Registration Dossier

Administrative data

Description of key information

Skin irritation: not irritating (OECD 404; GLP compliant)
Eye irritation: not irritating (OECD 405; GLP compliant)

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:
2004-04-26 to 2004-05-18
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study
Qualifier:
according to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Version / remarks:
adopted 2002-04-24
Deviations:
yes
Remarks:
body weight at end of study and clinical signs were missing in the study report
Qualifier:
according to
Guideline:
EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)
Version / remarks:
, 2004
Deviations:
yes
GLP compliance:
yes
Species:
rabbit
Strain:
Himalayan
Details on test animals and environmental conditions:
TEST ANIMALS - stock: Chbb:HM; SPF albino rabbits
- Source: Charles River Deutschland, Kißlegg, Germany
- Age at study initiation: approx. 8 months
- Weight at study initiation: 2.0 - 2.3 kg bw
- Housing: rabbits were caged individually in PPO cages (floor area: 2576 sq.cm) with perforated floor.
- Diet (ad libitum): a pelleted complete rabbit diet "Altromin 2123" (supplier: Altromin, Lage, Lippe; Germany)
- Water (ad libitum): domestic quality drinking water acidified with hydrochloric acid to pH 2.5 in order to prevent microbial growth
- Acclimation period: at least one week

ENVIRONMENTAL CONDITIONS
- Temperature: 20°C ± 3°C
- Relative humidity: 55% ± 15%
- Air changes: 10 times/hour
- Photoperiod (hrs dark / hrs light): 12/12
Type of coverage:
semiocclusive
Preparation of test site:
clipped
Vehicle:
other: olive oil
Controls:
no
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 g of the test material

VEHICLE
- Amount(s) applied (volume or weight with unit): 0.1 mL olive oil
Duration of treatment / exposure:
initial animal: 3 minutes, 1 hour and 4 hours
Confirmatory animals:
Observation period:
immediately, 1 hour, 24 hours, 48 hours and 72 hours as well as on day 7 after termination
Number of animals:
3 female rabbits
Details on study design:
An initial test with one animal was carried out first followed by a confirmatory test with two animals..

TEST SITE
The day before the treatment the skin area on the back of the rabbits was clipped as closely as possible with an electric clipper.
The test item was applied to a 16-layer gauze patch (2.5 x 2.5 cm) and moistened with the vehicle, the patch was placed on the skin and secured semi-occlusively with adhesive Gothaplast tape (2.5 cm). After an exposure time of 3 minutes. The first patch was removed, the treated skin was cleaned with mild soap and lukewarm water. A first assessment of the skin reaction took place immediately after the termination of exposure.
No corrosive effects were observed and a second patch with test item was applied on the rabbit back. In order to improve the patch securing the trunk of the animal was additionally wound with 5 cm wide adhesive Gothaplast tape. After an exposure time of 1 hour the second patch was removed, the treated skin was cleaned with mild soap and lukewarm water. The skin reaction was first assessed immediately after the termination of exposure.
Again no corrosive effects were observed and the exposure time was extended to 4 hours. An amount of the test item was applied on a third patch, was moistened with 0.1 ml olive oil and put on the skin. Adhesive Gothaplast tape (2.5 cm and 5 cm wide) served again as the semiocclusive securing. After a 4-hour exposure time the third patch was removed, the treated skin was cleaned with mild soap and lukewarm water. The first assessment of the skin reaction took place again immediately after the termination of exposure.

A confirmatory test with two animals was carried out after the initial test. The animals were treated the same way as in the initial test except that the animals were only exposed for 4 hours.

