Registration Dossier

Administrative data

Description of key information

In one skin irritation study moderate to severe erythema and moderate edema after an exposure of 20 hours to 2-ethyl-4-methylimidazole was observed. No signs of erythema nor edema were observed after an exposure of 1, 5 or 15 minutes. In another study, after 1 and 4 hours exposure, well defined to severe erythema and very slight to moderate edema was observed. Furthermore, necrosis and parchment-like skin developed which remained throughout the 8-day observation period. In a third study, no erythema or edema was observed.
Application of the test substance to the eyes led to a conjunctivea score of 2, a cornea score of 3 and a chemosis score of 3. These effects were not reversible within 8 days. In another eye irritation study, exposure to the substance led to a cornea score of 1, an iris score of 1, a conjunctivea score of 3 and a chemosis score of 3.3.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records
Reference
Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
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:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Principles of method if other than guideline:
BASF-Test: Animals were treated for 4 hour using occlusive conditions. An application site of 2x2 cm was covered with the test substance. After the application time (4 h) the skin was washed with Lutrol (50%). The animals were observed for 8 days and skin changes were recorded daily. The report describes findings after 24 and 48 hours and at the end of the observation period (8 days).
GLP compliance:
no
Species:
rabbit
Strain:
Vienna White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: M.GAUKLER (6050 Offenbach)
- Weight at study initiation: male ca. 2.80 kg, female ca. 2.65 kg
- Diet: Sniff K, standard diet for rabbits and guinea pigs (Firma INTERMAST GMBH, Soest), ad libitum
- Water: ad libitum
Type of coverage:
occlusive
Preparation of test site:
shaved
Vehicle:
water
Controls:
no
Amount / concentration applied:
80 % aquatic solution (0.5 g)
Duration of treatment / exposure:
4 hours and 1 hour
Observation period:
8 days
Number of animals:
2 per exposure duration
Details on study design:
TEST SITE
- Area of exposure: 2 x 2 cm
- Type of wrap: rubberised linnencloth, fixed with adhesive tape

REMOVAL OF TEST SUBSTANCE
- Washing: with Lutrol (50% or 100%) and dried with cellulose towels
- Time after start of exposure: 4 h and 1 h

Irritation parameter:
erythema score
Remarks:
4 h exposure
Basis:
mean
Time point:
other: 4, 24, 48 hour
Score:
3
Max. score:
4
Reversibility:
not reversible
Remarks on result:
other: necrosis (soft movable, patchy)
Irritation parameter:
erythema score
Remarks:
4 h exposure
Basis:
mean
Time point:
other: 8 days
Score:
4
Max. score:
4
Reversibility:
not reversible
Remarks on result:
other: necrosis (parchment-like)
Irritation parameter:
edema score
Remarks:
4 h exposure
Basis:
mean
Time point:
other: 4 h
Score:
2
Max. score:
4
Reversibility:
not reversible
Irritation parameter:
edema score
Remarks:
4 h exposure
Basis:
mean
Time point:
other: 24, 48 h
Score:
2.5
Max. score:
4
Reversibility:
not reversible
Irritation parameter:
edema score
Remarks:
4 h exposure
Basis:
mean
Time point:
other: 8 d
Score:
1.5
Max. score:
4
Reversibility:
not reversible
Irritation parameter:
erythema score
Remarks:
1 h exposure
Basis:
mean
Time point:
other: 4, 24, 48 h and 8 d
Score:
0
Max. score:
4
Irritation parameter:
edema score
Remarks:
1 h exposure
Basis:
mean
Time point:
other: 4, 24, 48 h and 8 d
Score:
0
Max. score:
4
Irritant / corrosive response data:
Moderate to severe erythema and edema was observed after an exposure of 4 hours. No signs of erythema nor edema were observed after an exposure of 1 hour.
Other effects:
Clinical symptoms were not observed
Interpretation of results:
other: irritating
Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Eye irritation

