Registration Dossier

Administrative data

Description of key information

Skin
In-vitro:

- EpiDerm Corrosivity test: not corrosive (2004, OECD 431, reliability 2)
In vivo:
- Rabbit, 4 h, semiocclusive: not irritating to skin (2004, acc. OECD 404, GLP, reliability 1)
- Rabbit, 4 h, semiocclusive: mildly irritating to skin Cat. 3 (2002, acc. OECD 404, GLP, reliability 1)
- Rabbit, 4 h, occlusive: not irritating to skin (1982, comp. OECD 404, reliability 2)
Eye
In-vitro:

- HET-CAM corrosion test: non corrosive (2004, reliability 2)
In vivo:
- Rabbit, 24 h, substance was not washed out: irritating Cat. 2B (2004, acc. OECD 405, GLP, reliability 1)
- Rabbit, 24 h, substance was not washed out: severely irritating Cat. 1 (1982, comp. OECD 405, reliability 2)

Respiratory system
No data available

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:
24 Nov. - 18. Dec. 2003
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
GLP compliant
Qualifier:
according to
Guideline:
OECD Guideline 404 (Acute Dermal Irritation / Corrosion)
Version / remarks:
2002
Qualifier:
according to
Guideline:
EPA OPPTS 870.2500 (Acute Dermal Irritation)
Version / remarks:
1998
Qualifier:
according to
Guideline:
EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)
Version / remarks:
1992
GLP compliance:
yes
Remarks:
Landesanstalt für Pflanzenbau und Pflanzenschutz Rheinland Pfalz, Sep 2001
Species:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Centre Lago S.A., Vonnas, France
- Weight at study initiation: 3.80 - 4.63 kg
- Housing: individually in stainless steel wire mesh cages with grating, floor area: 3000 cm2
- Diet: Kliba-Labordiaet, about 130 g/animal per day
- Water: ad libitum, tap water
- Acclimation period: at least 5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24 °C
- Humidity (%): 30-70 %
- Photoperiod (hrs dark / hrs light): 12/12
Type of coverage:
semiocclusive
Preparation of test site:
clipped
Vehicle:
unchanged (no vehicle)
Controls:
other: untreated skin sites of the same animals
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied: 0.5 ml, undiluted
Duration of treatment / exposure:
4 hours
Observation period:
72 hours
Number of animals:
3
Details on study design:
TEST SITE
- Area of exposure: 2.5 cm x 2.5 cm
- Type of wrap if used: The test substance was covered with a test patch (Idealbinde, Pfälzische Verbandstoff-Fabrik, Kaiserslautern) and Fixomull
stretch (adhesive fleece), Beiersdorf AG, semiocclusive

REMOVAL OF TEST SUBSTANCE
- Washing: The test substance was removed at the end of the exposure period with Lutrol and Lutrol / water (1:1).
- Time after start of exposure: after the 4 hours of exposure


SCORING SYSTEM: accodring to OECD guideline 404
Irritation parameter:
erythema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
4
Reversibility:
fully reversible within: the first 24 hours before the reading
Irritation parameter:
edema score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritation parameter:
erythema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0.33
Max. score:
4
Reversibility:
fully reversible within: 48 hours
Irritation parameter:
edema score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0
Max. score:
4
Irritation parameter:
erythema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0.33
Max. score:
4
Reversibility:
fully reversible within: 48 hours
Irritation parameter:
edema score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0
Max. score:
4
Other effects:
Slight eryrthema (grade 1) was observed in two animals immediately and 1 hour after removal of the patch and persisted in one animal up to 24 hours. Moderate erythema (grade 2), noted in one animal immediately and 1 hour after removal of the patch, decreased to slight erythema after 24 hours.
No other cutaneous reactions were observed during the study.
The cutaneous reactions were reversible in one animal within 24 hours and in two animals within 48 hours after removal of the patch.
Interpretation of results:
GHS criteria not met
Conclusions:
under the conditions of the present in vivo study with rabbits the test item was considered to be non-irritating to the skin.
Executive summary:

