2-ethyl-4-methylimidazole

Endpoint summary

Description of key information

The oral LD50 was ca 731 mg/kg bw, the inhalation LC50 (after 8 h exposure) was >0.03 mg/L and the dermal LD50 was >400 mg/kg bw.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Principles of method if other than guideline:

Three test groups (three doses) consisting of 5 animals/sex each were treated by single gavage application with an emulsion of the test substance. The animals were observed for mortality and for clinical symptoms of toxicity. At the end of the observation period of 14 days, the surviving animals were sacrificed for the purpose of necropsy; animals that died during the observations period also were subjected to necropsy.

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Dr. K. Thomae GmbH, D-7950 Biberach, FRG
- Weight at study initiation: 170-189 g
- Fasting period before study: yes
- Housing: 5 animals per stainless steel mesh cage, type DK-III (Becker & Co., Castrop-Rauxel, FRG)
- Diet (e.g. ad libitum): Kliba-Labordiaet, FA, Klingentalmuehle AG, CH-4303 Kaiseraugst, Switserland, ad libitum
- Water (e.g. ad libitum): tap water ad libitum
- Acclimation period: at least 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24
- Humidity (%): 30 - 70
- Photoperiod (hrs dark / hrs light): 12 / 12

Route of administration:

oral: gavage

Vehicle:

CMC (carboxymethyl cellulose)

Remarks:

0.5 % emulsion

Details on oral exposure:

VEHICLE
- Concentration in vehicle (w/v): 10, 6.81, 4.64 mg/mL

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg

Doses:

1000, 681, 464 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: recording of signs and symptoms several times on day of administration, at least once each workday. Check for moribund and dead animals twice each workday and once on holidays.
- Necropsy performed on died animals as well as sacrificed animals.
- Other examinations performed: clinical signs and body weight.

Sex:

male

Dose descriptor:

LD50

Effect level:

ca. 754 mg/kg bw

Based on:

test mat.

Remarks on result:

other: Value from interpolation

Sex:

female

Dose descriptor:

LD50

Effect level:

ca. 681 mg/kg bw

Based on:

test mat.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

ca. 731 mg/kg bw

Based on:

test mat.

Remarks on result:

other: value from interpolation

Mortality:

1000 mg/kg bw: all animals died within 1 day
681 mg/kg bw: 1 male and 2 female animals died within 1 day
464 mg/kg bw 1 female animal died within 1 day

Clinical signs:

other: Dyspnea, abnormal position. Apathy, staggering, tremors, twitching, convulsion of the jaws, fibr. contractions, intense yellow urine, piloerection, poor general state

Gross pathology:

Animals that died (male and female): general congestive hyperemia
Sacrificed animals (male and female): no abnormalies detected

Interpretation of results:

Category 4 based on GHS criteria

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

731 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Principles of method if other than guideline:

Method: BASF-Test: Test was performed in principle as described in OECD Guideline 403. The test demonstrates the toxicity of an atmosphere saturated with vapours of the volatile components of a test substance at the temperature chosen for vapour generation (20°C). 3 rats per sex were exposed sequentially to the vapours, generated by bubbling 200 l/h air through a substance column of about 5 cm above a fritted glassdisc in a glass cylinder for 8h. The documentation of clinical signs was performed over a period of 7 days. In order to verify the results, the test was repeated once.

GLP compliance:

no

Test type:

other: Inhalation-risk test (IRT)

Limit test:

no

Species:

rat

Strain:

not specified

Sex:

male/female

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

other: unchanged (no vehicle)

Analytical verification of test atmosphere concentrations:

not specified

Duration of exposure:

8 h

Concentrations:

Saturated vapour at 20°C (0.03 mg/L)

No. of animals per sex per dose:

3

Control animals:

no

Details on study design:

- Duration of observation period following administration: 7days
- Frequency of observations and weighing: observations: daily; weighing: at the beginning and end of the study
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight (group only, no single animal weights)

Sex:

male/female

Dose descriptor:

discriminating conc.

Effect level:

0.03 other: Saturated vapour at 20 ºC

Based on:

test mat.

Exp. duration:

8 h

Remarks on result:

other: none of the animals died

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 0.03 mg/L air

Based on:

test mat.

Exp. duration:

8 h

Remarks on result:

other: theoretical value, calculated based on vapour pressure

Mortality:

No mortality occurred.

Clinical signs:

other: distinct mucous membrane irritation

Body weight:

No data.

Gross pathology:

No treatment related findings.

Interpretation of results:

GHS criteria not met

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating conc.

