A case study using benzoic acid demonstrating how integration of in silico analogue selection tools with mechanistic in vitro NAM and toxicological data enhances the accuracy of RAX assessments of low systemic toxicity chemicals

ABSTRACT: Benzoic acid and its related derivatives are preservatives widely used in the cosmetic and food industries. This study aimed to quantitatively assess the suitability of benzoic acid derivatives for read-across (RAX) in a Next Generation Risk Assessment. We employed in silico Matched Molecular Pair and Quantitative Similarity approaches to distinguish sub-groups within a broad category of benzoic acid-related substances. These were complemented with metabolism data to refine the category definitions. Pharmacology profiling, ToxCast and transcriptomic data further substantiated the low bioactivity of benzoic acid analogues and highlighted differences in reactivity for analogues outside the RAX category. Analogues with the highest TotalScore of 3.0 were salts of benzoic acid and p- and m-toluic acids, which exhibit similar metabolic pathways to benzoic acid. Small alkyl derivatives of benzoic acid exhibited slight metabolic differences, with TotalScores from <3.0 to ≥2.5. Based on the RAX evaluation, the category of benzoates using benzoic acid as a source of toxicological data included the sodium, potassium, calcium, magnesium and ammonium salts of benzoic acid and m- and p-toluic acid. Physiologically Based Kinetic modelling was used to better understand the discordance of in vivo toxicity data due to the administration route, and the lack of bioactivity of benzoic acid and its analogues in in vitro tests. In conclusion, this case study illustrates a structured approach to evaluating the suitability and safety of analogues and demonstrates the utility of integrating in silico tools with mechanistic and toxicological data to enhance the accuracy of RAX assessments.

ORGANISM(S): Homo sapiens

PROVIDER: GSE309098 | GEO | 2026/09/25

REPOSITORIES: GEO