Mechanistic aspects of the metabolism of 1,3-dichloropropene in rats and mice.
1,3-Dichloropropene (DCP) is used in agriculture for the control of nematodes in a variety of food crops. The major routes of metabolism for this halogenated aliphatic compound involve conjugation with glutathione and oxidation to carbon dioxide. An additional, minor route of metabolism proposed for this compound involves epoxidation to the corresponding 1,3-dichloropropene oxide (DCPO). Recent in vivo studies have provided evidence for the formation of DCPO in mice following intraperitoneal (ip) administration of 350-700 mg of DCP/kg, which is equal to, or exceeds, the reported oral LD(50) for this compound in mice [Schneider, M., et al. (1998) Chem. Res. Toxicol. 11, 1137-1144]. The potential for epoxidation of DCP in rats and mice at lower doses administered orally was therefore examined. Following oral administration of 100 mg of DCP/kg of body weight to F344 rats and B(6)C(3)F(1) mice, no DCPO was found in the liver or blood 0-90 min postdosing at a relatively low detection limit (10 ng/g of tissue). Only very low levels of DCPO were seen following ip administration of 100 mg of DCP/kg of body weight in blood of B(6)C(3)F(1) mice. Substantial levels of DCPO were only seen as a metabolite of DCP following ip administration of 700 mg of DCP/kg to B(6)C(3)F(1) or Swiss-Webster mice. Significant nonlinearity of DCP epoxidation was evident following ip administration, with approximately 130-fold less DCPO in mice given 100 vs 700 mg/kg. The time course of DCPO formation could only be followed for 76 min, due to 100% mortality in Swiss-Webster mice at the 700 mg/kg dose level. The formation of measurable DCPO in mice was also accompanied by acute hepatic damage following ip administration of 100 or 700 mg of DCP/kg to mice. In contrast, no evidence of acute toxicity was noted in mice treated with 100 mg/kg via oral gavage. These data suggest that measurable epoxidation of DCP to DCPO, in the rodent, occurs only at relatively high dose levels which result in acute hepatic injury or death. It was concluded that findings of DCPO formation at lethal doses administered via bolus internal injections do not reflect DCPO formation at lower doses administered via the natural portal of entry.
Bartels
M J
MJ
Health and Environmental Research Laboratory, 1803 Building, The Dow Chemical Company, Midland, Michigan 48674, USA. mjbartels@dow.com
Brzak
K A
KA
Mendrala
A L
AL
Stott
W T
WT
D000284:Administration, Oral; D000410:Alanine Transaminase / Q000097:blood; D000498:Allyl Compounds / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004852:Epoxy Compounds / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D005615:Freezing; D008401:Gas Chromatography-Mass Spectrometry; D006843:Hydrocarbons, Chlorinated; D007274:Injections, Intraperitoneal; D007306:Insecticides / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D010084:Oxidation-Reduction; D051381:Rats; D011916:Rats, Inbred F344; D013045:Species Specificity
D000498:Allyl Compounds; D004852:Epoxy Compounds; D006843:Hydrocarbons, Chlorinated; D007306:Insecticides; C036490:2-chloro-3-(chloromethyl)oxirane; C023891:1,3-dichloro-1-propene; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase