A Next-Generation Risk Assessment Case Study for Coumarin in Cosmetic Products

TLDR

Next‑Generation Risk Assessment integrates exposure‑led, hypothesis‑driven approaches and NAMs to assure safety without animal testing. They applied this approach to 0.1 % coumarin in face cream and body lotion, estimating dermal plasma Cmax with a physiologically based kinetic model and assessing systemic toxicity through in‑vitro NAMs (receptor, immunomodulatory, bioactivity panels, ToxCast, transcriptomics) and in‑silico genotoxicity alerts, then comparing points of departure to exposure to derive a safety margin. Predicted Cmax values were below all points of departure with a margin of safety greater than 100; coumarin showed no genotoxicity, receptor binding, or immunomodulatory effects at consumer‑relevant exposures, demonstrating the value of integrating exposure science, computational modeling, and in‑vitro bioactivity data to reach a safety decision without animal data.

Abstract

Abstract Next-Generation Risk Assessment is defined as an exposure-led, hypothesis-driven risk assessment approach that integrates new approach methodologies (NAMs) to assure safety without the use of animal testing. These principles were applied to a hypothetical safety assessment of 0.1% coumarin in face cream and body lotion. For the purpose of evaluating the use of NAMs, existing animal and human data on coumarin were excluded. Internal concentrations (plasma Cmax) were estimated using a physiologically based kinetic model for dermally applied coumarin. Systemic toxicity was assessed using a battery of in vitro NAMs to identify points of departure (PoDs) for a variety of biological effects such as receptor-mediated and immunomodulatory effects (Eurofins SafetyScreen44 and BioMap Diversity 8 Panel, respectively), and general bioactivity (ToxCast data, an in vitro cell stress panel and high-throughput transcriptomics). In addition, in silico alerts for genotoxicity were followed up with the ToxTracker tool. The PoDs from the in vitro assays were plotted against the calculated in vivo exposure to calculate a margin of safety with associated uncertainty. The predicted Cmax values for face cream and body lotion were lower than all PoDs with margin of safety higher than 100. Furthermore, coumarin was not genotoxic, did not bind to any of the 44 receptors tested and did not show any immunomodulatory effects at consumer-relevant exposures. In conclusion, this case study demonstrated the value of integrating exposure science, computational modeling and in vitro bioactivity data, to reach a safety decision without animal data.