4-Methylimidazole

Last updated

Contents

4-Methylimidazole
4-Methylimidazole.svg
Names
Preferred IUPAC name
4-Methyl-1H-imidazole
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
ECHA InfoCard 100.011.361 OOjs UI icon edit-ltr-progressive.svg
PubChem CID
UNII
  • InChI=1S/C4H6N2/c1-4-2-5-3-6-4/h2-3H,1H3,(H,5,6) Yes check.svgY
    Key: XLSZMDLNRCVEIJ-UHFFFAOYSA-N Yes check.svgY
  • InChI=1/C4H6N2/c1-4-2-5-3-6-4/h2-3H,1H3,(H,5,6)
    Key: XLSZMDLNRCVEIJ-UHFFFAOYAA
  • [nH]1cc(nc1)C
Properties
C4H6N2
Molar mass 82.106 g·mol−1
AppearanceSlightly yellowish solid
Density 1.02 g/cm3
Melting point 46 to 48 °C (115 to 118 °F; 319 to 321 K)
Boiling point 263 °C (505 °F; 536 K)
Hazards
Flash point 157 °C (315 °F; 430 K)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

4-Methylimidazole (4-MeI or 4-MEI) is a heterocyclic organic chemical compound with molecular formula H
3
C
C
3
H
3
N
2
or C
4
H
6
N
2
. It is formally derived from imidazole through replacement of the hydrogen in position 4 by a methyl group. It is a slightly yellowish solid.

4-MeI may be formed in the browning of certain foods through the Maillard reaction between carbohydrates and amino-containing compounds. In particular, it is found in roasted foods, grilled meats, coffee and in types of caramel coloring produced with ammonia-based processes. [1] [2] It may arise also by fermentation.

Preparation and structure

4-MeI may be prepared using the Debus-Radziszewski imidazole synthesis, by reacting methylglyoxal with ammonia and formaldehyde. [3] It may also be prepared by the reaction of hydroxyacetone and formamide in ammonia. [4]

Small energy difference separates 4-methylimidazole from its tautomer 5-methylimidazole. [5]

Safety

Carcinogenicity studies

Concern has arisen about the presence of 4-MeI in caramel color (which is the most-used food and beverage coloring), typically at a concentration between 50 and 700  ppm. [6] Dark beers and common brands of cola drinks may contain more than 100  μg of this compound per 12-ounce serving, i.e. 300ppm. [1]

At very high doses (360  mg/kg of body weight), 4-MeI is a convulsant for rabbits, mice and chicks, and was the likely cause of acute intoxication observed in cattle fed with ammoniated, sugar-containing cattle feed supplements in the 1960s. [6] However, several studies found no ill effect in rats and dogs for the concentrations found in caramel coloring. [6] For an average weighted person (68 kg) to receive a 360 mg/kg dose from consuming dark beer or cola drinks, they would have to consume approximately 244,800 12-oz drinks.[ citation needed ]

A 2007 study by the United States National Toxicology Program (NTP) examined the potential carcinogenicity of 4-MeI in mice and rats. [7]

Regulatory response

The United States Food and Drug Administration has stated that it has "no reason to believe that there is any immediate or short term danger presented by 4-MeI at levels expected in food from the use of caramel coloring". The Agency describes the NTP carcinogenicity study as having been conducted at doses that "far exceed" current estimates of human exposure from the consumption of caramel coloring in foods and soft drinks. The Agency has stated that it is reviewing current exposure levels but does not recommend consumers change their diets based on concerns about 4-MeI. [8] In response to statements by the Center for Science in the Public Interest that levels of 4-MeI in soft drinks "needlessly expose consumers to a chemical that causes cancer", an FDA spokesperson stated "[a] person would have to drink more than a thousand cans of soda in a day to match the doses administered in studies that showed links to cancer in rodents." [9]

The European Food Safety Authority (EFSA) reviewed the safety of caramel colorings in 2011 and revised the previously established Acceptable Daily Intakes for these products for reasons unrelated to 4-MeI exposure. The Administration's review concluded that there is no evidence to show that caramel colors have any adverse effect on human reproduction. The review further concluded that the highest level of 4-MeI that could result from the consumption of foods containing caramel colors are not of concern. [10]

Health Canada has stated that 4-MeI levels found in foods do not represent a risk. [11]

The Hong Kong Centre for Food Safety has stated that based on levels of 4-MeI found in soft drinks, a person would have to consume over 300 cans of soda each day to reach the doses found to cause cancer in the NFT study, after adjusting for a 100-fold uncertainty factor. [12]

In January 2011, California added 4-MeI to its list of probable carcinogens and stipulated 29 μg per day as the "No Significant Risk Level" intake. [13] Studies have found levels of up to 700 μg per liter in cola soft drinks, up to 1450 μg per liter in coffee, and up to 28,030 μg/liter in dark beer. [14]

