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Administrative data

Description of key information

Skin irritation:

Two studies are available:

1) An primary skin irritation/corrosion study (van Sas, 2017) is available which is key study. This study showed that the test substance is not irritating.

2) An in vitro skin corrosion study (Buskens, 2017) 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/corrosion study (van Sas, 2017) is available which is key study. This study showed that the test substance is moderate irritant to the rabbit eye

2) An in vitro eye irritation BCOP study (Westerink, 2017) is available which is supporting study. This study showed that the test substance did not induce ocular irritation.

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 2017-02-03 to 2017-02-20
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Version / remarks:
2015
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)
Version / remarks:
May 2008
Deviations:
no
GLP compliance:
yes
Specific details on test material used for the study:
Batch No.: APM0005851606003
Purity/Composition: 99.8% w/w
Test item storage: At room temperature
Species:
rabbit
Strain:
New Zealand White
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River France, L’Arbresle
- Age at study initiation: approximately 28-29 weeks old
- Weight at study initiation: 4069 to 4086 g
- Housing: On arrival and following assignment to the study, animals were housed individually in labeled cages with perforated floors (Ebeco, Germany, dimensions 67 x 62 x 55 cm) equipped with water bottles.
- Diet (e.g. ad libitum): Pelleted diet for rabbits provided once daily throughout the study
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18°C to 24°C
- Humidity (%): 40% to 70%
- Air changes (per hr): Ten or greater
- Photoperiod (hrs dark / hrs light): 12-hour light/12-hour dark cycle

IN-LIFE DATES: From: 2017-02-03 To: 2017-02-20
Type of coverage:
semiocclusive
Preparation of test site:
clipped
Vehicle:
water
Controls:
no
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 grams

VEHICLE
- Amount(s) applied (volume or weight with unit): 0.4 mL
Duration of treatment / exposure:
4 hours
Observation period:
14 days
Number of animals:
3 Males
Details on study design:
TEST SITE
- Area of exposure: 2x3 cm
- Type of wrap if used: Coban elastic bandage

REMOVAL OF TEST SUBSTANCE
- Washing (if done): the skin cleaned of residual test item using tap water
- Time after start of exposure: Four hours

OBSERVATION TIME POINTS
- Mortality/Moribundity Checks: twice daily, once in the morning and once in the afternoon
- Clinical Observations: once daily
- Body Weights: on Day 1 (predose) and on the day of the final observation.
- Irritation: assessed at approximately 1, 24, 48 and 72 hours after the removal of the dressings and test item.

SCORING SYSTEM:
- Method of calculation: 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:
- Irritation: No skin irritation was caused by 4 hours exposure to test substance.
- Corrosion: There was no evidence of a corrosive effect on the skin.
Other effects:
- Coloration / Remnants: No staining of the treated skin by the test item was observed and no test item remnants were seen.
- Toxicity / Mortality: No signs of systemic toxicity were observed in the animals during the test period and no mortality occurred.

Individual skin irritation scores:

Animal

227

218

222

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:
GHS criteria not met
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 (2015) (including all amendments) and Regulation (EC) No 1272/2008 on classification, labelling and packaging of items and mixtures (including all amendments).
Executive summary:

The objective of this primary skin irritation study was to assess the possible irritation or corrosion potential of a single dose of test subbstance when administered to the intact skin of rabbits according to OECD 404.

Three rabbits were exposed to 0.5 grams of test substance, moistened with water by application onto clipped skin for 4 hours using a semi-occlusive dressing. Skin reactions were assessed 1, 24, 48 and 72 hours after exposure.

No skin irritation was caused by 4 hours exposure to test substance.

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 (2015) (including all amendments) and Regulation (EC) No 1272/2008 on classification, labelling and packaging of items 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 2017-03-12 to 2017-04-11
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Version / remarks:
2012
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)
Version / remarks:
2008
Deviations:
no
GLP compliance:
yes
Specific details on test material used for the study:
Batch No.: APM0005851606003
Purity/Composition: 99.8% w/w
Test item storage: At room temperature
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: approximately 29-35 weeks old
- Weight at study initiation: 3926 to 4316 g
- Housing: housed individually in labeled cages with perforated floors (dimensions 67 x 62 x 55 cm) equipped with water bottles
- Diet: Pelleted diet for rabbits was provided once daily throughout the study. In addition, hay was available during the study period.
- Water: ad libitum
- Acclimation period: at least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature: 20°C
- Humidity: 58 to 63%
- Air changes: Ten or greater per hour
- Photoperiod: 12-hour light/12-hour dark cycle

IN-LIFE DATES: From: 2017-03-12 To: 2017-04-11
Vehicle:
unchanged (no vehicle)
Controls:
yes, concurrent no treatment
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 99.7 mg (range 99.1 – 100.0 mg)
Duration of treatment / exposure:
14 days
Observation period (in vivo):
14 days
Number of animals or in vitro replicates:
3 rabbits
Details on study design:
In-life Procedures, Observations, and Measurements
Mortality
Throughout the study, animals were observed for general health/mortality and moribundity twice daily, in the morning and at the end of the working day.
Clinical Observations
Postdose Observations
Postdose observations were performed once daily throughout the study, the observation period was 14 days.
Body Weights
Animals were weighed individually on Day 1 (predose) and on the day of the final observation.
Irritation
The eyes of each animal were examined approximately 1, 24, 48 and 72 hours and 7 and 14 days after instillation of the test item. The irritation scores and a description of all other (local) effects were recorded.

