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Description of key information

Skin irritation: not irritating (OECD 404, GLP, K, Rel.2)

Eye irritation: irritating (OECD 405, GLP, K, Rel.2)

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:
24 February to 17 March 2009
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Remarks:
GLP study conducted according to OECD 404 Guideline without any deviation. The substance is adequately identified, but some data on composition is missing. Therefore validation applies with restrictions.
Justification for type of information:
An in vivo study was performed for worldwide (Asia) notification purposes.
Qualifier:
according to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Version / remarks:
24 April 2002.
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)
Principles of method if other than guideline:
Not applicable
GLP compliance:
yes (incl. QA statement)
Remarks:
Inspected on 2008-04-14&15 /Signed on 2008-07-16.
Specific details on test material used for the study:
- Date received: 10 February 2009 (Flask 1); 18 February 2009 (Flask 2)
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Elevage de Gérome (Quartier Labaste – F40260 Linxe)
- Age at study initiation: 12-13 weeks
- Weight at study initiation: 2.64-3.33 kg
- Housing: Each animal was kept in an individual box installed in conventional air conditioned animal husbanding.
- Diet: Foodstuff (SDS –C15), ad libitum
- Water: Drinking water (tap-water from public distribution system), ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature: 19-24 °C
- Humidity: 48-64 %
- Air changes: ca. 15 changes per hour
- Photoperiod: 12 h dark / 12 h light

IN-LIFE DATES: 24 February to 17 March 2009
Type of coverage:
semiocclusive
Preparation of test site:
clipped
Vehicle:
unchanged (no vehicle)
Controls:
yes
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 mL
Duration of treatment / exposure:
4 hours
Observation period:
Skin reactions were appreciated 1, 24, 48 and 72 hours, Day 4 to 14 after removal of the patch.
Number of animals:
3 females
Details on study design:
PRETEST
Initially, a single animal was treated. After consideration of the cutaneous responses produced in the first treated animal, two additional animals were treated during 4 hours.

TEST SITE
- Area of exposure: Approximately 24 h before the test, the rabbit’s back and flanks were shorn using electric clippers equipped with a fine comb, so as to expose an area of skin about 6 cm^2 per patch.
- As no tissue destruction was noted after a treatment during 3 minutes and 1 hour, the test item was applied, as supplied, at a dose of 0.5 mL, on an undamaged skin area of one flank of each animal, during 4 hours.
- Type of wrap if used: The patch was secured in position with a strip of surgical adhesive tape under semiocclusive dressing.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): After the removal of the patch, the treated area was rinsed with distilled water.
- Time after start of exposure: 4 h

SCORING SYSTEM: According to OECD guideline 404
Irritation parameter:
erythema score
Basis:
animal #1
Remarks:
mean individual score
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 72 hours
Remarks on result:
probability of weak irritation
Irritation parameter:
edema score
Basis:
animal #1
Remarks:
mean individual score
Time point:
24/48/72 h
Score:
0.3
Max. score:
4
Reversibility:
fully reversible within: 48 hours
Remarks on result:
probability of weak irritation
Irritation parameter:
erythema score
Basis:
animal #2
Remarks:
mean individual score
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 7 days
Remarks on result:
probability of mild irritation
Irritation parameter:
edema score
Basis:
animal #2
Remarks:
mean individual score
Time point:
24/48/72 h
Score:
2.3
Max. score:
4
Reversibility:
fully reversible within: 6 days
Remarks on result:
positive indication of irritation
Irritation parameter:
erythema score
Basis:
animal #3
Remarks:
mean individual score
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 6 days
Remarks on result:
probability of mild irritation
Irritation parameter:
edema score
Basis:
animal #3
Remarks:
mean individual score
Time point:
24/48/72 h
Score:
1.3
Max. score:
4
Reversibility:
fully reversible within: 5 days
Remarks on result:
probability of weak irritation
Irritant / corrosive response data:
- A well defined erythema was noted on the treated area of all animals, 24 hours after the patch removal. This erythematous reaction was totally reversible between day 3 and day 7.
- A very slight to moderate oedema was noted on the treated area of all animals, 24 hours after the patch removal. This oedematous reaction was totally reversible between day 2 and day 6.
- Regarding the cutaneous structure, a slight dryness was noted in all animals from day 2, day 3 or day 5. This cutaneous reaction was totally reversible on day 9 in one animal but slight dryness was registered until the last day of the test (day 14) in the two others.
Other effects:
None

Table 7.3.1/1: Individual and mean skin reactions following 4 hour exposure

Skin reaction

Observation time (following patch removal)