The non-profit Center for Science in the Public Interest has petitioned the FDA to require the removal of methylimidazole containing caramel colors from soft drinks. [15]

In March 2012, both The Coca-Cola Company and PepsiCo announced they had their caramel color suppliers modify their manufacturing processes to meet the new California standard; as of the announcement, the changes had already been made for beverages sold in California. [16] The recipe is not changing in Europe, so the 4-MeI level will remain the same. [17] [18] Similarly, Pepsi and some Coke lots sold in the states other than California in the United States contain 4-MeI levels considered safe by the FDA and EFSA, but exceeding California standards. [19] In 2016 PepsiCo lost The Pepsi Carcinogen Class Action Lawsuit Stacy Sciortino, et al. v. Pepsico Inc., Case No. 3:14-cv-00478, in the U.S. District Court for the Northern District of California. This affects all PepsiCo products shipped for sale within the United States. [20] [21]

See also

Related Research Articles

<span class="mw-page-title-main">Aspartame</span> Artificial non-saccharide sweetener

Aspartame is an artificial non-saccharide sweetener 200 times sweeter than sucrose and is commonly used as a sugar substitute in foods and beverages. It is a methyl ester of the aspartic acid/phenylalanine dipeptide with brand names NutraSweet, Equal, and Canderel. Aspartame was approved by the US Food and Drug Administration (FDA) in 1974, and then again in 1981, after approval was revoked in 1980.

<span class="mw-page-title-main">Cola</span> Carbonated soft drink

Cola is a carbonated soft drink flavored with vanilla, cinnamon, citrus oils, and other flavorings. Cola became popular worldwide after the American pharmacist John Stith Pemberton invented Coca-Cola, a trademarked brand, in 1886, which was imitated by other manufacturers. Most colas originally contained caffeine from the kola nut, leading to the drink's name, though other sources of caffeine are generally used in modern formulations. The Pemberton cola drink also contained a coca plant extract. His non-alcoholic recipe was inspired by the coca wine of pharmacist Angelo Mariani, created in 1863.

<span class="mw-page-title-main">Stevia</span> Sweetener and sugar substitute

Stevia is a sweet sugar substitute that is about 50 to 300 times sweeter than sugar. It is extracted from the leaves of Stevia rebaudiana, a plant native to areas of Paraguay and Brazil in the southern Amazon rainforest. The active compounds in stevia are steviol glycosides. Stevia is heat-stable, pH-stable, and not fermentable. Humans cannot metabolize the glycosides in stevia, and therefore it has zero calories. Its taste has a slower onset and longer duration than that of sugar, and at high concentrations some of its extracts may have an aftertaste described as licorice-like or bitter. Stevia is used in sugar- and calorie-reduced food and beverage products as an alternative for variants with sugar.

<span class="mw-page-title-main">Sucralose</span> Non-nutritive sweetener

Sucralose is an artificial sweetener and sugar substitute. As the majority of ingested sucralose is not metabolized by the body, it adds no calories. In the European Union, it is also known under the E number E955. It is produced by chlorination of sucrose, selectively replacing three of the hydroxy groups—in the C1 and C6 positions of the fructose portion and the C4 position of the glucose portion—to give a 1,6-dichloro-1,6-dideoxyfructose–4-chloro-4-deoxygalactose disaccharide. Sucralose is about 600 times sweeter than sucrose, three times as sweet as both aspartame and acesulfame potassium, and twice as sweet as sodium saccharin.

<span class="mw-page-title-main">Root beer</span> North American carbonated beverage

Root beer is a sweet North American soft drink traditionally made using the root bark of the sassafras tree Sassafras albidum or the vine of Smilax ornata as the primary flavor. Root beer is typically, but not exclusively, non-alcoholic, caffeine-free, sweet, and carbonated. Like cola, it usually has a thick and foamy head. A common use is to add vanilla ice cream to make a root beer float.

<span class="mw-page-title-main">Butylated hydroxyanisole</span> Chemical compound

Butylated hydroxyanisole (BHA) is a synthetic, waxy, solid petrochemical. Its antioxidant properties have caused it to be widely used as a preservative in food, food packaging, animal feed, cosmetics, pharmaceuticals, rubber, and petroleum products. BHA has been used in food since around 1947.

<span class="mw-page-title-main">Coca-Cola formula</span> Coca-Cola Companys recipe for Coca-Cola syrup

The Coca-Cola Company's formula for Coca-Cola syrup, which bottlers combine with carbonated water to create the company's flagship cola soft drink, is a closely guarded trade secret. Company founder Asa Candler initiated the veil of secrecy that surrounds the formula in 1891 as a publicity, marketing, and intellectual property protection strategy. While several recipes, each purporting to be the authentic formula, have been published, the company maintains that the actual formula remains a secret, known only to a very few select employees.

