Registration Dossier

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Administrative data

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
The study was conducted between 04 August 2015 and 18 August 2015
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2015
Report date:
2015

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
Principles of method if other than guideline:
None
GLP compliance:
yes
Test type:
fixed dose procedure
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder
Details on test material:
None
Specific details on test material used for the study:
None

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
Five male and five female Wistar (RccHan™:WIST) strain rats were supplied by Envigo RMS (UK) Limited, Oxon, UK. On receipt the animals were randomly allocated to cages. The females were nulliparous and non pregnant. After an acclimatization period of at least 5 days the animals were selected at random and given a number unique within the study by indelible ink marking on the tail and a number written on a cage card. At the start of the study the animals weighed at least 200 g, and were 8 to 12 weeks of age. The weight variation did not exceed ±20% of the mean weight for each sex.

The animals were housed in suspended solid floor polypropylene cages furnished with woodflakes. The animals were housed individually during the 24 Hour exposure period and in groups of five, by sex, for the remainder of the study. Free access to mains drinking water and food (2014C Teklad Global Rodent diet supplied by Envigo RMS (UK) Limited, Oxon, UK) was allowed throughout the study. The diet, drinking water and bedding were routinely analyzed and were considered not to contain any contaminants that could reasonably be expected to affect the purpose or integrity of the study.

The temperature and relative humidity were set to achieve limits of 19 to 25 °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 12 hours continuous light (06:00 to 18:00) and 12 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.

Justification
Rats are the preferred species of choice as historically used for safety evaluation studies and are specified in the appropriate test guidelines.

Administration / exposure

Type of coverage:
semiocclusive
Vehicle:
water
Details on dermal exposure:
Test Item Formulation and Experimental Preparation
For the purpose of the study the test item was weighed out according to each animal’s individual body weight and moistened with distilled water prior to application. The absorption of the test item was not determined.

Procedure
On the day before treatment the back and flanks of each animal were clipped free of hair.

Using available information on the toxicity of the test item, a group of five male and five female rats was treated with the test item at a dose level of 2000 mg/kg bw.

The appropriate amount of test item, moistened with distilled water, was applied as evenly as possible to an area of shorn skin (approximately 10% of the total body surface area). A piece of surgical gauze was placed over the treatment area and semi occluded with a piece of self adhesive bandage. The animals were caged individually for the 24 Hour exposure period. Shortly after dosing the dressings were examined to ensure that they were securely in place.

After the 24 Hour contact period the bandage was carefully removed and the treated skin and surrounding hair wiped with cotton wool moistened with distilled water to remove any residual test item. The animals were returned to group housing for the remainder of the study period.
Duration of exposure:
24 hours
Doses:
2000 mg/kg body weight
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
The animals were observed for deaths or overt signs of toxicity at 30 minutes, 1, 2 and 4 hours after dosing and subsequently once daily for 14 days.

After removal of the dressings and subsequently once daily for fourteen days, the test sites were examined for evidence of primary irritation and scored. Any other skin reactions, if present were also recorded.

Individual body weights were recorded prior to application of the test item on Day 0 and on Days 7 and 14.

At the end of the study the animals were killed by cervical dislocation. All animals were subjected to gross necropsy. This consisted of an external examination and opening of the abdominal and thoracic cavities. The appearance of any macroscopic abnormalities was recorded. No tissues were retained.
Statistics:
No data

Results and discussion

Preliminary study:
No data
Effect levels
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
There were no deaths.
Clinical signs:
No signs of systemic toxicity were noted during the observation period.
Body weight:
All animals showed expected gains in body weight over the observation period.
Gross pathology:
Patchy pallor of the liver was noted at necropsy of all animals.
Other findings:
Dermal Reactions
Black/dark blue colored staining was commonly noted at the test sites of all animals. The staining prevented accurate evaluation of erythema in all animals on Days 1 to 3. Very slight edema was noted at the test site of one male 3 days after dosing. Crust formation was noted at the test sites of three males 8 to 14 days after dosing. There were no signs of dermal irritation noted at the test sites of two males and all females.

Any other information on results incl. tables

Individual Clinical Observations and Mortality Data

Dose Level mg/kg

Animal Number and Sex

Effects Noted After Dosing
(Hours)

Effects Noted During Period After Dosing
(Days)

½

1

2

4

1

2

3

4

5

6

7

8

9

10

11

12

13

14

2000

1-0

Male

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

1-1

Male

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

1-2

Male

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

1-3

Male

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

1-4

Male

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

2-0

Female

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

2-1

Female

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

2-2

Female

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

2-3

Female

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

2-4

Female

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0=   No signs of systemic toxicity

Individual Dermal Reactions - Males

Dose Level mg/kg

Animal Number and Sex

Observation

Effects Noted After Initiation of Exposure (Days)

1

2

3

4

5

6

7

8

9

10

11

12

13

14

2000

1-0

Male

Erythema

?s

?s

?s

0

0

0

0

0

0

0

0

0

0

0

Edema

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Other

0

0

0

STA

STA

STA

STA

STA

0

0

0

0

0

0

1-1

Male

Erythema

?s

?s

?s

0

0

0

0

0

0

0

0

0

0

0

Edema

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Other

0

0

0

STA

STA

STA

STA

STA

0

0

0

0

0

0

1-2

Male

Erythema

?s

?s

?s

0

0

0

0

0

0

0

0

0

0

0

Edema

0

0

1

0

0

0

0

0

0

0

0

0

0

0

Other

0

0

0

STA

STA

STA

STA

STACf

STACf

STACf

STACf

STACf

STACf

STACf

1-3

Male

Erythema

?s

?s

?s

0

0

0

0

0

0

0

0

0

0

0

Edema

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Other

0

0

0

STA

STA

STA

STA

STACf

STACf

STACf

STACf

STACf

STACf

STACf

1-4

Male

Erythema

?s

?s

?s

0

0

0

0

0

0

0

0

0

0

0

Edema

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Other

0

0

0

STA

STA

STA

STA

STACf

STACf

STACf

STACf

STACf

STACf

STACf

0= No reactions

?s = Black/dark blue colored staining prevented accurate evaluation of erythema

STA = Black/dark blue colored staining

Cf = Crust formation

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
The acute dermal median lethal dose (LD50) of the test item in the Wistar rats was found to be >2000 mg/kg body weight.
Executive summary:

The acute dermal toxicity of FAT 40868 in Wistar rats was evaluated in a study conducted according to OECD Guideline 402 and EU Method B.3. A group of ten rats (five males and five females) was given a single, 24 hour, semioccluded dermal application of the test item to intact skin at a dose level of 2000 mg/kg body weight. Clinical signs and body weight development were monitored during the study. All animals were subjected to gross necropsy. There were no deaths. There were no signs of systemic toxicity. Black/dark blue colored staining, which prevented accurate evaluation of erythema, was noted at all test sites on Days 1 to 3. Very slight edema and/or crust formation was noted at the test sites of three males 8 to 14 days after dosing. There were no other signs of dermal irritation noted. All animals showed expected gains in body weight. Patchy pallor of the liver was noted at necropsy of all animals. Hence, based on the findings of the study, the acute dermal median lethal dose (LD50) of the test item in the Wistar rats was found to be >2000 mg/kg body weight.