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Description of key information

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.

Key value for chemical safety assessment

Additional information

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.

 

Physical-chemical properties

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 toxicity studies

Oral toxicity

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.

 

Inhalation toxicity

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).

 

Dermal toxicity

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 DNEL derivation

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% is assumed.