Individual Scores – Rabbit Number and Sex

A9499Female

A9523Female

A9524Female

Erythema/Eschar formation

1 h

2

1

2

24 h

2

2

2

48 h

1

2

2

72 h

0

2

2

Day 4

-

2

2

Day 5

-

1

1

Day 6

-

1

0

Day 7

-

0

-

Total (24, 48 and 72 hours)

3

6

6

Mean (24, 48 and 72 hours)

1.0

2.0

2.0

Oedema formation

1 h

2

2

1

24 h

1

3

2

48 h

0

2

1

72 h

0

2

1

Day 4

-

1

1

Day 5

-

1

0

Day 6

-

0

0

Day 7

-

0

-

Total (24, 48 and 72 hours)

1

7

4

Mean (24, 48 and 72 hours)

0.3

2.3

1.3

 

Note:

A9499: slight dryness at D2, D3, D6, D7 & D8

A9523: slight dryness at D3, D4, D9, D10, D13 & D14; dryness between D5 and D8

A9524: slight dryness at D5, D8, D9, D10, D13 & D14; dryness at D6 & D7

Interpretation of results:
Category 3 (mild irritant) based on GHS criteria
Conclusions:
Under the test conditions, test item is not classified according to CLP Regulation (EC) No. 1272/2008 but is classified as "Category 3 (mild irritant)" based on Globally Harmonized System (GHS).
Executive summary:

In a dermal irritation study performed according to the OECD Guideline No. 404, and in compliance with GLP, 0.5 mL of undiluted test item was applied on the shorn skin of the flanks of 3 female New Zealand White rabbits. On the opposite flank an untreated area was served as the control. Test sites were covered with a semi-occlusive dressing for 4 h. Skin irritation was assessed and scored according to the Draize scale at 1, 24, 48 and 72 hours, Day 4 to 14 after removal of the patch. Initially, a single animal was treated. After consideration of the cutaneous responses produced in the first treated animal, two additional animals were treated during 4 hours.


 


A well defined erythema was noted on the treated area of all animals, 24 hours after the patch removal. This erythematous reaction was totally reversible between day 3 and day 7. A very slight to moderate oedema was noted on the treated area of all animals, 24 hours after the patch removal. This oedematous reaction was totally reversible between day 2 and day 6. Regarding the cutaneous structure, a slight dryness was noted in all animals from day 2, day 3 or day 5. This cutaneous reaction was totally reversible on day 9 in one animal but slight dryness was registered until the last day of the test (day 14) in the two others.


 


The individual scores for each animal within 3 scoring times (24, 48 and 72 h) were 1.0 / 2.0 / 2.0 for erythema and 0.3 / 2.3 / 1.3 for oedema.


 


Under the test conditions, test item is not classified according to CLP Regulation (EC) No. 1272/2008 but is classified as "Category 3 (mild irritant)" based on Globally Harmonized System (GHS).


This study is considered as acceptable and satisfies the requirement for skin irritation endpoint.

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:
02 - 19 March 2009
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Remarks:
GLP study conducted according to OECD 405 Guideline without any deviation. The substance is adequately identified, but some data on composition is missing. Therefore validation applies with restrictions.
Justification for type of information:
An in vivo study was performed for worldwide notification purposes.
Qualifier:
according to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Version / remarks:
24 April 2002.
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)
Principles of method if other than guideline:
Not applicable
GLP compliance:
yes (incl. QA statement)
Remarks:
Inspected on 2008-04-14&15 /Signed on 2008-07-16.
Specific details on test material used for the study:
- Date received: 10 February 2009 (Flask 1); 18 February 2009 (Flask 2)
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Elevage de Gérome (Quartier Labaste – F40260 Linxe)
- Age at study initiation: 14-15 weeks
- Weight at study initiation: 3.10-3.57 kg
- Housing: Each animal was kept in an individual box installed in conventional air conditioned animal husbanding.
- Diet: Foodstuff (SDS- C15), ad libitum
- Water: Drinking water (tap-water from public distribution system), ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature: 17–23 °C
- Humidity: 30-70 %
- Air changes: ca. 15 changes per hour
- Photoperiod: 12 h dark / 12 h light

IN-LIFE DATES: 02 - 19 March 2009
Vehicle:
unchanged (no vehicle)
Controls:
yes
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 mL
Duration of treatment / exposure:
No washing was done
Observation period (in vivo):
Ocular examinations were performed on both right and left eyes 1, 24, 48 and 72 h & Days 4 to 10 following treatment, according to a numerical evaluation.
Number of animals or in vitro replicates:
3 males
Details on study design:
TREATMENT
- 0.1 mL of the test item was instilled into the conjunctival sac of one eye. The other eye remained untreated serving as control.
- Initially, a single animal was treated. After consideration of the ocular responses produced in the first treated animal, two additional animals were treated.

