Registration Dossier

Administrative data

Description of key information

Skin:
At 100% 2 animals showed necrosis and exfoliation.
At 50% 1 animal showed blanching
Evidence of skin irritation was observed at concentration down to 6.25%.
As the study was terminated at 72 hours there is no evidence that the results seen at the higher concentrations would be reversible.
Eye:
There is in vivo evidence of severe effects to the eye of rabbits

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:
1991-10-25 to 1991-11-2
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP Guideline study with 24 hour exposure and termination at 72 hours without evidence of reversibility
Qualifier:
equivalent or similar to
Guideline:
EPA OPP 81-5 (Acute Dermal Irritation)
Deviations:
yes
Remarks:
skin was not abraded
Principles of method if other than guideline:
Group 1:
One intact site per rabbit treated with pure (100%) test material.
Group 2:
4 intact sites per rabbit treated with four single applications of the test material at concentrations of 50, 25, 12.5 and 6.25% in light, white mineral oil.
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Hazleton Research Products Inc., Denve, Pennsylvania, USA
- Age at study initiation: Young adult
- Weight at study initiation: 2715 - 3176 g
- Housing: Individual suspended wire mesh cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 66 - 70°F
- Humidity (%): 43 - 72%
- Air changes (per hr): Not specified
- Photoperiod (hrs dark / hrs light): 12 hour light/dark cycle

IN-LIFE DATES: From: 1991-10-25 To: 1991-11-02
Type of coverage:
semiocclusive
Preparation of test site:
shaved
Vehicle:
other: light white mineral oil
Controls:
no
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 mL/site
- Concentration (if solution): 100%

VEHICLE
- Amount(s) applied (volume or weight with unit): 0.5 mL
- Concentration (if solution): 50, 25, 12.5 and 6.5%
Duration of treatment / exposure:
4 hours
Observation period:
72 hours
Number of animals:
12 rabbits (3 male, 9 female)
2 x group of 6 rabbits
Details on study design:
TEST SITE
Group 1
- Area of exposure: back, 1" x 1" patch, one site only
- % coverage: not specified
Group 2
- Area of exposure: back, 1" x 1" patch, 4 sites per rabbit
- % coverage: not specified

- Type of wrap if used: 2 ply gauze patch overwrapped with a gauze binder and secured with Dermiform tape.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): yes, disposal paper towels moistened with tepid tap water
- Time after start of exposure: 4 hours

SCORING SYSTEM: Draize
Irritation parameter:
erythema score
Basis:
mean
Time point:
other: 24 and 72 hour
Score:
4
Max. score:
4
Reversibility:
not fully reversible within: 72 hours
Remarks on result:
other: 100% test material
Irritation parameter:
edema score
Basis:
mean
Time point:
other: 24 and 72 hours
Score:
2.5
Max. score:
3
Reversibility:
not fully reversible within: 72 hours
Remarks on result:
other: 100% test material
Irritation parameter:
erythema score
Basis:
mean
Time point:
other: 24 and 72 hours
Score:
4
Max. score:
4
Reversibility:
not fully reversible within: 72 hours
Remarks on result:
other: 50% test material
Irritation parameter:
edema score
Basis:
mean
Time point:
other: 24 and 72 hours
Score:
3.4
Max. score:
4
Reversibility:
not fully reversible within: 72 hours
Remarks on result:
other: 50% test material
Irritation parameter:
erythema score
Basis:
mean
Time point:
other: 24 and 72 hours
Score:
2.9
Max. score:
4
Reversibility:
not fully reversible within: 72 hours
Remarks on result:
other: 25% test material
Irritation parameter:
edema score
Basis:
mean
Time point:
other: 24 and 72 hours
Score:
2.67
Max. score:
4
Reversibility:
not fully reversible within: 72 hours
Remarks on result:
other: 25% test material
Irritation parameter:
erythema score
Basis:
mean
Time point:
other: 24 and 72 hours
Score:
2
Max. score:
3
Reversibility:
not fully reversible within: 72 hours
Remarks on result:
other: 12.5% test material
Irritation parameter:
edema score
Basis:
mean
Time point:
other: 24 and 72 hours
Score:
1.5
Max. score:
2
Reversibility:
not fully reversible within: 72 hours
Remarks on result:
other: 12.5% test material
Irritation parameter:
erythema score
Basis:
mean
Time point:
other: 24 and 72 hours
Score:
1.5
Max. score:
2
Reversibility:
not fully reversible within: 72 hours
Remarks on result:
other: 6.25% test material
Irritation parameter:
edema score
Basis:
mean
Time point:
other: 24 and 72 hours
Score:
0.58
Max. score:
2
Reversibility:
fully reversible
Remarks on result:
other: 6.25% test material
Irritant / corrosive response data:
Dermal observations (See Table 1)

In Group 1, neat (100%) test material induced severe erythema and slight to moderate oedema. Eschar was present on all sites. Exfoliation and necrosis were noted on two sites each. There were no other dermal findings.

