5-bromo-1,3-dichloro-2-fluorobenzene

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Remarks:

The study was conducted to meet the national regulatory requirements in a non-EEA country.

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2018

Report date:

2018

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 425 (Acute Oral Toxicity: Up-and-Down Procedure)

Version / remarks:

2008

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

up-and-down procedure

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

5-bromo-1,3-dichloro-2-fluorobenzene

EC Number:

640-454-2

Cas Number:

17318-08-0

Molecular formula:

C6H2 BrCl2F

IUPAC Name:

5-bromo-1,3-dichloro-2-fluorobenzene

Test material form:

liquid

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: SAGE® Labs
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: 8-12 weeks
- Weight at study initiation: 164-210 grams
- Fasting period before study: overnight
- Housing: Animals were group housed, except on the day of administration, at which time they were single housed and until the animals were deemed acceptable, based on observations, to return to group housing
- Diet (e.g. ad libitum): Envigo Teklad Global 16% Protein Rodent Diet #2016 ad libitum (except for pre-dose fast)
- Water (e.g. ad libitum): Filtered tap water ad libitum
- Acclimation period: 6-25 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-23
- Humidity (%): 51-77
- Air changes (per hr): 12 or 13
- Photoperiod (hrs dark / hrs light): 12-hour light/dark cycle

IN-LIFE DATES: Start: June 5, 2018; End: July 19, 2018

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

In an acute oral toxicity study, a group of fasted,
8-12 weeks old, female, Sprague-Dawley derived, albino rats were given a single oral dose of CA5528. Prior to dosing, the rats were fasted overnight. During the fasting period, the rats were examined for health and weighed. Individual doses were calculated based on the initial body weights, taking into account the density of the test substance.

Doses:

5000 mg/kg or 2000 mg/kg

No. of animals per sex per dose:

Four at 5000 mg/kg; five at 2000 mg/kg

Control animals:

no

Details on study design:

The animals were observed for mortality, signs of gross toxicity, and behavioural changes within the first several hours post-dosing and at least once daily thereafter for up to 14 days after dosing or until death occurred. Observations included gross evaluation of skin and fur, eyes and mucous membranes, respiratory, circulatory, autonomic and central nervous systems, somatomotor activity and behaviour pattern. Particular attention was directed to observation of tremors, convulsions, salivation, diarrhea and coma.
Individual body weights of the animals were recorded prior to test substance administration (initial day 0) and again on days 7 and 14 (termination) following dosing or after death.

One rat was euthanized for humane reasons due to test substance exposure. Surviving rats were euthanized on Day 14. All animals were euthanized via CO2 inhalation. Gross necropsies were performed on all deceased and euthanized animals. Tissues and organs of the thoracic and abdominal cavities were examined.

Statistics:

Statistical analysis was limited to the calculation of the mean density value for dosing.

Results and discussion

Effect levels

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 - < 5 000 mg/kg bw

Based on:

test mat.

Mortality:

Three of four animals receiving 5000 mg/kg died, whereas there was no mortality at 2000 mg/kg.

Clinical signs:

other: 5000 mg/kg dose level (4 animals): Two females died within six days of test substance administration. One animal was euthanized for humane reasons on Day 3. Prior to death, all animals were hypoactive and exhibited irregular respiration, nasal discharge

Gross pathology:

5000 mg/kg dose level (4 animals): Gross necropsy of the deceased animals revealed distention of the intestines and/or stomach. No gross abnormalities were noted for the animal euthanized for humane reasons on Day 3. No gross abnormalities were noted for the surviving animal when necropsied at the conclusion of the 14-day observation period.
2000 mg/kg dose level (5 animals): No gross abnormalities were noted for any of the animals when necropsied at the conclusion of the 14-day observation period.

Applicant's summary and conclusion

Interpretation of results:

Category 5 based on GHS criteria

Conclusions:

Under the conditions of this study, the acute oral median lethal dose (LD50) of CA5528 is between 2000 mg/kg and 5000 mg/kg of body weight in female rats.

Executive summary:

The acute oral toxicity test was conducted with rats to determine the potential for CA5528 - (Composition: CA5528, 99.8% w/w) to produce toxicity from a single dose via the oral route.

An initial limit dose of 5000 mg/kg of body weight was administered to one healthy female rat by oral gavage.  Due to the absence of mortality in this animal, two additional females received the same dose level, simultaneously.  Since both animals died, one additional animal was tested. Due to the mortality in this animal, the study proceeded to a limit test at 2000 mg/kg of body weight at the request of the Sponsor.  An initial limit dose of 2000 mg/kg was administered to one healthy rat by oral gavage.  Due to the absence of mortality in this animal, four additional females received the same dose level, sequentially.  Since these animals survived, no additional animals were tested.  Females were selected for the test because they are frequently more sensitive to the toxicity of test compounds than males.

The animals were examined daily during the acclimatization period and mortality, viability and clinical signs were recorded. All animals were examined for clinical signs at approximately 30-60 minutes, 1 and approximately 3 hours after treatment on day 1 and once daily during test days 2 to 14 or until death.  Body weights were recorded on day 1 (prior to test substance administration) and on days 7 and 14 or after death.  All animals were examined macroscopically.

Of the 4 animals administered a limit dose of 5000 mg/kg, two females died within six days of test substance administration.  One animal was euthanized for humane reasons on Day 3.  Prior to death, all animals were hypoactive and exhibited irregular respiration, nasal discharge, reduced fecal volume, ocular discharge, piloerection, soft feces, prone posture and/or was moribund. One animal survived the limit dose of 5000 mg/kg.  Following administration, the surviving animal was hypoactive and exhibited irregular respiration, abnormal gait, facial staining, ocular discharge, hunched posture, abdominal distention and ano-genital staining.  However, the animal recovered by Day 6 and appeared active and for the remainder of the 14-day observation period, gaining body weight over the course of the study.  Gross necropsy of the deceased animals revealed distention of the intestines and/or stomach.

At 2000 mg/kg dose level (5 animals), all animals survived exposure to the test substance and gained body weight.  Following administration, two animals were hypoactive and four animals exhibited irregular respiration, facial staining, reduced fecal volume, oral discharge ano-genital staining and/or were cold to the touch.  However, these animals recovered by Day 6 and appeared active and healthy for the remainder of the study. One animal did not exhibit any signs of toxicity.

The body weight of the surviving animals was within the range commonly recorded for this strain and age.

No macroscopic findings were recorded for the survivors at necropsy.