Link to relevant study records
Reference
Endpoint:
eye irritation: in vivo
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:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
GLP compliance:
no
Species:
rabbit
Strain:
Vienna White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Gaukler; D-6050 Offenbach/Main, FRG
- Weight at study initiation: male, 3.17 kg; females, 2.93 kg
- Housing: singly in a stainless steel cage with wire mesh walk floors (floor area: 40 x 51 cm)
- Diet (e.g. ad libitum): Kliba 341, 4 mm; Firma Klingentalmuehle AG, CH-43-3 Kaiseraugst, Switserland (about 130 g per animal per day)
- Water (e.g. ad libitum): about 250 ml tap water per animal per day
- Acclimation period: at least 8 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 30-70
- Air changes (per hr): fully airconditioned rooms
- Photoperiod (hrs dark / hrs light): 12 / 12
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
0.1 ml
Duration of treatment / exposure:
Single application to the conjunctival sac of the right eyelid (not washed out)
Observation period (in vivo):
72 hours
Number of animals or in vitro replicates:
2 male, 1 female
Details on study design:
Readings: 1 hr, 24 hr, 48 hr, 72 hr after application.
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
other: 1, 24 h
Score:
1.7
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
other: 48, 72 h
Score:
1
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Remarks on result:
other: irritation index could not be read due to severe corneal opacity
Irritation parameter:
iris score
Basis:
mean
Time point:
other: 1 h
Score:
0
Max. score:
2
Irritation parameter:
iris score
Basis:
mean
Time point:
other: 24, 48, 72 h
Score:
1
Max. score:
2
Reversibility:
not fully reversible within: 72 h
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
other: 1 h
Score:
2.3
Max. score:
3
Reversibility:
not fully reversible within: 72 h
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
other: 24, 48, 72 h
Score:
3
Max. score:
3
Reversibility:
not fully reversible within: 72 h
Irritation parameter:
chemosis score
Basis:
mean
Time point:
other: 1 h
Score:
2.3
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Irritation parameter:
chemosis score
Basis:
mean
Time point:
other: 24 h
Score:
2.7
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Irritation parameter:
chemosis score
Basis:
mean
Time point:
other: 48, 72 h
Score:
3.3
Max. score:
4
Reversibility:
not fully reversible within: 72 h
Other effects:
Other effects observed were contracted pupils (1, 24 h), discharge of blood (1, 24, 48 h), detachment of the cornea (1, 24 h), small retractions in the eyelids (24, 48, 72 h), suppuration (48, 72 h).
The study was discontinued after 72 h because of severe irritation.
Interpretation of results:
other: highly irritating
Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irreversible damage)

Additional information

Skin irritation

In a skin irritation test similar to OECD guideline 404, the test substance was applied in 80% aqueous solution to the skin of Vienna White Rabbits (1977). Animals were treated for 1, 5, 15 min and 20 hours using occlusive conditions. Observation took place for 8 days and skin changes were recorded daily. Moderate to severe erythema and moderate edema was observed after an exposure of 20 hours on the first day after exposure. At day 8 symptoms had dissapeared. No signs of erythema nor edema were observed after an exposure of 1, 5 or 15 minutes.

In another study performed similarly to OECD guideline 404, animals were exposed to an 80% aqueous solution of 2-ethyl-4-methylimidazole for 1 and 4 hours using occlusive conditions followed by an eight day observation period (1979). Animals exposed for one hour showed no signs of erythema or edema. Animals exposed for 4 hours showed well defined to severe erythema as well as edema ranging from very slight to moderate. Signs of necrosis were also observed.

In a third skin irritation test performed in accordance to OECD guideline 404, the test substance, in liquid form (normal melting point between 36-42°C but lower this time due to impurities) was applied semi-occlusive to the skin of Vienna White Rabbits using a 2.5 cm x 2.5 cm test patch absorbed with ca 0.5 ml test liquid (1985). After 4 hour exposure a 72 hours observation period followed. No erythema or edema was observed during the 72 hr after exposure.

A weight of evidence approach was applied to classify the test substance. All studies were performed similar to OECD guideline 404, however only one study (1985) applied the test substance semi-occlusive as stated by the OECD guideline. No corrosive effects were observed in that study. The observed necrosis in the other two studies could be a result of the occlusive application. Furthermore, only the study of 1985 indicated that the test substance was not irritating to the skin while the other two studies showed severe irritation as a result of the application of the test substance. There is the possibility that the aqueous solution of the test substance increases the irritating potential of the test substance in comparison with the liquid form of the test substance and therefore the test substance is considered to be irritating to the skin instead of being corrosive.

Eye irritation

In an eye irritation test comparable to OECD guideline 405, 50 µL of the test substance was applied to the conjunctival sac of the eyes of 2 rabbits (1977). The animals were observed for eight days after exposure and findings recorded at 1h, 24h and 8 days. Application of the test substance led (on day 8) to a chemosis score of 3, a conjuctivea score of 2 and a cornea score of 3. In addition during the observation period bloody secretion, iritis, suppuration, and hairloss was observed.

In another study performed in accordance to OECD guideline 405, 0.1 mL of the test substance was applied to the conjunctival sac of the eyes of 3 rabbits (1985). The animals were observed for 72 hours and findings recorded at 1 hr, 24 hr, 48 hr, 72 hr after application. After 72 hours a cornea score of 1, an iris score of 1, a conjunctivea score of 3 and a chemosis score of 3.3 was observed. Due to the severe effects the study was terminated after 72 hours.

Justification for classification or non-classification

Based on the available studies, 2-ethyl-4-methylimidazole has to be classified for skin irritation and eye damage. According to the EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008, the classification is Skin Irrit. 2, H315 and Eye Damage 1, H318.

2-ethyl-4-methylimidazole crude contains 4 -methylimidazole (CAS 822 -36 -6), which is classified as H314, Skin category 1B according to Regulation EC1272/2008. Hence, 2-ethyl-4-methylimidazole crude also has to be classified as H314, Skin category 1B according to Regulation EC1272/2008.