<span class="mw-page-title-main">Ethyl carbamate</span> Chemical compound

Ethyl carbamate (also called urethane) is an organic compound with the formula CH3CH2OC(O)NH2. It is an ester of carbamic acid and a white solid. Despite its name, it is not a component of polyurethanes. Because it is a carcinogen, it is rarely used, but naturally forms in low quantities in many types of fermented foods and drinks.

<span class="mw-page-title-main">Pepsi One</span> Brand of cola produced by Pepsi

Pepsi One, corporately styled PEPSI ONE, was a sugar-free cola, marketed by PepsiCo in the United States as an alternative to regular Pepsi and Diet Pepsi.

<span class="mw-page-title-main">Brominated vegetable oil</span> Type of vegetable oil used in the soft drinks industry

Brominated vegetable oil (BVO) is a complex mixture of plant-derived triglycerides that have been modified by atoms of the element bromine bonded to the fat molecules. Brominated vegetable oil is used to help emulsify citrus-flavored soft drinks, preventing them from separating during distribution. Brominated vegetable oil has been used by the soft drink industry since 1931, generally at a level of about 8 ppm.

<span class="mw-page-title-main">Diet soda</span> Type of sugar-free or artificially sweetened soda

Diet or light beverages are generally sugar-free, artificially sweetened beverages with few or no calories. They are marketed for diabetics and other people who want to reduce their sugar and/or caloric intake.

<span class="mw-page-title-main">Tab (drink)</span> Diet cola brand

Tab was a diet cola soft drink produced and distributed by The Coca-Cola Company, introduced in 1963 and discontinued in 2020. The company's first diet drink, Tab was popular among some people throughout the 1960s and 1970s as an alternative to Coca-Cola. Several variations were made, including a number of fruit-flavored, root beer, and ginger ale versions. Caffeine-free and clear variations were released in the late 1980s and early 1990s.

<span class="mw-page-title-main">Diet Pepsi</span> Sugar-free, artificially sweetened soda

Diet Pepsi is a diet carbonated cola soft drink produced by PepsiCo, introduced in 1964 as a variant of Pepsi with no sugar. First test marketed in 1963 under the name Patio Diet Cola, it was re-branded as Diet Pepsi the following year, becoming the first diet cola to be distributed on a national scale in the United States. In the 1960s and 1970s, its competition consisted of the Coca-Cola Company's subsequently discontinued Tab. The United States represents the largest single market for Diet Pepsi.

<span class="mw-page-title-main">Erythrosine</span> Iodo-derivative of fluorone used as a pink dye

Erythrosine, also known as Red No. 3, is an organoiodine compound, specifically a derivative of fluorone. It is a pink dye which is primarily used for food coloring. It is the disodium salt of 2,4,5,7-tetraiodofluorescein. Its maximum absorbance is at 530 nm in an aqueous solution, and it is subject to photodegradation.

Benzene in soft drinks is of potential concern due to the carcinogenic nature of the molecule. This contamination is a public health concern and has caused significant outcry among environmental and health advocates. Benzene levels are regulated in drinking water nationally and internationally, and in bottled water in the United States, but only informally in soft drinks. The benzene forms from decarboxylation of the preservative benzoic acid in the presence of ascorbic acid and metal ions that act as catalysts, especially under heat and light. Hot peppers naturally contain vitamin C so the observation about soft drinks applies to pepper sauces containing sodium benzoate, like Texas Pete.

<span class="mw-page-title-main">Caramel color</span> Water soluble food coloring

Caramel color or caramel coloring is a water-soluble food coloring. It is made by heat treatment of carbohydrates (sugars), in general in the presence of acids, alkalis, or salts, in a process called caramelization. It is more fully oxidized than caramel candy, and has an odor of burnt sugar and a somewhat bitter taste. Its color ranges from pale yellow to amber to dark brown.

The artificial sweetener aspartame has been the subject of several controversies since its initial approval by the U.S. Food and Drug Administration (FDA) in 1974. The FDA approval of aspartame was highly contested, beginning with suspicions of its involvement in brain cancer, alleging that the quality of the initial research supporting its safety was inadequate and flawed, and that conflicts of interest marred the 1981 approval of aspartame, previously evaluated by two FDA panels that concluded to keep the approval on hold before further investigation. In 1987, the U.S. Government Accountability Office concluded that the food additive approval process had been followed properly for aspartame. The irregularities fueled a conspiracy theory, which the "Nancy Markle" email hoax circulated, along with claims—counter to the weight of medical evidence—that numerous health conditions are caused by the consumption of aspartame in normal doses.

