Registration Dossier

Skin: not irritating (BASF, 2008)
Eye: irritating (BASF, 2008)

Reference

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

April - June 2008

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:

April 24, 2002

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

(from the competent authority) Landesamt für Umwelt, Wasserwirtschaft und Gewerbeaufsicht Rheinland-Pfalz

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Batch No.of test material: 8712 / 056
- Purity: 99.6 g / 100 g
pH-value: ca. 5 (undiluted test substance, moistened with water)

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: The solid test substance was minimally moistened with a suitable amount of doubly distilled water to guarantee skin contact immediately before test substance application. Because of the natural moisture of the skin doubly distilled water was used for moistening, so that the test was carried out unter conditions as physiological as possible.

FORM OF APPLICATION
minimally moistened with doubly distilled water

Species:

rabbit

Strain:

New Zealand White

Remarks:

A 1077 INRA (SPF)

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Centre Lago S. A., 01540 Vonnas, France
- Age at study initiation: ca. 6 months
- Weight at study initiation: 3.62 - 4.01 kg
- Housing: the animals were housed in fully air-conditioned rooms
- Diet (e.g. ad libitum): Kliba-Labordiät, Provimi Kliba SA, Kaiseraugst, Basel, Switzerland (about 130 g/animal per day)
- Water (e.g. ad libitum): tap water ad libitum
- Acclimation period: at least 5 days before application

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24 °C
- Humidity (%): 30 - 70 %
- Air changes (per hr): the animals were housed in fully air-conditioned rooms
- Photoperiod (hrs dark / hrs light): 12 h / 12 h

Type of coverage:

semiocclusive

Preparation of test site:

clipped

Vehicle:

unchanged (no vehicle)

Controls:

yes, concurrent no treatment

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.5 g

Duration of treatment / exposure:

4 h

Observation period:

14 days

Number of animals:

3

Details on study design:

TEST SITE
- Area of exposure: 2.5 x 2.5 cm

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

OBSERVATION TIME POINTS
Immediately after removal of the patch, approx. 1, 24, 48 and 72 hours after removal of the patch and then in weekly intervals maximally up to day 14

SCORING SYSTEM:
- Method of calculation: For evaluation, the calculation of the mean values of erythema and edema for readings at 24, 48 and 72 hours were quoted. Additionally, the reversibility of the observed findings was taken into account. The evaluation is based on the criteria of the Commission Directive 67/548/EEC and the OECD Harmonized Integrated Classification System that were in place on the date of report signature.

Irritation parameter:

erythema score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Remarks on result:

no indication of irritation

Irritation parameter:

edema score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

Slight erythema (grade 1) was observed in all animals immediately and 1 hour after removal of the patch.
The cutaneous reactions were reversible in all animals within 24 hours after removal of the patch.
Mean scores over 24, 48 and 72 hours for each animal were 0.0 for erythema and for edema.

Table 1: Irritant response data for each individual animal at each observation time as well as calculation of the means

Readings	Animal	Exposure period: 4 h
Readings	Animal	Erythema	Edema	Additional findings
0 h	01	1	0
	02	1	0
	03	1	0
1 h	01	1	0
	02	1	0
	03	1	0
24 h	01	0	0
	02	0	0
	03	0	0
48 h	01	0	0
	02	0	0
	03	0	0
72 h	01	0	0
	02	0	0
	03	0	0
Mean 24 – 72 h	01	0.0	0.0
	02	0.0	0.0
	03	0.0	0.0
Mean		0.0	0.0

Interpretation of results:

GHS criteria not met

Conclusions:

Considering the described cutaneous reactions as well as the average score for irritation, the test substance does not show a skin irritation potential under the test conditions chosen.

Executive summary:

The potential of the test substance to cause acute dermal irritation or corrosion was assessed by a single topical application of an amount of 0.5 g of the test substance for 4 hours to the intact skin of three White New Zealand rabbits, using a patch of 2.5 cm x 2.5 cm, covered with semiocclusive dressing. After removal of the patch the application area was washed off.

The cutaneous reactions were assessed immediately after removal of the patch and approximately 1, 24, 48 and 72 hours after removal of the patch.

Slight erythema was observed in all animals immediately and 1 hour after removal of the patch.

The cutaneous reactions were reversible in all animals within 24 hours after removal of the patch.

The average score (24 to 72 hours) for irritation was calculated to be 0.0 for erythema and 0.0 for edema.

Considering the described cutaneous reactions as well as the average score for irritation, the test substance does not show a skin irritation potential under the test conditions chosen.

