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Applied chemical safety assessment case study for repeated dose toxicity integrating non-animal methods

Abstract : The SEURAT-1 (“Safety Evaluation Ultimately Replacing Animal Testing”) Research Initiative set up a conceptual framework for safety assessment as well as applied proof-of-concept case studies for repeated dose toxicity (Gocht et al., 2015). In particular, the ab initio case study set out to identify relevant biological pathway concentration effect levels and to evaluate the safe use of a cosmetic ingredient for specific exposure scenarios, focusing on liver toxicity. As a result a general workflow was developed aiming at integrating alternative methods from different sources to build a weight of evidence and at guiding through the safety assessment process in a structured sequential way, taking into account specifically non-animal methods. Results from in silico structural alert and QSAR profiling as well as in vitro assays, including high throughput/content screening from SEURAT-1 and ToxCast were integrated with exposure considerations and physiologically-based kinetic (PBK) modelling. These play a fundamental role in identifying potential target organs and the related internal concentrations to build a mode-of action hypothesis anchored on adverse outcome pathways (AOPs), where possible. Furthermore, the applicability of threshold of toxicological concern (TTC) and read-across approaches was examined. In vitro to in vivo extrapolation (IVIVE) modelling and refinement supported the final overall conclusion of the safe use, regarding repeated dose toxicity, for the specific chemical and use scenario.
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Andrea-Nicole Richarz, Frédéric Y. Bois, T. Exner, R. Judson, Catherine Mahony, et al.. Applied chemical safety assessment case study for repeated dose toxicity integrating non-animal methods. 52. Congress of the European Societies of Toxicology (EUROTOX 2016), Sep 2016, Seville, Spain. pp.S224-225, ⟨10.1016/j.toxlet.2016.06.1807⟩. ⟨ineris-01854316⟩



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