Registration Dossier

Diss Factsheets

Administrative data

Description of key information

Skin irritation, in vivo (rabbit): non-irritating, OECD TG 404, 2007

Supporting study: Skin Irritation, in vivo (rat): mild transient irritation, OECD TG 402, 2008

Eye irritation, in vivo (rabbit): non-eye irritating, OECD TG 405, 2007

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:
18-04-2007 to 25-04-2007
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study performed under GLP. All relevant validity criteria were met.
Qualifier:
according to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Remarks:
inspected: August 2005; signature: November 2005
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: recognised animal supplier
- Age at study initiation: 12 - 20 weeks
- Weight at study initiation: 2.0 to 3.5 kg
- Housing: Individually housed in suspended cages.
- Diet: certified rabbit diet ad libitum
- Water: mains drinking water ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17 - 23
- Humidity (%): 30 - 70
- Air changes (per hr): at least 15
- Photoperiod: 12 hours light / 12 hours dark

IN-LIFE DATES: From: 18-04-2007 To: 25-04-2007
Type of coverage:
semiocclusive
Preparation of test site:
clipped
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5mL
- Concentration (if solution): Test material was used as supplied; moistened with 0.5 mL water.
Duration of treatment / exposure:
4 hours
Observation period:
72 hours (initial observation); additional observations are made on Days 7 and 14 to assess the reversibility of skin reactions (as appropriate).
Number of animals:
3
Details on study design:
TEST SITE
- Area of exposure: dorsal
- Type of wrap if used: semi-occlusive (2.5 cm x 2.5 cm cotton gauze patch secured with surgical adhesive tape)

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Yes, any residual test item removed by gentle swabbing with cotton wool soaked in distilled water.
- Time after start of exposure: 4 hours

SCORING SYSTEM:
Erythema and Eschar Formation
No erythema _________________________________________________________________________0
Very slight erythema (barely perceptible) ________________________________________________1
Well-defined erythema ________________________________________________________________2
Moderate to severe erythema __________________________________________________________3
Severe erythema (beet redness) to slight eschar formation (injuries in depth) ________________4

Oedema Formation
No oedema __________________________________________________________________________0
Very slight oedema (barely perceptible) _________________________________________________1
Slight oedema (edges of area well-defined by definite raising) _____________________________2
Moderate oedema (raised approximately 1 millimetre) ____________________________________3
Severe oedema (raised more than 1 millimetre and extending beyond the area of exposure) ___4
Any other skin reactions and clinical signs of toxicity, if present, were also recorded.
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
other: 1h
Score:
0
Max. score:
4
Reversibility:
other: 7 days - slight desquamation
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
other: 1h
Score:
0
Max. score:
4
Remarks on result:
no indication of irritation
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
other: 1h
Score:
0
Max. score:
4
Remarks on result:
no indication of irritation
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0.7
Max. score:
4
Reversibility:
other:
Remarks:
7 days - slight desquamation
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0.7
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
4
Remarks on result:
no indication of irritation
Irritation parameter:
edema score
Basis:
animal #1
Time point:
other: 1h
Score:
0
Max. score:
4
Remarks on result:
no indication of irritation
Irritation parameter:
edema score
Basis:
animal #2
Time point:
other: 1h
Score:
0
Max. score:
4
Remarks on result:
no indication of irritation
Irritation parameter:
edema score
Basis:
animal #3
Time point:
other: 1h
Score:
0
Max. score:
4
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
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
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
Remarks on result:
no indication of irritation
Irritant / corrosive response data:
- Erythema: Very slight erythema (score = 1) at two treated skin sites at 48 and 72 hours after patch removal.
- Edema: No evidence of skin irritation was noted during the study.
- Reversibility of effects: All effects reversed within 7 days (2/3 sites) ; slight desquamtation was observed at day 7 (1/3 sites)
Other effects:
- Other adverse local effects: None reported
- Other adverse systemic effects: None reported.

