybdenum trioxide, and seleniumsulphide) (NTP 1998 – quoted from TERA 1999).The available data raises the question of whether soluble forms of nickel differ from insoluble forms of nickel incarcinogenic potential (i.e., qualitatively) or only in potency (i.e., quantitatively) in experimental animalsfollowing exposure by inhalation; however, the available data are not sufficient for an evaluation of thisquestion.The suggestion of a difference in carcinogenic potential or potency between soluble and insoluble forms ofnickel might be supported by data indicating that the cellular uptake of soluble and insoluble nickel compounds aredifferent (see section 4.1.2.1.2) as insoluble nickel compounds enter the cell via phagocytosis, while soluble nickelcompounds are not phagocytised, but enter the cell via metal ion transport systems or through membrane diffusion.The latter two processes are, according to TERA (1999), much less efficient implicating that the same extracellularlevels of soluble and insoluble nickel compounds lead to lower nickel levels intracellularly for soluble nickel 122
  • R_NickelBackground_0308_hh_chapter0124567.doccompounds. Soluble forms of nickel interact with the cell in a way that maximises cytotoxicity and minimises nickeldelivery to the nucleus, while insoluble forms of nickel interact with cells in a way that decreases the cytotoxicpotential while increasing the delivery of nickel to the nucleus.Overall, there is no evidence of carcinogenic activity following inhalation of nickel sulphate hexahydrate in ratsand mice under the conditions of the available inhalation studies (NTP 1996a); however, it should be noted, asdiscussed above, that some arguments have been raised that the negative evidence from the NTP studies onnickel sulphate cannot be considered definitive. The studies in experimental animals on the carcinogenicity ofnickel metal following inhalation or intratracheal instillation suffer from inadequacies and are consideredinadequate for an evaluation of the carcinogenic activity of nickel metal following inhalation. No studiesregarding carcinogenic activity following inhalation exposure or intratracheal instillation of nickel chloride,nickel nitrate, and nickel carbonate in experimental animals have been located. The inhalation studies on nickeloxide (NTP 1996b) and nickel subsulphide (NTP 1996c) showed some evidence and clear evidence,respectively, for carcinogenic activity following inhalation in rats, and there was equivocal evidence for nickeloxide in female mice. No other data considered as being relevant for the conclusion on the carcinogenicity of thefive prioritised nickel compounds in experimental animals following inhalation have been located.In conclusion, the available data on carcinogenicity of various nickel compounds is considered as beinginsufficient for a conclusion on the carcinogenic potential of the five prioritised nickel compounds (nickelsulphate, nickel chloride, nickel nitrate, nickel carbonate, and nickel metal) in experimental animals followinginhalation. It should be noted that soluble forms of nickel might differ from insoluble forms of nickel incarcinogenic potential or in potency in experimental animals following exposure by inhalation; however, theavailable data are not sufficient for an evaluation of this suggestion.4.1.2.7.1.6.2 OralThe carcinogenicity of nickel sulphate following oral administration has been studied in two old non-guidelinestudies with rats and dogs. No neoplasms were revealed in either rats or dogs in these studies . A 2-yearcarcinogenicity study with rats performed according to OECD 451 did not show any carcinogenic potential ofexposure to nickel sulphate following oral (gavage) administration.No data regarding carcinogenicity of nickel chloride, nickel nitrate, nickel carbonate, and nickel metal inexperimental animals following oral administration have been located.When nickel acetate was tested for carcinogenic effects in drinking water studies with rats and mice, noexposure-related neoplasms was observed in either rats or mice; however, the studies suffer from severallimitations and are therefore not conclusively negative.In conclusion, based on the available data on nickel sulphate, the water soluble nickel compounds should beconsidered without carcinogenic concern as well. Data are too limited for a direct evaluation of the carcinogenicpotential in experimental animals following oral administration of nickel carbonate and nickel metal as well as ofother insoluble nickel compounds. However, given the lower solubility of these compounds, carcinogenicpotential following this route of administration is considered unlikely.4.1.2.7.1.6.3 DermalNo data regarding carcinogenicity following dermal contact to nickel sulphate, nickel chloride, nickel nitrate,nickel carbonate, and nickel metal in experimental animals have been located.No tumours developed in the buccal pouch, oral cavity, or intestinal tract of male hamsters painted on themucosa of the buccal pouches with α-nickel subsulphide.In conclusion, although the available data are sparse, the lack of carcinogenic potential after oral exposure tonickel sulphate make carcinogenic effects following dermal exposure to nickel chloride, nickel nitrate, nickelcarbonate, and nickel metal very unlikely.4.1.2.7.1.6.4 Other routes of administrationStudies on the carcinogenicity of nickel sulphate following intramuscular injections or implants, orintraperitoneal injections have been performed in rats; tumours were observed following administration byintraperitoneal injections and by intramuscular implants but not by intramuscular injections. 123
  • R_NickelBackground_0308_hh_chapter0124567.docStudies on the carcinogenicity of nickel chloride following intramuscular implants or intraperitoneal injectionshave been performed in rats; tumours were observed following administration by intraperitoneal injections butnot by intramuscular implants.No data regarding carcinogenicity following exposure by other routes of administration of nickel nitrate inexperimental animals have been located.Studies on the carcinogenicity of nickel carbonate following intramuscular implants or intraperitonealinjections have been performed in rats; tumours were observed following both administration routes.One study on the carcinogenicity of nickel metal following subcutaneous implantation has been performed inrats; local tumours were observed. A number of studies have been performed in which nickel metal powder hasbeen injected at various sites to experimental animals; with few exceptions these studies showed that nickelmetal caused local tumours.A large number of studies have been performed in which nickel subsulphide or nickel oxide have been injectedat various sites to experimental animals; with few exceptions these studies showed that these two nickelcompounds caused local tumours.In conclusion, the available data show that nickel compounds, with a few exceptions, produce local tumoursfollowing injection at various sites to experimental animals. These routes of administration are not directlyrelevant for humans exposed via inhalation, oral intake or dermal contact. They are however relevant inevaluating exposure to nickel by implants of nickel metal or nickel-containing alloys (iatrogenic exposure). Inaddition, the results of these studies with animals exposed by these routes (injections, installations etc), is also ofrelevance in the evaluation of effects from other routes of exposure in humans, as they constitute examples ofhow mammalian cells may react under certain circumstances.4.1.2.7.1.6.5 Initiator-Promoter studiesThree studies evaluating the promoting effect of nickel sulphate in experimental animals have been located,which may indicate a promoter effect of nickel sulphate, if applied locally to the nasopharynx or the oral cavity,or by the feed to pups from initiated dams; however, the indications are rather weak.In a two-stage carcinogenesis assay, orally administered nickel chloride enhanced the renal carcinogenicity ofN-ethyl-N-hydroxyethylnitrosamine in rats, but not the hepatocarcinogenicity in rats after initiation with N-nitrosodiethylamine, the gastric carcinogenicity in rats after initiation with of N-methyl-N-nitro-N-nitrosoguanidine, the pancreatic carcinogenicity in Syrian golden hamsters following initiation with N-nitrosobis(2-oxopropyl)amine, or the skin carcinogenicity in mice initiated with 7,12-dimethylbenzanthracene.When female Wistar rats received intratracheal instillations of 20-methylcholanthrene with nickel metal powder,nickel seemed to enhance the lung carcinogenicity of 20-methylcholanthrene (squamous-cell carcinomas).No data regarding the promoting effect of nickel nitrate and nickel carbonate in experimental animals havebeen located.No data regarding the promoting effect of other nickel compounds and considered as being relevant for theconclusion on the carcinogenicity of the five prioritised nickel compounds in experimental animals followinginhalation have been located.In conclusion, the available data indicate that nickel sulphate, nickel chloride, and nickel metal may have apromoting effect in combination with selected initiators.The two soluble nickel compounds, nickel sulphate and nickel chloride, were tested for promoter activity afteroral administration. The data for the soluble nickel salts suggests that these salts do not cause cancer followingoral administration on their own, although the available data is limited. The study of nickel sulphate followingoral administration currently being carried out will provide more reliable data. This study will not howeverprovide any additional information on possible effects of soluble nickel salts as promoters.Nickel metal was tested as a promoter after intratracheal instillation. The significance of this study is not clear inthe evaluation of the inhalational carcinogenicity of the metal. 124
  • R_NickelBackground_0308_hh_chapter0124567.docNickel acetate administered intraperitoneally has been shown to initiate renal tumours in rats and rat offspringwhen administered to pregnant rats. In the latter situation, nickel acted as a complete carcinogen producingpituitary tumours.4.1.2.7.1.6.6 Conclusions in reviews on nickel compounds4.1.2.7.1.6.6.1 CSTEE (2001)The lack of evidence for carcinogenicity of nickel sulphate hexahydrate can be due to the relatively low lungburden that was tested, since the exposure levels had to be kept lower than for nickel oxide and nickelsubsulphide due to respiratory toxicity of nickel sulphate hexahydrate. Thus, the lung burden (amount nickel perg of lung) from the highest exposure concentration of nickel sulphate hexahydrate was approximately 6 timeslower than the lowest exposure concentrations to nickel subsulphide. In studies with parenteral administration,soluble nickel compounds induce local tumours, albeit with much lower potency than that seen with insolublenickel compounds. Therefore, the CSTEE concludes that the lack of evidence of carcinogenicity of nickelsulphate hexahydrate in the NTP study cannot be taken as evidence of lack of carcinogenic potential for solublenickel compounds. Nickel carcinogenicity will be dependent on the time-integrated intracellular concentration ofnickel ions as the active entity, so that the relative potency of various nickel species will be related to theirbioavailability and lung burden. In the rat experiments it is the insoluble nickel compounds that are most potentwith respect to carcinogenicity.4.1.2.7.1.6.6.2 TERA (1999)Standard animal bioassays of soluble nickel compounds administered to rats or mice by the oral or inhalationroutes have not shown soluble nickel compounds to be carcinogenic. Studies of insoluble nickel compounds,nickel oxide (NTP 1996b) and nickel subsulphide (NTP 1996c), provided evidence for carcinogenicity of thesecompounds in rats, and there was equivocal evidence for nickel oxide carcinogenicity in female mice.4.1.2.7.1.6.6.3 IARC (1999)There is sufficient evidence in experimental animals for the carcinogenicity of implants of metallic nickel andfor nickel alloy powder containing approximately 66-67% nickel, 13-16% chromium and 7% iron. There islimited evidence in experimental animals for the carcinogenicity of implants of alloys containing nickel, otherthan the specific aforementioned alloy.4.1.2.7.1.6.6.4 NiPERA (1996)Studies on inhalation of metallic nickel powder are essentially negative for carcinogenicity. Intratrachealinstillation of nickel powder has been shown to produce malignant lung tumours in animals, but the relevance ofsuch studies in the aetiology of lung cancer in humans is questionable. The review concludes that animalevidence of carcinogenicity for metallic nickel is lacking.The carcinogenicity of green nickel oxide via routes relevant to occupational exposures suggests that it iscapable of inducing lung tumours in animals, although it does not appear to be a very strong carcinogen.Unlike NiO, the evidence for lung cancer in rats of nickel subsulphide is more definitive. Nickel subsulphide atthe doses tested is not a particularly strong carcinogen.Exposure to nickel sulphate at the highest doses tested in the NTP study failed to produce any carcinogeniceffects in the lung or elsewhere in rats and mice. Soluble nickel compounds via other relevant routes of exposurehave also failed to produce tumours.4.1.2.7.1.6.6.5 IPCS (1991)There is a lack of evidence of a carcinogenic risk from oral exposure to nickel, but the possibility that it acts as apromoter has been raised.There is evidence of a carcinogenic risk through the inhalation of nickel metal dusts and some nickelcompounds.4.1.2.7.1.6.6.6 IARC (1990)There is sufficient evidence in experimental animals for the carcinogenicity of metallic nickel, nickel monoxides,nickel hydroxides and crystalline nickel sulphides. 125
