Cinnamyl anthranilate is a synthetic food flavouring and fragrance agent, formerly used at very low levels. There is currently some concern over the potential risk to man from its use, since it has been found to cause liver tumours in mice, following the administration of very large doses. This paper reports studies of its disposition and hepatic effects in B6C3F1 mice in relation to dose. Following a single oral dose of 500 mg
cinnamyl anthranilate/kg
body weight to B6C3F1 mice peak plasma levels of unchanged compound were reached in 30 min, and were higher in males than in females. Unchanged
cinnamyl anthranilate in the urine accounted for 0.3-0.4% of the dose.
Anthranilic acid (c. 17%) and
hippuric acid (35%; the major metabolite of
cinnamyl alcohol) were present in the urine, and recoveries of both were higher in females. Groups of male and female B6C3F1 mice were given 0, 10, 100, 1000, 5000, 15,000 and 30,000 ppm
cinnamyl anthranilate in the diet. After 4 days, the diet was removed and urine collected for 24 hr. This contained
cinnamyl anthranilate (more in males) hippuric and
anthranilic acids (more in females) in concentrations that increased with dose. Other animals were given these diets for 19 days and then killed. Relative liver weight and hepatic microsomal
cytochrome P-450 increased with increasing dose above 1000 ppm
cinnamyl anthranilate, more markedly in males than in females although the maximum response (roughly twofold) was very similar in the two sexes. SDS-PAGE examination of the microsomes revealed the induction of a
cytochrome P-450 isozyme of 53.1 kDa, but the
aniline hydroxylase and
p-nitroanisole O-demethylase activities of the 9000 g supernatant of liver were not induced. The data are discussed in terms of their significance for the human safety evaluation of
cinnamyl anthranilate. It is important to note that liver
hypertrophy, microsomal enzyme induction and the excretion of unchanged
cinnamyl anthranilate all have the same dose-threshold for their appearance. This suggests that the hepatic effects of
cinnamyl anthranilate may be mediated by unhydrolysed
cinnamyl anthranilate, which is present only at very high doses due to the saturation of its hydrolysis.