In-vivo, a skin irritation test was performed with three New Zealand White rabbits, according to OECD guideline 404 and in compliance with GLP (reliability 1). At least 24 hours before substance administration the dorsolateral part of the trunk of the animals was clipped. The untreated skin sites of the animals served as control. A 4-hour semiocclusive exposure to ca. 0.5 ml of the undiluted test substance produced the following effects: slight eryrthema (grade 1) was observed in two animals immediately and 1 hour after removal of the patch and persisted in one animal up to 24 hours. Moderate erythema (grade 2), noted in one animal immediately and 1 hour after removal of the patch, decreased to slight erythema after 24 hours. No other cutaneous reactions were observed during the study. The cutaneous reactions were reversible in one animal within 24 hours and in two animals within 48 hours after removal of the patch.

Based on this study findings the test item was considered to be non iriitating to the skin of rabbits.

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:
24. Nov - 18. Dec. 2003
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
GLP compliant
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Version / remarks:
2002
Qualifier:
according to
Guideline:
EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)
Version / remarks:
1992
Qualifier:
according to
Guideline:
EPA OPPTS 870.2400 (Acute Eye Irritation)
Version / remarks:
1998
Guideline:
other: MAFF Testing Guideline of 12 Nousan No. 8147
Version / remarks:
2000
GLP compliance:
yes
Remarks:
Landesanstalt für Pflanzenbau und Pflanzenschutz Rheinland Pfalz, Sep 2001
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Centre Lago S.A., Vonnas, France
- Weight at study initiation: 3.12 - 3.22 kg
- Housing: individually in stainless steel wire mesh cages with grating, floor acrea: 3000 cm2
- Diet: Kliba-Labordiaet, about 130 g/animal per day
- Water: ad libitum
- Acclimation period: at least 5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24 °C
- Humidity (%): 30-70 %
- Photoperiod (hrs dark / hrs light): 12/12

Vehicle:
unchanged (no vehicle)
Controls:
other: untreated eye of the same animals
Amount / concentration applied:
TEST MATERIAL
- Amount applied: 0.1 ml
Duration of treatment / exposure:
24 hours
Observation period (in vivo):
7 days
Number of animals or in vitro replicates:
3 (2 females, 1 male)
Details on study design:
REMOVAL OF TEST SUBSTANCE
- Washing: with 3 to 6 ml of hand warm tap water for 1 to 2 minutes using a syringe with a blunt probe.
- Time after start of exposure: 24 hours after application

SCORING SYSTEM: according to OECD guideline 405

TOOL USED TO ASSESS SCORE: daylight tubes "Lumilux" (L 58/860 Plus Eco 25x1, Osram, Germany)
Irritation parameter:
cornea opacity score
Basis:
animal #1
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
iris score
Basis:
animal #1
Time point:
24/48/72 h
Score:
0.33
Max. score:
2
Reversibility:
fully reversible within: 72 hours
Irritation parameter:
conjunctivae score
Basis:
animal #1
Time point:
24/48/72 h
Score:
2
Max. score:
3
Reversibility:
fully reversible within: 7 days
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
24/48/72 h
Score:
1.67
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
cornea opacity score
Basis:
animal #2
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
iris score
Basis:
animal #2
Time point:
24/48/72 h
Score:
0.67
Max. score:
2
Reversibility:
fully reversible within: 72 hours
Irritation parameter:
conjunctivae score
Basis:
animal #2
Time point:
24/48/72 h
Score:
2.33
Max. score:
3
Reversibility:
fully reversible within: 7 days
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
24/48/72 h
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
cornea opacity score
Basis:
animal #3
Time point:
24/48/72 h
Score:
1
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
iris score
Basis:
animal #3
Time point:
24/48/72 h
Score:
0.33
Max. score:
2
Reversibility:
fully reversible within: 72 hours
Irritation parameter:
conjunctivae score
Basis:
animal #3
Time point:
24/48/72 h
Score:
2.67
Max. score:
3
Reversibility:
fully reversible within: 7 days
Irritation parameter:
chemosis score
Basis:
animal #3
Time point:
24/48/72 h
Score:
1.33
Max. score:
4
Reversibility:
fully reversible within: 72 hours
Irritant / corrosive response data:
Suppuration, contracted pupil, discharge of blood and injected scleral vessels in a circumscribed area or circular were noted during the observation period within the first 72 hours. All findings were fully reversible within 7 days at the latest.
Interpretation of results:
Category 2B (mildly irritating to eyes) based on GHS criteria
Conclusions:
The substance has to be classified as mildly irritating to eyes (Category 2B) according to GHS-criteria.
Executive summary:

