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

Acute Toxicity: inhalation

Administrative data

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

3 May 2000 (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:

2000

Report date:

2000

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1300 (Acute inhalation toxicity)

Deviations:

no

Test guideline 3

Qualifier:

according to guideline

Guideline:

EU Method B.2 (Acute Toxicity (Inhalation))

Deviations:

no

Test guideline 4

Qualifier:

according to guideline

Guideline:

other: Japan MAFF Testing Guidelines

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:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: approximately 9 weeks of age (when exposed to the test material)
- Housing: Animals were housed in groups of 2-3 in stainless steel cages during acclimatisation. Animals were housed individually during exposure and the observation period.
- Diet: Pelleted rodent diet, ad libitum.
- Water: Water from the municipal supply, ad libitum.
- Acclimation period: Rats were acclimatised to test conditions at least 7 days prior to study initiation, and to nose cones for a single 2 hour period on the day preceding exposure.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): Under controlled conditions.
- Humidity (%): Under controlled conditions.
- Photoperiod (hrs dark / hrs light): 12hr light/dark photoperiod.

Administration / exposure

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

air

Details on inhalation exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Modified ADG nose-only chamber, 30 cm diameter x 60 cm height.
- Exposure chamber volume: 42 litres.
- Method of holding animals in test chamber: Animals were held in a chamber so that their nose was located in the exposure port.
- Source and rate of air: Compressed air (ambient temperature) was supplied at an approximate rate of 30 L/min, sufficient to provide 43 air changes per hour.
- System of generating particulates/aerosols: Dust aerosol of the test material was generated using a Jet Mill. A cyclone was placed between the dust generator and the chamber to further reduce the particle size of the aerosol in the chamber.
- Method of particle size determination: The aerodynamic particle size was determined twice during the exposure period through a six-stage cascade impactor by drawing samples, at a set rate, using a Sierra series 110 constant flow air sampler, through a vertical stainless steel tube which projected into the animal breathing zone. The mass median aerodynamic diameter and geometric standard deviation were determined for each sample as well as the average of both samples.
Samples were obtained at 65 and 195 minutes into the exposure time, at a sample rae of 3 L/min for 1 minute.
- Treatment of exhaust air: Air exiting the exposure chamber was passed through an absolute filter before the air was exhausted. The test material was not recycled.
- Temperature, humidity, pressure in air chamber: exposure was performed at room temperature, chamber temperature, humidity and airflow were recorded approximately every 30 minutes during the exposure period.
Mean values:
Chamber temperature: 19.5 ± 0.10 °C
Exposure room temperature: 19.7 ± 0.12 °C
Relative humidity: 40.3 ± 0.5 %
Chamber airflow: 30 L/minute

TEST ATMOSPHERE
- Brief description of analytical method used: The mass concentration of aerosol present in the chamber was determined gravimetrically five times during the exposure period. Samples were taken by drawing air, at a set rate, through a vertical stainless steel tube that projected into the animal breathing zone. Aerosol particles were collected on pre-weight 0.45 mircron TefSep, Teflon laminated 47 mm filters. The time-weighted average (TWA) exposure concentration was calculated from the gravimetric measurements.
Nominal concentrations were calculated based on the amount of test material fed into the generation system and the total chamber airflow.
- Samples taken from breathing zone: Yes.

TEST ATMOSPHERE
- Particle size distribution: Approximately 9 % of the total mass of particles were less than 1 micron in size and approximately 84 % were less than 6 microns in size.
- MMAD (Mass median aerodynamic diameter): The average MMAD of the aerosol particles was 3.86 microns (based on two determinations), with geometric standard deviation of 1.62. MMAD ranged from 1 to 4 µm.

Analytical verification of test atmosphere concentrations:

yes

Remarks:

determined gravimetrically

Duration of exposure:

4 h

Concentrations:

TWA 5.24 mg/L, nominal concentration 11.40 mg/L.