REMOVAL OF TEST SUBSTANCE
- Washing: No

SCORING SYSTEM: According to OECD guideline 405
Irritation parameter:
cornea opacity score
Basis:
animal #1
Remarks:
mean individual score
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable
Remarks on result:
no indication of irritation
Irritation parameter:
iris score
Basis:
animal #1
Remarks:
mean individual score
Time point:
24/48/72 h
Score:
0
Max. score:
2
Reversibility:
other: not applicable
Remarks on result:
no indication of irritation
Irritation parameter:
conjunctivae score
Basis:
animal #1
Remarks:
mean individual score
Time point:
24/48/72 h
Score:
1
Max. score:
3
Reversibility:
fully reversible within: 6 days
Remarks on result:
probability of weak irritation
Irritation parameter:
chemosis score
Basis:
animal #1
Remarks:
mean individual score
Time point:
24/48/72 h
Score:
2.3
Max. score:
4
Reversibility:
fully reversible within: 5 days
Remarks on result:
probability of mild irritation
Irritation parameter:
cornea opacity score
Basis:
animal #2
Remarks:
mean individual score
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable
Remarks on result:
no indication of irritation
Irritation parameter:
iris score
Basis:
animal #2
Remarks:
mean individual score
Time point:
24/48/72 h
Score:
0
Max. score:
2
Reversibility:
other: not applicable
Remarks on result:
no indication of irritation
Irritation parameter:
conjunctivae score
Basis:
animal #2
Remarks:
mean individual score
Time point:
24/48/72 h
Score:
1
Max. score:
3
Reversibility:
fully reversible within: 9 days
Remarks on result:
probability of weak irritation
Irritation parameter:
chemosis score
Basis:
animal #2
Remarks:
mean individual score
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 8 days
Remarks on result:
probability of weak irritation
Irritation parameter:
cornea opacity score
Basis:
animal #3
Remarks:
mean individual score
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: not applicable
Remarks on result:
no indication of irritation
Irritation parameter:
iris score
Basis:
animal #3
Remarks:
mean individual score
Time point:
24/48/72 h
Score:
0
Max. score:
2
Reversibility:
other: not applicable
Remarks on result:
no indication of irritation
Irritation parameter:
conjunctivae score
Basis:
animal #3
Remarks:
mean individual score
Time point:
24/48/72 h
Score:
2
Max. score:
3
Reversibility:
fully reversible within: 10 days
Remarks on result:
positive indication of irritation
Irritation parameter:
chemosis score
Basis:
animal #3
Remarks:
mean individual score
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 8 days
Remarks on result:
positive indication of irritation
Irritant / corrosive response data:
The ocular conjunctivae reactions observed during the study have been moderate to severe and totally reversible in the three animals: a moderate redness, noted 1 hour after the test item instillation and totally reversible between day 6 and day 10, associated with a moderate to severe chemosis, noted 1 hour after the test item instillation and totally reversible between day 5 and day 8.
Other effects:
None

Table 7.3.2/1: Individual and Mean Scores for Cornea, Iris and Conjunctivae

Rabbit Number and Sex

 

Time After Treatment

 

Corneal Opacity

 

Iris lesion

Conjunctival Redness

 

Conjunctival Chemosis

 

A9477 male

 

1 h

0

0

2

2

24 h

0

0

1

3

48 h

0

0

1

3

72 h

0

0

1

1

Day 4

0

0

1

1

Day 5

0

0

1

0

Day 6

0

0

0

0

Total (24, 48 and 72 h)

0

0

3

7

Mean (24, 48 and 72 h)

0.0

0.0

1.0

2.3

A9482 male

 

1 h

0

0

2

2

24 h

0

0

1

1

48 h

0

0

1

1

72 h

0

0

1

1

Day 4

0

0

1

1

Day 7

0

0

1

1

Day 8

0

0

1

0

Day 9

0

0

0

0

Total (24, 48 and 72 h)

0

0

3

3

Mean (24, 48 and 72 h)

0.0

0.0

1.0

1.0

A9483 male

 

1 h

0

0

2

3

24 h

0

0

2

2

48 h

0

0

2

2

72 h

0

0

2

2

Day 4

0

0

1

2

Day 7

0

0

1

1

Day 8

0

0

1

0

Day 9

0

0

1

0

Day 10

0

0

0

0

Total (24, 48 and 72 h)

