A next generation risk assessment was carried out to evaluate the safety of benzophenone-4 (BP-4), a UV filter present at 5% in a body lotion, to compare a non-animal approach with a traditional safety assessment based on historical animal data. Exposure characterization indicated that BP-4 is poorly absorbed through the skin, poorly metabolized by the liver, a substrate of influx and efflux transporters, and excreted by the kidney. The resulting physiologically-based kinetic model predicted an upper bound (95th percentile) plasma Cmax of 1.27 μM, and liver and kidney concentrations of 0.32 μM and 0.44 μM, respectively. To characterize bioactivity, in silico and in vitro new approach methodologies were used. Points of departure (PoDs) were derived from four bioactivity platforms, including in vitro pharmacological profiling, CALUX assays, high-throughput transcriptomics, and a cell stress panel. By dividing the in vitro PoDs (PoDNAM) from these assays by the 95th percentile plasma Cmax value, bioactivity exposure ratios (BERs) were calculated. The lowest PoD was from a single gene expression change, and the highest PoD from phenotypic biomarkers using a primary renal cell model. Most BERs were above 11, except for those from gene-level PoDNAM in HepG2 and MCF-7 cells, which were 3.3 and 4.3. These lowest PoDNAM values are linked to gene transcription changes and are likely indicative of adaptive biological activity rather than adverse health effects. This work demonstrates the usefulness of next generation risk assessment in addressing pressing relevant regulatory questions without using animals.
Keywords: alternative approaches; animal-free risk-assessment; cosmetics safety; exposure scenario; new approach methodologies (NAMs); next-generation risk assessment (NGRA).
This study on the UV filter benzophenone-4 (BP-4) highlights the potential of modern, non-animal testing methods to provide comprehensive safety evaluations. The study shows that BP-4 applied in a sunscreen lotion is poorly absorbed through the skin and efficiently excreted by the kidneys, resulting in low exposure of the inner organs. The use of advanced computational and in vitro techniques revealed that most biological responses would occur at levels higher than the predicted exposure a consumer would have. This approach aligns with the 3Rs principle by reducing reliance on animal testing and offers a more ethical and potentially faster pathway for regulatory safety assessments. The findings suggest that next generation risk assessments can effectively address safety concerns and pave the way for broader acceptance and implementation of these innovative methods by regulators.