Registration Dossier

Administrative data

Description of key information

Skin irritation: Not irritating (OECD 404, GLP, Rel.1, K).
Eye irritation: Not irritating (OECD 405, GLP, Rel. 1, K).

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 13 to February 05, 2009
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Version / remarks:
Adopted 24th April 2002
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:
UK GLP Compliance Programme (inspected on August 19, 2008/ signed on March 04, 2009)
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan Laboratories UK Limited, Bicester, Oxon, UK.
- Age at study initiation: 12-20 weeks
- Weight at study initiation: 2-3.5 kg
- Housing: Animals were housed individually in suspended cages.
- Diet: Food (2030 Teklad Global Rabbit diet supplied by Harlan Teklad, Bicester, Oxon, UK), ad libitum
- Water: Mains drinking water, ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature: 17-23 °C
- Humidity: 30-70 %
- Air changes: 15 changes/h
- Photoperiod: 12 h dark / 12 h light

IN-LIFE DATES: From: January 13, 2009 To: February 05, 2009
Type of coverage:
semiocclusive
Preparation of test site:
clipped
Vehicle:
other: test material was moistened with distilled water
Controls:
not required
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 g
- Test material was ground to a fine powder prior to application.
- 0.5 g of the test material was moistened with 0.5 mL of distilled water before applied on to the skin.
Duration of treatment / exposure:
First animal: 3 minutes, 1 and 4 h
Second and third animal: 4 h
Observation period:
1, 24, 48 and 72 h and 7 and 14 days after the removal of the patch
Number of animals:
3 males
Details on study design:
TEST SITE
- Area of exposure: Dorsal/flank area
- Type of wrap if used: Test material moistened with distilled water was introduced under a 2.5 cm x 2.5 cm cotton gauze patch and placed in position on the shorn skin. The patch was secured in position with a strip of surgical adhesive tape.
- To prevent the animal interfering with the patches, the trunk of the rabbit was wrapped in an elasticated corset for the duration of the exposure period.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): One patch was removed at each of three time points: 3 minutes, 1 and 4 h after application of test material. Any residual test material was removed by gentle swabbing with cotton wool soaked in distilled water.
- Time after start of exposure: 3 minutes, 1 and 4 h

SCORING SYSTEM: Draize scale, as described in OECD Guideline No. 404
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
other: mean 24, 48 and 72 h
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 14 days
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
other: mean 24, 48 and 72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 14 days
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
other: mean 24, 48 and 72 h
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 14 days
Irritation parameter:
edema score
Basis:
animal #1
Time point:
other: mean 24, 48 and 72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
edema score
Basis:
animal #2
Time point:
other: mean 24, 48 and 72 h
Score:
0
Max. score:
4
Irritation parameter:
edema score
Basis:
animal #3
Time point:
other: mean 24, 48 and 72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritant / corrosive response data:
- Following 3 minutes exposure period, no evidence of skin irritation was observed.
- Following 1 h exposure period, very slight erythema was observed at the treated skin site at the 24, 48 and 72 h. The treated skin site appeared normal at the 7-day observation.
- Following 4 h exposure period, well-defined erythema was noted at two treated skin sites with very slight erythema noted at the remaining treated skin site at the 24, 48 and 72 h. Very slight oedema was noted at two treated skin sites at the 24, 48 and 72 h. Loss of skin flexibility and/or elasticity was noted at two treated skin sites and light brown discolouration of the epidermis was noted at one treated skin site at the 48 and 72 h. Slight desquamation was noted at all treated skin sites on Day 7. Two treated skin sites were fully reversible on Day 14.
Other effects:
- Animals showed expected gain in bodyweight during the 14 day study.

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

0 / 0 / 0

0 / 0/ 0

24 h

2 / 1 / 2

1/ 0 / 1

48 h

2 / 1 Le / 2 Le Br

1/ 0 / 1

72 h

2 / 1 Le / 2 Le Lf Br

1/ 0 / 1

7 days

0 D / 0 D / 0 D

0 / 0 / 0

14 days

* / 0 / 0

* / 0 / 0

Average 24h, 48h, 72h

2 / 1 / 2

1 / 0 / 1

Le = loss of skin elasticity; Lf = loss of skin flexibility; Br = light brown discolouration of the epidermis; D = slight desquamation; * = observation not required

Interpretation of results:
Category 3 (mild irritant) based on GHS criteria
Conclusions:
Under the test conditions :
- no additional self-classification is proposed for the registered substance regarding skin irritation according to the Annex VI of the Regulation (EC) No. 1272/2008 (CLP)
- the registered substance is classified as Category 3 according to the GHS based on the individual scores for each animal within 3 scoring times (24, 48 and 72 h) for erythema (2.0 / 1.0 / 2.0).

