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National Toxicology Program. 15th Report on Carcinogens [Internet]. Research Triangle Park (NC): National Toxicology Program; 2021 Dec 21.

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Methyleugenol

CAS No. 93-15-2

Reasonably anticipated to be a human carcinogen

First listed in the Tenth Report on Carcinogens (2002)

Figure 1

Figure 1

Chemical Structure of Methyleugenol

Carcinogenicity

Methyleugenol is reasonably anticipated to be a human carcinogen based on sufficient evidence of carcinogenicity from studies in experimental animals.

Cancer Studies in Experimental Animals

Oral exposure to methyleugenol caused tumors in two rodent species and at several different tissue sites. Methyleugenol administered by stomach tube caused benign or malignant liver tumors (hepatocellular adenoma or carcinoma) in rats and mice of both sexes. In rats, methyleugenol also caused benign or malignant stomach tumors (neuroendocrine tumors) in both sexes and tumors of the kidney (renal-tubule adenoma), mammary gland (fibroadenoma), and skin (fibroma or fibrosarcoma) in males. Malignant neuroendocrine tumors of the stomach in male mice also were considered to be related to methyleugenol exposure (NTP 2000). Earlier studies found that methyleugenol and two structurally related allylbenzenes, safrole and estragole, caused liver tumors in mice when administered by intraperitoneal injection (IARC 1976; Miller et al. 1983). Safrole is listed in the Report on Carcinogens as reasonably anticipated to be a human carcinogen and by the International Agency for Research on Cancer as possibly carcinogenic to humans.

Studies on Mechanisms of Carcinogenesis

Mechanistic studies indicate that liver tumors induced by methyleugenol and structurally related allylbenzenes result from metabolism of these compounds to DNA-reactive intermediates. Methyleugenol may be bioactivated by three different pathways: (1) hydroxylation at the 1′ position of the allylic side chain to yield 1′-hydroxymethyleugenol, followed by sulfation of this intermediate to form 1′-hydroxymethyleugenol sulfate, (2) oxidation of the 2′,3′-double bond of the allylic side chain to form methyleugenol-2,3-oxide, and (3) O-demethylation followed by spontaneous rearrangement to form eugenol quinone methide. Formation of protein adducts and DNA adducts in the livers of animals (and in cultured human hepatocytes) exposed to allylbenzenes and induction of liver tumors by these compounds in animals have been attributed to activation via the hydroxylation pathway, because similar effects were produced by the 1′-hydroxy metabolites and because these effects were inhibited by pretreatment with sulfotransferase inhibitors (Boberg et al. 1983; Gardner et al. 1996; Miller et al. 1983; NTP 2000; Randerath et al. 1984).

Methyleugenol, safrole, and estragole caused unscheduled DNA synthesis in rat hepatocytes, and their corresponding 1′-hydroxy metabolites were more potent genotoxic agents than were the parent compounds (Chan and Caldwell 1992; Howes et al. 1990). Methyleugenol caused morphological transformation of Syrian hamster embryo cells (Kerckaert et al. 1996), sister chromatid exchange in Chinese hamster ovary (CHO) cells (NTP 2000), intrachromosomal recombination in yeast (Schiestl et al. 1989), and DNA repair in Bacillus subtilis (Sekizawa and Shibamoto 1982). It did not cause mutations in Salmonella typhimurium (NTP 2000) or Escherichia coli (Sekizawa and Shibamoto 1982), chromosomal aberrations in CHO cells (NTP 2000), or micronucleus formation in the peripheral-blood erythrocytes of mice (NTP 2000). A higher frequency of β-catenin mutations was observed in liver tumors from mice exposed to methyleugenol than in spontaneous liver tumors from unexposed mice (Devereux et al. 1999). Methyleugenol’s lack of mutagenicity in bacteria may be due to the need for sulfation in the metabolic activation of methyleugenol to its ultimate mutagenic or carcinogenic form.

Cancer Studies in Humans

No epidemiological studies were identified that evaluated the relationship between human cancer and exposure specifically to methyleugenol.

Properties

Methyleugenol is an allyl-chain-substituted guaiacol that structurally resembles safrole (NTP 2000). It is a colorless to pale yellow, oily liquid with an odor of cloves and carnations. It is insoluble in water, glycol, and propylene glycol and soluble in ethanol, ethyl ether, chloroform, and many other organic solvents. Methyleugenol is unstable at room temperature; it darkens and thickens when exposed to air and readily evaporates at room temperature (NTP 2000). Physical and chemical properties of methyleugenol are listed in Table 1.

