Registration Dossier

Administrative data

Description of key information

In-vivo, the substance was slightly irritant to skin and produced in eyes transient conjunctival, iris and cornea reactions that cleared within 72 hours.

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 28 september 2010 to 10 october 2010
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Deviations:
yes
Remarks:
: the relative humidity recorded in the animal room was sometimes outside of the target ranges specified in the study plan.
GLP compliance:
yes (incl. certificate)
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: CEGAV, Saint Mars d'Egrenne, France
- Age at study initiation: 2 to 4 months old
- Weight at study initiation: From 2.2 to 3.5 kg
- Fasting period before study: the animals were fasted during the night before treatment but had free access to water. Food was given back approximately 4 hours after administration of the test item.
- Housing: in polystyrene cages ().
- Diet (e.g. ad libitum): ad libitum (SAFE, Villemoisson, Epinay-sur-Orge, France)
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 ± 3°C
- Humidity (%): 30 to 70%
- Air changes (per hr): approximately 12 cycles/hour of filtered, non-recycled air
- Photoperiod (hrs dark / hrs light): 12h/12h

IN-LIFE DATES: no data
Type of coverage:
semiocclusive
Preparation of test site:
clipped
Vehicle:
unchanged (no vehicle)
Controls:
other: each animal served as its own control
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 500 mg
The test item was placed on a gauze pad moistened with purified water

Duration of treatment / exposure:
3 minutes, 1 hour or 4 hours
Observation period:
1, 24, 48 and 72 h after removal of the dressing and if relevant, daily until reversibility of reactions.
Number of animals:
3
Details on study design:
TEST SITE
- Area of exposure: dorso-lumbar region
- % coverage: 6 cm²
- Type of wrap if used: gauze pad held by a non-irritating semi-occlusive dressing and a restraining bandage

REMOVAL OF TEST SUBSTANCE
- Washing (if done): after removal of the dressing, any residual test item was removed using a cotton pad moistened with tap water
- Time after start of exposure: 3 minutes, 1 hour or 4 hours

SCORING SYSTEM: in accordance with the OECD guideline 404
Irritation parameter:
erythema score
Basis:
animal #1
Remarks:
Mean individual score
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritation parameter:
erythema score
Basis:
animal #2
Remarks:
Mean individual scores
Time point:
24/48/72 h
Score:
0.3
Max. score:
4
Reversibility:
fully reversible within: 2 days
Irritation parameter:
erythema score
Basis:
animal #3
Remarks:
Mean individual scores
Time point:
24/48/72 h
Score:
0.3
Max. score:
4
Reversibility:
fully reversible within: 2 days
Irritation parameter:
edema score
Basis:
animal #1
Remarks:
Mean individual scores
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritation parameter:
edema score
Basis:
animal #2
Remarks:
Mean individual scores
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritation parameter:
edema score
Basis:
animal #3
Remarks:
Mean individual scores
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritant / corrosive response data:
After a 3-minute or 1-hour exposure (one animal), no cutaneous reactions (scores 0 for edema and erythema) were observed.
After a 4-hour exposure (three animals), a very slight erythema (grade 1) was noted in 2 animals within 24h.
Mean scores over 24, 48 and 72 hours for each animal were 0.0, 0.3, and 0.3 for erythema and 0.0, 0.0 and 0.0 for edema.

Table 7.3.1/1: Irritant/corrosive response data for each animal at each observation time up to removal of each animal from the test (4 -hour exposure)

Score at time point / Reversibility

Erythema

Edema

Max. score: 4

Max. score: 4

60 min

0/1/1

0/0/0

24 h

0/1/1

0/0/0

48 h

0/0/0

0/0/0

72 h

0/0/0

0/0/0

Average 24h, 48h, 72h

0.0/0.3/0.3

0.0/0.0/0.0

Reversibility*)

-/c/c

-/-/-

Average time (day) for reversion

-/2/2

-/-/-

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

Interpretation of results:
GHS criteria not met
Conclusions:
The substance is not classified according to Regulation (EC) No. 1272/2008 and its subsequent amendments on classification, labeling and packaging (CLP) of substances and mixtures.
Executive summary:

In an acute dermal irritation study, the potential of the test substanceto induce skin irritation in New Zealand Whiterabbits was evaluated following a single topical application according to OECD 404guideline.The study was conducted in compliance with the principles of Good Laboratory Practices.

