Development and prospective validation of a read-across approach to assess the in vivo toxicokinetic profiles of chemicals in humans

Development and prospective validation of a read-across approach to assess the in vivo toxicokinetic profiles of chemicals in humans

Food and Chemical Toxicology

10.1016/j.fct.2026.116169

https://doi.org/10.1016/j.fct.2026.116169

Sheng Yuan Chin, Eleanor Jing Yi Cheong, Geraldine Oh, Boon Ling Tay, Gang Yan, Jolene Chee, Melissa PS. Toh, Lay Kien Yang, Pnelope Ng, Yoganathan Kanagasundaram, Jeroen A.J. Schmitt, Corie A. Ellison, James Chun Yip Chan

19 May 2026

Chin, S. Y., Yi Cheong, E. J., Oh, G., Tay, B. L., Yan, G., Chee, J., Toh, M. PS., Yang, L. K., Ng, P., Kanagasundaram, Y., Schmitt, J. A. J., Ellison, C. A., & Yip Chan, J. C. (2026). Development and prospective validation of a read-across approach to assess the in vivo toxicokinetic profiles of chemicals in humans. Food and Chemical Toxicology, 215, 116169. https://doi.org/10.1016/j.fct.2026.116169

The use of read-across is established for assessing toxicological hazards based on structural and biological similarities. Toxicokinetic (TK) read-across extends this concept to infer in vivo TK of target compounds from source analogs with available data, but its application to non-pharmaceutical chemicals remains limited. Here, we evaluated TK read-across for non-pharmaceutical compounds, focusing on cosmetic ingredients across multiple administration routes and diverse TK properties, including poor oral bioavailability. A TK analog workflow was applied to identify analogs, with suitability ratings assigned based on structure, reactivity, metabolism, and physicochemical properties. Case studies showed that “suitable” pairs exhibited comparable in vivo TK and in vitro absorption, distribution, metabolism and excretion (ADME) characteristics, typically within 0.5-2-fold differences. Pairs rated “suitable with interpretation” displayed >2-fold TK differences, consistent with structural or ADME dissimilarities. “Suitable with pre-condition” pairs were poor TK analogs, as analogs were often metabolites or metabolic precursors of targets, with >5-fold differences in clearance. “Not suitable” pairs showed divergent TK profiles and structures. A human study using a “suitable” pair demonstrated that terpinolene TK aligned with limonene data within two-fold. Overall, this workflow supports evidence-based analog selection and enables TK read-across to inform safety and TK assessments when human data are limited.

Attribution 4.0 International (CC BY 4.0)

This research / project is supported by the A*STAR & P&G - Industry Alignment Fund – Industry Collaboration Project
Grant Reference no. : I24PGE0012

https://oar.a-star.edu.sg/communities-collections/articles/23302

0278-6915

Singapore Institute of Food and Biotechnology Innovation

https://doi.org/10.1016/j.fct.2026.116169