1. Home
  2. Proposition 65
  3. Changed Notice of Proposed Rulemaking Specific ...

Changed Notice of Proposed Rulemaking Specific Regulatory Levels Posing No Significant Risk: 4-Methylimidazole (4-MEI)

As required by Government Code section 11346.8(c), and Title 1, Section 44 of the California Code of Regulations, the Office of Environmental Health Hazard Assessment (OEHHA) is providing notice of a change made to the proposed regulation establishing a No Significant Risk Level (NSRL) for 4-MEI (Title 27, California Code of Regulations, section 25705), and augmentation of the record with additional scientific references.  This proposed regulatory action is being taken pursuant to OEHHA’s authority under the Safe Drinking Water and Toxic Enforcement Act of 1986, commonly known as Proposition 65, and codified at Health and Safety Code section 25249.5 et seq. This proposed regulation was originally the subject of a Notice of Proposed Rulemaking published on January 7, 2011, in the California Regulatory Notice Register (Register 2011, No 1-Z), which initiated a public comment period. A Notice Extending the Public Comment Period and Announcement of a Public Hearing was published in the California Regulatory Notice Register on February 18, 2011 (Register 2011, #7-Z), p. 228. A public hearing on this regulatory proposal was held on March 10, 2011.  Written comments from the public were received during the comment period which ended March 24, 2011. 

The proposed NSRL for 4-MEI has been changed to 29 micrograms per day. A copy of the text of the amended proposed regulation is attached.  The new modifications are shown in double-underline and double-strike-out. OEHHA is making available (1) a copy of the text of the amended proposed regulation, and (2) a modified technical support document describing the information that OEHHA relied on in its determination on the revised proposed NSRL. These are available on the OEHHA website at www.oehha.ca.gov, or may be requested from Monet Vela at the OEHHA Legal Office at (916) 323-2517. The public comments received during the prior comment period are available upon request.

OEHHA will accept written comments on these amendments to the proposed regulation between October 7, 2011, and October 24, 2011.  All written comments must be submitted to OEHHA by mail, fax, courier, e-mail, or hand-delivery by no later than 5:00 p.m. on October 24, 2011. Comments should be addressed to:

Fran Kammerer
Office of Environmental Health Hazard Assessment
P. O. Box 4010
1001 I Street
Sacramento, California 95812-4010
Fax No.: 916-324-1786
E-mail: fran.kammerer@oehha.ca.gov

Inquiries concerning the action described in this notice may be directed to Fran Kammerer at the address given above, or by telephone at (916) 445-4693. Monet Vela is a back-up contact person and is available at (916) 323-2517.

OEHHA is augmenting the record to include the following references used in the development of the proposed NSRL for 4-MEI.

Downloads

Footnotes and References

Back DJ, Tjia JF (1985). Inhibition of tolbutamide metabolism by substituted imidazole drugs in vivo: evidence for a structure-activity relationship. Br J Pharmacol 85(1):121-6.

Back DJ, Tjia JF, Karbwang J, Colbert J (1988). In vitro inhibition studies of tolbutamide hydroxylase activity of human liver microsomes by azoles, sulphonamides and quinolines. Br J Clin Pharmacol 26(1):23-9.

Casal S, Fernandes JO, Oliveira MB, Ferreira MA (2002). Gas chromatographic-mass spectrometric quantification of 4-(5-)-methylimidazole in roasted coffee after ion-pair extraction. J Chromatogr A 976(1-2):285-91.

Chan PC, Hill GD, Kissling GE, Nyska A (2008). Toxicity and carcinogenicity studies of 4-methylimidazole in F344/N rats and B6C3F1 mice. Arch Toxicol 82(1):45-53.

Dalvie DK, Kalgutkar AS, Khojasteh-Bakht SC, Obach RS, O'Donnell JP (2002). Biotransformation reactions of five-membered aromatic heterocyclic rings. Chem Res Toxicol 15(3):269-99.

