Registration Dossier

Administrative data

Description of key information

Skin irritation / corrosion: not irritating (rabbit, OECD 404, GLP, K. rel.1)

Serious eye damage / eye irritation: irritating (rabbit, OECD 405, GLP, K, rel.1)

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:
From January 18 to 28, 2000
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
GLP study conducted in compliance with OECD Guideline 404 without any deviation.
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
Principles of method if other than guideline:
Not applicable
GLP compliance:
yes (incl. certificate)
Remarks:
inspected on September 22, 1999 / signed on January 18, 2000
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Elevage Cunicole de Val de Selle, 80160 Prouzel, France
- Age at study initiation: No data available
- Weight at study initiation: 2.5 ± 0.2 kg
- Housing: Animals were housed individually in polystyrene cages (48.2 cm x 58 cm x 36.5 cm).
- Diet: 112 C pelleted diet (UAR, 91360 Villemoisson-sur-Orge, France), ad libitum
- Water: Drinking water filtered by a FG Millipore membrane (0.22 micron), ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature: 18 ± 3 °C
- Humidity: 30–70%
- Air changes: Approximately 12 cycles/hour of filtered, non-recycled air.
- Photoperiod: 12 hrs dark / 12 hrs light

IN-LIFE DATES: From: January 18, 2000 To: January 28, 2000
Type of coverage:
semiocclusive
Preparation of test site:
clipped
Vehicle:
other: moistened with water
Controls:
other: untreated skin served as control
Amount / concentration applied:
TEST MATERIAL
- Amount applied: 500 mg (ground to a fine powder using a mortar and pestle)
- Purified water was used to moisten the test substance and ensure good contact with the skin
Duration of treatment / exposure:
4 hours
Observation period:
Observations at 1, 24, 48 and 72 hours and daily as needed up to 14 days after removal of the dressing.
Number of animals:
3 male animals
Details on study design:
TEST SITE
- Area of exposure: Right flank
- % coverage: no data available
- Type of wrap if used: The test substance and the gauze pad were held in contact with the skin by means of an adhesive hypoallergenic aerated semi-occlusive dressing and a restraining bandage.

REMOVAL OF TEST SUBSTANCE
- Washing: After removal of the dressing, any residual test substance was wiped off by means of a dry gauze pad.
- Time after start of exposure: 4 hours

SCORING SYSTEM: Draize scale, as described in OECD Guideline 404

Irritation parameter:
erythema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 6 days
Remarks on result:
probability of weak irritation
Remarks:
A well-defined erythema (score 2) was noted on Day 1, then a very slight erythema (score 1) persisted up to Day 5. Dryness of the skin was recorded between Day 6 and Day 10
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0.3
Max. score:
4
Reversibility:
fully reversible within: 48 hours
Remarks on result:
probability of weak irritation
Remarks:
A very slight erythema was observed on Day 1 and 2 only
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:
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:
In one animal, a well-defined erythema (grade 2) was noted on day 1, then a very slight erythema (grade 1) persisted up to day 5. Dryness of the skin was recorded between day 6 and day 10.
In a second animal, a very slight erythema (grade 1) was observed on days 1 and 2 only.
No cutaneous reactions were observed in the third animal.
Other effects:
None

Table 7.3.1/1: Mean irritant/corrosive response data for each animal at each observation time

 

Score at time point

Erythema (Animal no 1 / 2 / 3)

Max. score 4

Oedema (Animal no 1 / 2 / 3)

Max. score 4

1 h (D1)

2 / 1 / 0

0 / 0 / 0

24 h (D2)

1 / 1 / 0

0 / 0 / 0

48 h (D3)

1 / 0 / 0

0 / 0 / 0

72 h (D4)

1 / 0 / 0

0 / 0 / 0

D5

1 / - / -

0 / - / -

D6

0 / - / -

0 / - / -

D7

0 / - / -

0 / - / -

D8

0 / - / -

0 / - / -

D9

0 / - / -

0 / - / -

D10

0 / - / -

0 / - / -

D11

0 / - / -

0 / - / -

Average 24, 48 and 72 h

1.0 / 0.3 / 0.0

0.0 / 0.0 / 0.0

 

-:Cutaneous examination not performed

Interpretation of results:
not irritating
Conclusions:
Under the test conditions, test material is not classified as irritating to skin according to the annex I of the Regulation EC No. 1272/2008 (CLP) and of the GHS.
Executive summary:

In a primary dermal irritation study performed according to the OECD Guideline No. 404/EU Method B.4, and in compliance with GLP, 500 mg of test material moistened with purified water was applied on the clipped skin of the right flank area of 3 male New Zealand White rabbits. Test sites were covered with a semi-occlusive dressing for 4 h. The untreated skin served as control. Skin irritation was assessed and scored according to the Draize scale at 1, 24, 48, 72 hours after removal of the dressing and then daily until reversibility of cutaneous reactions.

 

In one animal, a well-defined erythema was noted on day 1, then a very slight erythema persisted up to day 5. Dryness of the skin was recorded between day 6 and day 10. In a second animal, a very slight erythema was observed on days 1 and 2 only. No cutaneous reactions were observed in the third animal. Mean scores over 24, 48 and 72 hours for each animal were 1.0, 0.3 and 0.0 for erythema and 0.0, 0.0 and 0.0 for oedema.

 

Therefore, test material is not classified as irritating to skin according to the annex I of the Regulation EC No. 1272/2008 (CLP) and of the GHS.

This study is considered as acceptable and satisfies the requirement for skin irritation endpoint.

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:
From January 25 to February 05, 2000
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
GLP study conducted in compliance with OECD Guideline No. 405 without any deviation.
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
Principles of method if other than guideline:
Not applicable
GLP compliance:
yes (incl. certificate)
Remarks:
inspected on September 22, 1999 / signed on January 18, 2000
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Elevage Cunicole de Val de Selle, 80160 Prouzel, France
- Age at study initiation: No data available
- Weight at study initiation: 2.7 ± 0.2 kg
- Housing: Animals were housed individually in polystyrene cages (48.2 cm x 58 cm x 36.5 cm).
- Diet: 112 C pelleted diet (UAR, 91360 Villemoisson-sur-Orge, France), ad libitum
- Water: Drinking water filtered by a FG Millipore membrane (0.22 micron), ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature: 18 ± 3 °C
- Humidity: 30–70%
- Air changes: Approximately 12 cycles/hour of filtered, non-recycled air.
- Photoperiod: 12 hrs dark / 12 hrs light

IN-LIFE DATES: From: January 25, 2000 To: February 05, 2000
Vehicle:
unchanged (no vehicle)
Controls:
other: The right eye was untreated, serving as the control.
Amount / concentration applied:
TEST MATERIAL
- Amount applied: 100 mg (ground to a fine powder)


Duration of treatment / exposure:
Single application to the left eye. The eyes were not rinsed after administration of the test substance.
Observation period (in vivo):
Observations at 1, 24, 48 and 72 hours and then daily until reversibility of the ocular reactions. When there was persistent ocular irritation after 72 hours, the observation period was extended to a maximum of 21 days (until day 22) in order to determine the progress of the lesions and their reversibility.
Number of animals or in vitro replicates:
3 male animals
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing: not done. The eyes were not rinsed after administration of the test substance.
- Time after start of exposure: not applicable

SCORING SYSTEM: Draize scale as described in the OECD guideline No. 405.

