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EC number: 213-234-5
CAS number: 931-36-2
Since it is likely that 2-ethyl-4-methylimidazole will be absorbed and
in the absence of substance-specific absorption data, the default
absorption values from the REACH guidance (Chapter 8, R.8.4.2) are used
for DNEL derivation, namely: 100% for inhalation and 50% for oral
absorption. Based on the difference in systemic effects observed after
intraperitoneal injection and after dermal exposure in the LLNA study, a
dermal absorption of 25% is assumed.
No data are available that describe
the toxicokinetics of 2-ethyl-4-methylimidazole, therefore relevant
substance properties and data from toxicity studies indicating systemic
bioavailability were taken together to assess the general toxicokinetics
of the substance.
2-Ethyl-4-methylimidazole is a solid
with a molecular weight of 110.2 g/mol. The log Pow value is 1.13 and
the solubility in water is 1000 g/L.
Data from acute and repeated dose
In an acute oral toxicity study in
rats, exposure to 464, 681 and 1000 mg/kg bw 2-ethyl-4-methylimidazole
resulted in mortality, dyspnea, abnormal position, apathy, staggering,
tremors, twitching, convulsion of the jaws, fibr. contractions, urine
intense yellow, piloerection and poor general state. In the animals that
died general congestive hyperemia was observed at necropsy (1985). In
another acute oral toxicity study in rats, exposure to 1000, 4640 and
10000 mg/kg bw 2-ethyl-4-methylimidazole resulted in mortality, dyspnea,
apathy, belly-side position, staggering, tremors, twitching, spastic
gait, convulsion of the jaws, slight hair loss, salivation, poor general
condition (1977). Findings at necropsy included, heart: acute
dilatation, acute passive congestion; glandular stomach diffusely
reddened, astringent; intestine: bloody, diarrhoea-like content. In a
GLP compliant combined 28 -days repeated dose toxicity study with
reproduction/developmental toxicity screening test, 2-ethyl-4
-methylimidazole at dose levels of 15, 50, or 150 mg/kg/d was given to
rats by oral gavage (2012). Lower levels of total protein and albumin at
150 mg/kg bw/d were noted for females, and higher liver weights
(absolute and relative to body weight) were recorded at 15, 50 and 150
mg/kg bw/day for males. These changes were minor or showed no
dose-related response. No other treatment-related changes indicative of
systemic availability were observed. The administration of
2-Ethyl-4-Methyl-Imidazole by gavage to male and female Wistar rats for
3 months caused signs of systemic toxicity only at the high dose level
of 230 mg/kg bw/d (2016): decreased body weight and body weight gain;
increased total white blood cell (WBC) and absolute neutrophil counts in
males, increased urea, cholesterol and inorganic phosphate levels in
both sexes, decreased chloride levels in both sexes, increased
triglyceride levels in females and decreased albumin levels in females;
decreased terminal body weight in both sexes, increased mean absolute
and relative liver weights in females and minimal centrilobular
hepatocellular hypertrophy in 9/10 female animals.
Therefore, under the conditions of the
present study the no observed adverse effect level (NOAEL) was 80 mg/kg
bw/d for male and female Wistar rats.
In an acute inhalation toxicity study
in rats, exposure to a saturated 2-ethyl-4-methylimidazole atmosphere
vapour at 20°C (0.03 mg/L), no mortality was observed. Clinical signs
consisted of distinct mucous membrane irritation and necropsy was
without findings (1977).
In an acute dermal toxicity study in
rabbits, exposure to 400 mg/kg bw 2-ethyl-4-methylimidazole did not
result in mortality, clinical signs, altered body weight and treatment
related findings during macroscopic observation (1979).
Absorption figures used for the
The results of the acute oral and the
repeated dose oral toxicity study with reproduction/developmental
toxicity screening test indicate absorption of the test substance by the
oral route. Secondly, 2-ethyl-4-methylimidazole has a log Pow value
between -1 and 4, which favors absorption by passive diffusion.
Furthermore, the molecular weight below 200 makes the test substance
also favorable for adsorption. Overall, this suggests that
2-ethyl-4-methylimidazole may be readily absorbed by the
gastrointestinal and respiratory tract.
The results of the acute
dermal toxicity study in rabbits (1979) do not indicate absorption of
the test substance by the dermal route. Furthermore, the
acute LD50 after intraperitoneal injection for NMRI and BI6 mice lies
between 180 and 200 mg/kg bw (1977). In the LLNA study CBA mice were
exposed to 50 µL of 25% 2-ethyl-4-methylimidazole for three days (2012).
Since the animals weight about 20g, this amount is the equivalent of 625
mg/kg bw. The penetration through the skin is therefore maximal 200 /
625 * 100 = 32%, but probably lower since the dermal LD50 will be higher
than 625 mg/kg bw. QSAR model DERMWIN (part of the model
EPI suite) results in an estimated Kp = 0.00467 cm/hr. According to the
user manual of the Danish QSAR database, May 2005 this indicates low
dermal absorption (range: very low/low/moderate/high). The comparison of
the effects after dermal absorption in the LLNA versus the acute LD50
after ip administration supports this assumption of a low dermal
absorption. Therefore, in a Weight of Evidence the dermal absorption
could be considered to be 50 % of the oral absorption.
Since it is likely that
2-ethyl-4-methylimidazole will be absorbed and in the absence of
substance-specific absorption data, the default absorption values from
the REACH guidance (Chapter 8, R.8.4.2) are used for DNEL derivation,
namely: 100% for inhalation and 50% for oral absorption. Based on the
difference in systemic effects observed after intraperitoneal injection
and after dermal exposure in the LLNA study, a dermal absorption of 25%
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