Safety evaluation of certain food additives - ipcs inchem

438 ALKOXY-SUBSTITUTED ALLYLBENZENES
3.2 Evaluation of toxicological data
Most of the data in rodents indicate that at relatively high doses, several
alkoxy-substituted allylbenzenes exhibit hepatocarcinogenic potential and DNA
binding in the liver. In addition, neuroendocrine tumours of the stomach were
induced by estragole and methyl eugenol. Current scientific evidence supports a
non-linear relationship between dose and the potential for carcinogenicity of these
substances. The mechanism or mechanisms by which these substances induce
cancer in animals have not been established.
The current database for rodents has a number of limitations that have an
impact on its direct application to human risk assessment, including those listed
below.
3.2.1 Interpretation of carcinogenicity data from studies in which high doses were
administered by gavage
Many of the studies of carcinogenicity after oral administration involved
gavage. Gavage administration of high doses delivered as a bolus coupled with
rapid absorption represents an acute high-level exposure of the liver, the main target
organ. For many other substances, it has been shown that dosing by gavage can
produce metabolic and toxicological effects that do not occur when the same daily
dose is given in the diet.
3.2.2 Nature of the dose–response relationship for hepatocarcinogenicity
Hepatocarcinogenicity in rodents has been reported only at high doses,
usually in excess of the MTD.
At high doses, there is a dose-dependent saturation of the principal pathways
of metabolic detoxication, leading to an increased proportion of the dose undergoing
metabolic activation of the allyl side-chain to the sulfate conjugates of 1-hydroxy
metabolites, which are the putative carcinogenic products. In addition, there is
evidence for auto-induction of CYP-mediated metabolic activation at high doses.
DNA adducts have been quantified in rodents and, in some studies, appear
to occur with a linear dose–response relationship over a wide range of doses, but
the relationship of DNA adducts to hepatocarcinogenesis has not been studied in
detail. Information is lacking on the efficiency of repair of these adducts and on the
dose–response relationship for DNA repair by either rodent or human hepatocytes.
Studies that further investigate the relationship between DNA adduct formation and
toxicity, especially bioindicators of carcinogenicity, would provide valuable
information.
Doses producing hepatotoxicity have the potential to enhance
carcinogenicity by induced liver cell regeneration, which serves to fix DNA damage
as mutations. Studies are needed to investigate bioindicators of neoplasia in
rodents, at doses below and including those that produce hepatotoxicity.