4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl)-N-(2-ethyl-3-oxo-1,2-oxazolidin-4-yl)-2-methylbenzamide

Acute Toxicity: dermal

Administrative data

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

8 Mar 2016 to 24 Mar 2016

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2016

Report date:

2016

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Version / remarks:

February 1987

Test guideline 2

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1200 (Acute Dermal Toxicity)

Version / remarks:

August 1998

Test guideline 3

Qualifier:

according to guideline

Guideline:

other: Commission Regulation (EC) No 440/2008, B.3 (L 142)

Version / remarks:

May 2008

GLP compliance:

yes (incl. QA statement)

Test type:

standard acute method

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl)-N-(2-ethyl-3-oxo-1,2-oxazolidin-4-yl)-2-methylbenzamide

Cas Number:

2061933-85-3

Molecular formula:

C23H19Cl2F4N3O4

IUPAC Name:

4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl)-N-(2-ethyl-3-oxo-1,2-oxazolidin-4-yl)-2-methylbenzamide

Test material form:

solid: particulate/powder

Test animals

Species:

rat

Strain:

Wistar

Remarks:

Crl:(WI) Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Female rats were nulliparous and nonpregnant
- Age at study initiation: Young adult rats
- Weight at study initiation: 212 - 251 g
- Identification: Animals were identified by numbers written on the tail with an indelible marker. The cages were marked with individual identity cards with information about study number, sex, cage number, dose group and individual animal number.
- Housing: Animals were housed individually in Type II polypropylene/polycarbonate cages. Rodents were housed with deep wood sawdust bedding to allow digging and other normal rodent activities.
- Randomization: Selected by hand at time of delivery
- Acclimatization time: 5 or 7 days
- Diet: Autoclavable complete diet for rats and mice – breeding and maintenance, ad libitum
- Water: tap water, from the municipal supply, provided in 500 mL bottles ad libitum.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.0 – 24.4
- Humidity (%): 31 - 61
- Air changes (per hr): 15 - 20
- Photoperiod (hrs dark / hrs light): 12 / 12

IN-LIFE DATES: From: 08 Mar 2017 To: 24 Mar 2017

Administration / exposure

Type of coverage:

semiocclusive

Vehicle:

water

Details on dermal exposure:

The back of the animal was shaven (approximately 10 % area of the total body surface) approximately 24 hours prior to the treatment. Only those animals without injury or irritation on the skin were used in the test.
On test Day 0, the test substance was applied as a single dose of 5000 mg/kg body weight, moistened with water, and distributed as uniformly as possible over the skin and remained on the skin throughout a 24-hour exposure period. Sterile gauze pads were placed on the skin of rats at the site of application. These gauze pads were kept in contact with the skin by a patch with adhesive hypoallergenic plaster. The entire trunk of the animal was then wrapped with semi occlusive plastic wrap for 24 hours. At the end of the exposure period, residual testsubstance was removed, using body temperature water

Duration of exposure:

24 hours

Doses:

5000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

no

Details on study design:

EXPERIMENTAL DESIGN
A single administration was performed by the dermal route and was followed by a 14-day observation period.
One male and one female sentinel rats were dosed initially and the remaining four male and four female rats were dosed 48 hours later when it was clear there were no adverse effects.

CLINICAL OBSERVATIONS
A clinical examination was performed on the day of treatment, at 1 and 5 hours after the application of the test item, and once each day for 14 days thereafter.
Observations included the skin and fur, eyes and mucous membranes, and also respiratory, circulatory, autonomic and central nervous system, and somatomotor activity and behaviour pattern. Particular attention was directed to the observation of tremors, convulsions, salivation, diarrhoea, lethargy, sleep and coma.

SKIN IRRITATION
Adverse skin reactions at the site of application were recorded daily following the removal of the dressing.

MEASUREMENT OF BODY WEIGHT
The body weight of all animals was recorded on Day 0 (day of treatment), and on Days 7 and 14.

POST MORTEM INVESTIGATIONS
All animals were subjected to gross macroscopic examination. All animals were anaesthetised with Euthanimal 40% (Pentobarbital sodium 400 mg/mL) and exsanguinated. After examination of the external appearance, the cranial, thoracic and abdominal cavities were opened and the appearance of the tissues and organs were observed. Any gross macroscopic findings were recorded.

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 occurred during the study.

Clinical signs:

other: There were no adverse clinical signs noted in any animals throughout the study.

Gross pathology:

There was no evidence of the test item-related observations at a dose level of 5000 mg/kg bw at necropsy.

Other findings:

No treatment related skin irritation was observed in any animal throughout the study.

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

The median lethal dose of the test substance after a single dermal administration was found to be greater than 5000 mg/kg bw in male and female CRL:(WI) Wistar rats.

Executive summary:

In a OECD 402 study, in compliance with GLP, five male and five female Crl:WI rats were treated with a single semi-occlusive dermal application of test substance at the limit dose of 5000 mg/kg bw. The application period was 24 hours, followed by a 14-day observation period. Clinical observations along with a check of viability and mortality were performed on all animals at 1 and 5 hours after dosing and daily for 14 days thereafter. Body weight was measured prior to dosing on Day 0 and on Days 7 and 14. All animals were euthanised and subjected to a gross macroscopic examination at the end of the 2 week observation period (Day 14).

No mortality occurred during the study. No adverse clinical signs were observed after treatment with the test substance or during the 14 day observation period and no effects were observed at the site of application. There were no treatment related body weight changes. Body weights for the animals were within the range commonly recorded for this strain and age. No macroscopic changes were observed at necropsy. The median lethal dose (LD50) of test substance after a single dermal administration was greater than 5000 mg/kg bw in male and female Crl:WI rats