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EC number: 211-765-7 | CAS number: 693-98-1
In the 2-year feeding studies with rats and mice, 2-methylimidazole produced malignant neoplasms of thyroid gland and liver. The relevance of the thyroid gland tumours for humans is questionable; while the induction of hepatocellular neoplasms was marginal. As the substance is not a directly acting mutagen in vivo, a threshold for the tumour induction exists, below which no tumourigenicity occurs.
Two 2-year feeding studies, one with F344/N rats and one with B6C3F1 mice were available for assessment (National Toxicology Program, 2004; Tani et al., 2005; Chan et al., 2008). In the study with rats, groups of 60 male and female rats received the test substance in feed at concentrations 0, 300, 1000 and 3000 ppm (males) and 0, 1000, 2500 and 5000 ppm (females). This corresponded to average daily intakes of 0, 13, 40 and 130 mg/kg bw/day for males and 0, 50, 120 and 230 mg/kg bw/day for females. In the study with mice, dose levels were 0, 625, 1250 and 2500 ppm in diet, which corresponded to the average daily intakes of 0, 75, 150 and 315 mg/kg bw/day for males and 0, 80, 150 and 325 mg/kg bw/day for females.
The detailed results are reported in the section on repeated dose toxicity.
In rats, the incidences of thyroid gland follicular cell adenoma, follicular cell carcinoma and adenoma or carcinoma (combined) in high dose females were significantly greater than those in the controls at 2 years, and the incidences exceeded the historical range in controls. The incidences of thyroid gland follicular cell adenoma or carcinoma (combined) occurred with a positive trend in males, and the incidence in high dose male exceeded the historical control range.
The thyroid hormone data indicated that rats administered 2-methylimidazole developed alterations in thyroid hormone concentrations; serum thyroxine and triiodothyronin concentrations were decreased, and thyroid stimulating hormone levels were increased. In general, the thyroid hormone effects were most pronounced early in the study and ameliorated with time. The results for the tissue enzyme content analyses of these 2-year feed studies indicated that exposure of rats to 2-methylimidazole induced an increase in total hepatic UDP-glucuronosyltransferase at all time points evaluated through 6 months. The thyroid gland weights of high-dose males and mid- and high-dose females were significantly increased at 6 months.
The serum TSH, T4, and T3 data, thyroid gland histopathology, and liver UDP-GT levels suggested enhanced glucuronidation of T4 leading to a decrease in serum T4 and an increase in serum TSH levels. Thyroid tumours observed in rats might result from persistent TSH stimulation of the thyroid gland, causing the thyroid gland cells firstly become hyperplastic and eventually develop into follicular cell adenomas and carcinomas. Whether 2-methylimidazole interacts directly with cellular macromolecules in thyroid gland has not been clarified. Theoretically, 2-methylimidazole may disrupt one or more of the possible steps in the biosynthesis, secretion, and/or metabolism of thyroidal hormones, resulting in thyroid follicular cell neoplasm development. The components of thyroid hormonal synthesis, secretion, and metabolism have not been investigated specifically for effects of 2-methylimidazole except serum UDPGT levels. 2-methylimidazole appears to have similar effects on the thyroid gland of male and female rats although toxicokinetic data showed that male rats metabolize and clear 2-methylimidazole faster than female rats. Furthermore, the data indicated that 2-methylimidazole induction of thyroid follicular cell neoplasm is dose and time dependent: at high dose levels, neoplastic development takes a shorter time, whereas, at lower dose levels, it takes longer.
In the liver, the incidences of hepatocellular adenoma or carcinoma (combined) in the mid- and high-dose exposure groups of males and females exceeded the historical ranges for controls, and the incidences of hepatocellular adenoma in females occurred with a positive trend. The NTP itself considered the hepatocellular adenoma and carcinoma in male and female rats as equivocal findings.
The incidence of preputial gland adenoma or carcinoma (combined) in mid-dose males was significantly increased, but was not considered to be exposure-related since the incidence was within the historical range. Furthermore, there was no exposure concentration-response for these neoplasms and no supportive increases of hyperplastic lesions.
Based on the results of the study, the NOAEL for carcinogenicity was 13 mg/kg bw/day for males and 50 mg/kg bw/day for females, based on the increased incidence of hepatocellular adenoma or carcinoma (combined).
In the study with mice, the incidence of thyroid gland follicular-cell adenoma in male mice exposed to 2,500 ppm 2-methylimidazole was significantly increased; no significantly increased incidence of thyroid-gland follicular cell neoplasm occurred in females.
The incidences of thyroid follicular- cell hypertrophy/hyperplasia were significantly increased in exposed groups of male and female mice at 2 years. Thyroid follicular-cell hypertrophy occurred commonly accompanied by follicular-cell hyperplasia at the 2-year sacrifice, however, in sacrifices at 6 months follicular-cell hyperplasia was seen in males only. Follicular-cell hyperplasia is considered a precursor lesion to follicular-cell adenomas and carcinomas. The male mice apparently were more sensitive to the 2-methylimidazole thyroid carcinogenic effects than female mice. The sensitivity may be related to the difference in metabolism of 2-methylimidazole between the males and females.