Table 1. Individual skin reactions

Skin Reaction

Reading

(hours)

Individual Scores

 

 

Other

 

 

Male 1

Male 2

 Male 3

 

Erythema/Eschar Formation

1

0

0

0

 

24

0

0

0

 

48

1

1

0

 

72

1 D

1

0

D = slight desquamation

Total

2

2

0

 

Mean

0.7

0.7

0.0

 

 

 

 

 

 

 

Edema Formation

1

0

0

0

 

24

0

0

0

 

48

0

0

0

 

72

0

0

0

 

Total

0

0

0

 

Mean

0.0

0.0

0.0

 

 

 

 

 

 

 

Mean scores per organism at 24, 48 and 72h:

Erythemea/Escar Formation:

1: total = 2.0 ; mean score = 0.7

2: total = 2.0 ; mean score = 0.7

3: total = 0.0 ; mean score = 0.0

Edema Formation:

1: total = 0.0 ; mean score = 0.0

2. total = 0.0 ; mean score = 0.0

3: total = 0.0 ; mean score = 0.0

Interpretation of results:
GHS criteria not met
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
Under the conditions of this study the test item is not considered to be irritating.
Executive summary:

The study was performed to OECD TG 404 and EU Method B.4 in accordance with GLP to assess the primary skin irritancy potential of the test item in New Zealand White rabbits. Following single 4-Hour, semi-occluded applications to the intact rabbit skin. 0.5 ml of the test material was introduced under a 2.5 cm x 2.5 cm cotton gauze patch and placed in position on the clipped skin to assess the irritancy potential of the test item. The patch was secured in position with a strip of surgical adhesive tape. After 4 hours of exposure to the test substance, the patches were removed, and individual dose sites were scored at approximately 1, 24, 48, and 72 hours. A single 4-Hour, semi occluded application of the test item to the intact skin of two rabbits produced very slight erythema at one treated skin site 48 and 72 hours after patch removal. Mean scores for following grading at 24, 48 and 72h were 0.7, 0.7 and 0 in erythema and eschar and 0 in all for the edema scoring criteria. Under the conditions of the study, the substance is not considered to be a skin irritant.

Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
02-09-2008 to 23-09-2008
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Guideline study performed under GLP. All relevant validity criteria were met; note that for local effects only: the reshaving at day 8 is a deviation is suggestive of effects that are non-test item related, which limits the reliability for assessment.
Reason / purpose for cross-reference:
reference to same study
Qualifier:
according to guideline
Guideline:
other: OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
yes
Remarks:
note that for local effects only: the reshaving at day 8 is a deviation is suggestive of effects that are non-test item related, which limits the reliability for assessment.
Qualifier:
according to guideline
Guideline:
other: EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
yes
Remarks:
See above
GLP compliance:
yes
Species:
rat
Strain:
Wistar
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Recognised supplier
- Age at study initiation: 9 - 11 weeks.
- Weight at study initiation: 197.3 - 264.0 g; the weight variation did not exceed ±20% of the mean weight for each sex.
- Fasting period before study: Not applicable
- Housing: during acclimation: group housed by sex; during study: individually housed in Makrolon type-4 cages furnished with softwood bedding.
- Diet (e.g. ad libitum): Certified diet from recognised supplier, provided ad libitum.
- Water (e.g. ad libitum): ad libitum.
- Acclimation period: At least 5 days.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3 °C
- Humidity (%): 30 - 70%
- Air changes (per hr): 10 to 15 air changes per hour
- Photoperiod: 12 h light / 12 h dark

IN-LIFE DATES: From: To: 2008-09-02 to 2008-09-23
Type of coverage:
semiocclusive
Preparation of test site:
shaved
Vehicle:
other: polyethylene glycol
Remarks:
PEG 300 (details available in full study report)
Controls:
not required
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg
- Concentration (if solution): See below.
- Constant volume or concentration used: 4 mL volume ; at a dose level of 2000 mg/kg bw test item.
Duration of treatment / exposure:
24 hours
Observation period:
Once daily during days 2-15. All abnormalities were recorded.
Number of animals:
5 per sex per dose (5 male/5 female)
Details on study design:
TEST SITE
- Area of exposure: the day before treatment the back and flanks were clipped free of hair. Dorsal area application. Note: that the skin was re-shaved on day 8 to facilitate the reading of local reactions.
- % coverage: Approximately 10% of total body surface
- Type of wrap if used: The area of application was covered by a semi-occlusive dressing and wrapped with a piece of elastic adhesive bandage.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): The treated skin and surrounding hair wiped with luke warm water and dried with disposable towl to remove any residual test item
- Time after start of exposure: 24 h

