Registration Dossier

Administrative data

Description of key information

The skin irritation potential of the substance has been investigated in three in vivo studies. Based on the results obtained in the key study, conducted in accordance with OECD 404 and GLP, the substance does not need to be classified for skin irritation.

The eye irritation potential of the substance has been investigated in 4 in vivo and 2 in vitro studies, which were used in a weight-of-evidence approach. Based on the results obtained in one of the two key studies, conducted in accordance with OECD 405 and GLP, the substance is classified for eye 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:
January 15, 2001 - June 18, 2001
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 amount of the aqueous solution applied was 0.5 g instead of 0.5 mL
Qualifier:
according to
Guideline:
EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)
Deviations:
yes
Remarks:
the amount of the aqueous solution applied was 0.5 g instead of 0.5 mL
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Italia S.p.A. (Como) and bred by P.O.A.D.A.,  Mandello Lario (Como), Italy.
- Age at study initiation: 9 to 11 weeks at ordering; 10-12 weeks at study initiation
- Weight at study initiation: approximately 2 kg at ordering; 2.3-2.7 kg at study initiation
- Housing: stainless steel cages (63x48x41 cm) equipped with grid floors. Cages were suspended over trays and each tray held an absorbent materiel inspected and changed as necessary.
- Diet (e.g. ad libitum): ad libitum (pelleted diet from Altromin MSK, Altromin, D-32770 Lage,  Postfach 1120, Germany)
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 10 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 15-21 °C
- Humidity (%): 40-70%
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12 hrs dark/12 hrs light
Type of coverage:
semiocclusive
Preparation of test site:
other: the day before dosing the dorsal surfaces of the trunk of each animal, on both sides of the midline, were clipped free of hair using an electric clipper equipped with a suitable blade
Vehicle:
unchanged (no vehicle)
Controls:
other: comparison with adjacent untreated skin
Amount / concentration applied:
TEST MATERIAL
- Amount applied: 0.5 g
- Concentration: the test material was applied as such (aqueous solution)
Duration of treatment / exposure:
4 hours
Observation period:
4 days
Number of animals:
3 females
Details on study design:
TEST SITE
- Area of exposure: 2.5 x 2.5 cm (6.25 cm^2)
- Type of wrap if used: gauze + aluminium

REMOVAL OF TEST SUBSTANCE
- Washing (if done): treated sites were cleaned by gentle swabbing of the skin with cotton wool soaked in water at approximate body temperature
- Time after start of exposure: 4 hours

SCORING SYSTEM: according OECD 404
Irritation parameter:
erythema score
Basis:
other: mean for animals #1, #2 and #3
Time point:
24/48/72 h
Score:
0.6
Max. score:
4
Reversibility:
fully reversible within: 72 hours (in all animals)
Remarks on result:
other: Individual mean scores: 0.7-0.7-0.3; Note: solid content of the test material: 50%
Irritation parameter:
edema score
Basis:
other: mean for animals #1, #2 and #3
Time point:
24/48/72 h
Score:
0.3
Max. score:
4
Reversibility:
fully reversible within: 48 hours (in all animals)
Remarks on result:
other: Individual mean scores: 0.3-0.3-0.3; Note: solid content of the test material: 50%
Irritant / corrosive response data:
See section "Any other information on results incl. tables"
 Scores for erythema reactions  
ERYTHEMA 1h 24h 48h 72h Individual mean scores
 (24, 48 and 72h)
Rabbit 1 1 1 1 0 0.7
Rabbit 2 1 1 1 0 0.7
Rabbit 3 1 1 0 0 0.3

 Scores for oedema reactions  
OEDEMA 1h 24h 48h 72h Individual mean scores
 (24, 48 and 72h)
Rabbit 1 1 1 0 0 0.3
Rabbit 2 1 1 0 0 0.3
Rabbit 3 1 1 0 0 0.3

Other information:

- The animals had a normal weight gain during the 4 days(0.1 kg)

- No indication of a systemic effect

Interpretation of results:
GHS criteria not met
Conclusions:
On the basis of these results, the test material (solid content 50%) is not classified as a skin irritant according to the criteria of the CLP Regulation.
Executive summary:

The test material (aqueous solution at approx. 50% solids) was tested for acute dermal irritation in 3 female New Zealand White rabbits, according to OECD 404/EC method B.4, and in compliance with Good Laboratory Practice. The test material, was applied as such on a gauze, in a single dermal dose of 0.5 g, to a 2.5 x 2.5 cm clipped area of the skin, during 4 hours under a semi-occlusive dressing. The cutaneous examinations were performed at 1, 24, 48 and 72 hours after removal of the dressing. The application of the preparation produced very slight erythema (score 1) in all animals at 24 hours but only in two animals at 48 hours after patch removal. The reversibility was complete at 72 hours in all animals. Very slight edema was observed in all animals but only at 24 hours. No other reactions were observed after. The mean individual scores calculated over the 24-72 hour period for each animal were (0.7-0.7-0.3) for erythema, and (0.3-0.3-0.3) for edema. On the basis of these results, the test material (solid content 50%) is not classified as a skin irritant according to the criteria of the CLP Regulation.

