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Description of key information

Skin irritation = Not irritating, male/female rabbit, OECD 404, EU method B.4, EPA OPPTS 870.2500, Rattray 2004

Eye irritation = Not irritating, male/female rabbit, OECD 405, EU method B.5, EPA OPPTS 870.2400, Rattray 2004

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:
05 August 2003 to 17 August 2003
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline 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
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.2500 (Acute Dermal Irritation)
Deviations:
no
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: Young adult
- Weight at study initiation: 2517-3466 g
- Housing: Individually
- Diet: ad libitum
- Water: ad libitum mains water
- Acclimation period: A minimum of 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 ± 3 °C
- Humidity (%): 30-70 %
- Air changes (per hr): 15 changes minimum
- Photoperiod (hrs dark / hrs light): 12 hours light (artificial), 12 hours dark

IN-LIFE DATES: From: 5 August 2003 To: 17 August 2003
Type of coverage:
occlusive
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 g moistened with 0.5 mL of deionised water to form a dry paste to allow good skin contact.
Duration of treatment / exposure:
4 hours
Observation period:
3 days post administration
Number of animals:
1 male, 2 females (3 animals in total)
Details on study design:
TEST SITE
- Area of exposure: On the day prior to application, the hair was removed with a pair of veterinary clippers from an area approximately 7 cm x 13 cm on the left flank of each animal. The test material was moistened to a dry paste with 0.5 mL deionised water and applied with a metal spatula to the test site with an approximate size of 2.5 cm x 2.5 cm.
- Type of wrap if used: The treated area was covered with a piece of 4-ply surgical gauze (approximate size 2.5 cm x 2.5 cm) which was secured by two strips of surgical tape (approximate size 1 cm x 8 cm). This was covered by a piece of impermeable rubber sheeting (approximate size 35 cm x 13 cm) wrapped once around the trunk of the animal and secured with adhesive impermeable polyethylene tape.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): At the end of the exposure period, the dressing was carefully removed using blunt-tipped scissors and the application site was gently cleansed of any residual test material using clean swabs of absorbent cotton wool soaked in clean warm water and then dried gently with clean tissue paper.
- Time after start of exposure: approximately 4 hours

SCORING SYSTEM:
The Draize scale (Draize 1959), presented as table 1 in the field "Any other information on material and methods incl. tables" was used to assess the degree of erythema and oedema at the application sites approximately 1 hour and 1, 2 and 3 days after the removal of the dressings. Any other signs of skin irritation were also noted.
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
other: 1 hour
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 1 day
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
4
Remarks on result:
no indication of irritation
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
other: 1 hour
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 1 day
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
4
Remarks on result:
no indication of irritation
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
other: 1 hour
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 1 day
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:
Very slight erythema was seen in all animals approximately 1 hour after application and very slight erythema was seen in one animal at the same time. There were no other signs of skin irritation. All irritation scores are presented in table 2 in the field "Any other information on results incl. tables".
Other effects:
There were no signs of ill-health in any animal during the study.

Table 2: Erythema and Oedema Scores

Animal No.

Erythema

Oedema

Time after decontamination

Mean Score

Time after decontamination

Mean Score

1 hour

1 day

2 days

3 days

1 hour

1 day

2 days

3 days

76 (M)

1

0

0

0

0.0

1

0

0

0

0.0

103 (F)

1

0

0

0

0.0

0

0

0

0

0.0

104 (F)

1

0

0

0

0.0

0

0

0

0

0.0

The mean values have been calculated using the day 1, 2 and 3 values.

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Under the conditions of the test, the test material did not elicit any reaction in any of the animals during the course of the study that meant the test material required classification as a skin irritant. The study is considered to be reliable, relevant and adequate for risk assessment and classification and labelling purposes.
Executive summary:

The skin irritation of the test material was determined in accordance with the standardised guidelines OECD 404, EU Method B.4 and EPA OPPTS 870.2500. Three rabbits received a single four hour application of 0.5 g of the test material and were assessed for the following 3 days for any signs of skin irritation. Very slight erythema was seen in all animals approximately one hour after application and very slight oedema was seen in one animal at the same time. There were no other signs of skin irritation.

Under the conditions of the study, the test material is considered to be practically non-irritating to the skin based on an internal system for description of irritation responses. The test material does not require classification for skin irritation in line with Regulation No. 1272/2008.

