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Description of key information

Since it is likely that 1,2-dimethylimidazole 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 QSAR and 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 1,2-dimethylimidazole, 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

1,2 -dimethylimidazole is a solid with a melting point of 38°C, a boiling point of 205°C, and a molecular weight of 96.1 g/mol. The log Pow value is 0.11, the vapour pressure is 0.224 hPa (at 20°C), the dissociation constant (pKa) is 7.63, and the substance is freely soluble with water.

 

Data from acute and repeated dose toxicity studies

Oral toxicity

In an acute oral toxicity study in rats, exposure to 200, 800, 1000, 1250 and 1600 mg/kg bw 1,2 -dimethylimidazole resulted in mortality, staggering, slight dyspnoea, shaking, mild cramps, trembling, apathy, rough coat, and bloody crusted nose and eyes. Findings at necropsy showed stomach filled with test substance and bleeding of gastric mucosa. The LD50 was ca. 1300 mg/kg bw (1965; reliability (RL) = 2). In a GLP compliant combined 28-days repeated dose toxicity study with reproduction/developmental toxicity screening test, 1,2 -dimethylimidazole was given to rats by oral gavage at dose levels of 15, 50, or 150 mg/kg bw/day (2013; RL1). The salivation which occurred post-dosing in most animals at 150 mg/kg bw/day and in individual males at 50 mg/kg bw/day was considered to be a local reaction to the taste of the substance and therefore not as adverse. In the absence of any toxicologically relevant changes, the pale faeces which were observed in most females at 150 mg/kg bw/day towards the end of the treatment period, were considered not to be of an adverse nature. Thus, no treatment-related changes indicative of systemic availability were observed up to 150 mg/kg bw/day, the highest dose tested. However, in the preceding 14-day range finding study in which rats were given 1,2 -dimethylimidazole at a dose of 300 mg/kg bw/day by oral gavage, body weight loss was observed in both sexes. In addition, lethargy, hunched posture and/or piloerection was observed during the last 3 -4 days of treatment.

 

Inhalation toxicity

In an acute inhalation toxicity study in which rats were exposed for 4 hours to 3.01 or 2.39 mg/L 1,2-dimethylimidazole, no mortality was observed. Clinical signs included watery, reddish eyes, nasal secretions, shock manner or rapid breathing, long-legged and tumbling movement, scruffy look, matted fur, alopecia and nose burns. No macroscopic abnormalities were observed at necropsy (1979; RL2). In another study, no mortality or clinical/macroscopic abnormalities were observed in rats exposed for 8 hours to an atmosphere saturated with 1,2-dimethylimidazole vapour at 20°C (1965; RL2).

 

Dermal toxicity

In an acute dermal toxicity study in rabbits, exposure to 200 mg/kg bw 1,2-dimethylimidazole for 24 hours under occlusive conditions did not result in mortality, clinical signs, altered body weight or treatment-related macroscopic abnormalities at necropsy (1979; RL2). Skin irritation was observed 24 hours after application, which remained consistent for almost 48 hours. Mild skin irritation was confirmed in rabbits exposed to an 80% aqueous solution of 1,2-dimethylimidazole for up to 4 hours under occlusive conditions in a skin irritation test (1980; RL2). In a local lymph node assay, 1,2 -dimethylimidazole was demonstrated to be a sensitizer after dermal exposure of mice to concentrations of 10% and 25% (2012; RL1), indicating that 1,2-dimethylimidazale is able to penetrate the skin.

 

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, 1,2 -dimethylimidazole has a log Pow value between -1 and 4, which favors absorption by passive diffusion. Furthermore, the molecular weight just below 100 makes the test substance also favorable for adsorption. Overall, this suggests that 1,2 -dimethylimidazole may be readily absorbed by the gastrointestinal and respiratory tract.

The results of the acute dermal toxicity study do not indicate absorption of the test substance by the dermal route. Furthermore, the acute LD50 after intraperitoneal injection for mice is approximately 300 mg/kg bw (1965; RL2). In the Local Lymph Node Assay, mice were exposed up to a dose of 50 µl 25% 1,2 -dimethylimidazole on three consecutive days. Since the animals - which all survived - weighed about 20 g, this amount is equivalent to 509 mg/kw bw on three consecutive days (calculation based on the assumption that the densitiy of the 25% formulation is the same as that of the vehicle, namely 0.815; [50 x 0.815 x 0.25]/0.020 = 509 mg/kg bw). The penetration through the skin is therefore maximal 100 * 300 / 509 = 59%, but probably lower since the dermal LD50 will be higher than 509 mg/kg bw. QSAR model DERMWIN (part of the model EPI suite) results in an estimated Kp of 0.00264 cm/h. According to the user manual of the Danish QSAR database (May 2005) this indicates low dermal absorption. The comparison of the effects after dermal exposure in the LLNA versus the acute LD50 after ip administration (LD50 ca. 300 mg/kg bw) supports this assumption of a low dermal absorption. Therefore, in a Weight of Evidence approach, the dermal absorption is considered to be 50% of the oral absorption.

Since it is likely that 1,2 -dimethylimidazole 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.