The effect of (R,S)-ornidazole on the fertility of male mice and the excretion and metabolism of 36Cl-(R,S)-ornidazole and 36Cl-(R,S)-alpha-chlorohydrin in male mice and rats.

(R,S)-Ornidazole, an effective antifertility agent for male rats at 400 mg/kg/day, was ineffective at this dose in male mice and at 1000 mg/kg/day caused neural effects. The compound was not excreted unchanged and more polar metabolites and Cl- were detected in 0-8 h urine following a single injection (400 mg/kg). In 8-24 h urine even these metabolites and most Cl ion were absent, indicating rapid metabolism of ornidazole. There was no organ specific accumulation of 36Cl-(R,S)-ornidazole in murine tissues. After injection of 36Cl-(R,S)-alpha-chlorohydrin, another antifertility agent in the rat but not the mouse, there was also no tissue-specific accumulation of radioactivity in the reproductive tract of either species. Urinary excretion rates of alpha-chlorohydrin were twice as rapid in mice as in rats. In mice, alpha-chlorohydrin was the major urinary metabolite, but in the rat metabolites included Cl-, 3-chlorolactate (BCLA) at 5 and 10 h and BCLA only at 24 h. BCLA was the major metabolite detected in most tissues at 10 and 24 h. In the rat cauda (but not caput) epididymidis the glycolytic inhibitor 3-chlorolactaldehyde was present at 5 h (but not 10 h), indicative of early metabolism. These results demonstrate a greater metabolism and excretion of putative antifertility agents in the mouse than the rat, lowering the amount of effective inhibitor circulating in the animal, which may explain why (R,S)-alpha-chlorohydrin and (R,S)-ornidazole are ineffective in this species at the dosages and injection times used, despite their spermatozoa being sensitive to inhibition by (R,S)-alpha-chlorohydrin in vitro.

Identification and quantitative determination of 3-chloro-2-hydroxypropylmercapturic acid and alpha-chlorohydrin in urine of rats treated with epichlorohydrin.

Epichlorohydrin (ECH) is used in many industrial processes. Different toxic effects of ECH were found in rodents. The metabolism of ECH was investigated before in rats using [14C]ECH. The aim of this investigation was the development of non-radioactive quantitative analytical methods for measuring two urinary metabolites of ECH, namely 3-chloro-2-hydroxypropylmercapturic acid (CHPMA) and alpha-chlorohydrin (alpha-CH). The identity of CHPMA and alpha-CH excreted in urine of rats treated with 5 to 35 mg/kg ECH was confirmed by GC-MS. The quantitative analysis of CHPMA, involving ethyl acetate extraction from acidified urine and subsequent methylation and analysis by gas chromatography-flame photometric detection (GC-FPD), showed a method limit of detection of 2 micrograms/ml. The analysis of alpha-CH based on ethyl acetate extraction and subsequent analysis by GC-ECD, showed a method limit of detection of 2 micrograms/ml. CHPMA and alpha-CH derivatives could be determined quantitatively down to concentrations of 0.5 and 0.4 micrograms/ml urine, respectively, by selected-ion monitoring GC-MS under EI conditions. Cumulative urinary excretion of CHPMA and alpha-CH by rats treated with ECH were found to be 31 +/- 10 and 1.4 +/- 0.6% (n = 13) of the ECH dose, respectively. For CHPMA, the dose-excretion relationship suggested partially saturated ECH metabolism. For alpha-CH, the doe-excretion relationship was linear. With fractionated urine collection it was found that approximately 74 and 84% of the total cumulative excretion of CHPMA and alpha-CH, respectively, took place within the first 6 h after administration of ECH. From these investigations it is concluded that the GC-FPD and GC-ECD based methods developed are sufficiently sensitive to measure urinary excretion of CHPMA and alpha-CH in urine from rats administered 5 to 35 mg/kg ECH. It is anticipated that the analysis of CHPMA and alpha-CH based on GC-MS may be sufficiently sensitive to investigate urinary excretion from humans occupationally exposed to ECH.

Identification and quantitative analysis of urinary metabolites of dichloropropanols in rats.

Urinary metabolites of dichloropropanols in rats were analyzed by gas chromatography-mass spectrometry (GC/MS). Solutions of dichloropropanols consisting of 1, 3-dichloro-2-propanol (DC2P) and 2, 3-dichloro-1-propanol (DC1P) were diluted in a saline at the concentration of 100 mg/ml, and 0.1 ml of the solutions were subcutaneously injected into male Wistar rats weighing about 160g. The urine samples were collected over a period of 24 hours after the injections. DC2P and DC1P in the urine were extracted with ethylacetate and analyzed by a GC/MS. The derivatization procedure with 4-bromophenylboric acid after acetonitril extraction was applied for the analyses of diols in the urine. By the GC/MS analysis, 3-chloro-1, 2-propanediol (3CPD), 2-chloro-1, 3-propanediol (2CPD) and 1, 2-propanediol (PPD) were identified as the hydroxylated metabolites of dichlorpropanols. Based on the analytical results, the metabolic pathways of dichlorpropanols forming 3CPD and 2CPD, and then hydroxylating to PPD were elucidated.

1,2-Dichloropropane: metabolism and fate in the rat.

