BACKGROUND
The 2020 EU Chemicals Strategy for Sustainability towards a toxic-free environment (CSS) is intended to form a key part of the European Green Deal. While the CSS recognises the fundamental role that chemicals play in daily life, it also aims to address concerns over the perceived negative impacts of chemicals on human health or on the environment. The CSS therefore promotes a ‘safe and sustainable by design’ approach to chemicals, while proposing bans or restrictions on the use of those chemicals recognised as being hazardous and which are already on the market. Endocrine Disrupting (ED) chemicals are a particular focus of the CSS which states that exposure to ED chemicals is not only ‘a threat to human health’ but also ‘one of the key drivers putting the Earth at risk’, requiring specific attention due to their increased use and reported links to chronic and delayed health conditions. The CSS notes that exposure to ED chemicals during fetal development or puberty can cause subtle but irreversible effects, which often only become apparent many years later. The continued use of ED chemicals is seen as posing a serious risk to human health and wildlife, with consequent economic costs for society. Accompanying the CSS is the 2019 Commission Working document ‘Fitness Check on Endocrine Disruptors’ (1), which is intended to address inconsistencies between different pieces of EU Chemicals legislation.
BIOCIDES AND PESTICIDES
ED properties have been routinely assessed under EU biocides and pesticides (PPP) legislation for a number of years. The approach taken to ED under these regulations therefore provides an indication of the approach likely to be implemented across other regulations, including REACH. Under biocides legislation, ED is an exclusion criterion, meaning that products containing ED chemicals may only be used in situations where there is negligible risk to humans or the environment, there is an essential need to prevent or control a serious danger, or where the lack of approval would have a disproportionately negative impact on society. Under pesticides legislation, ED is one of the hazard-based ‘cut-off’ criteria for approval, meaning that product uses are limited to those where human and environmental exposure is negligible – a condition not possible to demonstrate in most cases. The registration of biocides and pesticides in the EU in all cases requires the provision of comprehensive toxicological and ecotoxicological datasets covering a multitude of EDrelevant endpoints. Evidence for ED properties is subject to a specific and detailed assessment, following the principles detailed in the 2018 joint ECHA/EFSA Guidance Document (2). Evidence for endocrine activity or ‘endocrine-mediated adversity’ within this dataset is likely to result in additional studies being requested, or lead to a non-approval decision. Final decisions on ED status are made by EFSA for pesticides, or by the ECHA Endocrine Disruptor Expert Group (EDEG) for biocides. Application of the 2018 Guidance has resulted in the loss of a number of biocidal and pesticidal active substances, either following assessment or through withdrawal from the registration process by the applicant company. At the time of writing 113 chemicals have been considered by the EDEG, of which 17 were considered to be ED for effects on human health, the environment, or both. Six chemicals were concluded not to be ED, with decisions on the remaining substances inconclusive, postponed or under development.
ED AND REACH
The CSS envisages that REACH and CLP should be reinforced as the cornerstones of EU policy for chemical regulation. Currently, under REACH, substances identified as ED are likely to be considered substances of very high concern (SVHC), with decisions on ED status made following substance evaluation by the EDEG. A legally binding definition of ED based on WHO criteria and consistent with the definition used under biocides and pesticides legislation will be introduced under REACH, with ED chemicals being introduced as a separate SVHC category. Specific guidance for the assessment of ED under REACH is expected to be introduced in 2024, with Registrants advised to use the 2018 joint ECHA/EFSA guidance in the interim. ED chemicals will continue to be prioritised under REACH and subject to individual restrictions, although a substance grouping approach is also envisaged. Evidence of this change in approach is seen in the recent ECHA proposal (3) to restrict per- and polyfluoroalkyl substances (PFASs) under Annex XV of REACH, a move driven in part by concerns over ED potential. This is the broadest restriction proposal in the history of the EU and demonstrates a willingness to legislate against entire chemical classes. In the longer term, the CSS proposes a ‘generic approach’ to the risk management of ED chemicals, including strengthening information requirements across different pieces of legislation, such as REACH. Assessment of ED properties under REACH is currently problematic as, with the exception of the highest tonnage band, registered chemicals are not required to have a dataset considered to be ‘sufficient’ according to the 2018 ECHA/EFSA Guidance. Nevertheless, substances showing evidence of ED are likely to be subject to additional data requests following evaluation by ECHA. The need for alignment of the REACH ED assessment framework with the pesticides and biocides criteria is recognised and has been coordinated by a CARACAL (Competent Authorities for REACH and CLP) subgroup since 2020. The increased emphasis on ED is likely to be reflected in the planned revision of the REACH Regulation with the introduction of ED-specific information requirements, potentially at all tonnage bands. The outcome of these initiatives will be increased scrutiny of registered substance and increased testing costs for industry. Chemicals (or groups of chemicals) identified as ED will ultimately face a blanket prohibition in consumer products, with other uses permitted only where essential. The approach is similar to one already in place for carcinogens and is justified by the CSS based on a lack of consensus over the existence of thresholds for the activity of ED chemicals (4), meaning that (in the Commission’s view) safe levels of exposure cannot be assumed.
