Conversion of trichloroacetic acid to dichloroacetic acid in biological samples.

Trichloroethylene (TCE) has been identified as an environmental contaminant in groundwater. Trichloroacetic acid (TCA), dichloroacetic acid (DCA), chloral hydrate (CH), trichloroethanol (TCOH), and trichloroethanol glucuronide (TCOG) have been identified as metabolites of TCE. Studies have shown that TCA and DCA are toxicologically significant metabolites that can induce liver tumors in B6C3F1 mice. Methods for the analysis of these metabolites are important for conducting pharmacokinetic studies. In this study, TCA and DCA were derivatized to their methyl esters by dimethyl sulfate under acidic conditions and analyzed by gas chromatography with electron capture detection. In developing a method for esterifying TCA and DCA, the conversion of TCA to DCA was observed in freshly drawn blood upon the addition of acid. After blood was drawn from the animals, the amount of TCA converted to DCA by the addition of acid decreased with time. This conversion could be prevented by freezing blood samples overnight prior to the addition of acid. Further experiments demonstrated that this activity could be restored by the addition of dithionite to inactivate blood samples or the addition of dithionite to methemoglobin prior to the addition of acid. The results reported here show that reduced hemoglobin may be involved in the acid-catalyzed conversion of TCA to DCA.

N-methyl-N'-nitroguanidine: irritation, sensitization, and acute oral toxicity, genotoxicity, and methods for analysis in biological samples.

Currently, N-methyl-N'-nitroguanidine (MNG) is being considered by the U.S. Air Force Armament Laboratory for use in explosive formulations. A mammalian toxicity profile has been performed which includes the analysis of chemical impurities and an assessment of the potential for the metabolism of MNG to 1-methyl-3-nitro-1-nitrosoguanidine (MNNG). Potential in situ gastric conversion of MNG to MNNG is a toxicological concern because MNNG is both mutagenic and carcinogenic. The compound was also evaluated in several bioassays to assess its potential genotoxic activity. The acute oral toxicity was determined in male and female Fischer 344 rats administered a single dose of MNG in corn oil. The maximum suspension of MNG that could be delivered, 1 mg MNG/kg body weight, produced no signs of toxic stress during the 14-day observation period. The primary eye and skin irritation potential of MNG was determined in female New Zealand white rabbits using the Draize technique. MNG produced no irritation to intact skin but did produce mild conjunctival irritation. The response of a single guinea pig to the dermal sensitization evaluation indicated that MNG is a weak sensitizer. The results of three genetic tests indicated that MNG does not interact with genetic material. Gastric contents and feces from treated animals showed no evidence of conversion of MNG to MNNG.