1. The metabolism of 1,2-dichloropropane in the rat has been investigated. The major urinary metabolite has been isolated and identified as N-acetyl-S-(2-hydroxypropyl)cysteine. Two minor metabolites of 1,2-dichloropropane have been identified as beta-chlorolactate and N-acetyl-S-(2,3-dihydroxypropyl)cysteine. 2. The fate of 1-chloro-2-hydroxypropane, a proposed intermediate metabolite of 1,2-dichloropropane, has been investigated. Apart from its known urinary metabolite, N-acetyl-S-(2-hydroxypropyl)cysteine, two oxidative metabolites were detected. These were identified as beta-chlorolactaldehyde and beta-chlorolactate. 3. A pathway is proposed for the metabolism and fate of 1,2-dichloropropane in the rat. This accounts for previous observations made for the fate of radioactivity from administration of 1,2-dichloro[1-14C]propane. 4. The microbial and mammalian metabolism of several halogen-containing foreign compounds is discussed.

Analysis of chlormethiazole, ethchlorvynol and trichloroethanol in biological fluids by gas-liquid chromatography as an aid to the diagnosis of acute poisoning.

A simple method has been developed whereby chlormethiazole, ethchlorvynol and trichloroethanol can be simultaneously detected and measured in biological fluids. The procedure is based upon the rapid extraction of a small (50-microliter) sample volume with an equal volume of chloroform containing an internal standard, followed by the gas-liquid chromatographic analysis of this extract. Specimens of blood plasma or serum, urine and gastric contents can be used, and no interference from either endogenous or exogenous sources has been observed. The method is suitable for the measurement of the plasma concentrations of these compounds attained after overdosage.

[Excretion of trichloroethanol and trichloracetic acid in the urine of rats exposed repeatedly to trichlorethylene (author's transl)].

In a single and repeated exposures to trichloroethylene, the behavior of urinary trichlorethanol (TCE) and trichloracetic acid (TCA) in rats was investigated. In the single exposures rats were exposed to 200 ppm of trichlorethylene once for 3 hours, and in the repeated exposures rats were exposed to trichlorethylene at the same concentration for the same hours on 5 successive days. The results obtained were as follows: 1) In rats exposed once most of the urinary TCE was excreted within 24 hours after the beginning of exposure, whereas the urinary excretion of TCA continued for 4 days. 2) In repeated exposures, the urinary excretion of TCE reached a maximal level following the second exposure and remained constant thereafter. In contrast to this, the urinary excretion of TCA increased continuously from the first day to the fifth. 3) The ratio of TCE: TCA showed a decrease from 2.8 in the first day to 1.2 in the fifth day of the repeated exposures.

The metabolism of the male antifertility agent 1-amino-3-chloropropan-2-ol in the rat.

PIP: The metabolism of 1-amino-3-chloropropan-2-o1, a male antifertility agent, in the rat was studied. The agent was found to be metabolized to alpha-chlorohydrin (3-chlor-propane-1,2-diol, III) and metabolites of alpha-chlorohydrin. These properties account for the similar antifertility and renal toxic effects of both compounds.^ieng

Exposure to trichloroethylene II. Metabolites in blood and urine.

Fifteen men were exposed to trichloroethylene (TRI) in three different ways with regard to the concentration of TRI in the air as well as exercise on a bicycle ergometer. The total amount of TRI supplied and taken up by each person was measured. The concentrations of trichloroethanol (TCE) and trichloroacetic acid (TCA) were determined in blood and urine. In spite of large differences in uptake, there were only small differences in the concentration of TCA in blood during the day of exposure. There was a large scatter for the values of TCA in urine within each group. The concentration of TCE in arterial blood increased during exposure. Thereafter the concentrations were almost constant for 2 h and differed among the groups. These results can be interpreted as being due to balanced rates of the formation and elimination of TCE. The levels mentioned were related to the uptake of TRI. The same was found for the rate of excretion of TCE in urine when calculations were made from the morning sample obtained the day after exposure.

[Metabolism of tetrachloroethylene in guinea pigs (author's transl)].

Tetrachloroethylene oxide was chemically prepared from tetrachloroethylene, and the metabolites of the oxide in guinea pigs were analyzed by gaschromatography and Fujiwara reaction. The results obtained are as follows: 1) Trichloroacetic acid appeared in gaschromatogram after injection of tetrachloroethylene oxide, but trichloroethanol did not. 2) The metabolites analyzed by Fujiwara reaction after injection of tetrachloroethylene oxide were composed of large proportion of trichloroacetic acid and small proportion of trichloroethanol. 3) The ratio of trichloroacetic acid to trichloroethanol in the urine in case of tetrachloroethylene oxide was relatively similar to that of tetrachloroethylene. 4) The effects of pH (2.0 and 10.0) and temperature (4 degrees C and 37 degrees C) on the urinary metabolites suggest that the substance equivalent to trichloroethanol by Fujiwara reaction in metabolites may not be a real one. 5) Toxicity of tetrachloroethylene oxide seems to be much higher as compared with that of tetrachloroethylene in consideration of the maximum allowable dose in guinea pigs. 6) It is supposed from our experiments that tetrachloroethylene oxide is an intermediary metabolite of tetrachloroethylene.

Methods for measuring trichloroethanol and trichloroacetic acid in blood and urine after exposure to trichloroethylene.

A description is given of procedures for the analysis of trichloroethanol, conjugated trichloroethanol, and trichloroacetic acid (TCA) in blood and urine. The determination of TCA is effected by measuring its decarboxylation product chloroform. The methods depend on extraction with isooctane and subsequent analysis by gas chromatography.

Determination of trichloroethanol at therapeutic and overdose levels in blood and urine by electron capture gas chromatography.

A specific and sensitive gas chromatographic method for the determination of trichloroethanol, the active metabolite of chloral hydrate, in blood and urine is reported. A simple dilution of the sample with an ethanolic solution of internal standard followed by gas chromatography with electron capture detection is described. The method has been used to determine plasma levels after therapeutic dosing with chloral preparations.