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Endocrine disruptors as they are regulated in the EU
- 1. Implementation of regulatory issues C. Rovida CAAT Europe – University of Konstanz
- 2. Regulating Chemicals • Chemicals: Regulation 1907/2006 • Plant Protection Product: Regulation 1107/2009 • Biocidal products: Regulation 528/2012
- 4. History of the Endocrine disruptors concept • 1936, Dodds & Lawson Dodds E.C., Lawson W. (1936). Synthetic estrogenic agents without the phenanthrene nucleus. Nature 137: 996
- 5. History of the Endocrine disruptors concept • 1936, Dodds & Lawson Dodds E.C., Lawson W. (1936). Synthetic estrogenic agents without the phenanthrene nucleus. Nature 137: 996 • 1946, Study on the effect of DDT Mitchell, R.T. (1946). Effects of DDT spray on eggs and nestlings of birds. Journal of Wildlife Management 10(3): 192
- 6. History of the Endocrine disruptors concept • 1936, Dodds & Lawson Dodds E.C., Lawson W. (1936). Synthetic estrogenic agents without the phenanthrene nucleus. Nature 137: 996 • 1946, Study on the effect of DDT Mitchell, R.T. (1946). Effects of DDT spray on eggs and nestlings of birds. Journal of Wildlife Management 10(3): 192 • 1962, Silent Spring Rachael Carson, 1962, Silent Spring
- 7. 1991 – Wingspring conference We are certain of the following: • A large number of man-made chemicals that have been released into the environment, as well as a few natural ones, have the potential to disrupt the endocrine system • Many wildlife populations are already affected by these compounds. • The pattern for effects vary among species and among compounds. • Laboratory studies corroborate the abnormal sexual development observed in the field and provide biological mechanisms to explain the observations in wildlife. • Humans have been affected by compounds of this nature, too.
- 8. Definition of "endocrine disruptor" (WHO, 2002): “… an exogenous substance or mixture that alters function(s) of the endocrine system and consequently causes adverse health effects in an intact organism, or its progeny, or (sub)populations.”. WHO, 2002, Global assessment of the state-of-the-science of endocrine disruptors
- 9. REGULATION (EC) 1107/2009 on plant protection products • Article 3: ? • Article 23: Approval criteria for basic substances …(b) does not have an inherent capacity to cause endocrine disrupting, neurotoxic or immunotoxic effects REGULATION (EC) No 1107/2009 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 21 October 2009 concerning the placing of plant protection products on the market and repealing Council Directives 79/117/EEC and 91/414/EEC, L309
- 11. REGULATION (EC) No 528/2012 on biocidal products • Article 3: ? • Article 5: Exclusion criteria …(d) active substances which … are considered as having endocrine-disrupting properties that may cause adverse effects in humans or which are identified in accordance with Articles 57(f) and 59(1) of Regulation (EC) No 1907/2006 as having endocrine disrupting properties REGULATION (EU) No 528/2012 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 22 May 2012 concerning the making available on the market and use of biocidal products
- 12. Article 3: ? REGULATION (EC) No 1907/2006 - REACH Article 57: Substances to be included in Annex XIV …(f) substances — such as those having endocrine disrupting properties … for which there is scientific evidence of probable serious effects to human health or the environment Information requirements: 12.6. Other adverse effects - If available, include information on any other adverse effects on the environment, e.g. ozone depletion potential, photochemical ozone creation potential, endocrine disrupting potential and/or global warming potential.
- 13. Regulation 1272/2008 - CLP Reproductive toxicity, Category 2 H361: Suspected of damaging fertility or the unborn child REGULATION (EC) No 1907/2006 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 18 December 2006 concerning the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH), establishing a European Chemicals Agency, amending Directive 1999/45/EC and repealing CouncilRegulation (EEC) No 793/93 and Commission Regulation (EC) No 1488/94 as well as Council Directive 76/769/EEC and Commission Directives 91/155/EEC, 93/67/EEC, 93/105/EC and 2000/21/EC, L136 REGULATION (EC) No 1272/2008 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 16 December 2008 on classification, labelling and packaging of substances and mixtures, amending and repealing Directives 67/548/EEC and 1999/45/EC, and amending Regulation (EC) No 1907/2006, L353
- 14. ECHA Database on registered substances http://echa.europa.eu/web/guest/information-on-chemicals/registered-substances
- 18. Resumee: The available data show different results when investigating the estrogenic activity of 4,4'-sulphonyldiphenol. … In mammalian cellular systems (reporter gene assay in MCF7 cells), 4,4'-sulphonyldiphenol shows a similar estrogenic activity as bisphenol A. Nevertheless, the biological relevance of these results remains questionable, as for a lot of chemicals with similar findings (positive effects in such screening assays) no effects (or effects at severely systemic toxic doses) were noted in well accepted state of the art in vivo tests according to OECD/EU guidelines.
- 19. Resumee: The available data show different results when investigating the estrogenic activity of 4,4'-sulphonyldiphenol. … In mammalian cellular systems (reporter gene assay in MCF7 cells), 4,4'-sulphonyldiphenol shows a similar estrogenic activity as bisphenol A. Nevertheless, the biological relevance of these results remains questionable, as for a lot of chemicals with similar findings (positive effects in such screening assays) no effects (or effects at severely systemic toxic doses) were noted in well accepted state of the art in vivo tests according to OECD/EU guidelines.