  • R_NickelBackground_0308_hh_chapter0124567.docThere is limited evidence in experimental animals for the carcinogenicity of nickel alloys, nickelocene, nickelcarbonyl, nickel salts, nickel arsenides, nickel antimonide, nickel selenides and nickel telluride.There is inadequate evidence in experimental animals for the carcinogenicity of nickel trioxide, amorphousnickel sulphide and nickel titanate.4.1.2.7.1.7 Conclusion, carcinogenicity in experimental animalsThe data in experimental animals on nickel compounds as reported here give some evidence for thecarcinogenicity of the five prioritised nickel compounds (nickel sulphate, nickel chloride, nickel nitrate, nickelcarbonate, and nickel metal) in experimental animals. There is evidence for carcinogenicity following inhalationfor some nickel compounds.Based on the available oral data on nickel sulphate the water-soluble nickel compounds should be consideredwithout carcinogenic concern as well. However, data are too limited for an evaluation of the carcinogenicpotential in experimental animals following oral administration of nickel carbonate and nickel metal as well as ofother nickel compounds.Although there is no data on carcinogenicity following dermal exposure, the lack of carcinogenic potential afteroral exposure to nickel sulphate make carcinogenic effects following dermal exposure to nickel chloride, nickelnitrate, nickel carbonate, and nickel metal very unlikely.The available data show that some nickel compounds can produce local tumours following injection at varioussites to experimental animals. It should be noted that these routes of administration are irrelevant for humansexposed via inhalation, oral intake or dermal contact. These studies are however relevant when evaluatingexposure to nickel metal by implants of nickel metal or of nickel containing alloys (iatrogenic exposures). Itshould be noted that IARC (1999) for implants of nickel metal or nickel containing alloys has concluded thatthere is “sufficient evidence in experimental animals for the carcinogenicity of implants of metallic nickel andfor nickel alloy powder containing approximately 66-67% nickel, 13-16% chromium and 7% iron.”4.1.2.7.2 Human data4.1.2.7.2.1 EpidemiologyIn the final report from the International Committee on Nickel Carcinogenesis in Man (ICNCM), quantitativeexposure estimates were introduced for four forms of nickel (water-soluble, sulphidic, oxidic, and metallicnickel), with the aim to identify which form(s) of nickel that contributed to the cancer risk in exposed humans(Doll et al., 1990). The analyses were based on calculation of standardised mortality ratios from lung cancer andnasal cancer according to duration of work in different departments and to cumulative exposures to the fourforms of nickel. The variables were used in a categorical form, and the workers were cross-classified accordingto dichotomised nickel exposure variables (low or high exposure). Multivariable regression analyses orcontinuous variables were not used.Although a standardized strategy of analysis was used, the uncertainty and variation in the exposure measuresmade it difficult to compare across cohorts. Somewhat more confidence was put in comparisons made betweengroups at the same refinery. The most informative cohorts of nickel exposed workers proved to be the Welsh, theNorwegian, and some of the Canadian cohorts.For exposure to water soluble nickel compounds, strong evidence of a dose related increase in lung cancer riskcame from the electrolysis workers in the Norwegian cohort. These workers had only low exposure to lesssoluble forms of nickel. Some evidence, but slightly less convincing, was found in the Welsh cohort. Both theNorwegian and the Welsh cohorts gave evidence that water-soluble nickel increased the lung cancer riskassociated with exposure to oxidic nickel, the Welsh also for the combination of water-soluble and sulphidicnickel. The lack of evidence of risk associated with water-soluble nickel among the Port Colborne electrolysisworkers was explained by lower exposures to water-soluble as well as to less soluble forms.The results from Wales suggested a separate effect on lung cancer risk from sulphidic nickel, but no supportwas found for this view in the other cohorts. Some evidence from the Norwegian and Welsh cohort suggested alung cancer risk from exposure to oxidic nickel, although a possible contribution from water-soluble nickelcould not be excluded in the Welsh data. A potential effect from the concomitant exposure to copper oxides wasalso discussed. No evidence was found of increased lung cancer risk from exposure to metallic nickel. As anoverall conclusion, much of the lung cancer was ascribed to high exposures to the combination of nickel oxides 126
  • R_NickelBackground_0308_hh_chapter0124567.docand nickel sulphides, or to high levels of oxidic nickel in the absence of sulphidic nickel. Water-soluble nickelwas found to increase the risk of lung cancer alone or together with less soluble forms. The data suggested thatwater-soluble nickel compounds might increase lung cancer risk at exposure levels below those of less solubleforms of nickel (1 mg Ni/m3 versus 10 mg/m3).Since the ICNCM study, two of the cohorts have been analysed with more or less the same exposure estimatesand with regression methods that allow a simultaneous estimation of the effect of the four forms of nickel.Easton et al., (1992).Compared to the Welsh contribution in the ICNCM study, the Easton et al., (1992) paper was based on anadditional year of follow-up (through 1985). The same exposure matrix was used. Initially, the risk of lung (andnasal) cancer was estimated by duration of employment in the high-risk areas identified by Kaldor et al., (1986).Additionally, based on 172 lung cancer deaths before 1930, a model was fitted with each of the four types ofnickel included in their continuous form. The strongest effect was suggested for water-soluble nickel, and theauthors concluded that some of the risk was due to water-soluble nickel with contributions also from at least oneinsoluble form of nickel.Andersen et al., (1996).Andersen and co-workers analysed a cancer update of the Norwegian nickel workers using the exposureestimates and the cohort sample from the ICNCM study extended with workers who had 3 years service or morefrom the years before 1946. Standardized incidence ratios were calculated and internal comparisons performed inmultivariable analyses with Poisson regression including cumulative exposure to water-soluble and oxidicnickel, age, observation period, and smoking habits. Based on 200 cases of lung cancer, there was an excess riskfrom cumulative exposure to water soluble and oxidic nickel. A strong dose related increase was seen forwater-soluble nickel, not equally clear for oxidic nickel. The effect of the combination of smoking and nickelexposure seemed to fit into a multiplicative pattern.Anttila et al., (1998).Some workers from this Finnish refinery were considered in the ICNCM study, but only one case of lung cancerwas found. The cohort was enlarged to include workers with a minimum of 3 months employment at acopper/nickel smelter and a nickel refinery, and analysed by Anttila and co-workers. Although the number ofcases was small, with 6 lung cancers and 2 nasal cancers among the refinery workers, the risk was increasedsignificantly at the 5% level among the workers who had mostly been exposed to water-soluble nickel. Anothertwo nasal cancers had been detected in the same group of workers, one probably misclassified and one diagnosedafter the end of follow-up.Grimsrud et al., (2002).In the Norwegian cohort of nickel workers, Grimsrud and co-workers performed a case-control study of lungcancer including 213 of the identified cases and their age-matched controls (94% participation rate). Thehistorical nickel exposures had been reassessment in a study based on a large number of personal measurementsand speciation analyses in the 1990s. Detailed information on smoking habits was collected through interviewswith participants or next-of-kin. A strong dose-related effect from water-soluble nickel on the relative risk oflung cancer was found when adjustment was made for smoking, other exposures at the refinery, andoccupational lung carcinogens outside the refinery. The effect from the insoluble forms of nickel was less clear.Grimsrud et al., (2003).An update of the cancer incidence in the Norwegian cohort confirmed the findings from the case-control study.The risk pattern in the nickel electrolysis was of the same size before and after the change from a nickel sulphatebased process to a predominantly nickel chloride based electrolysis. Only minor differences were found whenthe smoking habits in the cohort and smoking data from the case-control study were compared with the nationaldata.Some other small studies on nickel workers elsewhere also have been published, but due to the size and designof the studies the information that can be drawn from them is very limited.4.1.2.7.2.2 ExposuresDuring the 1990s, further studies on exposures in the nickel producing industries indicated that most nickelspecies were present wherever nickel was found, although in varying proportions. On the basis of these findings,some characteristics of the earlier exposure estimates can be questioned.Kiilunen et al., (1997). 127