SCORING SYSTEM: according to the Draize scale
Irritation parameter:
erythema score
Basis:
mean
Remarks:
animal #1
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
4
Irritation parameter:
edema score
Basis:
mean
Remarks:
animal #1
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
4
Irritation parameter:
erythema score
Basis:
mean
Remarks:
animal #2
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
4
Irritation parameter:
edema score
Basis:
mean
Remarks:
animal #2
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
4
Irritation parameter:
erythema score
Basis:
mean
Remarks:
animal #3
Time point:
other: 24, 48 and 72 hours
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
edema score
Basis:
mean
Remarks:
animal #3
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
4
Irritant / corrosive response data:
The animal used in the initial test showed no skin reactions immediately after the application.
1 hour after the termination of exposure no signs of skin irritation were observed at any animal.
24, 48 and 72 hours after the termination of exposure one animal showed a very slight erythema, whereas the other animals were free of any signs of skin irritation. 7 days after the termination of exposure this animal was free of any signs of skin irritation
Other effects:
1 hour after the termination of exposure no signs of skin
irritation were observed at the 3 animals.

24, 48 and 72 hours after the termination of exposure one of
the animals showed a very slight erythema on the anterior
right test field, whereas no skin reactions were observed

at the other two animals.
Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The test item is not irritating to the skin.
According to the EC-Commission directive 67/548/EEC and its subsequent amendments, the test substance is not classified as skin irritating.
According to the EC-Regulation 1272/2008 and subsequent regulations, the test item is not classified as skin irritating.
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:
2005-11-17 to 2005-12-05
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
GLP guideline study Deviation from OECD 405(2012), which are not considered to have an effect on the study results: The guideline recommends the use of topical anaesthetics and systemic analgesics during the study. This procedure was not used during this study. In addition, the guideline states that the animals should be observed several times during the first days. During this study the animals were observed daily only.
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Version / remarks:
adopted 2002-04-24
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)
Version / remarks:
, 2004
Deviations:
no
GLP compliance:
yes (incl. certificate)
Remarks:
signed 2005-04-15
Species:
rabbit
Strain:
Himalayan
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: LPT Laboratory of Pharmacology and Toxicology KG, branch Löhndorf, Löhndorf/Post Wankendorf, Germany
- Age at study initiation: approx. 4.5 months
- Weight at study initiation: 2.2 - 2.5 kg
- Housing: for 8 hours following test item application, the animals were kept singly in restrainers which allowed free movement of the head but prevented a complete body turn, wiping of the eyes with the paws and excluded Irritation of the eye by excrements and urine. During the acclimatisation period and after the 8-hour period in restrainers, the animals were kept singly in cages with dimensions of 400 mm x 500 mm x 370 mm (manufacturer: Dipl.ing. W. EHRET GmbH, Schönenwalde, Germany)
- Diet (ad libitum): ssniff® K-H V2333 (ssniff Spezialdiäten GmbH, Soest, Germany)
- Water (ad libitum): tap water
- Acclimation period: at least 20 adaptation day

ENVIRONMENTAL CONDITIONS
- Temperature: 20°C ± 3°C (maximum range)
- Relative humidity: 30% - 70% (maximum range)
- Photoperiod (hrs dark / hrs light): 12/12
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 100 mg of the test item was placed into the conjunctival sac of the right eye of each animal after gently pulling the lower lid away from the eyeball. The lids were then gently held together for about one second in order to prevent loss of the material. The left eye, which remained untreated, served as a control.
Duration of treatment / exposure:
24 hours
Observation period (in vivo):
prior to the administration and 1, 24, 48, 72 hours and 4 to 6 days after the administration
Number of animals or in vitro replicates:
3 male rabbits
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing: the eyes were rinsed several times with portions of 20 mL 0.9% aqueous NaCI solution.
- Time after start of exposure: 24 hours after administration

SCORING SYSTEM: according to the Draize scale
Any further lesions are Iisted.
Body weight of all animals was measured at the beginning of the study. Behaviour and food consumption were monitored.

