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Administrative data

Description of key information

Skin: OECD 404; no dermal irritation in rabbits. Reliability = 1
Eye: OECD 405; slight irritation in rabbits. Reliability = 1

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
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
no
Remarks:
The study was conducted according to the guideline in effect at the time of study conduct.
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.2500 (Acute Dermal Irritation)
Deviations:
no
Remarks:
The study was conducted according to the guideline in effect at the time of study conduct.
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: Young adult
- Weight at study initiation: 2284, 2059, 2320 g
- Housing: Singly in suspended stainless steel caging with mesh floors. Enrichment (e.g., toy) was placed in each cage. Litter paper was placed beneath the cage and was changed at least 3 times per week
- Diet (e.g. ad libitum): amount not reported
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 6 or 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-21ºC
- Humidity (%): 24-60%. Low humidity was noted during the study. Portable humidifiers were used to increase the humidity levels during this time.
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): 12-hour light/dark cycle
Type of coverage:
semiocclusive
Preparation of test site:
shaved
Vehicle:
unchanged (no vehicle)
Controls:
other: The adjacent areas of untreated skin were used for comparison.
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 m/L
Duration of treatment / exposure:
4 hours
Observation period:
immediately following patch removal and 30-60 minutes, and 24, 48, and 72 hours after patch removal
Number of animals:
3
Details on study design:
TEST SITE
- Area of exposure: approximately 6 cm2
- % coverage: 100
- Type of wrap if used: 4-ply gauze pad. The pad and entire trunk of each animal were then wrapped with semi-occlusive 3-inch Micropore tape to avoid dislocation of the pad.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): test sites were gently cleansed of any residual test substance
- Time after start of exposure: 4 hours

SCORING SYSTEM: Draize Scale
Irritation parameter:
erythema score
Basis:
animal:
Time point:
24/48/72 h
Score:
0
Max. score:
4
Remarks on result:
no indication of irritation
Irritation parameter:
edema score
Basis:
animal:
Time point:
24/48/72 h
Score:
0
Max. score:
4
Remarks on result:
no indication of irritation
Irritant / corrosive response data:
There was no dermal irritation noted for any treated dose site during the study.
Other effects:
All animals appeared active and healthy and gained body weight during the study. There were no signs of gross toxicity, adverse pharmacologic effects, or abnormal behavior.
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
There was no dermal irritation noted for any treated dose site during the study.

This study and the conclusions which are drawn from it fulfill the quality criteria (validity, reliability, repeatability).
Executive summary:

A primary skin irritation test was conducted with rabbits to determine the potential for the test substance to produce irritation after a single topical application. At the request of the Sponsor, the study was conducted in a stepwise manner using a single patch applied initially to one rabbit for 4-hours. Five-tenths of a milliliter of the test substance was applied to the skin of one healthy rabbit for 4-hours. The dose site was evaluated for dermal irritation by the method of Draize et al. immediately following patch removal, and at 30-60 minutes and 24, 48, and 72 hours after patch removal. Since there was no dermal irritation observed in this animal, the test was completed on two additional animals, as described above. There was no dermal irritation noted for any treated dose site during the study.

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:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Justification for type of information:
An existing in vivo test from 2009 was used to replace the required in vitro test.
Qualifier:
according to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
no
Remarks:
The study was conducted according to guideline in effect at time of study conduct.
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.2400 (Acute Eye Irritation)
Deviations:
no
Remarks:
The study was conducted according to guideline in effect at time of study conduct.
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Age at study initiation: Young adult
- Weight at study initiation: 2534, 2710, 2530 g
- Housing: Singly in suspended stainless steel caging with mesh floors. Enrichment (e.g., toy) was placed in each cage. Litter paper was placed beneath the cage and was changed at least 3 times per week
- Diet: amount not reported
- Water: ad libitum
- Acclimation period: 12 or 14 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-21°C
- Humidity (%): 30-59%
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): 12-hour light/dark cycle
Vehicle:
unchanged (no vehicle)
Controls:
other: other eye of each rabbit remained untreated and served as a control
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 mL

Duration of treatment / exposure:
After treatment, the upper and lower lids were gently held together for about one second before releasing to minimize loss of the test substance.
Observation period (in vivo):
1, 24, 48 and 72 hours
Number of animals or in vitro replicates:
3
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing: unwashed

