Registration Dossier

Administrative data

Description of key information

Skin irritation: 
Key study: Experimental results: OECD guideline 404 and EU method B.4. GLP study.
The substance is considered to be non-irritant to the skin.
Key study: Experimental results: OECD guideline 404 and EU method B.4. GLP study.
The substance is considered to be non-irritant to the skin.
Key study: Experimental results: OECD guideline 404 and EU method B.4. GLP study.
The substance is considered to be non-irritant to the skin.
Eye irritation:
Key study: Experimental results: OECD guideline 405 and EU method B.5. GLP study.
The substance is considered to be non-irritant to the eye.
Key study: Experimental results: OECD guideline 405 and EU method B.5. GLP study.
The substance is considered to be non-irritant to the eye.
Key study: Experimental results: OECD guideline 405 and EU method B.5. GLP study.
The substance is considered to be non-irritant to the eye.

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:
From 23rd December 1998 to 25th February 1999
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: B & K Universal G.J., S.L.
- Age at study initiation: 10-12 weeks old
- Weight at study initiation: 2.5-2.7 kg
- Housing: The rabbits were housed individually in stainless steel cages (48 x 59 x 37 cm) with a grille floor, placed on racks.
- Diet (e.g. ad libitum): standard rabbit diet UAR 112, ad libitum.
- Water (e.g. ad libitum): ad libitum
- Acclimation period: At least 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 15-18 ºC
- Humidity (%): 55 ± 10%
- Photoperiod (hrs dark / hrs light): 12-hour light and 12-hour dark cycle per day.

IN-LIFE DATES: From: 21st December 1998 To: 15th January 1999
Type of coverage:
semiocclusive
Preparation of test site:
shaved
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 mL
Duration of treatment / exposure:
4 hours
Observation period:
60 minutes, 24, 48 and 72 hours after the end of the exposure period
Number of animals:
Three
Details on study design:
TEST SITE
- Area of exposure: One square test zone, measuring approximately 6 cm2.
- Type of wrap if used: The substance was placed on 2.5 x 2.5 cm squares of surgical gauze and applied to the test area. The patches were held close to the body using strips of adhesive tape. A strip of gauze was wrapped around the trunk of the animal in order to hold the patches in place. The gauze was fixed to the body using additional adhesive tape.

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 to slight eschar formation 4


Edema formation:
No edema 0
Very slight edema (barely perceptible) 1
Slight edema 2
Moderate edema 3
Severe edema 4
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
other: 24-72 h
Score:
0.67
Max. score:
4
Reversibility:
fully reversible within: 72 h
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
other: 24-72 h
Score:
0.67
Max. score:
4
Reversibility:
fully reversible within: 72 h
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
other: 24-72 h
Score:
0
Max. score:
4
Irritation parameter:
edema score
Basis:
animal #1
Time point:
other: 24-72 h
Score:
0
Max. score:
4
Irritation parameter:
edema score
Basis:
animal #2
Time point:
other: 24-72 h
Score:
0
Max. score:
4
Irritation parameter:
edema score
Basis:
animal #3
Time point:
other: 24-72 h
Score:
0
Max. score:
4
Irritant / corrosive response data:
Approximately 60 minutes after the patches were removed, well-defined erythema (grade 2) was observed in all animals. This lesion was accompanied by very slight edema (grade 1) in all of the animals.

After 24 hours, two of the animals presented very slight erythema (grade 1).

However, after 48 hours, only two animals continued to present very slight erythema (grade 1).

After 72 hours, no dermal lesions were observed in any animal.
Other effects:
The behaviour and physical condition of the rabbits were normal throughout the study.

 

Table 1: Primary skin irritation test

 

Animal

Reaction

60 min

24 h

48 h

72 h

1

Erythema

2

1

1

0

Edema

1

0

0

0

2

Erythema

2

1

1

0

Edema

1

0

0

0

3

Erythema

2

0

0

0

Edema

1

0

0

0

Interpretation of results:
GHS criteria not met
Conclusions:
The substance is considered to be non-irritant to the skin.
Executive summary:

The degree of skin initation caused by the test substance was detemined after it was applied to shaved rabbit skin, under a semi-occlusive patch, and left for 4 hours. The study was conducted according to EU method B.4 and OECD guideline 404.

