(2S)-1,1-bis(4-fluorophenyl)propan-2-yl L-alaninate hydrochloride

Acute Toxicity: inhalation

Administrative data

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2021

Report date:

2021

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 436 (Acute Inhalation Toxicity: Acute Toxic Class Method)

Deviations:

no

GLP compliance:

yes

Test type:

acute toxic class method

Test material

Test material information

Constituent 1

Reference substance name:

(2S)-1,1-bis(4-fluorophenyl)propan-2-yl L-alaninate hydrochloride

Cas Number:

2171323-89-8

Molecular formula:

C18H20CIF2NO2

IUPAC Name:

(2S)-1,1-bis(4-fluorophenyl)propan-2-yl L-alaninate hydrochloride

Specific details on test material used for the study:

Substance name: X12485647
Lot #: SS17000602-2 (TSN402954)
Purity: 98%

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Administration / exposure

Route of administration:

inhalation: dust

Type of inhalation exposure:

nose only

Vehicle:

air

Mass median aerodynamic diameter (MMAD):

2.74 µm

Geometric standard deviation (GSD):

1.78

Analytical verification of test atmosphere concentrations:

no

Duration of exposure:

4 h

Concentrations:

0.52 and 0.051 mg/L

No. of animals per sex per dose:

3

Control animals:

no

Results and discussion

Effect levels

Key result

Sex:

male/female

Dose descriptor:

LC50 cut-off

Effect level:

0.125 mg/L air

Based on:

other: TWA

Exp. duration:

4 h

Mortality:

Group I: All rats exposed to 0.52 mg/L air (TWA) found dead.
Group II: No mortality was observed in male or female rats exposed for 4 hours to an aerosol concentration of 0.051 mg/L air (TWA).

Clinical signs:

other: abdominal breathing were observed in all animals during exposure and lethargy was observed in rats which survived post 4-hour exposure period, exposed to a dust aerosol concentration of 0.52 mg/L air (TWA).

Body weight:

Group II: A decrease in the body weight was observed on day 1, which recovered by day 3. Body weight then continued to increase until the end of the observation period, when compared with day 0 body weight in male rat. A decrease in the body weight was observed on day 1 and 3, which recovered by day 7. Body weight then continued to increase until the end of the observation period, when compared with day 0 body weight in all female rats.

Gross pathology:

An external examination of rats, which were found dead or terminally sacrificed did not reveal any abnormality.
The visceral examination of the rats, which were found dead, revealed reddish discolouration in the lungs (rat N˚ 3, 4 and 6) whereas the other rats which were found dead or terminally sacrificed, did not reveal any abnormality.
The lesions observed in rats which had died were considered to be related to the treatment with the test item.

Applicant's summary and conclusion

Interpretation of results:

Category 2 based on GHS criteria

Conclusions:

Inhalation LC50 cut off (Rat): 0.125 mg/L

Executive summary:

The acute inhalation toxicity of the test substance was investigated in the Wistar rats (RccHan:WIST) using the acute toxic class method. Two sets of 3 male and 3 female rats each, approximately 9-10 weeks old and weighing 183.3-245.8 g on the day of exposure, were exposed to dust aerosol of the test substance using a nose-only inhalation exposure system. Rats were exposed for 4 hours, followed by a 14-day post-exposure observation period, during which body weight and clinical observations were recorded. Survivors were sacrificed and a necropsy was performed in all rats.

Initially, one group (group I) was exposed with a time-weighted average concentration of 0.52 mg/L air. The mass median aerodynamic diameter (MMAD) of the test substance aerosol was determined to be 2.74 µm with a geometric standard deviation (GSD) of 1.78. All rats were found dead by day 1 post exposure. Clinical signs of abdominal breathing were observed in all animals during exposure and lethargy was also observed in rats which survived post end of the 4 hour exposure period. Macroscopic examination of rats which died revealed reddish discolouration of the lungs in 3/6 rats while other found dead rats did not reveal any abnormality.

As more than 2 mortalities were observed, a second group of rats (group II) was exposed to a time-weighted average concentration of 0.051 mg/L air. The mass median aerodynamic diameter (MMAD) of the test substance aerosol was determined to be 2.95 µm with a geometric standard deviation (GSD) of 1.68. No mortality or clinical signs were observed in any (male or female) rats, exposed to a dust aerosol concentration of 0.051 mg/L air. A decrease in the body weight was observed on day 1, which recovered by day 3. Body weight then continued to increase until the end of the observation period, when compared with day 0 body weight in male rats. A decrease in the body weight was observed on day 1 and 3, which recovered by day 7. Body weight then continued to increase until the end of the observation period, when compared with day 0 body weight in female rats. No internal or external gross abnormality was recorded at the post-mortem examination.

In conclusion, based on these results generated under the experimental conditions of this study, the 4-hour acute inhalation median lethal concentration of the test substance, in Wistar rats (male and female combined), was greater than 0.05 to 0.5 mg/L air and the LC₅₀ cut-off value was 0.125 mg/L air.

Based on results of this study, the GHS classification of the test substance for acute inhalation toxicity is as mentioned below: Globally Harmonized System of Classification and Labelling of Chemicals (GHS 2019): Category 2