Assessing the resource and animal use implications of new EU REACH endocrine disruptor assessment information requirements

The European Union’s Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) Regulation is in place to ensure a high level of protection of human health and the environment from chemical substances that are manufactured, imported, placed on the market, or used within the EU. Two information requirement options specifically for endocrine disruptor (ED) assessment of chemicals under EU REACH were proposed by the European Commission in 2021. Once implemented in the coming years, this will substantially increase demands for data from animal studies. 

Supported by an expert working group with representatives from regulatory agencies and industry (covering agrochemical and industrial chemicals) alongside expert consultants, we have led an analysis of the potential animal use and financial resource associated with the new ED-specific information requirement options. The results of this analysis were presented in a report, which was shared with the Commission in June 2023, and have subsequently been published in Regulatory Toxicology and Pharmacology. The analysis showed that there are considerable implications in terms of the animal use, resource and cost associated with either of the two policy options. In addition, the testing demands are expected to exceed the capacity of laboratories and data assessors.

The key findings are that – regardless of which of the policy options are adopted – tens of millions of animals could be used to conduct the required testing, at a cost of tens of billions of euros. Both options include initial in vitro testing on most chemicals, but overall there is a lack of clarity over how in vitro test results would be used to minimise animal studies. The proposed approaches described in the policy options are unlikely to be feasible in practice as the high testing demands will exceed the capacity of contract research organisations (CROs) to conduct the studies and the European Chemicals Agency’s (ECHA) ability to process the testing proposals.

The working group assessed the differences between the two policy options, identifying clear differences in how and when in vivo testing is triggered following initial in vitro ED assessment, which will have significant implications on animal use. The difference which has the biggest impact in terms of animal use and cost is that option one focuses on a “weight-of-evidence” (WoE) assessment, using a combination of information from several sources such as in vitro and computational results alongside existing data to determine whether further animal testing is required or not. Whereas option two clearly states that further animal testing is required if positive results are obtained in initial in vitro studies. No information or guidance is, as yet, available on how WoE will be applied under option one. Additionally, the in vivo tests that may be triggered by positive in vitro results are not specified for either option.

The working group determined that around 12,000 substances would be subject to the new ED testing proposals. Their analysis predicts that 20 to 70% of all substances tested in vitro will trigger follow-on in vivo endocrine activity tests. The estimated animal numbers used in each study are based on relevant Organisation for Economic Co-operation and Development (OECD) test guidelines and typical study designs and assume the minimum number of animals used, and therefore represent a best-case scenario. The cost estimates for testing were made based on experience of placement of studies in European or North American CROs over the last two to three years and where a range was given the midpoint was chosen. The estimated number of studies, cost and animal numbers used under each policy option were:

Under REACH, testing on vertebrate animals should only be used as a last resort to fulfil information requirements. The working group considered the effects of various adaptations that could be used to avoid unnecessary animal testing, including applying WoE, use of QSAR models (mathematical predictions of a compounds properties from its chemical structure) and read across (predicting endpoint information for a target substance using data from another similar substance). They found that in general, both proposed policy options lacked sufficient guidance on how these would be implemented to uphold the ‘last resort’ principle for ED assessment.

Given the challenges with implementing either of the new proposed requirements and the need to minimise the reliance on animal testing as much as possible, the working group also identified several areas for further consideration and clarification:

• To address capacity issues a proportionate approach to testing should be taken, for example a phase-in schedule for testing based on a substance’s tonnage band (production/import volume).
• This would also provide time to build capacity and expertise at ECHA and CROs, including in the development and validation of new approach methodologies (NAMs) to inform prioritisation/waiving of animal testing.
• Regulatory flexibility and guidance is required to understand how data from NAMs can be used to replace animal testing for ED assessment, particularly for difficult to test substances and mixtures.
• Greater consideration is needed on how to support the use of read across to reduce the animal testing needed for ED assessment.
• Clear guidance is needed on how animal testing will be triggered and how to apply WoE approaches, as well as consideration around how data from existing REACH information requirements could be used to inform on ED potential, to avoid unnecessary or duplicative animal testing.

The revision of EU REACH Regulation for ED assessment provides a clear opportunity for the European Commission to lead the way in developing a pragmatic, robust and transparent process which fully implements 3Rs opportunities, in line with the EU’s Chemicals Strategy for Sustainability to “innovate in order to reduce dependency on animal testing but also to improve the quality, efficiency and speed of chemical hazard and risk assessments”. The analysis and perspectives of the working group will inform ongoing discussions on EU REACH ED-specific information requirements as well as the revision of other international chemicals regulations such as UK REACH.