A comparative 90-day toxicity study of allyl acetate, allyl alcohol and acrolein.
Allyl acetate (AAC), allyl alcohol (AAL), and acrolein (ACR) are used in the manufacture of detergents, plastics, pharmaceuticals, and chemicals and as agricultural agents. A metabolic relationship exists between these chemicals in which allyl acetate is metabolized to allyl alcohol and subsequently to the highly reactive, alpha,beta-unsaturated aldehyde, acrolein. Due to the weaker reactivity of the protoxicants, allyl acetate and allyl alcohol, relative to acrolien we hypothesized the protoxicants would attain greater systemic exposure and therefore deliver higher doses of acrolein to the internal organs. By extension, the higher systemic exposure to acrolein we hypothesized should lead to more internal organ toxicity in the allyl acetate and allyl alcohol treated animals relative to those treated with acrolein. To address our hypothesis we compared the range of toxicities produced by all three chemicals in male and female Fischer 344/N rats and B6C3F1 mice exposed 5 days a week for 3 months by gavage in 0.5% methylcellulose. Rats (10/group) were dosed with 0-100mg/kg allyl acetate, 0-25mg/kg allyl alcohol, or 0-10mg/kg acrolein. Mice (10/group) were dosed with 0-125mg/kg allyl acetate, 0-50mg/kg allyl alcohol, or 0-20mg/kg acrolein. The highest dose of allyl acetate and acrolein decreased survival in both mice and rats. The primary target organ for the toxicity of all three chemicals in both species and sexes was the forestomach; squamous epithelial hyperplasia was observed following exposure to each chemical. In both species the highest allyl acetate dose group exhibited forestomach epithelium necrosis and hemorrhage and the highest dose of acrolein led to glandular stomach hemorrhage. Liver histopathology was the most apparent with allyl acetate, was also observed with allyl alcohol, but was not observed with acrolein. All chemicals had effects on the hematopoietic system with allyl acetate having the most pronounced effect. When dosed at quantities limited by toxicity, allyl acetate and allyl alcohol produce higher levels of urinary mercapturic acids than the minimally toxic dose of acrolein. This observation is likely due to biotransformation of allyl acetate and ally alcohol to acrolein that occurs after absorption and suggests that these chemicals are protoxicants that increase systemic exposure of acrolein. Increased systemic exposure to acrolein is likely responsible for the differences in hepatic toxicological profile observed with these chemicals.
Auerbach
Scott S
SS
National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, United States. auerbachs@niehs.nih.gov
Mahler
Joel
J
Travlos
Gregory S
GS
Irwin
Richard D
RD
D000085:Acetates / Q000008:administration & dosage / Q000633:toxicity*; D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000652:urine; D000171:Acrolein / Q000008:administration & dosage / Q000633:toxicity*; D000498:Allyl Compounds / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D001772:Blood Cell Count; D005260:Female; D005753:Gastric Mucosa / Q000187:drug effects / Q000473:pathology; D006413:Hematopoietic System / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008221:Lymphoid Tissue / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D020005:Propanols / Q000008:administration & dosage / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344; D013270:Stomach / Q000187:drug effects / Q000473:pathology; D015996:Survival Rate; D018675:Toxicity Tests
D000085:Acetates; D000498:Allyl Compounds; D020005:Propanols; C006463:allyl alcohol; D000171:Acrolein; C001423:S-(3-hydroxypropyl)cysteine N-acetate; C498551:allyl acetate; D000111:Acetylcysteine