Approximately 60 minutes after the patches were removed, well-defined erythema (grade 2) was observed in all of the animals. This lesion was accompanied by very slight edema (grade 1) in all of the animals.

After 24 hours, two of the animals presented very slight erythema (grade 1)

However, after 48 hours, very slight erythema (grade 1) was observed in only two animals.

After 72 hours, no dermal alterations were observed in any of the animals.

The mean etythema and edema scores for the substance, at 24, 48 and 72 hours after application, were 0.44 and 0.00 respectively.

The substance is considered to be non-irritant to the skin.

Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From 15 October 1996 to 22 October 1996
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: David Percival Ltd, Moston, Sandbach, Cheshire, UK
- Age at study initiation: 12 to 16 weeks old
- Weight at study initiation: 2.42 to 2.84 kg
- Housing: The animals were individually housed in suspended metal cages.
- Diet (e.g. ad libitum): STANRAB SQC Rabbit Diet, Special Diets Services Ltd, Witham, Essex, UK, ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: At least five days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17-20 ºC
- Humidity (%): 52-70%
- Air changes (per hr): fifteen changes per hour
- Photoperiod (hrs dark / hrs light): twelve hours continuous light and twelve hours darkness

Type of coverage:
semiocclusive
Preparation of test site:
other: clipped free of fur
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 ml
Duration of treatment / exposure:
4 hours
Observation period:
1, 24, 48 and 72 hours and Day 7 after the end of the exposure period
Number of animals:
Three
Details on study design:
TEST SITE
- Area of exposure: Approximately 6 cm2
- Type of wrap if used: A 2.5 cm x 2.5 cm cotton gauze patch was placed in position on the shorn skin. The patch was secured with a strip of surgical adhesive tape. To prevent the animals interfering with the patches, the trunk of each animal was wrapped in an elasticated corset.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Any residual test material was removed by gentle swabbing with cotton wool soaked in 74% Industrial Methylated Spirits.
- Time after start of exposure: Four hours after application of the test substance

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 to slight eschar formation 4


Oedema formation:
No oedema 0
Very slight oedema (barely perceptible) 1
Slight oedema 2
Moderate oedema 3
Severe oedema 4
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
other: 24-72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
other: 24-72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
other: 24-72 h
Score:
1.67
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
edema score
Basis:
animal #1
Time point:
other: 24-72 h
Score:
0
Max. score:
4
Irritation parameter:
edema score
Basis:
animal #2
Time point:
other: 24-72 h
Score:
0
Max. score:
4
Irritation parameter:
edema score
Basis:
animal #3
Time point:
other: 24-72 h
Score:
0.67
Max. score:
4
Reversibility:
fully reversible within: 72 h
Irritant / corrosive response data:
Well-defined erythema was noted at one treated skin site with very slight erythema at two treated skin sites one hour after patch removal and at the subsequent 24 and 48-hour observations. Very slight erythema was noted at all treated skin sites at the 72-hour observation.

Very slight oedema was noted at one treated skin site one hour after patch removal and at the subsequent 24 and 48-hour observations. No other evidence of oedema was noted.

Treated skin sites appeared normal at the 7-day observation.

Table 1: Acute dermal irritation test in the rabbit

 

Animal

Reaction

1 h

24 h

48 h

72 h

7 d

1

Erythema

1

1

1

1

0

Edema

0

0

0

0

0

2

Erythema

1

1

1

1

0

Edema

0

0

0

0

0

3

Erythema

2

2

2

1

0

Edema

1

1

1

0

0

Interpretation of results:
GHS criteria not met
Conclusions:
The substance is considered to be non-irritant to the skin.
Executive summary:

A study was performed to assess the irritancy potential of the test material to the skin of the New Zealand White rabbit. The method used followed the recommendations of the OECD guidelines for Testing of Chemicals No. 404 "Acute Dermal Irritation/Corrosion" and Method 84 of Commission Directive 92/69/EEC.

A single 4-hour, semi-occluded application of the test material to the intact skin of three rabbits produced very slight to well-defined erythema and very slight oedema. Treated skin sites appeared normal at the 7-day observation.

The test material produced a primary irritation index of 1.3 and was classified as a mild irritant to rabbit skin according to the Draize classification scheme. No corrosive effects were noted.