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:
weight of evidence
Study period:
January 15, 2001 - July 5, 2001
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.5 (Acute Toxicity: 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 Italia S.p.A., Como, Italy
- Age at study initiation: 9 to 11 weeks
- Weight at study initiation: 2.4 - 2.8 kg
- Housing:
The animals were individually housed in stainless steel cages measuring 48x63x41 cm and equipped with grid floors. Cages were suspended over trays and each tray held an absorbent material which was inspected daily and changed as necessary.
- Diet (e.g. ad libitum): ad libitum (pelleted laboratory diet from Altromin MSK, Altromin,  D-32770 Lage, Postfach 1120, Germany)
- Water (e.g. ad libitum): ad libitum
- Acclimation period: minimum period of 10 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 15 to 21 °C
- Humidity (%): 45 to 65%
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12 hrs dark/12 hrs light
Vehicle:
unchanged (no vehicle)
Controls:
other: the left eye of each animal remained untreated and served as a control
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 mL
- Concentration (if solution): not applicable, the aqueous solution was tested as such
Duration of treatment / exposure:
Not applicable (the eyes were not rinsed)
Observation period (in vivo):
14 days
Number of animals or in vitro replicates:
3 female rabbits
Details on study design:
REMOVAL OF TEST SUBSTANCE: not applicable
SCORING SYSTEM: in accordance with OECD 405
TOOL USED TO ASSESS SCORE: no data
Irritation parameter:
cornea opacity score
Basis:
other: Mean for animals #1, #2 and #3
Time point:
24/48/72 h
Score:
1.2
Max. score:
4
Reversibility:
fully reversible within: 14 days (in all animals)
Remarks on result:
other: Individual mean scores: 1-1.3-1.3; Note: solid content of the test material: 50%
Irritation parameter:
iris score
Basis:
other: Mean for animals #1, #2 and #3
Time point:
24/48/72 h
Score:
0
Max. score:
2
Reversibility:
fully reversible within: 24 hours (in all animals)
Remarks on result:
other: Individual mean scores: 0-0-0; Note: solid content of the test material: 50%
Irritation parameter:
conjunctivae score
Basis:
other: Mean for animals #1, #2 and #3
Time point:
24/48/72 h
Score:
1.7
Max. score:
3
Reversibility:
fully reversible within: 7 days (in all animals)
Remarks on result:
other: Individual mean scores: 1.3-1.7-2; Note: solid content of the test material: 50%
Irritation parameter:
chemosis score
Basis:
other: Mean for animals #1, #2 and #3
Time point:
24/48/72 h
Score:
1.1
Max. score:
4
Reversibility:
fully reversible within: 7 days (in all animals)
Remarks on result:
other: Individual mean scores: 1-1.3-1; Note: solid content of the test material: 50%
Irritant / corrosive response data:
See section "Any other information on results incl. tables"
 Scores for corneal opacity  
CORNEA 1h 24h 48h 72h Individual mean scores
 (24, 48 and 72h)
Rabbit 1 1 1 1 1 1.0
Rabbit 2 0 1 1 2 1.3
Rabbit 3 0 1 1 2 1.3

 Scores for iris lesion  
IRIS 1h 24h 48h 72h Individual mean scores
 (24, 48 and 72h)
Rabbit 1 1 0 0 0 0.0
Rabbit 2 1 0 0 0 0.0
Rabbit 3 1 0 0 0 0.0

 Scores for Redness and Chemosis of conjunctivae  
CONJUNCTIVAE 1h 24h 48h 72h Individual mean scores
 (24, 48 and 72h)
Rabbit 1 Redness 3 1 1 2 1.3
Chemosis 2 1 1 1 1.0
Rabbit 2 Redness 2 2 2 1 1.7
Chemosis 2 1 2 1 1.3
Rabbit 3 Redness 3 2 2 2 2.0
Chemosis 3 1 1 1 1.0

Other information:

- The animals had a normal weight gain during the 14 days(0.1 -0.3 kg)

