Abstract
4-Methylimidazole (4-MI) is formed as a result of the Maillard reaction process, and therefore is found in many foods and beverages. It is also found in soft drinks (i.e., cola) as a by-product in the production of some caramel colors. NTP bioassays revealed clear evidence of lung carcinogenicity of 4-MI in male and female mice, but not in rats and then IARC classified 4-MI as group 2B carcinogen. Genotoxicity studies with 4-MI were negative in the Ames tests and in the erythrocyte micronucleus tests with mice or rats. US California EPA (CEPA) evaluated the testing has not been adequately comprehensive to rule out a genotoxic mode of action; as target tissue of the carcinogenicity of 4-MI was lung, the lung should be used as a source tissue for in vitro metabolic activation system. Thus, CEPA defined the No Significant Risk Level (NSRL) for 10−5 lifetime risk level of cancer by 4-MI as 29 μg/day based on the non-threshold approach. As higher levels of 4-MI than the NSRL were identified in some kinds of cola, health concerns of 4-MI were drawn the attention. On the other hand, other regulatory bodies (e.g., European Food Safety Authority, EFSA) showed no concerns of 4-MI from the use of caramel colors in food. EFSA evaluated 4-MI is not genotoxic, so, non-observed adverse effect level of 4-MI was considered to be 80 mg/kg/day. In this paper, genotoxic assessments of 4-MI in different regulatory bodies are presented and the risk evaluation of 4-MI is discussed based on new genotoxicity data.
Highlights
4-Methylimidazole (4-MI) is formed as a result of the Maillard reaction process, and is found in many foods and beverages
4-Methylimidazole (4-MI) 4-MI (CAS RN 822-36-6) is light yellow crystalline solid. It is used as a chemical intermediate, raw material or component in the manufacture of pharmaceuticals, photographic chemicals, dyes and pigments, agricultural chemicals and rubber. 4-MI is formed as a result of the interaction of ammonia with reducing sugars [1]. It will be found as byproduct in some foods and beverages during the normal cooking process associated with heat and browning. 4-MI forms as a trace impurity during the manufacturing of class III and class IV caramel coloring [3]
Genotoxicity of 4-MI Genotoxicity data on 4-MI is summarized in Table 1. 4MI was negative in bacterial reverse mutation assay with Salmonella typhimurium TA97, TA98, TA100, TA1535, TA1537 or TA1538 up to 10,000 μg/plate in the presence or absence of S9 from rat or hamster liver, or Escherichia coli WP2 uvrA. 4-MI did not induce micronucleated erythrocytes in male or female mice treated by feeding up to 10,000 ppm (3200 or 1900 mg/kg/day, respectively) for 92 days in the peripheral blood micronucleus test. 4-MI was evaluated in bone marrow micronucleus test in male rats or mice treated by intraperitoneal injection up to 100 or 200 mg/kg, respectively
Summary
4-Methylimidazole (4-MI) is formed as a result of the Maillard reaction process, and is found in many foods and beverages. 4-MI was evaluated in bone marrow micronucleus test in male rats or mice treated by intraperitoneal injection (three times once a day) up to 100 or 200 mg/kg, respectively.
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