Safety assessment of allylalkoxybenzene derivatives used as flavouring substances — methyl eugenol and estragole

Smith, Robert L.; Adams, Timothy B.; Doull, John; Feron, V.J.; Goodman, Jay I.; Marnett, Lawrence J.; Portoghese, Philip S.; Waddell, William J.; Wagner, Bernard M.; Rogers, Adrianne E.; Caldwell, John; Sipes, I. G.

doi:10.1016/s0278-6915(02)00012-1

Cited by 221 publications

(221 citation statements)

References 35 publications

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“…This conclusion is in line with that of Smith et al (2002) who published a safety assessment of allylalkoxybenzene derivatives, including estragole, used as flavouring substances. The Working Group notes that these were qualitative safety assessments.…”

Section: Estragolesupporting

confidence: 90%

ESCO report: Advice on the EFSA guidance document for the safety assessment of botanicals and botanical preparations intended for use as food supplements, based on real case studies

Dusemund¹

2009

EFSA Supporting Publications

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SUMMARYIn June 2008, after an initial public consultation, the Scientific Committee of EFSA published a guidance document for the safety assessment of botanicals and botanical preparations intended for use as ingredients in food supplements. Recommendation was made at the same time to test the proposed approach for safety assessment with a number of examples, and consider amending the Compendia i) of botanicals reported to contain toxic, addictive or psychotropic substances and ii) of botanicals reported to have also a medicinal use.An EFSA Scientific Cooperation (ESCO) Working Group composed of experts identified by the members of the Advisory Forum, and by the Scientific Committee was created to fulfill this request, and advise on the adequacy of the proposed approach for the safety assessment of botanicals and botanical preparations for EFSA and the European Member States" needs. In addition the Working Group was asked to update the Compendia.The ESCO Working Group considered six botanical preparations to test the science-based framework described the guidance document: i) hydroalcoholic extract of dried peel of Citrus aurantium L. ssp. aurantium L., ii) dried green tea extract of Camellia sinensis (L.) Kuntze, iii) dried leaves extract of Ocimum tenuiflorum L., iv) dried fruits water extract of Foeniculum vulgare Mill. ssp. vulgare var. vulgare, v) dried ripe seeds of Linum usitatissimum L., and vi) wheat bran from Triticum aestivum L. These examples were selected in order to address various safety issues, such as misidentification / adulteration, liver toxicity, possible presence of genotoxic and carcinogenic compounds. Based on the experience acquired through the examples, the ESCO Working Group identified a number of possible amendments and additions for the guidance document of the Scientific Committee.

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Section: Estragolesupporting

confidence: 90%

ESCO report: Advice on the EFSA guidance document for the safety assessment of botanicals and botanical preparations intended for use as food supplements, based on real case studies

Dusemund¹

2009

EFSA Supporting Publications

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“…Since EG generates malignant liver tumors in the rat, it is necessary to restrict and to reduce its exposure (European Commission 2001;Rietjens et al 2005;Smith et al 2002). The present study reveals the transformation of harmful EG.…”

mentioning

confidence: 56%

Biotransformation of estragole by the plant cultured cells of Caragana chamlagu

Itoh

Nakamura

Murakami

et al. 2011

Plant Biotechnology

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Estragole (EG) is biosynthesized in herbs including anise, basil, bay, tarragon, fennel and marjoram, and is thought to be a useful biomass for the food and health industries. Moreover, the metabolites from estragole are useful intermediates in organic synthetic chemistry. However, estragole has been transformed only by chemical methods, and no biocatalysts have been reported. In this paper, we report the biotransformation of estragole using the plant cells of Caragana chamlagu gave 4-methoxycinnamaldehyde (MCAL), 4-methoxycinnamyl alcohol (MCA) and 4-methoxybenzaldehyde (MBAL). In addition, we propose a reaction mechanism in the biotransformation of estragole using Caragana chamlagu. Since estragole generates malignant liver tumors in the rat, it is necessary to reduce exposure. The present study reveals the transformation of harmful estragole. Furthermore, we succeeded in biotransforming estragole as biomass using plant cells into useful compounds.

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“…Whereas previous investigations on incubations of liver microsomes treated with 11 as a substrate (Gardner et al, 1997;Smith et al, 2002;Jeurissen et al, 2006) were performed to clarify the formation of the proximate carcinogen 9, no reports dealing with investigations on the metabolism of 1 in liver microsomes are available.…”

Section: Discussionmentioning

confidence: 99%

Metabolism of Methylisoeugenol in Liver Microsomes of Human, Rat, and Bovine Origin

Cartus¹,

Merz²,

Schrenk³

2011

Drug Metab Dispos

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ABSTRACT:Methylisoeugenol (1,2-dimethoxy-4-propenylbenzene, 1) is a minor constituent of essential oils, naturally occurring as a mixture of cis/trans isomers. 1 is a U.S. Food and Drug Administration-approved food additive and has been given "Generally Recognized as Safe" status. Previously, metabolism of 1 has been studied in the rat, revealing mainly nontoxic cinnamoyl derivatives as major metabolites. However, data concerning the possible formation of reactive intermediary metabolites are not available to date. In this study, the oxidative metabolism of 1 was studied using liver microsomes of rat [not induced, rat liver microsomes (RLM); Aroclor1254 induced RLM (ARLM)], bovine, and human (pooled from 150 donors) origin. Incubations of these microsomes with 1 provided phase I metabolites that were separated by high-performance liquid chromatography (HPLC) and identified by NMR and UV-visible spectroscopy and/or liquid chromatography-mass spectrometry. Identity was confirmed by comparison with 1 H NMR spectra of synthesized reference compounds. Formation of metabolites was quantified by HPLC/UV using dihydromethyleugenol (10) synthesized as the internal standard. From incubations of ARLM with 1, seven metabolites could be detected, with 3-hydroxymethylisoeugenol (2), isoeugenol and isochavibetol (3 ؉ 4), and 6-hydroxymethylisoeugenol (5) being the main metabolites. Secondary metabolites derived from 1 were identified as the ␣,␤-unsaturated aldehyde 3-oxomethylisoeugenol (6) and 1,2-dihydroxy-dihydromethylisoeugenol (7). We were surprised to find that formation of allylic 6-hydroxymethyleugenol (8) was observed starting at approximately 30 min after the beginning of incubations with ARLM. HLM did not form ring-hydroxylated metabolites but were most active in the formation of 6 and 7. ARLM incubations displayed the highest turnover rate and broadest metabolic pattern, presumably resulting from an increased expression of cytochrome P450 enzymes. In conclusion, we present a virtually complete pattern of nonconjugated microsomal metabolites of 1 comprising reactive metabolites and suggest the formation of reactive intermediates that need more investigation with respect to their possible adverse properties.

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Safety assessment of allylalkoxybenzene derivatives used as flavouring substances — methyl eugenol and estragole

Cited by 221 publications

References 35 publications

ESCO report: Advice on the EFSA guidance document for the safety assessment of botanicals and botanical preparations intended for use as food supplements, based on real case studies

ESCO report: Advice on the EFSA guidance document for the safety assessment of botanicals and botanical preparations intended for use as food supplements, based on real case studies

Biotransformation of estragole by the plant cultured cells of Caragana chamlagu

Metabolism of Methylisoeugenol in Liver Microsomes of Human, Rat, and Bovine Origin

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