Endpoint conclusion:

no adverse effect observed (not irritating)

Reference

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

April - June 2008

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:

April 24, 2002

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Remarks:

(from the competent authority) Landesamt für Umwelt, Wasserwirtschaft und Gewerbeaufsicht Rheinland-Pfalz

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Batch No.of test material: 8712 / 056
- Purity: 99.6 g / 100 g
- pH value: ca. 5 (undiluted test substance, moistened with water)

FORM OF APPLICATION
undiluted

Species:

rabbit

Strain:

New Zealand White

Remarks:

A 1077 INRA (SPF)

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Centre Lago S. A., 01540 Vonnas, France
- Age at study initiation: 3 - 4 months
- Weight at study initiation: 2.63 - 3.04 kg
- Housing: The animals were housed in fully air-conditioned rooms.
- Diet (e.g. ad libitum): Kliba-Labordiät, Provimi Kliba SA, Kaiseraugst, Basel, Switzerland (about 130 g/animal per day)
- Water (e.g. ad libitum): tap water ad libitum
- Acclimation period: at least 5 days before application

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24 °C
- Humidity (%): 30 - 70 %
- Air changes (per hr): The animals were housed in fully air-conditioned rooms.
- Photoperiod (hrs dark / hrs light): 12 h / 12 h

Vehicle:

unchanged (no vehicle)

Controls:

yes, concurrent no treatment

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 mL bulk volume (about 31 mg of the comminuted test substance)

Duration of treatment / exposure:

24 hours

Observation period (in vivo):

28 days

Number of animals or in vitro replicates:

3

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing (if done): About 24 hours after application of the test substance the treated eye of the animal(s) was rinsed 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

SCORING SYSTEM: The evaluation of eye irritation was performed according to the quoted guideline. In addition to specific observations recommended by the regulatory authorities, evaluations were made of discharge from the eye and the area of cornea affected by the lesions.

TOOL USED TO ASSESS SCORE: daylight tubes "Lumilux"

Irritation parameter:

cornea opacity score

Basis:

animal #1

Time point:

24/48/72 h

Score:

1

Reversibility:

fully reversible within: 7 days

Irritation parameter:

cornea opacity score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0.7

Reversibility:

fully reversible within: 7 days

Irritation parameter:

cornea opacity score

Basis:

animal #3

Time point:

24/48/72 h

Score:

1

Reversibility:

fully reversible within: 7 days

Irritation parameter:

iris score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0.7

Reversibility:

fully reversible within: 7 days

Irritation parameter:

iris score

Basis:

animal #2

Time point:

24/48/72 h

Score:

0.3

Reversibility:

fully reversible within: 7 days

Irritation parameter:

iris score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0.3

Reversibility:

fully reversible within: 7 days

Irritation parameter:

conjunctivae score

Basis:

mean

Time point:

24/48/72 h

Score:

2

Reversibility:

fully reversible within: 7 days

Irritation parameter:

chemosis score

Basis:

animal #1

Time point:

24/48/72 h

Score:

1

Reversibility:

fully reversible within: 7 days

Irritation parameter:

chemosis score

Basis:

animal #2

Time point:

24/48/72 h

Score:

1.7

Reversibility:

fully reversible within: 7 days

Irritation parameter:

chemosis score

Basis:

animal #3

Time point:

24/48/72 h

Score:

1

Reversibility:

fully reversible within: 7 days

Irritant / corrosive response data:

Slight corneal opacity (grade 1) was observed in all animals 24 and 48 hours after application and persisted in two animals until the 72 hour reading. Moderate iritis (grade 1) was observed in all animals 24 hours after application and in one animal again after 72 hours. Moderate conjunctival redness (grade 2) was noted in all animals from 1 hour up to 72 hours after application. Moderate or marked conjunctival chemosis (grade 2 or 3) was noted in all animals 1 hour after application. Slight or moderate conjunctival chemosis (grade 1 or 2) was observed in all animals at the 24- and 48-hour reading. Slight conjunctival chemosis was seen in two animals after 72 hours. Slight to severe discharge (grade 1 to 3) was noted in all animals from 1 hour up to 24 hours. Moderate discharge (grade 2) was observed in a single animal after 48 hours. Slight discharge was noted in two animals after 72 hours.
Additional findings like contracted pupil and injected scleral vessels in a circumscribed area or circular were noted in all animals during the observation period.
The ocular reactions were reversible in all animals within 7 days after application.

