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Description of key information

The primary skin irritation potential of the test item was investigated according to OECD test guideline no. 404. The test item was applied by topical semi-occlusive application of 0.5 g to the intact left flank of rabbits. The duration of treatment was four hours. The scoring of skin reactions was performed 1, 24, 48 and 72 hours, as well as 7, 10 and 14 days after removal of the dressing.

The mean erythema/eschar score of the three animals was 0.00, 0.33 and 0.00, respectively and the mean oedema score was 0.00 for all three animals.

Effects were reversible and were no longer evident 48 hours after treatment for all animals. However, staining by the red test item prevented the assessment of a possible erythema in all animals one hour after treatment. The slight to marked staining of the treated skin was noted in all animals throughout the whole study. No corrosive effects were noted on the treated skin of any animal and no clinical signs were observed.

A study according to OECD Guideline 405 and EU Method B.5 was performed to investigate the irritation potential to the rabbit eye.

One and 24 hours after treatment the conjunctivae of the animals showed definitely injected blood vessels up to a diffuse crimson red colour. Additionally, a very slight swelling and slightly coloured eye discharge (from intensely red substance) were

observed in one animal one hour after treatment. Fourty-eight hours after treatment all signs of irritation had disappeared.

As the mean values of the observed eye responses fall below the critical values for classification according to the criteria of Regulation (EC) No 1272/2008, the test material is not irritating to eyes.

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
Study period:
28 June 2005 to 10 August 2005
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study meets or exceeds the requirements of OECD Guideline 404 and EU Method B.4
Qualifier:
according to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
yes
Remarks:
A gauze patch of approximately 4 cm x 4 cm (instead of 6 cm2) was used to guarantee good contact and uniform distribution of the test substance on the skin
Qualifier:
according to guideline
Guideline:
EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)
Deviations:
yes
Remarks:
as above
GLP compliance:
yes (incl. QA statement)
Remarks:
Study in compliance with Swiss Ordinance relating to GLP, which is based on OECD Principles of GLP
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Animal specifics: SPF
- Source: Charles River Laboratories, L'Arbresle, France
- Age at study initiation: 12 weeks (male), 12-13 weeks (females)
- Weight at study initiation: 2741 g for the male, 2873 g and 2674 g for the two females, all within the normal range of variability
- Housing: Individually in stainless steel cages equipped with feed hoppers and drinking water bowls
- Diet (e.g. ad libitum): standard laboratory diet ad libitum
- Water (e.g. ad libitum): community tap water, ad libitum
- Acclimation period: 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17-23 °C (air-condition)
- Humidity (%): 30-70%
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12
Type of coverage:
semiocclusive
Preparation of test site:
shaved
Vehicle:
water
Controls:
not required
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 g

VEHICLE
- Amount(s) applied (volume or weight with unit): 0.5 ml of purified water were used to moisten the test item
Duration of treatment / exposure:
4 hours
Observation period:
14 days
Number of animals:
3
Details on study design:
TEST SITE
- Area of exposure: approximately 4 cm x 4 cm
- Type of wrap if used: surgical gauze patch

REMOVAL OF TEST SUBSTANCE
- Washing (if done): flushed with lukewarm tap water
- Time after start of exposure: 4 hours

SCORING SYSTEM:
as in EU Method B.4, assessed approximately 1, 24, 48, and 72 h after the romoval of the test item as well as after 7, 10 and 14 d
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: not relevant since no effects
Remarks on result:
no indication of irritation
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0.33
Max. score:
4
Reversibility:
fully reversible within: 48 h after treatment
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: not relevant since no effects
Remarks on result:
no indication of irritation
Irritation parameter:
edema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: not relevant since no effects
Remarks on result:
no indication of irritation
Irritation parameter:
edema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: not relevant since no effects
Remarks on result:
no indication of irritation
Irritation parameter:
edema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: not relevant since no effects
Remarks on result:
no indication of irritation
Irritant / corrosive response data:
Apart from animal #2 at 24 h, all other scores (oedema or erythema) were 0 at all time points in all animals (see below for individual data).
Other effects:
No clinical signs or effects on body weight were observed. Erythema scores could not be assessed in all animals at 1 h due to marked staining produced by the test item