In Group 2, the 6.25% w/v concentration induced very slight to slight erythema and oedema on six and three sites respectively. Desquamation was noted on one site. There were no other dermal findings

In Group 2, the 12.5% w/v concentration induced slight to moderate erythema and very slight to slight oedema. Desquamation was present on one site. There were no other dermal findings.

In Group 2, the 25% w/v concentration induced slight to severe erythema and oedema. Eschar was noted on two sites. There were no other dermal findings.

In Group 2, the 50% w/v concentration induced severe erythema and moderate to severe oedema. Eschar was present on all sites. Blanching was noted on one site.
Other effects:
Mortality:
None of the rabbits died.

Body weights:
There were no treatment related effects on bodyweight

Table 1: Observations

Rabbit Number

Erythema

Oedema

24 h

72 h

24 h

72 h

100%

1

4e

4e

3

3

2

4e

4e

3

2

3

4e

4ex

2

2

4

4e

4en

3

2

5

4e

4en

3

2

6

4e

4ex

2

3

Mean Total

4.0

2.5

50%

1

4e

4e

3

3

2

4e

4e

4

3

3

4e

4e

4

3

4

4e

4e

4

3

5

4be

4be

4

4

6

4e

4e

3

3

Mean Total

4.0

3.4

25%

1

4e

4e

4

4

2

2

2

2

2

3

3

3

3

3

4

2

2

2

2

5

3

4e

3

3

6

3

3

2

2

Mean Total

2.9

2.67

12.5%

1

3

2

2

2

2

2

1d

1

0

3

2

2

2

2

4

2

2

1

1

5

2

2

2

2

6

2

2

1

2

Mean Total

2.0

1.5

6.25%

1

2

2

2

1

2

2

2

1

1

3

2

2

1

1

4

1

1

0

0

5

1

1d

0

0

6

1

1

0

0

Mean Total

1.5

0.58

e = eschar

n = necrosis

x = exfoliation

d = desquamation

b = blanching

Interpretation of results:
Category 1C (corrosive)
Remarks:
Migrated information Pure test material Criteria used for interpretation of results: EU
Conclusions:
Under the conditions of the study the pure test material induced necrosis in 2 out of 6 animals by the 72 hour observation period and at the 50% w/v concentration, blanching was seen in one out of 6 animals. In accordance with EU CLP Regulation (EC) No. 1272/2008, classification of this substance is required for skin corrosivity/irritation.
Erythema and oedema scores for the 12.5% w/v concentration would preclude the classification as a skin irritant at this dose level. However in the absence of observations beyond the 72 hour time point the potential for reversibilty of these effects is unknown. Therefore classification as Cat 2: Irritant is applicable at this concentration level.
Executive summary:

Test Guidance

Skin irritation study performed by a similar method to US OPP 81-5.

Method and Material

Group 1:

Six New Zealand White rabbits were shaved and a 0.5 mL portion of the test material was applied to an intact skin site. A gauze patch was placed over each application site and an impervious material was wrapped around the trunk of the animal to hold the patches. The wrapping was removed after 4 hours and washed .

Group 2:

Six New Zealand White rabbits were shaved and 4 intact sites per rabbit treated with four single applications of 0.5 mL each of the test material at concentrations of 50, 25, 12.5 and 6.25% in light, white mineral oil. A gauze patch was placed over each application site and an impervious material was wrapped around the trunk of the animal to hold the patches. The wrapping was removed after 4 hours and washed .

Treated areas were examined for erythema and oedema using the Draize method of scoring at 24 and 72 hours.

Results

In Group 1, neat (100%) test material induced severe erythema and slight to moderate oedema. Eschar was present on all sites. Exfoliation and necrosis were noted on two sites each. There were no other dermal findings.

In Group 2, the 6.25% w/v concentration induced very slight to slight erythema and oedema on six and three sites respectively. Desquamation was noted on one site. There were no other dermal findings In Group 2, the 12.5% w/v concentration induced slight to moderate erythema and very slight to slight oedema. Desquamation was present on one site. There were no other dermal findings.