ED CHEMICALS AND CLP
The recently published Delegated Regulation revising the CLP Regulation (5) includes new hazard classes for ED chemicals. This defines criteria for two ED classification categories, Category 1 (for substances known or presumed to be endocrine disruptors) and Category 2 (for substances suspected of being endocrine disruptors). Substances may be classified for their effects on human health and/or on the environment. Substances already having a decision on ED from the EDEG (biocides, REACH substances) or from EFSA (pesticides) will be considered as Category 1 ED under CLP, without any further consideration by ECHA’s Committee for Risk Assessment (RAC). Concentration limits of 0.1% and 1% will apply to mixtures containing Category 1 and 2 ED substances, respectively. This move to unilaterally amend CLP risks divergence from the UN GHS, although the Commission envisages that the new hazard classes will also be negotiated into GHS.
SAFE AND SUSTAINABLE BY DESIGN
This pre-market approach is proposed to ensure (presumably using knowledge-based screening methods) that new chemicals lack properties of concern, including ED. However, current methods such as (Q)SAR and high-throughput cell-based screening assays are over-predictive and not fully representative of human physiology. Consequently, while this approach would prevent the development and commercialisation of some chemicals predicted to be ED, it would not be completely effective and risks the loss of some non-ED chemicals. Additionally, the potential for ED properties being detected in subsequent higher tier regulatory tests cannot be excluded.
SPECIFIC CONCERNS FOR NERVOUS SYSTEM DEVELOPMENT
The CSS notes the potential for ED chemicals to influence early brain development, causing delayed but permanent effects. This is the case for ED chemicals affecting thyroid hormone levels, raising concerns for the exposure of pregnant women and the very young. However, thyroid effects are relatively common in experimental animal studies and, in most cases, are a consequence of the exaggerated dose levels used to support the risk assessment, and/or are likely to be caused by mechanisms not relevant to humans. Measurement of thyroid hormone levels has been incorporated into some standard OECD test guidelines only recently, meaning that data are absent for the majority of chemicals. Most chemicals causing effects on the thyroid therefore require additional testing, not only to clarify the mechanism but also to exclude other (human-relevant) mechanisms. Even then, the potential for chemicals to affect the developing nervous system is likely to result in requests for additional data including a developmental neurotoxicity study. This study is being more commonly requested for pesticides, and is a standard data requirement for biocides.
IMPLICATIONS FOR ANIMAL TESTING
According to the ECHA/EFSA guidance, a key study relied on is the rat extended one-generation reproductive toxicity study (EOGRTS). This study (OECD 443) has a flexible modular design intended to be guided by the nature of the chemical and any concerns identified in other studies. The study is expensive to conduct (typical costs €0.8-1.3m) and intensive in terms of animal usage (~1600-3100 rats per study). For chemicals registered under REACH, ECHA has defined a ‘basic study design’ with additional cohorts to be added only if triggered. Under BPR, however, the latest information requirements (6) specify an EOGRTS of full design, regardless of the existence of specific triggers or concerns. ECHA has also identified concerns (7) about the quality of studies submitted by Registrants and on at least one occasion has requested that the study be repeated. The CSS recognises that EU policy is to move away from and ultimately replace animal testing with alternative (i.e., non-animal) methods. Despite this aim, acceptance of the currently available alternative methods by EU bodies is limited. Furthermore, the increasing concerns for worker and consumer protection resulting from ED chemicals highlighted by the CSS, and the likely extension of REACH information requirements to include ED, will only serve to drive an increase in the extent of animal testing.
CONCLUSION
The concerns over the potential for ED chemicals to cause harm to human health and the environment highlighted in the CSS will result in an increased focus and extension of testing under legislation including REACH. The current limited regulatory acceptance of alternative testing methods together with an increased focus on animal-intensive studies will result, at least in the short-term, in more animal testing which runs counter to another aim of the CSS. For industry this will mean increased costs and regulatory uncertainty as their products come under scrutiny. An early assessment of the vulnerability of individual substances to ED classification is therefore recommended. At the same time, some of the assumptions underlying the focus on ED chemicals as a cause for concern are questioned by the scientific community (8).
REFERENCES AND NOTES
- European Commission. SWD(2020)251 final (2020).
- ECHA and EFSA. EFSA J. 16(6): 5311-5445 (2018).
- ECHA Annex XV Restriction Report: Per- and Polyfluoroalkyl substances (PFASs) (2023).
- Solecki, J., Kortenkamp, A. et al., Arch. Toxicol. 91:1001-1006 (2017).
- The European Parliament and The Council, Delegated Regulation (EU) 2023/7074, Off. J. Eur. Commun. L93, 7-39 (2023).
- ECHA. Guidance on the Biocidal Products Regulation Volume III: Human health Part A Information requirements Version 2 (2022).
- ECHA. Evaluating results from 55 extended one-generation reproductive toxicity studies under REACH. Final report of the EOGRTS review project (2023)
- Herzler, M., Marx-Stoelting, P, et al., Arch. Toxicol. 95:2589-2601 (2021).