- 20. Resumee: The available data show different results when investigating the estrogenic activity of 4,4'-sulphonyldiphenol. … In mammalian cellular systems (reporter gene assay in MCF7 cells), 4,4'-sulphonyldiphenol shows a similar estrogenic activity as bisphenol A. Nevertheless, the biological relevance of these results remains questionable, as for a lot of chemicals with similar findings (positive effects in such screening assays) no effects (or effects at severely systemic toxic doses) were noted in well accepted state of the art in vivo tests according to OECD/EU guidelines.
- 21. Candidate list for SVHC (Substance of Very High Concern) • 25 out of 84 substances are included as toxic for reproduction CoRAP list of substances • 20 out of 90 are suspected endocrine disruptors • 26 out of 90 are suspected PBT (Persistent Bioaccumulative and Toxic) • 46 out of 90 are suspected CMR (Carcinogenic, Mutagenic, toxic for Reproduction)
- 22. General rules for the adaptation of the data requirements ANNEX IV, Biocides 1.4. In vitro methods: Where such in vitro tests are positive, it is necessary to confirm the dangerous property by adequate in vivo tests. However, such confirmation may be waived if the following conditions are met … In the case of negative results, these exemptions do not apply. A confirmation test may be requested on a case- by-case basis ANNEX XI, REACH 1.4. In vitro methods: If the results obtained from the use of such in vitro methods do not indicate a certain dangerous property, the relevant test shall nevertheless be carried out at the appropriate tonnage level to confirm the negative result
Editor's Notes
- The history The British biochemists Edward Charles Dodds and Wilfrid Lawson searched in 1936 for chemicals that were able to replace natural oestrogen in medical therapy. This female hormone was extremely expensive, since it had to be synthesized from the urine of pregnant horses. Nevertheless, bisphenol A did not pursue a career in pharmacy, since the same researchers soon identified much more potent synthetic oestrogens, including, above all, diethylstilbestrol (DES) I'll add nothing more
- "Over increasingly large areas of the United States spring now comes unheralded by the return of birds, and the early mornings are strangely silent where once they were filled with the beauty of bird song." At that time, the general idea was that there were some substances that were active on the hormones of some animals. Toxicologists were convinced that human exposure was too low to justify an effect on human beings as well
- 21 experts - involved 35 scientists, lawyers, policy makers and environmentalists from the United States, Canada and Europe - by the Science and Environmental Health Network, an organization that links science with the public interest The Food Quality Protection Act of 1996 and the Safe Drinking Water Act of 1996 simultaneously provided the first legislative direction requiring the EPA to address endocrine disruption through establishment of a program for screening and testing of chemical substances.
- However, endocrine disruption is not a toxicological endpoint in itself, but rather a class of modes and mechanisms of action. The WHO/IPCS definition states that an adverse effect should be observed in an intact organism. In terms of regulatory requirements, this can only be interpreted to mean demonstration of a positive result in an in vivo assay.
- Article 3 definition, there is nothing Does not have endocrine activity unless exposure to both farmers and consumers may be completely excluded (ANNEX II Procedure and criteria for the approval of active substances, safeners and synergists pursuant to Chapter II ) By 14 December 2013, the Commission shall present to the Standing Committee on the Food Chain and Animal Health a draft of the measures concerning specific scientific criteria for the determination of endocrine disrupting properties to be adopted in accordance with the regulatory procedure with scrutiny referred to in Article 79(4). Pending the adoption of these criteria, substances that are or have to be classified, in accordance with the provisions of Regulation (EC) No 1272/2008, as carcinogenic category 2 and toxic for reproduction category 2, shall be considered to have endocrine disrupting properties. Also activity towards the environment is considered No mention about how to define the endocrine disruptors activity
- Endocrine disruptors are classified only because of their final effect and in the CLP they're considered only as they may interfere with the reproductive system. Test results are considered only in a weight of evidence approach, triggering only the classification as H361 and the pictogram with the sick man.
- Bisphenol S is very simililar to the discussed Bisphenol A having the sulphonyl group instead of the dimethyl. However it is linear with the two phenolic OH at the extremes. This is supposed to be the characteristic for triggering endocrine disruptor activity.
- In the area of toxicity to reproduction, there is an OECD 421, i.e. the screening test performed in vivo on rats by oral route. In this study some effects of the reproductive system are shown, but probably considered as a general systemic effect. The main problem of this database is that it reports the single studies, but the general summary and the chemical safety report are omitted and therefore there is no way to understand the real consideration that the lead registrant has done to get to a conclusion.
- This was a sort of review of all the in vitro data that are available on the chemical class of Bisphenols. The conclusion of the lead registrant is clear
- And explained in the conclusion
- The conclusion may be questionable, but perfectly in line with what the regulation asks. I don't fully agree, and I think also that this is not the spirit of REACH, but legally speaking it is correct
- But what does ECHA do for risk assessment. First of all there is a list of candidate SVHC. Those are chemicals that may enter in the authorisation process in the future. At the moment there are about 30% that are selected because of endocrine disruptors concern. This number, about 30%, is not well defined as we don't know whether all of them are ED, or whether there are some ED among those classified as carcinogenic or more probable as PBT. However there are already three phthalates in the Authorisation list. The Corap list of substances are those registered substances that have been picked up for furtyer evaluation. Among those 20 have been selected because suspected to be endocrine disruptors (Bisphenol S is among them). Then there are others like, PBT or CMR that may also belong to the endocrine disruptor family.
- In the Annex IV of the Biocide regulation it is stated that positive results in vitro must be confirmed in vivo. Negative results are considered in a case by case basis, but in principle they are accepted. In annex XI of REACH is exactely the opposite. Negative results must be confirmed while positive ones are accepted. This is in general, but in the area of endocrine disruptors this contradiction is enhanced.