A category approach to predicting the hemolytic effects of ethylene glycol alkyl ethers in repeated-dose toxicity

Categorizing chemicals is an approach with the potential to reduce animal testing for hazard assessment of chemicals. In this study we investigated the category approach for testing the hemolytic effects of ethylene glycol alkyl ethers (EGAEs) for repeated-dose toxicity (RDT). Using mechanistic information on the hemolytic effects of ethylene glycol butyl ether, a toxicologically meaningful category was built on the basis of similarity of metabolism, mode of action and the hemolytic effects of several EGAEs and related chemicals. The developed category was then evaluated for analogs from a different data source. Given all structural information on category chemicals, the category can be finally defined as EGAEs (alkyl chain carbon number: 1-4) and their acetates. Current RDT test data suggest that EGAEs with 3 and 4 alkyl carbons primarily cause hemolytic effects, while EGAEs with 1 and 2 alkyl carbon(s) show toxicity to the testis before demonstrating any hemolytic effects. Hence, the category approach appears to be applicable to hemolytic effects of EGAEs with 3 and 4 alkyl carbons and their acetates to estimate the no observable adverse effect level (NOAEL) for RDT. It consists of three steps: structure-based primary screening of untested chemicals, categorization of compounds that form hemolytic alkoxyacetic acids by predicting how they are metabolized, and finally estimation of hemolytic levels by employing read-across. Our results clearly demonstrate the usefulness of the category approach for predicting the hemolytic effects of untested EGAEs and their acetates in RDT.