Registration Dossier

Administrative data

Description of key information

Skin irritation:
A primary skin irritation study (Simon, 2008) is available which is key study. This study showed the test substance is not irritating to rabbit skin.
Eye irritation:
A primary eye irritation study (Simon, 2008) is available which is key study. This study showed the test substance is not irritating to rabbit eye.

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 to 13 December 2007
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study run to a method comparable with current guidelines and to GLP.
Qualifier:
according to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan Netherlands BV
- Age at study initiation: 12 weeks
- Weight at study initiation: 2355g, 2322g, 2447g
- Fasting period before study:
- Housing: Individually in stainless steel cages equipped with feed hoppers and drinking water bowls. Wood blocks and haysticks 4642 were provided for gnawing.
- Diet (e.g. ad libitum): Pelleted standard Provimi Kliba 3418 rabbit maintenance diet ad libitum.
- Water (e.g. ad libitum): Community tap water from Fullinsdorf ad libitum.
- Acclimation period: 4 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17-23°C
- Humidity (%): 30-70% (values above 70% during cleaning process possible)
- Air changes (per hr): 10-15 air changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours light and 12 hours dark

IN-LIFE DATES: From: 05 December 2007 To: 13 December 2007
Type of coverage:
semiocclusive
Preparation of test site:
abraded
Vehicle:
water
Controls:
not required
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 g/animal
- Concentration (if solution):

VEHICLE
- Amount(s) applied (volume or weight with unit): 0.5 mL
- Concentration (if solution):
- Lot/batch no. (if required):
- Purity:
Duration of treatment / exposure:
4 hours
Observation period:
72 hours
Number of animals:
one male and two females
Details on study design:
TEST SITE
- Area of exposure: 100 cm2 (10cm×10cm)
- % coverage:
- Type of wrap if used: The patch was covered with a semi-occlusive dressing which was wrapped around the abdomen and anchored with tap.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): The dressing was removed and the skin was flushed with lukewarm tap water.
- Time after start of exposure: 4 hours

SCORING SYSTEM: Draize score system

Any other information of method:
Observations
Mortality/Viability: Daily from acclimatization of the animals to the termination of test.
Body weights: At start of acclimatization, on the day of application and at termination of observation.
Clinical signs: Daily from acclimatization of the animals to the termination of test.
Skin Reaction: The skin reation was assessed at approximately 1, 24, 48 and 72 hours after exposure.
Irritation parameter:
erythema score
Basis:
mean
Time point:
other: Mean of 24, 48 and 72 hours
Score:
0
Max. score:
0
Remarks on result:
other: The exposure period is 4 hours.
Irritation parameter:
edema score
Basis:
mean
Time point:
other: Mean of 24, 48 and 72 hours
Score:
0
Max. score:
0
Remarks on result:
other: The exposure period is 4 hours.
Irritant / corrosive response data:
Irritation: The mean score was calculated across 3 scoring times (24, 48 and 72 hours after patch removal) for each animal for erythema/eschar grades and for oedema grades, separately.
The test item did not elicit any skin reactions at the application site of any animal at any of the observation time. The individual mean score for erythema/eschar and oedema for each of the three animals was therefore 0.

Corrosion: Neither alterlations of the treated skin were observed nor were corrosive effects evident on the skin.

Viability/Mortality/Clinical Signs: No clinical signs of systemic toxicity were observed in the animal during the study and no mortality occurred.

Coloration: No staining produced by the test item of the treated skin was observed.

Body Weights

Body weight in grams

Animal No.

Sex

First day of Acclimatization

Day of Treatment

Last Day of Observation

70

male

2128

2355

2536

71

female

2167

2322

2471

72

female

2304

2447

2547

Skin Irritation Scores-Individual Values

Animal Number

 

Sex

Evaluation Interval

 

Erythema

 

Oedema

Cumulative

Score

Mean

70

M

 

1 hour

0

0

0.00

 

0.00

71

F

0

0

0.00

72

F

0

0

0.00

70

M

 

24 hours

0

0

0.00

 

0.00

71

F

0

0

0.00

72

F

0

0

0.00

70

M

 

48 hours

0

0

0.00

 

0.00

71

F

0

0

0.00

72

F

0

0

0.00

70

 

72 hours

0

0

0.00

 

0.00

71

0

0

0.00

72

0

0

0.00

   M: male; F: female

 

Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The test substance is considered to be “not irritating” to rabbit skin.
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 03 to 16 January 2008
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study run to a method comparable with current guidelines and to GLP.
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute 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: Harlan Netherlands BV
- Age at study initiation: 13 weeks (male), 12-13 weeks (females)
- Weight at study initiation: No.67: 2991g, No.68: 2538g, No.69: 2690g
- Housing: Individually in stainless steel cages equipped with feed hoppers and drinking water bowls. Wood blocks and haysticks were provided for gnawing.
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period:

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17-23 °C
- Humidity (%): 30-70 %
- Air changes (per hr): Air-conditioned with 10-15 air change her hour
- Photoperiod (hrs dark / hrs light): automatically controlled lighte cycle of 12 hrs dark/12 hrs light

IN-LIFE DATES: From: 03 January 2008 To: 16 January 2008
Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 g per animal
- Concentration (if solution):