Endpoint:
skin irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From 14th October 1992 to 30th November 1992
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Granjas Jordi (Molins de Rei)
- Age at study initiation: Approximatey 13 weeks old
- Weight at study initiation: 2.0-2.6 kg
- Housing: The rabbits were housed individually in stainless steel cages (48 x 59 x 37 cm) with a wire floor, placed on cage racks.
- Diet (e.g. ad libitum): standard rabbit diet UAR 112, ad libitum.
- Water (e.g. ad libitum): ad libitum
- Acclimation period: At least 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-23 ºC
- Humidity (%): 40-65%
- Photoperiod (hrs dark / hrs light): 12-hour light and 12-hour dark cycle

IN-LIFE DATES: From: 14th October 1992 To: 30th October 1992
Type of coverage:
semiocclusive
Preparation of test site:
shaved
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 mL
Duration of treatment / exposure:
4 hours
Observation period:
30-60 minutes, 24, 48 and 72 hours after the end of the exposure period
Number of animals:
Three
Details on study design:
TEST SITE
- Area of exposure: One square test zone, measuring approximately 6 cm2.
- Type of wrap if used: The substance was placed on 2.5 x 2.5 cm squares of hydrophyllic gauze and applied to the corresponding test area. The patches were held close to the body using strips of adhesive tape. A strip of gauze was wrapped around the trunk of the animal in order to hold the patches in place. The gauze was fixed to the body using additional adhesive tape.

SCORING SYSTEM:
Erythema and eschar formation:
No erythema 0
Very slight erythema (barely perceptible) 1
Well defined erythema 2
Very marked erythema 3
Severe erythema to slight eschar formation 4


Edema formation:
No edema 0
Very slight edema (barely perceptible) 1
Slight edema 2
Moderate edema 3
Severe edema 4
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
other: 24-72 h
Score:
0.33
Max. score:
4
Reversibility:
fully reversible within: 48 h
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
other: 24-72 h
Score:
0
Max. score:
4
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
other: 24-72 h
Score:
0
Max. score:
4
Irritation parameter:
edema score
Basis:
animal #1
Time point:
other: 24-72 h
Score:
0
Max. score:
4
Irritation parameter:
edema score
Basis:
animal #2
Time point:
other: 24-72 h
Score:
0
Max. score:
4
Irritation parameter:
edema score
Basis:
animal #3
Time point:
other: 24-72 h
Score:
0
Max. score:
4
Irritant / corrosive response data:
In the examinations carried out in the first 30-60 minutes after removal of the patches, all the animals showed very slight erythema (grade 1). Two animals also showed very slight edema (grade 1).

Twenty-four hours after treatment, only one animal showed very slight erythema (grade 1).

In the readings carried out 48 and 72 hours after administration, no alterations were observed on the skin of any of the animals.

 

Table 1: Primary skin irritation test

 

Animal

Reaction

30-60 min

24 h

48 h

72 h

1

Erythema

1

1

0

0

Edema

1

0

0

0

2

Erythema

1

0

0

0

Edema

1

0

0

0

3

Erythema

1

0

0

0

Edema

0

0

0

0

Interpretation of results:
GHS criteria not met
Conclusions:
The substance is considered to be non-irritant to the skin.
Executive summary:

The degree of skin irritation caused by the test substance was determined after it was applied to rabbit skin, under semi-occlusive patch, and left for 4 hours. The study was carried out according to OECD Guideline 404 and EU method B.4.

In the examinations carried out in the first 30-60 minutes after removal of the patches, all the animals showed very slight erythema (grade 1). Two animals also showed very slight edema (grade 1).

Twenty-four hours after treatment, only one animal showed very slight erythema (grade 1).

In the readings carried out 48 and 72 hours after administration, no alterations were observed on the skin of any of the animals.

The mean erythema and edema scores, 24, 48 and 72 hours after application, were 0.1 and 0.0.

The substance is considered to be non-irritant to the skin.

