Toxicokinetics of 1,2-dibromo-3-chloropropane (DBCP) in the rat.

The objective of this study was to determine the kinetics of absorption, distribution, and elimination of DBCP after intravenous (iv) administration in plasma, and after oral administration in water or corn oil, to conscious, fed, male Fischer 344 rats. Rats were prepared with an external jugular vein cannula and were dosed with 0.1, 1, or 10 mg/kg DBCP into the penile sinus or orally as a solution in water or in corn oil (1 mg/kg only). Blood was sampled at various times up to 12 hr, concentrations of DBCP were determined by gas chromatography, and data were evaluated by classical pharmacokinetic techniques. After oral administration in water, absorption of DBCP was rapid, and the distribution and elimination phase was biexponential. There did not appear to be any saturation of DBCP absorption, distribution, or elimination at the high oral or iv dose. After oral administration of DBCP in a corn oil vehicle, absorption was prolonged, suggesting retention of DBCP in the stomach; this could contribute to the toxic effects of DBCP on the forestomach when chronically administered in corn oil. The areas under the blood concentration/time curve were similar regardless of vehicle, suggesting that systemic toxicity might be independent of the vehicle.

Evidence that epichlorohydrin is not a toxic metabolite of 1,2-dibromo-3-chloropropane.

The major urinary metabolite of 14C-epichlorohydrin, after oral administration to rats, was identified previously (Gingell et al. 1985) to be N-acetyl-S-(3-chloro-2-hydroxypropyl)-L-cysteine (ACPC) at 36% of the administered dose. In a similar study reported here, 1,2-dibromo-3-chloropropane (DBCP) was metabolized to at least 20 radioactive urinary metabolites. ACPC was only a minor metabolite (4%) of DBCP. Epichlorohydrin was metabolized in vitro by rat liver microsomes to alpha-chlorohydrin, but DBCP was not metabolized to epichlorohydrin or alpha-chlorohydrin under similar conditions. Covalent binding of radioactivity to liver microsomal proteins occurred for both substrates, but was less for 14C-epichlorohydrin than for 14C-DBCP. Addition of 3,3,3-trichloropropylene oxide, an inhibitor of epoxide hydrolase, increased the extent of protein binding of epichlorohydrin, but decreased the amount of 14C-DBCP which was bound. The data indicate the epichlorohydrin is not a significant in vivo nor in vitro metabolite of DBCP in the rat, and is unlikely to be responsible for the toxicity of DBCP.

Disposition and metabolism of [2-14C]epichlorohydrin after oral administration to rats.

A comprehensive disposition and metabolism study of epichlorohydrin (ECH) has not been previously reported. In this study, male Fischer 344 rats were dosed (6 mg/kg) orally with [2-14C]ECH (98% radiochemically pure) as an aqueous solution and killed after 3 days. Approximately 38% of the radioactive dose was exhaled as CO2, 50% was excreted as metabolites in the urine, and 3% was present in the feces. Radioactivity in tissues accounted for the remainder of the administered dose. When expressed per gram of tissue, radioactivity was highest in liver, kidney, and forestomach. The half-life of initial elimination of radioactivity in both the urine and exhaled air was about 2 hr, indicating that ECH was rapidly absorbed and metabolized. The major metabolites in the urine were identified as N-acetyl-S-(3-chloro-2-hydroxypropyl)-L-cysteine and alpha-chlorohydrin, about 36 and 4% of the administered dose, respectively. Finding these metabolites, which have not been previously reported, is consistent with the initial metabolic reactions being conjugation of the epoxide with glutathione and hydration of the epoxide.