The metabolism of p-propylanisole in the rat and mouse and its variation with dose.

We have studied the metabolism of the synthetic flavouring p-propylanisole in rats and mice and investigated the variation in its metabolism with dose. [methoxy-14C]-p-Propylanisole was given to female Wistar albino rats orally and male CD-1 mice ip at doses ranging from 0.05-1500 mg/kg body weight (0.2-20 20 microCi/animal). The urine, faeces and 14CO2 in the expired air were collected. The urinary metabolites were separated by solvent extraction, thin-layer chromatography and high-pressure liquid chromatography, and characterized by mass and nuclear magnetic resonance spectroscopy and comparison with authentic samples. Three major 14C-labelled urinary metabolites were excreted, 1'- and 2'-hydroxy-p-propylanisole and p-methoxyhippuric acid. 14CO2 was eliminated in the expired air, arising from oxidative O-demethylation. The relative quantities of the metabolites varied markedly with dose. The percentage of the dose that was O-demethylated fell as the dose increased and the proportion in the form of urinary metabolites increased. The relative proportions of the major urinary metabolites also changed with dose. In view of the great discrepancy between human exposure to p-propylanisole in foods (about 15 micrograms/day) and the doses used for its toxicological evaluation in animals, these results emphasize the importance of considering dose-dependent metabolism when interpreting the significance for man of animal data obtained at very high doses.