OBSERVATION TIME POINTS
(indicate if minutes, hours or days) : Clinical observations and mortality checks were conducted at approximately 0.5, 1, 3, and 5 hours and subsequently twice daily for days 2 to 15. Local effects were examined once daily days 2 to 15 after the completion of the 24-hour exposure period.

SCORING SYSTEM:
- Method of calculation: Full details on the scoring and criteria (appears consistent with Draize for Erythema) are given in the full study report. Individual bodyweights were recorded prior to application of the test item on Day 1 and on Days 8 and 15.
Irritation parameter:
erythema score
Remarks:
mean
Basis:
animal #1
Remarks:
male
Time point:
other: 48/72/96h
Score:
1.33
Reversibility:
fully reversible within: 7 days
Irritation parameter:
erythema score
Remarks:
mean
Basis:
animal #2
Remarks:
male
Time point:
other: 48/72/96h
Score:
1.33
Reversibility:
fully reversible within: 7 days
Irritation parameter:
erythema score
Remarks:
mean
Basis:
animal #3
Remarks:
male
Time point:
other: 48/72/96h
Score:
1.33
Reversibility:
fully reversible within: 7 days
Irritation parameter:
erythema score
Remarks:
mean
Basis:
animal #4
Remarks:
male
Time point:
other: 48/72/96h
Score:
1.33
Reversibility:
fully reversible within: 7 days
Irritation parameter:
erythema score
Remarks:
mean
Basis:
animal #5
Remarks:
male
Time point:
other: 48/72/96h
Score:
1.33
Reversibility:
fully reversible within: 7 days
Irritation parameter:
erythema score
Remarks:
mean
Basis:
animal: #1
Remarks:
female
Time point:
other: 48/72/96h
Score:
1
Reversibility:
fully reversible within: 7 days
Irritation parameter:
erythema score
Remarks:
mean
Basis:
animal: #2
Remarks:
female
Time point:
other: 48/72/96h
Score:
1.33
Reversibility:
fully reversible within: 7 days
Irritation parameter:
erythema score
Basis:
animal: #3
Remarks:
female
Time point:
other: 48/72/96h
Score:
1.33
Reversibility:
fully reversible within: 7 days
Irritation parameter:
erythema score
Remarks:
mean
Basis:
animal: #4
Remarks:
female
Time point:
other: 48/72/96h
Score:
1.33
Reversibility:
fully reversible within: 7 days
Irritation parameter:
erythema score
Remarks:
mean
Basis:
animal: #5
Remarks:
female
Time point:
other: 48/72/96h
Score:
1
Reversibility:
fully reversible within: 7 days
Irritant / corrosive response data:
- Dermal reactions: All indicated slight (score = 1) to moderate (score =2) erythema from day 2 to day 6. The sites were re-shaved on day 8 after which one indication of slight erythema on days 8 to 12 and 9/10 indications of 'scaling'. See 'other information on results incl. tables' for further information.
Other effects:
- Other adverse local effects: None. See 'other information on results incl. tables' for further information.
- Other adverse systemic effects: None.

Applicant assessment indicates: within local effects the test item caused only mild transient irritation (score = 2) on day 2 which was then slight (score 1) on days 3, 4 and fully reversed by day 7. When the sites were re-shaved on day 8 this led to score = 1 slight irritation and scaling that persisted to the end of the observation period. This was clearly not a test item related effect, as the effects had already reversed on day 7 in all males/females (information provided in the full study report). The OECD TG 404 test guideline for skin irritation specifies that clipping of the fur is done at the start of the test and to attempts are to minimise abrasion of the skin which can interfere with assessment. It appears that the effects post day 8 were the result of a deviation for the reading of local effects which made fully reversed effects re-appear at the treated sites. Expert judgement indicates these were non-test item related effects.

