4-Methylimidazole (4-MeI or 4-MEI) is a

heterocyclic A heterocyclic compound or ring structure is a cyclic compound that has atoms of at least two different elements as members of its ring(s). Heterocyclic chemistry is the branch of organic chemistry dealing with the synthesis, properties, and ...

organic

chemical compound A chemical compound is a chemical substance composed of many identical molecules (or molecular entities) containing atoms from more than one chemical element held together by chemical bonds. A molecule consisting of atoms of only one element ...

with

molecular formula In chemistry, a chemical formula is a way of presenting information about the chemical proportions of atoms that constitute a particular chemical compound or molecule, using chemical element symbols, numbers, and sometimes also other symbols, ...

– or . It is formally derived from

imidazole Imidazole (ImH) is an organic compound with the formula C3N2H4. It is a white or colourless solid that is soluble in water, producing a mildly alkaline solution. In chemistry, it is an aromatic heterocycle, classified as a diazole Diazole refers ...

through replacement of the

hydrogen Hydrogen is the chemical element with the symbol H and atomic number 1. Hydrogen is the lightest element. At standard conditions hydrogen is a gas of diatomic molecules having the formula . It is colorless, odorless, tasteless, non-toxic, an ...

in position 4 by a

methyl In organic chemistry, a methyl group is an alkyl derived from methane, containing one carbon atom bonded to three hydrogen atoms, having chemical formula . In formulas, the group is often abbreviated as Me. This hydrocarbon group occurs in many ...

group A group is a number of persons or things that are located, gathered, or classed together. Groups of people * Cultural group, a group whose members share the same cultural identity * Ethnic group, a group whose members share the same ethnic ide ...

. It is a slightly yellowish solid. 4-MeI may be formed in the browning of certain foods through the

Maillard reaction The Maillard reaction ( ; ) is a chemical reaction between amino acids and reducing sugars that gives browned food its distinctive flavor. Seared steaks, fried dumplings, cookies and other kinds of biscuits, breads, toasted marshmallows, and man ...

between

carbohydrate In organic chemistry, a carbohydrate () is a biomolecule consisting of carbon (C), hydrogen (H) and oxygen (O) atoms, usually with a hydrogen–oxygen atom ratio of 2:1 (as in water) and thus with the empirical formula (where ''m'' may or ma ...

s and

amino In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituent s ...

-containing compounds. In particular, it is found in

roasted Roasting is a cooking method that uses dry heat where hot air covers the food, cooking it evenly on all sides with temperatures of at least from an open flame, oven, or other heat source. Roasting can enhance the flavor through caramelization ...

foods, grilled meats, coffee and in types of

caramel color 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 ...

ing produced with

ammonia Ammonia is an inorganic compound of nitrogen and hydrogen with the formula . A stable binary hydride, and the simplest pnictogen hydride, ammonia is a colourless gas with a distinct pungent smell. Biologically, it is a common nitrogenous was ...

-based processes. It may arise also by

fermentation Fermentation is a metabolic process that produces chemical changes in organic substrates through the action of enzymes. In biochemistry, it is narrowly defined as the extraction of energy from carbohydrates in the absence of oxygen. In food ...

Preparation and structure

4-MeI may be prepared using the Debus-Radziszewski imidazole synthesis, by reacting

methylglyoxal Methylglyoxal (MGO) is the organic compound with the formula CH3C(O)CHO. It is a reduced derivative of pyruvic acid. It is a reactive compound that is implicated in the biology of diabetes. Methylglyoxal is produced industrially by degradation ...

with

and

formaldehyde Formaldehyde ( , ) (systematic name methanal) is a naturally occurring organic compound with the formula and structure . The pure compound is a pungent, colourless gas that polymerises spontaneously into paraformaldehyde (refer to section F ...

