Dose-dependent nonlinear pharmacokinetics of ethylene glycol metabolites in pregnant (GD 10) and nonpregnant Sprague-Dawley rats following oral administration of ethylene glycol

The kinetics of orally administered ethylene glycol (EG) and its major meta bolites, glycolic acid (GA) and oxalic acid (OX), in pregnant (P; gestation day 10 at dosing, GD 10) rats were compared across doses, and between preg nant and nonpregnant (NP) rats. Groups of 4 jugular vein-cannulated female rats were administered 10 (P and NP), 150 (P), 500 (P), 1000 (P), or 2500 ( P and NP) mg C-13-labelled EG/kg body weight. Serial blood samples and urin e were collected over 24-hr postdosing, and analyzed for EG, GA, and OX usi ng GC/MS techniques. Pharmacokinetic parameters including Cmax, Tmax, AUG, and betat(1/2) were determined for EG and GA. Pregnancy status (GD 10-11) h ad no impact on the pharmacokinetic parameters investigated. Blood levels o f GA were roughly dose-proportional from 10 to 150 mg EG/kg, but increased disproportionately from 500 to 1000 mg EG/kg. EG and GA exhibited dose-depe ndent urinary elimination at doses greater than or equal to 500 mg EG/kg, p robably due to saturation of metabolic conversion of EG to GA, and of GA to downstream metabolites. The shift to nonlinear kinetics encompassed the NO EL (500 mg EG/kg) and LOEL (1000 mg EG/kg) for developmental toxicity of EG in rats, providing additional evidence for the role of GA in EG developmen tal toxicity. The peak maternal blood concentration of GA associated with t he LOEL for developmental toxicity in the rat was quite high (363 mug/g or 4.8 mM blood). OX was a very minor metabolite in both blood and urine at al l dose levels, suggesting that OX is not important for EG developmental tox icity.