Table 1. Properties of Methyleugenol.

Table 1

Properties of Methyleugenol.

Use

Methyleugenol is used in fragrances and as a flavoring agent in jellies, baked goods, nonalcoholic beverages, chewing gum, candy, pudding, relish, and ice cream. It is also used as an insect attractant in combination with insecticides and has been used as an anesthetic in rodents (HSDB 2009; NTP 2000).

Production

Annual production of methyleugenol in the United States in 1990 was estimated at 25,000 lb (NTP 2000). No data on current methyleugenol production or on U.S. imports or exports of methyleugenol were found.

Exposure

The general population may be exposed to methyleugenol through ingestion of foods or inhalation of fragrances containing the compound (HSDB 2009). Methyleugenol is a naturally occurring substance, present in many essential oils, including the oils of rose, pimento, basil, hyacinth, citronella, anise, nutmeg, mace, cinnamon leaves, pixuri seeds, and laurel fruits and leaves. It has also been found in blackberry essence, bananas, black pepper, and bilberries (NTP 2000). Methyleugenol is used in commercial products as a flavorant at concentrations of 5 to 52 ppm and in fragrances at concentrations of 0.002% to 0.3% (HSDB 2009). In a subset of serum samples from adults participating in the third National Health and Nutrition Examination Survey, methyleugenol was detected in 98% of the 206 samples analyzed. The average methyleugenol concentration was 24 pg/g, and the highest concentration was 390 pg/g (Barr et al. 2000). Daily per-capita consumption of methyleugenol in food was estimated by the World Health Organization to be 0.073 mg (WHO 1981) and, more recently, 0.26 mg/kg of body weight (NAS 1989; Strofberg and Grundschober 1987).

Although methyleugenol has been identified in various natural substances, no quantitative studies were found that assessed environmental (nondietary) exposure to methyleugenol. In air, methyleugenol exists as a vapor; it reacts with photochemically produced hydroxyl radicals and degrades with an estimated half-life of 5 hours (HSDB 2009). Methyleugenol has been detected in wastewater effluent from a paper mill (NTP 2000).

Occupational exposure to methyleugenol may occur through dermal contact, inhalation, and ingestion. The National Occupational Exposure Survey (conducted from 1981 to 1983) estimated that 12,682 workers, including 9,413 women, potentially were exposed to methyleugenol (NIOSH 1990).

Regulations

Environmental Protection Agency (EPA)

Emergency Planning and Community Right-to-Know Act

Toxics Release Inventory: Listed substance subject to reporting requirements.