  • R_NickelBackground_0308_hh_chapter0124567.docKiilunen and co-workers studied the past and present exposures in the nickel refinery where the workers studiedby Anttila et al., (1998). The predominating exposure at the refinery was water-soluble nickel, and the particlesize was large enough to explain deposition in the upper respiratory tract, and the average nickel levels in thebreathing zone were in the range 0.15 and 0.25 mg/m3.Andersen et al., (1998).Andersen and co-workers analysed airborne dust from the Norwegian refinery and identified between 4.6 and35.3% by weight of water-soluble nickel in the roasting area.Thomassen et al., (1999).Thomassen and co-workers studied the exposures in a Russian nickel refinery in Monchegorsk at the KolaPeninsula. The results were of particular interest for the Norwegian studies as the electrolysis were of the sametype (Hybinette method) as the one used in Norway until 1978. The rest of the process also followed much of thesame principles. In line with reports from the Norwegian and Canadian refineries, the results from the Russianplant identified the highest levels of water-soluble nickel in the roasting areas, especially at the upper floors ofthe roaster building.Werner et al., (1999a).Werner and co-workers studied the distribution of the four forms of nickel in aerosols from four differentdepartments at the Norwegian refinery. The results contrasted sharply with the estimates in ICNCM study, bothwith respect to the absolute levels and the distribution of species: In the matte grinding area, the ICNCM studytook the levels to be 1.3 mg/m3 sulphidic, 0.3 mg/m3 metallic, and no water-soluble nickel until 1984, while themeasurements taken in 1995 suggested levels of 0.4, 0.03, and 0.03 mg/m3, respectively (inhalable aerosolsampler).Werner et al., (1999b).In a study of particle size distribution in some departments at the Norwegian refinery, between 14 and 33% ofthe inhalable aerosols belonged to the fine fraction expected to pass beyond the larynx. When compared to ‘total’aerosol samples, which is the type used in the new exposure estimates for the Norwegian refinery (Grimsrud etal., 2000), the fraction passing to the bronchi and lung would constitute an even greater proportion, as thesesamplers leave out some of the largest particles.Vincent et al., (2001).In a study of nickel species in works and departments where raw ore is handled, the four forms of nickel werefound at all sites. The proportion of water-soluble nickel varied between 2 and 8%, while, in the ICNCM study,similar areas were assumed to have a zero level of water-soluble nickel.4.1.2.7.3 DiscussionA frequently stated criticism of the nickel-cancer epidemiology is directed towards the lack of good exposuremeasures and the lack of control for important confounders such as tobacco smoking and other occupationalexposures. Another question is the apparent discrepancy between the epidemiological results and the ease withwhich less soluble forms can induce cancer in experimental research, and the difficulties of achieving similarresults with water-soluble nickel. The following discussion is limited to these aspects.The most recent studies among the Norwegian refinery workers were based on an exposure matrix developedfrom personal measurements and speciation analyses of the four different forms of nickel in refinery dusts andaerosols. This approach led to some important changes in the exposure estimates: The previously assumed"negligible" exposure to water-soluble nickel in the Norwegian grinding, roasting, and smelting departments,taken to be zero in the ICNCM study, was replaced by some 10% of the total nickel in the new exposure matrix.The recent studies on nickel species in nickel production confirm the appropriateness of these changes inexposure estimates. They also suggest that the levels of water-soluble nickel may have been underestimated inthe ICNCM report even for other nickel works.The recent results from the Norwegian and Welsh cohorts are very much in agreement with each other.Additionally, the recent study from the Finnish nickel-refinery cohort concluded that exposure to water-solublenickel was the most likely explanation of the excess risk of lung and nasal cancer (Anttila et al., 1998). A studyamong Russian nickel workers reported the highest risk of lung cancer among electrolysis workers (Saknyn &Shabynina, 1973; quoted in IARC, 1990).The lung cancer mortality among electrolysis workers at the Canadian refinery in Port Colborne did not showany increased risk in the studies by Roberts and co-workers and the ICNCM (Roberts et al., 1984; Roberts et al., 128
  • R_NickelBackground_0308_hh_chapter0124567.doc1989; Doll et al., 1990) although the exposures were predominantly to water-soluble nickel. Loss to follow-upand the method of estimation of standardised mortality ratios in these studies probably led to an underestimationof the risk. The exposure estimates for the refinery were too imprecise to allow any formal comparison with theNorwegian refinery. Still, differences in the process do suggest that the exposures to water-soluble and even tothe less soluble forms of nickel in the electrolysis were lower at Port Colborne than in the Norwegian refinery, asthe Port Colborne electrolysis ran no copper leaching and a less intensive electrolyte purification, both activitiesknown to involve high exposures to soluble and insoluble nickel.Until 1990, the increase in respiratory cancer risk in the pyrometallurgical areas, especially roasting or calcining,was ascribed to oxidic or to the combination of oxidic and sulphidic nickel (Doll et al., 1990; IARC, 1990), andthe risk among hydrometallurgy workers was considered to be caused by water-soluble nickel, possibly incombination with less soluble forms (Doll et al., 1990; IARC, 1990). This traditional view is strongly supportedby experimental results. It has been shown beyond dispute that sulphidic nickel compounds produce tumours inexperimental animals after injection or inhalation (IARC, 1990). These results along with the abundance of thecompounds in the furnace departments made it easy to assume that they played an important role for the cancerhazard. However, it is not self-evident that the most predominant nickel species constitute the predominant oronly cancer cause.The strong carcinogenic effect in animals of the less soluble nickel forms has been explained by phagocytosisand a subsequent slow solubilisation in vacuoles inside the cells, leading to a steady delivery of nickel ions to thecell nucleus. It is, however, not certain that phagocytosis is involved in nickel carcinogenesis in human airwayepithelium. In addition to phagocytosis (Abbracchio et al., 1982), there are a number of ways in which nickel asnickel ions has been shown to enter animal or human cells: Through calcium channels (Refsvik & Andreassen,1995), as part of an active trans-cellular absorption (Tallkvist et al., 1998), transport within and between cells(Henriksson et al., 1997), and uptake of nickel bound to amino acids or proteins (Webb & Weinzierl, 1972).Inside the cell, nickel shows a low mutagenic activity in conventional assays (Denkhaus & Salnikow, 2002), butin vitro exposure of rodent and human cells may lead to transformation, i.e. changes in phenotype and growthpattern (Tveito et al., 1989; Patierno et al., 1993). In a comparative in vitro experiment, ionising radiation andnickel chloride produced immortalized cells more effectively than known mutagens (Trott et al., 1995). Butmutation in the important TP53 tumour suppressor gene (coding for the p53 protein) has indeed beendemonstrated after chronic exposure of human cells (Maehle et al., 1992), although similar mutations were notfound in nickel exposed rats (Weghorst et al., 1994). Chromosomal damage is seen in the form of sisterchromatid exchange (SCE), micronuclei, and DNA-protein cross-links (Denkhaus & Salnikow, 2002). Forfurther discussion of the mutagenicity, see 4.1.2.6.Cell damage has been proposed to arise from the formation of reactive oxygen species, via the binding of nickelto the amino acid histidine, or binding to nuclear proteins like histones (Kasprzak et al., 2003). A possible effectfrom nickel on sperm DNA has been proposed, which, also suggested by the author, may have consequences forchildhood cancer (Kasprzak et al., 2003). The effects may be genotoxic (damage of DNA) or epigenetic(changes in the regulation of genes). A number of important genes can be activated or silenced throughepigenetic mechanisms via methylation or deacetylation mechanisms, thereby inducing permanent changes incells, inheritable through cell division, even in the further absence of nickel (Bal & Kasprzak, 2002).Toxic effects can also be exerted through the binding of nickel to receptors on the surface of human cells (Martinet al., 2003), a mechanism that may have a relevance to lung cancer (Stabile et al., 2002). Effects on productionof hormones have been seen in in vitro experiments with rat cells (Laskey & Phelps, 1991). Nickel exposure caninfluence the calcium balance of the cell possibly linked to altered expression of genes associated with cellgrowth, differentiation, and apoptosis (Rosen et al., 1995; Nicotera & Orrenius, 1998). Nickel has been shown toinduce the expression of a specific gene via changes in the intracellular calcium level (Zhou et al., 1998). Nickelmay activate hypoxic signalling pathways, producing changes in the metabolism of the cells and making themmore resistant to lack of oxygen, a characteristic also seen in cancer cells (Salnikow & Costa, 2000).Another possible mechanism for nickel carcinogenicity may involve inhibition of DNA repair. Reconstruction ofDNA is vital after environmental damage or spontaneous changes. Impaired repair function has been seen invitro at low non-cytotoxic nickel doses (Hartwig & Schwerdtle, 2002).A large number of these effects can be exerted experimentally by water-soluble nickel as well as less solubleforms. Still, in animal experiments, water-soluble nickel tends to give negative results in a number of situationswhere less soluble compounds produce tumours (IARC, 1990). The negative results have been explained by themore rapid excretion of water-soluble nickel compared with the less soluble forms. This explanation may beespecially relevant to studies based on exposure by a single injection. Repeated intraperitoneal or subcutaneous 129
  • R_NickelBackground_0308_hh_chapter0124567.docinjections of water-soluble nickel compounds have, in some studies, produced malignant tumours in mice andrats (IARC, 1990; Pott et al., 1989, 1992; Teraki & Uchiumi, 1992).An important role of time or cumulative exposure was suggested in experiments with human monocytes in vitro,as adverse biological effects were observed for nickel ions after 3 to 4 weeks exposure to concentrations an orderof magnitude lower than the level known to be cytotoxic in 24-hour experiments (Wataha et al., 2000).A single intraperitoneal injection of nickel acetate, a water-soluble salt, has been shown to initiate renal cancer inrats (Kasprzak et al., 1990), and in another study, nickel chloride administered to rats in the drinking waterserved as a promoter for renal cancer (Kurokawa et al., 1985). An aqueous solution of nickel acetateadministered intraperitoneally to pregnant rats initiated epithelial tumours in foetal kidneys of male (only) pupsand was a complete transplacental carcinogen for rat pituitary gland (Diwan et al., 1992).Much attention has been directed towards the well-conducted series of long-term inhalation experimentsorganized under the U.S. National Toxicology Programme (NTP, 1996a, 1996b, 1996c). Rats and mice wereexposed to aerosols of nickel subsulphide, nickel oxide, or nickel sulphate hexahydrate for 2 years. In rats,tumours were found in a dose-dependent manner after exposure to the sulphidic compound, and some evidenceof carcinogenicity was found even for nickel oxide. On the other hand, no evidence of carcinogenicity appearedin mice, except for an equivocal result for nickel oxide in female mice. For the water-soluble nickel sulphate, nocarcinogenic activity was seen, either in mice or rats (Dunnick et al., 1995).The relevance of rodent inhalation experiments for assessment of human risk was recently reviewed byMauderly (1997). Results of studies on different rodent species are often inconsistent. For substances classifiedas human carcinogens by IARC, mice tended to give false negative results with particulate exposures, while ratsappeared to give falsely negative responses with gases and vapours. Hamsters were less susceptible to lungtumours than both rats and mice. Mauderly specifically commented on the NTP rodent experiments with nickelsulphate, since this was the only known case of a classified human lung carcinogen with negative high-qualityinhalation experiments in rats and mice. Nickel sulphate was considered by Mauderly (1997) as particles in theNTP experiments, as the water evaporated from the droplets after generation of aerosol from an aqueoussolution. The rodents therefore inhaled an aerosol of hydrated salts (NTP, 