Registration Dossier

Administrative data

Description of key information

1.  Skin irritation/corrosion (1994), GLP, OECD 404, rabbit, 0.5 g, moistened with water, 4 hours occlusive conditions, non-irritant
2. Eye irritation (1995), GLP, OECD 405, rabbit, 0.1 g pure substance, eye irritant category 2

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records
Reference
Endpoint:
skin irritation / corrosion, other
Remarks:
in vivo study, which was an Annex VII requirement at the time
Type of information:
experimental study
Adequacy of study:
key study
Study period:
November - December 1994
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP-guideline study
Reference:
Composition 0
Qualifier:
according to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test material information:
Composition 1
Specific details on test material used for the study:
Batch 3078183
Species:
rabbit
Strain:
other: young albino rabbits
Details on test animals and environmental conditions:
TEST ANIMALS
- Species: Young albino rabbits without morbid signs
- Source: Dr. Zimmerman, Schweizer Hof, Untergröningen, Germany
- Weight at study initiation: 3472 g, 2773 g and 2906 g
- Housing: Individually in wire grating cages (area 2450 cm2, height 42 cm) without bedding
- Diet: Raiffeisen-Ringfutter, Kaninchen Trockenfutter 52/P, Raiffeinsen Kraftfutterwerk Kehl, ad libitum
- Water: Community tap water from Karlsruhe, free access for the animals by daily changing of the watering-bottles
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 23 °C
- Humidity (%): 30 - 70 %
- Light-dark-rythm: 12 : 12
Type of coverage:
occlusive
Preparation of test site:
shaved
Vehicle:
water
Controls:
other: The shaved area next to the exposure area was employed such as control.
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 g per animal

VEHICLE
- test substance moistened with a small amount of water
Duration of treatment / exposure:
4 hours
Observation period:
7 days
Number of animals:
2 male, 1 female rabbit
Details on study design:
The test substance moistened with a small amount of water was dermally applied in a songle dose of 0.5 g / per animal onto a shaved area of 3 x 5 cm2 of the dorso-lumbar region of three albino rabbits. The region treated was protected with an occlusive patch. After the end of the exposure period of 4 hours the bandage was removed and residual test substance was removed by gently washing with water.
In the following observation period of 7 days mortality, toxicological symptoms, behaviour, body weight and skin reactions were reported. The shaved area next to the exposure area was employed such as control.
Irritation parameter:
erythema score
Basis:
mean
Time point:
other: 1 hour after bandage removal
Score:
1.3
Reversibility:
fully reversible within: 6 days
Irritation parameter:
edema score
Basis:
mean
Time point:
other: 1 hour after bandage removal
Score:
1.3
Reversibility:
fully reversible within: 6 days
Irritant / corrosive response data:
The test substance produced skin lesions in the form of erythemata and oedemata. The maximum grade of these lesions was 2. All effects observed turned out to be reversible.
Other effects:
Visible toxicological signs could not be observed; none of the animals died during the observation period.

Acute Dermal Irritation/Corrosion, Evaluation of the skin reaction.

Mean value of all animals.

Test substance Control
Time after application Erythema Oedema Erythema Oedema
1 hour after bandage removal 1.3 1.3 0 0
day 1 1 1 0 0
day 2 1 0.7 0 0
day 3 0.7 0.3 0 0
day 4 - - - -
day 5 0.3 0.3 0 0
day 6 0 0 0 0
day 7 0 0 0 0

Skin reaction control:

The shaved area close to the exposure area was employed such as control. The control area did not show any pathological skin reaction. According to table 1 of OECD-Guideline 404 at all times of evaluation the value was classified as 0.

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: other: EU-GHS
Conclusions:
The study was performed according to the OECD Guideline 404 with no deviations and according to the good laboratory practice principles, it is considered to be of the highest quality (reliability Klimisch 1). The criteria of validity of the test system are fulfilled. The mean grades of skin reactions at 24, 48 and 72 h after patch removal were lower than the value classified as irritant by the European regulation (EC) No. 1272/2008, amending regulation EC no. 1907/2006 (REACh). When applied to the skin, the test article may therefore be considered to be non-irritant. The test material did produce skin lesions in the form of erythemata and oedemata on the intact skin of rabbits. None of these lesions had a grade above 2 and all lesions were fully reversible latest within 6 days. The test substance is considered to be not irritating to the skin.
Executive summary:

The skin irritation potential of the test substance was investigated in rabbits (Dr. B. Grunert, 1994, according to TG OECD 404). The test substance was applied to the skin of rabbit (skin shaved, substance moistened with water, 0.5 g substance / animal applied) for 4 hours under occlusive conditions. The study was performed according to the OECD Guideline 404 with no deviations and according to the good laboratory practice principles, it is considered to be of the highest quality (reliability Klimisch 1). The criteria of validity of the test system are fulfilled. After this period the skin was evaluated 60 min and daily for 7 days after patch removal. The test substance produced skin lesions in the form of erythemata and oedemata. The mean grades of skin reactions were lower than the value classified as irritant by the European regulation (EC) No. 1272/2008, amending regulation EC no. 1907/2006 (REACh). When applied to the skin, the test article may therefore be considered to be non- irritant.

