lithium 3-((3,4-dicyanophenyl)sulfonyl)propane-1-sulfonate)

Skin irritation / corrosion

Administrative data

Endpoint:

skin irritation: in vivo

Remarks:

Study carried out before the entry into force of amendments to annex VII

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Between 22 May 2012 and 10 June 2012

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study conducted in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not affect the quality of the relevant results.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2012

Report date:

2012

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test material

Test material information

Constituent 1

Reference substance name:

lithium 3-((3,4-dicyanophenyl)sulfonyl)propane-1-sulfonate)

EC Number:

700-777-2

Cas Number:

667889-11-4

Molecular formula:

C11H9N2O5S2Li

IUPAC Name:

lithium 3-((3,4-dicyanophenyl)sulfonyl)propane-1-sulfonate)

Test material form:

solid: particulate/powder

Remarks:

migrated information: powder

Details on test material:

Sponsor's identification: S193308
Description : white powder
Batch number : 422 (Bag 3)
Purity : 98.9%
Date received : 02 May 2012
Expiry date : not supplied
Storage conditions: room temperature in the dark
The integrity of supplied data relating to the identity, purity and stability of the test item is the responsibility of the Sponsor.

Test animals

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

Three New Zealand White (Hsdlf:NZW) strain rabbits were supplied by Harlan Laboratories UK Ltd., Leicestershire, UK. At the start of the study the animals weighed 2.33 to 2.77 kg and were twelve to twenty weeks old. After an acclimatisation period of at least five days each animal was given a number unique within the study which was written with a black indelible marker-pen on the inner surface of the ear and on the cage label.

The animals were individually housed in suspended cages. Free access to mains drinking water and food (2930C Teklad Global Certified Rabbit diet supplied by Harlan Laboratories UK Ltd., Oxon, UK) was allowed throughout the study. The diet and drinking water were considered not to contain any contaminant of a level that might have affected the purpose or integrity of the study.

The temperature and relative humidity were set to achieve limits of 17 to 23°C and 30 to 70% respectively. Any occasional deviations from these targets were considered not to have affected the purpose or integrity of the study. The rate of air exchange was at least fifteen changes per hour and the lighting was controlled by a time switch to give twelve hours continuous light (06:00 to 18:00) and twelve hours darkness.

The animals were provided with environmental enrichment items which were considered not to contain any contaminant of a level that might have affected the purpose or integrity of the study.

Test system

Type of coverage:

semiocclusive

Preparation of test site:

other: clipped

Vehicle:

other: test material was moistened with 0.5 ml of distilled water.

Controls:

no

Amount / concentration applied:

0.5 g of the test item, moistened sufficiently with 0.5 ml of distilled water.

Duration of treatment / exposure:

4 hours

Observation period:

7 days

Number of animals:

3

Details on study design:

On the day before the test each of a group of three rabbits was clipped free of fur from the dorsal/flank area using veterinary clippers. Only animals with a healthy intact epidermis by gross observation were selected for the study.

On the day of the test a suitable test site was selected on the back of each rabbit. At each test site a quantity of 0.5 g of the test item, moistened sufficiently with 0.5 ml of distilled water, was introduced under a 2.5 cm x 2.5 cm cotton gauze patch. The patch was secured in position with a strip of surgical adhesive tape. To prevent the animals interfering with the patches, the trunk of each rabbit was wrapped in an elasticated corset and the animals were returned to their cages for the duration of the exposure period.
Four hours after application the corset and patches were removed from each animal and any residual test item removed by gentle swabbing with cotton wool soaked in distilled water.

Immediately following removal of the patches and approximately 1, 24, 48 and 72 hours later, the test sites were examined for evidence of primary irritation and scored according to the following scale:

EVALUATION OF SKIN REACTIONS
Erythema and Eschar Formation Value
No erythema 0
Very slight erythema (barely perceptible) 1
Well-defined erythema 2
Moderate to severe erythema 3
Severe erythema (beef redness) to eschar formation preventing grading of erythema 4
Oedema Formation Value
No oedema 0
Very slight oedema (barely perceptible) 1
Slight oedema (edges of area well-defined by definite raising) 2
Moderate oedema (raised approximately 1 millimetre) 3
Severe oedema (raised more than 1 millimetre and extending beyond the area of exposure) 4

Any other skin reactions and clinical signs of toxicity, if present, were also recorded. An additional observation was made on Day 7 to assess the reversibility of skin reactions. Individual bodyweights were recorded on Day 0 (the day of dosing) and at the end of the observation period.

Results and discussion

In vivo

Results

Results 1

Irritation parameter:

other: Erythema/Eschar Formation

Basis:

animal: 72047 male

Time point:

other: Highest score at 1, 24, 48 and 72 hours and 7 days

Score:

2

Max. score:

4

Reversibility:

fully reversible within: 7 days

Results 2

Irritation parameter:

other: Erythema/Eschar Formation

Basis:

animal: 72048 Male

Time point:

other: Highest score at 1, 24, 48 and 72 hours and 7 days

Score:

1

Max. score:

4

Reversibility:

fully reversible within: 7 days

Results 3

Irritation parameter:

other: Erythema/Eschar Formation

Basis:

animal: 72105 male

Time point:

other: Highest score at 1, 24, 48 and 72 hours and 7 days

Score:

1

Max. score:

4

Reversibility:

fully reversible within: 72 hours

Results 4

Irritation parameter:

other: Oedema Formation

Basis:

animal: 72047 male

Time point:

other: Highest score at 1, 24, 48 and 72 hours and 7 days

Score:

1

Max. score:

4

Reversibility:

fully reversible within: 7 days

Results 5

Irritation parameter:

other: Oedema Formation

Basis:

animal: 72048 male

Time point:

other: Highest score at 1, 24, 48 and 72 hours and 7 days

Score:

1

Max. score:

4

Reversibility:

fully reversible within: 7 days

Results 6

Irritation parameter:

other: Oedema Formation

Basis:

animal: 72105 male

Time point:

other: Highest score at 1, 24, 48 and 72 hours and 7 days

Score:

0

Max. score:

4

Reversibility:

other: No evidence of skin irritation

Irritant / corrosive response data:

The individual scores for erythema/eschar and oedema are given in Table 1.