1996a), but to what extent these highlysoluble crystals behaved as particles when they reached the airways was not discussed.The papers cited above constitute only a small part of the vast number of experimental studies and reviewarticles on nickel toxicology and carcinogenesis. Although some possible mechanisms have been described, theunderstanding is far from complete. Nickel demonstrates not only species specific but also tissue specificdifferences in response (Salnikow & Costa, 2000). If long-term animal experiments do not match the results ofepidemiological studies, mechanistic evidence as shown above may support the plausibility of biological effectsrelevant to carcinogenicity. The evidence from experimental studies suggest that any form of nickel that producenickel ions inside or outside cells may affect the cell by a number of pathways, leading to profound effects oncell growth, mutations, inhibition of DNA repair, and changes in the expression of a number of genes, therebyaltering the metabolism and regulatory systems in the cell.Still, the concomitant exposure in nickel refineries to more than one form of nickel makes it difficult to decideby epidemiological studies whether the effect of one type of nickel is independent of the others. In the ICNCMstudy, an important criterion for the evaluation was the degree of dose-dependent increase in risk associated withdifferent forms of nickel (Doll et al., 1990). The studies from the Welsh, the Finnish, and the Norwegian cohortsthat have been published after 1990 indicate that the water-soluble nickel species as a group satisfy the followingcriteria for causality to a higher degree than do the sulphidic, oxidic, and metallic species: The ‘strength of theassociation’, the ‘biological gradient’, and the ‘consistency’ across groups of nickel exposed workers (Hill,1965).There are also some negative studies among nickel-exposed workers that have not been cited in the presentreport due to limitations in the information on nickel exposure, in study size, and in study design.4.1.2.7.4 Overall Conclusion for carcinogenicity.Nickel compounds are considered as human carcinogens based on epidemiological studies, mechanisticinformation and evidence from animal studies. The overall findings indicate that nickel ions generated in targetcells are determinants for the carcinogenic process.Based on the epidemiological results discussed above following inhalational exposure and the variety of effectsdemonstrated in a large number of experimental studies with different nickel species, it is reasonable to assume 130
  • R_NickelBackground_0308_hh_chapter0124567.docthat all nickel compounds that can create nickel ions inside or outside the cell are carcinogenic to humansfollowing exposure by inhalation.For metallic nickel there is sufficient evidence of carcinogenicity in experimental studies, but no conclusion canbe drawn based on epidemiology. Whilst most nickel compounds are evaluated in terms of their (aqueous)solubility, metallic nickel is often treated separately. The C&L Health Effects Group have agreed that the currentclassification of Carc. Cat. 3; R40 should be maintained at the present time.Further studies of the inhalational carcinogenicity of metallic nickel in animals are currently in progress and themutagenicity of metallic nickel following inhalation will also be studied. The classification of nickel metal willbe reconsidered when further evidence becomes available from the studies currently in progress or beingplanned.There is also evidence for local carcinogenicity of some nickel compounds following direct injection. Thesestudies are relevant when evaluating exposure to nickel metal by implants of nickel metal or of nickel containingalloys (iatrogenic exposures).The experimental evidence for carcinogenicity following oral exposure suggests that this effect does not occurwith soluble nickel salts. A recent oral carcinogenicity study (CRL, 2005) using nickel sulphate administered torats (OECD 451) did not find any indications for a carcinogenic potential..At their meeting in April 2004, the Specialised Experts concluded that nickel sulphate and nickel chloride shouldbe considered as human carcinogens (Carc. Cat. 1). The data was considered to be sufficient to establish a causalassociation between the human exposure to the substances and the development of lung cancer. There wassupporting evidence for this conclusion from more limited data on nasal cancer (European Commission, 2004).In drawing this conclusion regarding lung cancer, it was recognised that the epidemiological data showed a clearexposure response relationship for water soluble compounds, consistency across and within studies and timeperiods, and high strength of association. Improved exposure characterisation based on personal air sampling andimproved analysis of the water soluble fractions added to the reliability of the findings. Confounding factorssuch as co-exposure to insoluble nickel compounds and smoking were adequately addressed, and did not lowerthe level of confidence in reaching the conclusion (European Commission, 2004).The Specialised Experts also agreed that nickel nitrate and nickel carbonate should be classified as Carc. Cat. 1.In reaching this conclusion for nickel nitrate the Specialised Experts recognised that the water solubility of thiscompound was sufficiently similar to that of nickel sulphate and nickel chloride to justify the same classification.Since both the water soluble nickel compounds considered at this meeting and the insoluble inorganic nickelcompounds already classified in Annex I are considered as human carcinogens consequently also the nickelcarbonate was considered to be a human carcinogen (European Commission, 2004).The TC C&L has agreed to classify nickel sulphate, nickel chloride, nickel nitrate and the nickel carbonates asCarc. Cat. 1; R49 14.4.1.2.8 Toxicity for reproduction4.1.2.8.1 Effects on fertility4.1.2.8.1.1 Animal studiesAn oral 1-generation study with two successive gestation periods and an oral 2-generation reproduction study ofnickel chloride are available (Smith et al. 1993, RTI 1988). No effects on fertility have been found in thesestudies at highest dose levels used, i.e. up to 42 mg Ni/kg bw/day. Effects on sperm and oestrus cyclicity werenot investigated in these studies. An increase in abnormalities was observed in spermatozoa from mice treatedorally with a single dose of nickel chloride (43 mg Ni/kg bw) (Sobti & Gill 1989). Dose related effects on spermmotility and count as well as decreased body weight gain were observed after repeated dosing with nickelchloride at 10 and 20 mg/kg bw/day, but not at a dose level of 5 mg/kg bw/day (Pandey & Srivastava 2000).However, due to the limited number of animals used in this study, the dose level of 5 mg/kg bw/day cannot beconsidered as a reliable NOAEL.14 These classifications are included in the 30th ATP. 131
  • R_NickelBackground_0308_hh_chapter0124567.docTwo oral multi-generation reproduction studies and a range-finding one-generation study of nickel sulphate areavailable (Ambrose et al. 1976, NiPERA 2000a, NiPERA 2000b). No effects on fertility have been found inthese studies. The study by Ambrose et al. (1976) and the one-generation range-finding study (NiPERA 2000a)indicate NOAELs of 52-80 mg Ni/kg bw/day and 16.8 mg Ni/kg bw/day, respectively. However, the Ambrose etal. study has a limited reporting of data and the range-finding study uses only a limited number of animals (8 pergroup). Therefore, the most reliable NOAEL for fertility effects is from the recent OECD TG 416 two-generation study (NiPERA et al. 2000b) where the NOAEL is the highest dose investigated, i.e. 2.2 mg Ni/kgbw/day.Effects on male sex organs in rats and mice have been reported in limited studies after oral, inhalation orsubcutaneous administration of nickel sulphate. These studies indicate a LOAEL for oral exposure of 5.6 mgNi/kg bw/day and an inhalation LOAEC at 1.6 mg Ni/m3. A repeated dose toxicity study provides a NOAEC foreffects on sperm and oestrus cyclicity of 0.45 mg Ni/m3 for inhalation exposure. No effects on male sex organsincluding sperm quality were found in the recent oral OECD TG 416 two-generation study (NiPERA 2000b) andthe NOAEL is therefore the highest dose studied, i.e. is 2.2 mg Ni/kg bw/day.No relevant studies regarding nickel carbonate, nickel nitrate, nickel sulphide, nickel oxide or metallic nickel havebeen found.4.1.2.8.1.2 Human dataNo relevant studies have been found.4.1.2.8.2 Developmental toxicity4.1.2.8.2.1 Animal studies4.1.2.8.2.1.1 Oral exposureNo standard prenatal developmental toxicity studies via either the oral or inhalation routes were located.For nickel chloride, a 1-generation study with two gestation periods, a 2-generation study and a one-generationstudy using a limited number of animals provide consistent evidence of developmental toxicity(postimplantation/perinatal death) in rats, but a reliable NOAEL cannot be set based on these studies. As all threemeasures of pup death were statistically significant or borderline significant at the low dose in the secondgeneration in the Smith et al study (1993) an equivocal LOAEL for this study was 1.33 mg Ni/kg bw/day.For nickel sulphate, multi-generation studies and a one-generation range-finding study provide consistentevidence of developmental toxicity (stillbirth, postimplantation/perinatal death) in rats at dose levels not causingmaternal toxicity. Based on the increased postimplantation/perinatal lethality in F1 generation in the OECD TG416 two-generation study (NIPERA 2000b) at 2.2 mg Ni/kg bw/day, the NOAEL that is used for developmentaltoxicity for regulatory purposes is set to 1.1 mg Ni/kg bw/day.No relevant studies regarding nickel carbonate, nickel nitrate, nickel sulphide, nickel oxide or metallic nickel havebeen found.Schroeder & Mitchener (1971) conducted a 3-generation study of rats administered nickel as an unspecific saltat 5 ppm in drinking water (estimated at 0.43 mg Ni/kg bw/day), and observed significantly increased neonatalmortality and incidence of runts. This study is significantly limited, however, by the use of only 5 matedpairs/dose group. In addition, the matings were not randomised and the males were not rotated. This study wasconducted in an environmentally controlled facility where rats had access to food and water containing minimallevels of essential trace metals. Because of the interactions of nickel with other trace metals (chromium wasestimated as inadequate), the restricted exposure to trace metals may have contributed to the toxicity of nickel.Therefore, this study does not present a reliable estimate of nickel toxicity.4.1.2.8.2.1.2 InhalationIn the only study located that evaluated developmental or reproductive effects after inhalation of nickelcompounds, Weischer et al. (1980), groups of 10-13 pregnant Wistar rats were continuously exposed to NiO at0.8, 1.6, or 3.2 mg/m3 NiO (0.6, 1.2, or 2.5 mg Ni/m3) for 21 days, beginning on gestation day 1. Maternalendpoints evaluated were body weight, organ weights, serum urea, and haematology. The only foetal endpointsevaluated were foetal weight, leukocytes, and serum urea. Maternal body weight gain was statisticallysignificantly reduced in all exposed groups, and statistically significant decreases in foetal body weight were 132