Table 1: Irritant response data for each individual animal at each observation time as well as calculation of the means

Readings	Animal	Cornea		Iris	Conjunctiva			Additional findings
Readings	Animal	Opacity	Area of cornea involved	Iris	Redness	Chemosis	Discharge	Additional findings
1 h	01	0	0	0	2	2	2	49
	02	0	0	0	2	3	3	49
	03	0	0	0	2	3	2	49
24 h	01	1	4	1	2	1	1	PC, 49
	02	1	3	1	2	2	3	PC, 48
	03	1	4	1	2	2	1	PC, 48
48 h	01	1	2	0	2	1	0	PC, 48
	02	1	2	0	2	2	2	PC, 48
	03	1	3	0	2	1	0	PC, 48
72 h	01	1	2	1	2	1	1	PC, 49
	02	0	0	0	2	1	1	48
	03	1	2	0	2	0	0	PC, 48
7 d	01	0	0	0	0	0	0
	02	0	0	0	0	0	0
	03	0	0	0	0	0	0
Mean 24 – 72 h	01	1.0		0.7	2.0	1.0
	02	0.7		0.3	2.0	1.7
	03	1.0		0.3	2.0	1.0
Mean		0.9		0.4	2.0	1.2

48: scleral vessels injected, circumscribed area

49: scleral vessels injected, circular

PC: pupil contracted

Interpretation of results:

Category 2B (mildly irritating to eyes) based on GHS criteria

Conclusions:

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.

Executive summary:

The potential of the test substance to cause damage to the conjunctiva, iris or cornea was assessed by a single ocular application of 0.1 mL bulk volume (about 31 mg) of the test substance to one eye of three 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 and 72 hours after application and on day 7.

Slight corneal opacity, moderate iritis, moderate conjunctival redness, slight to marked conjunctival chemosis and slight to severe discharge were observed in the animals during the course of the study.

Additional findings like contracted pupil and injected scleral vessels in a circumscribed area or circular were noted in the animals during the observation period.

The ocular reactions were reversible in all animals within 7 days after application.

Mean scores calculated for each animal over 24, 48 and 72 hours were 0.9 for corneal opacity, 0.4 for iris lesions, 2.0 for redness of the conjunctiva and 1.2 for chemosis.

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:

adverse effect observed (irritating)

Endpoint conclusion:

no study available

Skin irritation:

There is no skin irritation study for NPPT available but the following data is suitable for a read across:

The potential of the test substance to cause acute dermal irritation or corrosion was assessed by a single topical application of an amount of 0.5 g of the test substance for 4 hours to the intact skin of three White New Zealand rabbits, using a patch of 2.5 cm x 2.5 cm, covered with semiocclusive dressing. After removal of the patch the application area was washed off.

The cutaneous reactions were assessed immediately after removal of the patch and approximately 1, 24, 48 and 72 hours after removal of the patch.

Slight erythema was observed in all animals immediately and 1 hour after removal of the patch.

The cutaneous reactions were reversible in all animals within 24 hours after removal of the patch.

The average score (24 to 72 hours) for irritation was calculated to be 0.0 for erythema and 0.0 for edema.

Considering the described cutaneous reactions as well as the average score for irritation, the test substance does not show a skin irritation potential under the test conditions chosen.

Eye irritation:

There is no eye irritation study for NPPT available but the following data is suitable for a read across:

The potential of the test substance to cause damage to the conjunctiva, iris or cornea was assessed by a single ocular application of 0.1 mL bulk volume (about 31 mg) of the test substance to one eye of three 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 and 72 hours after application and on day 7.

Slight corneal opacity, moderate iritis, moderate conjunctival redness, slight to marked conjunctival chemosis and slight to severe discharge were observed in the animals during the course of the study.

Additional findings like contracted pupil and injected scleral vessels in a circumscribed area or circular were noted in the animals during the observation period.

The ocular reactions were reversible in all animals within 7 days after application.

Mean scores calculated for each animal over 24, 48 and 72 hours were 0.9 for corneal opacity, 0.4 for iris lesions, 2.0 for redness of the conjunctiva and 1.2 for chemosis.

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.

Classification, Labelling, and Packaging Regulation (EC) No. 1272/2008

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. A GLP-compliant OECD 405 study is available for eye irritation. In the skin irritation study, the scores for the test item treated tissue were below the threshold for classification as a skin irritant. In the eye irritation study, the test substance caused slight eye irritation potential. As a result, the substance is considered to be classified as Eye Irritant Category 2 under Regulation (EC) No. 1272/2008, as amended for the tenth time in Regulation (EC) No. 2017/776.