Executive summary:

In a dermal irritation study performed according to the OECD Guideline No. 404, and in compliance with GLP, 0.5 g of test material moistened with distilled water was applied on the clipped skin of the dorsal flank area of 3 male New Zealand White rabbits. Test sites were covered with a semi-occlusive dressing for 4 h. Skin irritation was assessed and scored according to the Draize scale at 1, 24, 48, 72 h and 7 and 14 days after the removal of the patch. First animal was exposed for 3 minutes, 1 and 4 h showed no corrosive effects.

No evidence of skin irritation was observed following 3 minutes exposure period. Very slight erythema was observed at the treated skin site at the 24, 48 and 72 h and found fully reversible on Day 7 after 1 h exposure. After 4 h exposure period, well-defined erythema was noted at two treated skin sites with very slight erythema noted at the remaining treated skin site at the 24, 48 and 72 h. Very slight oedema was noted at two treated skin sites at 24, 48 and 72 h. Loss of skin flexibility and elasticity was noted at two treated skin sites and light brown discolouration of the epidermis was noted at one treated skin site at 48 and 72 h. Slight desquamation was noted at all treated skin sites on Day 7. Two treated skin sites were fully reversible on Day 14.

The individual scores for each animal within 3 scoring times (24, 48 and 72 h) were 2.0 / 1.0 / 2.0 for erythema and 1.0 / 0.0 / 1.0 for oedema.

Based on the available data :

- no additional self-classification is proposed for the registered substance regarding skin irritation according to the Annex VI of the Regulation (EC) No. 1272/2008 (CLP)

- the registered substance is classified as Category 3 according to the GHS based on the individual scores for each animal within 3 scoring times (24, 48 and 72 h) for erythema (2.0 / 1.0 / 2.0).

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 February 09 to 19, 2009
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Version / remarks:
Adopted 24th April 2002
Deviations:
no
Remarks:
Only two animals were tested
Qualifier:
according to
Guideline:
EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)
Deviations:
no
Remarks:
Only two animals were tested
Principles of method if other than guideline:
Not applicable
GLP compliance:
yes (incl. certificate)
Remarks:
UK GLP Compliance Programme (inspected on August 19, 2008/ signed on March 04, 2009)
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Harlan Laboratories UK Limited, Bicester, Oxon, UK.
- Age at study initiation: 12-20 weeks
- Weight at study initiation: 2.71-2.90 kg
- Housing: Animals were housed individually in suspended cages.
- Diet: Food (2030 Teklad Global Rabbit diet supplied by Harlan Teklad, Blackthorn, Bicester, Oxon, UK), ad libitum.
- Water: Mains drinking water, ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature: 17-23 °C
- Humidity: 30-70 %
- Air changes: 15 changes/h
- Photoperiod: 12 h dark / 12 h light

IN-LIFE DATES: From: February 09, 2009 To: February 19, 2009.
Vehicle:
unchanged (no vehicle)
Controls:
other: untreated eye served as control
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 mL (approximately 0.73 mg)
- For the purpose of the study, the test material was ground to a fine powder prior to application.
Duration of treatment / exposure:
No washing was done.
Observation period (in vivo):
1, 24, 48 and 72 h after instillation of test material
Number of animals or in vitro replicates:
2 males
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing: No

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

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 and #2
Time point:
other: Mean 24, 48 and 72 h
Score:
0
Max. score:
4
Irritation parameter:
iris score
Basis:
animal: #1 and #2
Time point:
other: Mean 24, 48 and 72 h
Score:
0
Max. score:
2
Irritation parameter:
conjunctivae score
Basis:
animal: #1 and #2
Time point:
other: Mean 24, 48 and 72 h
Score:
1
Max. score:
3
Reversibility:
fully reversible within: 72 h
Irritation parameter:
chemosis score
Basis:
animal: #1 and #2
Time point:
other: Mean 24, 48 and 72 h
Score:
0.3
Max. score:
4
Reversibility:
fully reversible within: 48 h
Irritant / corrosive response data:
- No corneal or iridial effects were observed during the study.
- Moderate conjunctival irritation was observed in all treated eyes at 1 and 24 h after treatment and minimal conjunctival irritation was observed at the 48 h.
- All treated eyes appeared normal at the 72 h observation.
Other effects:
- All animals showed expected gain in bodyweight during the study.

