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Description of key information

Skin irritation/corrosion
Two studies are available:
1) A skin irritation study in rabbit (Beerens - Heijnen, 2010) is available which is key study. This study showed that the test substance is not irritating.
2) An in vitro skin corrosion study using a human skin model (Buskens, 2010) is available which is supporting study. This study showed that the test substance is not corrosive.
Eye irritation:
Two studies are available:
1) An eye irritation study in rabbit (Beerens - Heijnen, 2010) is available which is key study. This study showed that the test substance is not irritating.
2) An eye irritation study with an isolated bovine (Verspeek-Rip, 2010) is available which is supporting study. It is concluded that the test substance is not severe irritant or corrosive.

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 24 Aug to 02 Sep 2010
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
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River France, L'Arbresle Cedex, France
- Age at study initiation: between 10-20 weeks old
- Weight at study initiation: 2-4 kg
- Housing: housed in labeled cages with perforated floors and shelters
- Diet (e.g. ad libitum): Pelleted diet approximately 100 grams per day, Hay was provided at least three times a week.
- Water (e.g. ad libitum): Free access to tap water
- Acclimation period: At least 5 days before start of treatment under laboratory conditions.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.0 ± 3.0ºC (actual range: 19.0-19.9ºC)
- Humidity (%): 40-70% (actual range: 49 - 87%)
- Air changes (per hr): approximately 15 air changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours artificial fluorescent light and 12 hours darkness per day

IN-LIFE DATES: From: 2010-08-24 To: 2010-09-02
Type of coverage:
semiocclusive
Preparation of test site:
shaved
Vehicle:
water
Controls:
not required
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 grams
- 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:
3 males
Details on study design:
TEST SITE
- Area of exposure: approximately 150 square centimeters (10x15 cm)
- % coverage:
- Type of wrap if used: Micropore tape

REMOVAL OF TEST SUBSTANCE
- Washing (if done): tap water
- Time after start of exposure: 4 hours

SCORING SYSTEM: numerical scoring system
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:
No skin irritation was caused by 4 hours exposure to the test substance.
There was no evidence of a corrosive effect on the skin.
Other effects:
No staining of the treated skin by the test substance was observed and no test substance remnants were seen.
No symptoms of systemic toxicity were observed in the animals during the test period and no mortality occurred.

Individual skin irritation scores

Animal

473

500

496

Time after exposure

Erythema

(0-4)

Oedema

(0-4)

Erythema

(0-4)

Oedema

(0-4)

Erythema

(0-4)

Oedema

(0-4)

1 hour

0

0

0

0

0

0

24 hours

0

0

0

0

0

0

48 hours

0

0

0

0

0

0

72 hours

0

0

0

0

0

0

Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
No skin irritation was caused by 4 hours exposure to the test substance.
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 02 to 30 Aug 2010
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
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: Charles River France, L'Arbresle Cedex, France and Harlan, Belton, Leics, England
- Age at study initiation: Between 10-20 weeks old
- Weight at study initiation: 2-4 kg
- Housing: Labeled cages with perforated floors and shelters
- Diet (e.g. ad libitum): Pelleted diet approximately 100 grams per day, hay was provided at least three times a week
- Water (e.g. ad libitum): Free access to tap water
- Acclimation period: At least 5 days before start of treatment under laboratory conditions.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.0±3.0℃ (actual range: 19.0-20.0℃)
- Humidity (%): 40-70% (actual range: 50-87%)
- Air changes (per hr): Approximately 15 air changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours artificial fluorescent light and 12 hours darkness per day

IN-LIFE DATES: From: 2010-08-02 To: 2010-08-30
Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 66.9 mg (range 66.5-67.3 mg)
Duration of treatment / exposure:
24 hours
Observation period (in vivo):
7 days
Number of animals or in vitro replicates:
3 males
Details on study design:
The study was performed in a stepwise manner and was started by treatment of a single rabbit (sentinel). The two other animals were treated in a similar manner three weeks later, after considering the degree of eye irritation observed in the first animal.

