Registration Dossier

Administrative data

Description of key information

Skin irritation / corrosion: not irritating (OECD 404, GLP, Rel.1).
Eye irritation: not irritating (OECD 405, GLP, 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 05 May 2004 to 12 May 2004
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study performed according to OECD test guideline No. 404 and in compliance with GLP
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to other study
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
Principles of method if other than guideline:
Not applicable
GLP compliance:
yes (incl. QA statement)
Remarks:
UK GLP Compliance Programme (Inspected on 2002-12-01)
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: New Zealand White rabbits were supplied by David Percival Ltd, Moston, Sandbach, Cheshire, UK.
- Age at study initiation: 12 to 20 weeks old
- Weight at study initiation: 2.0 to 3.5 kg
- Housing: The animals were individually housed in suspended metal cages. The animals were provided with environmental enrichment items which were considered not to contain any contaminant of a level that might have affected the purpose or integrity of the study.
- Diet (e.g. ad libitum): Free access to food (Certified Rabbit Diet (Code 5322) supplied by BCM IPS Limited, London, UK)
- Water (e.g. ad libitum): Free access to main drinking water.
- Acclimation period: at least five days


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


IN-LIFE DATES: From: 05 May 2004 To: 12 May 2004
Type of coverage:
semiocclusive
Preparation of test site:
other: clipped
Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 mL of test material
Duration of treatment / exposure:
4 hours
Observation period:
Approximately one hour following the removal of the patches, and 24, 48 and 72 hours later
Number of animals:
3
Details on study design:
TEST SITE
- Area of exposure: 2.5 cm x 2.5 cm
- Type of wrap if used: cotton gauze patch and elasticated corset


REMOVAL OF TEST SUBSTANCE
- Washing (if done): 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 (beef redness) to eschar formation preventing grading of erythema 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 1mm) 3
Severe oedema (raised more than 1mm and extending beyond area of exposure) 4
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
other: Mean 24-48-72 hours
Score:
0
Max. score:
4
Remarks on result:
other: no erythema recorded
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
other: Mean 24-48-72 hours
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 7 Days
Remarks on result:
other: Very slight erythema at 24, 48 and 72h
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
other: Mean 24-48-72 hours
Score:
1.67
Max. score:
4
Reversibility:
fully reversible within: 7 Days
Remarks on result:
other: Very slight erythema at 24 h, well defined erythema at 48 and 72h observed.
Irritation parameter:
edema score
Basis:
animal #1
Time point:
other: Mean 24-48-72 hours
Score:
0
Max. score:
4
Remarks on result:
other: no oedema recorded
Irritation parameter:
edema score
Basis:
animal #2
Time point:
other: Mean 24-48-72 hours
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 7 Days
Remarks on result:
other: Very light oedema observed at 24, 48 and 72 h.
Irritation parameter:
edema score
Basis:
animal #3
Time point:
other: Mean 24-48-72 hours
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 7 Days
Remarks on result:
other: Very slight oedema observed at 24, 48 and 72 h.
Irritant / corrosive response data:
Very slight erythema was noted at one treated skin site one hour after patch removal. Well-defined erythema and very slight oedema were noted at one treated skin site with very slight erythema and very slight oedema noted at one other treated skin site at the 24 and 48-hour observations. Very slight erythema and very slight oedema were noted at both of these treated skin sites at the 72-hour observation. Loss of skin elasticity was noted at two treated skin sites at the 72-hour observation. Moderate desquamation was noted at one treated skin site at the 48 and 72-hour observations and at two treated skin sites at the 7-day observation. One treated skin site appeared normal throughout the study.
Other effects:
Loss of skin elasticity was noted at two treated skin sites at the 72-hour observation. Moderate desquamation was noted at one treated skin site at the 48 and 72-hour observations and at two treated skin sites at the 7-day observation. No other effects (toxic effects, etc.) were observed.

Table 7.3.1/1: Mean irritant/corrosive response data for each individual animal at each observation time up to removal of animals from the test

Score at time point / Reversibility

Erythema

Max. score 4

Edema

Max. score 4

1 h

0 / 0 / 1

0 / 0 / 0

24 h

0 / 1 / 2

0 / 1 / 1

48 h

0 / 1 / 2D

0 / 1 / 1

72 h

0 / 1 Le / 2 DLe

0 / 1 / 1

Average 24h, 48h, 72h

0 / 1 / 1.67

0 / 1 / 1

Reversibility*)

- / c. / c.

- / c. / c.

