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Description of key information

Based on available data, the substance is considered to be irritating to skin but not to eyes. 

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 Dec.10, 2009 to Jan.15, 2010
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
The study was conducted according to OECD Test Guideline 404, in compliance with GLP. The test substance characterization, provided by the sponsor, was not conducted according to the Good Laboratory Practices. However, it was approved under ISO 9001:2008 .
Qualifier:
according to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes
Remarks:
The test substance characterization, provided by the sponsor, was not conducted according to the Good Laboratory Practices. However, it was approved under ISO 9001:2008 .
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
- Source: Covance Research Products Inc., Denver. PA
- Housing: animals were individually housed in suspended cages
- Identification: the animals were identified by cage notation and a uniquely numbered metal ear tag
- Body weight range before the test: 2.8-3.0 kg
- Diet: fresh PMI Rabbit Chow (Diet #5321
- Water: ad libitum
- Photoperiod: 12 h light/dark cycle
Type of coverage:
semiocclusive
Preparation of test site:
clipped
Vehicle:
other: Distilled water
Amount / concentration applied:
500 mg/patch
Duration of treatment / exposure:
Rabbit 1: Site #1 exposure: 3 minutes postdose, site #2: 1 h postdose and site #3: 4 h postdose
Rabbit 2 and 3: 4 h postdose
Observation period:
The test sites of all animals were scored for dermal irritation at 60 min after removal of wrappings. Site #3 was scored at 24, 48 and 72 h and on Day 7 and 14 following patch removal for animals #H2936/F and H3001/F. Animal #H3002/F was scored at 24, 48 and 72 h and again on Day 7, 14, 15, 16 and 17.
Number of animals:
3
Details on study design:
Frequency of administrations: single dose
Preparation of the test substance: each animal was treated with 500 mg of test substance formed into a paste with 0.5 mL distilled water.
Test procedure:
Each dose site was approximately 9 cm2. Initially, one rabbit was dosed sequentially on sites #1, 2, and 3. The test substance was applied under a 2.5 x 2.5 cm gauze patch. Gentle pressure was applied to aid the distribution of the test substance over the prepared site. The rabbit was gently held in place and a piece of porous dressing was secured with non-irritating tape over dose site #1 (semi-occlusive) for the 3 min exposure period. The torso was covered with a piece of porous dressing large enough to cover dose sites #2 and 3 with at least 5 cm2 to spare on all sides of the gauze patch. Porous, non-irritating tape was used to encircle the trunk of the animal. The dressing and test substance patch covering site #1 were removed at 3 min after dosing, over site #2 at 1 h after dosing and the torso wrappings and patch covering site #3 at 4 h after dosing. All sites were gently washed with distilled water to remove residual test substance.
Two additional animals were added to the study. The animals were dosed at site #3 with 0.5 g of the test substance.
After an exposure period of 4 h, the wrappings and patches were removed and the sites were gently washed with distilled water.

Type of Observations: erythema, eschar formation and edema were evaluated numerically according to the score of Draize. All other changes of the skin were recorded.
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
other: 24, 48 and 72 h
Score:
3.33
Max. score:
4
Reversibility:
fully reversible within: 14 d
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
other: 24, 48 and 72 h
Score:
1.67
Max. score:
4
Reversibility:
fully reversible within: 14 d
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
other: 24, 48 and 72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 14 d
Irritation parameter:
edema score
Basis:
animal #1
Time point:
other: 24, 48 and 72 h
Score:
2.67
Max. score:
4
Reversibility:
fully reversible within: 14 d
Irritation parameter:
edema score
Basis:
animal #2
Time point:
other: 24, 48 and 72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 14 d
Irritation parameter:
edema score
Basis:
animal #3
Time point:
other: 24, 48 and 72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 14 d
Irritant / corrosive response data:
Initial animal: No erythema and no edema was observed at 60 minutes after patch removal following the 3 minute exposure. Well defined erythema and no edema was observed at 60 minutes after patch removal following the 1 h exposure and well defined erythema and very slight edema was observed at 60 minutes after patch removal following the 4 h exposure. Erythema was moderate at 24 and 48 h and severe at 72 h following the 4 h exposure. Dark areas and cracking skin were observed at 48 h. By Day 7, erythema was well defined with eschar and flaking skin and absent on Day 14. Slight edema was observed at 24 h and moderate edema was observed at 48 and 72 h following the 4 h exposure. By Day 7 slight edema was observed and no edema was observed on Day 14.