Interpretation of results:
GHS criteria not met
Conclusions:
Under the conditions of this study the dermal LD50 was established to exceed 2000 mg/kg bw in male/female Wistar rat. Under the conditions of this study and under the Globally Harmonized Classification System of Classification and Labelling of Chemicals (GHS), the LD50 cut-off value was considered to be greater than 5000 mg/kg body weight. The test item caused only mild transient irritation (score = 2) on day 2 which was then slight (score 1) on days 3, 4 and fully reversed by day 7. The test item was not considered to be skin irritating.
Executive summary:

The study was performed according to OECD TG 402 and EU Method B.3 Acute Toxicity (Dermal) and in accordance with GLP to assess the acute dermal toxicity of the test substance in the Wistar HanRcc: WIST (SPF) strain rat. A group of ten animals (five males and five females) was given a single, 24 hour, semi-occluded dermal application of the diluted test item in PEG 300 vehicle to intact skin at a dose level of 2000 mg/kg body weight. Clinical signs and body weight development were monitored during the study. All animals were subjected to gross necropsy. There was no mortality during the study. There were no signs of system toxicity or abnormalities on necropsy. Animals showed expected gains in body weight. Minimal signs of dermal irritation were noted (score 2) at day 2 and (score 1) days 4 to 5 or 6, which had fully reversed at day 7. The dermal LD50 was established to exceed 2000 mg/kg bw in male/female Wistar HanRcc: WIST (SPF) rat. Under the conditions of this study, and according to the GHS criteria, the LD50 cut-off value was considered to be greater than 5000 mg/kg body weight. The test item was not considered to be 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:
30-04-2007 to 11-05-2007
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study performed under GLP. All relevant validity criteria were met.
Qualifier:
according to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Remarks:
inspected: August 2005; signature: November 2005
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Recognised animal supplier
- Age at study initiation: 12 - 20 weeks old
- Weight at study initiation: 2.0 - 3.50 kg
- Housing: individually housed in suspended metal cages; with environment enrichment
- Diet: certified rabbit food ad libitum
- Water: mains water ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17 - 23
- Humidity (%): 30 - 70
- Air changes (per hr): at least 15
- Photoperiod (hrs dark / hrs light): 12 hour light / 12 hour dark

Vehicle:
unchanged (no vehicle)
Controls:
yes, concurrent no treatment
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 mL
- Concentration (if solution): undiluted

Duration of treatment / exposure:
A volume of 0.1 mL of the test material, was placed into the conjunctival sac of the right eye, formed by gently pulling the lower lid away from the eyeball. The upper and lower eyelids were held together for about one second immediately after treatment, to prevent loss of the test material, and then released. The left eye remained untreated and was used for control purposes.
Observation period (in vivo):
Ocular assessment was conducted at approximately 1, 24, 48 and 72 hours after instillation of the test item, according to numerical evaluation.
Number of animals or in vitro replicates:
3 (male).
Details on study design:
The study was performed in a stepwise manner and was started by treatment of a single rabbit. The other animals were treated in a similar manner after considering the degree of eye irritation observed in the first and/or second animal.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): none

SCORING SYSTEM:
The irritation was assessed according to Draize (1977) numerical scoring system. At each observation period, the highest scores given were recorded. Any other ocular effects were also noted.

TOOL USED TO ASSESS SCORE: Examination of the eye was facilitated by the use of the light source from a standard ophthalmoscope.
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
24/48/72 h
Score:
0
Max. score:
4
Remarks on result:
other: mean; n=2
Irritation parameter:
iris score
Basis:
mean
Time point:
24/48/72 h
Score:
0.1
Max. score:
2
Reversibility:
fully reversible within: 72 hours
Remarks on result:
other: mean; n=3
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
24/48/72 h
Score:
1
Max. score:
3
Reversibility:
fully reversible within: 72 hours
Remarks on result:
other: mean; n=3
Irritation parameter:
chemosis score
Basis:
mean
Time point:
24/48/72 h
Score:
0.3
Max. score:
4
Reversibility:
fully reversible within: 72 hours
Remarks on result:
other: mean; n=3
Irritant / corrosive response data:
No corneal effects were noted. Iridial inflammation was noted in one treated eyes 1 hour and 24 hours after treatment although fully resolved by 48 hour observation. Moderate conjunctival irritation was noted in treated eyes 1 hours after treatment with minimal conjunctival irritation noted at 48 hours observation. All treated eyes appeared normal at the 72 hours observation.