Average time for reversion

- / 7 days / 7 days

- / 7 days / 7 days

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

D = Moderate desquamation

Le = Loss of skin elasticity

Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Under the test conditions, the test material induced slight to moderate irritation being largely reversible within 7 days of dosing.
Therefore the test material does not require a classification as irritant to the skin according to the Annex VI of the Regulation (EC) No. 1272/2008 (CLP) and the Directive 67/548/EC.
Executive summary:

In a dermal irritation study performed according to the OECD guideline No. 404, and in compliance with GLP, 0.5 mL of undiluted test material was dermally applied on the clipped skin of the dorsal/flank area of 3 New Zealand White rabbits. Test sites were covered with a semi-occlusive dressing for 4 hours. Animals were then observed for 7 days for oedema and erythema. 

Skin irritation was assessed and scored according to the Draize scale at 1, 24, 48 and 72 hrs after the removal of the patch and on day 7.

The mean scores calculated for each individual animal tested within 3 scoring times (24, 48 and 72 hrs) were 0 / 1 / 1.67 for erythema and 0 / 1 / 1 for oedema.

Under the test conditions, the test material induced slight to well-defined erythema and very slight oedema at two treated skin sites being largely reversible within 7 days of dosing. Loss of skin elasticity was noted at two treated skin sites at the 72-hour observation. Moderate desquamation was noted at one treated skin site at the 48 and 72-hour observations and at two treated skin sites at the 7-day observation. No other effects were observed.

Therefore the test material does not require a classification as irritant to the skin according to the Annex VI of the Regulation (EC) No. 1272/2008 (CLP) and the Directive 67/548/EC.

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 13 May 2004 to 21 May 2004
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study performed according to OECD test guideline No. 405 and in compliance with GLP.
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to other study
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
Principles of method if other than guideline:
Not applicable
GLP compliance:
yes (incl. QA statement)
Remarks:
UK GLP Compliance Programme (Inspected on 2002-12-02)
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 20 weeks old
- Weight at study initiation: 2.0 to 3.5 kg
- Housing: The animals were individually housed in suspended metal cages
- Diet (e.g. ad libitum): Free access to food (Certified Rabbit Diet (Code 5322) supplied by BCM IPS Limited, London, UK)
- Water (e.g. ad libitum): Free access to main drinking water
- Acclimation period: at least five days

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

IN-LIFE DATES: From: 13 May 2004 To: 21 May 2004
Vehicle:
unchanged (no vehicle)
Controls:
other: contralateral eye served as control
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 mL
Duration of treatment / exposure:
Not applicable, the eyes were not rinsed after the instillation of the test item.
Observation period (in vivo):
Assessment of ocular damage/irritation was made approximately 1 hour and 24, 48 and 72 hours following treatment. An assessment of the initial pain reaction was made immediately after administration of the test material.
Number of animals or in vitro replicates:
3
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing (if done): None
- Time after start of exposure: NA

SCORING SYSTEM: Draize scale, according to OECD TG 405.

TOOL USED TO ASSESS SCORE: ophtalmoscope
Irritation parameter:
cornea opacity score
Basis:
animal: # 1, #2 & #3
Time point:
other: Mean 24-48-72 hours
Score:
0
Max. score:
4
Irritation parameter:
iris score
Basis:
animal: # 1, #2 & #3
Time point:
other: Mean 24-48-72 hours
Score:
0
Max. score:
2
Reversibility:
fully reversible within: No changes were recorded
Irritation parameter:
conjunctivae score
Basis:
animal: # 1 & #3
Time point:
other: Mean 24-48-72 hours
Score:
0.33
Max. score:
3
Reversibility:
fully reversible within: 72 hours
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
other: Mean 24-48-72 hours
Score:
0.67
Max. score:
3
Reversibility:
fully reversible within: 48 hours
Irritation parameter:
chemosis score
Basis:
animal: # 1, #2 & #3
Time point:
other: Mean 24-48-72 hours
Score:
0
Max. score:
4
Irritant / corrosive response data:
No corneal or iridial effects were noted during the study. Minimal conjunctival irritation was noted in all treated eyes one and 24 hours after treatment. Minimal conjunctival redness persisted in one treated eye at the 48-hour observation. Two treated eyes appeared normal at the 48-hour observation and the remaining treated eye appeared normal at the 72-hour observation.
Other effects:
None

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

 

Score at time point / Reversibility

Cornea

Iris

(/2)

Conjunctivae

Opacity

(/4)

Area

(/4)

Redness

(/3)

Chemosis

(/4)

Discharge

(/3)

