Registration Dossier

Administrative data

Description of key information

Skin irritation (OCED TG 404): not irritating

Eye irritation (OECD TG 405): irritating to the eye

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:
16 Jul 2013 - 01 Aug 2013
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP - Guideline Study
Qualifier:
according to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Version / remarks:
adopted in 1981
Deviations:
no
GLP compliance:
yes
Species:
rabbit
Strain:
other: NZW (Yac:NZW(KBL)),SPF
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Cheonan Yonan College, Laboratory Animal Center, Korea
- Age at study initiation: 11 weeks
- Weight at study initiation: 2.28-2.29 kg
- Housing: stainless wire mesh cages, 450W x 600D x 360H (mm). One animal per cage
- Diet: Purina experimental diet for rabbit 38302AF, ad libitum
- Water: public tap water in Cheongju-si was filtered and irradiated by ultraviolet light and provided ad libitum via an automatic watering system
- Acclimation period: at least 8 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.5-21.3
- Humidity (%): 48.0-65.4
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 08-07-2013 To: 01-08-2013
Type of coverage:
semiocclusive
Preparation of test site:
clipped
Vehicle:
unchanged (no vehicle)
Controls:
other: untreated sites of the same animal served as control
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 mL

Duration of treatment / exposure:
4 hours
Observation period:
14 days
Reading time points: 1, 24, 48, 72 h and once daily thereafter for up to 14 days
Number of animals:
3 males
Details on study design:
TEST SITE
- Area of exposure: three sites (2.5x2.5 cm) on the left and right area of the midline was used as the application site.
- % coverage: not stated
- Type of wrap if used: all application sites were covered with gauze (DaeHan Medical Supply Co., Ltd., Korea) and held in contact with the skin by semiocclusive dressing using elastic bandage (3M Co., Ltd., Korea) and paper tape (Masking Tape, DAESUN Com., Korea).

REMOVAL OF TEST SUBSTANCE
- Washing (if done): residual test material was removed using absorbent cotten moistened with tepid water
- Time after start of exposure: 4 h

SCORING SYSTEM: Draize (1959) scoring system
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
other: mean over 24, 48 and 72 h
Score:
1.3
Max. score:
4
Reversibility:
fully reversible within: 8 days
Remarks on result:
other: scaling was evident from day 5 to day 12
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
other: mean over 24, 48 and 72 h
Score:
1.3
Max. score:
4
Reversibility:
fully reversible within: 8 days
Remarks on result:
other: scaling was evident from day 5 to day 14
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
other: mean over 24, 48 and 72 h
Score:
1.3
Max. score:
4
Reversibility:
fully reversible within: 8 days
Remarks on result:
other: scaling was evident from day 5 to day 11
Irritation parameter:
edema score
Basis:
other: mean out of all 3 animals
Time point:
other: mean over 24, 48 and 72 h
Score:
0
Max. score:
4
Reversibility:
other: reversibility: not applicable
Irritant / corrosive response data:
Erythema (score 1-2) was evident from 1 hour after patch removal at the test substance sites of all animals. However, skin reactions were no longer evident on day 8 after application. In addition, scaling which was considered to be caused by the secondary changes of stimulation was evident from day 5 up to day 12 in two animals and from day 5 to day 14 in the remaining one animal. The control sites of all animals did not reveal any evidence of adverse skin reactions such as erythema or edema during the observation period.
Other effects:
No abnormal clinical signs or symptoms were evident in any animals throughout the duration of the study. All animals exhibited normal body weight gain. Mean body weight gain was 0.34 kg throughout the observation period.
Interpretation of results:
not irritating
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
CLP: not classified
DSD: not classified
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:
03 Sep 2013 - 14 Sep 2013
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP - Guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Version / remarks:
adopted in 1981
Deviations:
no
GLP compliance:
yes
Species:
rabbit
Strain:
other: NZW (Yac:NZW(KBL)), SPF
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Cheonan Yonan College, Laboratory Animal Center, Korea.
- Age at study initiation: 11 weeks
- Weight at study initiation: 2.19 - 2.31 kg
- Housing: stainless wire mesh cages, 450W x 600D x 360H (mm). One animal per cage
- Diet: Purina experimental diet for rabbit 38302AF, ad libitum
- Water: public tap water in Cheongju-si was filtered and irradiated by ultraviolet light and provided ad libitum via an automatic watering system
- Acclimation period: at least 8 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.9 - 21.5
- Humidity (%): 45.8 - 69.3
- Air changes (per hr): 10 - 15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 26-08-2013 To: 14-09-2013
Vehicle:
unchanged (no vehicle)
Controls:
other: the untreated eye served as control
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 mL
Duration of treatment / exposure:
single application without washing
Observation period (in vivo):
9 days
Reading time points: 1, 24, 48, 72, 96 h and once daily thereafter for up to 9 days
Number of animals or in vitro replicates:
3 males
Details on study design:
PRETREATMENT OF THE ANIMALS:
Sixty minutes prior to test substance application, buprenorphine was administered at 0.01 mg/kg bw by subcutaneous injection (SC) to provide a therapeutic level of systemic analgesia. Five minutes prior to test substance application, one drop of 0.5% proparacaine hydrochloride was applied to each eye.