References

  1. Barr DB, Barr JR, Bailey SL, Lapeza CR Jr, Beeson MD, Caudill SP, Maggio VL, Schecter A, Masten SA, Lucier GW, et al. 2000. Levels of methyleugenol in a subset of adults in the general U.S. population as determined by high resolution mass spectrometry. Environ Health Perspect. 108(4):323–328. 10.1289/ehp.00108323 [PMC free article: PMC1638031] [PubMed: 10753090] [CrossRef]
  2. Boberg EW, Miller EC, Miller JA, Poland A, Liem A. 1983. Strong evidence from studies with brachymorphic mice and pentachlorophenol that 1′-sulfooxysafrole is the major ultimate electrophilic and carcinogenic metabolite of 1′-hydroxysafrole in mouse liver. Cancer Res. 43(11):5163–5173. [PubMed: 6577945]
  3. Chan VS, Caldwell J. 1992. Comparative induction of unscheduled DNA synthesis in cultured rat hepatocytes by allylbenzenes and their 1′-hydroxy metabolites. Food Chem Toxicol. 30(10):831–836. 10.1016/0278-6915(92)90047-O [PubMed: 1427504] [CrossRef]
  4. ChemIDplus. 2009. ChemIDplus Advanced. Bethesda, MD: National Library of Medicine; http://chem​.sis.nlm.nih​.gov/chemidplus/chemidheavy.jsp and select Registry Number and search on CAS number.
  5. Devereux TR, Anna CH, Foley JF, White CM, Sills RC, Barrett JC. 1999. Mutation of beta-catenin is an early event in chemically induced mouse hepatocellular carcinogenesis. Oncogene. 18(33):4726–4733. 10.1038/sj.onc.1202858 [PubMed: 10467420] [CrossRef]
  6. Gardner I, Bergin P, Stening P, Kenna JG, Caldwell J. 1996. Immunochemical detection of covalently modified protein adducts in livers of rats treated with methyleugenol. Chem Res Toxicol. 9(4):713–721. 10.1021/tx950211v [PubMed: 8831815] [CrossRef]
  7. Howes AJ, Chan VS, Caldwell J. 1990. Structure-specificity of the genotoxicity of some naturally occurring alkenylbenzenes determined by the unscheduled DNA synthesis assay in rat hepatocytes. Food Chem Toxicol. 28(8):537–542. 10.1016/0278-6915(90)90152-D [PubMed: 2242826] [CrossRef]
  8. HSDB. 2009. Hazardous Substances Data Bank. Bethesda, MD: National Library of Medicine; http://toxnet​.nlm.nih​.gov/cgi-bin/sis/htmlgen?HSDB and search on CAS number.
  9. IARC. 1976. Safrole, isosafrole and dihydrosafrole. In Some Naturally Occurring Substances. IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Humans, vol. 10. Lyon, France: International Agency for Research on Cancer. pp. 231–244. [PubMed: 186386]
  10. Kerckaert GA, Brauninger R, LeBoeuf RA, Isfort RJ. 1996. Use of the Syrian hamster embryo cell transformation assay for carcinogenicity prediction of chemicals currently being tested by the National Toxicology Program in rodent bioassays. Environ Health Perspect. 104 Suppl 5:1075–1084. 10.1289/ehp.96104s51075 [PMC free article: PMC1469685] [PubMed: 8933057] [CrossRef]
  11. Miller EC, Swanson AB, Phillips DH, Fletcher TL, Liem A, Miller JA. 1983. Structure-activity studies of the carcinogenicities in the mouse and rat of some naturally occurring and synthetic alkenylbenzene derivatives related to safrole and estragole. Cancer Res. 43(3):1124–1134. [PubMed: 6825084]
  12. NAS. 1989. Poundage and Technical Effects Update of Substances Added to Food. Washington, DC: National Academy of Sciences.
  13. NIOSH. 1990. National Occupational Exposure Survey (1981-83). Washington, DC: National Institute for Occupational Safety and Health; https://www​.cdc.gov/noes/noes1/04500sic​.html
  14. NTP. 2000. Toxicology and Carcinogenesis Studies of Methyleugenol (CAS NO. 93-15-2) in F344/N Rats and B6C3F1 Mice (Gavage Studies). Research Triangle Park, NC: National Toxicology Program. NTP Technical Report Series no. 491. [PubMed: 12563349]
  15. Randerath K, Haglund RE, Phillips DH, Reddy MV. 1984. 32P-post-labelling analysis of DNA adducts formed in the livers of animals treated with safrole, estragole and other naturally-occurring alkenylbenzenes. I. Adult female CD-1 mice. Carcinogenesis. 5(12):1613–1622. 10.1093/carcin/5.12.1613 [PubMed: 6499112] [CrossRef]
  16. Schiestl RH, Chan WS, Gietz RD, Mehta RD, Hastings PJ. 1989. Safrole, eugenol and methyleugenol induce intrachromosomal recombination in yeast. Mutat Res. 224(4):427–436. 10.1016/0165-1218(89)90067-0 [PubMed: 2685589] [CrossRef]
  17. Sekizawa J, Shibamoto T. 1982. Genotoxicity of safrole-related chemicals in microbial test systems. Mutat Res. 101(2):127–140. 10.1016/0165-1218(82)90003-9 [PubMed: 6808388] [CrossRef]
  18. Strofberg J, Grundschober F. 1987. Consumption ratio and food predominance of flavoring materials. Perfum Flavor. 12:27–56.
  19. WHO. 1981. Evaluation of Certain Food Additives and Contaminants. Twenty-sixth Report of the Joint FAO/WHO Expert Committee on Food Additives. Geneva, Switzerland: World Health Organization. Technical Report Series no. 669. [PubMed: 9385867]
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This is a work of the US government and distributed under the terms of the Public Domain

Bookshelf ID: NBK590859
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