Registration Dossier

Administrative data

Description of key information

- Skin irritation/corrosion: not irritating; OECD TG 404; RL 1; GLP

- Eye irritation/corrosion: serious eye damage (Category 1); OECD TG 405; RL1; GLP

- Respiratory irritation: no study available

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:
key study
Study period:
1989-10-27 to 1989-12-28
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Version / remarks:
adopted February 24, 1987
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)
Version / remarks:
March, 1984
Deviations:
no
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: males: 14 weeks, females: 15 weeks
- Weight at study initiation: males: 2.9 kg, females: 2.4-2.6 kg
- Housing: Individually in stainless steel cages equipped with an automatic cleaning and drinking system (Dipl. Ing. W. Ehret GmbH, Versuchstiertechnik, D-7830 Emmendingen).
- Diet (e.g. ad libitum): ad libitum, Pelleted standard Kliba 341, Batch 48/89 rabbit maintenance diet ("Kliba", Klingentalmuehle AG, CH-4303 Kaiseraugst)
- Water (e.g. ad libitum): ad libitum
- Acclimation period: Four days under test conditions after veterinary examination.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 ± 3
- Humidity (%): 40-70
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:
semiocclusive
Preparation of test site:
shaved
Vehicle:
water
Remarks:
bi-distilled
Amount / concentration applied:
Amount(s) applied: 0.5 g / animal
Duration of treatment / exposure:
4 h
Observation period:
72 h, reading intervals: 1, 24, 48 and 72 h
Number of animals:
1 male and 2 females
Details on study design:
TEST SITE
- Area of exposure: 6 cm² intact shaved skin
- % coverage: 3.0 x 3.0 cm
- Type of wrap if used: A patch of surgical gauze was covered with a semi-occlusive dressing. The dressing was wrapped around the abdomen and anchored with an elastic bandage.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): After exposure the skin was flushed with lukewarm tap water.
- Time after start of exposure: 4 h

OBSERVATION TIME POINTS
1, 24, 48, 72 h

SCORING SYSTEM: according to OECD guideline
- Method of calculation: To classify the irritating property of the test article, the mean values of erythema/eschar as well as of edema formation were calculated for each individual, using the scores between 24 and 72 hours (EEC Council Directive 83/467/EEC, July 1983, Brussels/Belgium).
Irritation parameter:
erythema score
Basis:
animal: #1, #2, #3
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: reversibility not applicable
Remarks on result:
no indication of irritation
Irritation parameter:
edema score
Basis:
animal: #1, #2, #3
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: reversibility not applicable
Remarks on result:
no indication of irritation
Interpretation of results:
GHS criteria not met
Conclusions:
Under the conditions of the present study conducted according to OECD guideline 404, the test item caused no skin irritating/corrosive reactions. The individual mean values for both erythema and edema from gradings at 24, 48 and 72 h were 0 in all three animals. Therefore, the test item does not fulfil the criteria for classification according to Regulation (EC) 1272/2008 (CLP) and the Globally Harmonized system of Classification and Lablelling of Chemical (GHS), and is thus considered to be not skin irritating.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records
Reference
Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1989-11-02 to 1990-01-12
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Version / remarks:
adopted February 24, 1987
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)
Version / remarks:
March, 1984
Deviations:
no
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Age at study initiation: male 14 weeks, females 15 weeks
- Weight at study initiation: male 2.8 kg, females 2.3 - 2.5 kg
- Housing: Individually in stainless steel cages equipped with an automatic cleaning and drinking system (Dipl. Ing. W. Ehret GmbH, Versuchstiertechnik, D-7830 Emmendingen).
- Diet (e.g. ad libitum): ad libitum, Pelleted standard Kliba 341, Batch 48/89 and 49/89 rabbit maintenance diet ("Kliba", Klingentalmuehle AG, CH-4303 Kaiseraugst)
- Water (e.g. ad libitum): ad libitum, Community tap water from Itingen
- Acclimation period: Four days under laboratory conditions after veterinary examination.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 ± 3
- Humidity (%): 40-70
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12
Vehicle:
unchanged (no vehicle)
Controls:
other: the contralateral untreated eye served as control
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 g per animal were placed in the conjunctival sac of the left eye of each animal after gently pulling the lower lid away from the eyeball. The lids were then gently held together for about one second to prevent loss of the test article.

Duration of treatment / exposure:
Single instillation without rinsing
Observation period (in vivo):
21 days; reading intervals: 1, 24, 48 and 72 h, 14 and 21 days post-instillation
Number of animals or in vitro replicates:
1 male and 2 females
Details on study design:
SCORING SYSTEM: The irritation was assessed according to the numerical scoring system provided by OECD guideline 405
TOOL USED TO ASSESS SCORE: Eye examinations were made with a slit-lamp 30 SLIM (C. Zeiss AG, Zuerich/Switzerland) and a Varta Cliptrix diagnostic-lamp (A. Riegger, Basel/Switzerland).
Irritation parameter:
cornea opacity score
Basis:
animal: #1, #2, #3
Time point:
24/48/72 h
Score:
2.67
Max. score:
4
Reversibility:
not fully reversible within: 21 days
Remarks on result:
other: score 3 at day 21
Irritation parameter:
iris score
Basis:
animal #1
Time point:
24/48/72 h
Score:
1
Max. score:
2
Reversibility:
fully reversible within: 21 days
Irritation parameter:
iris score
Basis:
animal #2
Time point:
24/48/72 h
Score:
1
Max. score:
2
Reversibility:
not fully reversible within: 21 days
Remarks on result:
other: score 1 at day 21
Irritation parameter:
iris score
Basis:
animal #3
Time point:
24/48/72 h
Score:
1
Max. score:
2
Reversibility:
fully reversible within: 21 days
Irritation parameter:
conjunctivae score
Remarks:
conjunctival redness
Basis:
animal: #1, #2, #3
Time point:
24/48/72 h
Score:
2
Max. score:
3
Reversibility:
not fully reversible within: 21 days
Remarks on result:
other: score 1 at day 21
Irritation parameter:
chemosis score
Basis:
animal: #1, #2, #3
Time point:
24/48/72 h
Score:
3
Max. score:
4
Reversibility:
fully reversible within: 21 days
Irritant / corrosive response data:
Corneal opacity was observed in all animals at any of the measuring intervals. Partly corrosion of the conjunctivae was observed in two animals from 24 hours to 7 days, and in one animal from 48 hours to 7 days after treatment. Yellow staining of the eyelashes of the treated eyes by pigment or coloring of the test article was observed in all animals 1 hour after treatment.