  • R_NickelBackground_0308_hh_chapter0124567.docobserved at the top two exposure levels. Other developmental effects, such as foetal survival, were apparentlynot evaluated.4.1.2.8.2.1.3 Other routesStudies using intraperitoneal or intramuscular dosing of nickel chloride during pregnancy in mice and rats havereported reduced number of live pups, lower body weights in foetuses and offspring, or malformations(Sunderman et al. 1978b, Mas et al. 1985, Lu et al. 1979). These studies are not considered useful for riskassessment because of the route of exposure.4.1.2.8.2.2 Human dataA cross sectional study of female nickel hydrometallurgy workers in a Russian refinery plant suggestingincreased incidences of spontaneous abortions and malformations during exposure to soluble nickel exposurelevels around 0.2 mg/m3 is considered as inconclusive due to flaws in the study design and reporting(Chashschin et al. 1994). A subsequent study by Vaktskjold et al. (2006) investigated genital malformations innewborns of female nickel-refinery workers using a register-based cohort study design. No negative effects ongenital malformations was seen, but, as is also stated by the authors, this result should be interpreted with cautionsince there were few cases in the higher exposure groups.4.1.2.8.3 ConclusionsThere are no relevant studies in humans. Consequently, the risk assessment is based on experimental data.No relevant studies regarding nickel carbonate, nickel nitrate, nickel sulphide, nickel oxide or metallic nickel havebeen found. Data on nickel chloride and nickel sulphate are therefore used, as the basic assumption is made that afterintake nickel compounds are changed and that it is the nickel ion that is the determining factor for the reproductiveand developmental toxicity.No effects on fertility have been found in two-generation studies on nickel chloride or nickel sulphate using doselevels up to around 50 mg Ni/kg bw/day. Effects on male sex organs in rats and mice have been reported inlimited studies after oral, inhalation or subcutaneous administration of nickel chloride or nickel sulphate. TheNOAEC for effects on male sex organs of 0.45 mg Ni /m3 for inhalation exposure and the NOAEL of 2.2 mgNi/kg bw/day for oral administration is taken forward to the risk characterization.The potential for effects on sex organs has not been sufficiently investigated, as sperm quality and oestruscyclicity either was not investigated or the highest dose level did not induce any signs of toxicity in the adultanimals. Therefore, to be able to draw clear conclusions regarding the potential for effects on sex organs furtherstudies using higher dose levels and including these end points would be relevant. However, there is no reason toexpect that such testing would lead to lower NOAELs than the ones already determined for effects on sexorgans. Therefore, the results of such testing are unlikely to influence the outcome of the risk assessment.No standard prenatal developmental toxicity studies via either the oral or inhalation routes were located. Theavailable studies on nickel chloride, nickel sulphate and an unspecified nickel salt provide consistent evidence ofincreased postimplantation/perinatal lethality in rats after oral exposure. Based on an OECD TG 416 two-generation study on nickel sulphate, a NOAEL of 1.1 mg Ni/kg bw/day was identified. As this NOAEL is belowthe equivocal LOAEL of 1.33 mg Ni/kg bw/day for nickel chloride, the NOAEL that is used for developmentaltoxicity for regulatory purposes is set to 1.1 mg Ni/kg bw/day. This value is taken forward to the riskcharacterisation.In the only study located that evaluated developmental effects after inhalation, pregnant rats were exposed toNiO at 0.8, 1.6, or 3.2 mg/m3 NiO (0.6, 1.2, or 2.5 mg Ni/m3). Maternal body weight gain was reduced in allexposed groups, and decreases in foetal body weight were observed at the top two exposure levels. As otherdevelopmental effects, especially foetal survival, apparently were not evaluated, a NOAEC for developmentaleffects cannot be established.Based on the consistent evidence of developmental toxicity (stillbirth, postimplantation/perinatal lethality) in ratsat dose levels not causing maternal toxicity, soluble nickel compounds should be classified for developmentaltoxicity in Category 2 with R61. Classification of the nickel carbonates is justified on the evidence for significantabsorption of nickel carbonate after oral administration (see 4.1.2.1.1.2), supported by the acute toxicity data (see4.1.2.2.3.2).The TC C&L has agreed to classify nickel sulphate, nickel chloride, nickel nitrate and the nickel carbonates asRepr. Cat. 2; R61 and these classifications are included in the 30th ATP. 133
  • R_NickelBackground_0308_hh_chapter0124567.docAlthough there is a lack of a standard prenatal developmental toxicity studies (OECD 414) via either the oral orinhalation routes, there is not considered to be urgent need for further testing for developmental toxicity if nickelcompounds is classified for developmental toxicity.4.1.3 Risk characterisationThe risk characterisation of the production and use of metallic nickel, nickel sulphate, nickel chloride, nickelcarbonate and nickel nitrate is described in the individual risk assessment reports on these substances.A risk characterisation of the production and use of other nickel compounds described in Chapter 2.1.1 is notcovered here. The approach used in the risk assessments of the five nickel compounds listed above may provehelpful in preparing a risk characterisation for specific compounds.Risk characterisations of other scenarios described in Chapter 2.1.2 not directly related to the production and useof nickel and nickel compounds (e.g. combustion processes) where exposure to nickel occurs is outside the scopeof these risk assessments.4.2 HUMAN HEALTH (PHYSICO-CHEMICAL PROPERTIES)Risk assessment concerning the properties listed in Annex IIA of Regulation 1488/944.2.1 Exposure assessmentSee section 4.1.14.2.2 Effects assessment:The physical-chemical data for nickel metal, nickel sulphate, nickel chloride, nickel nitrate and nickel carbonateis shown in the individual risk assessment reports. Apart from water solubility, there is very limited physical-chemical data for other nickel compounds. In particular, there is very little physical-chemical data for thesesubstances in IUCLID (2002).4.2.2.1 ExplosivityNickel metal, nickel sulphate, nickel chloride, nickel nitrate and nickel carbonate are not explosive. There is nodata to indicate whether other nickel compounds have explosive properties.4.2.2.2 FlammabilityNickel metal, nickel sulphate, nickel chloride and nickel carbonate are not flammable. Nickel nitrate is a firerisk. There is no data to indicate whether other nickel compounds are flammable.4.2.2.3 Oxidising potentialNickel nitrate is an oxidiser, and the TC C&L has agreed to classify nickel nitrate as O; R8, and thisclassification is included in the 30th ATP. Nickel metal, nickel sulphate, nickel chloride and nickel carbonate arenot oxidisers. There is no data to indicate whether other nickel compounds are oxidisers.4.2.3 Risk characterisationThe risk characterisation for worker and consumer exposure to metallic nickel, nickel sulphate, nickel chloride,nickel carbonate and nickel nitrate is described in the individual risk assessment reports on these substances,whereas risk characterisation for human indirect exposure via environment and combined exposure for thesubstances is performed in the separate report: “Humans exposed indirectly via the environment and combinedexposure - exposure assessment and risk characterisation”.A risk characterisation of the production and use of other nickel compounds described in Chapter 2.1.1 is notcovered here. The approach used in the risk assessments of the five nickel compounds listed above may provehelpful in preparing a risk characterisation for specific compounds.Risk characterisations of other scenarios described in Chapter 2.1.2 not directly related to the production and useof nickel and nickel compounds (e.g. combustion processes) where exposure to nickel occurs is outside the scopeof these risk assessments. 134
  • R_NickelBackground_0308_hh_chapter0124567.doc5. CONCLUSIONS/RESULTSThe risk assessment for worker and consumer exposure to metallic nickel, nickel sulphate, nickel chloride, nickelcarbonate and nickel nitrate is described in the individual risk assessment reports on these substances, whereasrisk characterisation for human indirect exposure via environment and combined exposure for the substances isperformed in the separate report: “Humans exposed indirectly via the environment and combined exposure -exposure assessment and risk characterisation”.A full risk assessment of the production and use of the other nickel compounds described in this report has notbeen attempted by the Rapporteur, as these other nickel compounds are not included in a priority list under theExisting Substances Regulation. However, the Rapporteur considers that the approach used in the riskassessments of the five nickel compounds listed above may prove helpful to others when preparing a riskassessment for specific nickel compounds.Risk characterisations of scenarios not directly related to the production and use of nickel and nickel compounds(e.g. combustion processes) where exposure to nickel occurs is outside the scope of these risk assessments. 135
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  • R_NickelBackground_0308_hh_chapter0124567.doc7. APPENDICES7.1 WATER SOLUBILITY OF SELECTED NICKEL COMPOUNDS.Substance Structure CAS No. Solubility Referencemetallic nickel Ni 7440-02-0 insoluble IPCS, 1991 TERA, 1999nickel oxide NiO 1313-99-1 insoluble IPCS, 1991 TERA, 1999nickel sulfide NiS 16812-54-7 insoluble IPCS, 1991, 0.00036 g/100 ml @ 18°C TERA, 1999nickel disulfide NiS2 ?nickel subsulfide Ni3S2 12035-72-2 insoluble IPCS, 1991 TERA, 1999nickel carbonyl Ni(CO)4 13463-39-3 insoluble HSE, 1987nickel arsenate Ni3(AsO4)2 insoluble IPCS, 1991nickel carbonate 2NiCO3 3333-67-3 insoluble IPCS, 1991 (EC No: 222-068-2) 0.0093 g/100ml @ 25°C TERA, 1999nickel carbonate CH2O3.xNi 16337-48-1 (EC No: 240-408-8)nickel hydroxide Ni (OH)2 12054-48-7 insoluble IPCS, 1991 0.013 g/100ml TERA, 1999nickel hydroxy- 2NiCO3.3Ni (OH)2 insolublecarbonate, tetrahydrate .4H2Onickel phosphate Ni3(PO4)3 insoluble IPCS, 1991nickel acetate Ni (OOCCH3)2 soluble IPCS, 1991 17 g/100ml @ 20°C TERA, 1999nickel acetate Ni (OOCCH3)2 6018-89-9 soluble TERA, 1999tetrahydrate .4H2Onickel ammonium Ni(NH3)2.SO4 7785-20-8 2.5 g/100ml @ 0°C TERA, 1999sulphate .6H2Onickel bromide NiBr2 soluble IPCS, 1991nickel dichloride NiCl2 7718-54-9 soluble IPCS, 1991 (EC No: 231-743-0) 64.2 g/100ml @ 20°C TERA, 1999nickel dichloride NiCl2.6H2O 7791-20-0 254 g/100ml @ 20°C TERA, 1999hexahydratenickel chloride NiCl2 37211-05-5 (EC No: 253-399-0)nickel fluoroboride Ni(BF4)2.6H2O 14708-14-6 soluble TERA, 1999nickel fluoride NiF2 10028-18-9 slightly soluble IPCS, 1991 4 g/100ml TERA, 1999 @ 0°Cnickel formate Ni(CHO2)2.2H2O 3349-06-2 soluble TERA, 1999nickel nitrate Ni (NO3)2.6H2O 13138-45-9 soluble IPCS, 1991 (EC No: 236-068-5) 283.5 g/100ml @ 0°C TERA, 1999nickel nitrate (nitric HNO3.xNi 14216-75-2acid, nickel salt) (EC No: 238-076-4)nickel sulphamate Ni(SH2NO3)2 .4H2O 13770-89-3 soluble TERA, 1999nickel sulphate NiSO4 7786-81-4 soluble IPCS, 1991 29.3 g/100ml @ 0°C TERA, 1999nickel sulphate NiSO4.6H2O 10101-97-0 65.5 g/100ml @ 0°C TERA, 1999hexahydrate 154
  • R_NickelBackground_0308_hh_chapter0124567.doc7.2 NICKEL AND NICKEL COMPOUNDS IN EINECS7.2.1 Nickel, nickel compounds, and complex substances containing nickel included in EINECS.Nickel metal and metal compounds.EC Number CAS Chemical Name HPVC / LPVC CUS Number Number231-111-4 7440-02-0 Nickel- HPVC 11024234-439-6 12003-78-0 Aluminum, compd. with nickel (1:1)235-261-1 12142-92-6 Nickel, compd. with zirconium (1:2)234-807-6 12034-55-8 Nickel, compd. with niobium (1:1)235-034-7 12059-23-3 Nickel, compd. with tin (3:1)234-827-5 12035-52-8 Antimony, compd. with nickel (1:1)235-676-8 12503-49-0 Antimony, compd. with nickel (1:3)235-372-5 12196-72-4 Lanthanum, compd. with nickel (1:5)235-341-6 12175-27-8 Dysprosium, compd. with nickel (1:2)235-773-5 12688-64-1 Bismuth, compd. with nickel (1:1)257-510-3 51912-52-8 Copper, compd. with lanthanum and nickel (4:1:1)Inorganic nickel compounds.EC Number CAS Chemical Name HPVC / LPVC CUS Number Number215-215-7 1313-99-1 Nickel oxide (NiO) HPVC 20749215-217-8 1314-06-3 Nickel oxide (Ni2-O3) 20765234-323-5 11099-02-8 Nickel-oxide-234-823-3 12035-36-8 Nickel oxide (NiO2)234-454-8 12004-35-2 Aluminum nickel oxide (Al2-NiO4)234-825-4 12035-39-1 Nickel titanium oxide (NiTiO3)235-752-0 12653-76-8 Nickel-titanium-oxide-257-970-5 52502-12-2 Nickel vanadium oxide (NiV2-O6)234-636-7 12018-18-7 Chromium nickel oxide (Cr2-NiO4)235-335-3 12168-54-6 Iron nickel oxide (Fe2-NiO4)306-902-3 97435-21-7 Iron nickel zinc oxide (Fe2-NiZnO4)261-346-8 58591-45-0 Cobalt nickel oxide (CoNiO2)269-051-6 68186-89-0 Cobalt nickel gray periclase LPVC268-169-5 68016-03-5 Cobalt molybdenum nickel oxide (CoMo2-NiO8)274-755-1 70692-93-2 Nickel zirconium oxide (NiZrO3)305-835-7 95046-47-2 Spinels, cobalt nickel zinc grey238-034-5 14177-55-0 Molybdenum nickel oxide (MoNiO4)234-824-9 12035-38-0 Nickel tin oxide (NiSnO3) 20760238-032-4 14177-51-6 Nickel tungsten oxide (NiWO4)239-876-6 15780-33-3 Nickel uranium oxide (NiU3-O10)277-627-3 73892-02-1 Antimony oxide (Sb2-O3), solid soln. with nickel oxide (NiO) and titanium oxide (TiO2)232-353-3 8007-18-9 Antimony nickel titanium oxide yellow- LPVC269-071-5 68187-10-0 Nickel ferrite brown spinel LPVC271-112-7 68515-84-4 Olivine, nickel green271-853-6 68610-24-2 Nickel barium titanium primrose priderite; C.I. No. 77900271-892-9 68611-43-8 Nickel niobium titanium yellow rutile; C.I. No. 77895275-738-1 71631-15-7 Nickel iron chromite black spinel; C.I. No. 77504 LPVC309-018-6 99749-23-2 Cassiterite, cobalt manganese nickel grey273-686-4 69011-05-8 Nickel titanium oxide tungstate (NiTi20-O35-(WO6)2)269-047-4 68186-85-6 C.I.Pigment Green 50 155