1 h

0 / 0 / 0

0 / 0 / 0

0 / 0 / 0

1 / 1 / 1

1 / 1 / 1

1 / 1 / 1

24 h

0 / 0 / 0

0 / 0 / 0

0 / 0 / 0

1 / 1 / 1

0 / 0 / 0

1 / 1 / 1

48 h

0 / 0 / 0

0 / 0 / 0

0 / 0 / 0

0 / 1 / 0

0 / 0 / 0

0 / 0 / 0

72 h

0 / 0 / 0

0 / 0 / 0

0 / 0 / 0

0 / 0 / 0

0 / 0 / 0

0 / 0 / 0

Average 24h, 48h, 72h

0 / 0 / 0

0 / 0 / 0

0 / 0 / 0

0.3 / 0.7 / 0.3

0 / 0 / 0

0.3 / 0.3 / 0.3

Reversibility*)

-

-

-

c.

-

c.

Average time (hours) for reversion

-

-

-

48 / 72 / 48

-

48 / 48 / 48

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

 

Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Under the test conditions, the test material induced a slight irritation, being largely reversible within 72 hours following instillation. Therefore, 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 of the Directive 67/548/EEC.
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 was instilled into the right eye of 3 New Zealand White Rabbit. The eyes were not rinsed after the instillation of the test item. The left eye of each rabbit served as control. Animals were observed at 1, 24, 48 and 72 hours after dosing under a standard light source. The reactions in the conjunctiva (redness, chemosis and discharge), the iris and the cornea (opacity and area involved) were scored according to the Draize scale.

No corneal or iridial effects were noted during the study. Minimal conjunctival irritation was noted in all treated eyes one and 24 hours after treatment. Minimal conjunctival redness persisted in one treated eye at the 48-hour observation. Two treated eyes appeared normal at the 48-hour observation and the remaining treated eye appeared normal at the 72-hour observation

The calculated mean score for each individual lesion for each individual animal within 3 scoring times (24, 48 and 72 hrs) were as follows: 0.3/0.7/0.3 for redness, 0.3/0.3/0.3 for discharge and 0/0/0 for chemosis, iris and corneal lesions.

The effects observed were all reversible within 72 hours.

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 of the Directive 67/548/EEC.

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 (Sanders, 2004, Rel.1). In this dermal irritation study performed according to the OECD guideline No. 404, and in compliance with GLP, undiluted test material was applied on the skin of 3 New Zealand White rabbits. Test sites were covered with a semi-occlusive dressing for 4 hours. The mean scores calculated for each individual animal tested within 3 scoring times (24, 48 and 72 hrs) were 0 / 1 / 1.67 for erythema and 0 / 1 / 1 for oedema. Under the test conditions, the test material induced slight to well-defined erythema and very slight oedema at two treated skin sites being largely reversible within 7 days of dosing. Loss of skin elasticity was noted at two treated skin sites at the 72-hour observation. Moderate desquamation was noted at one treated skin site at the 48 and 72-hour observations and at two treated skin sites at the 7-day observation. No other effects were observed. Therefore the test material does not require a classification as irritant to the skin.

Eye irritation:

A key study was identified (Sanders, 2004, Rel.1). In this eye irritation study performed according to the OECD guideline No. 405, and in compliance with GLP, undiluted test material was instilled into the right eye of 3 New Zealand White Rabbit. The eyes were not rinsed after the instillation of the test item. The left eye of each rabbit served as control. Animals were observed at 1, 24, 48 and 72 hours after dosing under a standard light source. No corneal or iridial effects were noted during the study. Minimal conjunctival irritation was noted in all treated eyes one and 24 hours after treatment. Minimal conjunctival redness persisted in one treated eye at the 48-hour observation. Two treated eyes appeared normal at the 48-hour observation and the remaining treated eye appeared normal at the 72-hour observation. The calculated mean score for each individual lesion for each individual animal within 3 scoring times (24, 48 and 72 hrs) were as follows: 0.3/0.7/0.3 for redness, 0.3/0.3/0.3 for discharge and 0/0/0 for chemosis, iris and corneal lesions. The effects observed were all reversible within 72 hours. Under the test conditions, the test material is not classified as irritating to eyes.


Justification for selection of skin irritation / corrosion endpoint:
Only one study available, GLP-compliant and of high quality (Klimisch score = 1)

Justification for selection of eye irritation endpoint:
Only one study available, GLP-compliant and of high quality (Klimisch score = 1)

Justification for classification or non-classification

Harmonized classification:

The substance has no harmonized classification according to the Regulation (EC) No. 1272/2008 including ATP3.

Self-classification:

Based on the available information no additional self-classification is proposed regarding both skin and eye irritation according to the Annex VI of the Regulation (EC) No. 1272/2008 (CLP) and of the Directive 67/548/EEC.