Pharmacokinetics of ethylene glycol. II. Tissue distribution, dose-dependent elimination, and identification of urinary metabolites following single intravenous, peroral or percutaneous doses in female Sprague-Dawley rats and CD-1 mice.

Abstract

1. [1,2]-14C-Ethylene glycol (EG) was given to female CD (Sprague-Dawley) rats and CD-1 mice in order to determine tissue distribution and metabolic fate after intravenous (iv), peroral (po), and percutaneous (pc) doses. Rats were given doses of 10 or 1000 mg/kg by each route, and additional pc doses of 400, 600 or 800 mg/kg. Mice were also given iv and po doses of 10 or 1000 mg/kg, and intermediate po doses of 100, 200 or 400 mg/kg. Mice were given po doses of 100 or 1000 mg/kg, and both species were given a 50% (w/w) aqueous po dose to simulate antifreeze exposure. 2. For both species, EG is very rapidly and almost completely adsorbed after po doses. Perorally administered EG doses produced similar dose-dependent relationships described in prior studies for the disposition and excretion of iv doses. 3. The tissue distribution of EG following either iv or po routes was essentially the same, with similar percentages recovered for each dose by both routes and for either species. 4. Cutaneously-applied EG was slowly and rather poorly adsorbed in both species, in comparison with po-dose administration, and urinalysis after undiluted po doses indicated that EG probably penetrates rat skin in the parent form. There was an absence in both species of dose-dependent changes in disposition and elimination following the pc application of EG. 5. 14C-labelled EG, glycolic acid and/or oxalic acid accounted for the majority of the detectable radioactivity in the urine samples from all dose routes in the rat, while glycoaldehyde and glyoxylic acid were not detected in any of the urine fractions evaluated. Similar increases in glycolate production with increasing dose were also observed in mouse urine samples from iv and po dosing. Also, glyoxylate and oxalate were absent from mouse urine. 6. Oxidative metabolic pathways appeared to be saturated at high po doses in both species, resulting in a shift from principally 14CO2 exhalation to urinary 14C excretion, while the onset of capacity-limited metabolic changes appears to occur at lower doses for mice than for rats. 7. In summary, rats and mice displayed several similarities in the manner in which low doses of EG by several routes are distributed, metabolized, and excreted, but the onset of capacity-limited changes in metabolism occurs at lower doses for mice than for rats. Such differences in the disposition of EG may provide important interpretive information to help explain differences observed in developmental toxicity and nephrotoxic responses between these two rodent species.