  • R_NickelBackground_0308_hh_chapter0124567.doc234-348-1 11113-74-9 Nickel-hydroxide-235-008-5 12054-48-7 Nickel hydroxide (Ni(OH)2) LPVC 20745 156
  • R_NickelBackground_0308_hh_chapter0124567.docInorganic nickel compounds (continued).234-493-0 12007-00-0 Nickel boride (NiB)234-494-6 12007-01-1 Nickel boride (Ni2-B)234-495-1 12007-02-2 Nickel boride (Ni3-B)235-723-2 12619-90-8 Nickel-boride-235-033-1 12059-14-2 Nickel silicide (Ni2-Si)235-379-3 12201-89-7 Nickel silicide (NiSi2)234-828-0 12035-64-2 Nickel phosphide (Ni2-P)234-349-7 11113-75-0 Nickel-sulfide-234-829-6 12035-72-2 Nickel sulfide (Ni3-S2) 25517240-841-2 16812-54-7 Nickel sulfide (NiS) LPVC 25516235-103-1 12068-61-0 Nickel arsenide (NiAs2)248-169-1 27016-75-7 Nickel arsenide (NiAs)215-216-2 1314-05-2 Nickel selenide (NiSe)233-263-7 10101-96-9 Selenious acid, nickel(2+) salt (1:1)239-125-2 15060-62-5 Selenic acid, nickel(2+) salt (1:1) 20757235-260-6 12142-88-0 Nickel telluride (NiTe) 20758271-512-1 68583-44-8 Cadmium sulfide (CdS), solid soln. with zinc sulfide, nickel and silver-doped271-539-9 68584-42-9 Cadmium sulfide (CdS), solid soln. with zinc sulfide, copper and nickel-doped270-961-0 68512-22-1 Zinc sulfide (ZnS), nickel and silver-doped271-601-5 68585-93-3 Zinc sulfide (ZnS), copper and nickel-doped272-277-8 68784-84-9 Zinc sulfide (ZnS), copper and nickel and silver-doped236-669-2 13463-39-3 Nickel carbonyl (Ni(CO)4), (T-4)- 20730209-160-8 557-19-7 Nickel cyanide (Ni(CN)2) 20734254-261-2 39049-81-5 Nickelate(2-), tris(cyano-C)-, dipotassium238-082-7 14220-17-8 Nickelate(2-), tetrakis(cyano-C)-, dipotassium, (SP-4-1)-238-946-3 14874-78-3 Ferrate(4-), hexakis(cyano-C)-, nickel(2+) (1:2), (OC-6-11)- 20738222-068-2 3333-67-3 Carbonic acid, nickel(2+) salt (1:1) HPVC 20729240-408-8 16337-84-1 Carbonic acid, nickel salt235-715-9 12607-70-4 Nickel, [carbonato(2-)]tetrahydroxytri- LPVC (25626) 15265-748-4 65405-96-1 Nickel, [mu-[carbonato(2-)-O:O’]]dihydroxydi-233-071-3 10028-18-9 Nickel fluoride (NiF2) LPVC 20739231-743-0 7718-54-9 Nickel chloride (NiCl2) HPVC 20731 16253-399-0 37211-05-5 Nickel-chloride-267-897-0 67952-43-6 Chloric acid, nickel(2+) salt237-124-1 13637-71-3 Perchloric acid, nickel(2+) salt 20754236-665-0 13462-88-9 Nickel bromide (NiBr2) LPVC 20728238-596-1 14550-87-9 Bromic acid, nickel(2+) salt236-666-6 13462-90-3 Nickel iodide (NiI2) 20747231-827-7 7757-95-1 Sulfurous acid, nickel(2+) salt (1:1)232-104-9 7786-81-4 Sulfuric acid, nickel(2+) salt (1:1) HPVC 20762237-563-9 13842-46-1 Sulfuric acid, nickel(2+) potassium salt (2:1:2) 20756239-793-5 15699-18-0 Sulfuric acid, ammonium nickel(2+) salt (2:2:1) 11026275-897-7 71720-48-4 Sulfuric acid, monoethyl ester, nickel(2+) salt237-396-1 13770-89-3 Sulfamic acid, nickel(2+) salt (2:1) LPVC 20761239-967-0 15851-52-2 Telluric acid (H2-TeO3), nickel(2+) salt (1:1)239-974-9 15852-21-8 Telluric acid (H2-TeO4), nickel(2+) salt (1:1)15 CUS Number for the tetrahydrate, CAS No. 39430-27-8.16 Also nickel (II) chloride hexahydrate, CAS No.: 7791-20-0, CUS No.: 39096 157
  • R_NickelBackground_0308_hh_chapter0124567.docInorganic nickel compounds (continued).236-068-5 13138-45-9 Nitric acid, nickel(2+) salt HPVC 20750 17238-076-4 14216-75-2 Nitric acid, nickel salt238-278-2 14332-34-4 Phosphoric acid, nickel(2+) salt (1:1)242-522-3 18718-11-1 Phosphoric acid, nickel(2+) salt (2:1)233-844-5 10381-36-9 Phosphoric acid, nickel(2+) salt (2:3) 20751268-585-7 68130-36-9 Molybdenum-nickel-hydroxide-oxide-phosphate-238-426-6 14448-18-1 Diphosphoric acid, nickel(2+) salt (1:2)238-511-8 14507-36-9 Phosphinic acid, nickel(2+) salt 20746252-840-4 36026-88-7 Phosphinic acid, nickel salt236-771-7 13477-70-8 Arsenic acid (H3-AsO4), nickel(2+) salt (2:3) 20724244-578-4 21784-78-1 Silicic acid (H2-SiO3), nickel(2+) salt (1:1)237-411-1 13775-54-7 Silicic acid (H4-SiO4), nickel(2+) salt (1:2) 20759250-788-7 31748-25-1 Silicic acid (H2-SiO3), nickel(2+) salt (4:3)253-461-7 37321-15-6 Silicic acid, nickel salt235-688-3 12519-85-6 Nickel hydroxide silicate (Ni3-(OH)4-(Si2-O5))238-766-5 14721-18-7 Chromic acid (H2-CrO4), nickel(2+) salt (1:1) 20732239-646-5 15586-38-6 Dichromic acid (H2-Cr2-O7), nickel(2+) salt (1:1)237-595-3 13859-60-4 Nickelate(2-), tetrafluoro-, dipotassium, (T-4)-308-989-3 99587-11-8 Nickelate(2-), tetrachloro-, diammonium, (T-4)-246-378-2 24640-21-9 Nickelate(1-), trichloro-, ammonium 11021237-597-4 13859-65-9 Nickel, tetrakis(phosphorous trifluoride)-, (T-4)-238-753-4 14708-14-6 Borate(1-), tetrafluoro-, nickel(2+) (2:1) 20740237-638-6 13877-20-8 Nickel(2+), hexaammine-, (OC-6-11)-, bis[tetrafluoroborate(1-)]247-430-7 26043-11-8 Silicate(2-), hexafluoro-, nickel(2+) (1:1) 20741250-370-4 30868-55-4 Zirconate(2-), hexafluoro-, nickel(2+) (1:1), (OC-6-11)-235-531-9 12263-13-7 Molybdate(3-), tetracosa-mu-oxododecaoxo[mu12-[phosphato(3- )-O:O:O:O:O:O:O:O:O:O:O:O]]dodeca-, nickel(2+) (2:3)Organic nickel compounds.EC Number CAS Chemical Name HPVC / Number LPVC222-101-0 3349-06-2 Formic acid, nickel(2+) salt 20742239-946-6 15843-02-4 Formic acid, nickel salt268-755-0 68134-59-8 Formic acid, copper nickel salt272-149-1 68758-60-1 Nickel(2+), hexaammine-, (OC-6-11)-, diformate237-205-1 13689-92-4 Thiocyanic acid, nickel(2+) salt208-933-7 547-67-1 Ethanedioic acid, nickel(2+) salt (1:1) 20752243-867-2 20543-06-0 Ethanedioic acid, nickel salt206-761-7 373-02-4 Acetic acid, nickel(2+) salt LPVC 20723 18239-086-1 14998-37-9 Acetic acid, nickel salt LPVC240-235-8 16083-14-0 Acetic acid, trifluoro-, nickel(2+) salt262-383-2 60700-37-0 2-Propenoic acid, nickel(2+) salt257-066-0 51222-18-5 2-Propenoic acid, nickel salt267-961-8 67968-22-3 Nickelate(4-), [[[nitrilotris(methylene)]tris[phosphonato]](6-)]-, triammonium hydrogen, (T-4)-264-338-2 63588-33-0 Nickelate(4-), [[[nitrilotris(methylene)]tris[phosphonato]](6-)]-, tetrapotassium, (T-4)-268-296-6 68052-00-6 Nickelate(4-), [[[nitrilotris(methylene)]tris[phosphonato]](6-)- N,O,O,O]-, tetrasodium, (T-4)-222-102-6 3349-08-4 Propanoic acid, nickel(2+) salt267-923-0 67952-69-6 1,2,3-Propanetriol, mono(dihydrogen phosphate), nickel(2+) salt (1:1)269-946-1 68391-37-7 1,2,3-Propanetriol, 1-(dihydrogen phosphate), nickel(2+) salt (1:1)264-136-4 63427-32-7 Copper(2+), bis(1,2-ethanediamine-N,N’)-, (SP-4-1)- tetrakis(cyano-C)nickelate(2-) (1:1)17 Also nickel(II) nitrate hexahydrate, CAS No.: 13478-00-7, CUS No. 39097.18 Also nickel(II) acetate tetrahydrate, CAS No.: 6018-89-9, CUS No. 39093. 158
  • R_NickelBackground_0308_hh_chapter0124567.docOrganic nickel compounds (continued).273-379-5 68958-89-4 Nickel(2+), bis(1,2-ethanediamine-N,N’)-, bis[bis(cyano- C)aurate(1-)]244-300-1 21264-77-7 Nickel(2+), bis(ethylenediamine)-, sulfate (1:1)287-849-2 85586-46-5 Nickel, bis(1H-1,2,4-triazole-3-sulfonato-N(2)-,O(3))-228-501-1 6283-67-6 2-Butenedioic acid (E)-, nickel(2+) salt (1:1)237-618-7 13869-33-5 Nickel, [N-(carboxymethyl)glycinato(2-)-N,O,O(N)-]-268-711-0 68133-84-6 Nickel, [(2-amino-2-oxoethoxy)acetato(2-)]-268-195-7 68025-40-1 Nickelate(3-), [N,N-bis(phosphonomethyl)glycinato(5-)]-, triammonium, (T-4)-264-360-2 63597-34-2 Nickelate(3-), [N,N-bis(phosphonomethyl)glycinato(5-)]-, tripotassium, (T-4)-268-196-2 68025-41-2 Nickelate(3-), [N,N-bis(phosphonomethyl)glycinato(5-)]-, trisodium, (T-4)-257-963-7 52496-91-0 2-Propenoic acid, 2-methyl-, nickel(2+) salt304-466-9 94275-78-2 2-Propenoic acid, 2-methyl-, nickel salt267-894-4 67952-41-4 Butanedioic acid, 2,3-dihydroxy- [R-(R*,R*)]-, nickel(2+) salt (2:1)257-610-7 52022-10-3 Butanedioic acid, 2,3-dihydroxy- [R-(R*,R*)]-, nickel salt237-877-6 14038-85-8 Nickelate(2-), tetrakis(cyano-C)-, disodium, (SP-4-1)-273-375-3 68958-86-1 Nickelate(6-), [[[1,2- ethanediylbis[nitrilobis(methylene)]]tetrakis[phosphonato]](8-)]-, pentaammonium hydrogen, (OC-6-21)-273-376-9 68958-87-2 Nickelate(6-), [[[1,2- ethanediylbis[nitrilobis(methylene)]]tetrakis[phosphonato]](8-)]-, pentapotassium hydrogen, (OC-6-21)-273-377-4 68958-88-3 Nickelate(6-), [[[1,2- ethanediylbis[nitrilobis(methylene)]]tetrakis[phosphonato]](8-)]-, pentasodium hydrogen, (OC-6-21)-257-953-2 52486-98-3 Nickel, bis[(2-hydroxyethyl)carbamodithioato-S,S’]-, (SP-4-1)-239-560-8 15521-65-0 Nickel, bis(dimethylcarbamodithioato-S,S’)-, (SP-4-1)- 20737252-235-5 34831-03-3 Nickelate(1-), [N,N-bis(carboxymethyl)glycinato(3-)- N,O,O’,O’’]-, hydrogen, (T-4)-264-377-5 63640-18-6 Nickelate(1-), [N,N-bis(carboxymethyl)glycinato(3-)- N,O,O’,O’’]-, potassium, (T-4)-254-642-3 39819-65-3 Benzenesulfonic acid, nickel(2+) salt303-972-7 94232-44-7 1,2,3-Propanetricarboxylic acid, 2-hydroxy-, cobalt(2+) nickel(2+) salt (2:1:2)227-873-2 6018-92-4 1,2,3-Propanetricarboxylic acid, 2-hydroxy-, nickel(2+) salt (2:3) 20733304-013-5 94232-84-5 1,2,3-Propanetricarboxylic acid, 2-hydroxy-, cobalt(2+) nickel(2+) salt (2:2:1)268-176-3 68025-13-8 1,2,3-Propanetricarboxylic acid, 2-hydroxy-, ammonium nickel(2+) salt (2:2:1)242-533-3 18721-51-2 Citric acid, nickel(2+) salt (1:1)242-161-1 18283-82-4 Citric acid, ammonium nickel salt245-119-0 22605-92-1 1,2,3-Propanetricarboxylic acid, 2-hydroxy-, nickel salt209-046-8 553-71-9 Benzoic acid, nickel(2+) salt 20726254-210-4 38951-94-9 Nickel, bis[2-butene-2,3-dithiolato(2-)-S,S’]-, (SP-4-1)-275-994-4 71767-12-9 Uranate(2-), tetrakis(acetato-O)dioxo-, nickel(2+) (1:1), (OC-6- 20766 11)-236-782-7 13478-93-8 Nickel, bis[(2,3-butanedione dioximato)(1-)-N,N’]-, (SP-4-1)- 16135224-699-9 4454-16-4 Hexanoic acid, 2-ethyl-, nickel(2+) salt231-480-1 7580-31-6 Hexanoic acid, 2-ethyl-, nickel salt301-323-2 93983-68-7 Hexanoic acid, dimethyl-, nickel salt225-656-7 4995-91-9 Octanoic acid, nickel(2+) salt LPVC249-555-2 29317-63-3 Isooctanoic acid, nickel(2+) salt248-585-3 27637-46-3 Isooctanoic acid, nickel salt284-349-6 84852-37-9 Isononanoic acid, nickel(2+) salt300-094-6 93920-10-6 Neononanoic acid, nickel(2+) salt215-039-0 1271-28-9 Nickelocene-274-912-4 70824-02-1 Nickel, bis(5-oxo-L-prolinato-N(1)-,O(2))- 159