ENVIRON (2011). Evaluation of the Carcinogenicity of 4-Methylimidazole: Development of a No Significant Risk Level. Prepared by ENVIRON Internation Corporation. Principal, Annette M. Shipp, Ph.D. Monroe, Louisiana. Submitted to OEHHA on behalf of the American Beverage Association (Washington, DC) and the International Technical Caramel Association (Washington, DC). March 24, 2011.

European Commission (2000). IUCLID Dataset for 4-methylimidazole. International Uniform Chemical Information Database. A compilation based on data reported by the European Chemicals Industry following 'Council Regulation (EEC) No. 793/93 on the Evaluation and Control of the Risks of Existing Substances'.

Grosse Y, Baan R, Secretan-Lauby B, El Ghissassi F, Bouvard V, Benbrahim-Tallaa L, et al. (2011). Carcinogenicity of chemicals in industrial and consumer products, food contaminants and flavourings, and water chlorination byproducts. Lancet Oncol 12(4):328-9.

Hargreaves MB, Jones BC, Smith DA, Gescher A (1994). Inhibition of p-nitrophenol hydroxylase in rat liver microsomes by small aromatic and heterocyclic molecules. Drug Metab Dispos 22(5):806-10.

Haschek WM, Boyd MR, Hakkinen PJ, Owenby CS, Witschi H (1984). Acute inhalation toxicity of 3-methylfuran in the mouse: pathology, cell kinetics, and respiratory rate effects. Toxicol Appl Pharmacol 72(1):124-33.

Hasegawa R, Ogiso T, Imaida K, Shirai T, Ito N (1995). Analysis of the potential carcinogenicity of coffee and its related compounds in a medium-term liver bioassay of rats. Food Chem Toxicol 33(1):15-20.

Karangwa E, Mitchell GE, Jr., Tucker RE (1990). Pharmacokinetics of 4-methylimidazole in sheep. J Anim Sci 68(10):3277-84.

Kasai H, Kumeno K, Yamaizumi Z, Nishimura S, Nagao M, Fujita Y, et al. (1982). Mutagenicity of methylglyoxal in coffee. Gann 73(5):681-3.

Kim OS, Kim J, Kim CS, Kim NH, Kim JS (2010). KIOM-79 prevents methyglyoxal-induced retinal pericyte apoptosis in vitro and in vivo. J Ethnopharmacol 129(3):285-92.

Klejdus B, Moravcova J, Lojkova L, Vacek J, Kuban V (2006). Solid-phase extraction of 4(5)-methylimidazole (4MeI) and 2-acetyl-4(5)-(1,2,3,4-tetrahydroxybutyl)-imidazole (THI) from foods and beverages with subsequent liquid chromatographic-electrospray mass spectrometric quantification. J Sep Sci 29(3):378-84.

MacKenzie KM, Boysen BG, Field WE, Petsel SR, Chappel CI, Emerson JL, et al. (1992). Toxicity and carcinogenicity studies of Caramel Colour IV in F344 rats and B6C3F1 mice. Food Chem Toxicol 30(5):431-43.

Moon JK, Shibamoto T (2011). Formation of carcinogenic 4(5)-methylimidazole in Maillard reaction systems. J Agric Food Chem 59(2):615-8.

Nagao M, Fujita Y, Sugimura T, Kosuge T (1986). Methylglyoxal in beverages and foods: its mutagenicity and carcinogenicity. IARC Sci Publ(70):283-91.

National Research Council (2009). Science and Decisions: Advancing Risk Assessment.ed. Washington, D.C.: National Academies Press.

Nielsen P, Friis C, Kraul I, Olsen CE (1993). Disposition of 4-methylimidazole in goats and heifers. Res Vet Sci 54(1):72-9.

NTP (2004). National Toxicology Program. Toxicity Studies of 2- and 4-Methylimidazole (CAS No. 693-98-1 and 822-36-6) Administered in Feed to F344/N Rats and B6C3F1 Mice. Toxicity Report Series No. 67. NIH Publication No. 04-4409. U.S. Department of Health and Human Services. Public Health Service. National Institutes of Health.

