Registration Dossier

Administrative data

Description of key information

Skin irritation/corrosion
Two studies are available:
1) A primary skin irritation study (Latour, 2015) is available which is key study. This study showed that the test substance is not irritating.
2) An in vitro skin corrosion study (Buskens, 2014) is available which is supporting study. This study showed that the test substance is not corrosive.
Eye irritation
Two studies are available:
1) An acute eye irritation study (Latour, 2015) is available which is key study. This study showed that the test substance is slightly irritating.
2) An in vitro BCOP study (Verspeek-Rip, 2014) is available which is supporting study. This study showed that the test substance is not irritating.

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 19 to 30 Nov 2014
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: Charles River France, L’Arbresle Cedex, France
- Age at study initiation: between 12 and 24 weeks old
- Weight at study initiation: body weights were at least 1.5 kg
- Housing: labeled cages with perforated floors and shelters
- Diet (e.g. ad libitum): Pelleted diet for rabbits approximately 100 grams per day. Hay and wooden sticks were available during the study period.
- Water (e.g. ad libitum): Free access to tap water.
- Acclimation period: at least 5 days before start of treatment

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 to 24°C
- Humidity (%): 40 to 70%
- Air changes (per hr): at least 10 air changes/hour
- Photoperiod (hrs dark / hrs light): a 12-hour light/12-hour dark cycle

IN-LIFE DATES: From: To:
Type of coverage:
semiocclusive
Preparation of test site:
clipped
Vehicle:
other: watery ethanol (50% v/v)
Controls:
no
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 grams of the test substance

VEHICLE
- Amount(s) applied (volume or weight with unit): 1 mL
Duration of treatment / exposure:
4 h
Observation period:
72 hours after the removal of the dressings and test substance
Number of animals:
3 males
Details on study design:
TEST SITE
- Area of exposure: 2x3 cm
- Type of wrap if used: The metalline patch was mounted on Micropore tape, which was wrapped around the abdomen and secured with Coban elastic bandage.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): the dressing was removed and the skin cleaned of residual test substance using tap water.
- Time after start of exposure: Four hours

OBSERVATION:
-Mortality/Viability: Twice daily.
-Toxicity: At least once daily.
-Body Weight: Day of treatment (prior to application) and after the final observation.
-Necropsy: No necropsy was performed according to protocol.
-Irritation: The skin reactions were assessed at approximately 1, 24, 48 and 72 hours after the removal of the dressings and test substance. The irritation scores and a description of all other (local) effects were recorded. Adjacent areas of the untreated skin of each animal served as controls.

SCORING SYSTEM: Draize
Irritation parameter:
erythema score
Basis:
mean
Time point:
other: Mean of 24, 48 and 72 hours
Score:
0
Max. score:
0
Irritation parameter:
edema score
Basis:
mean
Time point:
other: Mean of 24, 48 and 72 hours
Score:
0
Max. score:
0
Irritant / corrosive response data:
No skin irritation was caused by 4 hours exposure to the test substance.
Other effects:
No staining of the treated skin by the test substance was observed and no test substance remnants were seen.
No signs of systemic toxicity were observed in the animals during the test period and no mortality occurred.

Individual skin irritation scores

Animal

815

812

816

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 classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Based on these results the test substance does not have to be classified and has no obligatory labelling requirement for skin irritation according to the:
- Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2011) (including all amendments);
- Regulation (EC) No 1272/2008 on classification, labelling and packaging of substances and mixtures (including all amendments).
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 26 Nov to 17 Dec 2014
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: Charles River France, L’Arbresle Cedex, France
- Age at study initiation: between 12 and 24 weeks old
- Weight at study initiation: at least 1.5 kg
- Housing: Animals were individually housed in labeled cages with perforated floors and shelters.
- Diet (e.g. ad libitum): Pelleted diet for rabbits approximately 100 grams per day. Hay and wooden sticks were available during the study period.
- Water (e.g. ad libitum): Free access to tap water.
- Acclimation period: at least 5 days before start of treatment

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 to 24°C
- Humidity (%): 40 to 70%
- Air changes (per hr): at least 10 air changes/hour
- Photoperiod (hrs dark / hrs light): a 12-hour light/12-hour dark cycle

IN-LIFE DATES: From 26 Nov to 17 Dec 2014
Vehicle:
unchanged (no vehicle)
Controls:
no
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): on average, 37.2 mg (range 36.8 - 37.3 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:
TREATMENT
Animals were treated by instillation of, on average, 37.2 mg (range 36.8 - 37.3 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.
Immediately after fluorescein examination on Day 2, in order to provide a continued level of systemic analgesia, buprenorphine 0.01 mg/kg and meloxicam 0.5 mg/kg were administered by subcutaneous injection.

OBSERVATION
-Mortality/Viability: Twice daily.
-Toxicity: At least once daily.
-Body Weight: Day of treatment (prior to instillation) and after the final observation.
-Necropsy: No necropsy was performed according to protocol.
-Irritation: The eyes of each animal were examined approximately 1, 24, 48 and 72 hours after instillation of the test substance. The irritation scores and a description of all other (local) effects were recorded.

SCORING SYSTEM: Draize
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. 0.89
Max. score:
2
Reversibility:
fully reversible within: 7 days
Remarks on result:
other: fully reversible within 72 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:
0
Max. score:
1
Reversibility:
fully reversible within: 24 hours
Remarks on result:
other: fully reversible within 24 hours in all three animals.
Irritant / corrosive response data:
Irritation:
Instillation of approximately 37 mg of test substance (a volume of approximately 0.1 mL) into one eye of each of three rabbits resulted in irritation of the conjunctivae, which consisted of redness, chemosis and discharge. The irritation had completely resolved within 72 hours in one animal and within 7 days in the other two animals.
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.

Corrosion:
There was no evidence of ocular corrosion.
Other effects:
Remnants of the test substance were present on the outside of the eyelids of all animals on Day 1.
No signs of systemic toxicity were observed in the animals during the test period and no mortality occurred.

Individual eye irritation scores

Animal

Time after dosing

Cornea opacity

Iris

Conjunctivae redness

Conjunctivae Chemosis

813

1 hour

0

0

2

1

24 hours

0

0

1

0

48 hours

0

0

1

0

72 hours

0

0

1

0

7 days

0

0

0

0

818

1 hour

0

0

2

1

24 hours

0

0

1

0

48 hours

0

0

1

0

72 hours

0

0

1

0

7 days

0

0

0

0

824

1 hour

0

0

2

1

24 hours

0

0

1

0

48 hours

0

0

1

0

72 hours

0

0

0

0

Interpretation of results:
slightly irritating
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Based on these results, the test substance does not have to be classified and has no obligatory labelling requirement for eye irritation according to the:
- Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2011) (including all amendments);
- Regulation (EC) No 1272/2008 on classification, labelling and packaging of substances and mixtures (including all amendments).
Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Additional information

Skin irritation/corrosion

Two studies are available:

1) A primary skin irritation study was conducted according to OECD 404 using rabbits (Latour, 2015). 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, 2014). 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 acute eye irritation study was conducted according to OECD 405 using rabbits (Latour, 2015). Key study.

This study showed that the test substance is slightly irritating.

2) An in vitro BCOP study was conducted according to OECD 437 using bovine cornea (Verspeek-Rip, 2014). Supporting study.

In the interest of animal welfare and to minimize any testing likely to produce severe responses in animals, an in vitro BCOP test was performed. This study showed that the test substance is not irritating. 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 using rabbits.

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

Effects on eye irritation: slightly irritating

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.

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).

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.