8-Chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylic acid

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

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:

2017

Report date:

2017

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

GLP compliance:

yes

Test type:

up-and-down procedure

Limit test:

no

Test material

Test material information

1

Reference substance name:

8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylic acid

Cas Number:

353258-35-2

Molecular formula:

C9H4ClF3N2O2

IUPAC Name:

8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylic acid

Specific details on test material used for the study:

Test substance: IN-QEK31-011
Batch No.: SG0312574
Purity: 98.2%

Test animals

Species:

rat

Strain:

other: Crl:CD(SD)

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories International, Inc., Raleigh, North Carolina, U.S.A.
- Females (if applicable) nulliparous and non-pregnant: Yes
- Age at study initiation: 10-11 weeks
- Weight at study initiation: 211.5–248.6 g
- Fasting period before study: Approximately 17-17.25 hours prior to dosing, with food being returned to the rats approximately 3 hours after dosing.
- Housing: Animals were housed individually in solid-bottom caging with bedding and appropriate species-specific enrichment.
- Diet: ad libitum, except during fasting
- Water: ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature: 20-25ºC (68-77ºF)
- Humidity: 30-70%
- Air changes (per hr): Not reported
- Photoperiod: 12-hour light/dark cycle

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: 0.1% Tween 80 (v/v) in 0.5% methylcellulose

Details on oral exposure:

VEHICLE
- Amount of vehicle (if gavage): 20 mL/kg/bw

MAXIMUM DOSE VOLUME APPLIED: 20 mL/kg/bw

DOSAGE PREPARATION (if unusual): IN-QEK31 was suspended in 0.1% Tween 80 (v/v) in 0.5% methylcellulose

Doses:

550, 1750 or 5000 mg/kg bw

No. of animals per sex per dose:

500 mg/kg bw: 2
1750 mg/kg bw: 3
5000 mg/kg bw: 1

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Daily animal health observations were conducted throughout the study for mortality and signs of illness, injury, or abnormal behavior. Animals were weighed on test days -1, 1, 8, and 15, and were observed for clinical signs at the beginning of fasting, just before dosing (test day 1), once during the first 30 minutes after dosing and at least 2 more times on the day of dosing, and once each day thereafter.
- Necropsy of survivors performed: Yes

Statistics:

A software package (AOT425StatPgm) was used to determine the dose progression and to estimate the LD50.

Results and discussion

Effect levels

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

1 750 mg/kg bw

Based on:

test mat.

Mortality:

At 550 mg/kg, both animals survived to scheduled sacrifice. Mortality occurred in 2/3 animals at 1750 mg/kg on test day 2 or 3, and in the one animal administered 5000 mg/kg on test day 1.

Clinical signs:

lethargy (hypoactivity)

other:

Body weight:

other body weight observations

Remarks:

There were no overall (test day 1-15) body weight losses among any animals surviving to scheduled sacrifice.

Gross pathology:

No gross findings were observed in the animals administered 550 mg/kg or 5000 mg/kg.

Gross findings were present in all 3 animals administered 1750 mg/kg of test substance; 2 found dead prior to scheduled sacrifice and 1 at scheduled sacrifice. The 2 found dead rats had multiple ulcers and erosions in the glandular portion of the stomach. This lesion is presumed to be related to test substance administration. The remainder of the gross lesions observed within this study are nonspecific: one found dead rat also had bright red discoloration of the lungs; one found dead rat had bilateral chromodacryorrhea and multiple dark foci in the thymus; and one scheduled sacrifice rat had minimal diffuse dark discoloration of the lung. No other gross findings were observed.

Applicant's summary and conclusion

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

LD50 (rat): 1750 mg/kg bw

Executive summary:

The study was conducted following OECD guideline 425 and US EPA OPPTS 870.1100. A single dose of IN-QEK31 was administered by oral gavage to fasted female rats at a dose level of 550, 1750 or 5000 mg/kg. The rats were dosed one at a time, at a minimum of 48-hour intervals. All rats were observed for mortality, body weight effects, and clinical signs for 14 days after dosing. The rats were necropsied to detect grossly observable evidence of organ or tissue damage.

At 550 mg/kg, both animals survived to scheduled sacrifice, with no clinical abnormalities or body weight losses. Mortality occurred in 2/3 animals at 1750 mg/kg on test day 2 or 3, and in the one animal administered 5000 mg/kg on test day 1. Clinical abnormalities observed in the early decedents included abnormal redness in ears and paws, loss of righting reflex, abnormal gait, labored breathing, coldness to touch, dehydration, decreased fecal output, ptosis, abnormal posture (high), piloerection, hypoactivity, prostration, decreased muscle tone, and/or moribundity. The surviving animal at 1750 mg/kg exhibited piloerection and hypoactivity, which resolved by test day 2, and did not exhibit overall (test day 1-15) body weight loss.

No gross findings were observed in the animals administered 550 mg/kg or 5000 mg/kg.

Gross findings were present in all 3 animals administered 1750 mg/kg of test substance; 2 found dead prior to scheduled sacrifice and 1 at scheduled sacrifice. The 2 found dead rats had multiple ulcers and erosions in the glandular portion of the stomach. This lesion is presumed to be related to test substance administration. The remainder of the gross lesions observed within this study are nonspecific: one found dead rat also had bright red discoloration of the lungs; one found dead rat had bilateral chromodacryorrhea and multiple dark foci in the thymus; and one scheduled sacrifice rat had minimal diffuse dark discoloration of the lung. No other gross findings were observed.

Under the conditions of this study, the oral LD50 for IN-QEK31 was 1750 mg/kg for female rats.