Dose-dependent fate of 1,4-dioxane in rats

A pharmacokinetic study was conducted to determine the fate of dioxane in rats at doses equivalent to those given in toxicological studies conducted previously. The results show that the fate of dioxane in rats is markedly dose-dependent because of a limited capacity to metabolize dioxane to beta-hydroxyethoxyacetic acid (HEAA). The pharmacokinetic data collected in support of these conclusions include plasma concentration-time curves for dioxane given to rats iv at dose levels of 3-1000 mg/kg and for an inhalation study of 50 ppm dioxane vapors for 6 h. The plasma curves at low doses by each route were linear with half-life values of about 1 h. As the dose was increased above 10 mg/kg the plasma clearance rate decreased, the fraction of the dose excreted as HEAA decreased, and the fraction of the dose excreted as dioxane per se in the urine and expired in the breath increased. These data could be described by a one-compartment open system model with parallel first-order (urinary and pulmonary excretion) and Michaelis-Menten (metabolism) elimination kinetics. At saturation, the maximum velocity of metabolism of dioxane to HEAA was about 18 mg/kg . h. Multiple daily oral doses of 1000 mg/kg, but not 10 mg/kg, were excreted more rapidly than equivalent single doses, indicating that at high daily doses dioxane induced its own metabolism. The correlation of the dose-dependent fate of dioxane with the results of toxicological studies in rats supports the conclusion that there is an apparent threshold for the toxic effects of dioxane that coincides with saturation of the metabolic pathway for its detoxification.