Development and validation of PBPK models for genistein and daidzein for use in a next-generation risk assessment.

Introduction: All cosmetic ingredients must be evaluated for their safety to consumers. In the absence of data, systemic concentrations of ingredients can be predicted using Physiologically based Pharmacokinetic (PBPK) models. However, more examples are needed to demonstrate how they can be validated and applied in Next-Generation Risk Assessments (NGRA) of cosmetic ingredients.

Effect of vehicle on the in vitro penetration and metabolism of genistein and daidzein in ex vivo skin explants and the Phenion full-thickness skin model.

In a read-across assessment of the safety of genistein and daidzein in cosmetic products, additional information was required to account for differences in their systemic exposure after topical application in a typical body lotion formulation. Therefore, we measured the penetration and metabolism of two doses (3 and 30 nmoles/cm) of genistein and daidzein applied in ethanol and in a body formulation to fresh pig skin, fresh and frozen human skin, and PhenionFT models. Both chemicals readily penetrated all skin models when applied in ethanol.

Next-generation risk assessment read-across case study: application of a 10-step framework to derive a safe concentration of daidzein in a body lotion.

We performed an exposure-based Next Generation Risk Assessment case read-across study using New Approach Methodologies (NAMs) to determine the highest safe concentration of daidzein in a body lotion, based on its similarities with its structural analogue, genistein. Two assumptions were: (1) daidzein is a new chemical and its dietary intake omitted; (2) only data were used for daidzein, while and legacy data for genistein were considered. The 10-step tiered approach evaluating systemic toxicity included toxicokinetics NAMs: PBPK models and biokinetics measurements in cells used for toxicogenomics and toxicodynamic NAMs: pharmacology profiling (i.