Registration Dossier

Administrative data

Description of key information

skin irritation in vivo (similar to OECD 404): not irritating
eye irritation in vivo (similar to OECD 405): not irritating

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Referenceopen allclose all

Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Reason / purpose for cross-reference:
reference to same study
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
yes
Remarks:
Analytical purity of test substance not specified, occlusive dressing according to former guideline, 24 h exposure time, test substance was not removed after exposure
GLP compliance:
no
Species:
rabbit
Strain:
Himalayan
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Own breeding
- Weight at study initiation: 2.16 - 2.45 kg
- Housing: Separated in single cages
- Diet: Standard diet ERKA 8300 (Robert Koch oHG, Hamm, Germany), ad libitum
- Water: ad libitum
Type of coverage:
occlusive
Preparation of test site:
other: 6 x 3 cm, one half shaved the other additionally abraded
Vehicle:
other: Polyethylenglycol 400
Controls:
not specified
Amount / concentration applied:
500 mg in 1.2 mL vehicle on 2.5 x 2.5 cm
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 500 mg
- Concentration: 500 mg moistened with 1.2 ml polyethyleneglycol 400

VEHICLE
- Amount(s) applied (volume or weight with unit): 1.2 ml
Duration of treatment / exposure:
24 h
Observation period:
Examinations after 24, 48 and 72 h
Number of animals:
6
Details on study design:
TEST SITE
- Area of exposure: shaved flank
- Type of wrap if used: Moistened test material was applied to 2.5 x 2.5 cm cellulose pads from Hansamed, the pads were fixed to the prepared application site and covered with an indifferent, impermeable polyethylene film (6 - 8 cm width). Subsequently, the whole trunk of the animals was wrapped with an elastic polyurethan warp bandage (permanent bandage K, Lohmann) left in place for 24 h.

REMOVAL OF TEST SUBSTANCE
- Washing: no

SCORING SYSTEM: Draize
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: Reversibility: not applicable
Remarks on result:
other: intact skin
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: Reversibility: not applicable
Remarks on result:
other: intact skin
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: Reversibility: not applicable
Remarks on result:
other: intact skin
Irritation parameter:
erythema score
Basis:
animal #4
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: Reversibility: not applicable
Remarks on result:
other: intact skin
Irritation parameter:
erythema score
Basis:
animal #5
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: Reversibility: not applicable
Remarks on result:
other: intact skin
Irritation parameter:
erythema score
Basis:
animal #6
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: Reversibility: not applicable
Remarks on result:
other: intact skin
Irritation parameter:
edema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: Reversibility: not applicable
Remarks on result:
other: intact skin
Irritation parameter:
edema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0.33
Max. score:
4
Reversibility:
fully reversible within: 48 h
Remarks on result:
other: intact skin
Irritation parameter:
edema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: Reversibility: not applicable
Remarks on result:
other: intact skin
Irritation parameter:
edema score
Basis:
animal #4
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: Reversibility: not applicable
Remarks on result:
other: intact skin
Irritation parameter:
edema score
Basis:
animal #5
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: Reversibility: not applicable
Remarks on result:
other: intact skin
Irritation parameter:
edema score
Basis:
animal #6
Time point:
24/48/72 h
Score:
0.33
Max. score:
4
Reversibility:
fully reversible within: 48 h
Remarks on result:
other: intact skin
Irritant / corrosive response data:
No erythema was observed in abraded skin, either. Edema of grade 1 was observed in 4/6 animals in abraded skin after 24 h which was fully reversible after 48 h.
Other effects:
No mortality occurred. There were no clinical signs of systemic toxicity from the dermal exposure.
Interpretation of results:
other: CLP/EU GHS criteria not met, no classification required according to Regulation (EC) No. 1272/2008.
Executive summary:

The test substance is not irritating and does not have to be classified according to the criteria of Regulation (EC) No. 1272/2008.

Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
yes
Remarks:
Solid substance not moistened, readings after 24 and 72 h only
GLP compliance:
no
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: adult, not further specified
Type of coverage:
occlusive
Preparation of test site:
other: shaved and abraded, respectively
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 mg
Duration of treatment / exposure:
24 h
Observation period:
24 and 72 h
Number of animals:
12 (6 non-abraded, 6 abraded)
Details on study design:
TEST SITE
- Area of exposure: shaved or shaved and abraded back, respectively
- Type of wrap if used: Surgical patch of 1 inch x 1 inch, fixed to the application site by means of adhesive tape. The entire trunk of the rabbits was wrapped with an impervious material to maintain the test patches in position. Six rabbits were treated on the intact skin, the other six on the abraded skin. Abrasions were minor incisions through the stratum corneum, but not sufficiently deep to disturb the derma or to produce bleeding.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): no

SCORING SYSTEM: Draize
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
other: 24, 72 hours
Score:
0
Max. score:
4
Reversibility:
other: Reversibility: not applicable
Remarks on result:
other: intact skin
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
other: 24, 72 hours
Score:
0.5
Max. score:
4
Reversibility:
fully reversible within: 72 hours
Remarks on result:
other: intact skin
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
other: 24, 72 hours
Score:
0.5
Max. score:
4
Reversibility:
fully reversible within: 72 hours
Remarks on result:
other: intact skin
Irritation parameter:
erythema score
Basis:
animal #4
Time point:
other: 24, 72 hours
Score:
1
Max. score:
4
Reversibility:
not fully reversible within: 72 hours
Remarks on result:
other: intact skin
Irritation parameter:
erythema score
Basis:
animal #5
Time point:
other: 24, 72 hours
Score:
0
Max. score:
4
Reversibility:
other: Reversibility: not applicable
Remarks on result:
other: intact skin
Irritation parameter:
erythema score
Basis:
animal #6
Time point:
other: 24, 72 hours
Score:
0.5
Max. score:
4
Reversibility:
fully reversible within: 72 hours
Remarks on result:
other: intact skin
Irritation parameter:
edema score
Basis:
animal #1
Time point:
other: 24, 72 hours
Score:
0
Max. score:
4
Reversibility:
other: Reversibility: not applicable
Remarks on result:
other: intact skin
Irritation parameter:
edema score
Basis:
animal #2
Time point:
other: 24, 72 hours
Score:
0
Max. score:
4
Reversibility:
other: Reversibility: not applicable
Remarks on result:
other: intact skin
Irritation parameter:
edema score
Basis:
animal #3
Time point:
other: 24, 72 hours
Score:
0
Max. score:
4
Reversibility:
other: Reversibility: not applicable
Remarks on result:
other: intact skin
Irritation parameter:
edema score
Basis:
animal #4
Time point:
other: 24, 72 hours
Score:
0
Max. score:
4
Reversibility:
other: Reversibility: not applicable
Remarks on result:
other: intact skin
Irritation parameter:
edema score
Basis:
animal #5
Time point:
other: 24, 72 hours
Score:
0
Max. score:
4
Reversibility:
other: Reversibility: not applicable
Remarks on result:
other: intact skin
Irritation parameter:
edema score
Basis:
animal #6
Time point:
other: 24, 72 hours
Score:
0
Max. score:
4
Reversibility:
other: Reversibility: not applicable
Remarks on result:
other: intact skin
Irritant / corrosive response data:
Irritants effects observed in abraded skin were even less pronounced and fully reversible within 72 h.
Interpretation of results:
other: CLP/EU GHS criteria not met, no classification required according to Regulation (EC) No. 1272/2008.
Executive summary:

Although observed erythema was not fully reversible within the observation period of 72 h in 1/6 animals after application to intact skin, the slight characteristics of the remaining effect and the full reversibility observed under more stringent experimental conditions in abraded skin make the assumption of full reversibility within a slightly longer period of time reasonable. Therefore, the test substance is considered not irritating to the skin and does not have to be classified according to the criteria of Regulation (EC) No. 1272/2008.

Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Qualifier:
according to guideline
Guideline:
other: Federal Regulations 16 CFR 1500.41
Deviations:
no
GLP compliance:
no
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 2.80 - 3.70 kg
Type of coverage:
occlusive
Preparation of test site:
other: shaved and abraded
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied: 0.5 g
Duration of treatment / exposure:
24 h
Observation period:
24 and 72 h
Number of animals:
6
Details on study design:
TEST SITE
- Area of exposure: Back and sides, closely clipped with an electric clipper, two sites per rabbit, each site 1 inch square in area. A site to the left of the spinal cord was abraded, while a site right to the spinal cord was left intact. The abrasions were sufficiently deep as to penetrate the stratum corneum, but not so deep as to disturb the derma or produce bleeding.
- Type of wrap if used: The test material was applied beneath a surgical gauze square 1 inch x 1 inch, eight single layers thick, placed directly on the test site and secured with Dermicel tape. The animals were then wrapped with plastic sheeting secured with masking tape. After 24 h the sheeting and gauze patches were removed.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): no

SCORING SYSTEM: Draize
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
other: 24, 72 hours
Score:
0
Max. score:
4
Reversibility:
other: Reversibility: not applicable
Remarks on result:
other: non-abraded
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
other: 24, 72 hours
Score:
0
Max. score:
4
Reversibility:
other: Reversibility: not applicable
Remarks on result:
other: non-abraded
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
other: 24, 72 hours
Score:
0
Max. score:
4
Reversibility:
other: Reversibility: not applicable
Remarks on result:
other: non-abraded
Irritation parameter:
erythema score
Basis:
animal #4
Time point:
other: 24, 72 hours
Score:
0
Max. score:
4
Reversibility:
other: Reversibility: not applicable
Remarks on result:
other: non-abraded
Irritation parameter:
erythema score
Basis:
animal #5
Time point:
other: 24, 72 hours
Score:
0
Max. score:
4
Reversibility:
other: Reversibility: not applicable
Remarks on result:
other: non-abraded
Irritation parameter:
erythema score
Basis:
animal #6
Time point:
other: 24, 72 hours
Score:
0
Max. score:
4
Reversibility:
other: Reversibility: not applicable
Remarks on result:
other: non-abraded
Irritation parameter:
edema score
Basis:
animal #1
Time point:
other: 24, 72 hours
Score:
0
Max. score:
4
Reversibility:
other: Reversibility: not applicable
Remarks on result:
other: non-abraded
Irritation parameter:
edema score
Basis:
animal #2
Time point:
other: 24, 72 hours
Score:
0
Max. score:
4
Reversibility:
other: Reversibility: not applicable
Remarks on result:
other: non-abraded
Irritation parameter:
edema score
Basis:
animal #3
Time point:
other: 24, 72 hours
Score:
0
Max. score:
4
Reversibility:
other: Reversibility: not applicable
Remarks on result:
other: non-abraded
Irritation parameter:
edema score
Basis:
animal #4
Time point:
other: 24, 72 hours
Score:
0
Max. score:
4
Reversibility:
other: Reversibility: not applicable
Remarks on result:
other: non-abraded
Irritation parameter:
edema score
Basis:
animal #5
Time point:
other: 24, 72 hours
Score:
0
Max. score:
4
Reversibility:
other: Reversibility: not applicable
Remarks on result:
other: non-abraded
Irritation parameter:
edema score
Basis:
animal #6
Time point:
other: 24, 72 hours
Score:
0
Max. score:
4
Reversibility:
other: Reversibility: not applicable
Remarks on result:
other: non-abraded
Irritant / corrosive response data:
No effects were observed, at all. The situation was identical in abraded skin, no effects were observed, either.
Interpretation of results:
other: CLP/EU GHS criteria not met, no classification required according to Regulation (EC) No. 1272/2008.
Executive summary:

According to the criteria of Regulation (EC) No. 1272/2008 the substance does not have to be classifed as irritating to the skin.