POST-TREATMENT OF THE ANIMALS:
Eight hours after test substance application, buprenorphine at 0.01 mg/kg and meloxicam at 0.5 mg/kg were administered by SC to provide a continued therapeutic level of systemic analgesia.
After the initial 8 h post- test substance application treatment, buprenorphine was administered at 0.01 mg/kg by SC every 12 hours until the ocular lesions resolved.

SCORING SYSTEM: Draize scoring system (1959)

TOOL USED TO ASSESS SCORE: hand-slit lamp (Kowa SL-15, Kowa Co., Ltd., Japan) and fluorescein
Irritation parameter:
cornea opacity score
Basis:
animal #1
Time point:
other: mean over 24, 48 and 72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 9 days
Irritation parameter:
cornea opacity score
Basis:
animal #2
Time point:
other: mean over 24, 48 and 72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 9 days
Irritation parameter:
cornea opacity score
Basis:
animal #3
Time point:
other: mean over 24, 48 and 72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 8 days
Irritation parameter:
iris score
Basis:
animal #1
Time point:
other: mean over 24, 48 and 72 h
Score:
1
Max. score:
2
Reversibility:
fully reversible within: 6 days
Irritation parameter:
iris score
Basis:
animal #2
Time point:
other: mean over 24, 48 and 72 h
Score:
1
Max. score:
2
Reversibility:
fully reversible within: 6 days
Irritation parameter:
iris score
Basis:
animal #3
Time point:
other: mean over 24, 48 and 72 h
Score:
1
Max. score:
2
Reversibility:
fully reversible within: 5 days
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
other: mean over 24, 48 and 72 h
Score:
2
Max. score:
3
Reversibility:
fully reversible within: 9 days
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
other: mean over 24, 48 and 72 h
Score:
2
Max. score:
3
Reversibility:
fully reversible within: 9 days
Irritation parameter:
conjunctivae score
Basis:
animal #3
Time point:
other: mean over 24, 48 and 72 h
Score:
2
Max. score:
3
Reversibility:
fully reversible within: 8 days
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
other: mean over 24, 48 and 72 h
Score:
1.3
Max. score:
4
Reversibility:
fully reversible within: 9 days
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
other: mean over 24, 48 and 72 h
Score:
1.3
Max. score:
4
Reversibility:
fully reversible within: 9 days
Irritation parameter:
chemosis score
Basis:
animal #3
Time point:
other: mean over 24, 48 and 72 h
Score:
1.3
Max. score:
4
Reversibility:
fully reversible within: 8 days
Irritant / corrosive response data:
Corneal opacity (score 1), area of the opacity (score 1-4), congestion of the iris (score 1), redness of the conjunctivae (score 1-2), chemosis of the conjunctivae (score 1-3) and discharge (score 1-3) were evident in all 3 animals from one hour after test substance application. Discharge was no longer evident at 72 hours after test substance application. Congestion of the iris was fully reversed within day 6. Redness and chemosis of the conjunctivae were no longer evident on day 9.
Other effects:
Excessive blinking and tearing were evident in the 3 animals at 1 and 8 hours after test substance application. These clinical signs of pain and distress were not evident from day 1 till day 9 after test substance application. In general no abnormal clinical signs or symptoms were evident in any animals throughout the duration of the study. All animals exhibited normal body weight gains. The mean body weight gain throughout the observation period was 0.20 kg.
Interpretation of results:
irritating
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
CLP: Eye irrit 2; H319
DSD: Xi; R36
Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin irritation/corrosion

