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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.
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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
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
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
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
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
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
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
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
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
Carcinogenicity: via oral route (target organ): digestive:
liver; glandular: thyroids
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