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Description of key information

2-Methylimidazole is rapidly absorbed, distributed and excreted by the body if administered orally. No data are available on inhalation and dermal absorption.

Key value for chemical safety assessment

Absorption rate - oral (%):
95
Absorption rate - dermal (%):
95
Absorption rate - inhalation (%):
100

Additional information

2-methylimidazole is rapidly absorbed, distributed and excreted by the body if administered orally.

In one study (National Toxicology Program, 2004; Johnson et al., 2002), male and female rats and mice received a single gavage dose of 25, 50 or 100 mg/kg bw 2-methylimidazole. Postdose plasma samples were analyzed for 2-methylimidazole, and the results were used to calculate toxicokinetic parameters. In rats, the absorption half-life values ranged from 10 to 18 minutes and were generally linear with dose. The peak 2-methylimidazole concentrations (Cmax) increased proportionally with dose. The Tmaxvalues were reached within approximately 30 to 45 minutes after gavage dosing and were independent of the dose. Absorption rate constants were much larger than elimination rate constants. The absolute bioavailability value for 2-methylimidazole was calculated using a one-compartment model using the results from the groups that did not exhibit a change in clearance, and was found to reach 97% or higher.

Elimination half-life values ranged from 61 to 96 minutes and were generally increased in the 100 mg/kg bw groups. Differences in clearance across the treatment groups were not all statistically significant, but clearance was decreased in all 100 mg/kg bw groups, indicating that the 100 mg/kg bw dose is approaching the upper limit of the linear dosing range and higher doses would result in higher internal doses than expected based on the lower doses. However, in a repeated dose scenario, the short absorption and elimination half lives of the chemical would prevent accumulation from one dose to the next.

Similar results were obtained in the study with mice (National Toxicology Program, 2004), administered the same dose levels (25, 50 and 100 mg/kg bw 2-methylimidazole) by gavage. The absorption half-life values ranged from 2 to 4 minutes and were generally linear with dose. Absorption rate constants were much larger than elimination rate constants and were similar in males and females. Elimination half-life values ranged from 15 to 20 minutes and were generally increased in the 100 mg/kg bw groups. Differences in clearance across the treatment groups were not all statistically significant, but clearance was decreased in all 100 mg/kg bw groups.

Upon intravenous administration of 10 mg/kg bw 2-methylimidazole to male and female rats (Johnson et al., 2002; National Toxicology Program, 2004), 2-methylimidazole was found to be rapidly distributed. The estimated distribution half-life was ca. 5 min for the males and 8 min for females.

In the study of Sanders et al. (1998), the disposition of radiolabelled 2-methylimidazole has been investigated following oral administration of 5, 50 and 150 mg/kg bw as aqueous solution or an intravenous administration of a single dose of 5 mg/kg bw to male rats. As estimated by the excretion data, only trace levels of 2-methylimidazoel-derived radioactivity remained in tissues 48 hours following oral administration. Skin, kidney, and liver, in that order, contained the highest concentrations of 14C following oral administration of any of the three dose concentrations. For 150 mg/kg bw dose group, the concentrations in skin, kidney and liver were 11.6 ± 0.6, 3.5± 0.2 and 2.9 ± 0.2 µg 2-methylimidazole per 1 g tissue. The lowest concentrations were observed in adipose tissue (max. 0.3 µg/g tissue). Concentrations of 14C in tissues increased proportionally to dose from 50 to 150 mg/kg bw, and tissue/blood ratios of 14C were relatively constant throughout the dose range.

After intravenous injection, radioactivity was rapidly distributed from blood to most tissues. Tissue/blood ratios of total 14C were greater than 1 for all assayed tissues except adipose at the initial time points. In fact, with the exception of the 2 hour time point, little 14C was distributed from blood to adipose tissue over time. Peak concentrations of 14C apparently occurred within 15 minutes of dosing in most tissues. The highest peak concentration of 14C was observed in kidney, probably as a result of the rapid excretion of 14C in urine. 2-methylimidazole radioactivity was eliminated rapidly from tissues, with more than 75% of the peak concentrations of 14C eliminated within 8 hours of dose administration.

