Strategic application of New Approach Methodologies (NAMs) in fragrance ingredient safety assessment: Integration of in vitro, in silico, and exposure-based approaches in RIFM evaluations.

New Approach Methodologies (NAMs) are transforming toxicological risk assessment by providing human-relevant, non-animal approaches for hazard identification, exposure assessment, and safety evaluation. This manuscript presents an overview of the Research Institute for Fragrance Materials (RIFM) New Approach Methodologies research program and describes how in vitro, in silico, and in chemico methods are integrated with exposure modeling, read-across frameworks, and weight-of-evidence approaches to support fragrance ingredient safety assessments. We describe the strategic application of NAMs across key toxicological endpoints and illustrate how these approaches contribute to point-of-departure derivation, mechanistic understanding, exposure-led risk assessment, and regulatory decision-making. The manuscript also discusses the scientific maturity and fitness-for-purpose of individual NAMs, highlighting their role in supporting next-generation risk assessment and advancing regulatory alignment. Progress achieved since the publication of the 2015 RIFM Criteria Document and subsequent RIFM research initiatives is summarized, demonstrating the evolution of NAM-based safety assessment frameworks. Collectively, these efforts illustrate how RIFM is incorporating New Approach Methodologies into fragrance safety assessment to enhance human relevance, strengthen scientific confidence, and support the ongoing transition toward animal-alternative toxicology and modern risk assessment.