Animal testing safety endpoints in chemical industry


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This presentation describes animal testing safety end points in chemical industry according to REACH(registration,evaluation,authorisation & restriction of chemicals).
REACH was established to control manufacturing and importing of chemicals in EU market & to minimize the risks to human health and environment.

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  • Substances which have long been on EU market are called phase-in substances & those which have not previously been placed on the EU market are called non phase in substances
  • IUCLID-international uniform chemical information database-IUCLID5 is built using internationally harmonized formats for reporting data on chemicals that were prepared and accepted by many national and international regulatory authorities within the OECD
  • 1.Sunset date-the date (called 'the sunset date") from which the placing on the market and the use of that substance shall be prohibited unless an exemption applies or an authorisation is granted or an authorisation application has been submitted before the application date also specified in Annex XIV, but the Commission decision on the application for authorisation has not yet been taken2.PBT-Persistent, bioaccumulative & toxic-PBTs are substances of very high concern (SVHC) and may be included in Annex XIV and by that be made subject to authorisation3.vPvB-very persistent & very bioaccumulative-these are the substances which are very difficult to break downand very bio-accumulative in living organisms
  • Socio economic analysis-is to evaluate what costs and benefits an action will create for society by comparing what will happen if this action is implemented as compared to the situation where the action is not implemented
  • CSR-chemical safety reportPBT-persistent, bioaccumulative & toxicES-exposure scenario-Set of conditions, including operational conditions and risk management measures, that describe how the substance is manufactured or used during its life-cycle(REACH Article 3 (37))eSDS-extended safety data sheet
  • It took 11 years to produce risk assessments for 140 chemicals, yet REACH proposes that industryproduce similar data for 30,000 chemicals, in the same timescale
  • In vitro-taking place outside the body of an organism. It refers to studies in the laboratory usually involving isolated organs, tissues, cells or biochemical systemIn vivo-testing within a living organism
  • 1.LD50:-is the dose that kills half(50%) of the animals tested2.LC50:-is the concentration of a chemical which kills 50% of a sample population3.Trevan (1927) was the first to attempt to standardize a method for assessing the toxicity of potent biologicaltoxicants, the progenitor of the "lethal dose, 50% (LD50) test.4.more recently, the acute toxicity test procedure has been modified in various ways to refine and furtherreduce the number of animals used to a maximum of 16.
  • In the “ReducedData Need” scenario, the overwhelming importance of the 2-generation reproductive study isvery evident accounting for 71% of animal use.When all reproduction or developmentaltests are considered together, this equates to >80% of animal use.
  • Intrinsic property-An intrinsic property of a chemical substance is a characteristic of the substance which can be used to determine its fate or to identify potential hazards.
  • Animal testing safety endpoints in chemical industry

    1. 1. ANIMAL TESTING SAFETY END POINTS IN CHEMICAL INDUSTRY<br />(Precisely EU legislation on registration, evaluation & authorisation of chemicals or REACH) <br />SUBMITTED BY-MIHIR PUJARA<br />DEPT. OF PHARMACEUTICAL MANAGEMENT,<br />NIPER,MOHALI<br />
    2. 2. FLOW OF PRESENTATION<br /><ul><li>Introduction
    3. 3. About REACH
    4. 4. REACH process in detail
    5. 5. What are “end points”?
    6. 6. Chart describing overall process related to chemical safety assessment
    7. 7. Testing involved in REACH proposal(annex V to X)
    8. 8. Acute toxicity tests
    9. 9. REACH-needed data of all the “end points”
    10. 10. Reproductive & developmental toxicology testing requirements
    11. 11. Examples
    12. 12. Brief introduction of other regulatory agencies</li></li></ul><li> INTRODUCTION<br /> CHEMICAL SECTOR<br /> ANIMAL TESTING<br /><ul><li>One of the biggest industrial sector in EU
    13. 13. Numerous regulations
    14. 14. Numerous substances
    15. 15. Numerous stakeholders
    16. 16. Different authorities
    17. 17. Agencies from several countries
    18. 18. Many companies/competitiors
    19. 19. Traders
    20. 20. Many customer(diverse usages</li></ul>& worldwide marketing)<br /><ul><li>At least 50 new chemicals in EU each</li></ul>year. Approximately 60 000 – 100 000 chemical substances are on the market<br /><ul><li>Proper regulation is mandatory
    21. 21. Animal tests were developed and testing demands increased along with increasing awareness and data of toxicity of chemicals in man.