An eye irritation test in rabbits was performed according to the method described in OECD guideline 405 (GLP, reliability 1). An amount of 0.1 ml of the test substance was applied to one eye of three White New Zealand rabbits (stepwise procedure starting with one animal and supplementing two additional animals). About 24 hours after application the eye was rinsed with tap water. The ocular reactions were assessed approximately 1, 24, 48, 72 hours and 7 days after application. Slight corneal opacity, moderate iritis, moderate or severe conjunctival redness, slight to marked conjunctival chemosis and slight to severe discharge were observed during the course of the study. In addition suppuration, contracted pupil, discharge of blood and injected scleral vessels in a circumscribed area or circular were noted during the observation period.

The ocular reactions were reversible in all animals within 7 days after application. The average score (24 to 72 hours) for irritation was calculated to be 1.0 for corneal opacity, 0.4 for iris, 2.3 for conjunctival redness and 1.7 for chemosis. There was one animal with a mean score of 2.67 for redness, the other two animals were at 2 and 2.33.

Considering the described ocular reactions as well as the average score for irritation, the test substance shows a slight eye irritation potential under the test conditions chosen.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

There are valid in-vitro and in-vivo data available for the assessment of the skin and eye irritation potential of the test item.

Skin

In an in-vitro EpiDerm test, the test substance was investigated for possible corrosive properties (2004, no GLP, reliability 2). The undiluted test material was exposed to the EpiDerm model for 3 minutes and for 1 hour. The evaluation of the results led to the conclusion, that the substance is non corrosive.

In-vivo, a reliable Key-study is available which was performed with three New Zealand White rabbits, according to OECD guideline 404 and in compliance with GLP (reliability 1). At least 24 hours before substance administration the dorsolateral part of the trunk of the animals was clipped. The untreated skin sites of the animals served as control. A 4-hour semiocclusive exposure to ca. 0.5 ml of the undiluted test substance produced the following effects: slight eryrthema (grade 1) was observed in two animals immediately and 1 hour after removal of the patch and persisted in one animal up to 24 hours. Moderate erythema (grade 2), noted in one animal immediately and 1 hour after removal of the patch, decreased to slight erythema after 24 hours. No other cutaneous reactions were observed during the study. The cutaneous reactions were reversible in one animal within 24 hours and in two animals within 48 hours after removal of the patch.

Also, in a further in-vivo study, in accordance with the OECD guideline 404 and in compliance with GLP (reliability 1). The rabbits received a single four hour, semi-ocdusive, dermal administration of 0.5 ml of the test substance as supplied and were observed for 15 days. Very-slight or well-defined erythema with or without very-slight or slight oedema was apparent throughout the first 72 hours after bandage removal. On Day 8 exfoliation was apparent in two animals one of which showed very-slight erythema; the animals were overtly normal a week later. The means of scores for the skin reactions at approximately 24, 48 and 72 hours after administration were calculated and revealed a mean score of 2.0, 1.7 and 1,7 for erythema and 1.0, 0.7, and 1.0 for oedema for animals 1 to 3, respectively.