  • R_NickelBackground_0308_hh_chapter0124567.docOrganic nickel compounds (continued).285-069-7 85026-81-9 Nickel, bis(5-oxo-DL-prolinto-N(1)-,O(2))-247-019-2 25481-21-4 Nickelate(2-), [[N,N-1,2-ethanediylbis[N- (carboxymethyl)glycinato]](4-)-N,N,O,O,O(N)-,O(N)-]-, dihydrogen, (OC-6-21)-267-686-3 67906-12-1 Nickelate(1-), [[N,N-1,2-ethanediylbis[N- (carboxymethyl)glycinato]](4-)-N,N,O,O,O(N)-,O(N)-]-, potassium, (OC-6-21)-221-875-7 3264-82-2 Nickel, bis(2,4-pentanedionato-O,O)-, (SP-4-1)-223-463-2 3906-55-6 Cyclohexanebutanoic acid, nickel(2+) salt 20735257-954-8 52486-99-4 Nickel, bis[bis(2-hydroxyethyl)carbamodithioato-S,S]-, (SP-4-1)-278-504-7 76625-10-0 Nickel, bis[N-(2-hydroxyethyl)-N-methylglycinato-N,O,O(N)-]-238-157-4 14267-17-5 Nickel, bis(diethylcarbamodithioato-S,S)-, (SP-4-1)-258-044-3 52610-81-8 Nickel, bis(diethylcarbamodithioato-S,S)-287-468-1 85508-43-6 Isodecanoic acid, nickel(2+) salt287-469-7 85508-44-7 Neodecanoic acid, nickel(2+) salt257-447-1 51818-56-5 Neodecanoic acid, nickel salt239-028-5 14949-69-0 Nickel, bis(1,1,1,5,5,5-hexafluoro-2,4-pentanedionato-O,O)-, (SP- 4-1)-300-093-0 93920-09-3 Neoundecanoic acid, nickel(2+) salt235-339-5 12170-92-2 Nickel, di-mu-carbonylbis(eta(5)-2,4-cyclopentadien-1-yl)di-, (Ni- Ni)255-387-0 41476-75-9 Nickel, bis(1-piperidinecarbodithioato-S,S)- 20753276-205-6 71957-07-8 Nickel, bis(D-gluconato-O(1)-,O(2))-258-051-1 52625-25-9 Benzoic acid, 3,5-bis(1,1-dimethylethyl)-4-hydroxy-, nickel(2+) salt (2:1)215-072-0 1295-35-8 Nickel, bis[(1,2,5,6-eta)-1,5-cyclooctadiene]- 32526238-536-4 14522-99-7 Nickel, bis(6-methyl-2,4-heptanedionato-O,O)-284-350-1 84852-38-0 Nickel, (2-ethylhexanoato-O)(isooctanoato-O)-237-138-8 13654-40-5 Hexadecanoic acid, nickel(2+) salt274-916-6 70833-37-3 Nickel, bis(3-amino-4,5,6,7-tetrachloro-1H-isoindol-1-one LPVC oximato-N(2)-,O(1))-250-401-1 30947-30-9 Phosphonic acid, [[3,5-bis(1,1-dimethylethyl)-4- hydroxyphenyl]methyl]-, monoethyl ester, nickel(2+) salt (2:1)287-470-2 85508-45-8 Nickel, (2-ethylhexanoato-O)(isononanoato-O)-287-471-8 85508-46-9 Nickel, (isononanoato-O)(isooctanoato-O)-265-022-7 64696-98-6 Nickel, [2,3-bis[[(2-hydroxyphenyl)methylene]amino]-2- butenedinitrilato(2-)-N(2)-,N(3)-,O(2)-,O(3)-]-, (SP-4-2)-237-950-2 14100-15-3 Nickel, bis(8-quinolinolato-N(1)-,O(8))-239-841-5 15751-00-5 Nickel(2+), hexakis(1H-imidazole-N(3))-, dichloride, (OC-6-11)-284-347-5 84852-35-7 Nickel, (isooctanoato-O)(neodecanoato-O)-284-351-7 84852-39-1 Nickel, (2-ethylhexanoato-O)(isodecanoato-O)-285-698-7 85135-77-9 Nickel, (2-ethylhexanoato-O)(neodecanoato-O)-285-909-2 85166-19-4 Nickel, (isodecanoato-O)(isooctanoato-O)-235-832-5 13001-15-5 9-Octadecenoic acid (Z)-, nickel(2+) salt237-696-2 13927-77-0 Nickel, bis(dibutylcarbamodithioato-S,S)-, (SP-4-1)- LPVC 20736239-354-8 15317-78-9 Nickel, bis[bis(2-methylpropyl)carbamodithioato-S,S]-, (SP-4-1)-218-744-1 2223-95-2 Octadecanoic acid, nickel(2+) salt 27634288-967-7 85958-80-1 Nickel, [2-hydroxybenzoic acid [3-[1-cyano-2-(methylamino)-2- oxoethylidene]-2,3-dihydro-1H-isoindol-1-ylidene]hydrazidato(2- )]-284-348-0 84852-36-8 Nickel, (isodecanoato-O)(isononanoato-O)-287-592-6 85551-28-6 Nickel, (isononanoato-O)(neodecanoato-O)-235-829-9 12794-26-2 Nickel, bis(1-nitroso-2-naphthalenolato)-238-380-7 14406-66-7 Nickel, bis(1-nitroso-2-naphthalenolato-N(1)-,O(2))-, (T-4)-249-503-9 29204-84-0 Nickel, bis[2,3-bis(hydroxyimino)-N-phenylbutanamidato-N(2)- LPVC ,N(3)-]-287-467-6 85508-42-5 Nickel, (isodecanoato-O)(neodecanoato-O)-300-092-5 93920-08-2 Nickel, (neononanoato-O)(neoundecanoato-O)-256-331-8 47726-62-5 Nickel, [[2,2-(4,8-dichlorobenzo[1,2-d:4,5-d]bisoxazole-2,6- diyl)bis[4,6-dichlorophenolato]](2-)]- 160
  • R_NickelBackground_0308_hh_chapter0124567.docOrganic nickel compounds (continued).255-924-9 42739-61-7 Nickel, bis[2,3-bis(hydroxyimino)-N-(2- LPVC methoxyphenyl)butanamidato]-252-937-1 36259-37-7 Nickel, bis(dipentylcarbamodithioato-S,S)-, (SP-4-1)-286-563-5 85269-39-2 Nickel, bis[N-(2,4-dimethoxyphenyl)-2,3- bis(hydroxyimino)butanamidato-N(2)-,N(3)-]-, (SP-4-1)-279-314-7 79817-91-7 Nickelate(3-), [5-[(4,5-dihydro-3-methyl-5-oxo-1-phenyl-1H- pyrazol-4-yl)azo]-4-hydroxy-3-[(2-hydroxy-3-nitro-5- sulfophenyl)azo]-2,7-naphthalenedisulfonato(5-)]-, trisodium243-820-6 20437-10-9 Nickel, [[1,1-[1,2-phenylenebis(nitrilomethylidyne)]bis[2- naphthalenolato]](2-)-N,N,O,O]-249-353-4 28984-20-5 Nickel, bis[1,2-diphenyl-1,2-ethenedithiolato(2-)-S,S]-, (SP-4-1)-248-536-6 27574-34-1 Nickel, [[2,2-thiobis[4-(1,1,3,3-tetramethylbutyl)phenolato]](2-)- O,O,S]-251-715-1 33882-09-6 Nickel, [[2,2-thiobis[3-octylphenolato]](2-)-O,O,S]-240-485-8 16432-37-4 Nickel, [[2,2-sulfonylbis[4-(1,1,3,3- tetramethylbutyl)phenolato]](2-)-O(1)-,O(1)-,O(2)-]-262-703-0 61300-98-9 Nickelate(1-), [3,4-bis[[(2-hydroxy-1- naphthalenyl)methylene]amino]benzoato(3-)-N(3)-,N(4)-,O(3)- ,O(4)-]-, hydrogen255-965-2 42844-93-9 Nickel, [1,3-dihydro-5,6-bis[[(2-hydroxy-1- naphthalenyl)methylene]amino]-2H-benzimidazol-2-onato(2-)- N(5)-,N(6)-,O(5)-,O(6)-]-, (SP-4-2)-257-521-3 51931-46-5 Nickel, bis[3-[(4-chlorophenyl)azo]-2,4(1H,3H)- quinolinedionato]-267-045-8 67763-27-3 Nickel, (2-propanol)[[2,2-thiobis[4-(1,1,3,3- tetramethylbutyl)phenolato]](2-)-O,O,S]-249-155-8 28680-76-4 Nickel, [29H,31H-phthalocyaninetetrasulfonyl tetrachloridato(2)- N(29)-,N(30)-,N(31)-,N(32)-]-237-893-3 14055-02-8 Nickel, [29H,31H-phthalocyaninato(2-)-N(29)-,N(30)-,N(31)- LPVC ,N(32)-]-, (SP-4-1)-254-212-5 38951-97-2 Nickel, bis[1,2-bis(4-methoxyphenyl)-1,2-ethenedithiolato(2-)- S,S]-, (SP-4-1)-253-958-9 38465-55-3 Nickel, bis[1-[4-(dimethylamino)phenyl]-2-phenyl-1,2- ethenedithiolato(2-)-S,S]-238-523-3 14516-71-3 Nickel, (1-butanamine)[[2,2-thiobis[4-(1,1,3,3- LPVC tetramethylbutyl)phenolato]](2-)-O,O,S]-276-364-1 72139-08-3 Nickelate(8-), bis[3-[(2-amino-8-hydroxy-6-sulfo-1- naphthalenyl)azo]-2-hydroxy-5-sulfobenzoato(5-)]-, hexasodium dihydrogen281-282-4 83898-70-8 Nickel, dimethoxy[29H,31H-phthalocyaninato(2-)-N(29)-,N(30)- ,N(31)-,N(32)-]-, (OC-6-12)-274-027-3 69524-96-5 Nickel, bis(4-benzoyl-2,4-dihydro-5-methyl-2-phenyl-3H-pyrazol- 3-onato-O,O)-238-400-4 14428-08-1 Nickel, bis[bis(2-ethylhexyl)carbamodithioato-S,S]-238-154-8 14264-16-5 Nickel, dichlorobis(triphenylphosphine)- 32583279-060-7 79102-62-8 Nickelate(4-), [[[(3-amino-4-sulfophenyl)amino]sulfonyl]- 29H,31H-phthalocyaninetrisulfonato(6-)-N(29)-,N(30)-,N(31)- ,N(32)-]-, tetrahydrogen300-365-9 93939-76-5 Nickelate(4-), [[[(3-amino-4-sulfophenyl)amino]sulfonyl]- 29H,31H-phthalocyaninetrisulfonato(6-)-N(29)-,N(30)-,N(31)- ,N(32)-]-, tetrasodium235-851-9 13007-90-4 Nickel, dicarbonylbis(triphenylphosphine)-, (T-4)- 32582283-380-2 84604-95-5 Nickel, bis[bis(3,5,5-trimethylhexyl)carbamodithioato-S,S’]-260-258-7 56557-00-7 Nickel, bis[2,4-dihydro-5-methyl-4-(1-oxodecyl)-2-phenyl-3H- pyrazol-3-onato-O,O’]-276-491-2 72229-81-3 Nickelate(3-), [[[[3-[(4-amino-6-chloro-1,3,5-triazin-2- yl)amino]phenyl]amino]sulfonyl]tris(aminosulfonyl)-29H,31H- phthalocyaninetrisulfonato(5-)-N(29)-,N(30)-,N(31)-,N(32)-]-, trisodium 161
  • R_NickelBackground_0308_hh_chapter0124567.docOrganic nickel compounds (continued).275-295-4 71243-96-4 Nickelate(3-), [22-[[[3-[(5-chloro-2,6-difluoro-4- pyrimidinyl)amino]phenyl]amino]sulfonyl]-29H,31H- phthalocyanine-1,8,15-trisulfonato(5-)-N(29)-,N(30)-,N(31)- ,N(32)-]-, trisodium, (SP-4-2)-276-168-6 71889-22-0 Nickel, [mu-(piperazine-N(1)-:N(4))]bis[3-[1-[(4,5,6,7- tetrachloro-1-oxo-1H-isoindol-3-yl)hydrazono]ethyl]-2,4(1H,3H)- quinolinedionato(2-)]di-239-949-2 15843-91-1 Nickel, bis[[2-hydroxy-4-(octyloxy)phenyl]phenylmethanonato]-306-462-2 97280-68-7 Nickelate(4-), [bis[[[4-[[2- (sulfooxy)ethyl]sulfonyl]phenyl]amino]sulfonyl]-29H,31H- phthalocyaninedisulfonato(6)-N(29)-,N(30)-,N(31)-,N(32)-]-, tetrasodium245-028-6 22484-07-7 Nickel, [mu-[[1,1’,1’’,1’’’-[1,2,4,5- benzenetetrayltetrakis(nitrilomethylidyne)]tetrakis[2- naphthalenolato]](4-)]]di-272-095-9 68698-80-6 Nickelate(6-), [4-[[5-[[(3,6-dichloro-4- pyridazinyl)carbonyl]amino]-2-sulfophenyl]azo]-4,5-dihydro-5- oxo-1-[5-[[(trisulfo-29H,31H-phthalocyaninyl)sulfonyl]amino]-2- sulfophenyl]-1H-pyrazole-3-carboxyla299-467-3 93891-86-2 Nickelate(6-), [4-[[5-[[(3,6-dichloro-4- pyridazinyl)carbonyl]amino]-2-sulfophenyl]azo]-4,5-dihydro-5- oxo-1-[2-sulfo-5-[[(trisulfo-29H,31H- phthalocyaninyl)sulfonyl]amino]phenyl]-1H-pyrazole-3-carboxyla272-799-6 68912-08-3 Nickel, bis(2-heptadecyl-1H-imidazole-N(3))bis(octanoato-O)-279-067-5 79121-51-0 Nickel, bis(4-benzoyl-2,4-dihydro-5-methyl-2-phenyl-3H-pyrazol- 3-onato-O,O’)(2,2,4,4-tetramethyl-7-oxa-3,20- diazadispiro[5.1.11.2]heneicosan-21-one-O(21))-276-399-2 72152-45-5 Nickelate(6-), [22-[[[3-[[4,5-dihydro-3-methyl-5-oxo-1-[3-sulfo- 4-[2-[2-sulfo-4-[(2,5,6-trichloro-4- pyrimidinyl)amino]phenyl]ethenyl]phenyl]-1H-pyrazol-4-yl]azo]- 4-sulfophenyl]amino]sulfonyl]-29H,31H-306-784-3 97404-21-2 Nickel, [[N,N’,N’’-[29H,31H- phthalocyaninetriyltris(sulfonylimino-3,1-phenylene)]tris[3- oxobutanamidato]](2-)-N(29)-,N(30)-,N(31)-,N(32)-]-269-684-8 68309-97-7 Nickel(2+), tris(4,7-diphenyl-1,10-phenanthroline-N(1)-,N(10))-, (OC-6-11)-, bis[tetrafluoroborate(1-)]254-127-3 38780-90-4 Nickel(2+), tris(4,7-diphenyl-1,10-phenanthroline-N(1)-,N(10))-, (OC-6-11)-, dinitrate277-174-1 72986-45-9 Nickel, [N,N’,N’’,N’’’-tetrakis[4-(4,5-dihydro-3-methyl-5-oxo- 1H-pyrazol-1-yl)phenyl]-29H,31H- phthalocyaninetetrasulfonamidato(2-)-N(29)-,N(30)-,N(31)- ,N(32)-]-306-785-9 97404-22-3 Nickel, [[N,N’,N’’,N’’’-[29H,31H- phthalocyaninetetrayltetrakis(sulfonylimino-3,1- phenylene)]tetrakis[3-oxobutanamidato]](2-)-N(29)-,N(30)- ,N(31)-,N(32)-]-252-777-2 35884-66-3 Nickel, tetrakis[tris(methylphenyl) phosphite-P]-262-934-7 61725-51-7 Nickel, 3-[(4-chlorophenyl)azo]-4-hydroxy-2(1H)-quinolinone complex; C.I. 12775263-000-1 61788-71-4 Naphthenic acids, nickel salts269-826-9 68334-36-1 Resin acids and Rosin acids, nickel salts271-764-2 68607-31-8 Resin acids and Rosin acids, calcium nickel salts270-174-2 68412-18-0 Nickel, [29H,31H-phthalocyaninato(2-)-N(29)-,N(30)-,N(31)- ,N(32)-]-, sulfo [[4-[[2- (sulfooxy)ethyl]sulfonyl]phenyl]amino]sulfonyl derivs.270-944-8 68511-62-6 Nickel, 5,5-azobis-2,4,6(1H,3H,5H)-pyrimidinetrione complexes LPVC276-877-0 72828-53-6 Nickel, [29H,31H-phthalocyaninato(2-)-N(29)-,N(30)-,N(31)- ,N(32)-]-, [[3-[(1,3-dioxobutyl)amino]phenyl]amino]sulfonyl derivs.294-302-1 91697-41-5 Fatty acids, C6-C19-branched, nickel salts 162
  • R_NickelBackground_0308_hh_chapter0124567.docOrganic nickel compounds (continued).283-972-0 84776-45-4 Fatty acids, C8-C18 and C18-unsatd., nickel salts287-356-2 85480-75-7 Nickel, 2,2-thiobis[4-nonylphenol] complexes291-676-8 90459-33-9 Nickel, isooctanoate naphthenate complexes287-801-0 85585-98-4 Nickel, isononanoate naphthenate complexes287-800-5 85585-97-3 Nickel, isodecanoate naphthenate complexes287-802-6 85585-99-5 Nickel, naphthenate neodecanoate complexes291-673-1 90459-30-6 Nickel, acetate carbonate C8-C10-branched fatty acids C9-C11- LPVC neofatty acids complexes291-674-7 90459-31-7 Nickel, borate C8-C10-branched carboxylate complexes291-675-2 90459-32-8 Nickel, C5-C23-branched carboxylate octanoate complexes291-677-3 90459-34-0 Nickel, acetylacetone 6-methyl-2,4-heptanedione complexes291-678-9 90459-35-1 Nickel, [29H,31H-phthalocyaninato(2-)-N(29)-,N(30)-,N(31)- ,N(32)-]-, [[3-[(5-chloro-2,6-difluoro-4- pyrimidinyl)amino]phenyl]amino]sulfonyl sulfo derivs., sodium salts291-679-4 90459-36-2 Nickelate(4-), [bis[[[3-[[4,5-dihydro-3-methyl-5-oxo-1-[4-[[2- (sulfooxy)ethyl]sulfonyl]phenyl]-1H-pyrazol-4- yl]azo]phenyl]amino]sulfonyl]-29H,31H- phthalocyaninedisulfonato(6-)-N(29)-,N(30)-,N(31)-,N(3295-925-1 92200-98-1 Nickel, C5-C23-branched carboxylate naphthenate complexes295-926-7 92200-99-2 Nickel, C5-C25-branched carboxylate naphthenate octanoate complexes296-343-0 92502-55-1 Nickel, borate neodecanoate complexes297-548-8 93573-14-9 Nickel, C5-C23-branched carboxylate C4-C10-fatty acids naphthenate complexes297-549-3 93573-15-0 Nickel, C4-C10 fatty acids naphthenate complexes297-550-9 93573-16-1 Nickel, C4-C10 fatty acids octanoate complexes297-774-7 93762-59-5 Nickel, C5-C23-branched carboxylate C4-C10 fatty acids complexes297-551-4 93573-17-2 Nickel, [29H,31H-phthalocyaninato(2-)-N(29)-,N(30)-,N(31)- ,N(32)-]-, chlorosulfonyl derivs., reaction products with 2-[(4- aminophenyl)sulfonyl]ethyl hydrogen sulfate monosodium salt, potassium sodium305-643-3 94891-42-6 Nickel, [29H,31H-phthalocyaninato(2-)-N(29)-,N(30)-,N(31)- ,N(32)-]-, chlorosulfonyl derivs., reaction products with 2-[(4- aminophenyl)sulfonyl]ethyl hydrogen sulfate monosodium salt, potassium salts305-644-9 94891-43-7 Nickel, [29H,31H-phthalocyaninato(2-)-N(29)-,N(30)-,N(31)- ,N(32)-]-, chlorosulfonyl derivs., reaction products with 2-[(4- aminophenyl)sulfonyl]ethyl hydrogen sulfate monosodium salt, sodium saltsDiverse Nickel compounds.EC Number CAS Chemical Name HPVC / LPVC CUS Number Number307-554-5 97660-42-9 Copper, bis(8-quinolinolato-N(1)-,O(8))-, reaction products with C8-C10-branched fatty acids, tert-decanoic acid, nickel(2+) diacetate, nickel(2+) carbonate (1:1) and nickel hydroxide (Ni(OH)2)283-945-3 84776-20-5 Bentonite, nickeloan232-490-9 8052-42-4 Asphalt HPVC266-046-0 65997-17-3 Glass, oxide, chemicals HPVC266-047-6 65997-18-4 Frits, chemicals HPVC266-048-1 65997-19-5 Steel manufacture, chemical266-340-9 66402-68-4 Ceramic materials and wares, chemicals HPVC266-965-7 67711-89-1 Calcines, copper roasting266-967-8 67711-91-5 Matte, copper HPVC266-968-3 67711-92-6 Slags, copper smelting HPVC268-627-4 68131-74-8 Ashes, residues HPVC 163