The test substance was first applied for periods of 3 minutes, 1 hour and 4 hours to a single male New Zealand White rabbit. Since the test item was not severely irritant or corrosive to the skin on the first animal, it was then applied for 4 hours simultaneously to two other animals.A quantity of 500 mg of the test substance was placed on a moistened gauze pad, which was then applied to an area of the skin of approximately 6 cm2of the animals. The gauze pad was held in place by a non-irritation semi-occlusive dressing and a restraining bandage. For each exposure period, cutaneous reactions were evaluated approximately 1 hour, 24, 48 and 72 hours after removal of the dressing.

On completion of the observation period, the animals were used subsequently for the evaluation of the ocular irritation potential of the same test item.

After a 3-minute or 1-hour exposure in the first animal, no cutaneous reactions were observed. After a 4-hour exposure in the three animals, a very slight erythema (grade 1) was noted in two animals within 24 hours. Mean individual scores over 24, 48 and 72 hours were 0.0, 0.3, and 0.3 for erythema and 0.0, 0.0 and 0.0 for edema.

It was concluded that the test item was slightly irritant when applied topically to 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 28 september 2010 to 18 october 2010
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
yes
Remarks:
The relative humidity recorded in the animal room was sometimes outside of the target ranges specified in the study plan.
GLP compliance:
yes (incl. certificate)
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Hypharm, La Corbière, Roussay, France (instead of CEGAV, Saint Mars d’Egrenne, France).
- Age at study initiation: 2 to 4 months
- Weight at study initiation: 2.7 ± 0.1 kg
- Housing: The animals were housed individually in Pajon cages (50 cm x 57 cm x 75 cm).
- Diet (e.g. ad libitum): ad libitum (SAFE, Villemoisson, Epinay-sur-Orge, France)
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 ± 3°C
- Humidity (%): 50 ± 20%
- Air changes (per hr): approximately 12 cycles/hour of filtered, non-recycled air
- Photoperiod (hrs dark / hrs light): 12h/12h

IN-LIFE DATES: no data
Vehicle:
unchanged (no vehicle)
Controls:
other: untreated eye served as a control
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 100 mg
- Concentration (if solution): not applicable

Duration of treatment / exposure:
Not applicable: single application not followed by rinsing.


Observation period (in vivo):
5 days.
Number of animals or in vitro replicates:
3
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing (if done): No

SCORING SYSTEM: Draize scale

- Conjunctival chemosis (lids and/or nictitating membranes):
0 no swelling
1 any swelling above normal (includes nictitating membranes)
2 obvious swelling with partial eversion of lids
3 swelling with lids about half-closed
4 swelling with lids more than half-closed

- Conjunctival redness (palpebral and bulbar conjunctivae, cornea and iris):
0 blood vessels normal
1 a number of blood vessels definitely hyperemic (injected)
2 diffuse, crimson colour, individual vessels not easily discernible
3 diffuse, beefy red

- Iris lesions
0 normal
1 markedly deepened rugae, congestion, swelling, moderate circum-corneal hyperemia,or injection, any of these or combination of any thereof, iris still reacting to light (sluggish reaction is positive)
2 no reaction to light, haemorrhage, gross destruction (any or all of these)

- Cornea intensity of opacity (direct examination and, if necessary, with an UV lamp)
0 no ulceration or opacity
1 scattered or diffuse areas of opacity (other than slight dulling or normal lustre), details of iris clearly visible
2 easily discernible translucent area, details of iris slightly obscured
3 nacreous areas, no details of iris visible, size of pupil barely discernible
4 opaque cornea, iris not discernible through the opacity