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:
04 August 2003 to 17 August 2003
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: The study was performed to GLP and in line with the standardised guidelines OECD 405, EU Method B.5 and EPA OPPTS 870.2400 with no deviations thought to impact the reliability of the presented results.
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
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.2400 (Acute Eye Irritation)
Deviations:
no
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Age at study initiation: Young adults
- Weight at study initiation: 2656-3148 g
- Housing: The animals were housed individually
- Diet: ad libitum
- Water: ad libitum, mains water
- Acclimation period: At least 5 days prior to study initiation

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 ± 3 °C
- Humidity (%): 30-70 %
- Air changes (per hr): 15 changes minimum
- Photoperiod (hrs dark / hrs light): 12 hours light (artificial), 12 hours dark

IN-LIFE DATES: From: 05 August 2003 To: 17 August 2003
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 100 mg
Duration of treatment / exposure:
- Dose administration: Approximately 100 mg of the test substance was applied into the conjunctival sac of the left eye of one rabbit by gently pulling the lower lid away from the eyeball to form a cup into which the test substance was dropped. The lids were then gently held together for 1-2 seconds after which the animal was released. The other eye was untreated (control eye).
Observation period (in vivo):
Animals were observed up to 7 days post administration
Number of animals or in vitro replicates:
One animal initially, followed by a further two animals once the irritation potential was fully assessed in the first animal.
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing (if done): Irrigation was not performed

SCORING SYSTEM:
The reactions observed were scored in accordance with the criteria of Draize (1959) and assessed using a modified form of the Kay and Calandra system (1962)

TOOL USED TO ASSESS SCORE: To aid scoring, animals were placed in an artificial daylight chamber for each assessment of irritation. In addition, as an aid in the assessment of corneal damage, fluorescing staining was used at all readings from 1 day after application.
Irritation parameter:
cornea opacity score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
4
Remarks on result:
no indication of irritation
Irritation parameter:
iris score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
2
Remarks on result:
no indication of irritation
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
24/48/72 h
Score:
1
Max. score:
3
Reversibility:
fully reversible within: 7 days
Remarks on result:
other: Time point until effect occurred is given
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
other: 1 hour
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 1 day
Remarks on result:
other: Time point until effect occurred is given
Irritation parameter:
cornea opacity score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
4
Remarks on result:
no indication of irritation
Irritation parameter:
iris score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
2
Remarks on result:
no indication of irritation
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
other: 1 hour
Score:
1
Max. score:
3
Reversibility:
fully reversible within: 1 day
Remarks on result:
other: Time point until effect occurred is given
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
4
Remarks on result:
no indication of irritation
Irritation parameter:
cornea opacity score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
4
Remarks on result:
no indication of irritation
Irritation parameter:
iris score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
2
Remarks on result:
no indication of irritation
Irritation parameter:
conjunctivae score
Basis:
animal #3
Time point:
other: 1 hour
Score:
1
Max. score:
3
Reversibility:
fully reversible within: 1 day
Remarks on result:
other: Time point until effect occurred is given
Irritation parameter:
chemosis score
Basis:
animal #3
Time point:
other: 1 hour
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 1 day
Remarks on result:
other: Time point until effect occurred is given
Irritant / corrosive response data:
The maximum score for each parameter was calculated using the Draize (1959) scoring system as presented in table 1 under the field "Any other information on materials and methods incl. tables".

Application into the eye caused practically no initial pain (Class 1 on a 0-5 scale). There were no corneal iridial effects. Conjunctival effects consisted of slight redness in all animals up to 4 days and slight chemosis in two animals approximately 1 hour after application. In addition, one animal had slight erythema of the eyelids approximately 1 hour after application. All signs of irritation had completely resolved within 7 days of application.

Under the conditions of the study, the test material was considered to be mildly irritating to the unrinsed eye according to a modified form of the Kay and Calandra system.
Other effects:
There were no signs of ill-health in any animal during the study.

