Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
7.9 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
10
Modified dose descriptor starting point:
NOAEC
DNEL value:
79 mg/m³
Explanation for the modification of the dose descriptor starting point:

Route-to-route extrapolation: NOAEL (90d, oral, rat): 90 mg/kg bw/d with only non-adverse findings (increase of relative liver weights in males and females of the mid and/or high dose group; dose-dependent, minimal to slight centrilobular liver hypertrophy in males and females of all test groups without correlating findings in clinical chemistry); /2 (absorption inhalation/oral); /0.38 m3/kg bw (rat SRV, corrected for 8h exposure); *6.7 m3/10 m3 (light/no work).

AF for dose response relationship:
1
Justification:
GLP compliant, OECD guidline study with 3 doses
AF for differences in duration of exposure:
2
Justification:
default for sub-chronic study
AF for interspecies differences (allometric scaling):
1
Justification:
oral to inhalation route-to-route extrapolation
AF for other interspecies differences:
1
Justification:
ECHA GD R.8., section 8.4.3.1: "For effects on the skin, eye or GI tract, where the mechanism of effect is direct chemical/pH reactivity, no further kinetic considerations apply. Furthermore, in terms of dynamics, one might assume that animals and humans will respond to the insult in the same way. In this case, the default factor for remaining uncertainties of 2.5 could be reduced to 1."
The corrosiveness of 1-methylimidazole - as a basic aqueous solution - is most probably responsible for the acute toxicity after oral and dermal administration and also for limiting the MTD (maximal tolerable dose) in the repeated dose and reproduction toxicity studies OECD422, OECD408 and OECD414 to 90 mg/kg bw/d (IUCLID section 7.5 and 7.8).
The observed systemic effects in the 90d-study were considered as non-adverse, but adaptive: increase of relative liver weights in males and females of the mid and/or high dose group; dose-dependent, minimal to slight centrilobular liver hypertrophy in males and females of all test groups without correlating findings in clinical chemistry. Metabolome analysis revealed no clear evidence for any organ specific toxicological modes of action. Additionally, weak effects on liver enzyme induction may be discussed for treatment of rats with 1-methylimidazole, but compared to known potent enzyme inducers such as typical ligands of the AhR or CAR, observed effects are negligible (IUCLID section 7.9.3).
Systemic toxicity might or might not occur at higher doses, but this cannot be proven experimentally, as the unspecific corrosiveness limits the amount of administered substance. As no systemic organ specific toxicity was observed up to the highest dose tested, an additional assessment factor for interspecies differences is not justified.
AF for intraspecies differences:
5
Justification:
default
AF for the quality of the whole database:
1
Justification:
GLP compliant OECD guideline studies
AF for remaining uncertainties:
1
Justification:
default
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.25 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
40
Modified dose descriptor starting point:
NOAEL
DNEL value:
90 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Route-to-route extrapolation: NOAEL (90d, oral, rat): 90 mg/kg bw/d with only non-adverse findings (increase of relative liver weights in males and females of the mid and/or high dose group; dose-dependent, minimal to slight centrilobular liver hypertrophy in males and females of all test groups without correlating findings in clinical chemistry); *1 (default factor for extrapolation from oral to dermal).

AF for dose response relationship:
1
Justification:
GLP compliant, OECD guideline study with 3 doses
AF for differences in duration of exposure:
2
Justification:
default for sub-chronic study
AF for interspecies differences (allometric scaling):
4
Justification:
default for rat-to-human
AF for other interspecies differences:
1
Justification:
ECHA GD R.8., section 8.4.3.1: "For effects on the skin, eye or GI tract, where the mechanism of effect is direct chemical/pH reactivity, no further kinetic considerations apply. Furthermore, in terms of dynamics, one might assume that animals and humans will respond to the insult in the same way. In this case, the default factor for remaining uncertainties of 2.5 could be reduced to 1."
The corrosiveness of 1-methylimidazole - as a basic aqueous solution - is most probably responsible for the acute toxicity after oral and dermal administration and also for limiting the MTD (maximal tolerable dose) in the repeated dose and reproduction toxicity studies OECD422, OECD408 and OECD414 to 90 mg/kg bw/d (IUCLID section 7.5 and 7.8).
The observed systemic effects in the 90d-study were considered as non-adverse, but adaptive: increase of relative liver weights in males and females of the mid and/or high dose group; dose-dependent, minimal to slight centrilobular liver hypertrophy in males and females of all test groups without correlating findings in clinical chemistry. Metabolome analysis revealed no clear evidence for any organ specific toxicological modes of action. Additionally, weak effects on liver enzyme induction may be discussed for treatment of rats with 1-methylimidazole, but compared to known potent enzyme inducers such as typical ligands of the AhR or CAR, observed effects are negligible (IUCLID section 7.9.3).
Systemic toxicity might or might not occur at higher doses, but this cannot be proven experimentally, as the unspecific corrosiveness limits the amount of administered substance. As no systemic organ specific toxicity was observed up to the highest dose tested, an additional assessment factor for interspecies differences is not justified.
AF for intraspecies differences:
5
Justification:
default
AF for the quality of the whole database:
1
Justification:
GLP compliant, OECD guideline studies
AF for remaining uncertainties:
1
Justification:
default
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - workers