In Group 2, the 25% w/v concentration induced slight to severe erythema and oedema. Eschar was noted on two sites. There were no other dermal findings.

In Group 2, the 50% w/v concentration induced severe erythema and moderate to severe oedema. Eschar was present on all sites. Blanching was noted on one site.

The only evidence of reversibility over the limited timeframe of the study was for oedema responses at the 6.25% test concentration.

Conclusion

In accordance with EU CLP Regulation (EC) No. 1272/2008, classification of this substance is required for skin corrosion/irritation.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (corrosive)

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:
1982-05-03 to 1982-05-24
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP-like study (QA signature), guideline study
Qualifier:
equivalent or similar to
Guideline:
other: Section 1500.3- Federal Hazardous Substances Act Regulations - 16 CFR
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Fasting period before study: No
- Housing: stainless steel cage with elevated wire mesh flooring
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°F): 70±2°F
- Humidity (%): 45±5%
- Photoperiod (hrs dark / hrs light): 12 hour light/dark cycle

IN-LIFE DATES: From: 1982-05-03 To: 1982-05-24
Vehicle:
unchanged (no vehicle)
Controls:
other: untreated eye served as control
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 mL
Duration of treatment / exposure:
Eyes were not rinsed throughout study
Observation period (in vivo):
21 days
Number of animals or in vitro replicates:
6
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing (if done): No

SCORING SYSTEM: Draize method
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
other: 24, 48 and 72 hour
Score:
0.72
Max. score:
3
Reversibility:
not fully reversible within: 21 days
Remarks on result:
other: Not reversible in 5/6 animals
Irritation parameter:
iris score
Basis:
mean
Time point:
other: 24, 48 and 72 hour
Score:
0
Max. score:
0
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
other: 24, 48 and 72 hour
Score:
2
Max. score:
2
Reversibility:
fully reversible within: 21 days
Irritation parameter:
chemosis score
Basis:
mean
Time point:
other: 24, 48 and 72 hour
Score:
4
Max. score:
4
Reversibility:
not fully reversible within: 21 days
Remarks on result:
other: Not reversible in 4/6 animals

Table 1: Observations

Rabbit Number

Cornea

Iris

Conjunctivae

Chemosis

24 h

48 h

72 h

24 h

48 h

72 h

24 h

48 h

72 h

24 h

48 h

72 h

1

1

1

1

0

0

0

2

2

2

4

4

4

2

1

1

1

0

0

0

2

2

2

4

4

4

3

0

0

0

0

0

0

2

2

2

4

4

4

4

1

1

1

0

0

0

2

2

2

4

4

4

5

0

0

1

0

0

0

2

2

2

4

4

4

6

1

1

1

0

0

0

2

2

2

4

4

4

Mean Total

0.72

0

2.0

4.0

Interpretation of results:
Category 1 (irreversible effects on the eye)
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
In accordance with EU CLP Regulation No. 1272/2008 classification of this substance is required for eye irritation.
Executive summary:

Test Guidance

Eye irritation study performed by a similar method to 16 CFR 1500.42 of the Federal Hazardous Substances Act,

Method and Material

0.1 mL of the test material was instilled into the right eye of six young adult albino rabbits. The left eye served as the untreated control. The test material was not washed from the eye. Treated eyes were examined at 1, 2, 3, 4 and 7 days following treatment. Interpretation of results was made in accordance with the Draize scale.

Results

No effects on the iris were observed in any animal at any observation period. Redness of the conjunctivae had dissipated in all animals by the 14 day observation period. Mild irreversible (5/6 animals) opacity of the cornea was observed throughout the study period. Severe chemosis was observed in all animals up to 7 days after test material installation. Chemosis in 3 animals appeared to have reversed by the 14 day observation but mild chemosis was seen at 21 days in these animals. One further animal showed no indication of reversibility of chemosis throughout the study period.

Conclusion

In accordance with EU CLP Regulation No. 1272/2008 classification of this substance as Cat 1: Irreversible effects on the eye, is required for eye irritation.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin

There is one key study and one supporting study on skin corrosion/irritation.

In the key skin irritation study performed by a similar method to US OPP 81-5. Two groups of rabbits were treated:

Group 1: Six New Zealand White rabbits were shaved and a 0.5 mL portion of the test material was applied to an intact skin site. A gauze patch was placed over each application site and an impervious material was wrapped around the trunk of the animal to hold the patches. The wrapping was removed after 4 hours and washed .

