Activities of the Commission related to endocrine disruptors

Information on the Commission procedure to define criteria for endocrine disruptors is available at:

http://ec.europa.eu/health/endocrine_disruptors/next_steps_en

The EFSA work (that is focused on PPP) is described at:

http://www.efsa.europa.eu/en/press/news/161202

The ECHA work (that is focused on BP) is described at:

https://echa.europa.eu/-/endocrine-disruptors-echa-and-efsa-start-work-on-guidance

(Websites were accessed March 2017.)

In 1999, the Commission adopted the Community strategy for endocrine disruptors COM(1999)706 (Commission, 1999) that set out the actions the Commission would undertake to address the potential environmental and human health impacts of endocrine disruption. Since, specific regulatory provisions for endocrine disruptors have been laid down in the areas of BPs and PPPs, covered by Regulation (EU) No 528/2012 concerning the making available on the market and use of biocidal products (EP and Council of the EU, 2012) and Regulation (EC) No 1107/2009 on the placing of plant protection products on the market (EP and Council of the EU, 2009). Appendix B of this ECETOC Report provides an overview of the respective provisions that refer to endocrine disruptors. Article 5(3) of the BP Regulation (EP and Council of the EU, 2012) requires the Commission to determine how the criteria for endocrine disruptors should be defined, by drawing up acts specifying scientific criteria for the determination of endocrine-disrupting properties.

Accordingly, in 2016, the Commission published the Communication COM(2016)350 final on endocrine disruptors and the draft Commission acts setting out scientific criteria for their determination in the context of the EU legislation on PPP and BP (Commission, 2016a); cf. Commission (2016b) for executive summary of the related impact assessment. Amendments to the respective relevant Annexes of the PPP and BP Regulations are being prepared and have been published in:

The Draft Commission Regulation (EU) setting out scientific criteria for the determination of endocrine disrupting properties and amending Annex II to the PPP Regulation (EC) 1107/2009 (Commission, 2017) – cf. Appendix C of this ECETOC Report for details on the (most recent) respective provisions.

The Draft Commission delegated Regulation (EC) setting out scientific criteria for the determination of endocrine-disrupting properties pursuant to the BP Regulation (EU) No 528/2012 (Commission, 2016c) – cf. Appendix C of this ECETOC Report for details on the (most recent) respective provisions.

The Commission Communication on endocrine disruptors

The Commission Communication COM(2016)350 final on endocrine disruptors and the draft Commission acts setting out scientific criteria for their determination in the context of the EU legislation on PPP and BP (Commission, 2016a) provides important information on issues that the Commission considers relevant for the identification of endocrine disruptors.

Specifically, the Commission states that it will follow the WHO/IPCS (2002) definition of endocrine disruptor, i.e. an exogenous substance or mixture that

1. alters function(s) of the endocrine system
2. and consequently causes
3. adverse health effects in an intact organism, or its progeny, or (sub)populations ( also WHO/UNEP, 2012).

In further specifying the three essential components of this definition, the Commission (2016a) refers to the following definitions:

Endocrine MoA (referring to bullet point 1 of the definition of endocrine disruptor, i.e. the way in which the function of the endocrine system is altered): The inherent ability of a substance to interact or interfere with one or more components of an endocrine system (EFSA, 2013). Consistent with the opinion of the EFSA, the Commission highlights that an endocrine MoA is not a (eco)toxicological hazard in itself (Commission, 2016a).

Adverse effect (referring to bullet point 3 of the definition of endocrine disruptor): Change in the morphology / physiology, growth, development, reproduction, or, life span of an organism, system, or (sub)population that results in an impairment of functional capacity, an impairment of the capacity to compensate for additional stress, or an increase in susceptibility to other influences (WHO/IPCS, 2009).

For the determination if an effect is adverse or adaptive, Commission (2016a) highlights that expert judgement will […] be required to assess on a case-by-case basis the toxicological relevance of [...] changes. In general, transient, inconsistent and minor fluctuations at the biochemical and molecular level may be considered adaptive (i.e. non-adverse), whilst sustained, consistent and permanent changes at the cell, organ- or organism-level, resulting in pathology or functional impairment in vivo, as well as altered timing of development, may be considered adverse (EFSA, 2013).

Commission (2016a) further explains that endocrine-related adverse effects which are only indirectly triggered by a non-endocrine-related toxicity are not adverse effects that are relevant for the identification of a substance as an endocrine disruptor. In such cases, the reactions of the endocrine system would be the consequence of any given generalised toxicity, rather than the cause of the specific adverse effect observed.

The EFSA (2013) cites the US National Research Council (NRC, 2007) that explore the different implications of adverse and adaptive effects: The consequences of a biologic perturbation depend on its magnitude, which is related to the dose, the timing and duration of the perturbation, and the susceptibility of the host. Accordingly, at low doses, many biologic systems may function normally within their homeostatic limits. At somewhat higher doses, clear biologic responses occur. They may be successfully handled by adaptation, although some susceptible people may respond. More intense or persistent perturbations may overwhelm the capacity of the system to adapt and lead to tissue injury and possible adverse health effects (NRC, 2007).