    22. 22. Current legislation dictates that animal test data is still required to help assess potential health hazards of chemicals to humans.
    23. 23. The new European REACH and CLP Regulations take this further and require approval to be obtained from ECHA, the European Chemicals Agency, before any animal tests are carried out, for both substances and preparations.
    24. 24. Approval for new testing on animals will only be granted once all other methods to generate the necessary data have been exhausted.</li></li></ul><li><ul><li>REACH is a European Union regulation concerning the Registration, Evaluation, Authorisation and restriction of Chemicals. It came into force on 1st June 2007 and replaced a number of European Directives and Regulations with a single system.
    25. 25. To protect human health & environment from the use of chemicals
    26. 26. Understand & manage risk associated with chemicals & their use
    27. 27. To allow free movement of substances on EU market
    28. 28. To enhance innovation in and the competitiveness of the EU chemicals industry
    29. 29. To promote the use of alternative methods for the assessment of the hazardous properties of substances. e.g.QSAR
    30. 30. REACH foresees data sharing between registrants to gather the required information
    31. 31. The regulation applies to substances manufactured in, or imported to the EU in annual quantities of 1 tonne or more per company, unless the regulation indicates otherwise.</li></ul> WHAT IS REACH?<br /> PROPOSAL FOR SAFETY DRIVERS:<br /> WHY THERE IS SAFETY TESTING?<br />
    32. 32. <ul><li>If the substances are not registered, then the data on them will not be available & as a result a firm will no longer be able to manufacture or supply them legally.
    33. 33. Pre registration
    34. 34. Applies from 1 june 2008
    35. 35. Chemicals currently on EU market are pre-registered between 1 june to 1 december,2008
    36. 36. Companies who pre-register their substances can benefit from extended registration deadlines
    37. 37. Late pre registration
    38. 38. It applies, when any company starts manufacturing or importing 1 tonne or more chemical substance per year after 1 dec,2008
    39. 39. Late pre-registration does not apply to companies that failed to meet the pre-registration deadline of 1 December 2008 for their substances
    40. 40. Chemicals manufactured or imported in large volumes have to register first</li></ul> NO DATA, NO MARKET<br />
    41. 41. REGISTRATION<br />NECESSARY THINGS FOR REGISTRATION<br />1.A technical dossier-for substances in quantities of 1 tonne or more per year<br /><ul><li>contains information on properties, classification, guidance & uses of chemical
    42. 42. Information is proportional to quantity. The higher the tonnage more information on the intrinsic properties of the chemical is required</li></ul>2.A chemical safety report-for substances in quantities of 10 tonnes or more per year<br /><ul><li>documents the hazards
    43. 43. classify the substances and make assessment as to whether the substance is persistent, bioaccumulative and toxic (PBT) or very persistent and very bio-accumulative (vPvB). </li></li></ul><li> PROCESS OF REGISTRATION<br /><ul><li>In cases where a substance is manufactured or imported by more than one company, they are required to jointly submit information on the hazardous properties of the substance and its classification. If registrants agree they can also submit a joint chemical safety report.
    44. 44. If the Agency does not indicate otherwise within 3 weeks of the registration, the registrant may begin (for non-phase-in substances) or continue (for phase-in substances) to manufacture or import the substance</li></li></ul><li> EVALUATION<br /><ul><li>Evaluation procedure deals with examination of testing proposals & compliance check of registrations & substances
    45. 45. Main objective behind evaluation:-
    46. 46. Reliable & adequate data are produced
    47. 47. Prevent unnecessary animal testing</li></ul> OBJECTIVES<br /> DOSSIER EVALUATION<br /> SUBSTANCE EVALUATION<br /><ul><li>If the substance is hazardous or pose a risk to human or environment, the agency will include that substance on list for “substance evaluation”.
