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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
11 December, 1991 to 10 January 1992
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study conducted under GLP conditions.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1992
Report Date:
1992

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)
Deviations:
not applicable
GLP compliance:
yes
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
other: Liquid
Details on test material:
- Name of test material (as cited in study report: T-5452
- Physical state: Clear liquid
- Storage condition of test material: Test material stored at room temperature

Test animals

Species:
rat
Strain:
other: Crl:CDBR VAF/Plus
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Inc. Portage, Michigan facility.
- Age at study initiation: Approximately 6 weeks old
- Weight at study initiation: Males: 185-225.5 g, Females: 134.6-164.4 g
- Fasting period before study: No Data
- Housing: Housed individually during testing in stainless steel, screen-bottom cages.
- Diet (e.g. ad libitum): Certified Rodent Chow #5002 meal (Purinia Mills, Inc.) ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 16 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-25
- Humidity (%): 30-70
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: 11 December 1991 To: 10 January 1992

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
Single unchanged dose of test article by oral gavage daily.
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
Single dose by oral gavage daily
Frequency of treatment:
Daily for 30 days
Doses / concentrations
Remarks:
Doses / Concentrations:

Basis:
actual ingested
No. of animals per sex per dose:
5
Control animals:
yes, concurrent no treatment
Details on study design:
Control animals received 1 mL/kg body weight of 0.9% sodium chloride.
Dose selection rationale: Doses selected by study sponsor.

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily (a.m. and p.m.)
- Cage side observations checked in table 1 and Appendix B were included.
BODY WEIGHT: Yes
- Time schedule for examinations: At randomization, on the first day of treatment and weekly thereafter.
FOOD CONSUMPTION:
- Food consumption for each animal determined: Weekly
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes
- Time schedule for collection of blood: During Week 5
- Anaesthetic used for blood collection: Yes, ketamine
- Animals fasted: Yes
- How many animals: All animals
- Parameters checked in tables 5-8 were examined.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: During Week 5
- Animals fasted: Yes
- How many animals: All animals
- Parameters checked in tables 5-8 were examined.
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Statistics:
Levene's test was done to test for variance homogeneity. ANOVA analysis was done on the homogenous or transformed data. If ANOVA was significatn, Dunnett's t-test was used for pairwise comparisons between treated and control groups. One-way ANOVA was used to analyze body weights, cumulative body weight gains, food consumption, clinical chemistry and hematology values( except red blood cell morphology), organ weights, organ-to-body weight percentages, and organ-to-brain weight ratios.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY: No treatment related effects observed. Two animals died, One male in the 1000 mg/kg/day group died on Day 8, the cause of death could not be determined. One female in the 2000 mg/kg/day group was sacrificed on Day 9 due to a probable gavage error. All other animals survived to scheduled sacrifice.
BODY WEIGHT AND WEIGHT GAIN: No treatment related effects observed.
FOOD EFFICIENCY: No treatment related effects observed.
HAEMATOLOGY: No treatment related effects observed.
CLINICAL CHEMISTRY: No treatment related effects observed.
ORGAN WEIGHTS: No treatment related effects observed.
GROSS PATHOLOGY: No treatment related effects observed.
HISTOPATHOLOGY: NON-NEOPLASTIC: No treatment related effects observed.

Effect levels

Dose descriptor:
NOAEL
Effect level:
ca. 2 000 mg/kg bw/day (actual dose received)
Sex:
male/female

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The No Observed Adverse Effect Level (NOAEL) is 2000 mg/kg/day.
Executive summary:

This study evaluated the potential short-term toxicity of the test article when administered daily at 200, 1000, and 2000 mg/kg of body weight by oral gavage to male and female Crl:CDBR VAF/Plus rats for 30 days. Animals (5/sex/group) were administered the test material at a dose volume of 0.118, 0.59, and 1.18 mL/kg, respectively. Control animals were administered 0.9% sodium chloride at a dose volume of 1 mL/kg. Rats were observed twice daily (a.m. and p.m.) for mortality and moribundity, and predose and 1.5 hours postdose for indications of toxic effects. Blood samples were collected from all animals before terminal sacrifice for hematology and clinical chemistry analyses. After 4 weeks of treatment, the animals were fasted overnight, anesthetized with sodium pentobarbital, weighed, exsanguinated, and necropsied. At necropsy, all animals were examined macroscopically and selected tissues were weighed and preserved in 10% phosphate buffered formalin. Tissues from all animals in control and high-dose groups were sectioned, stained, and examined microscopically. No significant treatment-related effects were observed. The NOAEL for the test article is 2000 mg/kg/day.