Mild skin effects were also seen in another study, with animals treated for 4 h with the undiluted test substance under occlusive conditions. Skin reactions were observed for a period of 8 days. The value for edema formation was 1 over all animals tested and 1 for individual animals. The value for erythema formation was 1.5 over all animals tested and 2 in the first animal and 1 in the second animal. In one animal, erythema formation was not fully reversible at the end of the observation period on day 8.

Eye

In an in-vitro HET-CAM test, the test substance was investigated for possible corrosive properties (2004, reliability 2). The test substance was applied to 3 eggs undiluted and to another 3 eggs as a 10 % solution in olive oil. The time (seconds) until appearance of haemorrhagia and coagulation was noted for each. No effects within the observation period of 300 seconds were noted. Neither haemorrhagia nor coagulation occured in any of the eggs tested. The test substance did not produce changes indicative for severe eye irritation.

An eye irritation test in rabbits was performed according to the method described in OECD guideline 405 (GLP, reliability 1, 2004). An amount of 0 .1 ml of the test substance was applied to one eye of three White New Zealand rabbits (stepwise procedure starting with one animal and supplementing two additional animals). About 24 hours after application the eye was rinsed with tap water. The ocular reactions were assessed approximately 1, 24, 48, 72 hours and 7 days after application. Slight corneal opacity, moderate iritis, moderate or severe conjunctival redness, slight to marked conjunctival chemosis and slight to severe discharge were observed during the course of the study. In addition suppuration, contracted pupil, discharge of blood and injected scleral vessels in a circumscribed area or circular were noted during the observation period . The ocular reactions were reversible in all animals within 7 days after application. The average score (24 to 72 hours) for irritation was calculated to be 1.0 for corneal

opacity, 0.4 for iris, 2.3 for conjunctival redness and 1.7 for chemosis. There was one animal with a mean score of 2.67 for redness, the other two animals were at 2 and 2.33.

In another study, a Draize test was conducted with 6 New Zealand White rabbits, the eyes were also left unwashed after application of 0.1 ml tripropylene glycol diacrylate and the animals were observed for 8 days (BASF AG 1982, Val. 2). Symptoms included ulceration, loss of hair at the border of the eye lids, scars on the eyelid and narrowed pupils. The mean scores were 1.17 for corneal opacity (1.0 for 3/6 rabbits and 1.33 for the other 3/6 animals), 1 for iris lesions (1 for 6/6 animals), 1.94 for redness of the conjunctivae (2.0 for 5/6 and 1.67 for the 6th animal) and 1.39 for edema formation (0.67, 1, 1, 1.67, 2 and 2 for the individual rabbits). The lesions were still present at the end of the observation period in most of the animals. This result, however, should be considered as overpredictive due to the harsh test conditions if compared to actual guideline recommendations (substance was not washed out after 24 hours, observation period was completed after 8 days). Additionally, no information was available in terms of the amount and definition of impurities within the test material.

 

Respiratory system: No data available

Justification for classification or non-classification

Skin

The available experimental test data are reliable and suitable for classification purposes under Regulation 1272/2008. A GLP-compliant OECD 404 study is available for skin irritation. In this study, the scores for the test item treated tissues were below the thresholds for classification as a skin irritant. Thus, the substance is not considered to be classified for skin or eye irritation under Regulation (EC) No. 1272/2008, as amended for the thirteenth time in Regulation (EC) No. 2018/1480.

Nevertheless, the test substance is legally classified as a skin irritant category 2 (Annex VI, 1272/2008).

Eye

The available experimental test data are reliable and suitable for classification purposes under Regulation 1272/2008. A GLP-compliant OECD 405 study is available for the assessment of the eye irritation potential. indicating that the substance is not considered to be classified for eye irritation Cat. 2B under Regulation (EC) No. 1272/2008, as amended for the thirteenth time in Regulation (EC) No. 2018/1480.

Additionally, the test item is legally classified as an eye irritant category 2 (Annex VI, 1272/2008).

 

Respiratory system

Actually, there are no data available for a classification according to this endpoint, but the test substance is classified to cause irritation of the respiratory tract (STOT SE 3) (Annex VI, 1272/2008).