- Cornea area of opacity (direct examination and, if necessary, with an UV lamp)
1 one quarter (or less) but not zero
2 greater than one quarter but less than a half
3 greater than one half but less than three quarters
4 greater than three quarters up to whole area


TOOL USED TO ASSESS SCORE: Fluorescein (batch No. S667)
Irritation parameter:
cornea opacity score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0.3
Max. score:
4
Reversibility:
fully reversible
Remarks:
within 2 days
Irritation parameter:
cornea opacity score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritation parameter:
cornea opacity score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritation parameter:
iris score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0.3
Max. score:
2
Reversibility:
fully reversible
Remarks:
within 2 days
Irritation parameter:
iris score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
2
Irritation parameter:
iris score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
2
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
24/48/72 h
Score:
1.3
Max. score:
3
Reversibility:
fully reversible
Remarks:
within 4 days
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0.3
Max. score:
3
Reversibility:
fully reversible
Remarks:
within 2 days
Irritation parameter:
conjunctivae score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
3
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible
Remarks:
within 4 days
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0.3
Max. score:
4
Reversibility:
fully reversible
Remarks:
within 2 days
Irritation parameter:
chemosis score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritant / corrosive response data:
A slight or moderate chemosis (grade 1 or 2) and a moderate or severe redness of the conjunctiva (grade 2 or 3) were noted in all animals 1h after the application of the test substance.
A slight chemosis and redness of the conjunctiva (grade 1) persisted in one animal within 24hrs, whereas a slight chemosis (grade 1) and moderate then slight redness of the conjunctiva (grade 2 then 1) persisted until day 3 (72 hrs) in another one .

Iris lesions were noted 1h after the application in one animal and within 24hrs in another one.

A slight corneal opacity (grade 1) was recorded in one animal 24hrs after the treatment.

Mean scores calculated for each animal over 24, 48 and 72 hrs were 1.0, 0.3 and 0.0 for chemosis, 1.3, 0.3 and 0.0 for redness of the conjunctiva, 0.3, 0.0 and 0.0 for iris lesions and 0.3, 0.0 and 0.0 for corneal opacity.
Other effects:
A clear discharge was observed in all animals 1 hour after the application of the test substance. It persisted within 24hrs in one animal.
Residual test item was observed in all animals 1hr after the application of the test substance. In one animal, residues were still observed 48hrs after the start of the test.

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

Score at time point / Reversibility

Cornea

Iris

Conjunctivae

Chemosis

Max. score: 4

Max. score: 2

Max. score: 3

Max. score: 4

60 min

0/0/0

1/1/0

3/3/2

2/2/1

24 h

1/0/0

1/0/0

2/1/0

1/1/0

48 h

0/0/0

0/0/0

1/0/0

1/0/0

72 h

0/0/0

0/0/0

1/0/0

1/0/0

Average 24h, 48h, 72h

0.3/0.0/0.0

0.3/0.0/0.0

1.3/0.3/0.0

1.0/0.3/0.0

Reversibility*)

c/-/-

c/-/-

c/c/c

c/c/c

Average time (day) for reversion

2/-/-

2/-/-

4/2/1

4/2/1

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

Interpretation of results:
GHS criteria not met
Conclusions:
The substance is not classified according to Regulation (EC) No. 1272/2008 and its subsequent amendments on classification, labeling and packaging (CLP) of substances and mixtures.
Executive summary:

In an eye irritation study, the test substance was administered to New Zealand White rabbits according to OECD 405 guideline. The study was conducted in compliance with the principles of Good Laboratory Pratices.

0.1 g of the test substance was placed into the conjunctival sac of one eye of three rabbits without irrigation. The other eye remained untreated and was used for control purposes. Assessment of ocular damage/irritation was made approximately 1, 24, 48 and 72 hours following treatment according to the Draize scoring method.