Animal number

Sex 

Evaluation interval (after removal of dressing )

Erythema score

Oedema score 

#1

M 

1 hour 

not assessible due to staining

0 

#2

F

0

#3

F

0

#1 

M 

24 hours

0

0 

#2

F

1

0

#3

F

0

0

#1

M

48 hours

0

0

#2

F

0

0

#3

F

0

0

#1

M

72 hours 

0

0

#2

F

0

0

#3

F 

0

0

#1

M

7 days 

0

0

#2

F

0

0

#3

F

0

0

#1

M

10 days

0

0

#2

F

0

0

#3

F

0

0

#1

M

14 days

0

0

#2

F

0

0

#3

F

0

0
Interpretation of results:
not irritating
Conclusions:
According to the classification criteria of Regulation (EC) No 1272/2008 the test item is not irritating to skin under these test conditions.
Executive summary:

The primary skin irritation potential of the test item was investigated according to OECD test guideline no. 404. The test item was applied by topical semi-occlusive application of 0.5 g to the intact left flank of each of three young adult New Zealand White rabbits. The duration of treatment was four hours. The scoring of skin reactions was performed 1, 24, 48 and 72 hours, as well as 7, 10 and 14 days after removal of the dressing.

The mean score was calculated across 3 scoring times (24, 48 and 72 hours after patch removal) for each animal for erythema/eschar grades and for oedema grades, separately. The mean erythema/eschar score of the three animals was 0.00, 0.33 and 0.00, respectively and the mean oedema score was 0.00 for all three animals.

The application of the test item to the skin resulted in mild, early-onset and transient signs of irritation such as redness. These effects were reversible and were no longer evident 48 hours after treatment for all animals. However, staining by the red test item prevented the assessment of a possible erythema in all animals one hour after treatment. The slight to marked staining of the treated skin was noted in all animals throughout the whole study, effectively. No corrosive effects were noted on the treated skin of any animal at any of the measuring intervals and no clinical signs were observed.

Thus, the test item did not induce significant or irreversible damage to the skin.

Therefore, the test item has not to be classified for skin irritation according to Regulation (EC) No 1272/2008.

Endpoint:
skin irritation: in vitro / ex vivo
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
an in vitro skin irritation study does not need to be conducted because adequate data from an in vivo skin irritation study are available
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Referenceopen allclose all

Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
6 October 1998 to 13 November 1998
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study conducted in compliance with OECD Guideline 405 and EU Method B.5
Qualifier:
according to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Qualifier:
according to guideline
Guideline:
EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland GmbH, Kißlegg, Germany
- Weight at study initiation: 3.51-3.91 kg
- Housing: separate cages arranged in a battery in fully air-conditioned rooms
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 1 week under study conditions

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 ± 3 °C
- Humidity (%): 50 ± 20 %
- Photoperiod (hrs dark / hrs light): 12/12
Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 100 mg
Duration of treatment / exposure:
One administration (for times of removal of the test substance see below)
Observation period (in vivo):
72 hours
Number of animals or in vitro replicates:
3
Details on study design:
- Application of the substance to the conjunctival sac of the left eye of each animal

REMOVAL OF TEST SUBSTANCE
- Washing: Washing with isotonic saline at approx. 37 °C 24 h after administration and at all other designated examination times at which the treated eyes still showed discharge or at which a corneal examination with fluorescein sodium solution (24 and 72 h after administration) took place
- Time after start of exposure: see above

