Next-Generation Risk Assessment for cosmetic ingredients: a critical evaluation of published case studies.

The replacement of animal testing in cosmetic safety evaluation remains an urgent scientific and regulatory imperative. Next Generation Risk Assessment (NGRA) offers a human-centric, exposure-led, hypothesis-based framework that integrates new approach methodologies (NAMs), including (1) in silico modeling and 2) mechanistically informed in vitro assays, and in chemico methods, to characterize potential human health hazards under realistic exposure conditions. The aim of this review was to critically evaluate current state of NGRA in cosmetic safety by analyzing 9 published case studies with 7 chemicals across various endpoints such as systemic toxicity, skin sensitization, reproductive and developmental toxicity, and organ-specific effects. This analysis encompassed key NGRA components including physiologically based kinetic (PBK) modeling, adverse outcome pathways (AOPs), integrated approaches to testing and assessment (IATA), threshold of toxicological concern (TTC), and defined approaches for skin sensitization. Data demonstrated that NGRA successfully identified safe concentrations for cosmetic ingredients with margins of safety above regulatory thresholds. There are currently no apparent validated NGRA frameworks for systemic toxicity endpoints where significant gaps remain for complex toxicological endpoints, even though defined approaches for skin sensitization and eye irritation have gained regulatory acceptance. Future advancement still requires integration of metabolically competent models, artificial intelligence-driven prediction tools, micro-physiological systems using multi-organs, and standardized frameworks for interpreting NAM-derived points of departure. This review provides by examining successful applications and limitations, a roadmap for strengthening NGRA as a robust, efficient, and ethically grounded approach to human health risk assessment.