TOOL USED TO ASSESS SCORE: the eyes were examined ophthalmoscopically with a slit lamp. 24 hours after administration, fluorescein was applied to the eyes before being examined to aid evaluation of the cornea for possible lesions.
Irritation parameter:
cornea opacity score
Basis:
mean
Remarks:
animal #1
Time point:
other: 24, 48 and 72 hours
Score:
0.67
Max. score:
4
Reversibility:
fully reversible within: 72 hours
Remarks on result:
other: 24 hour fluorescein test: corneal staining (1/2 to 3/4 of the surface
Irritation parameter:
iris score
Basis:
mean
Remarks:
animal #1
Time point:
other: 24, 48 and 72 hours
Score:
0.33
Max. score:
2
Reversibility:
fully reversible within: 48 hours
Irritation parameter:
conjunctivae score
Basis:
mean
Remarks:
animal #1
Time point:
other: 24, 48 and 72 hours
Score:
1.33
Max. score:
3
Reversibility:
fully reversible within: 6 days
Irritation parameter:
chemosis score
Basis:
mean
Remarks:
animal #1
Time point:
other: 24, 48 and 72 hours
Score:
1.67
Max. score:
4
Reversibility:
fully reversible within: 5 days
Remarks on result:
other: Secretion was observed.
Irritation parameter:
cornea opacity score
Basis:
mean
Remarks:
animal #2
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
4
Irritation parameter:
iris score
Basis:
mean
Remarks:
animal #2
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
2
Irritation parameter:
conjunctivae score
Basis:
mean
Remarks:
animal #2
Time point:
other: 24, 48 and 72 hours
Score:
1
Max. score:
3
Reversibility:
fully reversible within: 4 days
Irritation parameter:
chemosis score
Basis:
mean
Remarks:
animal #2
Time point:
other: 24, 48 and 72 hours
Score:
0.33
Max. score:
4
Reversibility:
fully reversible within: 48 hours
Irritation parameter:
cornea opacity score
Basis:
mean
Remarks:
animal #3
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
4
Irritation parameter:
iris score
Basis:
mean
Remarks:
animal #3
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
2
Irritation parameter:
conjunctivae score
Basis:
mean
Remarks:
animal #3
Time point:
other: 24, 48 and 72 hours
Score:
1
Max. score:
3
Reversibility:
fully reversible within: 4 days
Irritation parameter:
chemosis score
Basis:
mean
Remarks:
animal #3
Time point:
other: 24, 48 and 72 hours
Score:
0
Max. score:
4
Irritant / corrosive response data:
Corneal opacity (grade 1) was observed in one animal 24 and 48 hours after instillation. The fluorescein test performed 24 hours after instillation revealed corneal staining in this animal (1/2 to 3/4 of the surface). Irritation of the iris (grade 1) was also observed in this animal 24 hours after instillation. In addition, secretion was observed in this animal 1 hour after instillation.
Conjunctival redness was observed in one animal 24 hours (grade 2), 1 hour and 48 hours to 5 days (grade 1) after instillation and in the remaining two animals 1 hour to 72 hours (grade 1) after instillation.
Conjunctival chemosis was observed in one animal 24 hours (grade 3), 1 hour (grade 2) and 48 hours to 4 days (grade 1) after instillation. In another animal the conjunctival chemosis was observed 1 hour and 24 hours (grade 1) after instillation and in third animal 1 hour (grade 1) after instillation.
Other effects:
There were no systemic intolerance reactions.
Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The test item is not irritating to the eyes.
According to the EC-Commission directive 67/548/EEC and its subsequent amendments, the test substance is not classified as eye irritating.
According to the EC-Regulation 1272/2008 and subsequent regulations, the test item is not classified as eye irritating.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Additional information

Skin irritation

An acute skin irritation study according to OECD 404 (key_in vivo Skin irritation / corrosion_2004_Rel1) is considered to be reliable without restrictions. The test item is not irritating to skin.

Eye irritation

An acute eye irritation / corrosion test according to OECD 405 (key_in vivo eye irritation_2004_Rel1) is considered to be reliable without restrictions. The test item is not irritating to eyes.


Justification for selection of skin irritation / corrosion endpoint:
GLP guideline study with the test item

Justification for selection of eye irritation endpoint:
GLP guideline study with the test item

Justification for classification or non-classification

Skin irritation:

The test item does not possess a skin irritation potential and does not require classification as skin irritant according to Directive 67/548/EEC and Regulation (EC) No. 1272/2008.

 

Eye irritation:

The test item does not possess an eye irritation potential and does not require classification as eye irritant according to

Directive 67/548/EEC and Regulation (EC) No. 1272/2008.