4-Methylimidazole

4-Methylimidazole
IUPAC name 4-Methyl-1H-imidazole 5-Methyl-1H-imidazole
Identifiers
CAS number	822-36-6 Y
PubChem	13195
ChemSpider	12640 Y
ChEBI	CHEBI:40035 N
Jmol-3D images	Image 1
SMILES n1cc(nc1)C
InChI InChI=1S/C4H6N2/c1-4-2-5-3-6-4/h2-3H,1H3,(H,5,6) Y Key: XLSZMDLNRCVEIJ-UHFFFAOYSA-N Y InChI=1/C4H6N2/c1-4-2-5-3-6-4/h2-3H,1H3,(H,5,6) Key: XLSZMDLNRCVEIJ-UHFFFAOYAA
Properties
Molecular formula	C4H6N2
Molar mass	82.10 g mol−1
Appearance	Slightly 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
N (verify) (what is: Y/N?) Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa)
Infobox references

4-Methylimidazole, often abbreviated 4-MEI or 4-MeI, is a heterocyclic organic chemical compound with molecular formula H
3C–C
3H
3N
2 or C
4H
6N
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-Methylimidazole 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-Methylimidazole 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]

Health concerns

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.^[1]

At very high doses (360 mg/kg of body weight), 4-methylimidazole 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] A study even found 4-MEI had an anticarcinogenic effect on rats.^[1][7] It has been claimed, however, that the reduction in tumor rates seen by Chan and others were due to lower body weight rather than a true anticarcinogenic effect.^[1]

A 2007 study by the National Toxicology Program (NTP) found that high doses of 4-MEI were carcinogenic in mice and in female rats.^[8] The same study found no unusual lung tumors in mice and reduced tumors in rats.^[9] Similar effects were observed for the isomer 2-methylimidazole, which is not found in caramel coloring.^[10] Dose-related, statistically significant decreases in multiple tumors were observed in both male and female rats exposed to 4-MEI in the NTP bioassay. 4-MEI was associated with a 25-fold decrease in the incidence of mammary tumors among high-dose females.^[9] NTP noted briefly that the decreases in certain tumors, including mammary tumors, were greater than could be attributed to body weight alone.^[8] Reduced body weight offers a partial explanation for the reduction in tumors, but does not appear to be the primary cause of the decreased tumor incidences, indicating 4-MEI itself may possess an ability to prevent tumor formation.^[9] In response to high 4-MEI levels used in studies, US FDA spokesperson Doug Karas 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.” ^[11]

Based on these studies, caramel coloring of all types are considered safe and are approved by many leading regulatory agencies around the world, such as the European Food Safety Authority (EFSA), the US Food and Drug Administration (FDA) and the Joint FAO/WHO Expert Committee on Food Additives (JECFA) and, most recently, the Brazilian Health Surveillance Agency (ANVISA). The European Union requires class III caramels to contain <200 mg/kg 4-MeI and class IV caramels to contain <250 mg/kg 4-MEI (color adjusted).^[12][13]

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.^[14] This is considerably less than the mean intake of 4-MEI by regular cola drinkers.^[1] The food industry has strongly opposed that decision, as it implies the need for additional warning labels on many products, and it disputes the validity of the NTP study.^[1] According to Dr James Coughlin, a toxicologist who studies animal carcinogens, the risk posed by 4-MEI is even smaller than this government estimate suggests. In order for humans to reach the equivalent of even the lowest cancer-causing dose in mice, a woman would have to drink 37,000 cans (12 oz) a day for the rest of her life, and a man would have to drink 95,000 cans a day. These figures come from a slightly more conservative study of colas done last year that found an average of 130 μg of 4-MEI per can as opposed to the 138 μg found by CSPI.^[15]

In March 2012, both Coca-Cola and Pepsi 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]

In July 2013, the Center for Environmental Health issued a press release claiming that an independent study found little or no 4-MeI in nine out of ten Coke products, but showed high levels of 4-MeI in all ten Pepsi products.^[19] Soon after the report was made public, PepsiCo stated that their soft drinks will have reduced amounts of 4-MeI "by February 2014."^[20]

Review in United States

In January 2014, a consumer review of various beverages in the United States reported measurements of the amounts of 4-MEI found in them.^[21] The study found that Pepsi ONE and Malta Goya contain the chemical in excess of 29 micrograms per can or bottle, with that being California Proposition 65's daily allowed amount for foods without a warning label.^[21] Various other media sources reported the story, noting that the FDA says that there is no reason to believe that the products tested are unsafe but that they are conducting additional safety studies on 4-MEI found in foods and beverages.^[22][23][24]

Pepsi challenged the conclusions of this study because "the average amount of diet soda consumed by those who drink it is approximately 100 [milliliters] per day, or less than a third of a 12 [ounce] can".^[21] Because of this, Pepsi argues, consumers of its beverage would not get 29 micrograms of 4-MEI when drinking them.

See also

• 1-Methylimidazole

References

External links

• Questions & Answers on Caramel Coloring and 4-MEI, presented by the United States FDA
• 4- Methylimidazole at The Periodic Table of Videos (University of Nottingham)