Additional animals: Erythema was well defined 60 minutes after patch removal and very slight to well defined at 24 and 48 h. Very slight edema was observed at 72 h following the 4 h exposure. Flaking skin was observed at 24 h and cracking skin at 48 and 72 h. On Day 7, very slight erythema with flaking skin was observed. On Day 14, erythema was well defined for one animal (#H3002) with a shiny area, while the other animal had no erythema with some flaking skin. Animal# H3002 continued to be observed until no erythema was noted. Erythema was well defined on Day 15, very slight on Day 16 and absent on Day 17. Edema was very slight to slight 60 minutes after patch removal and very slight at 24, 48 and 72 h following the 4 h exposure. Edema was absent on Day 7, 14, 15, 16 and 17.
Other effects:
Systemic Observations- There were no abnormal physical signs noted during the observation period.
Body Weights- Body weight changes were normal.

Modified Primary Irritation Index (PDII) was calculated by adding mean erythema/eschar and edema values on the 4 h exposure, of all animals at 24 and 72 h (a total of 4 values) and dividing the sum by 2.

Table: Calculation of Modified Primary Irritation Index (PDII):

Mean erythema scores

Mean edema scores

24 h

72 h

24 h

72 h

2.00

2.00

1.33

1.67

Sum of Mean Scores =7.00

Modified Primary Irritation Index (PDII) = Sum of Mean Scores/2 = 3.50

Interpretation of results:
Category 2 (irritant)
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The test substance was found to be irritating to skin (DiDonato LJ, 2010).
Executive summary:

A study was conducted to evaluate the skin irritation potential of the test substance in rabbits according to OECD Guideline 404, in compliance with GLP. 0.5 g of test substance was moistened with 0.5 mL of distilled water to form a pasty consistency and applied at each test site under a 2.5 x 2.5 cm gauze patch, using semi-occlusive conditions. After an exposure period of 4 h, the wrappings and patches were removed and the sites gently washed with distilled water. The test sites were scored for signs of dermal irritation at 1, 24, 48 and 72 h as well as on Day 7, 14 and 17 after removal of the patches. Erythema and edema were scored according to the numerical Draize technique. The skin was also evaluated for ulceration and necrosis or any evidence of tissue destruction. Additional clinical signs were noted. Under the study conditions, the test substance was found to be irritating to skin (DiDonato LJ, 2010).

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (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 Dec. 02, 2009 to Dec. 24, 2009
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
The study was conducted according to OECD Test Guideline 405, in compliance with GLP. The test substance characterization, provided by the sponsor, was not conducted according to the Good Laboratory Practices. However, it was approved under ISO 9001: 2008 .
Qualifier:
according to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes
Remarks:
The test substance characterization, provided by the sponsor, was not conducted according to the Good Laboratory Practices. However, it was approved under ISO 9001: 2008 .
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
Source: Covance Research Products Inc., Denver. PA
Housing: the animals were housed 1/cage in suspended cages. Paper bedding was placed beneath the cages and changed at least three times/week.
Body weight range before the test: 2.9-3.1 kg
Diet: fresh PMI Rabbit Chow (Diet #5321)
Water: ad libitum
Photoperiod: 12 h light/dark cycle
Vehicle:
unchanged (no vehicle)
Controls:
other: The contralateral eye served as a control.
Amount / concentration applied:
61.3 mg (equivalent to 0.1 mL)
Observation period (in vivo):
1, 24, 48 and 72 h following administration of the test substance.
Number of animals or in vitro replicates:
3
Details on study design:
0.1 mL of test substance was instilled into one eye of each animal. Contralateral eye served as a control. Using a Mini-Maglite flashlight equipped with a high intensity bulb, the treated and control eye of each rabbit was examined for irritation of the cornea, iris and conjunctiva at 1, 24, 48 and 72 h following administration of test substance. Sodium fluorescein dye procedures were used at the 24 h observation interval. The eye was examined with the aid of an ultraviolet light source. Ocular reactions were graded according to the numerical Draize technique.