Group 2: Six New Zealand White rabbits were shaved and 4 intact sites per rabbit treated with four single applications of 0.5 mL each of the test material at concentrations of 50, 25, 12.5 and 6.25% in light, white mineral oil. A gauze patch was placed over each application site and an impervious material was wrapped around the trunk of the animal to hold the patches. The wrapping was removed after 4 hours and washed .

Treated areas were examined for erythema and oedema using the Draize method of scoring at 24 and 72 hours.

In Group 1, neat (100%) test material induced severe erythema and slight to moderate oedema. Eschar was present on all sites. Exfoliation and necrosis were noted on two sites each. There were no other dermal findings.

In Group 2, the 6.25% w/v concentration induced very slight to slight erythema and oedema on six and three sites respectively. Desquamation was noted on one site. There were no other dermal findings In Group 2, the 12.5% w/v concentration induced slight to moderate erythema and very slight to slight oedema. Desquamation was present on one site. There were no other dermal findings.

In Group 2, the 25% w/v concentration induced slight to severe erythema and oedema. Eschar was noted on two sites. There were no other dermal findings.

In Group 2, the 50% w/v concentration induced severe erythema and moderate to severe oedema. Eschar was present on all sites. Blanching was noted on one site.

The only evidence of reversibility over the limited timeframe of the study was for oedema responses at the 6.25% test concentration.

In the supporting study by Costello (1982) the study was performed by a similar method to 16 CFR 1500.41 of the Federal Hazardous Substances Act Regulations.

Six New Zealand White rabbits were clipped and then one side of the back was abraded to penetrate the stratum corneum with the other side kept intact. A 0.5 mL portion of the test material was applied to an abraded and an intact skin site of the same rabbit. A gauze patch was placed over each application site and an impervious material was wrapped around the trunk of the animal to hold the patches. The wrapping was removed after 24 hours. Treated areas were examined for erythema and edema using the Draize method of scoring at 24 and 72 hours.

Well-defined erythema and slight oedema formation was observed at the intact and abraded sites of all animals at 24 hours. At 72 hours well-defined erythema and very slight oedema was observed at the intact and abraded sites of all animals was observed at all intact sites and abraded sites of all animals. There was no evidence of reversibility over the limited timeframe of the study.

In accordance with EU CLP Regulation (EC) No. 1272/2008, classification of this substance is required for skin corrosion/irritation.

Eye

The key eye irritation study was performed by a similar method to 16 CFR 1500.42 of the Federal Hazardous Substances Act,

0.1 mL of the test material was instilled into the right eye of six young adult albino rabbits. The left eye served as the untreated control. The test material was not washed from the eye. Treated eyes were examined at 1, 2, 3, 4 and 7 days following treatment. Interpretation of results was made in accordance with the Draize scale.

No effects on the iris were observed in any animal at any observation period. Redness of the conjunctivae had dissipated in all animals by the 14 day observation period. Mild irreversible (5/6 animals) opacity of the cornea was observed throughout the study period. Severe chemosis was observed in all animals up to 7 days after test material installation. Chemosis in 3 animals appeared to have reversed by the 14 day observation but mild chemosis was seen at 21 days in these animals. One further animal showed no indication of reversibility of chemosis throughout the study period.

In accordance with EU CLP Regulation No. 1272/2008 classification of this substance as Cat 1: Irreversible effects on the eye, is required for eye irritation.


Justification for selection of skin irritation / corrosion endpoint:
GLP Guideline study performed at various concentrations.

Justification for selection of eye irritation endpoint:
GLP Guideline study

Effects on skin irritation/corrosion: corrosive

Effects on eye irritation: irritating

Justification for classification or non-classification

Skin:

At 100% 2 animals showed necrosis and exfoliation.

At 50% 1 animal showed blanching

Evidence of skin irritation was observed at concentration down to 6.25%.

As the study was terminated at 72 hours there is no evidence that the results seen at the higher concentrations would be reversible.

Therefore with regard to classification the following Specific Concentration Levels (SCL) are suggested:

25%≥ Cat 1C ≤100%.

6.25%≥ Cat 2 <25%

Skin Cat 3 < 6.25% (ie not classified according to CLP)

Eye:

There is in vivo evidence of severe effects to the eye of rabbits. In addition the classification of the substance as corrosive/irritant automatically assumes effects to the eye.