7,17,28,38-tetraazatridecacyclo[24.16.2.2²,⁵.1⁸,¹².1²⁹,³³.0³,²².0⁴,¹⁹.0⁶,¹⁷.0²³,⁴³.0²⁷,³⁸.0⁴⁰,⁴⁴.0¹⁶,⁴⁶.0³⁷,⁴⁵]octatetraconta-1(42),2(48),3,5(47),6,8,10,12(46),13,15,19,21,23,25,27,29(45),30,32,34,36,40,43-docosaene-18,39-dione; 7,17,28,38-tetraazatridecacyclo[24.16.2.2²,⁵.1⁸,¹².1²⁹,³³.0³,²².0⁴,¹⁹.0⁶,¹⁷.0²³,⁴³.0²⁸,³⁹.0⁴⁰,⁴⁴.0¹⁶,⁴⁶.0³⁷,⁴⁵]octatetraconta-1(42),2(48),3,5(47),6,8,10,12(46),13,15,19,21,23,25,29,31,33,35,37(45),38,40,43-docosaene-18,27-dione

Skin irritation / corrosion

Administrative data

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Aug. 08, 2005 - Sep. 14, 2005

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

2005

Report date:

2005

Reference 2

Reference Type:

other: Amendment

Title:

Unnamed

Year:

2006

Report date:

2006

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Version / remarks:

adopted April 24, 2002

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)

Test guideline 3

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.2500 (Acute Dermal Irritation)

GLP compliance:

yes (incl. QA statement)

Test material

Test material information

Constituent 1

Test material form:

solid: nanoform, no surface treatment

Details on test material:

- State of aggregation: solid, powder
- Particle size distribution (TEM): 29.1 nm (D50)
- Mass median aerodynamic diameter (MMAD): not specified
- Geometric standard deviation (GSD): not specified
- Shape of particles: plate
- Surface area of particles: 89 m²/g
- Crystal structure: crystalline
- Coating: no
- Surface properties: not applicable
- Density: 1566 kg/m³ at 20°C
- Moisture content: refer to IUCLID chapter 1
- Residual solvent: refer to IUCLID chapter 1
- Activation: not applicable
- Stabilisation: not applicable

Specific details on test material used for the study:

- Physical state: Powder / black
- Storage condition of test material: Room temperature
- Expiration date of the lot/batch: unlimited at room temperature
- Analytical purity: 99.9%

Test animals

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: 8 - 9 months
- Weight at study initiation: 3.02 kg - 4.16 kg
- Housing: Individually in stainless steel wire mesh cages with grating, floor area: 3000 cm2
- Diet: Kliba-Labordiät (Kaninchen & Meerschweinchenhaltung "GLP"), Provimi Kliba SA, Kaiseraugst, Basel, Switzerland (about 130 g/animal per day)
- Water: Tap water ad libitum
- Acclimation period: At least 5 days before the beginning of the study.

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

IN-LIFE DATES: From: Feb. 01, 2005 (Arrival of the animals) To: Aug. 15, 2005 (Day of last observation)

Test system

Type of coverage:

semiocclusive

Preparation of test site:

shaved

Vehicle:

other: minimally moistened with a suitable amount of doubly-distilled water

Controls:

other: untreated skin of the same animals served as control

Amount / concentration applied:

TEST MATERIAL:
- Amount(s) applied (volume or weight with unit): The solid test substance was minimally moistened with a suitable amount of doubly-distilled water to guarantee skin contact immediately before test substance application (corresponding to a dose of 0.5 g of unchanged test substance). Because of the natural moisture of the skin doubly-distilled water was used for moistening, so that the test was carried out under conditions as physiological as possible.

Duration of treatment / exposure:

4 h

Observation period:

7 days

Number of animals:

3 (2 males, 1 female animal)

Details on study design:

TEST SITE
- Area of exposure: flank
- Type of wrap if used: The test substance was covered with a test patch (2.5 x 2.5 cm) Idealbinde, Pfälzische Verbandstoff-Fabrik, Kaiserslautern) and Fixomull stretch (adhesive fleece), Beiersdorf AG

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

SCORING SYSTEM: according to OECD 404

Results and discussion

In vivo

Results

Results 1

Irritation parameter:

erythema score

Basis:

animal #1

Time point:

24/48/72 h

Score:

0.7

Max. score:

4

Reversibility:

fully reversible within: 72 h

Results 2

Irritation parameter:

erythema score

Basis:

animal #2

Time point:

24/48/72 h

Score:

2

Max. score:

4

Reversibility:

fully reversible within: 7 days

Remarks on result:

other: Scaling at the end of the observation period (7 days)

Results 3

Irritation parameter:

erythema score

Basis:

animal #3

Time point:

24/48/72 h

Score:

1

Max. score:

4

Reversibility:

fully reversible within: 72 h

Results 4

Irritation parameter:

edema score

Basis:

mean

Time point:

24/48/72 h

Score:

0

Max. score:

4

Reversibility:

other: no effects

Irritant / corrosive response data:

Slight or moderate erythema was observed in the animals during the course of the study.

The application area was slight black discolored in two animals during the observation period. Scaling was noticed in one animal at study termination, only.

The cutaneous reactions, with the exception of scaling, were reversible in all animals within 7 days after removal of the patch at latest.

The average score (24 to 72 hours) for irritation was calculated to be 1.2 for erythema and 0.0 for edema.

Any other information on results incl. tables

Exposition:	4 h (semiocclusive)
Animal	Reading	Erythema	Edema	Comments
1	0 h	1	0
2	0 h	2	0	Application area slight black discolored
3	0 h	2	0	Application area slight black discolored
1	1 h	2	0
2	1 h	2	0	Application area slight black discolored
3	1 h	2	0	Application area slight black discolored
1	24 h	1	0
2	24 h	2	0	Application area slight black discolored
3	24 h	2	0	Application area slight black discolored
1	48 h	1	0
2	48 h	2	0	Application area slight black discolored
3	48 h	1	0	Application area slight black discolored
1	72 h	0	0	Study discontinued because the animal was free of findings
2	72 h	2	0	Application area slight black discolored
3	72 h	0	0	Study discontinued because the animal was free of findings
2	7 days	0	0	Scaling
mean (animal 1)	24 - 72 h	0.7	0
mean (animal 2)	24 - 72 h	2	0
mean (animal 3)	24 - 72 h	1	0
mean (animal 1-3)	24 - 72 h	1.2	0

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

Considering the described cutaneous reactions as well as the average score for irritation, the test substance shows a slight skin irritation potential below the regulatory threshold under the test conditions chosen.

Executive summary:

The test article's potential to cause acute dermal irritation or corrosion was assessed by a GLP-compliant study according to OECD guideline 404. An amount of 0.5 g of the test substance was applied topically 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, approximately 1, 24, 48 and 72 hours after removal of the patch and on day 7. Slight or moderate erythema was observed in the animals during the course of the study. The application area was slight black discolored in two animals during the observation period. Scaling was noticed in one animal at study termination, only. The cutaneous reactions, with the exception of scaling, were reversible in all animals within 7 days after removal of the patch at latest. The average score (24 to 72 hours) for irritation was calculated to be 1.2 for erythema and 0.0 for edema. Therefore, under the test conditions chosen, the test article is considered to be non irritating according to GHS and EU regulations.