Body weights were recorded pretest and at termination.

Observations for toxicity and pharmacological effects were recorded at each ocular observation period and mortality observations were performed daily. All animals were humanely sacrificed using CO2 following study termination

Irritation parameter:
conjunctivae score
Remarks:
redness
Basis:
animal #1
Remarks:
(mean score)
Time point:
other: Overall at 24, 48 and 72 h
Score:
0
Max. score:
4
Irritation parameter:
conjunctivae score
Remarks:
redenss
Basis:
animal #2
Remarks:
(mean score)
Time point:
other: Overall at 24, 48 and 72 h
Score:
0.33
Max. score:
4
Reversibility:
fully reversible within: 72 h
Irritation parameter:
conjunctivae score
Remarks:
redness
Basis:
animal #3
Remarks:
(mean score)
Time point:
other: Overall at 24, 48 and 72 h
Score:
0.67
Max. score:
4
Reversibility:
fully reversible within: 72 h
Irritation parameter:
iris score
Basis:
animal #1
Remarks:
(mean score)
Time point:
other: Overall at 24, 48 and 72 h
Score:
0
Max. score:
4
Irritation parameter:
iris score
Basis:
animal #2
Remarks:
(mean score)
Time point:
other: Overall at 24, 48 and 72 h
Score:
0
Max. score:
4
Irritation parameter:
iris score
Basis:
animal #3
Remarks:
(mean score)
Time point:
other: Overall at 24, 48 and 72 h
Score:
0
Max. score:
4
Irritation parameter:
cornea opacity score
Basis:
animal #1
Remarks:
(mean score)
Time point:
other: Overall at 24, 48 and 72 h
Score:
0
Max. score:
4
Irritation parameter:
cornea opacity score
Basis:
animal #2
Remarks:
(mean score)
Time point:
other: Overall at 24, 48 and 72 h
Score:
0
Max. score:
4
Irritation parameter:
cornea opacity score
Basis:
animal #3
Remarks:
(mean score)
Time point:
other: Overall at 24, 48 and 72 h
Score:
0
Max. score:
4
Irritant / corrosive response data:
There was no corneal opacity or iritis noted at any observation period. Conjunctival irritation. noted in 3/3 eyes. cleared in one eye by 24 h and in two eyes by 72 h.
Other effects:
No clinical signs of systemic toxicity were observed. Body weights were also normal.
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The test substance produced mild eye irritation (Hall DA, 2010).
Executive summary:

A study was conducted to evaluate the eye irritation potential of the test substance in rabbits according to OECD Guideline 405, in compliance with GLP. Test substance (0.1 mL, which is equivalent to 61.3 mg) was instilled in one eye of three New Zealand White rabbits with the help of a syringe-type applicator. The contralateral eye served as control. The treated and control eyes of each rabbit were examined for irritation of the cornea, iris and conjunctiva at 1, 24, 48 and 72 h following instillation of the test substance. The eye was examined with the aid of an ultraviolet light source. Ocular reactions were graded according to the numerical Draize technique. Toxicity and pharmacological effects were recorded at each ocular observation period and mortality was checked daily. All animals were humanely sacrificed using C02following study termination. There was no corneal opacity or iritis noted at any observation period. Conjunctival irritation, seen all animals, cleared in one eye by 24 h and in the other two by 72 h. The control eyes appeared normal at all observation periods. No abnormal physical signs were recorded. Under the study conditions, the test substance was not irritating to eyes (Hall DA, 2010).