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

Eye irritation

Link to relevant study records
Reference
Endpoint:
eye irritation, other
Remarks:
in vivo study, which was an Annex VII requirement at the time
Type of information:
experimental study
Adequacy of study:
key study
Study period:
November 1994 - February 1995
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP-guideline study
Reference:
Composition 0
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test material information:
Composition 1
Specific details on test material used for the study:
Batch 3078183
Species:
rabbit
Strain:
other: Albino rabbit
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Dr. Zimmermann, Untergröningen, Germany
- Weight at study initiation: 2736 g, 2453 g, 2768 g
- Housing: individually in wire grating cages (area 2450 cm2, height 42 cm) without bedding
- Diet: Raiffeisen Ringfutter Kaninchen Trockenfutter 52/P, ad libitum
- Water: Community tab water from Karlsruhe; free access for the animals by daily changing of the watering-bottles
- Acclimation period:

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 22 °C
- Humidity (%): 30 - 70 %
- Light - dark - rhythm: 12 : 12
Vehicle:
unchanged (no vehicle)
Controls:
other: the left eye was not treated and was used for control.
Amount / concentration applied:
0.1 g
Duration of treatment / exposure:
24 h
Observation period (in vivo):
21 days
Number of animals or in vitro replicates:
1 female, 2 male
Details on study design:
The test substance was applied undiluted in a single dose of 0.1 g into the right eye to each of 3 albino rabbits.
The substance was placed into the conjunctival sac of one eye 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.
24 h after administration the eye was carefully rinsed with NaCl 0.9 % in order to remove the residual test substance. The left eye was not treated and was used for control.
Mortality, toxicological symptoms, behaviour, body weight, eye reaction according to OECD-guideline 405 were observed 1 hour after administration and then daily for the observation period of 21 days.
On the first day, on the seventh and on the 21st day after exposure the cornea was tested with fluorescein solution to detect defects.
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
other: 1st hour, day 1 to 3, day 7
Score:
3
Reversibility:
not fully reversible within: 21 days
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
other: day 14
Score:
1.7
Reversibility:
not fully reversible within: 21 days
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
other: day 21
Score:
1
Reversibility:
not fully reversible within: 21 days
Irritation parameter:
iris score
Basis:
mean
Time point:
other: 1st hour
Score:
0
Reversibility:
fully reversible within: 14 days
Irritation parameter:
iris score
Basis:
mean
Time point:
other: day 1 to day 3
Score:
1
Reversibility:
fully reversible within: 14 days
Irritation parameter:
iris score
Basis:
mean
Time point:
other: day 7
Score:
1.3
Reversibility:
fully reversible within: 14 days
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
other: 1st hour, day 1 to 3
Score:
3
Reversibility:
fully reversible within: 16 days
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
other: day 7
Score:
2
Reversibility:
fully reversible within: 16 days
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
other: day 14
Score:
1
Reversibility:
fully reversible within: 16 days
Irritation parameter:
chemosis score
Basis:
mean
Time point:
other: 1st hour, day 1 and day 3
Score:
4
Reversibility:
not fully reversible within: 21 days
Irritation parameter:
chemosis score
Basis:
mean
Time point:
other: day 7
Score:
3.3
Reversibility:
not fully reversible within: 21 days
Irritation parameter:
chemosis score
Basis:
mean
Time point:
other: day 14
Score:
1
Reversibility:
not fully reversible within: 21 days
Irritation parameter:
chemosis score
Basis:
mean
Time point:
other: day 21
Score:
0.3
Reversibility:
not fully reversible within: 21 days
Irritant / corrosive response data:
All three rabbits suffered from severe conjunctivitis combined with suppuration. Despite the medical treatment of the eyes, all three rabbits showed ocular lesions of the cornea up to the end of the study. The chemosis effects on conjunctivae are reversible in the eyes of two rabbits. One rabbit had swelling of lids up to the end of the study.
A fluorescein test to demonstrate defects of the cornea was performed on day 1, day 7 and day 21. It was positive for the test substance for all rabbits on day 1 and day 7. On day 21 this test was negative for all rabbits.
Other effects:
Two animals yelled with pain at the administration of the test substance. The test substance did not cause mortality. In the course of the experiment the body weight of all three rabbits increased.

