Quantitative next generation risk assessment for skin sensitization - application of regression models based on in vitro data to estimate point of departure

Quantitative risk assessment (QRA) for dermal sensitization is essential for determining safe concentrations of skin sensitizers in consumer products. The fragrance industry developed the QRA2 approach, which uses the No Expected Sensitization Induction Level (NESIL) as a starting reference dose or point of departure (PoD). Animal alternatives for potency assessment have emerged to calculate quantitative PoDs. One such alternative is in vitro-based regression models. Herein, a framework for incorporating regression models into next-generation risk assessment (NGRA) is presented. The framework begins with hazard assessment using in vitro methods (OECD Guideline 497), followed by PoD calculation through regression models, and completed with QRA2. After determining a PoD, uncertainty factors may be considered to derive a new approach methodology NESIL (NAM-NESIL). Case studies are presented with two sensitizers, p-mentha-1,8-dien-7-al (CAS # 2111-75-3) and 3-propylidenephthalide (CAS # 17369-59-4), calculating acceptable exposure levels (AELs) for products like deodorants and bar soaps. Ratios of the AELs to consumer exposure levels (CELs) were then calculated to determine whether the current use is safe. Comparison of QRA based on NAM-NESILs to historically human-derived NESILs supports the reliability of in vitro models. This approach offers a promising alternative for PoD derivation, potentially eliminating the dependence on in-vivo data.