- No indication of systemic effects


Interpretation of results:
Category 2 (irritating to eyes) based on GHS criteria
Conclusions:
Based on the results of this study, conducted in accordance with OECD 405 and GLP, the aqueous solution of the test material (solid content 50%) is classified as Irritating to eyes (Category 2) according to the criteria of the CLP Regulation.
Executive summary:

The test material was tested as an aqueous solution at 50% solids for acute ocular irritation in 3 female New-Zealand White rabbits, according to OECD 405 / EC method B.5, and in compliance with Good Laboratory Practice. The test material, was instillated as such in a single dose of 0.1 ml into the conjunctival sac of the right eye of each animal. The left eye remained untreated and served as a control. The eyes were not rinsed. Ocular examinations were performed 1, 24, 48 and 72 hours after the instillation. Slight corneal opacity (grade 1) was observed at 1 hour after instillation in one animal, then between day 1 and 7 in all animals (grade 1 or 2). Iris inflammation (grade 1) was only noted at 1 hour. The mean scores (24-48-72 hours) calculated for each animal were 1.0 - 1.3 - 1.3 for corneal opacity, and 0.0 - 0.0 - 0.0 for iritis. Conjunctival redness and chemosis (grades 2 or 3) was observed in all three animals at 1 hour after instillation, and persisted until 72 hours (grade 1 or 2). These reactions were no longer present at day 7. The mean scores (24-48-72 hours) calculated for each animal were 1.3 - 1.7 - 2.0 for conjunctival redness, and 1.0 - 1.3 - 1.0 for chemosis. The test material (solid content 50%) is classified as irritating to eyes (Category 2) according to the criteria of the CLP Regulation.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin irritation

An aqueous solution of the substance was tested for acute dermal irritation in 3 female New Zealand White rabbits, according to OECD 404/EC method B.4 and in compliance with GLP. The application produced very slight erythema (score 1) in all animals at 24 hours but only in two animals at 48 hours after patch removal. The reversibility was complete at 72 hours in all animals. Very slight edema was observed in all animals but only at 24 hours. No other reactions were observed. The mean individual scores calculated over the 24-72 hour period for each animal were (0.7-0.7-0.3) for erythema, and (0.3-0.3-0.3) for edema. On the basis of these results, an aqueous solution of the substance (solid content 50%) is not classified as a skin irritant according to the criteria of the CLP Regulation.

This result from the key study was confirmed in a supporting study, also conducted in accordance with OECD 404 but not in compliance with GLP and with test material containing less solids.

These results are consistent with results obtained on similar substances in aqueous formulations.

Eye irritation

An aqueous solution of the substance was tested for acute ocular irritation in 3 female New-Zealand White rabbits, according to OECD 405 / EC method B.5, and in compliance with GLP. Slight corneal opacity (grade 1) was observed at 1 hour after instillation in one animal, then between day 1 and 7 in all animals (grade 1 or 2). Iris inflammation (grade 1) was only noted at 1 hour. The mean scores (24-48-72 hours) calculated for each animal were 1.0 - 1.3 - 1.3 for corneal opacity, and 0.0 - 0.0 - 0.0 for iritis. Conjunctival redness and chemosis (grades 2 or 3) was observed in all three animals at 1 hour after instillation, and persisted until 72 hours (grade 1 or 2). These reactions were no longer present at day 7. The mean scores (24-48-72 hours) calculated for each animal were 1.3 - 1.7 - 2.0 for conjunctival redness, and 1.0 - 1.3 - 1.0 for chemosis. On the basis of these results, an aqueous solution of the substance (solid content 50%) is classified as irritating to eyes (Category 2) according to the criteria of the CLP Regulation.


Effects on eye irritation: irritating

Justification for classification or non-classification

Skin irritation

The effects seen in the key study, conducted in accordance with OECD 404 and GLP, do not warrant classification.

The registered substance is never available as a neat solid (as isolated for the purpose of this registration), thus the experimental results on the aqueous solutions are relevant for human exposure and risk assessment.

Eye irritation

Based on the effects seen in one of the two key studies, conducted in accordance with OECD 405 and GLP, the substance needs to be classified as Irritating to eyes (Category 2) in accordance with the CLP Regulation. Another study with a similar solid content (and slightly lower surfactant content) showed effects with a lower intensity, below the classification criteria.

Based on additional supporting studies conducted using test materials with a lower solid content, an aqueous solution of the substance at 15% or less does not need to be classified. Therefore a specific concentration limit of ≥15% is set for the eye irritation hazard of the substance.