REACH & CLP Hub: Echa/Efsa guidance on endocrine disruptors – challenges and experiences - Chemical Watch

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Dr Martina Duft, ecotoxicology/regulatory affairs expert at knoell Germany GmbH, examines the best practice for implementing and dealing with the new ED criteria.

Endocrine disruptors (EDs), their definition and criteria, along with feasible options for testing and assessment have been extensively worked on and discussed in science and regulatory panels, in public and in the arena of national and global politics.

Since 2002, the WHO/International Programme on Chemical Safety definition of an endocrine disruptor has been unanimously agreed upon as "an exogenous substance or mixture that alters function(s) of the endocrine system and consequently causes adverse effects in an intact organism, or its progeny, or (sub)populations."

Consequently, distinct adverse effects and their causal relationship to substance exposure need to be established by a proven endocrine mode of action (see Fig 1 below).

Only as a result of tediously detailed and fierce discussions, were the scientific criteria for their identification in the field of plant protection products (PPPs) and biocides agreed according to the same definition. Thus, the WHO definition, which does not consider potency, is now the chosen regulatory approach in the EU. 

Overall, for PPPs and biocides a ‘hazard-based' approach (for the general public) is being applied, with its implications that substances can be banned without taking into account exposure or risk assessments. 

Derogations for PPPs and biocides (professional uses) may be granted, but only if:

  • negligible exposure (PPPs) or negligible risk (biocides) can be demonstrated; or
  • the necessity of the substance to combat serious pests, which cannot be achieved by other available means, can be shown (PPPs and biocides); or
  • there are disproportionate negative impacts on society by non-approval of the substance compared with the risks (biocides only).

The criteria have been applicable since April 2018 for biocides and since November 2018 for PPPs.

'Several pieces of legislation are relevant to endocrine disruption in the EU. In addition to the plant protection products Regulation (PPPR) and the biocidal products Regulation (BPR), REACH and the cosmetics Regulation are the main focus'

Several pieces of legislation are relevant to endocrine disruption in the EU. In addition to the plant protection products Regulation (PPPR) and the biocidal products Regulation (BPR), REACH and the cosmetics Regulation are the main focus.

Under REACH Article 57(f), endocrine disruptors are eligible as SVHCs with an equivalent level of concern as for PBT (persistent, bioaccumulative, toxic) or CMR (cancerogenic, mutagenic, toxic for reproduction) substances. Thus, generally they might be subject to authorisation, including socio-economic analysis. 

The cosmetics Regulation is still under review (since 2015) and, with the criteria adopted for PPPs and biocides, new developments should be notified soon.

To enable authorities and applicants to properly implement and deal with the new criteria in practice, in June 2018, Echa and the European Food Safety Authority (Efsa) published a guidance document.

It must be noted that the new ED guidance is, to date, only applicable for PPPs and biocides (as are the ED criteria). However, it is a comprehensive guidance document prepared with Echa's involvement and because harmonisation across legislation is desirable, it is likely to be a reference when looking at ED properties under REACH and other regulations.

New ED guidance – overview and important elements

ED assessment, as specified by the guidance, is divided into five consecutive steps:

1. Gather information
During this first step, all available data are compiled, evaluated and summarised. This not only implies data or studies included in the respective dossiers, but also relevant and reliable results from a comprehensive literature search, in silico profiling and all other available data (for example, information from ToxCast, or any other database). The data are fed in every detail into Table Annex E, an excel template provided by Echa/Efsa, and a related data matrix is created.

2. Assess the evidence
Next, the obtained data and results are assembled, assessed, integrated and reported into lines of evidence both for adverse effects and endocrine activity, considering oestrogen, androgen, thyroid, steroidogenic (EATS) modalities.

3. Initial analysis of the evidence
During this analysis, several questions need to be addressed: whether EATS-mediated parameters and/or endocrine activity have been sufficiently investigated and/or EATS-mediated adverse effects/endocrine activity have been observed. Depending on the outcome (see Fig 2 below), generation of new data or a mode-of-action analysis is triggered.

4. Mode-of-action analysis
If triggered, a mode-of-action analysis is requested: a mode of action should be postulated, considering all observed effects or data on endocrine activity. If there is sufficient evidence to support this hypothesis, the biological plausibility of this link should be substantially supported including relevant evidence.