Value:

30 mg/m³ air

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Principles of method if other than guideline:

BASF-Test. Rabbits were dermally exposed to a 50% aqueous solution of 2-ethyl-4-methylimidazol (400mg/kg) for 24 hour. Mortality and clinical symptoms were recorded over 8 days. Section was performed after the 8 day follow up.

GLP compliance:

no

Test type:

standard acute method

Limit test:

yes

Species:

rabbit

Strain:

Vienna White

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: M.GAUKLER (6050 Offenbach, Germany)
- Weight at study initiation: 2.77 kg (males) and 2.81kg (females)
- Diet: Ssniff K, standard diet for rabbits and guinea pigs (Firma INTERMAST GMBH, Soest), ad libitum
- Water: ad libitum

Type of coverage:

occlusive

Vehicle:

water

Details on dermal exposure:

TEST SITE
- Dorsal and lateral sides of the animals were shaved with an electric clipper approximately 15-24 hour prior to exposure.
- Only animals with a healthy appearance and unijured skin were used for the experiments
- Coverage: approximately 180 cm2
- Type of wrap if used: aluminium foil fixed with adhesive tape

REMOVAL OF TEST SUBSTANCE
- Washing: with warm water or a water/Lutrol mixture
- Time after start of exposure: 24 hours

TEST MATERIAL
- Concentration: 50% solution
- Dose: 400 mg/kg bw

Duration of exposure:

24 hour

Doses:

400 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

- Duration of observation period following administration: 8 days
- Frequency of observations and weighing: after 1, 24 and 48 hours and on day 8
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs and body weight

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 400 mg/kg bw

Based on:

test mat.

Mortality:

None of the animals died during the observation period.

Clinical signs:

other: No abnormal observations were reported.

Gross pathology:

No treatment related findings.

Interpretation of results:

GHS criteria not met

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

discriminating dose

Value:

400 mg/kg bw

Additional information

Oral toxicity

In an acute oral toxicity study, comparable to OECD 401, Wistar rats (5/sex/dose) were administered 2-ethyl-4-methylimidazole at 464, 681 and 1000 mg/kg bw by single dose (gavage) followed by a 14-day observation period (1985). Clinical signs included dyspnea, abnormal position, apathy, staggering, tremors, twitching, convulsion of the jaws, fibr. contractions, urine intense yellow, piloerection and poor general state. Findings at necropsy included: general congestive hyperemia (only in animals that died). The LD50 for males was ca. 754 mg/kg bw. The LD50 for females was ca. 681 mg/kg bw. The LD50 for males/females was ca. 731 mg/kg bw.

 

In another study, comparable to OECD 401, Sprague-Dawley rats (5/sex/dose) were administered 2-ethyl-4-methylimidazole at at 1000, 4640 and 10000 mg/kg bw by single dose (gavage) followed by a 14-day observation period (1977). Clinical signs included Dyspnea, apathy, belly-side position, staggering, tremors, twitching, spastic gait, convulsion of the jaws, slight hair loss, salivation, poor general condition. Findings at necropsy included, heart: acute dilatation, acute passive congestion; glandular stomach diffusely reddened, astringent; intestine: bloody, diarrhoea-like content. The LD50 was 1000 mg/kg bw.

 

Inhalation toxicity

In an acute inhalation toxicity study, comparable to OECD 403, rats (3/sex-dose) were exposed for 8 hours to a saturated 2-ethyl-4-methylimidazole atmosphere vapour at 20°C (0.03 mg/L) followed by a 14-day observation period (1977). No mortality occurred. Clinical signs consisted of distinct mucous membrane irritation and necropsy was without findings.The LC50 was > 0.03 mg/L.

 

Dermal toxicity

In an acute dermal toxicity study, comparable to OECD 402, Vienna White Rabbits (5/sex) were administered 2-ethyl-4-methylimidazole (400 mg/kg bw) (1979). 2-ethyl-4-methylimidazole was dissolved in distilled water and applied on the skin (skin area of approx 180 cm2) and covered in aluminium foil fixed with adhesive tape. The treated skin was washed after 24 hours and a 8 day observation period followed. No mortality was observed during this period resulting in a LD50 > 400mg/kg bw.

Justification for classification or non-classification

As no mortality was observed in the acute inhalation toxicity study (LC50 > 0.03 mg/L, highest possible concentration) and acute dermal study (LD50 > 400 mg/kg bw), classification for acute inhalation and dermal toxicity is not needed. Based on the available data, 2-ethyl-4-methylimidazole has to be classified for acute oral toxicity. According to the EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008, the classification is H302, Cat. 4.