Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.3 mg/m³
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
12.5
Modified dose descriptor starting point:
NOAEC
Explanation for the modification of the dose descriptor starting point:

NOAEC = NOAEL (repro, oral, rat) *100%/95% /0.38 m3/kg *6.7/10 = 3.71 mg/m3

According to ECHA guidance, R.8.4.2: Ratio of inhalation to oral absorption; standard respiratory volume of a rat corrected for 8 h exposure; correction for activity driven differences of respiratory volumes in workers compared to workers in rest.

AF for dose response relationship:
1
Justification:
GLP OECD TG study with 3 doses
AF for differences in duration of exposure:
1
Justification:
Substance was given in the period critical for causing the developmental effect (gestation).
AF for interspecies differences (allometric scaling):
1
Justification:
route-to-route extrapolation: oral --> inhalation
AF for other interspecies differences:
2.5
Justification:
default
AF for intraspecies differences:
5
Justification:
default for workers
AF for the quality of the whole database:
1
Justification:
sufficient reliable data
AF for remaining uncertainties:
1
Justification:
default
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.04 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
50
Dose descriptor starting point:
NOAEL
Modified dose descriptor starting point:
NOAEL
Explanation for the modification of the dose descriptor starting point:

NOAEL = NOAEL (repro, oral, rat) * 95%/95% *1 = 2 mg/kg bw/d

According to ECHA guidance, R.8: Same ratio of dermal to oral absorption; default extrapolation factor from oral to dermal route.

AF for dose response relationship:
1
Justification:
GLP OECD TG study with 3 doses
AF for differences in duration of exposure:
1
Justification:
Substance was given in the period critical for causing the developmental effect (gestation).
AF for interspecies differences (allometric scaling):
4
Justification:
default for scaling from rat to human
AF for other interspecies differences:
2.5
Justification:
default
AF for intraspecies differences:
5
Justification:
default for workers
AF for the quality of the whole database:
1
Justification:
sufficient reliable data
AF for remaining uncertainties:
1
Justification:
default
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
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

Absorption, metabolism and excretion

2-Methylimidazole is almost completely and rapidly absorbed when administered orally. No data are available on inhalation and dermal absorption. 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 for oral-to-inhalation extrapolation of 2. However, oral absorption has experimentally been shown to approach 100% and 95% was used for route-to-route extrapolation. For inhalation absorption the worst case value of 100% was assumed. For dermal absorption, by default the same value as for oral absorption was used, which is 95% for 1 -methylimidazole.

 

Acute toxicity

2-Methylimidazoleis classified for acute oral toxicity. The substance does not need to be classified for acute 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. Though data on respiratory irritation are lacking, a respiratory irritation hazard is likely based on the corrosivity of the substance. The substance is not sensitisatizing to the skin. Data on respiratory sensitisation are lacking.

Repeated-dose toxicity

For repeated-dose toxicity several studies are available in which the substance was administered via the diet or by oral gavage to rats or mice. No repeated-dose dermal or inhalation studies are available. Target organs in the repeated-dose oral toxicity studies included the thyroid, pituitary, red blood (anaemia), liver, kidney, spleen, heart (mouse only), bone marrow (mouse only), testis and epididymidis. In the 2-year feeding studies with rats and mice, 2-methylimidazole induced malignant neoplasms of the thyroid gland and liver in rats and mice. The available repeated-dose studies with their endpoints, effect levels, doses tested and basis for NOAEL/LOAEL are presented in the table below:

 

Duration

Route

Species

Endpoint

Effect level

Dose levels tested and basis for (no) effect level

4 weeks

Oral (gavage)

Rat

LOAEL

100 mg/kg bw/day

100, 200, 400, 800 mg/kg bw/day.

Decreased plasma protein.

15 days

Oral (diet)

Rat

NOAEL

108 mg/kg bw/day

108, 297 and 900 mg/kg bw/day.

Increased incidences of thyroid gland follicular cell hyperplasia (a precursor lesion to follicular-cell adenomas and carcinomas) and hypertrophy of thyroid-stimulating hormone cells in the pituitary pars distalis.

15 days

Oral (diet)

Mouse

LOAEL

232 mg/kg bw/day

232, 638 and 1933 mg/kg bw/day.

Increased incidences of thyroid gland follicular cell hypertrophy and hematopoietic-cell proliferation in the spleen.

14 weeks

Oral (diet)

rat

NOAEL

80 mg/kg bw/day

40, 80, 160, 300 and 560 mg/kg bw/day.

Increased incidences of thyroid gland follicular cell hyperplasia, effects on kidney and erythropoietic system >= 160 mg/kg/day.

14 weeks

Oral (diet)

mouse

NOAEL

100 mg/kg bw/day

Males/females: 100/90, 165/190, 360/400, 780/800 and 1740/1860 mg/kgbw/day.

Effects on liver, anaemia and associated microscpic changes in spleen and kidneys >= 165/190 mg/kg/day.

2 years

Oral (diet)

rat

systemic toxicity:

LOAEL

13 mg/kg bw/day

Males/females: 13/50, 40/120 and 130/230 mg/kg bw/day.

Increased incidence of thyroid gland follicular cell hyperplasia.

carcinogenicity:

NOAEL

13 mg/kg bw/day

Increased incidence of hepatocellular adenoma or carcinoma (combined).

2 years

Oral (diet)

mouse

systemic toxicity:

LOAEL

75 mg/kg bw/day

Males/females: 75/80, 150/150 and 315/325 mg/kg bw/day.

