02880nas a2200457   4500000000100000000000100001008004100002260000900043653003200052653001200084653001800096653001100114653002000125653002400145653002700169653003200196653002100228653002200249653003800271653004300309100002200352700001700374700002200391700002100413700001800434700001800452700001300470700002100483700001600504700002100520700001300541700001700554700001700571700002100588700002000609245012700629300001200756490000700768520163300775022001402408       2025                            d  c202510aAnimal Testing Alternatives10aAnimals10aBenzophenones10aHumans10aRisk Assessment10aSunscreening Agents10aAlternative approaches10aanimal-free risk-assessment10acosmetics safety10aexposure scenario10aNew Approach Methodologies (NAMs)10aNext-Generation Risk Assessment (NGRA)1 aMaria T. Baltazar1 aSophie Cable1 aRichard Cubberley1 aNicola J. Hewitt1 aJade Houghton1 aPredrag Kukic1 aHequn Li1 aSophie Malcomber1 aBeate Nicol1 aRuth Pendlington1 aAns Punt1 aJoe Reynolds1 aSharon Scott1 aSandrine Spriggs1 aMatthew P. Dent00aMaking safety decisions for a sunscreen active ingredient using next-generation risk assessment: Benzophenone-4 case study  a511-5300 v423 aA 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.  a1868-8551