Physiologically based modeling of 2-butoxyethanol disposition in rats following different routes of exposure.
2-Butoxyethanol (BE) is widely used as a solvent in coatings and other consumer products and has shown hematotoxicity in laboratory animals. To provide a physiological basis for extrapolating toxicokinetic data observed in rats to humans, a blood flow rate-limited, physiologically based pharmacokinetic model was developed to describe the distribution and metabolism of BE in rats following drinking water, dermal, and inhalation exposures. The major urinary metabolite, butoxyacetic acid, represented 45 to 60% of the absorbed dose in all three routes of exposure. Other identified urinary metabolites in our studies included ethylene glycol and BE-glucuronide. A model formulation of the possible metabolic pathways based on the experimental data was proposed. The amounts of individual urinary metabolites were used to develop the model. Metabolic constants were estimated by fitting the data within the constraints of in vitro measurements. The model explained the change of profiles of urinary metabolites in different exposure routes by taking into account the differences in absorption rate and by incorporating a minor pathway for metabolism by skin. Sensitivity analysis showed that metabolic constants and blood flow rate to liver had a relatively larger influence on the production of urinary metabolites than the organ volume or the partition coefficient for BE.
Shyr
L J
LJ
Inhalation Toxicology Research Institute, Lovelace Biomedical and Environmental Research Institute, Albuquerque, New Mexico.
Sabourin
P J
PJ
Medinsky
M A
MA
Birnbaum
L S
LS
Henderson
R F
RF
D000279:Administration, Cutaneous; D000280:Administration, Inhalation; D000284:Administration, Oral; D000818:Animals; D005026:Ethylene Glycols / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006016:Glycolates / Q000652:urine*; D008099:Liver / Q000378:metabolism*; D008954:Models, Biological; D051381:Rats; D011916:Rats, Inbred F344; D014018:Tissue Distribution
D005026:Ethylene Glycols; D006016:Glycolates; C017095:n-butoxyacetic acid; C017096:n-butoxyethanol