Technical Report 130

1.INTRODUCTION

In December 2016, the European Chemicals Agency (ECHA) and the European Food Safety Authority (EFSA) published an Outline of draft Guidance Document for the implementation of the hazard-based criteria to identify endocrine disruptors (ECHA and EFSA, 2016) that was compiled with support from the Joint Research Centre (JRC). The Guidance Document that is outlined in ECHA and EFSA (2016) shall be applicable in the context of Regulation (EC) No 1107/2009 on the placing of plant protection products on the market (EP and Council of the EU, 2009) and Regulation (EU) No 528/2012 concerning the making available on the market and use of biocidal products (EP and Council of the EU, 2012). Section V of ECHA and EFSA (2016) presents seven steps of a Hazard identification strategy for endocrine disrupting properties that follow a weight-of-evidence (WoE) approach. As highlighted in ECHA and EFSA (2016), the identification of endocrine disruptors will be based exclusively on the evaluation of the relevant hazardous properties of a substance, and the Guidance is intended [to] be suitable for both applicants and regulatory authorities.

Against this background, the European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) convened an Endocrine Disruptors Task Force (ED TF) to provide guidance on how the ECHA and EFSA (2016) draft outline can be put into practice. The ECETOC ED TF has focused its expertise on providing input for consideration under the seven steps of the hazard identification strategy presented in Section V of ECHA and EFSA (2016). This has resulted in the development of the ECETOC Seven Steps for the Identification of Endocrine Disrupting properties (ECETOC 7SI-ED). The ECETOC 7SI-ED, that covers both human and environmental health, aligns with the steps presented in ECHA and EFSA (2016).

In this ECETOC Report, the ECETOC 7SI-ED is presented as text and as a flow-chart with detailed explanatory notes on how to address each of the seven steps (cf. also Figure 1):

    • Step I: Gathering of relevant information with regard to adverse effects and endocrine modes-of-action (MoA; cf. Section 2: Definitions);
    • Step II: Evaluation of quality, reliability, reproducibility and consistency of the individual studies;
    • Step III: Evaluation and summary of the evidence for an adverse effect;
    • Step IV: Evaluation and summary of evidence for endocrine activity (and non-endocrine activity, if available);
    • Step V: Integration of the evidence and evaluation of biological plausibility that adverse effect and endocrine activity are linked by specific endocrine MoA;
    • Step VI: Identification of uncertainties;
    • Step VII: Conclusions on endocrine disrupting properties.

The three elements of the definition for an endocrine disruptor published by the World Health Organisation / International Programme on Chemical Safety (WHO/IPCS, 2002) are reflected in Steps III-V.

This definition is equally acknowledged in the EU plant protection products and biocidal products legislations:

      1. An exogenous substance or mixture that alters function(s) of the endocrine system (Step IV);
      2. And consequently causes (Step V);
      3. Adverse health effects in an intact organism, or its progeny, or (sub)populations (Step III).

As described in the Commission Communication on endocrine disruptors and the draft Commission acts setting out scientific criteria for their determination in the context of the EU legislation on plant protection products and biocidal products (Commission, 2016), the legal framework underlying the ECHA and EFSA (2016) outline is driven by the ongoing revision of the EU plant protection products and biocidal products legislation. Notwithstanding, the legal framework is likely to eventually apply within further substance-specific legislations.

Consistent with the seven steps outlined in Section V of ECHA and EFSA (2016) and the EU plant protection products and biocidal products legislation, the guidance proposed in the ECETOC 7SI-ED is restricted to the identification of endocrine disrupting properties. Notwithstanding, it is the opinion of the ECETOC ED TF that substances that are identified as possessing endocrine disrupting properties should undergo a comprehensive hazard and risk assessment. This entails the determination of safety thresholds, exposure assessment, potency assessment and the determination whether acceptable risk can be demonstrated. Such an approach has already been implemented internationally, e.g., in the USA and Japan. The hazard characterisation and risk assessment of substances that are identified as possessing endocrine disrupting properties should also establish the human health or environmental population-specific relevance of observed effects (cf. Appendix A: Background Information for further details on the rationale to draw up the ECETOC 7SI-ED) .

While the ECETOC 7SI-ED has been structured in line with the seven steps described in Section V of the ECHA and EFSA (2016) outline, in practice, Steps I-VII of the ECETOC 7SI-ED will not necessarily always be followed in a consecutive order. Depending on the substance under investigation, it may be more appropriate to conduct, e.g., Steps III and IV in parallel or to conduct Step IV before Step III, etc. The most appropriate sequence of steps should be determined on a case-by-case basis. This requires expert judgement, and a scientific justification for the selected sequence should be provided.

