Disposition of 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5h)-furanone (mx) in b6c3f1 mice and f344 rats.
3-Chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX) is a mutagenic by-product of chlorination of drinking water, particularly where the water contains humic matter. MX has been estimated to account for 50% of the mutagenic activity in some drinking water. A bioassay in rats demonstrated an increased tumor incidence, primarily in liver and thyroid glands. This study was designed to provide disposition/metabolism information in mice to evaluate the necessity of a National Toxicology Program chronic bioassay and to provide data for female rats. Radioactivity was rapidly absorbed and excreted near equally in urine (42-54%) and feces (40-51%) 72 h following oral administration of (14)C-labeled MX at single doses from 0.2 to 20 mg/kg to male and female mice and female rats. A larger percentage (71-73%) of MX-derived radioactivity was excreted in urine after an iv dose (0.2 mg/kg) in both female rats and male mice. Most MX-derived radioactivity was excreted within the first 24 h postdosing. MX was transformed to urinary and biliary metabolites. A major extremely polar urinary metabolite was tentatively identified as 1-hydroxy-1,2,2-ethanetricarboxylic acid. This metabolite is likely transformed from the MX degradation product 2-hydroxy-3-formyl-4-oxo-2-butenoic acid. Oral administration produced highest tissue/blood ratios in the following order: forestomach (>100), glandular stomach, intestine, and kidney. Intravenous administration resulted in high, prolonged levels of radioactivity in blood compared to oral dosing. Therefore, MX disposition appears to be dominated by its chemical reactivity with highest concentrations of radioactivity being found at the site of administration.
Lebetkin
Edward H
EH
Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.
Chen
Ling-Jen
LJ
Burka
Leo T
LT
D000818:Animals; D001646:Bile / Q000378:metabolism; D001711:Biotransformation; D002273:Carcinogens / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D005243:Feces / Q000737:chemistry; D005260:Female; D005663:Furans / Q000493:pharmacokinetics*; D006863:Hydrogen-Ion Concentration; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D051381:Rats; D011916:Rats, Inbred F344; D021241:Spectrometry, Mass, Electrospray Ionization; D013056:Spectrophotometry, Ultraviolet; D014018:Tissue Distribution; D014874:Water Pollutants, Chemical / Q000493:pharmacokinetics*
D002273:Carcinogens; D005663:Furans; D014874:Water Pollutants, Chemical; C054121:3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone