ABSORPTION, DISPOSITION KINETICS, AND METABOLIC PATHWAYS OF CYCLOHEXENE OXIDE IN THE MALE FISCHER-344 RAT AND FEMALE B6C3F(1) MOUSE

Cyclohexene oxide (CHO) is a monomer intermediate used in the synthesi s of pesticides, pharmaceuticals, and perfumes. Although CHO has a var iety of industrial uses where direct human exposure is possible, very little is known about its fate in the body. Therefore, the objectives of this study were to determine the absorption, distribution, metaboli sm, and excretion of cyclohexene oxide after oral, intravenous, and de rmal exposure in male Fischer 344 rats and female B6C3F(1) mice. After intravenous administration of [C-14]CHO (50 mg/kg), CHO was rapidly d istributed, metabolized, and excreted into the urine. Plasma concentra tions of CHO rapidly declined and were below the limit of detection wi thin 60 min. Average (+/- SD) values for terminal disposition half-lif e, apparent volume of distribution at steady-state, and systemic body clearance were: 19.3 +/- 1.6 min; 0.44 +/- 0.08 liter/kg; and 31.3 +/- 0.5 ml/kg min, respectively, After oral administration of [C-14]CHO (10 and 100 mg/kg), it was found that C-14-equivalents were rapidly e xcreted in the urine of both species, At 48 hr, the majority of the do se (73-93%) was recovered in urine, whereas fecal elimination accounte d for only 2-5% of the dose. At no time after oral administration was parent CHO detected in the blood. However, its primary metabolite cycl ohexane-1,2-diol was present for different lengths of time depending o n the dose. Four metabolites were detected and identified in mouse uri ne by MS: cyclohexane-1,2-diol; cyclohexane-1,2-diol-O-glucuronide; N- acetyl-S-(2-hydroxycyclohexyl)-L-cysteine; and cyclohexane-1,2-diol-O- sulfate. The sulfate conjugate was not present in rat urine. Topical a pplication of [C-14]CHO (60 mg/kg) provided poor absorption in both sp ecies. The majority of C-14-equivalents applied dermally were recovere d from the charcoal skin trap (similar to 90% of the dose). Only 4% of the dose was absorbed, and the major route of elimination was via the urine. To evaluate the toxicity of CHO, animals were given daily dose s of CHO orally and topically for 28 days. No statistically significan t changes in final body weights or relative organ weights were noted i n rats or mice treated orally with CHO up to 100 mg/kg or up to 60 mg/ kg when given topically. Very few lesions were found at necropsy, and none were considered compound related. In conclusion, regardless of ro ute, CHO is rapidly eliminated and excreted into the urine. Furthermor e, after either oral or dermal administration, it is unlikely that CHO reaches the systemic circulation intact due to its rapid metabolism, and is therefore unable to cause toxicity in the whole animal under th e test conditions used in this study.