Ethyl acrylate distribution, macromolecular binding, excretion, and metabolism in male Fisher 344 rats.
We have demonstrated previously that ethyl acrylate causes severe acute forestomach (nonglandular portion of the stomach) toxicity in rats. Ethyl acrylate was also shown to cause forestomach tumors when administered to rats chronically by gavage. The current studies were designed to investigate ethyl acrylate distribution, excretion, and metabolism, as well as the macromolecular interactions of ethyl acrylate (EtAc) in the forestomach (target organ) and liver (nontarget organ). 2,3-[14C]Ethyl acrylate was administered in corn oil at 100, 200, or 400 mg/kg by gavage. Data presented here show that the radioactivity derived from EtAc is rapidly absorbed after gavage administration and distributed into all major tissues of male F344 rats. The highest concentration of EtAc-derived radioactivity was detected in the forestomach, glandular stomach, intestine, liver, and kidney at 4 and 24 hr after dosing. The highest percentage of EtAc-derived radioactivity was found in the lipid fraction of the liver. In the forestomach, the highest percentage of EtAc-derived radioactivity was found in the protein fraction. The major route of EtAc excretion was CO2 exhalation (approximately 70% of the administered dose in 24 hr) followed by the urinary excretion. Two metabolites were identified in the urine, namely, N-acetyl-s-(2-carboxyethyl)cysteine and N-acetyl-s-(2-carboxyethyl) cysteine ethyl ester. This suggests that Michael-like addition of sulfhydryls to acrylate is a pathway of EtAc metabolism. Hydrolysis of the ethyl ester may occur before or after conjugation. Further degradation of the GSH conjugates resulted in the formation of the mercapturic acids detected in the urine of EtAc-treated rats.
National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.
B I
BI
Ghanayem
L T
LT
Burka
H B
HB
Matthews
D000179:Acrylates / Q000378:metabolism*; D000818:Animals; D001711:Biotransformation; D005753:Gastric Mucosa / Q000378:metabolism; D007408:Intestinal Absorption; D008099:Liver / Q000378:metabolism; D008297:Male; D011485:Protein Binding; D051381:Rats; D011916:Rats, Inbred F344; D014018:Tissue Distribution
D000179:Acrylates; C040833:ethyl acrylate