COMPARATIVE DISPOSITION OF 2,3-EPOXY-1-PROPANOL (GLYCIDOL) IN RATS FOLLOWING ORAL AND INTRAVENOUS ADMINISTRATION

Glycidol (2,3-epoxy-1-propanol), an industrial chemical, has Been show n to be a reproductive toxicant in short-term studies and a carcinogen in rats and mice in oncogenicity studies. The reproductive toxicity o f glycidol was believed to result from its conversion to alpha-chloroh ydrin by the action of HCl in the stomach. The comparative disposition of glycidol was investigated in rats following oral (po) or intraveno us (iv) administration at doses of 37.5 and 75 mg/kg. These were the d oses used in the National Toxicology Program (NTP) oncogenicity study with glycidol. Approximately 87-92% of the dose was absorbed from the gastrointestinal tract of the rat. [C-14]Glycidol equivalents were eli minated in urine (40-48% or dose in 72 h) feces (5-12%) and exhaled as CO2 (26-32%). Al both doses, 9-12% and 7-8% (estimated) of the dose r emained in tissues at 24 and 72 h following dosing, respectively. In g eneral, the concentrations of glycidol equivalents in tissues were pro portional to the dose. The highest concentrations of radioactivity wer e observed in blood cells, thyroid, liver, kidney, and spleen, and the lowest in adipose tissue, skeletal muscle, and plasma. The pattern of distribution of radioactivity in tissues was similar for both tile iv and po routes. The total recovery oi radioactivity ranged from 87 to 91% of dose. Urinary radioactivity was resolved by high-performance li quid chromatography (HPLC) analysis into 15 metabolites. There were on e major (14-21% of the dose) and four lesser metabolites (each represe nting 2-8%); the others were minor, each representing 1% or less of th e dose. In general, the urinary metabolic profile was similar followin g either iv or po administration at the two doses studied. Previous st udies by other investigators suggested that alpha-chlorohydrin, which was presumably formed from glycidol by the HCl in the stomach, was met abolized and excreted in urine as beta-chlorolactic acid. The results of the present study show that very little, if any, urinary radioactiv ity coeluted with authentic beta-chlorolactic acid following either iv or po administration. Therefore, it is concluded that the conversion of glycidol to alpha-chlorohydrin is quantitatively insignificant. How ever, it may be significant with regard to glycidol reproductive toxic ity. Also, the NTP oncogenicity study with glycidol was carried out wi thin the dose range in which its disposition characteristics were line ar.