Table 1: Irritant/corrosive response data for each animal at each observation time up to removal of each animal from the test

Score at time point / Reversibility

Cornea

Iris

Conjunctivae

Chemosis

Max. score: 4

Max. score: 2

Max. score: 3

Max. score: 4

24 h

 2/2/2

1/1/1

2/2/2 

 3/3/3

48 h

 3/3/3

 1/1/1

 2/2/2

 3/3/3

72 h

 3/3/3

 1/1/1

 2/2/2

 3/3/3

Average 24h, 48h, 72h

2.67/2.67/2.67 

 1/1/1

 2/2/2

 3/3/3

Reversibility*)

 n.

 n.c.

n.c. 

c. 

Average time (unit) for reversion

 21 (d) 

21 (d)  

21 (d)  

21 (d) 

*) Reversibility: c. = completely reversible; n.c. = not completely reversible; n. = not reversible

Interpretation of results:
Category 1 (irreversible effects on the eye) based on GHS criteria
Conclusions:
Under the conditions of the study conducted according to OECD guideline 405, the test material was found to cause corrosive/irriversible effects to the rabbit eye. The mean scores for corneal opacity, iritis, conjunctival redness and chemosis from gradings at 24, 48 and 72 h were 2.67, 1, 2, 3in all three animals. Corneal opacity and conjunctival redness observed in all animals and iritis in one animal were not reversible up to the end of the 21-day observation period. Therefore, the test material fulfils the criteria for classification as eye corrosive Category 1 according to Regulation (EC) No 1272/2008 (CLP) and the Globally Harmonized System of Classification and Labelling of Chemicals (GHS), and is thus considered to cause serious eye damage.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irreversible damage)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin irritation

Approximately 24 h before treatment, the dorsal fur was shaved with an electric clipper, exposing an area of approximately 100 square centimeters (10 cm x 10 cm).

After removal of the test patch the skin reaction was assessed at 1, 24, 48 and 72 h. The corrosive properties of the test article and the staining of the treated skin area related to the test article were described and recorded. The scores for each type of lesion was calculated according to EEC Council Directive, 83/467/EEC, July 1983 Brussels, Belgium.

Viability of the animals was recorded daily, body weights were assessed at day 1 of the test and at termination of observation. The observation was terminated 72 h after application of the test article. All rabbits were killed and discarded.

Under the conditions of this experiment, 2,4 -Bismaleimidotoluene was found to cause a primary irritation score of 0.00 and local signs (mean 1 h to 72 h) of grade 0.00 erythema and grade 0.00 edema. No staining of the treated skin by pigment or colouring of the test article was observed. No corrosive effect had occurred on the skin at any measuring interval. Thus, 2,4 -Bismaleimidotoluene is considered to be not irritating to the skin.

Eye irritation

In a primary eye irritation study according to OECD guideline 405 (February 24, 1987) 0.1 g of 2,4 -Bismaleimidotoluene was instilled into the conjunctival sac of the left eye of 3 young adult New Zealand White rabbits. The untreated right eyes served as controls. The eyes were not rinsed after application. Animals were then observed for 21 days.

The cornea opacity, the iris, the conjunctivae and chemosis were scored 2.67, 1.00, 2.00 and 3.00, respectively, in all animals. All effects except the ones on the iris were not reversible in all animals (in one animal the iris was scored 0 at the end of the 21 days period) within 21 days.

Beside the irritation scores other effects like coloration, corrosion, toxic symptoms and body weights were observed. No acute clinical symptoms and no mortality occurred during the observation period. But yellow staining of the eyelashes of the treated eyes by pigment or colouring of the test article was observed in all animals 1 h after treatment. Corneal opacity was observed in all animals at any of the measuring intervals. Partly corrosion of the conjunctivae was observed in two animals from 24 h to 7 days, and in one animal from 48 h to 7 days after treatment. Thus, the substance is considered to cause "irreversible effects on the eye".

Respiratory irritation

No data on the respiratory irritation of 2,4 -Bismaleimidotoluene are available.

There are no data gaps for the endpoint irritation/corrosion. No human information is available for this endpoint. However, there is no reason to believe that these results would not be applicable to humans.

Justification for classification or non-classification

Skin irritation

Based on reliable, adequate and relevant data, 2,4 -Bismaleimidotoluene does not need to be classified for skin irritation according to Regulation (EC) 1272/2008 (CLP) and the Globally Harmonized System for Classification and Labelling of Chemicals (GHS).

Eye irritation

Based on reliable, adequate and relevant data, 2,4 -Bismaleimidotoluen has to be classified as Category 1, irreversible effects on the eye according to CLP, EU GHS (Regulation (EC) No 1272/2008 and the Globally Harmonized System for Classification and Labelling of Chemicals) and is assigned the hazard statement H318 and the signal word “Danger”.