Grouping of chemicals for safety assessment: the importance of toxicokinetic properties of salicylate esters.

Summary

Using in vitro skin absorption and metabolism tests combined with in silico modeling for 41 salicylate esters, the authors grouped chemicals by predicted systemic exposure to salicylic acid. Despite shared structural motifs, toxicokinetics varied widely with chain length/branching and lipophilicity, underscoring the need to integrate ADME into regulatory grouping.

Key Findings

• Compiled in vitro skin absorption and metabolism data for 41 salicylate esters and integrated with in silico models.
• Lipophilicity (LogP 0.21–10.88) and alcohol moiety structure drive large differences in skin absorption and esterase-mediated hydrolysis.
• Grouped salicylate esters by predicted systemic exposure to salicylic acid, demonstrating toxicokinetic heterogeneity despite structural similarity.
• Highlights the regulatory value of incorporating ADME to strengthen chemical grouping decisions.

Clinical Implications

Improved grouping by internal exposure can refine risk assessment of topical salicylates used in cosmetic products, potentially avoiding over- or under-regulation and guiding safer ingredient selection.

Limitations

• Lack of in vivo human kinetic validation
• Consumer exposure scenarios and dermal application conditions not explicitly quantified

Future Directions

Validate predictions with human-relevant kinetic data, extend the framework to other cosmetic ester classes, and build open datasets to standardize TK-informed grouping.