Reaction mass of (3R)-3-methyl-5-[(1R,3R)-2,2,3-trimethylcyclopentyl]pentan-2-one and (3S)-3-methyl-5-[(1R,3R)-2,2,3-trimethylcyclopentyl]pentan-2-one

Skin irritation / corrosion

Administrative data

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Between 17 June 2014 and 22 July 2014

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:

2014

Report date:

2014

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

Test guideline 3

Qualifier:

according to guideline

Guideline:

other: Japanese Ministry of Agriculture, Forestry and Fisheries, 2000

Deviations:

no

Test guideline 4

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.2500 (Acute Dermal Irritation)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test material

Test material information

Constituent 1

Reference substance name:

NACET00502

IUPAC Name:

NACET00502

Constituent 2

Reference substance name:

3-Methyl-5-((1R)-2,2,3-trimethylcyclopentyl)pentan-2-one

IUPAC Name:

3-Methyl-5-((1R)-2,2,3-trimethylcyclopentyl)pentan-2-one

Constituent 3

Reference substance name:

119464-63-0 (planar)

IUPAC Name:

119464-63-0 (planar)

Test material form:

other: liquid

Details on test material:

Identification: NACET00502
Common/Commercial name: NACET00502
Chemical name: 3-Methyl-5-((1R)-2,2,3-trimethylcyclopentyl)pentan-2-one
CAS number: 119464-63-0 (planar)
EC number: not allocated
Batch: S-13-11-1
Purity: 98.5%
Physical state / Appearance: clear colorless liquid
Expiry date: 24 December 2015
Storage Conditions: room temperature in the dark

Test animals

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

Two 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 2.47 or 2.78 kg and were twelve to twenty weeks old. After an acclimatization 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 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. 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:

clipped

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

0.5 mL of the test item was applied directly to the skin

Duration of treatment / exposure:

4 hours

Observation period:

14 days

Number of animals:

2

Details on study design:

On the day before the test two rabbits were 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.

One rabbit was initially treated. Three suitable sites were selected on the back of the rabbit. A quantity of 0.5 mL of the test item was applied directly to the skin under a 2.5 cm x 2.5 cm cotton gauze patch. Each patch was secured in position with a strip of surgical adhesive tape. To prevent the animal interfering with the patches, the trunk of the rabbit was wrapped in an elasticated corset for the duration of the exposure period.

One patch was removed at each of three time points: 3 minutes, 1 hour and 4 hours after application. Any residual test item was removed by gentle swabbing with cotton wool soaked in distilled water.

After consideration of the skin reactions produced in the first animal, an additional animal was treated with 0.5 mL of test item. One patch was applied to the back of the rabbit and was allowed to remain in contact with the skin for a period of four hours.

Results and discussion

In vivo

Results

Results 1

Irritation parameter:

other: Erythema/Eschar Formation

Basis:

animal: 74392 Male

Time point:

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

Score:

0

Max. score:

4

Reversibility:

other: No evidence of skin irritation

Results 2

Irritation parameter:

other: Erythema/Eschar Formation

Basis:

animal: 74489 Female

Time point:

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

Score:

2

Max. score:

4

Reversibility:

fully reversible within: 14 days

Remarks on result:

other: Moderate desquamation observed

Results 3

Irritation parameter:

edema score

Basis:

animal: 74392 Male

Time point:

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

Score:

0

Max. score:

4

Reversibility:

other: No evidence of skin irritation

Results 4

Irritation parameter:

edema score

Basis:

animal: 74489 Female

Time point:

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

Score:

2

Max. score:

4

Reversibility:

fully reversible

Remarks:

7 days

Irritant / corrosive response data:

3-Minute Exposure Period
The individual scores for erythema/eschar and edema are given in Table 1.
No evidence of skin irritation was noted during the study.

1-Hour Exposure Period
The individual scores for erythema/eschar and edema are given in Table 1.
No evidence of skin irritation was noted during the study.

4-Hour Exposure Period
The individual scores for erythema/eschar and edema are given in Table 2. The individual mean scores are given in Table 3.
Well-defined erythema and slight edema were noted at one treated skin site immediately and 1 hour after patch removal with well defined erythema and very slight edema noted at the 24, 48 and 72 Hour observations. Moderate desquamation was noted at this treated skin site at the 7 Day observation.
No evidence of skin irritation was noted at the other treated skin site during the study.