    48. 48. Then registrant will be requested to provide further information. </li></ul>COMPLIANCE CHECK<br />CHECKING OF TESTING PROPOSALS<br /><ul><li>Agency may select any reg. dossier to check whether the proper information is available & has been adequately reported.
    49. 49. They can also ask for further information if required.
    50. 50. For chemicals manufactured or imported in a quantity of 100 tonnes or more, a testing proposal must be submitted in the reg. dossier, agency then evaluate it.</li></li></ul><li> AUTHORISATION<br /><ul><li>Substances of very high concern will be gradually included in Annex XIV of the REACH Regulation. Once included, they cannot be placed on the market or used after a date to be set (the so-called “sunset date”) unless the company is granted an authorisation.
    51. 51. It is essential to regulate them because the effects they can have on humans and the environment are very serious and often irreversible. There is no tonnage threshold for a</li></ul>substance to be subject to authorisation.<br /><ul><li>These substances are Carcinogenic, Mutagenic or toxic to Reproduction (CMR) classified in category 1 or 2, PBT or vPvB according to the criteria in Annex XIII.
    52. 52. The authorisation process consist of four steps:-</li></ul>Step 1: Identification of substances of very high concern (by authorities)<br /><ul><li>Accordance with Annex XV, member state competent authorities prepare a dossier
    53. 53. The outcome of this identification process is a list of identified substances, which are candidates for prioritisation (the “candidate list”). </li></ul>Step 2: Prioritisation process (by authorities)<br /><ul><li>The substances on the candidate list are then prioritised to determine which ones should be subject to authorisation
    54. 54. Interested parties are invited to submit comments during this process</li></li></ul><li><ul><li>Finally whether the substance is subject to authorisation or not is decided & the “sunset date” by when a substance can no more be used without authorisation is decided
    55. 55. Step 3:Applications for authorisation (by industry)
    56. 56. Applicant have to provide chemical safety report, suitable alternatives or techniques to reduce overall risks & economically feasible.
    57. 57. Applicant can include socio-economic analysis in his application.
    58. 58. A fee has to be paid for each application.
    59. 59. For all applications, the Agency will provide expert opinions. The applicant can comment on these opinions.
    60. 60. Step 4: Granting of authorisations (by the European Commission)
    61. 61. If the risk associated with the use of substance is properly controlled authorisations will be granted.
    62. 62. If the risk is not adequately controlled, an authorisation may still be granted if it is proven that the socio-economic benefits outweigh the risks & there is no other option available.
    63. 63. All authorisations will be reviewed after a certain time-limit which will be set on a case-by-case basis.</li></li></ul><li> RESTRICTION<br /><ul><li>The Annex XV dossier should demonstrate that there is a risk to human health or the environment that needs to be addressed at Community level and should identify the most appropriate set of risk reduction measures.
