Current knowledge of xenobiotic metabolism in the skin, associated in vitro and in silico models and their application to Next Generation Risk Assessments.

In Next Generation Risk Assessments (NGRAs) of cosmetic ingredients, evaluations of systemic exposure after topical application range from conservative screening estimates to higher tier kinetic models. The latter need robust and predictive in silico and in vitro skin absorption and metabolism models to ensure regulatory confidence. This review provides an update on skin xenobiotic metabolizing enzymes (XMEs) and in vitro skin metabolism models of varying complexities. It is intended primarily for safety assessors and study planners who need to select and interpret skin-metabolism NGRA approaches for cosmetic ingredients. Qualitative information helps to inform subsequent tiers of the NGRA workflow by identifying potential reactive intermediates, while structural and SAR information helps assess bioactivation and detoxification pathways. Quantitative data should be of good quality, correctly interpreted and extrapolated to in vivo using appropriate equations and scaling factors to provide a relevant indication of first-pass skin metabolism. This can be influenced by access to XMEs, extrinsic and intrinsic factors. Challenges and open questions remain regarding standardized metabolism assays and related guidelines, as well as the development of in silico models to predict skin metabolites and skin bioavailability for integration into Physiologically Based Kinetic (PBK) models. Despite advances in technologies, efforts are still needed to improve our understanding of skin XMEs and their location, and to develop suitable models to predict and measure metabolic pathways. There are increasing efforts to integrate skin metabolism data into PBK models for dermal exposure. Further research into skin metabolism is needed for NGRAs of topically applied cosmetic ingredients.