Increased incidence of hematopoietic cell proliferation in the spleen. 

carcinogenicity:

LOAEL

75 mg/kg bw/day

Increased incidence of hepatocellular adenoma or carcinoma (combined).

 

Mutagenicity

2-Methylimidazole does not need to be classified as mutagenic.

 

Reproduction toxicity

2-Methylimidazole is classified for reproductive toxicity. In an oral (gavage) reproduction/developmental toxicity screening test in rats (according to OECD421) 150 mg/kg bw/day was a NOAEL for general toxicity and reproductive toxicity in the parents. For developmental toxicity no NOAEL could be established because dissecting aneurysms in the great vessels of the heart occurred up to the lowest dose tested (50 mg/kg bw/day). In a follow-up study pregnant females received the test substance by oral gavage from day 6 of gestation until the day before sacrifice (lactation day 4) at dose levels of 2, 10 and 50 mg/kg bw/day. In this follow-up study the NOAEL for developmental toxicity in the F1 offspring was 2 mg/kg bw/d, as dissecting aneurysms in the great vessels of the heart were noted at incidences beyond the historical background range at 10 mg/kg bw/d and above.

 

DNEL derivation

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

 

Short-term toxicity

Systemic effects:

Though the substance is classified for acute toxicity (oral only), 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 for2-methylimidazole.

Local effects:

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.

 

Long-term toxicity

Selection of study for DNEL derivation

Repeated-dose oral toxicity studies in rats and mice, lasting between 15 days and 2 years are available.

Regarding non-cancer effects, the lowest LOAEL was obtained in the 2-year rat study, namely 13 mg/kg bw/day based on a dose-related increase in the incidence of thyroid gland follicular hyperplasia (0/48, 17/45, 37/43 and 43/49 in the control, low-, mid- and high-dose group, respectively). Extrapolation of this LOAEL to a NAEL using a factor of 3 results in a NAEL of 4.3 (13/3) mg/kg bw/day.

Regarding carcinogenicity, the substance induced liver and thyroid tumours in rats and mice. As the substance is not classified as mutagenic, it was assumed that the substance exerted this effect by a threshold mode of action and that a DNEL could be derived for this endpoint. In the 2-year rat study, thelowest dose of 13 mg/kg bw/day was a NOAEL for carcinogenicity based on liver tumors at the next dose (40 and 120 mg/kg bw/day in male and female rats, respectively).In the 2-year mouse study, thelowest dose of 75 mg/kg bw/day was a LOAEL for carcinogenicity based on liver tumors in males. The B6C3F1 mouse strain used in this study is known for its high spontaneous liver tumor incidence. Therefore, the observed increase of liver tumors in the 2-year mouse study is considered not to be relevant for extrapolation to man.

Regarding reproductive toxicity, the NOAEL for developmental effects was 2 mg/kg bw/day as established in the follow-up developmental study. This developmental NOAEL is lower than the NAEL for non-cancer effects from the 2-year rat study (4.3 mg/kg bw/day). Though the exposure period of the study from which the developmental NOAEL originated was much shorter than 2 years, extrapolation for exposure duration is not necessary because the test substance was given in the period critical for causing the developmental effect (dissecting aneurysms in the great vessels of the heart), i.e. during gestation.

Thus, the DNEL derived from the developmental study was considered sufficiently low to protect against non-cancer and cancer effects. 

 

Inhalation exposure, systemic effects

As repeated-dose inhalation toxicity studies are not available, repeated-dose oral toxicity data were used to derive DNELs for long-term inhalation toxicity.Available data seem to indicate lack of route-specific toxicity. Oral absorption has experimentally been shown to approach 100% and this value (95%) was used for route-to-route extrapolation. The NOAEL (2 mg/kg bw/day) from thedevelopmental study in rats was used for derivation of the systemic long-term DNEL for the inhalation route.

 

Inhalation exposure, local effects: As no studies are available on local effects after long-term exposure by inhalation, no DNEL could be derived.

 

Dermal exposure, systemic effects

As repeated-dose dermal toxicity studies are not available, repeated-dose oral toxicity data were used to derive DNELs for long-term dermal toxicity. For dermal absorption, by default the same value as for oral absorption was used, which is 95% for 1 -methylimidazole. The NOAEL (2 mg/kg bw/day) from the developmental study in rats was used for derivation of the systemic long-term DNEL for the dermal route.

 

Dermal exposure, local effects: As the substance is not sensitizing to the skin, no long-term DNEL for local dermal effects needs to be derived.

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:
DNEL (Derived No Effect Level)
Value:
0.02 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
100
Dose descriptor starting point:
NOAEL
Explanation for the modification of the dose descriptor starting point:

PoD: NOAEL (teratogenicity study, oral, rat) --> DNEL = 2 mg/kg bw/d / (4*2.5*10*1*1*1) = 2 / 100 = 0.02 mg/kg bw/d

AF for dose response relationship:
1
Justification:
GLP OECD test guideline study
AF for differences in duration of exposure:
1
Justification:
Extrapolation for exposure duration is not necessary because the test substance was given in the period critical for causing the developmental effect (dissecting aneurysms in the great vessels of the heart), i.e. during gestation
AF for interspecies differences (allometric scaling):
4
Justification:
default for rat --> human
AF for other interspecies differences:
2.5
Justification:
default
AF for intraspecies differences:
10
Justification:
default for general population
AF for the quality of the whole database:
1
Justification:
GLP guideline studies available
AF for remaining uncertainties:
1
Justification:
default
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 but not for the general population; except for the LT systemic oral DNEL for the general population which is relevant for the assessment Man via Environment (ECHA GD R.16, Feb. 2016).