TOOL USED TO ASSESS SCORE: Fluorescein

Irritation parameter:
cornea opacity score
Basis:
animal #1
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 8 days
Remarks on result:
probability of mild irritation
Irritation parameter:
cornea opacity score
Basis:
animal #2
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 8 days
Remarks on result:
probability of mild irritation
Irritation parameter:
cornea opacity score
Basis:
animal #3
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 5 days
Remarks on result:
probability of mild irritation
Irritation parameter:
iris score
Basis:
animal #1
Time point:
24/48/72 h
Score:
1
Max. score:
2
Reversibility:
fully reversible within: 6 days
Remarks on result:
probability of weak irritation
Irritation parameter:
iris score
Basis:
animal #2
Time point:
24/48/72 h
Score:
1
Max. score:
2
Reversibility:
fully reversible within: 7 days
Remarks on result:
probability of weak irritation
Irritation parameter:
iris score
Basis:
animal #3
Time point:
24/48/72 h
Score:
1
Max. score:
2
Reversibility:
fully reversible within: 5 days
Remarks on result:
probability of weak irritation
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
24/48/72 h
Score:
3
Max. score:
3
Reversibility:
fully reversible within: 10 days
Remarks on result:
probability of severe irritation
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
24/48/72 h
Score:
3
Max. score:
3
Reversibility:
fully reversible within: 11 days
Remarks on result:
probability of severe irritation
Irritation parameter:
conjunctivae score
Basis:
animal #3
Time point:
24/48/72 h
Score:
2.7
Max. score:
3
Reversibility:
fully reversible within: 7 days
Remarks on result:
probability of severe irritation
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
24/48/72 h
Score:
2.3
Max. score:
4
Reversibility:
fully reversible within: 11 days
Remarks on result:
probability of moderate irritation
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
24/48/72 h
Score:
2.7
Max. score:
4
Reversibility:
fully reversible within: 12 days
Remarks on result:
probability of moderate irritation
Irritation parameter:
chemosis score
Basis:
animal #3
Time point:
24/48/72 h
Score:
2.3
Max. score:
4
Reversibility:
fully reversible within: 7 days
Remarks on result:
probability of moderate irritation
Irritant / corrosive response data:
Very slight to moderate conjunctival reactions were observed in all animals from day 1: a very slight to moderate chemosis (grades 1 to 3), a very slight to moderate redness of the conjunctiva (grades 1 to 3) and a clear discharge were noted. These reactions persisted up to day 6, 10 or 11.
A slight iritis (grade 1) was noted in all animals on day 2; it persisted up to day 4, 5 or 6.
A slight corneal opacity (grade 2) was recorded in all animals on day 2; a very slight or slight corneal opacity (grade I or 2) persisted up to day 4 (one animal) or 7.
Neovascularisation was noted in one animal, from day 6 up to day 9.
Other effects:
None

Table 7.3.2/1: Irritant/corrosive response data each animals at each observation time up to removal from the test

 

Score at time point / Reversibility

Cornea

Iris

(/2)

Conjunctivae

Opacity

(/4)

Redness

(/3)

Chemosis

(/4)

Discharge

(/3)

1 h

0 / 0 / 0

0 / 0 / 0

2 / 2 / 2

2 / 2 / 2

2 / 2 / 2

24 h

2 / 2 / 2

1 / 1 / 1

3 / 3 / 3

3 / 3 / 3

2 / 2 / 3

48 h

2 / 2 / 2

1 / 1 / 1

3 / 3 / 3

2 / 3 / 2

0 / 1 / 0

72 h

2 / 2 / 2

1 / 1 / 1

3 / 3 / 2

2 / 2 / 2

0 / 0 / 0

Average 24h, 48h, 72h

2 / 2 / 2

1 / 1 / 1

3 / 3 / 2.7

2.3 / 2.7 / 2.3

0.7 / 1 / 0.7

Reversibility*)

c.

c.

c.

c.

c

Average time for reversion

D8 / D8 / D5

D6 / D7 / D5

D10 / D11 / D7

D11 / D12 / D7

48h / 72h / 48h

*) Reversibility: c. = completely reversible; n.c. = not completely reversible; n. = not reversible

