Effects of dose, strain, and dosing vehicle on methacrylonitrile disposition in rats and identification of a novel-exhaled metabolite.
Methacrylonitrile (MAN), an aliphatic nitrile used in the production of plastics and elastomers, is structurally related to the known animal carcinogen, acrylonitrile. Although MAN has potential to cause significant toxicity, minimal information is available on its toxicity or fate. Current studies were designed to investigate the biological fate of [2-14C]MAN in male F344 rats. Following gavage administration of 115, 11.5, or 1.15 mg MAN/kg in water, male F344 rats were placed in glass metabolism cages and urine, expired air, and feces were collected. Rats were sacrificed at various times, and the concentration of MAN-derived radioactivity in tissues was determined. MAN was rapidly absorbed from the gastrointestinal tract and distributed to all major tissues. After gavage administration of 1.15-115 mg/kg, [2-14C]MAN is primarily eliminated in the expired air. Sixty to 70% of the low and medium doses were exhaled as 14CO2 in 72 hr compared with 25% of the highest dose. Whereas 40% of the high dose was expired as organic volatiles in 72 hr, only 9-12% of the low and medium doses were exhaled as such. It is therefore apparent that saturation of MAN metabolism occurs at the high dose. HPLC analysis of expired organic volatiles from MAN-treated rats showed that it contained two components that were identified as unchanged MAN and acetone. The MAN:acetone ratio was directly proportional to dose and decreased as a function of time. Urinary excretion accounted for 20-30% of all MAN doses within 72 hr after dosing. Investigating the effect of dosing vehicle on MAN disposition in rats revealed that administration of 115 mg MAN/kg in oil resulted in the death of rats within 24 hr after treatment. Furthermore, monitoring the fate of MAN in these rats before death showed that a significantly higher percentage of the dose was eliminated in urine and expired air. Analysis of this expired air also revealed that significantly more acetone and less unchanged MAN were exhaled by these animals. It is apparent that administration of MAN to F344 rats in oil resulted in slower absorption, decreased elimination of unchanged MAN, and increased metabolism to acetone and/or decreased degradation of acetone to CO2. The combination of these effects of an oil vehicle may have contributed to the death of rats by MAN. Comparison of the metabolism and disposition of MAN in F344 and Sprague-Dawley rats showed minor differences between the two strains.(ABSTRACT TRUNCATED AT 400 WORDS)
National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709.
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Ghanayem
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Sanchez
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Burka
D000818:Animals; D004305:Dose-Response Relationship, Drug; D008297:Male; D008689:Methacrylates / Q000008:administration & dosage / Q000493:pharmacokinetics*; D009570:Nitriles / Q000008:administration & dosage / Q000493:pharmacokinetics*; D014677:Pharmaceutical Vehicles; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D014018:Tissue Distribution
D008689:Methacrylates; D009570:Nitriles; D014677:Pharmaceutical Vehicles; C008385:methacrylonitrile