Data on mode of action (MoA) of rodent tumour formation have become an integral part of the information submitted in regulatory dossiers for some chemical substances registration or re-registration. Despite this, there is a lack of guidance or standardised approaches for addressing such results through evidence-based follow-up studies in dossiers within the agrochemical and chemical sectors. This instigates companies to proactively conduct extensive studies on vertebrates (including wild-type and transgenic mice and rats), which contradicts the principles of the 3Rs (Replacement, Reduction, and Refinement). Therefore, it is of general interest adhering to non-animal approaches and reducing reliance on animal studies, whenever possible. To better understand the role that in vitro mechanistic studies already can play in decision-making we conducted an analysis focusing on one of the most common MoAs involved in rodent liver carcinogenicity: the constitutive androstane receptor (CAR) MoA, which accounts for about 25% of tumours induced in rodents by agrochemicals. We collected information from 36 harmonised classification and labelling (CLH) dossiers on the actual use and weight of in vitro mechanistic data used to evaluate positive results from rodent cancer bioassays. The analysis showed that in vitro mechanistic studies play a relevant role in the weight of evidence evaluation to elucidate the human relevance of the CAR MoA in regulatory decision-making. Consequently, this information can give important hints on recommendations for in vitro mechanistic studies harmonisation in this specific regulatory field.
CAPELOA Tania;
PRIETO-PERAITA Pilar;
BERGGREN Elisabet;
CORVI Raffaella;
CAPELOA, T., PRIETO-PERAITA, P., BERGGREN, E. and CORVI, R., The usefulness of in vitro mechanistic information in regulatory dossiers: the case of the CAR mode of action in carcinogenicity assessment, Publications Office of the European Union, Luxembourg, 2024, doi:10.2760/7961005, JRC139783.
2024-11-19
Publications Office of the European Union
JRC139783
978-92-68-21944-7 (online),
1831-9424 (online),
EUR 40107,
OP KJ-01-24-136-EN-N (online),
https://publications.jrc.ec.europa.eu/repository/handle/JRC139783,
10.2760/7961005 (online),