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

Eye irritation

Link to relevant study records

Referenceopen allclose all

Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From 23rd December 1998 to 24th March 1999
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: B&K Universal G.J., S.L.
- Age at study initiation: 10-11 week old
- Weight at study initiation: 2.6-3.0 kg
- Housing: The rabbits were housed individually in stainless steel cages with a grille floor (48 x 595 x 37 cm), placed on racks.
- Diet (e.g. ad libitum): standard rabbit diet UAR 112, ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: At least 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 ± 3 ºC
- Humidity (%): 55 ± 10%
- Photoperiod (hrs dark / hrs light): 12 hours light and 12 hours dark

IN-LIFE DATES: From: 21st December 1998 To: 25th January 1999
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 mL
Observation period (in vivo):
1, 24, 48 and 72 hours, 7 and 14 day after treatment
Number of animals or in vitro replicates:
Three animals
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing (if done): no washing was done

SCORING SYSTEM:
Cornea: Opacity:
- No ulceration or opacity 0
- Scattered or diffuse areas of opacity, details of iris clearly visible 1
- Easily discernible translucent area, details of iris slightly obscured 2
- Nacrous area, no details of iris visible, size of pupil barely discernible 3
- Opaque cornea, iris not discernible through the opacity 4

Iris:
- Normal 0
- Markedly deepened rugae, congestion, swelling, moderate circumcorneal hyperaemia, or injection, any of these or combination of any thereof, iris still reating to light 1
- No reaction to light, haemorrhage, gross destruction 2

Conjunctivae: Redness:
- Blood vessels normal 0
- Some blood vessels definitely hyperaemic 1
- Diffuse, crimson colour, individual vessels not easily discernible 2
- Diffuse beefy red 3

Conjunctivae: Edema:
- No swelling 0
- Slight swelling 1
- Obvious swelling with partial eversion of lids 2
- Swelling with lids about half-closed 3
- Swelling with lids more than half-closed 4

TOOL USED TO ASSESS SCORE: Observation of the cornea was completed in each of the readings performed, with the exception of the one done one hour after administration, by applying a 2% aqueous sodium fluorescein solution.
Irritation parameter:
cornea opacity score
Basis:
animal #1
Time point:
other: 24-72 h
Score:
0
Max. score:
4
Irritation parameter:
cornea opacity score
Basis:
animal #2
Time point:
other: 24-72 h
Score:
0
Max. score:
4
Irritation parameter:
cornea opacity score
Basis:
animal #3
Time point:
other: 24-72 h
Score:
0
Max. score:
4
Irritation parameter:
iris score
Basis:
animal #1
Time point:
other: 24-72 h
Score:
0
Max. score:
2
Irritation parameter:
iris score
Basis:
animal #2
Time point:
other: 24-72 h
Score:
0
Max. score:
2
Irritation parameter:
iris score
Basis:
animal #3
Time point:
other: 24-72 h
Score:
0
Max. score:
2
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
other: 24-72 h
Score:
0.33
Max. score:
3
Reversibility:
fully reversible within: 48 hours
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
other: 24-72 h
Score:
0.67
Max. score:
3
Reversibility:
fully reversible within: 14 days
Irritation parameter:
conjunctivae score
Basis:
animal #3
Time point:
other: 24-72 h
Score:
1
Max. score:
3
Reversibility:
fully reversible within: 7 days
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
other: 24-72 h
Score:
0.67
Max. score:
4
Reversibility:
fully reversible within: 48 h
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
other: 24-72 h
Score:
0
Max. score:
4
Irritation parameter:
chemosis score
Basis:
animal #3
Time point:
other: 24-72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 72 hours
Irritant / corrosive response data:
In the course of the first hour after instillation, the test substance induced in all the animals, hyperaemia in the palpebral conjunctivae and all the animals presented diffuse, crimson-coloured redness (grade 2) and lacrimation ranging from lacrimation with wetness of the eyelids and adjacent fur to lacrimation affecting a considerable area around the eye. Similarly, two animals presented swelling with lids about half-closed (grade 3) and the remaining animal presented slight swelling (grade 2).
In the reading made 24 hours after application, some blood vessels definitely hyperaemic (grade 1) were recorded in the conjunctivae of all of the animals.
Two of these animals also presented obvious swelling with partial eversion of lids (grade 2).
Some blood vessels were still definitely hyperaemic (grade 1) in one of the animals after 48 hours. In addition, this animal presented slight edema (grade 1) in this reading.
In the subsequent readings, the ocular lesions were noted to have partially remitted.
Other effects:
The behaviour and physical condition of the rabbits were normal throughout the study.