Table 1. Individual scores and mean scores for 24, 48 and 72 hours

Organism number

1

2

3

Time After Treatment

1 Hour

24 Hours

48 Hours

72 Hours

1 Hour

24 Hours

48 Hours

72 Hours

1 Hour

24 Hours

48 Hours

72 Hours

CORNEA

 

 

 

 

 

 

 

 

 

 

 

 

Degree of Opacity

0

0

0

0

0

0

0

0

0

0

0

0

Mean (24 – 72 h)

 

 

 

0.0

 

 

 

0.0

 

 

 

0.0

 

 

 

 

 

 

 

 

 

 

 

 

 

IRIS

0

0

0

0

1

1

0

0

0

0

0

0

Mean (24 – 72 h)

 

 

 

0.0

 

 

 

0.3

 

 

 

0.0

 

 

 

 

 

 

 

 

 

 

 

 

 

CONJUNCTIVAE

 

 

 

 

 

 

 

 

 

 

 

 

Redness

2

2

1

0

2

2

1

0

2

2

1

0

Mean (24 – 72 h)

 

 

 

1.0

 

 

 

1.0

 

 

 

1.0

 

 

 

 

 

 

 

 

 

 

 

 

 

Chemosis

1

1

0

0

1

1

0

0

1

1

0

0

Mean (24 – 72 h)

 

 

 

0.3

 

 

 

0.3

 

 

 

0.3

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Interpretation of results:
GHS criteria not met
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
Under the conditions of this study the test item is not irritating to the eye.
Executive summary:

The study was performed to OECD TG 405 and EU Method B.5 under GLP to assess the irritancy potential of the test material to the eye following a single application in the New Zealand White rabbit. A volume of 0.1 ml of the test material was placed into the conjunctival sac of one eye of three animals. The other eye remained untreated and was used for control purposes. Assessment of ocular damage/irritation was made approximately 1 hour and 24, 48 and 72 hours following treatment. A single application of the test material to the non-irrigated eye of three rabbits produced no corneal effects. Iridial inflammation was noted in one treated eye 1 hour and 24 hours after treatment although was absent at 48 hours observation. Moderate conjunctival irritation was noted in treated eyes 1 hour through to 24 hours after treatment with minimal conjunctival irritation noted at the 48 hour observation. All treated eyes appeared normal at the 72 Hours observation. Under the conditions of this study, the test substance is not considered to be irritating to the eye.

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

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin Irritation:

Key study : In vivo, OECD TG 404, 2007 : The study was performed to OECD TG 404 and EU Method B.4 in accordance with GLP to assess the primary skin irritancy potential of the test item in New Zealand White rabbits. Following single 4-Hour, semi-occluded applications to the intact rabbit skin. 0.5 ml of the test material was introduced under a 2.5 cm x 2.5 cm cotton gauze patch and placed in position on the clipped skin to assess the irritancy potential of the test item. The patch was secured in position with a strip of surgical adhesive tape. After 4 hours of exposure to the test substance, the patches were removed, and individual dose sites were scored at approximately 1, 24, 48, and 72 hours. A single 4-Hour, semi occluded application of the test item to the intact skin of two rabbits produced very slight erythema at one treated skin site 48 and 72 hours after patch removal. Mean scores for following grading at 24, 48 and 72h were 0.7, 0.7 and 0 in erythema and eschar and 0 in all for the edema scoring criteria. Under the conditions of the study, the substance is not considered to be a skin irritant.