SCORING SYSTEM: Draize Scale

TOOL USED TO ASSESS SCORE: High-intensity white lite in accordance with Draize, et al. Fluorescein dye evaluation was used in the treated eyes at 24 hours to verify the absence of corneal damage.
Irritation parameter:
cornea opacity score
Remarks:
opacity
Basis:
animal:
Time point:
24/48/72 h
Score:
0
Max. score:
4
Remarks on result:
no indication of irritation
Irritation parameter:
iris score
Basis:
animal:
Time point:
24/48/72 h
Score:
> 0 - < 1
Max. score:
2
Reversibility:
fully reversible within: 24 hours
Remarks on result:
probability of weak irritation
Irritation parameter:
conjunctivae score
Remarks:
redness
Basis:
animal:
Time point:
24/48/72 h
Score:
> 0 - < 1
Max. score:
3
Reversibility:
fully reversible within: 48 hours
Remarks on result:
probability of weak irritation
Irritation parameter:
chemosis score
Basis:
animal:
Time point:
24/48/72 h
Score:
0
Max. score:
4
Remarks on result:
no indication of irritation
Irritation parameter:
other: Discharge
Basis:
other: range
Time point:
other: 1 to 72 hours
Score:
> 0 - < 1
Max. score:
3
Reversibility:
fully reversible within: 48 hours
Irritant / corrosive response data:
There was no corneal opacity noted in any treated eye during the study. One hour after test substance instillation, all three treated eyes exhibited iritis and conjunctivitis. The overall incidence of irritation decreased with time. All animals were free of ocular irritation by 48 hours. The ocular scores from the animal with respect to observation time are presented in Table 1.
Other effects:
All animals appeared active and healthy and gained body weight during the study. Apart from the eye irritation noted, there were no other signs of gross toxicity, adverse pharmacologic effects, or abnormal behaviour.

Table 1: Individual Scores for Ocular Irritation

 

Rabbit No.: 3401 (Female)

Rabbit No.: 3402 (Female)

Rabbit No.: 3403 (Female)

 

Hours

Hours

Hours

 

1

24

48

72

1

24

48

72

1

24

48

72

I. Cornea

 

A. Opacity

0

01

0

0

0

01

0

0

0

01

0

0

B. Area

4

4

4

4

4

4

4

4

4

4

4

4

II. Iris

 

A. Values

1

0

0

0

1

0

0

0

1

0

0

0

III. Conjunctivae

 

A. Redness

1

0

0

0

1

1

0

0

1

0

0

0

B. Chemosis

0

0

0

0

0

0

0

0

0

0

0

0

C. Discharge

1

0

0

0

1

1

0

0

1

0

0

0

12% ophthalmic fluorescein sodium used to verify the absence of corneal opacity. 
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Iritis and conjunctivitis (score of 1) were observed. All animals were free of ocular irritation by 48 hours.

This study and the conclusions which are drawn from it fulfill the quality criteria (validity, reliability, repeatability).
Executive summary:

A primary eye irritation test was conducted with rabbits to determine the potential for the test substance to produce irritation from a single instillation via the ocular route. A skin irritation study was previously conducted. The test substance was not a severe skin irritant or corrosive to the skin. At the request of the Sponsor, the study was conducted in a stepwise fashion. Initially, one-tenth of a milliliter of the test substance was instilled into the conjunctival sac of the right eye of one healthy rabbit by pulling the lower lid away from the eyeball. The upper and lower lids were then gently held together for about one second before releasing to minimize loss of the test substance. The left eye remained untreated and served as a control. Ocular irritation was evaluated by the method of Draize et al. Since there was no significant irritation observed in this animal, the test was completed on two additional animals, as described above.

There was no corneal opacity noted in any treated eye during the study. One hour after test substance instillation, all three treated eyes exhibited iritis and conjunctivitis. The overall incidence of irritation decreased with time. All animals were free of ocular irritation by 48 hours.

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

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

After application of a single 0.5 mL dermal dose to the shaved intact skin of rabbits for 4 hours, no dermal irritation was observed at any time point evaluated.

After instillation of 0.1 mL of test substance into the lower conjunctival sac of the eye of 3 rabbits, slight conjunctival redness (score of 1) and iritis (score of 1) were observed in 3 rabbits one hour after test substance instillation. The overall incidence of irritation decreased with time and all animals were free of ocular irritation by 48 hours.


Justification for selection of skin irritation / corrosion endpoint:
OECD Guideline, GLP study

Justification for selection of eye irritation endpoint:
OECD Guideline, GLP study

Justification for classification or non-classification

There was no evidence of skin irritation and only minimal, transient eye irritation in rabbit studies. Therefore, the substance does not need to be classified for skin or eye irritation according the EU Directive 67/548/EEC and EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.