Findings, mean value of grades of ocular lesions

Administration: test substance in the right eye

Control: untreated left eye

conjunctivae
time after administration cornea iris redness chemosis
right left right left right left right left
1st hour 3 0 0 0 3 0 4 0
day 1 3 0 1 0 3 0 4 0
day 2 3 0 1 0 3 0 3.7 0
day 3 3 0 1 0 3 0 4 0
day 4 - - - - - - - -
day 5 - - - - - - - -
day 6 3 0 1 0 3 0 3.3 0
day 7 3 0 1.3 0 2 0 3.3 0
day 8 3.7 0 1.7 0 2 0 4 0
day 9 3.7 0 1.7 0 2 0 2 0
day 10 3.7 0 1.7 0 2 0 2 0
day 11 - - - - - - - -
day 12 - - - - - - - -
day 13 3 0 1 0 1 0 1 0
day 14 1.7 0 0 0 1 0 1 0
day 15 1.7 0 0 0 1 0 1 0
day 16 1.7 0 0 0 0 0 1 0
day 17 1 0 0 0 0 0 0.7 0
day 18 - - - - - - - -
day 19 - - - - - - - -
day 20 1 0 0 0 0 0 0.3 0
day 21 1 0 0 0 0 0 0.4 1

A fluorescein-test was perfomed on day 1, day 7 and day 21 in order to demonstrate defects of the cornea. On day 1 and day 7 this test was positive for the test substance for all rabbits. On day 21 this test was negative for the test substance for all rabbits.

Exsudation was observed in the right eye of all rabbits from day 0 to day 9. The symptom was strong suppuration for all rabbits.

Interpretation of results:
irritating
Remarks:
Migrated information Category 2 Criteria used for interpretation of results: other: EU-GHS
Conclusions:
The study was performed according to the OECD TG405 without deviations and according to the good laboratory practice principles, it is considered to be of the highest quality (reliability Klimisch 1). The criteria of validity of the test system are fulfilled. The test material did induce effects on rabbit eyes. The test material was considered to be irritating under the conditions of the test.
Executive summary:

The test substance was investigated for its potential to cause irritation in the rabbit eye according to OECD TG 405. 0.1 g of pure substance were instilled into the conjunctival sac, the untreated eye served as control. Under the conditions of this experiment the test substance was found to cause irritation when applied to the rabbit eye mucosa. No corrosion effect was observed at each of the measuring intervals. Additionally no corrosive or acute toxicological signs were observed in the animals during the test period. According to classification criteria in the European regulation (EC) No. 1272/2008, amending regulation EC no. 1907/2006 (REACh) the test substance is irritating to eyes and should be classified as eye irritant, category 2. There were no systemic intolerance reactions.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Additional information

Skin irritation

The skin irritation potential of the test substance was investigated in rabbits (Dr. B. Grunert, 1994, according to TG OECD 404). The test substance was applied to the skin of rabbit (skin shaved, substance moistened with water, 0.5 g substance / animal applied) for 4 hours under occlusive conditions. The study was performed according to the OECD Guideline 404 with no deviations and according to the good laboratory practice principles, it is considered to be of the highest quality (reliability Klimisch 1). The criteria of validity of the test system are fulfilled. After this period the skin was evaluated 60 min and daily for 7 days after patch removal. The test substance produced skin lesions in the form of erythemata and oedemata. The mean grades of skin reactions were lower than the value classified as irritant by the European regulation (EC) No. 1272/2008, amending regulation EC no. 1907/2006 (REACh). When applied to the skin, the test article may therefore be considered to be non- irritant.

Eye irritation

The test substance was investigated for its potential to cause irritation in the rabbit eye according to OECD TG 405. 0.1 g of pure substance were instilled into the conjunctival sac, the untreated eye served as control. Under the conditions of this experiment the test substance was found to cause irritation when applied to the rabbit eye mucosa. No corrosion effect was observed at each of the measuring intervals. Additionally no corrosive or acute toxicological signs were observed in the animals during the test period. According to classification criteria in the European regulation (EC) No. 1272/2008, amending regulation EC no. 1907/2006 (REACh) the test substance is irritating to eyes and should be classified as eye irritant, category 2. There were no systemic intolerance reactions.


Justification for selection of skin irritation / corrosion endpoint:
well documented study with GLP certificate

Justification for selection of eye irritation endpoint:
well documented study with GLP certificate

Effects on eye irritation: irritating

Justification for classification or non-classification

Skin irritation

According to the Regulation (EC) No. 1272/2008, the test material does not meet the criteria for classification and will not require labelling as irritating to the skin.

 

Eye irritation

The mean grades of ocular reactions at 24, 48 and 72 h p.a. require a classification as irritating to the eyes by the Regulation (EC) No. 1272/2008, therefore the substance should be classified as eye irritant, category 2.