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

The disposition and metabolic fate of [4-C-14]coumarin in a 70% aqueous eth anol solution was studied in male Lister Hooded rats after occluded dermal application and in three male volunteers after an exposure designed to simu late that which may be encountered when using an alcohol-based perfumed pro duct. In both cases, the 6-h exposure was 0.02 mg/cm(2) (rats 0.023 mg/kg a nd humans 0.77 mg/kg). In both, coumarin was quickly absorbed, distributed and excreted in urine and feces, although fecal excretion of coumarin in hu mans was only 1% of the applied dose as opposed to 21% in rats. Total absor ption was 72% of the applied dose with rats and 60% with humans. Peak plasm a radioactivity in both was at 1 h. The mean plasma half-life of coumarin a nd metabolites was approximately 1.7 h for humans and 5 h for rats. In huma ns, coumarin was primarily metabolized to and excreted in urine as 7-hydrox ycoumarin glucuronide and 7-hydroxycoumarin sulfate. Small amounts of uncon jugated 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. (C) 2001 Elsevier Science Ltd. All rights reserved.