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
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Reason / purpose for cross-reference:
reference to same study
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
yes
Remarks:
only 72 h observation time, no informations on full reversibility
GLP compliance:
no
Species:
rabbit
Strain:
Himalayan
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Own breeding
- Weight at study initiation: 2.02 - 2.59 kg
- Housing: Separated in single cages
- Diet: Standard diet ERKA 8300 (Robert Koch oHG, Hamm, Germany), ad libitum
- Water: ad libitum
Vehicle:
other: Polyethylene glycol 400
Controls:
other: right eye served as untreated control
Amount / concentration applied:
TEST MATERIAL
- Amount applied: 100 mg, moistened with 0.4 mL vehicle

VEHICLE
- Amount applied: 0.4 mL
Duration of treatment / exposure:
24 h
Observation period (in vivo):
1, 7, 24, 48 and 72 h
Number of animals or in vitro replicates:
6
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing: physiol. saline
- Time after start of exposure: 24 h

SCORING SYSTEM: Draize

TOOL USED TO ASSESS SCORE: hand lens, additionally at 48 and 72 h timepoints: one drop of fluorescein 0.01 %
Irritation parameter:
cornea opacity score
Basis:
animal: #1, #2, #4 - #6
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: Reversibility: not applicable
Irritation parameter:
cornea opacity score
Basis:
animal #3
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
not fully reversible within: 72 h (end of observation period)
Irritation parameter:
iris score
Basis:
animal: #1 - #6
Time point:
24/48/72 h
Score:
0
Max. score:
2
Reversibility:
other: Reversibility: not applicable
Irritation parameter:
conjunctivae score
Basis:
animal: #1, #2
Time point:
24/48/72 h
Score:
0.66
Max. score:
3
Reversibility:
fully reversible within: 72 h
Irritation parameter:
conjunctivae score
Basis:
animal #3
Time point:
24/48/72 h
Score:
1
Max. score:
3
Reversibility:
not fully reversible within: 72 h (end of observation period)
Irritation parameter:
conjunctivae score
Basis:
animal: #4, #5
Time point:
24/48/72 h
Score:
1
Max. score:
3
Reversibility:
fully reversible within: 72 h
Irritation parameter:
conjunctivae score
Basis:
animal #6
Time point:
24/48/72 h
Score:
0
Max. score:
3
Reversibility:
other: Reversibility: not applicable
Irritation parameter:
chemosis score
Basis:
animal: #1 to #6
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: Reversibility: not applicable
Irritant / corrosive response data:
Although there is slight redness and corneal opacity left in 1/6 animals after 72 hours, the decrease of the scores over the observation time and the slight characteristics of the observations make it reasonable to anticipate full reversibility after a slightly longer observation period.

Table 1: Eye irritation scores after 1 and 7 h

 

1 h

7 h

Rabbit No.

1

2

3

4

5

6

1

2

3

4

5

6

Cornea score

0

1

0

0

0

0

0

0

1

0

0

0

Iris score

0

0

0

0

0

0

0

0

0

0

0

0

Cojunctiva score

2

2

2

2

2

2

2

2

2

2

2

1

Chemosis score

2

2

2

2

2

2

1

1

1

1

1

1

Discharge score

3

3

3

3

2

3

2

1

1

1

0

1

Table 2: Eye irritation scores after 24, 48 and 72 h

 

24 h

48 h

72 h

Rabbit No.

1

2

3

4

5

6

1

2

3

4

5

6

1

2

3

4

5

6

Cornea score

0

0

1

0

0

0

0

0

1

0

0

0

0

0

1

0

0

0

Iris score

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Cojunctiva score

1

1

1

2

2

0

1

1

1

1

1

0

0

0

1

0

0

0

Chemosis score

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Discharge score

1

1

2

1

0

1

0

0

0

0

0

0

0

0

0

0

0

0

Interpretation of results:
other: CLP/EU GHS criteria not met, no classification required according to Regulation (EC) No. 1272/2008.
Executive summary:

Although there is slight redness and corneal opacity left in one animal after 72 h, the decrease of the scores over the observation time and the slight characteristics of the observations make it reasonable to anticipate full reversibility after a slightly longer observation period. Therefore, the substance does not have to be classified according to the criteria of Regulation (EC) No. 1272/2008.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin irritation / corrosion

Four studies are available addressing skin irritation. In the key study (Hoechst, 1981) the test substance was applied under occlusive conditions to intact and abraded skin, respectively, of 6 albino Himalayan rabbits. Readings were performed after 24, 48 and 72 h. The only observed effect on intact skin was a slight edema (grade 1 according to Draize) in 2/6 animals at the 24 h reading which was fully reversible after 48 h. No erythema was observed. Although not relevant for classification, the situation was comparable in abraded skin; no erythema was observed, the only effect was slight edema in 4/6 animals which completely reversed within 48 h.

This finding was supported by the second available study on skin irritation (TNO, 1981). Here, readings were only performed after 24 and 72 h. No edema was observed in this study. The only observed effect was slight erythema (grade 1) in 4/6 animals, which was not fully reversible in 1/6 animals after 72 h. In contrast, erythema observed in abraded skin in 4/6 animals (grade 1) was fully reversible within 72 h. Although erythema after application to intact skin was not fully reversible within the observation period of 72 h, the slight characteristics of the remaining effect (grade 1, only 1/6 animals) and the full reversibility observed under more stringent experimental conditions in abraded skin make the assumption of full reversibility within a slightly longer period of time reasonable. Therefore, the test substance was not considered to be irritating to the skin in this study, either.

In the third available study (Biodynamics, 1978), no effects were observed in the intact skin of 6 treated animals, at all, and the same observation was made in abraded skin. Therefore, this study further supports the overall view that the substance is not irritating to the skin.

The fourth study was performed with only one animal (EG&G Mason, 1981). Although not demonstrating any irritative effects, this study is not acceptable for assessment, as the animal was exposed for 2 h only and the only relevant reading of effects was done at 24 hours.

In conclusion, there is data available for occlusive exposure to intact and abraded skin, and under both conditions the substance did not induce effects sufficient for a classification as skin irritant.

Eye irritation / serious eye damage

There are three studies available addressing eye irritation. In the key study (Hoechst, 1981) 100 mg of test substance were moistened with 0.4 mL of polyethyleneglycol 400 to form a paste. This was applied to the left conjunctival sac of 6 albino Himalayan rabbits. The right eyes remained untreated and served as controls. After 24 h the eyes were washed with physiological saline and irritation reactions assessed at 24, 48 and 72 h after application. Corneal damage was additionally confirmed by application of 0.01% fluorescein at the 48- and 72-h readings. No iritis or chemosis were observed. Slight corneal opacity (grade 1) was observed in 1/6 animals which remained at the 72-h reading. Erythema was observed in 5/6 animals after 24 and 48 h ranging from slight to moderate (grade 1 and 2), which declined at 48 h and fully reversed in 4 of the 5 concerned animals within 72 h. Slight erythema remained in 1/6 animals at the 72-h reading, the same animal also demonstrating corneal opacity. However, although there is slight redness and corneal opacity left in 1/6 animals after 72 h, which is the end of the observation period, the decrease of the scores over the observation time and the slight characteristics of the observations make it reasonable to anticipate full reversibility after a slightly longer observation period. Therefore, the test substance was not considered to be irritating to the eyes.

Additional information on reversibility is available from 2 further studies (EG&G Mason, 1981; EG&G Mason, 1983), which were done for screening purposes and were performed with only one animal each. In both studies the test substance was not washed out and remained in the eye, the last reading was done after 7 days. Although some irritant effects on the iris and the conjunctiva were observed in both studies, which were reversible within 7 days at the latest, they were not acceptable for assessment, as this data was obtained from one animal only, and confirmation from further animals was lacking.

Justification for classification or non-classification

The available data on skin and eye irritation of the test substance do not meet the criteria for classification according to Regulation (EC) No. 1272/2008 and are therefore conclusive but not sufficient for classification.