Table 7.3.2/1: Eye irritation response data for each animal at each observation time

Score at time point

Cornea

Iris

(/2)

Conjunctivae

Opacity

(/4)

Area

(/4)

Redness

(/3)

Chemosis

(/4)

Discharge

(/3)

1 h

0 / 0

0 / 0

0 / 0

2 / 2

2 / 2

2 / 2

24 h

0 / 0

0 / 0

0 / 0

2 / 2

1 / 1

1 / 1

48 h

0 / 0

0 / 0

0 / 0

1 / 1

0 / 0

0 / 0

72 h

0 / 0

0 / 0

0 / 0

0 / 0

0 / 0

0 / 0

Average 24, 48 and 72 h

0.0

0.0

0.0

1.0 / 1.0

0.3 / 0.3

0.3 / 0.3

Reversibility

 -

 -

-

Completely

reversible

Completely reversible

Completely reversible

Average time (unit) for reversion

-

-

-

72 h

48 h

48 h

Interpretation of results:
GHS criteria not met
Conclusions:
Under the test conditions, the test material is not classified as irritating to eyes according to the criteria of the Annex VI 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, and in compliance with GLP, 0.1 mL of undiluted test material (approximately 0.73 mg) was instilled into the right eye of 2 male New Zealand White rabbits following a sequential testing strategy. The left eye remained untreated and served as control. The upper and lower eyelids were held together for about one second immediately after application, to prevent loss of the test material, and then released. The eyes were examined and the changes were observed at 1, 24, 48 and 72 h after treatment and graded according to the Draize method.

No corneal or iridial effects were observed during the study. Moderate conjunctival irritation was observed in all treated eyes at 1 and 24 h after treatment and minimal conjunctival irritation was observed at the 48 h. All treated eyes appeared normal at the 72 h observation.

Mean individual scores at 24, 48 and 72 h after exposure for the 2 animals were 0.0 / 0.0 for cornea score; 0.0 / 0.0 for iris score; 1.0 / 1.0 for conjunctivae score and 0.3 / 0.3 for chemosis score.

Under the test conditions, the test material is not classified as irritating to eyes according to the criteria of the Annex VI of the Regulation (EC) No. 1272/2008 (CLP) and to the GHS.

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

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

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin irritation:

A key study was identified (Harlan, 2009, rel. 1). This dermal irritation study was performed according to the OECD Guideline No. 404, and in compliance with GLP.

No evidence of skin irritation was observed following 3 minutes exposure period. Very slight erythema was observed at the treated skin site at the 24, 48 and 72 h and found fully reversible on Day 7 after 1 h exposure. After 4 h exposure period, well-defined erythema was noted at two treated skin sites with very slight erythema noted at the remaining treated skin site at the 24, 48 and 72 h. Very slight oedema was noted at two treated skin sites at 24, 48 and 72 h. Loss of skin flexibility and elasticity was noted at two treated skin sites and light brown discolouration of the epidermis was noted at one treated skin site at 48 and 72 h. Slight desquamation was noted at all treated skin sites on Day 7. Two treated skin sites were fully reversible on Day 14.

The individual scores for each animal within 3 scoring times (24, 48 and 72 h) were 2.0 / 1.0 / 2.0 for erythema and 1.0 / 0.0 / 1.0 for oedema.

Eye irritation:

A key study was identified (Harlan, 2008, rel.1). This eye irritation study was performed according to the OECD Guideline No. 405, and in compliance with GLP, and followed a sequential testing strategy. Results from the two animals were sufficient to allow for a hazard classification determination, therefore no further testing on a third animal was conducted.

No corneal or iridial effects were observed during the study. Moderate conjunctival irritation was observed in all treated eyes at 1 and 24 h after treatment and minimal conjunctival irritation was observed at the 48 h. All treated eyes appeared normal at the 72 h observation.

Mean individual scores at 24, 48 and 72 h after exposure for the 2 animals were 0.0 / 0.0 for cornea score; 0.0 / 0.0 for iris score; 1.0 / 1.0 for conjunctivae score and 0.3 / 0.3 for chemosis score.

Justification for classification or non-classification

Harmonized classification:

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

Self classification:

Based on the available data :

- no additional self-classification is proposed for the registered substance regarding skin irritation according to the Annex VI of the Regulation (EC) No. 1272/2008 (CLP)

- the registered substance is classified as Category 3 according to the GHS based on the individual scores for each animal within 3 scoring times (24, 48 and 72 h) for erythema (2.0 / 1.0 / 2.0).

Based on the available data no additional self-classification is proposed regarding eye irritation according to the Annex VI of the Regulation (EC) No. 1272/2008 (CLP) and to the GHS.

No data was available regarding respiratory irritation.