    64. 64. Annex XVII of the REACH Regulation contains the list of all restricted substances, specifying which uses are restricted</li></ul>e.g. the ban on asbestos and restrictions on the uses of certain azo-dyes<br /><ul><li> There is no tonnage threshold for a substance to be subject to restriction</li></ul> SO WHAT IS “END POINT”?<br /><ul><li>An endpoint is an observable or measurable inherent property of a chemical</li></ul>substance. <br /><ul><li>It can for example refer to a physical-chemical property like vapour pressure or to degradability or to a biological effect that a given substance has on human health or the environment. e.g. carcinogenicity, irritation, aquatic toxicity
    65. 65. In order to register a substance under REACH, the registrant must submit specific information about the intrinsic properties of the substance in each of the following areas:-physical/chemical properties, human toxicological information, ecotoxicological information.Data on the intrinsic properties of a substance are categorised into endpoints. For instance, “carcinogenicity” is a human toxicological endpoint.</li></li></ul><li> OVERALL REACH PROCESS-SUMMARY<br />Consortia/partner build up<br />Inform European Chemical Agency<br />SIEF(data exchange)<br />PRE REGISTRATION<br />Chemical safety report to ECA<br />Testing proposals<br />Allocation of competent authority<br />Pay reg. fees<br /> REGISTRATION<br />Dossier audit &/or evaluation<br />Agree testing plans<br /> EVALUATION<br />Socio economic analysis<br />Risk management checks<br />Replacement plans<br />Time limit authorisation<br /> AUTHORISATION<br />
    66. 66. Overall process related to information requirements and chemicals safety assessment under REACH<br />Ref:- document/information requirement r2 .pdf<br />
    67. 67. TESTING INVOLVED IN THE REACH PROPOSAL<br /><ul><li>Annexes V to VIII of the REACH proposal include lists of tests which will be involved in the chemical safety testing programme.</li></li></ul><li>Annex V – all chemicals<br /><ul><li>Skin irritation or skin corrosion (in vitro)
    68. 68. Eye irritation (in vitro)
    69. 69. Skin sensitisation (Local Lymph Node Assay)
    70. 70. Mutagenicity (in vitro)
    71. 71. Proposal to include an acute toxicity test (in vivo or in vitro)</li></ul>Annex VI – above 10 tonnes<br /><ul><li>Skin irritation (in vivo)
    72. 72. Eye irritation (in vivo)
    73. 73. Mutagenicity (in vitro)
    74. 74. Acute toxicity (in vivo by oral route and/or by inhalation and/or dermal route)
    75. 75. Repeated dose toxicity (28-day in vivo study, one species, male and female)
    76. 76. Reproductive toxicity (Screening for developmental toxicity in vivo, if there is no (Q)SAR estimates that the substance may be a developmental toxicant. A positive result in the screening should be confirmed by further in vivo tests)
    77. 77. Toxicokinetics – if it can be derived from the available information
    78. 78. Short term toxicity testing on fish
    79. 79. Adsoption/desorption screening</li></li></ul><li>Annex VII – above 100 tonnes<br /><ul><li>Mutagenicity in vivo – if positive results from the Annex V and VI tests
    80. 80. 28-day repeated dose toxicity or sub-chronic toxicity study (90-day, one species, rodent)
    81. 81. Developmental toxicity study (two species)
    82. 82. Two-generation reproductive toxicity study (in vivo, one species, male and female)
    83. 83. Long term toxicity testing on fish (fish early-life stage toxicity test or fish short term toxicity test on
    84. 84. embryo and sac-fry stages or fish juvenile growth test)
    85. 85. Accumulation in one aquatic species, preferably fish
    86. 86. Further studies on adsoption/desorption depending on results of studies required in Annex
    87. 87. If appropriate, further mutagenicity studies shall be proposed
    88. 88. A long term (12 month) repeated toxicity study may be proposed
    89. 89. Two generation reproductive toxicity study, one species, male and female, if not provided as part of
    90. 90. Annex VII requirements
    91. 91. A carcinogenicity study may be proposed by the applicant or requested by the competent authority
    92. 92. Long term or reproductive toxicity in birds</li></ul> Annex VIII – above 1,000 tonnes<br />
    93. 93. ANNEX IX: GENERAL RULES FOR ADAPTATION OF THE STANDARD TESTING SET OUT IN ANNEXES V TO VIII <br /><ul><li>The standard testing regime for all substances may be adapted for the following accepted reasons:-</li></ul>Existing data (physical-chemical properties, animal experiments, historical human data)<br /><ul><li>If exposure duration is comparable & if adequate & reliable documentation is provided, data consider to be equivalent to test</li></ul>2.Weight of evidence<br /><ul><li>If newly develop test methods or other independent sources indicate that substance has not a particular dangerous property, further testing on vertebrate animals for that property shall be omitted(and reverse is also true).</li></ul>3.QSAR<br /><ul><li>Results obtained from valid qualitative or quantitative structure activity</li></ul>relationship models ((Q)SARs) may indicate the presence or absence of a certain dangerous property.<br />4.In vitro methods<br /><ul><li>In some cases in vitro data indicate the presence or absence of certain dangerous property. So there is no need to carry out animal experiments.</li></ul>e.g. VIABLITY (end point) measured by MTT test using epidermal cells.<br />
    94. 94. 5.Grouping of substances and read-across approach<br /><ul><li>Substances whose physicochemical, toxicological and ecotoxicological properties are likely to be similar are considered as group and their human health effects & environmental fate may be predicted by comparing with reference substance within the group.</li></ul> ACUTE TOXICITY TESTS<br /><ul><li>Acute toxicity data is mainly to label and classify chemicals based on their toxicity, for application to the human situation.
