Next-Generation Risk Assessment of Resveratrol: An External Exposure Approach Based on Comprehensive Read-Across with Independent Internal Exposure Verification.

Following the 2013 EU ban on animal testing for cosmetics, new approach methodologies (NAMs) have become essential. This study presents a next-generation risk assessment (NGRA) for resveratrol (RES) to demonstrate a framework where a primary external exposure approach is validated through an independent internal exposure challenge. Hypothetical scenarios for 1% RES in face cream and body lotion yielded systemic exposure doses exceeding the threshold of toxicological concern (TTC) levels. Consequently, a comprehensive read-across was conducted using structure-derived parameters and transcriptomic profiling (PCA and Wasserstein distance). Based on four identified stilbene analogs, a conservative surrogate NOAEL of 100 mg/kg/day was established, providing a margin of safety exceeding 100. Furthermore, internal exposure was evaluated using physiologically based kinetic (PBK) modeling. The predicted peak plasma concentrations (0.009 μM for face cream and 0.065 μM for body lotion) were well below the internal TTC of 1 μM. Additionally, margin of internal exposure based on a transcriptomic point of departure (2.4 μM) exceeded safety benchmarks. These consistent results demonstrate that cross-validating a primary external exposure approach with an independent internal challenge provides a high level of certainty in animal-free cosmetic safety assessments.