NGRA in Cosmetic Safety: Moving From the Frameworks and Case Studies to Wide Adoption

The cosmetic safety evaluation has undergone a paradigm shift driven by animal testing bans now implemented across countries representing one-third of the global population and nearly half of worldwide cosmetics sales. The legislative mandates have accelerated the development and adoption of Next Generation Risk Assessment (NGRA), an innovative framework that proposes making of context-specific safety decisions using exposure-driven, mechanism-based approaches based on non-animal test methods. Significant progress has been achieved in replacing animal tests for specific endpoints including skin sensitization, irritation, and phototoxicity through validated New Approach Methodologies (NAMs). However, major gaps remain for one-for-one replacement of systemic toxicity, reproductive and developmental toxicity, and carcinogenicity animal tests. Recent advances demonstrate that NGRA can successfully address many of these complex endpoints through integrated approaches combining physiologically-based kinetic (PBK) modeling, high-throughput transcriptomics and in vitro phenotyping to derive Bioactivity-Exposure Ratios (BERs) for risk characterization. Numerous case studies across diverse chemical types, including coumarin, benzophenone-4, caffeine, and benzyl salicylate, have demonstrated NGRA's utility for making protective safety decisions without animal data. These examples highlight critical considerations that need to be addressed in NGRA, including metabolite assessment, dose metric selection, and quantitative uncertainty characterization. While like-for-like replacement of all animal tests remains unachievable, NGRA provides a scientifically robust pathway for protective assessments where an absence of systemic effects is the primary goal, particularly for cosmetic ingredients. The challenge now lies in harmonizing methodologies, building regulatory confidence in these approaches, and evolving institutional structures to enable routine NGRA implementation across global regulatory regimes.