5. Conclusion
Finally, a conclusion regarding the decision 'ED criteria met or not met' should be drawn based on the above mentioned steps and weight-of-evidence argumentation.

When involved in ED assessments, one quickly realises that, due to the focus of the guidance, an in-depth reevaluation of all available relevant (eco)tox studies is required in most cases.

In this context, the 'Table Annex E' is a central element and considered the basic tool for data gathering and subsequent assessment of potential ED properties. 

It should be user friendly to facilitate the data gathering/evaluation process. Experience has shown that existing evaluations and summaries of good quality guideline studies can be transferred into this table only to a limited extent and a great deal of manual work is still required.

Besides this, the integration and assessment of the lines of evidence and potentially a subsequent substantial mode-of-action analysis (which depending on the effects observed may or may not be required) are core elements in the guidance and represent further big challenges in the assessment. 

Impressions and first experiences

The words 'mammoth guidance' is the first impression of the document.

Without question, it is science-based and in-depth covering all facets for the assessment of potential endocrine disrupting properties with a focus on EATS-mediated endpoints. In fact, there is limited room for escape clauses or 'waivers'. And it is evident that the guidance is mainly applicable for data-rich substances; those with a complete data package consisting of studies complying with the most recent guidelines (OECD; the US Office of Prevention, Pesticides & Toxic Substance, etc) and investigating the required ED endpoints. This is, to date, only the position for very few substances and concerns mostly active substances already suspected of possessing such properties.

All parties applying the guidance are still in the learning process. However, initial experiences show it to be very time-consuming, and presenting a substantial cost factor in active substance approval/renewal processes as well as PPP and biocidal product authorisations.

New testing requirements vs minimising animal testing – what is 'sufficiently investigated'?

There are justified concerns that the testing foreseen to investigate ED properties will conflict with the overall regulatory and ethical goals to minimise animal testing.

As stated in the guidance, in principle the ED assessment should be performed on the basis of all available data and testing shall not be foreseen in the first instance. This approach is in accordance with the principles of the BPR and PPPR where animal testing shall be the last resort.

However, the critical issue encountered is that even for data-rich substances with a complete (eco)tox data package (thus in complete accordance with the data requirements) consisting of high quality guideline studies, the relevant endpoints/targets and the information required for a proper and conclusive ED assessment have not "sufficiently been investigated" – not to mention for (biocidal) active substance for which the data package has been built on many waivers. From a strict scientific but also "tick the box" perspective, these data gaps would need to be filled and the generation of new data required.

Since the burden of proof on the absence or presence of ED potential is on the applicant, a pragmatic approach should be applied and the assessment conducted on the basis of information available, not least with regard for animal welfare.

Specifically for non-target organisms, a huge number of animals (fish and amphibians) would be needed to conduct the required comprehensive time- and cost-intensive studies for all substances. If animal studies are indicated of necessity, the testing strategy is to be developed, discussed and decided upon in close collaboration with the evaluating competent authority, possibly including Echa's ED expert group.

Recommendations for applicants and registrants

Assessment of ED properties (specifically according to the new ED guidance), as well as the generation of relevant data, is new territory for many applicants.

Without in-depth experience and training in (eco)toxicological evaluations in general, and in ED assessments in particular, expert advice and support is indispensable in order to avoid a 'got lost' situation.

'It is highly recommended that applicants and registrants have support from experts who have built up comprehensive knowledge in this area in order to avoid wasted time and resources.'

When dealing with such assessments for the first time, it is highly recommended that applicants and registrants have support from experts who have built up comprehensive knowledge in this area in order to avoid wasted time and resources.

Filling in Table Annex E and the integration of the lines of evidence are very time consuming and need to be meticulously conducted, requiring expertise in the fields of (eco)toxicology.

With respect to 'data generation', it is extremely important to discuss and align the testing strategy with the competent authority in case further data is required and in order to draw a definitive conclusion on the presence or absence of potential ED properties.

Based on the principles of the PPPR and BPR as well as ethical considerations, animal testing should not be the favoured option in the first instance.

The views expressed in this article are those of the author and are not necessarily shared by Chemical Watch. 



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