The test item was investigated for skin irritation/corrosion according to OECD TG 404 and in compliance with GLP (Yang, 2013a). 0.5 mL of the neat test material was applied to clipped sites of 3 male New Zealand White rabbits for 4 h using a semi-occlusive dressing respectively.The skin reaction was examined at 1, 24, 48, 72 h and then once daily thereafter for up to 14 days after removal of the patch. Erythema (score 1-2) was evident from 1 hour after patch removal at the test substance sites of all animals, but were fully reversed by day 8. In addition, scaling which was considered to be caused by the secondary changes of stimulation was evident from day 5 up to day 12 in two animals and from day 5 to day 14 in the remaining one animal. The mean erythema score of all 3 animals over 24, 48 and 72 h was calculated to be 1.3. No edema was evident after patch removal at the test substance sites of all animals. The control sites of all animals did not reveal any evidence of adverse skin reactions such as erythema or edema during the observation period. Furthermore,no clinical signs or effect on the body weights were observed in any of the animals. Hence, the test item was concluded to be non-irritating to the skin

Eye irritation/corrosion

 

The test item was investigated for eye irritation/corrosion according to the OECD TG 405 and in compliance with GLP (Yang, 2013b). Three male New Zealand White rabbits each received 0.1 mL of the neat test substance as a single treatment into the conjunctival sac of the right eyes respectively. Eye reactions of the cornea, iris and conjunctiva were recorded at 1, 24, 48, 72, 96 h and then once daily thereafter for up to 9 days after test substance application. Topical anesthetics and systemic analgesics were administered before and after test substance application to all animals.

Corneal opacity (score 1), area of the opacity (score 1-4), congestion of the iris (score 1), redness of the conjunctivae (score 1-2), chemosis of the conjunctivae (score 1-3) and discharge (score 1-3) were evident in all 3 animals from one hour after test substance application. Discharge was no longer evident at 72 hours after test substance application. Congestion of the iris was fully reversed within day 6. Redness and chemosis of the conjunctivae were no longer evident on day 9. Mean scores of all three animals over 24, 48, and 72 h were 1.0 for corneal damage, 1.0 for iritis, 2.0 for conjunctivae scores, and 1.3 for chemosis, respectively. Excessive blinking and tearing were evident in the 3 animals at 1 and 8 hours after test substance application. These clinical signs of pain and distress were not evident from day 1 till day 9 after test substance application. In general no abnormal clinical signs or symptoms were evident in any animals throughout the duration of the study. All animals exhibited normal body weight gains. In conclusion, the test substance is concluded to be a eye irritant.

Justification for selection of skin irritation / corrosion endpoint:

There is only one study available.

Justification for selection of eye irritation endpoint:

There is only one study available.

Effects on eye irritation: irritating

Justification for classification or non-classification

The available data on skin irritation of the test substance do not meet the criteria for classification according to Regulation EC 1272/2008 or Directive 67/548/EEC, and are therefore conclusive but not sufficient for classification.

The available data on eye irritation/corrosion of the test substance meets the criteria to be classified for reversible effects in the eye (Cat 2, H319) according to Regulation EC 1272/2008/EC and as Irritant (Xi, R36) according to Directive 67/548/EEC.