title: Subchronic oral toxicity study on the three flavouring substances: octan-3-ol, 2-methylcrotonic acid and oct-3-yl 2-methylcrotonate in Wistar rats.
abstract: Groups of 10 male and 10 female rats were administered 0, 25, 100 or 400 mg octan-3-ol/kg body weight per day, 77 mg 2-methylcrotonic acid/kg body weight per day or 163 mg oct-3-yl 2-methylcrotonate/kg body weight per day by gavage for 90 days. Relative liver weights of high-dose octan-3-ol males, and males and females dosed with oct-3-yl 2-methylcrotonate were significantly greater than those of the control. In male and female rats dosed with the highest level of octan-3-ol and in male rats dosed with 2-methylcrotonic acid, incidences of bile duct proliferation were increased. In the kidneys of males dosed with mid- and high level of octan-3-ol and oct-3-yl 2-methylcrotonate, tubular karyomegaly and desquamation of tubular epithelial cells were observed. Based on increased liver weight and microscopic evaluation of the liver and kidney, a no-observed-effect level (NOEL) of 25 mg/kg for octan-3-ol in rats was established. The histopathological evaluation of the liver of rats dosed with oct-3-yl 2-methylcrotonate revealed lesions corresponding to the lesions seen in rats dosed mid-dose with octan-3-ol. This observation is in accordance with the general assumption that oct-3-yl 2-methylcrotonate is completely hydrolysed to octan-3-ol and 2-methylcrotonic acid. However, when comparing the liver histopathology of oct-3-yl 2-methylcrotonate and 2-methylcrotonic acid and the kidney lesions of all three substances, conflicting results were seen and the present study does not allow the conclusion to be drawn that oct-3-yl 2-methylcrotonate and structurally-related esters are completely hydrolysed, at least under the conditions of the present study.
authors.affiliation: Danish Veterinary and Food Administration, Institute of Food Safety and Nutrition, Mørkhøj Bygade 19, DK-2860 Søborg, Denmark. rhl@fdir.dk
authors.forename: R H
authors.initials: RH
authors.lastname: Lindecrona
authors.forename: A-M
authors.initials: AM
authors.lastname: Mølck
authors.forename: J
authors.initials: J
authors.lastname: Gry
authors.forename: M
authors.initials: M
authors.lastname: Poulsen
authors.forename: R
authors.initials: R
authors.lastname: Andersen
authors.forename: I
authors.initials: I
authors.lastname: Thorup
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001652:Bile Ducts / Q000187:drug effects / Q000473:pathology; D003437:Crotonates / Q000008:administration & dosage / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005421:Flavoring Agents / Q000008:administration & dosage / Q000633:toxicity*; D045782:Hemiterpenes; D006868:Hydrolysis; D007668:Kidney / Q000187:drug effects / Q000473:pathology*; D008099:Liver / Q000187:drug effects / Q000473:pathology*; D008297:Male; D000442:Octanols / Q000008:administration & dosage / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D003437:Crotonates; D005421:Flavoring Agents; D045782:Hemiterpenes; D000442:Octanols; C473443:oct-3-yl 2-methylcrotonate; C009489:tiglic acid