Application of a next generation risk assessment framework, integrated testing strategy defined approaches and...

Evaluating skin sensitization is crucial for the safety of cosmetics and pharmaceuticals. Regulatory bans on animal testing have spurred the development of New Approach Methodologies (NAMs), Integrated Testing Strategies (ITS), and Next Generation Risk Assessment (NGRA). Defined Approaches (DAs) that combine various NAMs have been developed to assess skin sensitization hazards and potency, as recognized by the OECD. However, deriving a quantitative point of departure (PoD) through NAMs in accordance with NGRA remains challenging. This study evaluated the skin sensitization hazard and potency of 5-hydroxymethylfurfural (5-HMF) and 5,5'-oxydimethylenebis(2-furfural) (OBMF), which are by-products of saccharide-containing botanical ingredients in cosmetics and preparations, using an NGRA workflow that integrated ITS DAs and read-across. Within the NGRA framework, NAMs classified 5-HMF and OBMF as weak to moderate skin sensitizers based on the Schiff base formation mechanism. Case studies on hypothetical consumer exposure scenarios (leave-on and rinse-off) for 5-HMF and OBMF derived PoDs and acceptable concentration thresholds raise safety concerns regarding human skin sensitization from topical exposure to 5-HMF and OBMF. The study assessed uncertainties in NGRA and NAMs for exposure-driven risk assessments without animal testing. It advocated for further research to refine tiered NGRA workflows, enhance the protective sufficiency of NAMs, and expand their applicability to botanical ingredients.