Consequently causes (bullet point 2 of the definition of endocrine disruptor): The Commission (2016a) explains that this link between the MoA and the adverse effect is the heart of the definition. In accordance with Commission (2016a), the question remains about the extent to which this link should be clearly established, i.e. the degree to which a strict causality should be required. The Commission follows the conclusion from the EFSA (2013) that there must be a reasonable evidence base for a biologically plausible causal relationship between the [endocrine MoA] and the adverse effects seen in intact organism studies, i.e. a reasonable evidence base to determine causality.

Commission (2016a) explains that the alternative would have been a more rigid approach to causality, asking for example for conclusive evidence of the connection and that the Commission considers that in practice, it will be very difficult to demonstrate conclusive evidence of causality. Therefore, the Commission intends to follow a concept of a reasonable evidence (biological plausibility) to determine causality (Commission, 2016a).

The following definitions for the terms conclusive and reasonable are provided in the online version of Black’s Law Dictionary (available at: http://thelawdictionary.org):

Conclusive: Shutting up a matter; shutting out all further evidence; not admitting of explanation or contradiction; putting an end to inquiry; final; decisive.

Reasonable: Agreeable to reason; just; proper. Ordinary or usual.

The explanations from the Commission point to the importance of determining whether a link between endocrine disrupting activity and adverse effect is biologically plausible. In the JRC Report of the Endocrine Disrupters Expert Advisory Group: Key scientific issues relevant to the identification and characterisation of endocrine disrupting substances (Munn and Goumenou, 2013), a biologically plausible linkage would constitute a causal chain of events from initial interaction of a substance with its target site in the organism through to the adverse outcome … biologically plausible linkage… depends on MoA and type of effect observed.

With respect to biologically plausible linkage, the EFSA (2013) states: Demonstration of all the key events of an endocrine MoA leading to the adverse outcome is not necessary, as this requires a very high burden of proof. However, it is important that there is logical and plausible reasoning to explain any (potential) causal relationship between the observed endocrine activity and the endocrine-mediated adverse effects. This concept of „plausibility‟ implies expert judgement. A minimum set of criteria was described by Bradford Hill (Bradford Hill, 1965) to provide adequate evidence of a causal relationship between an incidence and a consequence (e.g. exposure and ill health), including biological plausibility, consistency of findings, specificity, predictivity, coherence, concordance of dose response relationships and temporal associations and characterisation of uncertainties.

Since different scientific issues have to be addressed for the identification of endocrine properties, different types of data have to be combined in WoE approaches to come to a conclusion on endocrine disruption, as also the EFSA (2013) highlights: In principle, no single assay is likely to provide all the information needed to decide whether a substance is an ED (according to the WHO/IPCS definition endorsed by the Scientific Committee) because of the need to provide both mechanistic information showing how the substance interacts with the endocrine system, and apical information describing the adverse effects this interaction may cause. The results from a combination of tests increase the WoE and further elucidate the AOP (EFSA, 2013).

ECHA and EFSA outline of draft Guidance Document for the implementation of the hazard-based criteria to identify endocrine disruptors

On 20 December 2016, the ECHA and the EFSA published an Outline of draft guidance document for the identification of the hazard-based criteria to identify endocrine disruptors (ECHA and EFSA, 2016) that was prepared with support from the Commission’s Joint Research Centre (JRC). ECHA and EFSA (2016) describes that although the (identical) criteria for endocrine disruptors will formally apply only in the context of the BP and PPP legislation, the scientific approach(es) described in the Guidance could be relevant for other substances as well, since the endocrine disruptor identification step will be based exclusively on the evaluation of the relevant hazardous properties of a substance.

The Guidance outlined in ECHA and EFSA (2016) will focus on the data and information needed for endocrine disruption hazard identification. It will also provide an indication on which information may be considered sufficient to conclude on the endocrine disrupting properties of a substance in accordance with the criteria. The evaluation approach will take toxicological and ecotoxicological information into account in an integrated manner and provide guidance for identifying data gaps that would trigger the need for additional data across the human health and environment domains. The scope of the Guidance will be restricted to the EATS pathways, which are the best characterized pathways. Regarding the groups of (non-target) organisms to be considered in the Guidance, its coverage will be limited to vertebrates, including mammals, fish, birds, amphibians and reptiles. This is also justified on the basis of the available test methods.

In accordance with ECHA and EFSA (2016), the Guidance will describe information sources for the identification of endocrine disruptors (Section IV of the Guidance). This Section will distinguish between:

• In vivo tests for the identification of endocrine disruptor-relevant adverse effects;
• Mechanistic information from in vitro and in vivo tests;
• (Quantitative) structure activity relationships ((Q)SAR), read across and category approaches;
• Epidemiological data, field studies and population models.