Patulin is an organic compound classified as a polyketide. It is named after the fungus from which it was isolated, Penicillium patulum. It is a white powder soluble in acidic water and in organic solvents. It is a lactone that is heat-stable, so it is not destroyed by pasteurization or thermal denaturation. However, stability following fermentation is lessened. It is a mycotoxin produced by a variety of molds, in particular, Aspergillus and Penicillium and Byssochlamys. Most commonly found in rotting apples, the amount of patulin in apple products is generally viewed as a measure of the quality of the apples used in production. In addition, patulin has been found in other foods such as grains, fruits, and vegetables. Its presence is highly regulated.

<span class="mw-page-title-main">Microcystin-LR</span> Chemical compound

Microcystin-LR (MC-LR) is a toxin produced by cyanobacteria. It is the most toxic of the microcystins.

<span class="mw-page-title-main">Glycidamide</span> Chemical compound

Glycidamide is an organic compound with the formula H2NC(O)C2H3O. It is a colorless oil. Structurally, it contains adjacent amides and epoxide functional groups. It is a bioactive, potentially toxic or even carcinogenic metabolite of acrylonitrile and acrylamide. It is a chiral molecule.

References

  1. 1 2 Jacobson, Michael F. (2011). "Petition to Bar the Use of Caramel Colorings Produced With Ammonia and Containing the Carcinogens 2-Methylimidazole and 4-Methylimidazole" (PDF). Center for Science in the Public Interest . Retrieved 11 January 2011.
  2. "4MEIfacts_021012.pdf" (PDF). California Office of Environmental Health Hazard Assessment. Archived from the original (PDF) on 4 March 2016.
  3. US 4377696,Fritz Graf,"Preparation of 4-methylimidazoles",issued 1983-03-22, assigned to BASF Aktiengesellschaft
  4. US 4803281,Walter Mesch,"Preparation of 4-methylimidazole",issued 1989-02-07, assigned to BASF Aktiengesellschaft
  5. G.-S. Li, M. F. Ruiz-López, B. Maigret "Ab Initio Study of 4(5)-Methylimidazole in Aqueous Solution" J. Phys. Chem. A, 1997, vol. 101, pp 7885–7892. doi : 10.1021/jp971390n
  6. 1 2 3 World Health Organization (1975) Toxicological evaluation of some food colours, enzymes, flavour enhancers, thickening agents, and certain food additives. Accessed on 2011-01-11.
  7. National Toxicology Program (2007) Toxicology and Carcinogenesis Studies of 4-Methylimidazole (CAS No. 822-36-6) in F344/N Rats and B6C3F1 Mice (Feed Studies) Archived 22 October 2011 at the Wayback Machine . NTP report TR-535. Accessed on 2011-01-11.
  8. "Questions & Answers on Caramel Coloring and 4-MEI". FDA. 3 June 2021.
  9. Armour, Stephanie (5 March 2012). "FDA Skeptical Chemical in Sodas Harm Consumers". Bloomberg.com. Retrieved 15 August 2012.
  10. "EFSA reviews safety of caramel colours". 8 March 2011. Retrieved 8 January 2015.
  11. "Coke changes recipe; Pepsi still contains cancer-causing chemical, U.S. watchdog says" . Retrieved 8 January 2015.
  12. "4-Methylimidazole in Cola Drinks". Hong Kong Centre for Food Safety. Retrieved 8 January 2015.
  13. "Specific Regulatory Levels Posing No Significant Risk: 4-Methylimidazole (4-MEI)". Proposition 65. OEHHA. 7 October 2011. Retrieved 15 August 2012.
  14. monographs.iarc.fr (PDF).
  15. "Center for Science in the Public Interest". 5 March 2012. Retrieved 8 January 2015.
  16. "Coke and Pepsi change recipe to avoid cancer warning". The Guardian. London. Associated Press. 9 March 2012. Retrieved 9 March 2012.
  17. Associated Press in New York (9 March 2012). "Coke and Pepsi change recipe to avoid cancer warning". The Guardian. London. Retrieved 9 March 2012.
  18. "Coke and Pepsi alter recipe to avoid cancer warning". BBC News. 10 March 2012. Retrieved 10 March 2012.
  19. "One Year Later, Pepsi Still Contains Cancer-Causing Food Coloring". Center for Environmental Health. 2 July 2013. Archived from the original on 1 February 2014. Retrieved 28 January 2014.
  20. Tassin, Paul (30 June 2016). "Pepsi Reaches Settlement in Carcinogen Class Action Lawsuit". Top Class Actions LLC. Phoenix, AZ. Retrieved 17 November 2017.
  21. Chen, Edward M. (21 April 2016). "Case 3:14-cv-00478-EMC" (PDF). California Department of Justice, Office of Attorney General. Gibson, Dunn & Crutcher LLP.