Other effects:

Body Weight
Individual body weights and body weight change are given in Table 4.
Both animals showed expected gain in body weight during the study.

Any other information on results incl. tables

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

 

The scores for erythema and edema at the 24 and 72‑Hour readings were totaled for the 2 test rabbits (8 values) and this total was divided by 4 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):

 

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 also interpreted according to Regulation (EC) No 1272/2008, relating to the Classification, Labelling and Packaging of Substances and Mixtures and the Globally Harmonized System of Classification and Labelling of Chemicals.

Table 1     Individual Skin Reactions Following 3-Minute and 1-Hour Exposures

Skin Reaction	Observation Time (following patch removal)	Individual Scores
		Rabbit Number and Sex
		74392Male
		3-Minute Exposure	1-Hour Exposure
Erythema/Eschar Formation	Immediately	0	0
	1 Hour	0	0
	24 Hours	0	0
	48 Hours	0	0
	72 Hours	0	0
Edema Formation	Immediately	0	0
	1 Hour	0	0
	24 Hours	0	0
	48 Hours	0	0
	72 Hours	0	0

Table 2     Individual Skin Reactions Following 4-Hour Exposure

Skin Reaction	Observation Time (following patch removal)	Individual Scores		Total
		Rabbit Number and Sex
		74392Male	74489Female
Erythema/Eschar Formation	Immediately	0	2	(2 )
	1 Hour	0	2	( 2 )
	24 Hours	0	2	2
	48 Hours	0	2	( 2 )
	72 Hours	0	2	2
	7 Days	-	0D	( 0 )
	14 Days	-	0	( 0 )
Edema Formation	Immediately	0	2	( 2 )
	1 Hour	0	2	( 2 )
	24 Hours	0	1	1
	48 Hours	0	1	( 1 )
	72 Hours	0	1	1
	7 Days	-	0	( 0 )
	14 Days	-	0	( 0 )
Sum of 24 and 72‑Hour Readings (S)           :          6
Primary Irritation Index (S/4)            :          6/4 = 1.5
Classification                                     :          MILDIRRITANT

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

D =         Moderate desquamation

- =          Not applicable

Table3     Individual and Mean Scores for Skin Reactions Following 4-Hour Exposure

Skin Reaction	Reading (Hours)	Individual Scores – Rabbit Number and Sex
		74392Male	74489Female
Erythema/Eschar Formation	24	0	2
	48	0	2
	72	0	2
Total		0	6
Mean Score		0.0	2.0
Edema Formation	24	0	1
	48	0	1
	72	0	1
Total		0	3
Mean Score		0.0	1.0

Table 4     Individual Body Weights and Body Weight Change

Rabbit Number and Sex	Individual Body Weight (kg)		Body Weight Change (kg)
74392 Male	Day 0	Day 3	0.06
	2.78	2.84
74489 Female	Day 0	Day 14	0.24
	2.47	2.71

Applicant's summary and conclusion

Interpretation of results:

study cannot be used for classification

Remarks:

Migrated information

Conclusions:

The test item produced a primary irritation index of 1.5 and was classified as a mild irritant to rabbit skin according to the Draize classification scheme. No corrosive effects were noted.

The test item does not meet the criteria for classification according to Regulation (EC) No 1272/2008, relating to the Classification, Labelling and Packaging of Substances and Mixtures and the Globally Harmonized System of Classification and Labelling of Chemicals.

Executive summary:

Introduction

The study was performed to assess the irritancy potential of the test item following single, 3‑Minute, 1 and 4‑Hour, semi‑occluded applications to the intact rabbit skin.

Results

3‑Minute and 1‑Hour semi-occluded applications of the test item to the intact skin of one rabbit produced no evidence of skin irritation.

A single 4‑Hour, semi occluded application of the test item to the intact skin of two rabbits produced well-defined erythema, slight edema and moderate desquamation at one treated skin site. No evidence of skin irritation was noted at the other treated skin site.

Conclusion

The test item produced a primary irritation index of 1.5 and was classified as a mild irritant to rabbit skin according to the Draize classification scheme. No corrosive effects were noted.

The test item does not meet the criteria for classification according to Regulation (EC) No 1272/2008, relating to the Classification, Labelling and Packaging of Substances and Mixtures and the Globally Harmonized System of Classification and Labelling of Chemicals.