The in vivo dermal absorption and metabolism of [4- 14C]coumarin by rats and by human volunteers under simulated conditions of use in fragrances

The disposition and metabolic fate of [4- 14C]coumarin in a 70% aqueous ethanol solution was studied in male Lister Hooded rats after occluded dermal application and in three male volunteers after an exposure designed to simulate that which may be encountered when using an alcohol-based perfumed pro...

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Bibliographic Details
Published in:Food and chemical toxicology 2001-02, Vol.39 (2), p.153-162
Main Authors: Ford, R.A, Hawkins, D.R, Mayo, B.C, Api, A.M
Format: Article
Language:English
Subjects:
Administration, Topical
Adult
Animals
Biological and medical sciences
Biotransformation
Chromatography, High Pressure Liquid
Chromatography, Thin Layer
Coumarin
Coumarins - administration & dosage
Coumarins - pharmacokinetics
Coumarins - urine
Human
Humans
Male
Medical sciences
Middle Aged
Perfume - pharmacokinetics
Plant poisons toxicology
Rat
Rats
Skin Absorption
Solutions
Toxicology
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Summary:The disposition and metabolic fate of [4- 14C]coumarin in a 70% aqueous ethanol solution was studied in male Lister Hooded rats after occluded dermal application and in three male volunteers after an exposure designed to simulate that which may be encountered when using an alcohol-based perfumed product. In both cases, the 6-h exposure was 0.02 mg/cm 2 (rats 0.023 mg/kg and humans 0.77 mg/kg). In both, coumarin was quickly absorbed, distributed and excreted in urine and feces, although fecal excretion of coumarin in humans was only 1% of the applied dose as opposed to 21% in rats. Total absorption was 72% of the applied dose with rats and 60% with humans. Peak plasma radioactivity in both was at 1 h. The mean plasma half-life of coumarin and metabolites was approximately 1.7 h for humans and 5 h for rats. In humans, coumarin was primarily metabolized to and excreted in urine as 7-hydroxycoumarin glucuronide and 7-hydroxycoumarin sulfate. Small amounts of unconjugated 7-hydroxycoumarin and o-hydroxyphenylacetic acid ( o-HPAA) were also excreted. In rats, about twenty metabolites were present, but only o-HPAA was identified. These studies show the rat is a very poor model for humans and toxicity in the rat cannot be extrapolated to humans.
ISSN:0278-6915
1873-6351
DOI:10.1016/S0278-6915(00)00123-X