Supporting study : In vivo, OECD TG 402, 2008 : The study was performed according to OECD TG 402 and EU Method B.3 Acute Toxicity (Dermal) and in accordance with GLP to assess the acute dermal toxicity of the test substance in the Wistar HanRcc: WIST (SPF) strain rat. A group of ten animals (five males and five females) was given a single, 24 hour, semi-occluded dermal application of the diluted test item in PEG 300 vehicle to intact skin at a dose level of 2000 mg/kg body weight. Clinical signs and body weight development were monitored during the study. All animals were subjected to gross necropsy. There was no mortality during the study. There were no signs of system toxicity or abnormalities on necropsy. Animals showed expected gains in body weight. Minimal signs of dermal irritation were noted (score 2) at day 2 and (score 1) days 4 to 5 or 6, which had fully reversed at day 7. The dermal LD50 was established to exceed 2000 mg/kg bw in male/female Wistar HanRcc: WIST (SPF) rat. Under the conditions of this study, and according to the GHS criteria, the LD50 cut-off value was considered to be greater than 5000 mg/kg body weight.

Applicant assessment indicates: within local effects the test item caused only mild transient irritation (score = 2) on day 2 which was then slight (score 1) on days 3, 4 and fully reversed by day 7. When the sites were re-shaved on day 8 this led to score = 1 slight irritation and scaling that persisted to the end of the observation period. This was clearly not a test item related effect, as the effects had already reversed on day 7 in all males/females (information provided in the full study report). The OECD TG 404 test guideline for skin irritation specifies that clipping of the fur is done at the start of the test and to attempts are to minimise abrasion of the skin which can interfere with assessment. It appears that the effects post day 8 were the result of a deviation for the reading of local effects which made fully reversed effects re-appear at the treated sites. Expert judgement indicates these were non-test item related effects. The test item would not be considered to be skin irritating. The test item is capable of causing transient mild irritation to the skin.

Eye Irritation:

Key study : In vivo, OECD TG 405, 2007 : The study was performed to OECD TG 405 and EU Method B.5 under GLP to assess the irritancy potential of the test material to the eye following a single application in the New Zealand White rabbit. A volume of 0.1 ml of the test material was placed into the conjunctival sac of one eye of three animals. The other eye remained untreated and was used for control purposes. Assessment of ocular damage/irritation was made approximately 1 hour and 24, 48 and 72 hours following treatment. A single application of the test material to the non-irrigated eye of three rabbits produced no corneal effects. Iridial inflammation was noted in one treated eye 1 hour and 24 hours after treatment although was absent at 48 hours observation. Moderate conjunctival irritation was noted in treated eyes 1 hour through to 24 hours after treatment with minimal conjunctival irritation noted at the 48 hour observation. All treated eyes appeared normal at the 72 Hours observation. Under the conditions of this study, the test substance is not considered to be irritating to the eye.

Respiratory Irritation:

No study available

Justification for classification or non-classification

The substance does not meet classification criteria under Regulation (EC) No 1272/2008 for dermal irritation.

The substance does not meet classification criteria under Regulation (EC) No 1272/2008 for eye irritation.

 

For skin irritation, further in vitro skin corrosion testing does not need to be conducted based on the available information allowing a definitive conclusion on the classification of the substance. The substance does not demonstrate significant skin irritation potential necessary for classification and labelling within an available skin irritation in vivo assay (OECD TG 404) and supporting acute dermal toxicity study (OECD TG 402) at 2000 mg/kg bw dose level. The substance can cause transient mild irritation but which is not sufficient for classification and labelling.

 

For eye irritation, the weight of evidence indicates that the substance has the potential to cause transient irritating effects to the eye but which is not sufficient for classification based on the mean scoring and evaluation of the results in three organisms demonstrating that the EU criteria had not been met. Effects in vivo on corneal opacity and iritis are low to non-existent and conjunctival effects are low to moderate which fully reversed within 72 hours; the overall evidence is indicative of moderate but transient and reversible effects on the eye.

References:

1. Guidance on Application of the CLP Criteria, ECHA, version 5.0, July 2017