Disposition and metabolism of [ 14C]1,2-dichloropropane following oral and inhalation exposure in Fischer 344 rats

Abstract

The objective of this study was to compare the disposition and metabolism of [ 14C]1,2-dichloropropane ([ 14C]DCP) following oral and inhalation exposure since these two routes are of interest with regards to occupational and accidental exposure. [ 14C]DCP was administered orally to groups of four rats of each sex as a single dose of 1 or 100 mg/kg and as a multiple 1 mg/kg non-radiolabeled dose for 7 days followed by a single 1 mg [ 14C]DCP/kg dose on day 8. In addition, four rats of each sex were exposed to [ 14C]DCP vapors for a 6-h period in a head-only inhalation chamber at target concentrations of 5, 50 and 100 ppm. [ 14C]DCP was readily absorbed, metabolized and excreted after oral or inhalation exposure. For all treatment groups the principal routes of elimination were via the urine (37–65%) and expired air (18–40%). The tissues, carcass, feces and cage wash contained < 11, 9.7 and 3.8% of the dose, respectively. The major urinary metabolites, as a group, from the oral and inhalation exposures were identified as three N-acetylcysteine conjugates of DCP, N- acetyl-S- (2- hydroxypropyl)- L - cysteine , N- acetyl-S-(2- oxopropyl)- L - cysteine and N- acetyl-S-(1- carboxythel)- L - cysteine . The majority (61–87%) of the expired volatile organic material was found to be parent DCP in all samples analyzed. Increasing the dose/concentration of [ 14C]DCP resulted in an increase in the amount of exhaled [ 14C]-volatile organics. The peak DCP blood concentrations (inhalation exposure) were not proportional to dose, indicating a dose-dependency in the blood clearance of DCP. Nonetheless, upon termination of exposure, DCP was rapidly eliminated from the blood. In all treatment groups, following oral and inhalation exposure the majority of the radioactivity was eliminated by 24 h postdosing and no differences were noted between sexes. Therefore, it can be concluded that in the rat the pharmacokinetics and metabolism of [ 14C]DCP are similar regardless of route of exposure or sex.