TOOL USED TO ASSESS SCORE: fluorescein-sodium, under UV light
Irritation parameter:
cornea opacity score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: not relevant since no effects
Remarks on result:
no indication of irritation
Irritation parameter:
cornea opacity score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: not relevant since no effects
Remarks on result:
no indication of irritation
Irritation parameter:
cornea opacity score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: not relevant since no effects
Remarks on result:
no indication of irritation
Irritation parameter:
iris score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
2
Reversibility:
other: not relevant since no effects
Remarks on result:
no indication of irritation
Irritation parameter:
iris score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
2
Reversibility:
other: not relevant since no effects
Remarks on result:
no indication of irritation
Irritation parameter:
iris score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
2
Reversibility:
other: not relevant since no effects
Remarks on result:
no indication of irritation
Irritation parameter:
conjunctivae score
Remarks:
redness
Basis:
animal #1
Time point:
24/48/72 h
Score:
0.3
Max. score:
3
Reversibility:
fully reversible within: 48 hours
Irritation parameter:
conjunctivae score
Remarks:
redness
Basis:
animal #2
Time point:
24/48/72 h
Score:
0.3
Max. score:
3
Reversibility:
fully reversible within: 48 hours
Irritation parameter:
conjunctivae score
Remarks:
redness
Basis:
animal #3
Time point:
24/48/72 h
Score:
0.3
Max. score:
3
Reversibility:
fully reversible within: 48 hours
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: effects observed at 1 hour, but reversible by 24 hour observation
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: not relevant since no effects
Remarks on result:
no indication of irritation
Irritation parameter:
chemosis score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
other: not relevant since no effects
Remarks on result:
no indication of irritation

Animal no. -- observation time -- cornea opacity -- cornea area -- iris -- conjunctiva redness -- conjunctiva chemosis -- conjunctiva discharge

311 -- 1 hour ---- 0 -- 0 -- 0 -- 2 -- 1 -- 1

311 -- 24 hours -- 0 -- 0 -- 0 -- 1 -- 0 -- 0

311 -- 48 hours -- 0 -- 0 -- 0 -- 0 -- 0 -- 0

311 -- 72 hours -- 0 -- 0 -- 0 -- 0 -- 0 -- 0

314 -- 1 hour -- --0 -- 0 -- 0 -- 1 -- 0 -- 0

314 -- 24 hours -- 0 -- 0 -- 0 -- 1 -- 0 -- 0

314 -- 48 hours -- 0 -- 0 -- 0 -- 0 -- 0 -- 0

314 -- 72 hours -- 0 -- 0 -- 0 -- 0 -- 0 -- 0

315 -- 1 hour ---- 0 -- 0 -- 0 -- 1 -- 0 -- 0

315 -- 24 hours -- 0 -- 0 -- 0 -- 1 -- 0 -- 0

315 -- 48 hours -- 0 -- 0 -- 0 -- 0 -- 0 -- 0

315 -- 72 hours -- 0 -- 0 -- 0 -- 0 -- 0 -- 0

Mean individual scores after 24, 48 and 72 hours for animal no. -- corneal opacity -- iris -- conjunctivae redness -- conjunctivae chemosis

311 -- 0.0 -- 0.0 -- 0.3 -- 0.0

314 -- 0.0 -- 0.0 -- 0.3 -- 0.0

315 -- 0.0 -- 0.0 -- 0.3 -- 0.0

Interpretation of results:
not irritating
Conclusions:
According to the classification criteria of Regulation (EC) No 1272/2008 the test material is not irritating to eyes under these test conditions.
Executive summary:

A study according to OECD Guideline 405 and EU Method B.5 was performed to investigate the irritation potential to the rabbit eye.

One and 24 hours after treatment the conjunctivae of the animals showed definitely injected blood vessels up to a diffuse crimson red colour. Additionally, a very slight swelling and slight from substance coloured eye discharge were observed in one animal one hour after treatment. Fourty-eight hours after treatment all signs of irritation were reversible.

As the mean values of the observed eye responses fall below the critical values for classification according to the criteria of Regulation (EC) No 1272/2008, the test material is not irritating to eyes and has not to be classified for eye irritation.

Endpoint:
eye irritation: in vitro / ex vivo
Data waiving:
study technically not feasible
Justification for data waiving:
an in vitro eye irritation study does not need to be conducted because adequate data from an in vivo eye irritation study are available
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Justification for classification or non-classification

No classification

The test material was not irritant to skin and eyes in in vivo assays in rabbits.