Safety assessment of allylalkoxybenzene derivatives used as flavouring substances - Methyl eugenol and estragole

R. L. Smith, T. B. Adams, J. Doull, V. J. Feron, J. I. Goodman, L. J. Marnett, P. S. Portoghese, W. J. Waddell, B. M. Wagner, A. E. Rogers, J. Caldwell, I. G. Sipes

Research output: Contribution to journalReview articlepeer-review

226 Scopus citations


This publication is the seventh in a series of safety evaluations performed by the Expert Panel of the Flavor and Extract Manufacturers' Association (FEMA). In 1993, the Panel initiated a comprehensive program to re-evaluate the safety of more than 1700 GRAS flavouring substances under conditions of intended use. In this review, scientific data relevant to the safety evaluation of the allylalkoxybenzene derivatives methyl eugenol and estragole is critically evaluated by the FEMA Expert Panel. The hazard determination uses a mechanism-based approach in which production of the hepatotoxic sulfate conjugate of the 1′-hydroxy metabolite is used to interpret the pathological changes observed in different species of laboratory rodents in chronic and subchronic studies. In the risk evaluation, the effect of dose and metabolic activation on the production of the 1′-hydroxy metabolite in humans and laboratory animals is compared to assess the risk to humans from use of methyl eugenol and estragole as naturally occurring components of a traditional diet and as added flavouring substances. Both the qualitative and quantitative aspects of the molecular disposition of methyl eugenol and estragole and their associated toxicological sequelae have been relatively well defined from mammalian studies. Several studies have clearly established that the profiles of metabolism, metabolic activation, and covalent binding are dose dependent and that the relative importance diminishes markedly at low levels of exposure (i.e. these events are not linear with respect to dose). In particular, rodent studies show that these events are minimal probably in the dose range of 1-10 mg/kg body weight, which is approximately 100-1000 times the anticipated human exposure to these substances. For these reasons it is concluded that present exposure to methyl eugenol and estragole resulting from consumption of food, mainly spices and added as such, does not pose a significant cancer risk. Nevertheless, further studies are needed to define both the nature and implications of the dose-response curve in rats at low levels of exposure to methyl eugenol and estragole.

Original languageEnglish (US)
Pages (from-to)851-870
Number of pages20
JournalFood and Chemical Toxicology
Issue number7
StatePublished - 2002


  • Allylalkoxybenzenes
  • Carcinogenicity
  • Dose-related
  • Estragole
  • Generally recognised as safe (GRAS)
  • Hepatotoxicity
  • Methyl eugenol
  • National Toxicology Program


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