According to the REACH “Guidance on information requirements and chemical safety assessment”, a leading DN(M)EL needs to be derived for every relevant human population and every relevant route, duration and frequency of exposure, if feasible.

- Kinetics (absorption figures for oral, dermal and inhalation route of exposure): No data on absorption are available. According to Chapter R.8 of REACH Guidance on information requirements and chemical safety assessment, it is proposed in the absence of route-specific information on the starting route, to include a default factor of 2 in the case of oral-to-inhalation extrapolation. This approach will be taken forward to DNEL derivation. For dermal absorption, based on the physico-chemical properties of the substance (log Kow < 0 and high water solubility), and based on the estimated Kp, low dermal uptake is expected. However, as in the acute dermal toxicity study mortality and clinical effects were observed, 100% dermal absorption cannot be excluded. Therefore a default factor of 1 in the case of oral-to-dermal extrapolation is included.

- Acute toxicity: 1-Methylimidazole is classified for acute oral and dermal toxicity. Testing for acute inhalation toxicity was not necessary because the substance is classified as corrosive to the skin.

- Irritation/corrosion and sensitisation: The substance is classified as corrosive to the skin and eye. Testing for skin sensitisation was not necessary because the substance is classified as corrosive to the skin.

- Repeated dose toxicity: The study considered for DNEL derivation of 1-methylimidazole is the 90-day study in rats (OECD408, gavage). 1-Methylimidazole was administered daily as an aqueous preparation to 10 male and female Wistar rats by gavage at doses of 0, 10, 30 and 90 mg/kg bw/d. Due to severe effects in the first range finding study, this was the highest possible dose to be tested. No test substance-related adverse findings were observed up to the highest dose level tested. Therefore, the NOAEL was 90 mg/kg bw/d, which is the point of departure for the DNEL derivation.

- Mutagenicity: 1-Methylimidazole did not cause gene mutations in Salmonella typhimurium (Ames test). 1-Methylimidazole is not mutagenic in the HPRT locus assay in CHO cells and is considered not to have a chromosome-damaging (clastogenic) effect nor to induce numerical chromosomal aberrations (aneugenic activity) under in vitro conditions in V79 cells in the absence and the presence of metabolic activation.

- Reproduction toxicity: No test substance-related adverse findings with regard to reproductive performance and with regard to clinical examinations and gross findings were observed in a GLP-compliant combined repeated dose toxicity study with the reproduction/developmental toxicity screening test (OECD 422, gavage) in rats with 1-methylimidazole; tested at 0, 10, 30 and 90 mg/kg bw/d. Additionally, no effects on reproduction organs were observed in a GLP-compliant repeated dose toxicity study (OECD408, gavage) in rats; tested at 0, 10, 30 and 90 mg/kg bw/d). Furthermore, no test substance-related adverse findings were observed in a GLP-compliant teratogenicity study (OECD414, gavage) in rats with 1-methylimidazole; tested at 0, 10, 30 and 90 mg/kg bw/d. Thus, the NOAEL for reproductive and developmental toxicity was considered 90 mg/kg bw/day, the highest dose tested. No DNEL has to be derived for reproductive and developmental toxicity.

DNEL derivation

Though the substance is classified for acute toxicity (oral and dermal), no short-term DNELs were derived because the long-term DNELs were considered to ensure sufficient protection to prevent peak exposure. As oral and dermal exposure is expressed as amount (per kg bw) per day, acute oral and dermal exposure peaks (in mg/kg bw/day) will not be higher than a calculated total exposure per day (chronic; in mg/kg bw/day). Therefore, practically relevant peak exposures via the oral and dermal routes do not occur for 1-methylimidazole.

Though the substance is classified as corrosive to the skin and eye, no data are available from which a DNEL for local effects can be derived.

For long-term toxicity, regarding systemic effects, a NOAEL of 90 mg/kg bw/d was observed in a sub-chronic repeated dose toxicity study (OECD 408). This NOAEL is used for the DNEL derivation.

Long-term dermal and inhalation toxicity data is not available.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected

Additional information - General Population

As the substance has no consumer uses DNELs were derived only for workplace exposure.