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:
Animals were weighted and examined prior to exposure. Animals were observed at least every 30 minutes during the exposure period and each working day during the post exposure observation period.
Observations included an evaluation of the fur, eyes, mucous membranes and respiration.
Behaviour pattern and nervous system activity were assessed by specific observation for tremors, convulsions, salivation, lacrimation and diarrhoea, lethargy and other signs of altered central nervous system function.
An additional daily observation and routine monitoring on weekends (and holidays) was limited to husbandry procedures required to ensure the availability of feed and water.
All surviving rats were weighed on test days 2, 4, 8, 11 and 15 during the post exposure observation period.
Detailed clinical observations were conducted on all animals once prior to the start of treatment and daily thereafter. This was conducted at approximately the same time each day and included cage-side, hand-held and open-field observations that were recorded categorically or using a explicitly defined scales.
- Necropsy of survivors performed: Yes, all rats were submitted for a complete gross necropsy examination on test day 15.
Necropsy included examination of the eyes with a microscope slide using fluorescent illumination. Tissues were not saved, and no histopathologic examination was performed.

Statistics:

Mean and standard deviations were calculated for descriptive purposes for chamber concentration (mean only), animal room humidity, animal body weights, exposure room and chamber temperature, humidity and airflow. The range of the animal room temperature was reported.

Results and discussion

Effect levels

Key result

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 5.24 mg/L air

Based on:

test mat.

Exp. duration:

4 h

Mortality:

No mortality occured during the study.

Clinical signs:

other: The only clinical effect noted during the exposure was soiled furcoat (faecal soiling). Following exposure (test day 1), treatment related clinical observations included perineal soiling (urine and/or faecal), extensive body soiling (urine and faecal), or

Body weight:

Mean body weight losses of approximately 5 % and 4 % were noted on test day 2 in male and females, respectively. The body weight of the rats exceeded the pre-exposure mean value by test day 8.

Gross pathology:

There were no visible lesions attributable to exposure noted in any rats exposed to the test material at the test day 15-scheduled necropsy.

Any other information on results incl. tables

Table 1: Individual Body Weights

Dose (mg/L)	Animal Sex	Animal No.	Day of Test
			1	2	4	8	11	15
5.24	Male	2243	208.7	195.2	204.2	214.1	219.4	230.6
		2244	207.9	199.0	207.6	219.5	227.2	235.5
		2245	208.5	200.4	207.2	216.4	225.9	240.1
		2246	213.1	200.6	208.7	222.6	232.9	245.4
		2247	217.6	208.5	215.3	226.1	236.9	248.6
		Mean	211.2	200.7	208.6	219.7	228.5	240.0
		SD	4.2	4.8	4.1	4.8	6.7	7.3
	Female	2248	132.8	128.3	131.4	138.8	142.9	148.1
		2249	133.6	128.8	132.5	136.6	140.3	145.4
		2250	134.9	129.4	137.1	141.2	145.3	150.1
		2251	137.8	132.3	135.1	139.9	142.7	148.0
		2252	140.7	125.2	140.6	147.8	152.1	155.5
		Mean	136.0	130.8	135.3	140.9	144.7	149.4
		SD	3.3	2.9	3.7	4.2	4.5	3.8

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 inhalation LC50 of the aerosolized test material in male and female Fischer 344 rats was greater than 5.24 mg/L air.

Executive summary:

The acute inhalation toxicity of the test material was determined in an aerosol inhalation study performed under GLP conditions and in accordance with the standardised guidelines OECD 403, EPA OPPTS 870.1300, EU Method B.3, and Japan MAFF testing guidelines.

Five male and five female Fischer 344 rats were nose-only exposed to a concentration of 5.24 mg/L. The aerosol particle size distribution mass median aerodynamic diameter (MMAD) averaged 3.86 microns with an average geometric standard deviation of 1.62 microns. Approximately 9 % of the mean mass particles were less than 1 micron. Approximately 84 % of the mean mass particles were less than 6 microns.

All animals survived the 4-hour exposure as well as the 2-week post-exposure period. Treatment-related in-life effects observed following exposure included perineal soiling (urine and/or faecal), abdominal soiling (faecal), or extensive body soiling (urine and faecal). All animals appeared normal by test day 3. The mean body weights, for the male and female rats, were decreased by approximately 4 and 5 % on test day 2 respectively, and had exceeded pre-exposure mean values by test day 8. There were no visible lesions attributable to exposure noted in any rats exposed to the test material at the test day 15-scheduled necropsy.

Under the conditions of the test, the 4 hour acute inhalation LC50 of the aerosolised test material in male and female Fischer 344 rats was greater than 5.24 mg/L air.