OEHHA (2009). Office of Environmental Health Hazard Assessment. Air Toxicology and Epidemiology Branch. Technical Support Document for Cancer Potency Factors: Methodologies for Derivation, Listing of Available Values, and Adjustments to Allow for Early Life Stage Exposures. May 2009.

Ohgiya S, Komori M, Ohi H, Shiramatsu K, Shinriki N, Kamataki T (1992). Six-base deletion occurring in messages of human cytochrome P-450 in the CYP2C subfamily results in reduction of tolbutamide hydroxylase activity. Biochem Int 27(6):1073-81.

Ravindranath V, McMenamin MG, Dees JH, Boyd MR (1986). 2-Methylfuran toxicity in rats--role of metabolic activation in vivo. Toxicol Appl Pharmacol 85(1):78-91.

Rehm S, Ward JM, Sass B (1994). Tumours of the lungs. In: Pathology of Tumours in Laboratory Animals. Tumours of the Mouse. IARC Scientific Publications. No. 111. VS Turusov and U Mohr (Eds.). 2nd ed., Vol. 2. Lyon, France: International Agency for Research on Cancer, pp. 325-55.

Reynolds SD, Malkinson AM (2010). Clara cell: progenitor for the bronchiolar epithelium. Int J Biochem Cell Biol 42(1):1-4.

Sells DM, Brix AE, Nyska A, Jokinen MP, Orzech DP, Walker NJ (2007). Respiratory tract lesions in noninhalation studies. Toxicol Pathol 35(1):170-7.

Thornalley PJ, Waris S, Fleming T, Santarius T, Larkin SJ, Winklhofer-Roob BM, et al. (2010). Imidazopurinones are markers of physiological genomic damage linked to DNA instability and glyoxalase 1-associated tumour multidrug resistance. Nucleic Acids Res 38(16):5432-42.

U.S. EPA (1986). U.S. Environmental Protection Agency. Guidelines for Carcinogen Risk Assessment, Risk Assessment Forum, Washington, DC. EPA/630/R-00/004, September 1986.

U.S. EPA (2002). U.S. Enviromental Protection Agency. Health Assessment of 1,3-Butadiene. National Center for Environmental Assessment. Office of Research and Development.Washington, DC. EPA/600/P-98/001F October 2002

U.S. EPA (2005). U.S. Environmental Protection Agency. Guidelines for Carcinogen Risk Assessment. Risk Assessment Forum. Washington, DC. EPA/630/P-03/001B. March 2005.

Voogd CE, van der Stel JJ, Jacobs JJ (1979). The mutagenic action of nitroimidazoles. IV. A comparison of the mutagenic action of several nitroimidazoles and some imidazoles. Mutat Res 66(3):207-21.

Voulgaridou GP, Anestopoulos I, Franco R, Panayiotidis MI, Pappa A (2011). DNA damage induced by endogenous aldehydes: Current state of knowledge. Mutat Res 711(1-2):13-27.

Weems JM, Lamb JG, D'Agostino J, Ding X, Yost GS (2010). Potent mutagenicity of 3-methylindole requires pulmonary cytochrome P450-mediated bioactivation: a comparison to the prototype cigarette smoke mutagens B(a)P and NNK. Chem Res Toxicol 23(11):1682-90.

Wistuba II, Gazdar AF (2006). Lung cancer preneoplasia. Annu Rev Pathol 1:331-48.

Witschi HP, Tryka AF, Mauderly JL, Haschek WM, Satterfield LC, Bowles ND, et al. (1985). Long-term effects of repeated exposure to 3-methylfuran in hamsters and mice. J Toxicol Environ Health 16(3-4):581-92.

Yuan B, Cao H, Jiang Y, Hong H, Wang Y (2008). Efficient and accurate bypass of N2-(1-carboxyethyl)-2'-deoxyguanosine by DinB DNA polymerase in vitro and in vivo. Proc Natl Acad Sci U S A 105(25):8679-84.

Yuan JH, Burka LT (1995). Toxicokinetics of 4-methylimidazole in the male F344 rat. Xenobiotica 25(8):885-94.