VEHICLE
- Amount(s) applied (volume or weight with unit):
- Concentration (if solution):
- Lot/batch no. (if required):
- Purity:
Duration of treatment / exposure:
Single instillation, eye unwashed
Observation period (in vivo):
7 days
Number of animals or in vitro replicates:
One male, two females
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing (if done):
- Time after start of exposure:

SCORING SYSTEM: Commission Directive 2004/73/EC, April 29, 2004

TOOL USED TO ASSESS SCORE: Varta Cliptrix diagnostic-lamp
The eyes of each animal were examined approximately 1, 24, 48, 72 hours, as well as 7 days after administration.
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
other: Mean of 24, 48 and 72 hours
Score:
0
Max. score:
1
Reversibility:
fully reversible within: 24 hours
Irritation parameter:
iris score
Basis:
mean
Time point:
other: Mean of 24, 48 and 72 hours
Score:
0
Max. score:
0
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
other: Mean of 24, 48 and 72 hours
Score:
ca. 0.89
Max. score:
2
Reversibility:
fully reversible within: 7 days
Remarks on result:
other: Two animals were reversible with 72 hours and one reversible within 7 days.
Irritation parameter:
chemosis score
Basis:
mean
Time point:
other: Mean of 24, 48 and 72 hours
Score:
ca. 0.22
Max. score:
2
Reversibility:
fully reversible within: 72 hours
Remarks on result:
other: Two animals were reversible with 24 hours and one reversible within 72 hours.
Irritant / corrosive response data:
The mean score was calculated across 3 scoring times (24, 48 and 72 hours after instillation) for each animal for corneal opacity, iris, redness and chemosis of the conjunctivae, separately. The individual mean scores for corneal opacity and iris were 0.00 for all the animals. The individual mean scores for the conjunctivae were 0.67, 1.33 and 0.67 for reddening and 0.00, 0.67 and 0.00 for chemosis, respectively.
A very slight opacity affecting the whole was observed in both females 1 hour after instillation.
A moderate reddening of the conjunctivae was noted in all animals at the same observation time point and persisted as slight up to the 48- and 72- hour reading, respectively. Additionally, a slightly to obvious swelling of the conjunctivae with partial eversion of lids was observed in all animals at the 1- hour observation and persisted as slight up to the 48- hour evaluation in the first treated female.
A slight to moderate reddening of the sclera was present in the three animals 1 hour after treatment and persisted as slight up to the 24- and 72- hour reading, respectively.
Slight to moderate ocular discharge was present in all animals 1 hour after instillation.
No abnormal findings were observed in the treated eye of any animal 72 hours of 7 days after treatment.
No corrosion of the cornea was observed at any of the reading times.

No clinical signs of systemic toxicity were observed in the animals during the study and no mortality occurred.

 

No staining produced by the test item of the treated eye was observed.

 

Brown test item remnants were evident in the eye or conjunctival sac of all animals 1 hour after instillation and persisted up to the 24- or 48- hour reading in both females.

 

The body weights of all rabbits were considered to be within the normal range of variability.

Body weight in grams

Animal No.

Sex

First Day of Acclimatization

Day of Treatment

Last Day of Observation

67

male

2700

2991

3238

68

female

2419

2538

2784

69

female

2284

2690

2966

Eye Irritation Scores- Individual Values

Animal Number

Sex

Evaluation Interval

Corneal Opacity

Area of Corneal Opacity

Iris

Conjunctivae

Sclera

Redness

Chemosis

67

68

69

M

F

F

1 hour

0

1

1

0

4

4

0

0

0

2

2

2

1

2

1

2

2

1

67

68

69

M

F

F

24 hours

0

0

0

0

0

0

0

0

0

1

2

1

0

1

0

1

1

1

67

68

69

M

F

F

48 hours

0

0

0

0

0

0

0

0

0

1

1

1

0

1

0

0

1

0

67

68

69

M

F

F

72 hours

0

0

0

0

0

0

0

0

0

0

1

0

0

0

0

0

1

0

67

68

69

M

F

F

7 days

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The test substance is considered to be not irritating to the rabbit eye.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Additional information

Skin irritation:

A primary skin irritation study was conducted according to OECD 404 using rabbits (Simon, 2008). Key study.

This study showed the test substance is not irritating to rabbit skin.

Eye irritation:

A primary eye irritation study was conducted according to OECD 405 using rabbits (Simon, 2008). Key study.

This study showed the test substance is not irritating to rabbit eye.


Justification for selection of skin irritation / corrosion endpoint:
This study was conducted according to OECD 404 under GLP.

Justification for selection of eye irritation endpoint:
This study was conducted according to OECD 405 under GLP.

Justification for classification or non-classification

Skin irritation/corrosion: Mean scores at 24, 48 & 72 hours for erythema were < 2.3 (actual value 0) for oedema were < 2.3 (actual value 0). In addition all reactions were fully reversible within the observation period (actual value within 72 hours).

Serious eye damage/eye irritation: Mean scores at 24, 48 & 72 hours for corneal opacity were < 1 (actual value 0), for iritis were < 1 (actual value 0), for conjunctival redness were < 2 (actual value 0.89) and for conjunctival oedema were < 1 (actual value 0.22).

Therefore in accordance with Regulation (EC) No. 1272/2008 Tables 3.2.2 & 3.3.2 the substance is not classified for the skin corrosion/irritation and serious eye damage/eye irritation endpoint.