    95. 95. Lethality has been the primary toxicological endpoint in acute toxicity tests, which have been in use for nearly 80 years but a large number of animals has been sacrificed.
    96. 96. For testing acute toxicity by the oral route, the LD50 method has been replaced in the OECD guidelines by other protocols which use fewer animals.
    97. 97. Fixed dose procedure
    98. 98. Up & down procedure
    99. 99. Acute toxic class method
    100. 100. For testing acute toxicity by inhalation or by the dermal (skin) route, LD50/LC50 tests are still most predominantly used.
    101. 101. These tests are highly criticised due to extent of animal suffering that it causes.</li></ul>All serve to provide an estimated LD50 value<br />
    102. 102. Ref:-the report of CONAM/ecopa chemical policy working group, March 2007<br />
    105. 105.
    106. 106. <ul><li>Accordance with REACH Annex XI Section 2, testing for specific endpoints may be omitted if it is technically not possible to conduct the study as a consequence of the properties of the substance
    107. 107. e.g. very volatile, highly reactive or unstable</li></ul>substances (specific cases can be found in Column 2 of REACH Annexes VII-X). <br /><ul><li>Where possible, scientifically sound approaches to the implementation of the 3Rs (reduction, refinement or replacement of animal use) which are already stipulated under the REACH Regulation, should be used </li></li></ul><li>
    108. 108. EXAMPLE 1<br />Ref:-the report of CONAM/ecopa chemical policy working group, March 2007<br />
    109. 109. EXAMPLE 2<br />
    110. 110. REGULATORY AGENCIES OTHER THAN REACH INFLUENCING<br />CHEMICAL INDUSTRY & ANIMAL TESTING<br /><ul><li>CLP-New European Regulation on Classification, Labelling and Packaging of chemical substances and mixtures
    111. 111. It is about the hazards of chemical substances & mixtures & how to inform others about them.
    112. 112. NC3Rs-The National Centre for the Replacement, Refinement and Reduction of Animals in Research
    113. 113. Established by the UK Government, is an independent scientific organization
    114. 114. ECETOC-European Center for Ecotoxicology and Toxicology Of Chemicals
    115. 115. Concerned with the identification of research needs and provision of scientific rationale for the assessment of health effects and environmental impact, and thereby to justify industry's licence and freedom to operate.
    116. 116. EPAA-European Partnership for Alternative Approaches to Animal Testing
    117. 117. Accelerate the development, validation and acceptance of alternative approaches to further the reduction, refinement and replacement (3Rs) of animal use in regulatory testing.
    118. 118. CEFIC-European Chemical Industry Council
    119. 119. Ensuring chemical safety and maintaining animal welfare are both issues of great societal and ethical concern.</li></li></ul><li> REFRENCES<br /><br /><br /><br />4. Ppt presentation on “regulatory animal testing” by Dr. Karsten Muller, EPAA WG4, product safety chemicals<br /><br />6.The impact of REACH-the report of CONAM/ecopa chemical policy working group, March 2007<br /><br />8.REACH navigator<br />9.Regulatory Toxicology and Pharmacology<br />Journal<br />10.Dangerous Preparations Directive<br /><br />11.A report on-Acute toxicity testing by Animal Defenders International National Anti-Vivisection Society, London.<br /><br /><br /><br />