A toxicokinetic study of inhaled ethylene glycol ethyl ether acetate and validation of a physiologically based pharmacokinetic model for rat and human

The solvents ethylene glycol monoethyl ether acetate (EGEEA) and ethylene g lycol monoethyl ether (EGEE), at sufficiently high doses, are known to be r odent developmental toxicants, exerting their toxic effects through the act ion of their metabolite 2-ethoxyacetic acid (2-EAA). Thus risks associated with exposure to these compounds are best evaluated based on a measure of t he internal dose of 2-EAA. The goals of the work reported here were to deve lop physiologically based pharmacokinetic (PBPK) models of EGEEA and EGEE f or pregnant rats and humans. These models were used to identify human expos ure levels (ppm in air) equivalent to the rat no observed effect level (NOE L) and lowest observed effect level (LOEL) for developmental effects (Hanle y ef al., 1984). We exposed pregnant Sprague-Dawley rats to concentrations of EGEEA corresponding to the NOEL and LOEL. Maternal blood, urine, and fet al tissue concentrations of EGEE and 2-EAA measured in these experiments we re used to validate the rat EGEEA and EGEE models. Data collected by other researchers were used to validate the capabilities of the rodent EGEEA and EGEE models to predict the kinetics in humans. The models for estimating ci rculating blood concentrations of 2-EAA were considered valid based on the ability of the model to accurately predict 2-EAA concentrations in rat bloo d, urine, and fetal tissue. The human inhaled concentration equivalent to t he rat NOEL for EGEEA (50 ppm) was predicted to be 25 ppm using the materna l blood average daily area under the curve (AUC) and 40 ppm using the maxim um concentration achieved in maternal blood (C-max). The human inhaled conc entration equivalent to the rat LOEL for EGEEA (100 ppm) was determined to be 55 ppm using the maternal blood average daily AUC and 80 ppm using the m aternal blood C-max. (C) 2000 Academic Press.