Table 1: Primary eye irritation test

 

Animal

Region of eye

1 h

24 h

48 h

72 h

7 d

14 d

1

Cornea

 

0

0

0

0

0

-

Iris

 

0

0

0

0

0

-

Conjunctivae

Hyperaemia

2

1

0

0

0

-

Conjunctivae

Edema

3

2

0

0

0

-

2

Cornea

 

0

0

0

0

0

0

Iris

 

0

0

0

0

0

0

Conjunctivae

Hyperaemia

2

1

0

1

1

0

Conjunctivae

Edema

2

0

0

0

0

0

3

Cornea

 

0

0

0

0

0

-

Iris

 

0

0

0

0

0

-

Conjunctivae

Hyperaemia

2

1

1

1

0

-

Conjunctivae

Edema

3

2

1

0

0

-

Interpretation of results:
GHS criteria not met
Conclusions:
The substance is considered to be non-irritant to the eye.
Executive summary:

The test substance was administered for the study of primary eye irritation. The study was conducted according to EU method B.5 and OECD guideline 405.

In the course of the first hour after instillation, the test substance induced in all the animals, hyperaemia in the palpebral conjunctivae and all the animals presented diffuse, crimson-coloured redness (grade 2) and lacrimation ranging from lacrimation with wetness of the eyelids and adjacent fur to lacrimation affecting a considerable area around the eye. Similarly, two animals presented swelling with lids about half-closed (grade 3) and the remaining animal presented slight swelling (grade 2).

In the reading made 24 hours after application, some blood vessels definitely hyperaemic (grade 1) were recorded in the conjunctivae of all of the animals.

Two of these animals also presented obvious swelling with partial eversion of lids (grade 2).

Some blood vessels were still definitely hyperaemic (grade 1) in one of the animals after 48 hours. In addition, this animal presented slight edema (grade 1) in this reading.

In the subsequent readings, the ocular lesions were noted to have partially remitted.

The mean values at 24, 48 and 72 hours post-administration, for each type of lesion for the three animals were:

- Corneal opacity 0

- Iridal lesions 0

- Hyperaemia 0.67

- Edema 0.56

The substance is considered to be non-irritant to the eye.

Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From 28 October 1996 to 3 November 1996
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: David Percival Ltd, Moston, Sandbach, Cheshire, UK
- Age at study initiation: 12 to 16 weeks old
- Weight at study initiation: 2.44 to 2.58 kg
- Housing: The animals were individually housed in suspended metal cages.
- Diet (e.g. ad libitum): STANRAB SQC Rabbit Diet, Special Diets Services Ltd, Witham, Essex, UK, ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: At least five days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17-20 ºC
- Humidity (%): 45-70%
- Air changes (per hr): fifteen changes per hour
- Photoperiod (hrs dark / hrs light): twelve hours continuous light and twelve hours darkness

Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 ml
Observation period (in vivo):
1, 24, 48 and 72 hours
Number of animals or in vitro replicates:
Three animals
Details on study design:
SCORING SYSTEM: Draize scale for scoring ocular irritation

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:
animal #1
Time point:
other: 24-72 h
Score:
0
Max. score:
4
Irritation parameter:
cornea opacity score
Basis:
animal #2
Time point:
other: 24-72 h
Score:
0
Max. score:
4
Irritation parameter:
cornea opacity score
Basis:
animal #3
Time point:
other: 24-72 h
Score:
0
Max. score:
4
Irritation parameter:
iris score
Basis:
animal #1
Time point:
other: 24-72 h
Score:
0
Max. score:
2
Irritation parameter:
iris score
Basis:
animal #2
Time point:
other: 24-72 h
Score:
0
Max. score:
2
Irritation parameter:
iris score
Basis:
animal #3
Time point:
other: 24-72 h
Score:
0
Max. score:
2
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
other: 24-72 h
Score:
0.33
Max. score:
3
Reversibility:
fully reversible within: 48 h
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
other: 24-72 h
Score:
0.33
Max. score:
3
Reversibility:
fully reversible within: 48 h
Irritation parameter:
conjunctivae score
Basis:
animal #3
Time point:
other: 24-72 h
Score:
0.33
Max. score:
3
Reversibility:
fully reversible within: 48 h
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
other: 24-72 h
Score:
0
Max. score:
4
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
other: 24-72 h
Score:
0
Max. score:
4
Irritation parameter:
chemosis score
Basis:
animal #3
Time point:
other: 24-72 h
Score:
0
Max. score:
4
Irritant / corrosive response data:
No corneal or iridial effects were noted during the study.

