S06-01 Setting the scene: Dose level selection for development and reproductive toxicity studies

Following advice on dose selection issued by the European Chemicals Agency (ECHA) in 2022 ^[1] for reproductive toxicity studies conducted under REACH, this presentation will cover the implications of this advice from both a 3Rs (Replacement, Reduction and Refinement of animals in research) and scientific perspective. The ECHA advice followed an evaluation of existing extended one generation reproductive toxicity (EOGRT) studies with respect to design, conduct and toxicological findings, and concerns that potential hazardous effects could be missed due to inadequate dosing. The resulting advice specified that the highest dose tested should “demonstrate an aim to induce clear evidence of reproductive toxicity without excessive other toxicity and severe suffering in parental animals (e.g. prostration, severe inappetence (lack of appetite), excessive mortality as signs of severe suffering) that would compromise the interpretation of co-occurring reproductive effects.” These recommendations have been evaluated by a number of expert groups, including the European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) Task Force on Dose Selection ^[2], in relation to advice in existing Organisation for Economic Cooperation and Development (OECD) test guidelines and guidance document, including on humane endpoints and selection of the maximum tolerated dose. Other considerations relevant to dose selection include factors such as maternal clinical signs of toxicity, food consumption/nutritional intake, clinical chemistry parameters, circulatory/cardiovascular changes, target organ toxicity, maternal stress and toxicokinetics. The results of these evaluations, as well as recent discussions with ECHA and the wider scientific community (including at the EUROTOX 2024 satellite session ^[3]) which aimed to better understand the advice, will be presented, recognising a shared goal of ensuring a high level of human health protection whilst balancing scientific pragmatism and impact on animal welfare.