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

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.