Moderate conjunctival irritation was noted in two treated eyes with minimal conjunctival irritation in the remaining treated eye one hour after treatment. Minimal
conjunctival redness was noted in all treated eyes at the 24-hour observation.

Treated eyes appeared normal at the 48-hour observation.

 

Table 1: Acute eye irritation test in the rabbit

 

Animal

Region of eye

1 h

24 h

48 h

72 h

1

Cornea

 

0

0

0

0

Iris

 

0

0

0

0

Conjunctivae

Redness

1

1

0

0

Conjunctivae

Chemosis

1

0

0

0

2

Cornea

 

0

0

0

0

Iris

 

0

0

0

0

Conjunctivae

Redness

1

1

0

0

Conjunctivae

Chemosis

1

0

0

0

3

Cornea

 

0

0

0

0

Iris

 

0

0

0

0

Conjunctivae

Redness

2

1

0

0

Conjunctivae

Chemosis

1

0

0

0

 

Interpretation of results:
GHS criteria not met
Conclusions:
The substance is considered to be non-irritant to the eye.
Executive summary:

A study was perforrned to assess the irritancy potential of the test material to the eye of the New Zealand White rabbit. The method used followed that described in the OECD Guidelines for Testing of Chernicals No. 405 "Acute Eye Irritation/Corrosion" and Method B5 of Commission Directive 92/69/EEC.

A single instillation of the test material to the non-irrigated eye of three rabbits produced minirnal to moderate conjunctival irritation. Treated eyes appeared normal at the 48-hour observation.

The test material produced a rnaximum group mean score of 7.3 and was classified as a minimal irritant (Class 3 on a 1 to 8 scale) to the rabbit eye according to a modified Kay and Calandra classification system.

Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From 14th October 1992 to 17th December 1992
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Granjas Jordi (Molins de Rei)
- Age at study initiation: Approximately 13 week old
- Weight at study initiation: 2.0-2.3 kg
- Housing: The rabbits were housed individually in stainless steel cages with a grille floor (48 x 595 x 37 cm), placed on racks.
- Diet (e.g. ad libitum): standard rabbit diet UAR 112, ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: At least 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 ± 2 ºC
- Humidity (%): 40-70%
- Photoperiod (hrs dark / hrs light): 12 hours light and 12 hours dark

IN-LIFE DATES: From: 5th October 1992 To: 30th October 1992
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 mL
Observation period (in vivo):
1, 24, 48 and 72 hours and 4 day after treatment
Number of animals or in vitro replicates:
Three animals
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing (if done): no washing was done

SCORING SYSTEM:
Cornea: Opacity:
- No ulceration or opacity 0
- Scattered or diffuse areas of opacity, details of iris clearly visible 1
- Easily discernible translucent area, details of iris slightly blurred 2
- Opalest area, details of iris not visible, contour of pupil barely perceptible 3
- Corneal opacity, iris not perceptible through opacity 4

Iris:
- Normal 0
-Deeply marked folds, congestion, swelling, moderate hyperaemia around cornea or injection, one or more o the afore-mentioned, iris conserving rection to light 1
- No reaction to light, haemorrhage, serious damage 2

Conjunctivae: Redness:
- Normal blood vessels 0
- Some clearly hyperemic blood vessels 1
- Diffuse, crimson red, individual vessels difficult to discern 2
- Diffuse deep red 3

Conjunctivae: Edema:
- No swelling 0
- Some swelling above normal 1
- Obvious swelling with partial eversion of lids 2
- Swelling with lids about half-closed 3
- Swelling with lids more than half-closed 4