SCORING SYSTEM: Draize

TOOL USED TO ASSESS SCORE: fluorescein
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
24/48/72 h
Score:
0.56
Max. score:
1
Reversibility:
fully reversible within: 72 hours
Irritation parameter:
iris score
Basis:
mean
Time point:
24/48/72 h
Score:
0.44
Max. score:
1
Reversibility:
fully reversible within: 72 hours
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
24/48/72 h
Score:
2
Max. score:
2
Reversibility:
fully reversible within: 14 days
Irritation parameter:
chemosis score
Basis:
mean
Time point:
24/48/72 h
Score:
1.44
Max. score:
3
Reversibility:
fully reversible within: 7 days
Irritant / corrosive response data:
Instillation of test substance resulted in effects on the cornea, iris and conjunctivae. The corneal injury consisted of opacity and epithelial damage. The corneal injury resolved within 72 hours in one animal and within 7 days in the other two animals.
Iridial irritation was observed and resolved within 48 hours in two animals and within 72 hours in the third animal.
The irritation of the conjunctivae consisted of redness, chemosis and discharge and completely resolved within 14 days.
There was no evidence of ocular corrosion.
Other effects:
No staining of (peri) ocular tissues by the test item was observed and no test item remnants were seen.
No signs of systemic toxicity were observed in the animals during the test period and no mortality occurred.

Individual Eye Irritation Scores:

Eye reaction

Time after treatment

Individual scores-rabbit number and sex

236 Male

219 Male

221 Male

Cornea opacity

1 hour

24 hours

48 hours

72 hours

0

1

1

0

0

1

1

0

0

1

0

0

Iris

1 hour

24 hours

48 hours

72 hours

0

1

0

0

0

1

1

0

0

1

0

0

Conjunctivae redness

1 hour

24 hours

48 hours

72 hours

2

2

2

2

2

2

2

2

2

2

2

2

Chemosis

1 hour

24 hours

48 hours

72 hours

2

2

1

1

2

2

1

1

2

3

1

1

Interpretation of results:
Category 2A (irritating to eyes) based on GHS criteria
Conclusions:
Based on the test results:
• according to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2015) (including all amendments), test item should be classified as : irritating to eyes (Category 2A).
• according to the Regulation (EC) No 1272/2008 on classification, labelling and packaging of items and mixtures (including all amendments), test item should be classified as Irritating to eyes (Category 2) and labeled as H319: Causes serious eye irritation.
Based on the maximum group mean of 27.3, test item should be classified as moderate irritant to the rabbit eye according to the Kay and Calandra classification system.
Executive summary:

The objective of this acute eye irritation study was to assess the possible irritation or corrosion potential when a single dose of test item was placed in the conjunctival sac of the rabbit eye according to OECD No.405 (2012) and EC No 440/2008, part B.

Single samples of approximately 99.7 mg of test item (a volume of approximately 0.1 mL) were instilled into one eye of each of three rabbits. Observations were made 1, 24, 48 and 72 hours and 7 and 14 days after instillation.

Instillation of the test item resulted in effects on the cornea, iris and conjunctivae. The corneal injury consisted of opacity and epithelial damage. The corneal injury resolved within 72 hours in one animal and within 7 days in the other two animals. Iridial irritation was observed and resolved within 48 hours in two animals and within 72 hours in the third animal.

The irritation of the conjunctivae consisted of redness, chemosis and discharge and completely resolved within 14 days.

Based on the test results:

• according to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2015) (including all amendments), test item should be classified as : irritating to eyes (Category 2A).

• according to the Regulation (EC) No 1272/2008 on classification, labelling and packaging of items and mixtures (including all amendments), test item should be classified as Irritating to eyes (Category 2) and labeled as H319: Causes serious eye irritation.

Based on the maximum group mean of 27.3, test item should be classified as moderate irritant to the rabbit eye according to the Kay and Calandra classification system.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Justification for classification or non-classification

Skin irritation/corrosion: Mean scores at 24, 48 and 72 hours for erythema were < 2.3 (actual value 0) and for edema were < 2.3 (actual value 0). 

Therefore in accordance with Regulation (EC) No. 1272/2008 Table 3.2.2, this substance should not be classified for skin irritation/corrosion.

 

Eye irritation: Mean scores at 24, 48 and 72 hours for corneal opacity ≥ 1, and/or iritis ≥ 1, and/or conjunctival redness ≥ 2, and/or conjunctival oedema (chemosis) ≥ 2 (actual value: cornea opacity, iris, conjunctivae redness and chemosis were 0.56, 0.44, 2.0, 1.44). All the reactions were fully reversed within 14 days.

Therefore in accordance with Regulation (EC) No. 1272/2008 Table 3.3.2, this substance should be classified as eye irritation Category 2.