rac-(1R,4S,4aR,8R,8aS)-9-(dichloromethylidene)-8-hydroxyoctahydro-1,4-methanonaphthalen-5(1H)-one

Skin irritation / corrosion

Administrative data

Endpoint:

skin irritation: in vivo

Remarks:

This study was conducted solely to comply with a non-EU national registration requirement.

Type of information:

experimental study

Adequacy of study:

key study

Study period:

11 Mar 2014 to 16 Mar 2014

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

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)

Version / remarks:

Adopted April 24, 2002

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.2500 (Acute Dermal Irritation)

Version / remarks:

August 1998

Deviations:

no

Test guideline 3

Qualifier:

according to guideline

Guideline:

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

Version / remarks:

30 May 2008

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test material

Test material information

Constituent 1

Reference substance name:

rac-(1R,4S,4aR,8R,8aS)-9-(dichloromethylidene)-8-hydroxyoctahydro-1,4-methanonaphthalen-5(1H)-one

EC Number:

941-628-3

Cas Number:

1263184-87-7

Molecular formula:

C12H14Cl2O2

IUPAC Name:

rac-(1R,4S,4aR,8R,8aS)-9-(dichloromethylidene)-8-hydroxyoctahydro-1,4-methanonaphthalen-5(1H)-one

Test material form:

solid

Test animals

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: Approximately 12 weeks
- Weight at study initiation: 2979 – 3262 g
- Housing: Animals were housed individually in AAALAC approved metal wire rabbit cages. Cages are of an open wire structure and cages are placed together to allow some social interaction with rabbit(s) in adjoining cages.
- Diet: UNI diet for rabbits, ad libitum
- Water: Tap water, ad libitum
- Acclimation period: 26 Feb to 10/12 Mar 2014

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 ± 3
- Humidity (%): 24-48
- Air changes (per hr): 15-20
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES:
11 Mar 2014 to 16 Mar 2014

Test system

Type of coverage:

semiocclusive

Preparation of test site:

clipped

Vehicle:

unchanged (no vehicle)

Remarks:

(moistened with a small amount of water)

Controls:

no

Amount / concentration applied:

TEST MATERIAL
- Amount applied: 0.5 g of the test substance (moistened with small amount of water)

Duration of treatment / exposure:

4 hours

Observation period:

72 hours

Number of animals:

3

Details on study design:

TEST SITE
- Area of exposure: back and flanks
- % coverage: 2.5 x 2.5 cm
- Type of wrap if used: This gauze pad was applied to the intact skin of the clipped area and was kept in contact with the skin by a patch with a surrounding adhesive hypoallergenic plaster. The entire trunk of the animals was then wrapped with plastic wrap held in place with an elastic stocking.

REMOVAL OF TEST SUBSTANCE
- Washing: The dressing was removed and the skin was flushed with lukewarm tap water to clean the application site.
- Time after start of exposure: 4 hours

OBSERVATION TIME POINTS
- Clinical signs, including viability/mortality, were recorded daily from the day of application of the animals to the termination of the test.
- Body weights were recorded on the day of application and the end of the experiment.

SCORING SYSTEM:
- Method of calculation: Draize scoring system. The skin reaction was assessed at approximately 1, 24, 48 and 72 hours after the end of exposure (removal of the dressing, gauze patch and test item). The mean score was calculated across 3 scoring times (24, 48 and 72 hours after patch removal) for each animal for erythema/eschar grades and for oedema grades, separately. The Cumulative Scores for the Skin Irritation Scores were calculated and represent the sum of all numerical scores for each animal at each time point. The resulting Mean Cumulative Skin Irritation Score was calculated for all animals at each time point.
The Primary Irritation Index (P.I.I.) was calculated by totalling the mean cumulative scores at 24, 48 and 72 hours and then dividing by the number of data points. Skin irritation was scored based on the grading system presented in 'Any other information on materials methods incl. tables'.

Results and discussion

In vivo

Results

Results 1

Irritation parameter:

erythema score

Basis:

animal: #1, #2, #3

Time point:

24/48/72 h

Score:

0

Remarks on result:

no indication of irritation

Results 2

Irritation parameter:

edema score

Basis:

animal: #1, #2, #3

Time point:

24/48/72 h

Score:

0

Remarks on result:

no indication of irritation

Results 3

Irritation parameter:

primary dermal irritation index (PDII)

Basis:

other: #1, #2, #3

Time point:

24/48/72 h

Score:

0

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

The primary irritation index was 0.00 (out of a maximum score of 8.0). No corrosive effects were noted on the treated skin of any animal at any of the observation intervals.
No local dermal signs were observed in the treated animals throughout the study.

Other effects:

No clinical signs of systemic toxicity were observed in the animals during the study and no mortality occurred.
The body weights of all rabbits were considered to be within the normal range of variability.

Any other information on results incl. tables

Table 1. Skin Irritation Scores - Mean Values After 24, 48 and 72 Hours

Animal Number	Sex	Erythema	N	Oedema	N	Primary Skin Irritation Index
00840	male	0.00	3	0.00	3	0.00
00870	male	0.00	3	0.00	3
00842	male	0.00	3	0.00	3
Mean score		0.00		0.00
N= number of available data points.

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

The application of the test substance did not result in any signs of skin irritation. According to the Draize classification criteria, the test substance is considered to be “not irritant” to rabbit skin.

Executive summary:

In this GLP compliant, OECD 404 study, the primary skin irritation potential of the test substance was investigated using 3 young adult New Zealand White rabbits. The animals were treated by topical, semi-occlusive application of 0.5 g to their intact shaved flanks. The duration of treatment was 4 hours. The scoring of skin reactions was performed at 1, 24, 48 and 72 hours after removal of the dressing. The primary irritation index (P.I.I.) was calculated by totalling the mean cumulative scores at 24, 48 and 72 hours and then dividing by the number of data points.

The primary irritation index was 0.00. No local dermal signs were observed in the treated animals throughout the study. No clinical signs of systemic toxicity were observed in the animals during the study and no mortality occurred. As no clinical signs were observed up to 72 hours after patch removal, the study was terminated after the 72 hour observation. The body weights of all rabbits were considered to be within the normal range of variability.

The application of the test substance did not result in any signs of skin irritation. According to the Draize classification criteria, the test substance is considered to be “not irritant” to rabbit skin (P.I.I. = 0.00).