Table 3: Mean scores

Observation

1 h (3)*

1 d (3)

2 d (3)

3 d (3)

4 d (1)

7 d (1)

Cornea (Max 80)

0.0

0.0

0.0

0.0

0.0

0.0

Iris (Max 10)

0.0

0.0

0.0

0.0

0.0

0.0

Conjunctiva (Max 20)

3.3

0.7

0.7

0.7

2.0

0.0

Mean Total Score: (Max 110)

3.3

0.7

0.7

0.7

2.0

0.0

 *Numbers in parentheses indicate number of animals included in observation

Table 4: Individual scores

       Cornea        Iris     Conjunctiva           
 Animal number  Sex  Elapsed time  Opacity  Area  Score    Score  Redness  Chemosis  Discharge  Score  Total score
77   M  1 h  0  0  0  0  0  1  1  0  4  4
     1 d  0  0  0  0  0  1  0  0  2  2
     2 d  0  0  0  0  0  1  0  0  2  2
     3 d  0  0  0  0  0  1  0  0  2  2
     4 d  0  0  0  0  0  1  0  0  2  2
     7 d  0  0  0  0  0  0  0  0  0  0
 105  F  1.3 h  0  0  0  0  0  1  0  0  2  2
     1 d  0  0  0  0  0  0  0  0  0  0
     2 d  0  0  0  0  0  0  0  0  0  0
     3 d  0  0  0  0  0  0  0  0  0  0
 106 F  F  1.2 h  0  0  0  0  0  1  1  0  4  4
     1 d  0  0  0  0  0  0  0  0  0  0
     2 d  0  0  0  0  0  0  0  0  0  0
     3 d  0  0  0  0  0  0  0  0  0  0
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Under the conditions of the test, the test material only elicited slight reactions in any of the animals during the course of the study that meant the test material does not require classification as an eye irritant. The study is considered to be reliable, relevant and adequate for risk assessment and classification and labelling purposes.
Executive summary:

The eye irritation of the test material was determined in accordance with the standardised guidelines OECD 405, EU Method B.5 and EPA OPPTS 870.2400. Approximately 100 mg of test material was applied into one one of each of three rabbits and were assessed for up to 7 days to determine the grade of ocular reaction. There were no iridial effects. Conjunctival effects consisted of slight redness in all animals for up to 4 days and slight chemosis in two animals approximately 1 hour after application. In addition, one animal had slight erythema of the eyelids approximately 1 hour after application. All signs of irritation had completely resolved within 7 days of application.

Under the conditions of the study, the test material was considered to be mildly irritating to the unrinsed eye according to modified form of the Kay and Calandra system. The test material does not require classification for eye irritation in line with Regulation No. 1272/2008.

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

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin

The skin irritation and corrosion of the test material was determined in accordance with the standardised guidelines OECD 404, EU Method B.4 and EPA OPPTS 870.2500. Three rabbits received a single four hour application of 0.5 g of the test material and were assessed for the following 3 days for any signs of skin irritation. Very slight erythema was seen in all animals approximately one hour after application and very slight oedema was seen in one animal at the same time. There were no other signs of skin irritation.

Eye

The eye irritation of the test material was determined in accordance with the standardised guidelines OECD 405, EU Method B.5 and EPA OPPTS 870.2400. Approximately 100 mg of test material was applied into one eye of each of three rabbits and were assessed for up to 7 days to determine the grade of ocular reaction. There were no iridial effects. Conjunctival effects consisted of slight redness in all animals for up to 4 days and slight chemosis in two animals approximately 1 hour after application. In addition, one animal had slight erythema of the eyelids approximately 1 hour after application. All signs of irritation had completely resolved within 7 days of application.

Both studies presented to assess the irritation and corrosion potential of the test material were performed in line with GLP and accepted standardised guidelines with a high standard of reporting. Both studies were assigned a reliability score of 1 in accordance with the criteria for assessing data quality as outlined in Klimisch (1997) and considered suitable for assessment as an accurate reflection of the test material. The available data is considered to be complete and the conclusion for both skin irritation and corrosion and eye irritation, not irritating, was taken forward for risk assessment.


Justification for selection of skin irritation / corrosion endpoint:
Only one study available.

Justification for selection of eye irritation endpoint:
Only one study available.

Justification for classification or non-classification

Skin

In accordance with with criteria for classification as defined in Regulation (EC) No. 1272/2008, Annex I, 3.2.2.7, the test material does not require classification for skin irritation.

In accordance with the criteria for classification as set out by Directive 2001/59/EC, Annex 6, 3.2.6.1, the test material does not require classification for inflammation of the skin.

Eye

In accordance with the criteria for classification as defined in Regulation (EC) No. 1272/2008, Annex I, 3.3.2.7, the test material does not require classification for eye irritation.

In accordance with the criteria for classification as set out by Directive 2001/59/EC, Annex 6, 3.2.6.2, the test material does not require classification for ocular lesion.