Dose-level setting for DART studies

Developmental and reproductive toxicity (DART) studies typically involve rats and rabbits, with around 2,500 animals used for each substance tested. It is important that chemicals are tested at doses that avoid unnecessary animal suffering while maintaining the highest standards of human health protection.

The European Chemicals Agency (ECHA) issued new advice in 2022 on dose selection for DART studies intended to clarify how the legal requirement for testing at "appropriately high dose levels" should be applied in reproductive toxicity studies conducted under the European chemicals regulation, REACH – Registration, Evaluation, Authorisation and Restriction of Chemicals. The advice prompted extensive discussion across the toxicology community, primarily around around what constitutes a "high enough" dose and how this can be defined and identified in practice. Concern was raised that the advice could potentially lead to testing at unnecessarily high doses in animals, causing avoidable suffering, impacting on study outcomes and leading to differences in interpretation which could potentially lead to the need for studies to be repeated.

To reduce and refine the use of animals in DART studies, we are collaborating with industry and regulatory partners to better understand the ECHA advice and where there is a need for clarification, and make recommendations for the selection of appropriate dose levels to collect relevant scientific information, protect human reproductive health and maintain high standards of animal welfare.

As part of the European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) Task Force on Dose Selection, we co-authored a paper advocating for a scientific approach that considers a range of factors to avoid exposing animals to unnecessary high doses. The ECETOC Task Force highlighted that the 2022 ECHA advice does not align with OECD test guidelines or current guidance on the use of humane endpoints.

We held a satellite event to EUROTOX 2024, co-organised by the NC3Rs, ECETOC, Charles River Laboratories and ECHA, which brought together over 120 global stakeholders from a range of sectors to understand different perspectives on dose setting for DART studies. The workshop highlighted a lack of clarity and understanding about ECHA’s requirements, with agreement from ECHA that its advice would benefit from some further clarification.

ECHA held workshops in November 2024 to establish an open discussion between contract research organisations performing animal studies and ECHA’s regulatory scientists assessing those studies. We organised symposium sessions at the Society of Toxicology meeting in 2025/26 and EUROTOX 2025 to present the results from the workshop and provide a forum to explore challenges associated with selecting sufficiently high dose levels.

In June 2026, ECHA published revised advice on dose selection for reproductive toxicity studies. The changes are not a wholesale rewrite of the original guidance. However, several revisions provide additional clarification and place greater emphasis on topics that have featured prominently throughout our discussions with the global toxicology community. These include a stronger emphasis on evidence-based dose selection, additional consideration for steep dose-response relationships and dose spacing, clarification around sex-specific dosing considerations, expanded discussion of severe suffering and animal welfare and greater recognition of the importance of dose-range finding studies. We are continuing to facilitate discussion in this area and provide a neutral forum for sharing experience, data and best practice.