Comparative metabolism and disposition of acrylonitrile and methacrylonitrile in rats.
Aliphatic nitriles are a class of chemicals used in high volumes in the production of plastics and elastomers, in organic synthesis, and in production of a number of food packaging containers. Toxicity and metabolism of acrylonitrile (AN) are well characterized. On the other hand, minimal information is available on the toxicity or fate of structurally related, methacrylonitrile (MAN). In an attempt to predict the toxicity of MAN, the present studies were designed to compare the disposition of both nitriles in rats. After gavage administration of equimolar doses (0.87 mmol/kg) of 2-14C-MAN or 2-14C-AN to male F344 rats, both chemicals were well absorbed from the GI tract and distributed to all major tissues. However, major differences in the disposition of the two nitriles were observed. While approximately 39% of the administered MAN dose was eliminated as CO2 in 24 h after dosing, only 11% of an equimolar dose of AN was eliminated as such. In addition, 31% of the MAN dose was exhaled as organic volatiles in 24 h compared to less than 2% of an equivalent AN dose. MAN and acetone were identified by HPLC analysis of expired organic volatiles from MAN-treated rats. HPLC analysis showed that AN is the only organic volatile exhaled by AN-treated rats. Urinary excretion of MAN was 22% compared to 67% of an equivalent dose of AN. The major urinary metabolite from AN results from direct conjugation with GSH, whereas the major urinary metabolite from MAN results from conjugation of the epoxide with GSH.(ABSTRACT TRUNCATED AT 250 WORDS)
National Institute of Environmental Health Sciences Experimental Toxicology Branch, Research Triangle Park, North Carolina.
L T
LT
Burka
I M
IM
Sanchez
A E
AE
Ahmed
B I
BI
Ghanayem
D000096:Acetone / Q000378:metabolism; D000181:Acrylonitrile / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity / Q000652:urine; D000284:Administration, Oral; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D004064:Digestive System / Q000378:metabolism; D007408:Intestinal Absorption / Q000187:drug effects; D008168:Lung / Q000378:metabolism; D008297:Male; D008689:Methacrylates / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D009570:Nitriles / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D010634:Phenobarbital / Q000494:pharmacology; D011335:Proadifen / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
D008689:Methacrylates; D009570:Nitriles; C008385:methacrylonitrile; D000096:Acetone; D011335:Proadifen; D000181:Acrylonitrile; D010634:Phenobarbital