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

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin

A study was conducted to evaluate the skin irritation potential of the test substance in rabbits according to OECD Guideline 404, in compliance with GLP. 0.5 g of test substance was moistened with 0.5 mL of distilled water to form a pasty consistency and applied at each test site under a 2.5 x 2.5 cm gauze patch, using semi-occlusive conditions. After an exposure period of 4 h, the wrappings and patches were removed and the sites gently washed with distilled water. The test sites were scored for signs of dermal irritation at 1, 24, 48 and 72 h as well as on Day 7, 14 and 17 after removal of the patches. Erythema and edema were scored according to the numerical Draize technique. The skin was also evaluated for ulceration and necrosis or any evidence of tissue destruction. Additional clinical signs were noted. Under the study conditions, the test substance was found to be irritating to skin (DiDonato LJ, 2010).

A study was conducted to assess the skin irritation potential of the test substance to rabbit skin according to the modified Federal Hazardous Substance Act procedure. 0.5 mL of a 40% suspension of the test substance was applied to the skin of the test animals in corn oil under covered patch. Tissue structure at the site of contact was destroyed irreversibly within 24 h. Mean erythema scores at 24 h as well as 72 h in intact and abraded skin were 3.83. Mean edema scores in intact and abraded skin were 3.67 at 24 h and 3.17 at 72 h. Under the study conditions, the test substance could be considered corrosive based on the irreversible damage observed at the site of contact (Brown DR, 1979). However, no details on the test method are available. The study was therefore considered unreliable.

Eye

A study was conducted to evaluate the eye irritation potential of the test substance in rabbits according to OECD Guideline 405, in compliance with GLP. Test substance (0.1 mL, which is equivalent to 61.3 mg) was instilled in one eye of three New Zealand White rabbits with the help of a syringe-type applicator. The contralateral eye served as control. The treated and control eyes of each rabbit were examined for irritation of the cornea, iris and conjunctiva at 1, 24, 48 and 72 h following instillation of the test substance. The eye was examined with the aid of an ultraviolet light source. Ocular reactions were graded according to the numerical Draize technique. Toxicity and pharmacological effects were recorded at each ocular observation period and mortality was checked daily. All animals were humanely sacrificed using C02following study termination. There was no corneal opacity or iritis noted at any observation period. Conjunctival irritation, seen all animals, cleared in one eye by 24 h and in the other two by 72 h. The control eyes appeared normal at all observation periods. No abnormal physical signs were recorded. Under the study conditions, the test substance was not irritating to eyes (Hall DA, 2010).

A study was performed to assess the irritation potential of the test substance to rabbit eye according to the Federal Hazardous Substance Act procedure.100 mg of test substance were applied to the eyes of 6 New Zealand White rabbits. The degree of eye irritation/corrosion was evaluated by scoring lesions of conjunctiva, cornea and iris. No lesion in the iris was observed at any time point. A mean corneal score of 1.67 was observed at 24 h, which was fully reversible within 72 h. A mean conjunctivae score of 6.0 was observed at 24 h, which was not reversible until 72 h. Under the study conditions, the test substance was positive for eye irritation according to the criteria under Federal Hazardous Substance Act procedure (Brown DR, 1979). However, no details on the test method are available. The study was therefore considered unreliable.


Justification for selection of skin irritation / corrosion endpoint:
It is the most recent study. The study was conducted according to OECD Test Guideline 404, in compliance with GLP.

Justification for selection of eye irritation endpoint:
It is the most recent study. The study was conducted according to OECD Test Guideline 405, in compliance with GLP.

Effects on skin irritation/corrosion: irritating

Justification for classification or non-classification

Skin

Based on the available in vivo skin irritation studies, the test substance is classified as Skin irritation, Category 2 - H315 (causes skin irritation) according to CLP (EC 1272/2008).

Eye

Based on the results of the eye studies, the test substance does not need to be classified for this endpoint according to CLP (EC 1272/2008).