Dose-dependent disposition of ethylene glycol in the rat after intravenous administration

A dose-dependent change was observed in the disposition of 14C-labeled ethylene glycol (EG) after iv administration of 20, 200, 1000, and 2000 mg/kg to Fischer 344 rats. The part of the dose expired as CO2 decreased from 39% at 20 and 200 mg/kg to 26% at 1000 and 2000 mg/kg, while urinary excretion of radiocarbon increased from 35 to 56%. The increase in urinary 14C was almost entirely attributable to [14C] glycolate, which comprised 20% of the dose in 24 h at the two higher dose levels and only 2% at the lower doses. High doses of EG limited the processes responsible for glycolate metabolism, supporting the idea that this acid is a major contributing factor to the acute toxicity of EG. Compensatory urinary excretion of glycolate resulted in minimal dose-dependent effects on 14C blood clearance. Blood clearance of 14C occurred in an initial rapid phase (half-life, 3-5 h), when plasma was comprised predominantly of ethylene glycol, that persisted for 12 h at 20 mg/kg EG and 30 h at 2000 mg/kg. The dose-dependent profile of EG metabolism argues against the use of very high chronic doses in studies intended to estimate health risks of long-term, low-level exposure to EG.