A slight or moderate chemosis (grade 1 or 2) and a moderate or severe redness of the conjunctiva (grade 2 or 3) were noted in all animals 1 hour after the application of the test substance. A slight chemosis and redness of the conjunctiva (grade 1) persisted in one of them within 24 hours, whereas a slight chemosis (grade 1) and moderate then slight redness of the conjunctiva (grade 2 then 1) persisted until day 3 (72 hours) in another one. Iris lesions were noted 1 hour after the application in one animal and within 24 hours in another one. A slight corneal opacity (grade 1) was recorded in one animal 24 hours after the treatment.

Mean scores calculated for each animal over 24, 48 and 72 hours were 1.0, 0.3 and 0.0 for chemosis, 1.3, 0.3 and 0.0 for redness of the conjunctiva, 0.3, 0.0 and 0.0 for iris lesions and 0.3, 0.0 and 0.0 for corneal opacity.

It was concluded that the test item was slightly irritant when applied topically to eyes.


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

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin irritation:

In an acute dermal irritation study, the potential of the test substance to induce skin irritation in New Zealand White rabbits was evaluated following a single topical application according to OECD 404 guideline. The study was conducted in compliance with the principles of Good Laboratory Practices.

The test substance was first applied for periods of 3 minutes, 1 hour and 4 hours to a single male New Zealand White rabbit. Since the test item was not severely irritant or corrosive to the skin on the first animal, it was then applied for 4 hours simultaneously to two other animals.A quantity of 500 mg of the test substance was placed on a moistened gauze pad, which was then applied to an area of the skin of approximately 6 cm2 of the animals. The gauze pad was held in place by a non-irritation semi-occlusive dressing and a restraining bandage. For each exposure period, cutaneous reactions were evaluated approximately 1 hour, 24, 48 and 72 hours after removal of the dressing.

On completion of the observation period, the animals were used subsequently for the evaluation of the ocular irritation potential of the same test item.

After a 3-minute or 1-hour exposure in the first animal, no cutaneous reactions were observed. After a 4-hour exposure in the three animals, a very slight erythema (grade 1) was noted in two animals within 24 hours. Mean individual scores over 24, 48 and 72 hours were 0.0, 0.3, and 0.3 for erythema and 0.0, 0.0 and 0.0 for edema.

It was concluded that the test item was slightly irritant when applied topically to skin.

Eyes:

In an eye irritation study, the test substance was administered to New Zealand White rabbits according to OECD 405 guideline. The study was conducted in compliance with the principles of Good Laboratory Pratices.

0.1 g of the test substance was placed into the conjunctival sac of one eye of three rabbits without irrigation. The other eye remained untreated and was used for control purposes. Assessment of ocular damage/irritation was made approximately 1, 24, 48 and 72 hours following treatment according to the Draize scoring method.

A slight or moderate chemosis (grade 1 or 2) and a moderate or severe redness of the conjunctiva (grade 2 or 3) were noted in all animals 1 hour after the application of the test substance. A slight chemosis and redness of the conjunctiva (grade 1) persisted in one of them within 24 hours, whereas a slight chemosis (grade 1) and moderate then slight redness of the conjunctiva (grade 2 then 1) persisted until day 3 (72 hours) in another one. Iris lesions were noted 1 hour after the application in one animal and within 24 hours in another one. A slight corneal opacity (grade 1) was recorded in one animal 24 hours after the treatment.

Mean scores calculated for each animal over 24, 48 and 72 hours were 1.0, 0.3 and 0.0 for chemosis, 1.3, 0.3 and 0.0 for redness of the conjunctiva, 0.3, 0.0 and 0.0 for iris lesions and 0.3, 0.0 and 0.0 for corneal opacity.

It was concluded that the test item was slightly irritant when applied topically to eyes.


Justification for classification or non-classification

Based on the results from in vivo studies, the substance is not classified as a skin or eye irritant according to regulation EC No. 1272/2008 and its subsequent amendments on classification, labeling and packaging (CLP) of substances and mixtures.