The concentration of 2-methylimidazole derived radioactivity was also investigated in tissues of rats 2 hours following administration of 50 mg/kg bw by gavage. The concentrations of 14C in most tissues were ca. 10 times higher than those observed at the same time point following a 5 mg/kg bw intravenous dose, indicating that the distribution of 2-methylimidazole-derived radioactivity to tissues was proportional to dose and not affected by the route of exposure. As with intravenous administration, the highest concentration of 14C was observed in kidney.

2-methylimidazole-derived radioactivity was rapidly eliminated, primarily in urine, following oral administration of either 5, 50, or 150 mg/kg bw to male rats. About one-half of an administered dose was excreted in urine within 4 hours post-dosing, with total dose excretion approaching 90% within 24 hours of gavage. Fecal elimination accounted for most of the remaining 14C (max. 5.5 ± 2.3% of total dose); however, a small, but measurable amount (3.3%) of the dose was eliminated with 24 hours as 14CO2 in rats receiving 50 mg/kg bw. No more than 2% of the total dose was excreted in urine and feces beyond the 24-hour time period following administration of either 5, 50 or 150 mg/kg bw.

Elimination of radioactivity was somewhat more rapid over time following intravenous versus oral administration. Over 90% of the dose was recovered in urine within 12 hours of injection; consequently, intravenously treated rats were euthanized at 24 hour time point, rather than at 48 hours as were the gavaged treatment groups. In cannulated rats, only 2.1% of the total dose was excreted in bile within 6 hours of intravenous administration.

HPLC analysis of urine of rats treated with 2-methylimidazole either intravenously or by gavage indicated that in either case less than half of the dose was metabolized prior to excretion. Parent compound accounted for ca. 64, 68 and 75% of the total radioactivity excreted in cumulative 24-hour urine following oral administration of 5, 50 and 150 mg/kg bw, respectively. Similarly, radioactivity in cumulative 24-hour urine of rats receiving an intravenous dose of 5 mg/kg bw was composed of 60% parent compound. Most of the 2-methylimidazole-derived metabolites in all treatment groups were contained in 3 poorly resolved peaks eluting near the void volume of the HPLC system. Representative chromatograms of 2-methylimidazole-derived radioactivity excreted in urine indicated that elimination of 2-methylimidazole-derived metabolites, negligible through the first 4 hours postdosing, increased over time. Metabolic product accounted for 50% or more of the total14C excreted in urine after 12 hours; however, this radioactivity made up only about 5% of the total dose.

 

In summary, 2-methylimidazole is almost completely and rapidly absorbed when administered orally. Based on maximal fecal excretion of 5.5%, the value for oral absorption is set at 95%. This value will be taken forward to risk assessment. The substance is rapidly distributed throughout the body and excreted, with only trace levels of 2-methylimidazole-derived radioactivity remaining in tissues 48 hours following oral administration. The highest concentrations were found in skin, kidney and liver. Metabolism is relatively non-extensive, with less than half of the substance being metabolized. The degree of metabolism decreases when the dose increases. No metabolites were identified, except of CO2, which accounted for up to 3.3% of total excretion. The substance is rapidly eliminated from the body, with total excretion reaching 90% within 24 hours of gavage.

No data are available on inhalation and dermal absorption. Available data seem to indicate lack of route-specific toxicity, allowing route-to-route extrapolation. The substance has a very high water solubility (540 g/L) and log Kow of 0.61. According to Chapter R.7c of REACH Guidance on information requirements and chemical safety assessment the substance may be too hydrophilic to cross the lipid rich environment of the stratum corneum. Dermal uptake for these substances might be low, which is supported by the estimated Kp = 0.000783 cm/hr (DERMWIN v 2.02). However, as no experimental data are available, the dermal absorption is considered to be equal to the oral absorption. For inhalation absorption, a default factor of 2 is recommended for extrapolation from oral-to-inhalation absorption in the case of lack of data. However, oral absorption amounts to almost 100% and a value of 100% for inhalation absorption will be used for DNEL derivation.