  • R_NickelBackground_0308_hh_chapter0124567.doc273-700-9 69011-59-2 Lead alloy, base, dross LPVC273-701-4 69011-60-5 Lead alloy, base, Pb,Sn, dross HPVC273-704-0 69011-64-9 Babbitt, dross273-720-8 69012-20-0 Waste solids, copper electrolyte purifn. cathodes HPVC273-729-7 69012-29-9 Slags, ferronickel-manufg. HPVC273-749-6 69012-50-6 Matte, nickel HPVC273-795-7 69029-51-2 Lead, antimonial, dross282-214-6 84144-92-3 Leach residues, nickel-vanadium ore293-311-8 91053-46-2 Leach residues, zinc ore-calcine, cadmium-copper ppt. HPVC293-312-3 91053-47-3 Leach residues, zinc ore-calcine, iron contg. HPVC293-796-6 91082-81-4 Waste solids, chromium-nickel steel manuf.293-799-2 91082-84-7 Waste solids, nickel-manuf.295-859-3 92129-57-2 Slimes and Sludges, copper electrolyte refining, decopperised, Ni HPVC sulfate297-402-3 93571-76-7 Ashes (residues), heavy fuel oil fly LPVC305-433-1 94551-87-8 Slimes and Sludges, copper electrolyte refining, decopperised LPVC308-765-5 98246-91-4 Speiss, lead, nickel-contg.310-050-8 102110-49-6 Residues, copper-iron-lead-nickel matte, sulfuric acid-insol.Note: EINECS entries that include a reference to nickel as e.g. a catalyst rather than as a constituent have notbeen included.7.2.2 Nickel compounds included in ElincsEC Number CAS Chemical Name HPVC / LPVC CUS Number Number410-160-7 148732-74-5 Tetrasodium (c-(3-(1-(3-(e-6-dichloro-5-cyanopyrimidin-f- yl(methyl)amino)propyl)-1,6-dihydro-2-hydroxy-4-methyl-6-oxo- 3-pyridylazo)-4-sulfonatophenylsulfamoyl) phtalocyanine-a,b,d- trisulfonato(6-))nickelato II, where a is 1 or 2 or 3 or 4,b is 8 or 9 or 10 or 11, c is 15 or 16 or 17 or 18, d is 22 or 23 or 24 or 25 and where e and f together are 2 and 4 or 4 and 2 respectively407-110-1 - Trisodium (1-(3-carboxylato-2-oxido-5-sulfonatophenylazo)-5- hydroxy-7-sulfonatophthalen-2-amido)nickel(II)417-250-5 151436-99-6 Hexasodium (di(N-(3-(4-[5-(5-amino-3-methyl-1-phenylpyrazol- 4-yl-azo)-2,4-disulfo-anilino]-6-chloro-1,3,5-triazin-2- ylamino)phenyl)-sulfamoyl](disulfo)-phthalocyaninato)nickel 164
  • R_NickelBackground_0308_hh_chapter0124567.doc7.2.3 Additional Nickel compounds included in TSCA (through 08/2000) but not included in EINECS.CAS Number Chemical Name 12031-65-1 Lithium nickel oxide (LiNiO2) 12645-50-0 Iron-nickel-zinc-oxide- 12673-58-4 Molybdenum-nickel-oxide- 12737-30-3 Cobalt-nickel-oxide- 14221-00-2 Nickel, tetrakis(triphenyl phosphite-kappaP)-, (T-4)- 14406-71-4 Nickel, [[2,2-[1,2-phenylenebis[(nitrilo-kappaN)methylidyne]]bis[phenolato- kappaO]](2-)]-14434-67-4 Nickel, bis(hexahydro-1H-azepine-1-carbodithioato-kappaS,kappaS)-, (SP-4- 1)-17169-61-8 Phosphoric acid, calcium nickel salt18824-79-8 1,2-Benzenedicarboxylic acid, 3,4,5,6-tetrabromo-, nickel(2+) salt (1:1)18972-69-5 Nickel(2+), bis(1,2-propanediamine-kappaN,kappaN)-, bis[bis(cyano- kappaC)aurate(1-)]19372-20-4 Diphosphoric acid, nickel(2+) salt34109-80-3 Titanate(2-), hexafluoro-, nickel(2+), (1:1), (OC-6-11)-36545-21-8 Nickel, bis[(phenyldiazenecarbothioic acid-kappaS) 2-phenylhydrazidato- kappaN2]-51449-18-4 Nickel, bis[1-[4-(diethylamino)phenyl]-2-phenyl-1,2-ethenedithiolato(2-)- kappaS,kappaS]-53199-85-2 Nickel(1+), [1-[2-amino-4-(imino-kappaN)-5(4H)-thiazolylidene]-N-[1-[2- amino-4-(imino-kappaN)-5(4H)-thiazolylidene]-1H-isoindol-3-yl-kappaN]-1H- isoindol-3-aminato-kappaN2]-, chloride54576-53-3 Antimony-nickel-titanium-oxide-55868-93-4 Benzenepropanoic acid, 3,5-bis(1,1-dimethylethyl)-4-hydroxy-, nickel(2+) salt (2:1)65229-23-4 Nickel-boron-phosphide-68189-15-1 Nickel, bis[[2-(hydroxy-kappaO)-4-octylphenyl]phenylmethanonato-kappaO]-68412-19-1 Nickel, [29H,31H-phthalocyaninato(2-)-N29,N30,N31,N32]-, [(3- aminophenyl)amino]sulfonyl sulfo derivs.68412-20-4 Nickel, dextrin complexes68585-48-8 Sulfuric acid, nickel(2+) salt (1:1), reaction products with nickel and nickel oxide (NiO)69012-51-7 Copper cake, zinc-refining70776-98-6 Nickel, (2-ethylhexanoato-kappaO)(trifluoroacetato-kappaO)-71050-57-2 Acetic acid, nickel(2+) salt, polymer with formaldehyde and 4-(1,1,3,3- tetramethylbutyl)phenol71215-73-1 Nickel, [[2,2-[methylenebis(thio-kappaS)]bis[acetato-kappaO]](2-)]-71215-97-9 Nickel(2+), tris(1,2-ethanediamine-kappaN,kappaN)-, (OC-6-11)-, salt with dimethylbenzenesulfonic acid (1:2)71215-98-0 Nickel(2+), bis(1,2-ethanediamine-kappaN,kappaN)-, salt with dimethylbenzenesulfonic acid (1:2)71605-83-9 Nickel, bis[N-hydroxy-3-(hydroxyimino-kappaN)-N-(2- methoxyphenyl)butanimidamidato-kappaN]-71889-20-8 Nickel, [N-(4-chlorophenyl)-3-[[[1-(4-chlorophenyl)-4,5-dihydro-3-methyl-5- (oxo-kappaO)-1H-pyrazol-4-yl]methylene]hydrazino-kappaN2]-alpha-cyano- 1H-isoindole-3-acetamidato(2-)-kappaN2,kappaO3]-72162-32-4 Sulfuric acid, nickel salt, reaction products with sulfurized calcium phenolate72252-57-4 Nickel, [N,N,N-tris[4-(4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)phenyl]- 29H,31H-phthalocyanine-C,C,C-trisulfonamidato(2-)- kappaN29,kappaN30,kappaN31,kappaN32]-72319-19-8 2,7-Naphthalenedisulfonic acid, nickel(2+) salt (1:1)79357-65-6 Aluminum, triethyl-, reaction products with nickel(2+) bis(2-ethylhexanoate)83864-02-2 Nickel, bis[(cyano-C)triphenylborato(1-)-N]bis(hexanedinitrile-N,N)-91845-72-6 Fatty acids, C3-22, nickel salts, basic106316-55-6 Nickel, aqua[2-[[4,5-dihydro-3-methyl-5-(oxo-kappaO)-1H-pyrazol-4-yl]azo- kappaN1]benzoato(2-)-kappaO]- 165
  • R_NickelBackground_0308_hh_chapter0124567.docAdditional nickel compounds included in TSCA (through 08/2000) but not included in EINECS(continued). 108818-89-9 Nickel(2+), hexakis(1H-imidazole-kappaN3)-, (OC-6-11)-, 1,2- benzenedicarboxylate (1:1) 113894-88-5 Nickel, [29H,31H-phthalocyaninato(2-)-N29,N30,N31,N32]-, sulfo [[4-[[2- (sulfooxy)ethyl]sulfonyl]phenyl]amino]sulfonyl derivs., potassium sodium salts 131866-99-4 Nickel, [29H,31H-phthalocyaninato(2-)-N29,N30,N31,N32]-, sulfo [[4-[[2- (sulfooxy)ethyl]sulfonyl]phenyl]amino]sulfonyl derivs., sodium salts7.2.4 Additional Nickel compounds listed in ECICS (European Customs Inventory of chemical substances), but not included in EINECS or the TSCA Inventory. CAS No. Name CUS Number. 10471-42-8 nickel tartrate 20764 10534-88-0 hexaamminenickel dichloride 18196 12137-12-1 trinickel tetrasulfide 20763 12758-25-7 nickel metaborate 20727 13601-55-3 hexaamminenickel dibromide 11020 15651-35-1 tetraamminenickel dinitrate 11025 16039-61-5 nickel dilactate 20748 74195-78-1 diammonium nickel hexacyanoferrate 11023 74646-29-0 trinickel bis(arsenite) 207257.2.5 Additional Nickel compounds in Annex I to Directive 67/548/EEC but not in EINECS or TSCA.CAS Number Chemical Name Part of Group entry: 12256-33-6 nickel arsenide, Ni11As8 033-002-00-5 12255-80-0 nickel arsenide, Ni5As2 033-002-00-5 12255-10-6 nickel arsenide sulfide, NiAsS 033-002-00-5 12137-13-2 nickel selenide, Ni3Se2 034-002-00-8 71077-18-4 Rutile, antimony nickel yellow 051-003-00-9 68130-19-8 Silicic acid, lead nickel salt 082-001-00-67.2.6 Additional nickel compound found in the course of compiling the inventory of nickel compoundsEC No. CAS No. Name HPVC/ CUS LPVC Number 11132-10-8 nickel potassium fluoride 391864-36-1 nickel potassium cyanide (NiK2(CN)4) 55465-44-6 potassium nickel cyanide nickel calcium cyanide 19 131344-56-4 cobalt lithium nickel oxide 162004-08-2 cobalt lithium nickel oxide (Co,Li,Ni)O2 510727-46-5 cobalt lithium nickel oxide (Co,Li)NiO219 Marketed without CAS No. 166
  • R_NickelBackground_0308_hh_chapter0124567.doc7.2.7 Additional nickel hydroxycarbonate compounds not included in the lists aboveEC No. CAS No. Name, formula HPVC/ CUS LPVC Number 152008-07-6 4NiCO3.Ni(OH)2 128024-15-7 3NiCO3.Ni(OH)2 342774-56-5 Ni(CO3)0-1.5(OH)0-3 148522-90-1 3NiCO3.4Ni(OH)2 12122-15-5 pentanickel dicarbonate hexahydroxide, 2NiCO3.3Ni(OH)2 12274-86-1 NiCO3.3Ni(OH)2 404866-99-5 NiCO3.13Ni(OH)27.2.8 Nickel containing minerals (from IARC, 1990 and NiPERA, 1996).CAS Number Name Chemical composition 1 153809-86-2, 12174-14-0 Pentlandite (Fe,Ni)9S81314-04-1 Millerite NiS12035-71-1 Heazlewoodite Ni3S2 Polydymite Ni3S4 Siegenite (Co,Ni)3S4 Violarite Ni2FeS412035-50-6 Vaesite NiS2 2 Pyrrhotite, nickeliferous (Fe,Ni)1-xS1303-13-5 Niccolite, nickeline NiAs12044-65-4 Maucherite Ni11As8 Rammelsbergite NiAs212255-11-7 Gersdorffite NiAsS12201-85-3 Makinenite, Maekinenite NiSe12125-61-0 Breithauptite NiSb24270-51-7 Imgreite NiTe Garnierite (Ni, Mg)SiO3.nH2O Nickeliferous limonite (Fe,Ni)O(OH).nH2O34492-97-2 Bunsenite NiO39430-27-8 Zaratite (basic nickel carbonate, tetrahydrate) NiCO3.2Ni(OH)2.4H2O Morenosite (nickel sulphate heptahydrate) NiSO4.7H2O1) CAS No. 53809-86-2 corresponds to Fe9Ni9S16;CAS No. 12174-14-0 corresponds to (Fe0.4-0.6Ni0.4-0.6)9S8 (NiPERA, 1996).2) IARC also lists pure nickel sulphide (NiS2), CAS No. 12035-51-7. Both compounds are in the +4 oxidationstate.Minerals are exempted from registration under REACH. However, minerals should be classified if they fulfillthe classification criteria. 167
  • R_NickelBackground_0308_hh_chapter0124567.doc7.3 NICKEL CONTENT IN FOOD.Food μg Ni / g wet weight (1) μg Ni / kg (2) mean (range)BeveragesBeer 0.004Coffee 0.015Cola 0.001Juice 0.04 (0.01 – 0.17)Orange juice 0.015Tea 0.052Wine 0.028StarchesWheat flour 0.135 0.13 (0.03 – 0.3)Rye flour 0.1 (0.03 – 0.3)Oat meal 1.76 (0.80 – 4.7)Bread, white 0.053Bread, whole wheatRice 0.21 (0.08 – 0.45)Rice cereal cooked 0.083Pasta, plain, cooked 0.012Pasta, canned 0.081Biscuits 0.243Cookies 1.273Chocolate, Sugar and products thereof, Confectionary products.Sugar 0.05 (0.01 – 0.09)Sugar, white 0.003Honey 0.012Chocolate pudding 0.185Doughnuts 0.178Fruits, Vegetables and products thereof.Apples 0.042 0.01 (BLD (3) – 0.03)Pears 0.133 0.14…(0.07 – 0.42)Plums 0.12 (0.03 – 0.20)Plums, Prunes, dried, canned 0.284Grapes 0.01 0.02 (0.01 – 0.04)Raisins 0.074 0.03 (0.02 – 0.04)Currants 0.06 (0.01 – 0.2)Strawberries 0.05 (0.03 – 0.08)Rhubarb 0.13 (0.01 – 0.22)Bananas 0.078 0.02 (0.01 – 0.03)Citrus fruit 0.062 0.03 (0.01 – 0.04)Pineapple 0.162Canned fruits 0.31 (0.02 – 1.36)Asparagus 0.42Cucumber 0.187 0.04 (0.01 – 0.11)Tomatoes 0.036 0.07 (0.01 – 0.25Lettuce 0.097 0.36 (BLD – 1.4)Celery 0.058Celery root 0.06 (0.04 – 0.1)Mushrooms 0.045Mushrooms, canned 0.152Beans, raw and canned, cooked 0.222Broccoli 0.081Cabbage 0.17 (0.01 – 0.63) 168
  • R_NickelBackground_0308_hh_chapter0124567.docCabbage, cooked and coleslaw 0.027Kale 0.20 (0.15 – 0.24)Cauliflower 0.3 (0.03 – 1.0)Cauliflower, raw and cooked 0.069Peas 0.42 (0.13 – 0.8)Peas, raw and canned, cooked 0.225Spinach 0.52 (0.02 – 2.99)Beetroot 0.12 (0.01 – 0.3)Carrots 0.056 0.04 (<0.01 – 0.16)Carrots, cooked, canned 0.006Potatoes 0.14 (BLD – 0.44)Potato skins, cooked or boiled 0.982Potatoes, peeled, cooked or boiled 0.042Onions 0.06Onions, cooked or boiled 0.044Fats and OilsCooking fats and salad oils 0.045Butter 0.017 0.1 (0.03 – 0.2)Peanut butter & Peanuts 1.467Margarine 0.185 0.34 (0.2 – 2.5)Animal products and EggsFish 0.04 (0.005 – 0.303)Marine fish, cooked or boiled 0.211Freshwater fish, cooked or boiled 0.047Fish, canned 0.101Shellfish, fresh or frozen 0.118Beef 0.047 – 2.521 0.02 (0.01 – 0.03)Veal, cooked or boiled 0.067Pork 1.009 0.02 (<0.02 – 0.02)Pork, cooked or boiled 0.702Lamb 0.02 (<0.02 – 0.02)Liver, kidney 0.11 (0 – 0.94)Chicken 0.11 (0.02 – 0.24)Chicken, cooked or boiled 0.283Eggs 0.007 0.05 (0.01 – 0.35)Milk ProductsMilk 0.009 0.02 (BLD – 0.13)Cream 0.03 (0.01 – 0.04)Yogurt 0.014 0.01 (0.004 – 0.03)Cheese 0.066 0.10 (0.02 – 0.34Cheese, cottage 0.019Cheese, processed cheddar 0.100MiscellaneousIce cream 0.3231) Council of Europe (2001). Reference to “The Essentiality of Nickel”, NiPERA, 1999. The original source isgiven as CEPA (1994).2) Nickel content in foods in the average Danish diet. (Grandjean et. al., 1989), quoted in IARC (1990).3) BLD: Below detection Limit 169