In the ECETOC 7SI-ED, the framework presented in Section V of ECHA and EFSA (2016) (cf. also Appendix A: Background Information) has been elaborated applying existing best practice frameworks and methodologies. The ECETOC 7SI-ED uses the JRC Toxicological data Reliability Assessment Tool (ToxR Tool) to assess the quality of individual studies. The OECD Conceptual Framework (CF) for Testing and Assessment of Endocrine Disrupters (OECD, 2012a) is applied to frame available data for the identification of potential endocrine disrupting properties. The OECD Guidance Document (GD) No. 150 on standardised test guidelines for evaluating chemicals for endocrine disruption (OECD, 2012b) is referred to for detailed guidance on the types of assays and studies that may serve to identify endocrine activity or adverse effects that may be indicative of endocrine disrupting properties. OECD Test Guidelines (TGs) are considered preferred test methods. Nevertheless, sufficiently relevant and reliable assays and studies that can be used within the ECETOC 7SI-ED are not limited to OECD TGs so long as justification for their consideration is provided.

Currently, OECD GD 150 (OECD, 2012b) only covers the (o)estrogen, androgen, thyroid and steroidogenesis (EATS) pathways, which are also those for which targeted mechanistic and in vivo screening test methods are available. The revision of OECD GD 150, underway in 2017, may broaden its scope particularly with respect to the consideration of the recently validated ecotoxicological TGs.
The scope of the draft guidance document outlined in ECHA and EFSA (2016) is also restricted to the EATS pathways, which is further consistent with the United States Environmental Protection Agency (US EPA) Endocrine Disruptor Screening Program (https://www.epa.gov/endocrine-disruption). In regard to environmental hazard identification, ECHA and EFSA (2016) limit the scope to vertebrates (aquatic and terrestrial). Therefore, invertebrates are excluded from the ECHA and EFSA (2016) proposal. For many invertebrate taxa, the understanding of endocrine pathways and diagnostic endpoints for test methods using invertebrates are limited (deFur et al., 1999; deFur, 2004; OECD, 2012b). Consistent with the ECHA and EFSA (2016) outline, the ECETOC 7SI-ED has also been written with the intention to apply to both human health and the environment, however, where differentiation with regard to humans and non-target vertebrates is required, these aspects will be considered separately (ECHA and EFSA, 2016).

The ECETOC 7SI-ED is intended to provide general guidance to fulfil the EU legislative remits on plant protection products and biocidal products (Commission, 2016). It can be applied to cover those pathways of endocrine disruption and those taxa that are relevant to address a specific scientific question or that are mandatory for regulatory hazard assessment for the substance under investigation. For this reason, the ECETOC 7SI-ED describes how data and information that may be indicative of endocrine disruption can be collected and evaluated, but it does not identify data gaps or prescribe any specific testing. In regulatory (eco)toxicology, information requirements will be highly dependent on the specific legislation that is relevant for the substance under investigation (e.g. plant protection product or biocide active substance, personal care product, industrial chemical, etc.). This in turn may dictate the type of evaluation that is possible.

As is also consistent with the ECHA and EFSA (2016) outline, the information collected within the ECETOC 7SI-ED is evaluated using a WoE approach.

The ECETOC 7SI-ED conforms to the principles of best practice for WoE approaches published by Rhomberg et al. (2013) that defined four phases of WoE analyses:

      • Phase 1: Define causal question and develop criteria for study selection (covered in Steps I and II of the ECETOC 7SI-ED);
      • Phase 2: Develop and apply criteria for review of individual studies (Steps III and IV);
      • Phase 3: Integrate and evaluate evidence (Steps V and VI);
      • Phase 4: Draw conclusions based on inferences (Step VII).

The ECETOC 7SI-ED uses elements from the template for WoE presented in the most recent version of the WHO/IPCS MoA/species concordance framework (Meek et al., 2014a, b). Importantly, any WoE evaluation should begin with the formulation of a hypothesis or causal question (Rhomberg et al., 2013; Meek et al., 2014a; Dekant and Bridges, 2016a, b). For the identification of endocrine disrupting properties, the hypothesis will most likely state that the substance under investigation does (or does not) cause adverse effects in an intact organism or (sub)populations through an endocrine mechanism.

Figure 1: Simplified flow chart of the ECETOC 7SI-ED that follows the outline presented in Section V of ECHA and EFSA (2016)

Abbreviations: CF: Conceptual Framework; ED: Endocrine disrupting; GD: Guidance Document; MoA: Mode-of-action.

* cf. Explanatory note to Step VI on page 24.