N-[[3,5-dichloro-2-fluoro-4-(1,1,2,3,3,3-hexafluoropropoxy)phenyl]carbamoyl]-2,6-difluorobenzamide

Acute Toxicity: dermal

Administrative data

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

16 August 1999 (study initiation date)

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1999

Report date:

1999

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1200 (Acute Dermal Toxicity)

Deviations:

no

Test guideline 3

Qualifier:

according to guideline

Guideline:

EU Method B.3 (Acute Toxicity (Dermal))

Deviations:

no

Test guideline 4

Qualifier:

according to guideline

Guideline:

other: Japan MAFF Acute Dermal Toxicity Study, 1985

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

1-[3,5-dichloro-2-fluoro-4-(1,1,2,3,3,3-hexafluoropropoxy)phenyl]-3-(2,6-difluorobenzoyl)urea

EC Number:

601-779-5

Cas Number:

121451-02-3

Molecular formula:

C17H7Cl2F9N2O3

IUPAC Name:

1-[3,5-dichloro-2-fluoro-4-(1,1,2,3,3,3-hexafluoropropoxy)phenyl]-3-(2,6-difluorobenzoyl)urea

Test material form:

solid

Details on test material:

- Substance type: white solid

Test animals

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 2.3-2.5 kg
- Diet: 5 ounces of pelleted rodent feed per day.
- Water: Municipal water was provided ad libitum.
- Acclimation period: Animals were acclimated to the laboratory environment for at least two weeks prior to study start.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 ± 3 °C
- Humidity (%):40 - 60 %
- Air changes (per hr): approximately 12-15 times/hour
- Photoperiod (hrs dark / hrs light): 12- hour light/dark photocycle, lights on at 6:00 a.m. and off at 6:00 p.m.

IN-LIFE DATES: From: 1 May 1999 To: 31 August 1999

Administration / exposure

Type of coverage:

occlusive

Vehicle:

other: 0.5 % methylcellulose

Details on dermal exposure:

TEST SITE
- Area of exposure: Trunk of each rabbit.
- Site preparation: Clipped free of fur the day prior to application of the test material.
- % coverage: Approximately 10 % of the surface area of the rabbits.
- Type of wrap if used: The site was covered with a gauze/cotton patch (approximately 10 x 14 cm), held in place by an elastic jacket.

REMOVAL OF TEST SUBSTANCE
- Washing: The skin was wiped thoroughly with a water-moistened, soft disposable towel and dried with a soft disposable towel.
- Time after start of exposure: 24 hours.

VEHICLE
- Amount applied: The test material was moistened with 12.0 mL of 0.5 % methylcellulose.

Duration of exposure:

24 hours

Doses:

5000 mg/kg bw

No. of animals per sex per dose:

Five per sex per dose

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
A detailed clinical observation (DCO) was conducted for all rabbits prior to test material administration for comparison with the observations recorded throughout the study. Animals were observed a minimum of 2 times, one of which was a DCO, on the day of treatment. A DCO was done each day (including weekends and holidays) during the study. Hand-held and open-field observations included a careful physical examination.
For scored DCO’s, only observations other than normal were recorded. Observations were dictionary based, and the dictionary contained most of the common physical and neurologic abnormalities seen in toxicity studies. Since not all potential observations were contained in the dictionary, free-field descriptions also were allowed.
The rabbits were weighed pre-study, the day of treatment (day 1) and on test days 2, 8, and 15.
- Necropsy of survivors performed: Yes
At study termination, all animals were euthanized with Beuthanasia solution. A complete necropsy was conducted on all animals by a veterinary pathologist assisted by a team of trained individuals. The eyes were examined in situ using a moistened glass microscope slide applied to the corneal surface. Following inspection of the externum, including the treatment site and body orifices, the nasal, cranial, oral, thoracic, and abdominal cavities were opened and the visceral organs were examined both in situ and following dissection.

Statistics:

Means and standard deviations were calculated for body weights. The data were evaluated for statistical outliers by a sequential test (Grubbs, 1969), however, outliers were not routinely excluded from statistical analysis.

Results and discussion

Effect levels

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality occured during the study.

Clinical signs:

other: There were no clinical signs of systemic toxicity. All rabbits had reddened and thickened skin at the dermal test site on day 2. In addition, one male had perineal faecal soiling on day 2 only. In all animals, the reddening and thickening of the skin reso

Gross pathology:

There were no treatment-related gross pathologic observations.

Any other information on results incl. tables

Table 1: Individual Body Weights

Dose (mg/kg)	Animal Sex	Animal No.	Day of Test
			-4	1	2	8	15
5000	Male	3921	2368.0	2396.0	2305.6	2593.8	2621.1
		3922	2381.9	2402.7	2344.5	2665.3	2693.7
		3923	2354.8	2386.6	2341.8	2540.9	2542.6
		3924	2441.7	2507.3#	2406.6	2760.5	2737.1
		3925	2354.1	2401.1	2285.8	2621.9	2586.1
		Mean	2380.1	2418.7	2336.9	2636.5	2636.1
		SD	36.3	49.9	46.2	82.7	79.0
	Female	3926	2409.0	2336.1	2415.3	2516.7	2625.0
		3927	2257.0	2255.6	2078.7	2392.8	2449.1
		3928	2406.0	2400.9	2302.4	2575.0	2605.6
		3929	2382.4	2381.7	2270.2	2670.1	2542.9
		3930	2333.1	2334.3	2284.8	2481.0	2508.1
		Mean	2357.5	2341.7	2270.3	2527.1	2546.1
		SD	63.9	56.1	121.4	103.7	71.8

# statistical outliers inculded

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Remarks:

Criteria used for interpretation of results: EU

Conclusions:

Under the conditions of the test, the acute dermal LD50 of the test material for male and female New Zealand White rabbits was greater than 5000 mg/kg.

Executive summary:

The acute dermal toxicity of the test material was determined in a study performed under GLP conditions and in line with the standardised guidelines OECD 402, EPA OPPTS 870.1200, EU Method B.3 and Japan MAFF Acute Dermal Toxicity Study, 1985.

Five male and five female New Zealand White rabbits received a single 24 hour exposure to 5000 mg/kg body weight applied to shaved intact skin. The test material was moistened with 12.0 mL of 0.5 % methylcellulose. Parameters evaluated included body weights, detailed clinical observations, and gross pathologic evaluations.

All rabbits survived the 5000 mg/kg dose level. There were no clinical signs of systemic toxicity. All rabbits had reddened and thickened skin at the dermal test site on day 2. In addition, one male had perineal faecal soiling on day 2 only. In all animals, the reddening and thickening of the skin resolved by day 4. All rabbits lost body weight on days 1 or 2, and then surpassed their pre-study weights by study termination. There were no treatment-related gross pathologic observations.

Under the conditions of the test, the acute dermal LD50 of the test material for male and female New Zealand White rabbits was greater than 5000 mg/kg.