Safety evaluation of certain food additives - ipcs inchem

ALKOXY-SUBSTITUTED ALLYLBENZENES 397
for the performance of a 2-year bioassay, the identification of hazard should be
made only at levels of exposure less than the MTD. Clearly, the MTD was achieved
or exceeded at the three highest dose levels. Therefore, viewed from this
perspective, the methyl eugenol bioassay was compromised by inappropriately high
dose levels that were administered by gavage and that cause significant
hepatotoxicity, gastric damage and malnutrition in both mice and rats. Hepatic
tumours occurred in severely damaged livers, whereas the neuroendocrine tumours
of the glandular stomach were likely to have resulted from endocrine responses to
chronic gastric damage.
At dose levels of methyl eugenol at which hepatic tumours occurred in rats,
non-neoplastic liver changes, such as liver and hepatocyte enlargement, necrosis,
chronic inflammation, periportal fibrosis and nodular or adenomatoid hyperplasia,
were invariably present. Such recurrent liver damage, in particular chronic
inflammation and hyperplasia, undoubtedly altered methyl eugenol metabolism and
may have strongly enhanced the likelihood of DNA damage, fixation of relevant DNA
damage and development of initiated/preneoplastic cells to cancer. Therefore, the
hepatotoxicity induced by high dose levels of methyl eugenol most probably played
a very significant role, if not an essential one, in the formation of the hepatic tumours
in the NTP bioassay. However, if dose levels of methyl eugenol in humans are less
than those needed to induce hepatotoxicity (most probably in the range of 1–10 mg/
kg bw per day), exposure of humans to such non-hepatotoxic levels can be
assumed to be associated with a very low, possibly negligible, cancer risk. The
absence of carcinogenicity and the lack of significant liver toxicity at low doses
(25 and 5 mg/kg bw) in a 2-year dietary study with safrole (Long et al., 1963) provide
evidence that, in all likelihood, a rodent NOAEL can be established for methyl
eugenol and estragole and other alkoxy-substituted allylbenzenes, most probably
at dietary levels providing an intake of 10–20 mg/kg bw per day. Since human
exposure to alkoxy-substituted allylbenzenes, including methyl eugenol, from
consumption of food (0.5–1 mg/day or 0.008–0.017 mg/kg bw per day; see
Appendix 1) is approximately 3 orders of magnitude lower than the NOEL for
hepatotoxic effects in rodents, cancer risk from alkoxy-substituted allylbenzene
(methyl eugenol) exposure can be considered to be negligibly small for humans.
Similar to the liver, neoplastic effects in the glandular stomach must be
evaluated in the context of severe gastric damage. Toxicokinetic studies revealed
rapid absorption of methyl eugenol in rats and mice, with peak plasma levels
obtained within the first 5 min (National Toxicology Program, 2000). The
bioavailability of methyl eugenol administered orally increased in a non-linear
fashion with dose, suggesting saturation of first-pass metabolism or altered
absorption and metabolism owing to gastric and hepatic damage. Introduction of a
bolus dose of test material into the glandular stomach exposes the stomach and
upper intestines to high concentrations of methyl eugenol and leads to higher peak
blood plasma levels and increased metabolic demand compared with the slower,
more steady absorption of the substance from feed. The results of NTP 2-year
bioassays and related toxicokinetic studies (Yuan et al., 1995) in which the test
material was administered by gavage and in the feed (National Toxicology Program,
1986, 1993) have clearly demonstrated that peak plasma levels are significantly
higher in gavage-dosed animals.