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Toxicological information

Acute Toxicity: oral

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Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
2000
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
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
yes
Test type:
fixed dose procedure
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: Lot Number 2

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Room temperature, protected from light

FORM AS APPLIED IN THE TEST (if different from that of starting material): The test material was dissolved in 1% carboxymethylcellulose (CMC) in deionized water.

Test animals

Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Inc.
- Females (if applicable) nulliparous and non-pregnant: Yes
- Age at study initiation: Six to eight weeks
- Weight at study initiation: Males 271.6 +/- 8.7g, females 183.6 +/- 8.7g
- Fasting period before study: Feed held over night prior to dosing
- Housing: The animals will be individually housed in stainless steel cages. The cages conform to standards set forth in the Guide for the Care and Use of Laboratory Animals, National Academy Press, Washington, D.C., 1996.
- Diet (e.g. ad libitum): Tekiad Certified Rodent Diet #8728 will be provided ad libitum. This diet is routinely analyzed by the manufacturer for nutritional components and environmental contaminants. Results of the manufacturer's analyses are on file at Primedica Redfleid.
- Water (e.g. ad libitum): Filtered tap water will be provided ad libitum. Samples of the water are analyzed for total dissolved solids, hardness, specified microbiological
content, and for environmental contaminants. Results of these analyses are on file at Primedica Redfield.
- Acclimation period: Animals will be acclimated for a minimum of seven days prior to the study start.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18-26C
- Humidity (%): 30-70%
- Air changes (per hr): 10 or greater per hour
- Photoperiod (hrs dark / hrs light): 12:12 hour light:dark cycle

IN-LIFE DATES: From: 25 May 2000 To: 8 June 2000

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 200 mg/mL
- Amount of vehicle (if gavage): 10 mL/kg
- Lot/batch no. (if required): 69H0028

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg
- Concentration in vehicle: 200 mg/mL
- Amount of vehicle (if gavage): 10 mL/kg
- Lot/batch no. (if required): 69H008

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg

DOSAGE PREPARATION (if unusual): The vehicle was prepared to a concentration of 1% by mixing 10 grams of powdered medium viscosity carboxymethylcellulose with deionized water using a Waring blender. Additional deionized water was added to yield 1000 mL of prepared vehicle. The vehicle was stored refrigerated when not in use. The test material was dissolved in the prepared vehicle to the appropriate concentration and stirred on a magnetic stir plate.

Doses:
2000 mg/kg
No. of animals per sex per dose:
5/sex/dose
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Pretest and on study days 1, 8, and 15
- Necropsy of survivors performed: Yes
- Other examinations performed: clinical signs, body weight

Results and discussion

Effect levels
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
Observations for mortality and moribundity were recorded twice daily (a.m. and p.m.) with no incidence of either occurring throughout the study.
Clinical signs:
Clinical observationswere recorded predose and approximately hourly for four hours postdose on the day of dosing then daily thereafter for at least 14 days. Clinical observations included male localized alopecia, urine-stained abdominal fur, and one female had liquid feces at three and four hours postdose. The listed clinical observations did not appear to be related to the test material given that the three observations were unrelated and each occurred in different animals.
Body weight:
Bodyweights were recorded pretest and on Study Days 1, 8, and 15. Between Study Days 1 and 15, mean body weight increased in males (114.0 + 15.9g) and females (49.4 ± 17.4g). During the study, there was no record of body weight loss for either males or females suggesting no adverse effect of a single dose of 2000 mg/kg T-7485 on body weights or bodyweight changes.
Gross pathology:
On Study Day 15, all animals (non-fasted) were humanely euthanized via carbon dioxide asphyxiation followed by exsanguination and submitted for a complete necropsy examination. Necropsy examination failed to reveal any adverse findings with the exception of a single male and a single female with dilatation of the right kidney. Dilatation of the kidney is usually induced by hydronephritis of the kidney and this condition is not uncommon in rats. Therefore, these findings are not considered related to the test material.

Any other information on results incl. tables

Based on the results of the study, the rat oral LD50 of T-7485 is >2000 mg/kg.

 

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
Based on the results of the study, the rat oral LD50 of T-7485 is >2000 mg/kg.
Executive summary:

The acute oral lethality of T-7485 was determined in rats. Crl:CD®(SD) IGS BR stock albino rats (5/sex/dose) received 2000 mg/kg T-7485 dissolved in carboxymethylcellulose via oral gavage. Observations for mortality and morbundity (twice daily), body weights (pretest and day 1, 8, and 15), clinical signs (predose and approximately hourly for 4 hours postdose on day 1 and daily thereafter for at least 14 days), and macroscopic examination (at necropsy). At 2000 mg/kg all animals survived. Clinical observations included male localized alopecia, urine-stained abdominal fur, and one female had liquid feces at three and four hours post dose. These clinical observations did not appear to be related to the test material exposure. Mean body weights increased in males (114.1 g) and females (49.4 g) between study day 1 and day 15, however, no record of body weight loss occurred during the study in either sex suggesting no adverse effect of a single 2000 mg/kg T-7485 dose. On study day 15 all animals (non-fasted) were euthanized and necropsied. Necropsy failed to reveal any adverse findings with the exception of dilation of the right kidney in one male and one female, however, this effect is usually induced by hydronephritis of the kidney and is not uncommon in rats; these findings were not considered related to the test material. Based on the results of the study, the rat oral LD50 of T-7485 is >2000 mg/kg.