In contrast to the results in rat, no consistent changes appeared in circulating T3, T4, or TSH levels in mice at 8 days, 13 weeks, or 6 months. Consistent with these observations was the lack of any significant or consistent change in hepatic UDPGT activities in mice. Possibly, the mechanism accounting for the thyroid-gland follicular-cell neoplastic response in rats was not operative in mice, or the hormone changes in mice were too small to be detected. A combination of increased hepatic clearance and decreased synthesis of T3 and T4 is plausible and attributable to the actions of the substance on the thyroid gland.
The incidences of hepatocellular adenoma occurred with positive trends in males and females; and the incidences in high-dose males and females were significantly increased at 2 years. The incidence of hepatocellular carcinoma was significantly increased in mid-dose males. The incidences of hepatocellular adenoma or carcinoma (combined) were significantly increased and were at the upper end of the historical control range in all exposed groups of males. The incidences of hepatocellular adenoma in high-dose males and females and the incidence of hepatocellular carcinoma in high-dose males exceeded the historical ranges in controls.
Based on the increased incidences of hepatocellular adenoma or carcinoma in all exposed groups of males, the lowest dose level of 75 mg/kg bw/day was considered a LOAEL for male mice. For females, a NOAEL of 150 mg/kg bw/day was set, based on the increased incidence of hepatocellular adenoma at the next dose level.
Hepatocellular neoplasms and thyroid follicular-cell neoplasms often occur together in rodent carcinogenicity studies. For chemicals that produce tumours at both organ sites, microsomal enzyme induction has been suggested to be a mechanistic link that connects the pathogenesis of thyroid follicular tumour with hepatocellular neoplasms. The present study demonstrated that 2-methylimidazole induced increases in liver weights in mice and liver microsomal UDP-GT activity in rats and mice. The increases, however, were not accompanied by changes in liver cytochrome P450, and microsomal enzyme induction alone appears to be insufficient to account for the thyroid and liver neoplasms in these studies.
Carcinogenicity: via oral route (target organ): digestive: liver; glandular: thyroids
Based on increased incidences of thyroid gland follicular cell neoplasms in the NTP study, there was some evidence of carcinogenic activity of 2-methylimidazole in male F344/N rats, and clear evidence of carcinogenic activity in female F344/N rats.
As to the mechanism of carcinogenesis, the results indicate an indirect epigenetic mechanism that is characterized by a disturbance of the hormone levels and by an induction of UDP-glucuronyltransferase which leads to depletion of thyroxine and triiodothyronine and a responsive increase of TSH-level, followed by increased thyroid activity and hyperplasia. The same results had been obtained in the subacute and subchronic studies and thus were confirmed. For substances inducing tumours by epigenetic mechanism usually a threshold exists below which no tumour formation occurs. In addition, rodents are known to be more sensitive to hormonal fluctuations of the thyroid than humans, therefore the relevance of the formation of the thyroid gland tumours for humans is questionable.
This view is supported by the finding that no induction of liver P450-enzymes was seen in the 2-year study. It is therefore deemed unlikely, that phase-I metabolism and direct mechanisms do play a major role.
The incidences of hepatocellular neoplasms were slightly increased in male and female rats and increased in male and female mice. In rats the slight increases in hepatocellular neoplasms were not statistically significant, but the incidences in the highest two exposure groups of males and females exceeded their historical control ranges. These marginal increases may have been related to 2-methylimidazole exposure.
There was some evidence of carcinogenic activity in male B6C3F1 mice based on increased incidences of thyroid gland follicular cell adenoma. There was some evidence of carcinogenic activity in male and female B6C3F1 mice based on increased incidences of hepatocellular adenoma. Nonneoplastic lesions were noted in the thyroid gland, liver, spleen, bone marrow, kidney, epididymis and testes of male mice, and in the thyroid gland and spleen of female mice. The effect on thyroid hormones was less than in rats; however, the induction of liver UDP-glucuronyltransferase was also significantly less in mice compared to rats. The responsive anemia caused many of the changes noted in blood, bone marrow, spleen, and kidney. Splenic hematopoietic cell proliferation that was seen in the subchronic study was confirmed
The B6C3F1 mouse strain used in the bioassay is known for its high spontaneous liver tumour formation.
Available genotoxicity data suggest that 2-methylimidazole is not a directly acting mutagen in vivo, therefore a threshold most likely exists, below which no tumour induction occurs.
According to the EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008, the overall likelihood that a substance poses a carcinogenic hazard in humans needs to be considered. In case of 2-methylimidazole, the relevance of the thyroid gland tumours for humans is questionable; while the induction of hepatocellular neoplasms was marginal. As the substance is not a directly acting mutagen in vivo, a threshold for the tumour induction exists, below which no tumourigenicity occurs. Based on these results, it is concluded that the evidence of carcinogenicity of 2-methylimidazole in humans is not sufficient for placing the substance into Category 1B, and the classification of the substance as Category 2, H351 (suspected of causing cancer) is warranted according to the EU Classification, Labeling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008. According to EU Directive 67/548/EEC the substance should be classified as Category 3, R40 (limited evidence of carcinogenic effect).
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