D = Day

Interpretation of results:
irritating
Conclusions:
Under the test conditions, the test material is classified as "Category 2 irritating to eyes" according to the criteria of the Annex I of the Regulation (EC) No. 1272/2008 (CLP) and to the GHS.
Executive summary:

In an eye irritation study performed according to the OECD Guideline No. 405/EU Method B.5, and in compliance with GLP, asingle dose of 100 mg of the test substance, first ground to a fine powder, was introduced into the conjunctival sac of the left eye of three male New Zealand White rabbits. The lower and upper eyelids were held together for about one second to avoid any loss of test substance. The right eye was not treated and served as control. The eyes were not rinsed after administration of the test substance. Ocular reactions were observed approximately 1, 24, 48 and 72 hours after the administration and then daily until reversibility of the ocular reactions and graded according to the Draize method.

 

Very slight to moderate conjunctival reactions (very slight to moderate chemosis, very slight to moderate redness of the conjunctiva and clear discharge) were observed in all animals from day 1; these reactions persisted up to day 11 at the latest. A slight iritis was noted in all animals on day 2; it persisted up to day 4, 5 or 6. A slight corneal opacity was recorded in all animals on day 2; a very slight or slight corneal opacity persisted up to day 4 or 7. Neovascularisation was noted in one animal, from day 6 up to day 9.Mean scores calculated for each animal over 24, 48 and 72 hours were 2.3, 2.7 and 2.3 for chemosis, 3.0, 3.0 and 2.7 for redness of the conjunctiva, 1.0, 1.0 and 1.0 for iris lesions and 2.0, 2.0 and 2.0 for corneal opacity.

 

Under the test conditions, the test material is classified as "Category 2 irritating to eyes" according to the criteria of the Annex I of the Regulation (EC) No. 1272/2008 (CLP) to the GHS.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin irritation:

A key study was identified (CIT, 2000). This primary dermal irritation study was performed according to the OECD Guideline No. 404/EU Method B.4, and in compliance with GLP. 

In one animal, a well-defined erythema was noted on day 1, then a very slight erythema persisted up to day 5. Dryness of the skin was recorded between day 6 and day 10. In a second animal, a very slight erythema was observed on days 1 and 2 only. No cutaneous reactions were observed in the third animal. Mean scores over 24, 48 and 72 hours for each animal were 1.0, 0.3 and 0.0 for erythema and 0.0, 0.0 and 0.0 for oedema.

Therefore, test material is not classified as irritating to skin.

Eye irritation:

A key study was identified (CIT, 2000). This eye irritation study was performed according to the OECD Guideline No. 405/EU Method B.5, and in compliance with GLP. 

Very slight to moderate conjunctival reactions (very slight to moderate chemosis, very slight to moderate redness of the conjunctiva and clear discharge) were observed in all animals from day 1; these reactions persisted up to day 11 at the latest. A slight iritis was noted in all animals on day 2; it persisted up to day 4, 5 or 6. A slight corneal opacity was recorded in all animals on day 2; a very slight or slight corneal opacity persisted up to day 4 or 7. Neovascularisation was noted in one animal, from day 6 up to day 9.Mean scores calculated for each animal over 24, 48 and 72 hours were 2.3, 2.7 and 2.3 for chemosis, 3.0, 3.0 and 2.7 for redness of the conjunctiva, 1.0, 1.0 and 1.0 for iris lesions and 2.0, 2.0 and 2.0 for corneal opacity.

The test material is classified as irritating to eyes.

Justification for classification or non-classification

Harmonized classification:

The substance has no harmonized classification according to the Regulation (EC) No. 1272/2008.

Self-classification:

Skin irritation:

Based on the available information, no additional self-classification is proposed regarding skin irritation according to the Regulation (EC) No. 1272/2008 (CLP) and according to the GHS.

Eye irritation:

Based on the available information, the test material is classified as Eye irritant Category 2 (H319: Causes serious eye irritation.) according to the Regulation (EC) No. 1272/2008 (CLP) and according to the GHS.

Respiratory irritation:

No data was available.