Very slight erythema and very slight oedema were noted at two treated skin sites immediately and one hour after patch removal. Well-defined erythema and very slight oedema were noted at one treated skin site with very slight erythema, with or without very slight oedema, noted at two treated skin sites at the 24 and 48 Hour observations. Very slight erythema and very slight oedema were noted at two treated skin sites at the 72 Hour observation.
One treated skin site appeared normal at the 72 Hour observation and two treated skin sites appeared normal at the 7 Day observation.

Other effects:

Bodyweight

Individual bodyweights and bodyweight changes are given in Table 2.
All animals showed expected gain in bodyweight during the study.

Any other information on results incl. tables

Interpretation of Results

Calculation of Primary Irritation Index and Grading of Irritancy Potential Using the Draize Scheme

The scores for erythema and oedema at the 24 and 72‑Hour readings were totalled for the three test rabbits (12 values) and this total was divided by six to give the primary irritation index of the test item. The test item was classified according to the following scheme devised by Draize J H (1959) "Dermal Toxicity" In: Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics. Association of Food and Drug Officials of the,,, p.46‑59:

Primary Irritation Index	Classification of Irritancy
0	Non-irritant
> 0 to 2	Mild irritant
> 2 to 5	Moderate irritant
> 5 to 8	Severe irritant

If irreversible alteration of the dermal tissue is noted in any rabbit, as judged by the Study Director, which include ulceration and clear necrosis or signs of scar tissue, the test item is classified as corrosive to rabbit skin. Classification according to Draize may, therefore, not be applicable.

The results were evaluated according to EU labelling regulations Commission Directive 2001/59/EC for classification and labelling of dangerous substances andRegulation (EC) No 1272/2008, relating to the Classification, Packaging and Labelling of Dangerous Substances.

Table 1              Individual Skin Reactions

Skin Reaction	Observation Time (following patch removal)	Individual Scores – Rabbit Number and Sex			Total
		72047Male	72048Male	72105Male
Erythema/Eschar Formation	Immediately	1	1	0	(2 )
	1 Hour	1	1	0	( 2 )
	24 Hours	2	1	1	4
	48 Hours	2	1	1	( 4 )
	72 Hours	1	1	0	2
	7 Days	0	0	-	( 0 )
Oedema Formation	Immediately	1	1	0	( 2 )
	1 Hour	1	1	0	( 2 )
	24 Hours	1	1	0	2
	48 Hours	1	1	0	( 2 )
	72 Hours	1	1	0	2
	7 Days	0	0	-	( 0 )
Sum of 24 and 72‑Hour(S)    :          10
Primary Irritation Index (S/6)                  :          10/6 = 1.7
Classification                                       :          MILD IRRITANT

(   ) = Total values not used for calculation of primary irritation index

- =       Not applicable

Table 2              Individual Bodyweights and Bodyweight Changes

Rabbit Number and Sex	Individual Bodyweight (kg)		Bodyweight Change (kg)
72047Male	Day 0	Day 7	0.22
	2.65	2.87
72048Male	Day 0	Day 7	0.15
	2.33	2.48
72105Male	Day 0	Day 3	0.12
	2.77	2.89

Applicant's summary and conclusion

Interpretation of results:

other: mild irritant

Remarks:

Criteria used for interpretation of results: other: Draize classification scheme.

Conclusions:

The test item produced a primary irritation index of 1.7 and was classified as a mild irritant to rabbit skin according to the Draize classification scheme. No corrosive effects were noted.

The test item did not meet the criteria for classification as irritant or corrosive according to EU labelling regulations Commission Directive 2001/59/EC or the criteria for classification according to Regulation (EC) No 1272/2008, relating to the Classification, Packaging and Labelling of Dangerous Substances.

Executive summary:

Introduction. The study was performed to assess the irritancy potential of the test item to the skin of the New Zealand White rabbit. The method was designed to be compatible with the following:

OECD Guidelines for the Testing of Chemicals No. 404 "Acute Dermal Irritaion/Corrosion" (adopted 24 April 2002)

Method B4 Acute Toxicity (Skin Irritation) of Commsision Regulation (EC) No. 440/2008

Results. A single 4‑Hour, semi-occluded application of the test item to the intact skin of three rabbits produced very slight to well-defined erythema and very slight oedema. One treated skin site appeared normal at the 72‑Hour observation and two treated skin sites appeared normal at the 7‑Day observation.

Conclusion. The test item produced a primary irritation index of 1.7 and was classified as amild irritant to rabbit skin according to the Draize classification scheme. No corrosive effects were noted. The test item did not meet the criteria for classification as irritant or corrosive according to EU labelling regulations Commission Directive 2001/59/EC or thecriteria for classification according to Regulation (EC) No 1272/2008, relating to the Classification, Packaging and Labelling of Dangerous Substances.