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 shown to be a reproductive toxicant in short-term studies and a carcinogen in rats and mice in oncogenicity studies. The reproductive toxicity of glycidol was believed to result from its conversion to alpha-chlorohydrin by the action of HCl in the stomach. The comparative disposition of glycidol was investigated in rats following oral (po) or intravenous (iv) administration at doses of 37.5 and 75 mg/kg. These were the doses 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. [14C]Glycidol equivalents were eliminated in urine (40-48% of dose in 72 h), feces (5-12%), and exhaled as CO2 (26-32%). At both doses, 9-12% and 7-8% (estimated) of the dose remained in tissues at 24 and 72 h following dosing, respectively. In general, the concentrations of glycidol equivalents in tissues were proportional to the dose. The highest concentrations of radioactivity were 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 the iv and po routes. The total recovery of radioactivity ranged from 87 to 91% of dose. Urinary radioactivity was resolved by high-performance liquid chromatography (HPLC) analysis into 15 metabolites. There were one major (14-21% of the dose) and four lesser metabolites (each representing 2-8%); the others were minor, each representing 1% or less of the dose. In general, the urinary metabolic profile was similar following either iv or po administration at the two doses studied. Previous studies by other investigators suggested that alpha-chlorohydrin, which was presumably formed from glycidol by the HCl in the stomach, was metabolized and excreted in urine as beta-chlorolactic acid. The results of the present study show that very little, if any, urinary radioactivity 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. However, it may be significant with regard to glycidol reproductive toxicity. Also, the NTP oncogenicity study with glycidol was carried out within the dose range in which its disposition characteristics were linear.
Nomeir
A A
AA
Arthur D. Little, Inc., Cambridge, Massachusetts.
Silveira
D M
DM
Ferrala
N F
NF
Markham
P M
PM
McComish
M F
MF
Ghanayem
B I
BI
Chadwick
M
M
D000433:1-Propanol / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D000284:Administration, Oral; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004852:Epoxy Compounds / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D007408:Intestinal Absorption; D008297:Male; D020005:Propanols; D051381:Rats; D011916:Rats, Inbred F344; D014018:Tissue Distribution
D004852:Epoxy Compounds; D020005:Propanols; D000433:1-Propanol; C004312:glycidol