. It may also be prepared by the reaction of

hydroxyacetone Hydroxyacetone, also known as acetol, is the organic chemical with the formula CH3C(O)CH2OH. It consists of a primary alcohol substituent on acetone. It is an α-hydroxyketone, also called a ketol, and is the simplest hydroxy ketone structure. ...

and

formamide Formamide is an amide derived from formic acid. It is a colorless liquid which is miscible with water and has an ammonia-like odor. It is chemical feedstock for the manufacture of sulfa drugs and other pharmaceuticals, herbicides and pesticide ...

in ammonia. Small energy difference separates 4-methylimidazole from its

tautomer Tautomers () are structural isomers (constitutional isomers) of chemical compounds that readily interconvert. The chemical reaction interconverting the two is called tautomerization. This conversion commonly results from the relocation of a hydr ...

5-methylimidazole.

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.World Health Organization (1975
Toxicological evaluation of some food colours, enzymes, flavour enhancers, thickening agents, and certain food additives
Accessed on 2011-01-11. Dark beers and common brands of

cola drinks Cola is a Carbonation, carbonated soft drink flavored with vanilla, cinnamon, citrus essential oil, oils and other flavorings. Cola became popular worldwide after the American pharmacist John Stith Pemberton invented Coca-Cola, a trademarked bra ...

may contain more than 100 μg of this compound per 12-ounce serving, i.e. 300ppm. At very high doses (360 mg/ kg of body weight), 4-MeI is a

convulsant A convulsant is a drug which induces convulsions and/or epileptic seizures, the opposite of an anticonvulsant. These drugs generally act as stimulants at low doses, but are not used for this purpose due to the risk of convulsions and consequent exc ...

for rabbits, mice and chicks, and was the likely cause of acute intoxication observed in cattle fed with ammoniated, sugar-containing

cattle feed There are different systems of feeding cattle in animal husbandry. For pastured animals, grass is usually the forage that composes the majority of their diet. Cattle reared in feedlots are fed hay supplemented with grain, soy and other ingredi ...

supplements in the 1960s. However, several studies found no ill effect in rats and dogs for the concentrations found in caramel coloring. 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. A 2007 study by the United States

National Toxicology Program The National Toxicology Program (NTP) is an inter-agency program run by the United States Department of Health and Human Services to coordinate, evaluate, and report on toxicology within public agencies. The National Toxicology Program is headqua ...

(NTP) examined the potential carcinogenicity of 4-MeI in mice and rats.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)''
. NTP report TR-535. Accessed on 2011-01-11.

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. 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 " 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." The

European Food Safety Authority The European Food Safety Authority (EFSA) is the agency of the European Union (EU) that provides independent scientific advice and communicates on existing and emerging risks associated with the food chain. EFSA was established in February 2002, ...

(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.

Health Canada Health Canada (HC; french: Santé Canada, SC)Health Canada is the applied title under the Federal Identity Program; the legal title is Department of Health (). is the Structure of the Canadian federal government#Departments, with subsidiary unit ...

has stated that 4-MeI levels found in foods do not represent a risk. 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. In January 2011,

California California is a U.S. state, state in the Western United States, located along the West Coast of the United States, Pacific Coast. With nearly 39.2million residents across a total area of approximately , it is the List of states and territori ...

added 4-MeI to its list of probable carcinogens and stipulated 29 μg per day as the "No Significant Risk Level" intake. Studies have found levels of up to 700 μg per liter in cola soft drinks, up to 2000 μg per liter in coffee, and up to 28,000 μg/liter in dark beer. 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. In March 2012, both

The Coca-Cola Company The Coca-Cola Company is an American multinational beverage corporation founded in 1892, best known as the producer of Coca-Cola. The Coca-Cola Company also manufactures, sells, and markets other non-alcoholic beverage concentrates and syrups, ...

and

PepsiCo PepsiCo, Inc. is an American multinational food, snack, and beverage corporation headquartered in Harrison, New York, in the hamlet of Purchase. PepsiCo's business encompasses all aspects of the food and beverage market. It oversees the manuf ...

announced they had their

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. The recipe is not changing in Europe, so the 4-MeI level will remain the same. 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. 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.

References

External links