0

0

6

6

Mean (24, 48 and 72 h)

0.0

0.0

2.0

2.0

Interpretation of results:
Category 2A (irritating to eyes) based on GHS criteria
Conclusions:
Under the test conditions, test item is classified in Category 2 for eye irritation according to the annex I of the Regulation (EC) No. 1272/2008 (CLP) and in Category 2A according to the GHS.
Executive summary:

In an eye irritation study conducted according to OECD 405 guideline and in compliance with GLP, 3 New Zealand White male rabbits were exposed to 0.1 mL of test item in one eye while the contralateral eye remained untreated and served as control. The lids were then gently held together for about one second in order to prevent loss of the test item. The eyes were examined and the changes were observed at 1, 24, 48 and 72 h and Days 4 to 10 following treatment and graded according to the Draize method.

 

The ocular conjunctivae reactions observed during the study have been moderate to severe and totally reversible in the three animals: a moderate redness, noted 1 hour after the test item instillation and totally reversible between day 6 and day 10, associated with a moderate to severe chemosis, noted 1 hour after the test item instillation and totally reversible between day 5 and day 8.

 

Mean individual scores at 24, 48 and 72 h after exposure for the 3 animals were 0.0, 0.0, 0.0 for cornea score; 0.0, 0.0, 0.0 for iris score; 1.0, 1.0, 2.0 for conjunctivae score and 2.3, 1.0, 2.0 for chemosis score.

 

Under the test conditions, test item is classified in Category 2 as "irritating to eyes" according to the annex I of the Regulation (EC) No. 1272/2008 (CLP) and in Category 2A according to the GHS.

This study is considered as acceptable and satisfies the requirement for eye irritation endpoint.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin irritation:


A key study was identified (Phycher, 2009). In this dermal irritation study performed according to the OECD Guideline No. 404, and in compliance with GLP, 3 female New Zealand White rabbits were exposed for 4 hours to a semi-occluded application of 0.5 mL of undiluted test material to the intact skin. Initially, a single animal was treated. After consideration of the cutaneous responses produced in the first treated animal, two additional animals were treated.


A well defined erythema was noted on the treated area of all animals, 24 hours after the patch removal. This erythematous reaction was totally reversible between day 3 and day 7. A very slight to moderate oedema was noted on the treated area of all animals, 24 hours after the patch removal. This oedematous reaction was totally reversible between day 2 and day 6. Regarding the cutaneous structure, a slight dryness was noted in all animals from day 2, day 3 or day 5. This cutaneous reaction was totally reversible on day 9 in one animal but slight dryness was registered until the last day of the test (day 14) in the two others.


The individual scores for each animal within 3 scoring times (24, 48 and 72 h) were 1.0 / 2.0 / 2.0 for erythema and 0.3 / 2.3 / 1.3 for oedema.


 


Eye irritation:


A key study was identified (Phycher, 2009). In this eye irritation study performed according to the OECD guideline 405, and in compliance with GLP, 0.1 mL of undiluted test material was instilled into one eye of 3 female New Zealand White rabbits. The other eye remained untreated and served as control. The eyes were examined and the changes were observed at 1, 24, 48 and 72 h and Days 4 to 10 following treatment and graded according to the Draize method.


The ocular conjunctivae reactions observed during the study have been moderate to severe and totally reversible in the three animals: a moderate redness, noted 1 hour after the test item instillation and totally reversible between day 6 and day 10, associated with a moderate to severe chemosis, noted 1 hour after the test item instillation and totally reversible between day 5 and day 8.


Mean individual scores at 24, 48 and 72 h after exposure for the 3 animals were 0.0, 0.0, 0.0 for cornea score; 0.0, 0.0, 0.0 for iris score; 1.0, 1.0, 2.0 for conjunctivae score and 2.3, 1.0, 2.0 for chemosis score.

Justification for classification or non-classification

Harmonized classification:


The substance has no harmonized classification according to the Regulation (EC) No. 1272/2008 (CLP).


 


Self classification:


Skin irritation:


Based on the available data, no additional self-classification is proposed regarding skin irritation according to the CLP and a classification as "Category 3 (mild irritant)" is proposed according to the GHS.


 


Eye irritation:


Based on the available data, the substance should be classified as eye irritation Category 2 (H319: Causes serious eye irritation) according to the CLP and as Category 2A "irritating to eyes" according to the GHS.


 


Respiratory irritation:


No data was available regarding respiratory irritation.