TOOL USED TO ASSESS SCORE: Following the reading carried out 24 hours after treatment, Colircusí Fluoresceína R was appliedto the treated eye of each animal, following which the eye was washed with a 0.9% w/v sodium chloride solution.
Irritation parameter:
cornea opacity score
Basis:
animal #1
Time point:
other: 24-72 h
Score:
0
Max. score:
4
Irritation parameter:
cornea opacity score
Basis:
animal #2
Time point:
other: 24-72 h
Score:
0
Max. score:
4
Irritation parameter:
cornea opacity score
Basis:
animal #3
Time point:
other: 24-72 h
Score:
0
Max. score:
4
Irritation parameter:
iris score
Basis:
animal #1
Time point:
other: 24-72 h
Score:
0
Max. score:
2
Irritation parameter:
iris score
Basis:
animal #2
Time point:
other: 24-72 h
Score:
0
Max. score:
2
Irritation parameter:
iris score
Basis:
animal #3
Time point:
other: 24-72 h
Score:
0
Max. score:
2
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
other: 24-72 h
Score:
1.33
Max. score:
3
Reversibility:
fully reversible within: 4 days
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
other: 24-72 h
Score:
1
Max. score:
3
Reversibility:
fully reversible within: 4 days
Irritation parameter:
conjunctivae score
Basis:
animal #3
Time point:
other: 24-72 h
Score:
0.67
Max. score:
3
Reversibility:
fully reversible within: 72 hours
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
other: 24-72 h
Score:
0.33
Max. score:
4
Reversibility:
fully reversible within: 48 h
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
other: 24-72 h
Score:
0
Max. score:
4
Irritation parameter:
chemosis score
Basis:
animal #3
Time point:
other: 24-72 h
Score:
0
Max. score:
4
Irritant / corrosive response data:
In the course of the first 24 hours after administration, the above-mentioned substance induced hyperemic lesions in the palpebral conjunctivae of all animals, ranging from vessels clearly more injected than normal (grade 1) to diffuse crimson red vessels (grade 2 ) , accompanied by injected vessels in the bulbar conjunctivae and by edematous lesions ranging from obvious swelling with partial eversion of the lids (grade 2) to some swelling above normal (grade 1).
They also showed discharge with moistening of the lids and hair, in some cases affecting a considerable area around the eye.
Two and three days after administration, the alterations seen in the previous observations had subsided in most animals.
Four days after treatment, the eye injuries seen in the previous readings had totally subsided.
Other effects:
The behaviour and physical condition of the rabbits were normal throughout the study.

Table 1: Primary eye irritation test

Animal

Region of eye

1 h

24 h

48 h

72 h

4 d

1

Cornea

 

0

0

0

0

0

Iris

 

0

0

0

0

0

Conjunctivae

Hyperaemia

1

2

1

1

0

Conjunctivae

Edema

2

1

0

0

0

2

Cornea

 

0

0

0

0

0

Iris

 

0

0

0

0

0

Conjunctivae

Hyperaemia

1

1

1

1

0

Conjunctivae

Edema

1

0

0

0

0

3

Cornea

 

0

0

0

0

0

Iris

 

0

0

0

0

0

Conjunctivae

Hyperaemia

1

1

1

0

0

Conjunctivae

Edema

2

0

0

0

0

Interpretation of results:
GHS criteria not met
Conclusions:
The substance is considered to be non-irritant to the eye.
Executive summary:

The test substance was administered for the study of primary eye irritation. The study was conducted according to EU method B.5 and OECD guideline 405.

In the course of the first 24 hours after administration, the above-mentioned substance induced hyperemic lesions in the palpebral conjunctivae of all animals, ranging from vessels clearly more injected than normal (grade 1) to diffuse crimson red vessels (grade 2), accompanied by edematous lesions ranging from obvious swelling with partial eversion of the lids (grade 2) to some swelling above normal (grade 1) and discharge with moistening of the lids and hair, in some cases affecting a considerable area around the eye.

All the animals also showed injected vessels in the bulbar conjunctivae.

Two and 3 days after administration, the eye injuries observed had begun to subside.

In the reading carried out four days after instillation of the product, no eye injuries were observed.

The substance is considered to be non-irritant 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: Experimental results: OECD guideline 404 and EU method B.4. GLP study.

The substance is considered to be non-irritant to the skin.

Key study: Experimental results: OECD guideline 404 and EU method B.4. GLP study.

The substance is considered to be non-irritant to the skin.

Key study: Experimental results: OECD guideline 404 and EU method B.4. GLP study.

The substance is considered to be non-irritant to the skin.

Eye irritation:

Key study: Experimental results: OECD guideline 405 and EU method B.5. GLP study.

The substance is considered to be non-irritant to the eye.

Key study: Experimental results: OECD guideline 405 and EU method B.5. GLP study.

The substance is considered to be non-irritant to the eye.

Key study: Experimental results: OECD guideline 405 and EU method B.5. GLP study.

The substance is considered to be non-irritant to the eye.


Justification for classification or non-classification

Based on the available information, the substance is not classified for irritation / corrosion:

The substance is considered to be non-irritant to the skin.

The substance is considered to be non-irritant to the eye.