Treatment:
Animals were treated by instillation of, on average, 66.9 mg (range 66.5 - 67.3 mg) of the test substance (a volume of approximately 0.1 mL), in the conjunctival sac of one of the eyes after gently pulling the lower lid away from the eyeball. The lids were then gently held together for about one second to prevent loss of the test substance. The other eye remained untreated and served as the reference control.
Immediately after the 24-hour observation, a solution of 2% fluorescein in water (adjusted to pH 7.0) was instilled into both eyes of each animal to quantitatively determine corneal epithelial damage. Any bright green stained area, indicating epithelial damage, was estimated as a percentage of the total corneal area.
After the final observation, the animals were sacrificed by intra-venous injection of Euthasol® 20%.
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
other: Mean of 24, 48 and 72 hours
Score:
0
Max. score:
0
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. 1
Max. score:
2
Reversibility:
fully reversible within: 7 days
Remarks on result:
other: Fully reversible within 48 hours in one animal and within 7 days in the other two animals.
Irritation parameter:
chemosis score
Basis:
mean
Time point:
other: Mean of 24, 48 and 72 hours
Score:
ca. 0.3
Max. score:
2
Reversibility:
fully reversible within: 48 hours
Remarks on result:
other: Fully reversible within 48 hours in all of 3 animals.
Irritant / corrosive response data:
No iridial irritation or corneal opacity were observed, and treatment of the eyes with 2% fluorescein 24 hours after test substance instillation revealed no corneal epithelial damage.
There was no evidence of ocular corrosion.
Other effects:
No staining of (peri) ocular tissues by the test substance was observed. Remnants of the test substance were present in the eyes of two animals on Day 1.
No symptoms of systemic toxicity were observed in the animals during test period and no mortality occurred.

Individual eye irritation scores

Animal

Time after dosing

 

 

Cornea

(0-4)

Iris

(0-2)

Conjunctivae

Redness

(0-3)

Chemosis

(0-4)

Discharge

(0-3)

452

1 hour

24 hours

48 hours

72 hours

0

0

0

0

0

0

0

0

1

1

0

0

1

1

0

0

1

1

0

0

482

1 hour

24 hours

48 hours

72 hours

7 days

0

0

0

0

0

0

0

0

0

0

2

2

1

1

0

2

1

0

0

0

1

1

0

0

0

483

1 hour

24 hours

48 hours

72 hours

7 days

0

0

0

0

0

0

0

0

0

0

2

2

1

1

0

1

1

0

0

0

1

1

0

0

0

Interpretation of results:
not irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
No eye irritation was caused by exposure to the test substance.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Additional information

Skin irritation/corrosion

Two studies are available:

1) A skin irritation study was conducted according to OECD 404 using rabbits (Beerens - Heijnen, 2010). Key study.

This study showed that the test substance is not irritating.

2) An in vitro skin corrosion study was conducted according to OECD 431 using a human skin model (Buskens, 2010). Supporting study.

In the interest of animal welfare and to minimize any testing likely to produce severe responses in animals, a human skin model test was performed. This study showed that the test substance is not corrosive. Based on this, in vivo skin irritation study in rabbit was performed to establish the possible skin irritating properties of the test substance.

Eye irritation

Two studies are available:

1) An eye irritation study was conducted according to OECD 405 using rabbits (Beerens - Heijnen, 2010). Key study.

This study showed that the test substance is not irritating.

2) An eye irritation study was conducted according to OECD 437 using an isolated bovine (Verspeek-Rip, 2010). Supporting study.

In the interest of animal welfare and to minimize any testing likely to produce severe responses in animals, an in vitro Bovine Corneal Opacity and Permeability (BCOP) study was performed. This study showed that the test substance is not severe irritant or corrosive. Based on this, in vivo eye irritation study in rabbit was performed to establish the possible eye irritating properties of the test substance.


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 1) and for conjunctival oedema were < 1 (actual value 0.3).

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.