This section on information sources will be built, to a large extent, on the in vitro and in vivo laboratory studies identified in OECD GD 150 (OECD, 2012b), updated with additional information sources and considering the JRC methodology. Accordingly, in vivo studies for the identification of adverse effects will cover the OECD CF Levels 4 and 5; the mechanistic in vitro assays will cover OECD Level 2; and the mechanistic in vivo assays will cover OECD Level 3.

Regarding the test methods that are relevant for the identification of adverse effects, two sub-sections are envisioned to cover human health and ecotoxicology, and the Guidance will include an indication of which endpoint is informative on which of the EATS modalities. In order to facilitate the evaluation of adverse effects, it will be described which apical adverse effects could be considered as

• Diagnostic for endocrine MoA;
• Indicative for an endocrine MoA (i.e. possibly, but not exclusively linked to an endocrine MoA);
• and those adverse effects that in principle are not related to an endocrine MoA.

Similarly, test methods informative on the endocrine MoA of a substance will be identified, indicating the endocrine modalities (axes, pathways) that each specific test is aimed at or informative on. As some TGs include optional endpoints that are informative on alterations in the endocrine system, e.g. the level of hormones in the blood, the overview will also indicate whether the endpoint is standard or optional (at least according to the TGs).

As described in EFSA and ECHA (2016), Section V of the Guidance will present a hazard identification strategy for endocrine disrupting properties. The Guidance will describe endocrine disruptor hazard identification from two different starting points to ensure applicability of the proposed methodology for substances for which the available information differs in type. One approach will consider starting the evaluation with apical studies indicative of endocrine-mediated adverse effects and will set out how to evaluate if, indeed, an endocrine mechanism would be the cause of the adverse effect observed. The second approach will consider starting the evaluation with endocrine disruptor-relevant mechanistic information and set out how to investigate whether the observed endocrine activity would result in adverse effects in intact organisms.

The ECETOC 7SI-ED follows the structure of Section V of the ECHA and EFSA (2016) outline for a draft guidance document. As described in EFSA and ECHA (2016), the Commission hazard identification strategy for endocrine disrupting properties will be built to allow evaluating the information in a WoE approach. This WoE approach will cover the following seven steps:

1. Gathering of relevant information with regard to adverse effects and endocrine disrupting MoAs as described in Section IV of the ECHA and EFSA (2016) Guidance.
2. Evaluation of quality, reliability, reproducibility and consistency of the individual studies: Guidance on the evaluation of the relevant studies with regard to quality, reliability, reproducibility and consistency. Reference to documents describing such evaluation approaches, as appropriate.
3. Evaluation and summary of the evidence for an adverse effect: Guidance on how to assess and conclude on the strength of evidence in terms of adversity relevant to humans and non-target vertebrates. Where differentiation with regard to humans and non-target vertebrates is required, these aspects will be considered separately.
4. Evaluation and summary of the evidence for MoAs: Guidance on how to assess and conclude on strength of evidence in terms of MoA(s) for the EATS modalities with specific sub-sections on how to evaluate MoAs for (anti)oestrogenicity; (anti)androgenicity; thyroid effects; and steroidogenesis.
5. Integration of the evidence and evaluation of biological plausibility of a link between endocrine MoA and adverse effect: Guidance on how to integrate the available evidence on adverse effects for humans and non-target vertebrates with the evidence on (endocrine) MoA(s) in order to enable a conclusion on the existence of a biologically plausible link between the observed adverse effect(s) and the endocrine MoA(s). Approaches will be described on how the available information on adversity and endocrine activity should be considered together in a WoE approach, in order to conclude on the biological plausibility. The evaluation will cover human health and non-target vertebrates.
6. Identification of uncertainties: Guidance on how to assess uncertainties. Reference will also be made to existing documents addressing this issue.
7. Conclusions on endocrine disrupting properties: Guidance on how to conclude on the endocrine disrupting properties of a substance in accordance with the criteria for endocrine disruptors both with regard to human health and non-target vertebrates, considering WoE and identified uncertainties.

For the third step, i.e. the evaluation and summary of the evidence for an adverse effect, ECHA and EFSA (2016) suggest the following contents:

• How to evaluate conflicting results, e.g. both positive and negative results;
• Consistency of the data;
• Consideration of the pattern and coherence of the results between studies of a similar design and across different species;
• Route of exposure, toxicokinetic and metabolism studies;
• Concept of the limit dose, and international guidelines on maximum recommended doses and for evaluating confounding effects of excessive toxicity;
• Evaluation of the relevance of adverse effects for humans and at the population-level for non-target vertebrates.

For the seventh and final step, i.e. the conclusion on endocrine disrupting properties, ECHA and EFSA (2016) announces that indication will be provided on which information may be considered sufficient to conclude on the endocrine disrupting properties of a substance in accordance with the criteria. For some substances the information identified as relevant may not be sufficient to reach a firm conclusion. For such cases, guidance will be provided for different scenarios on what missing information should be generated in order to enable a conclusion on the endocrine disrupting properties of the substance in question.