Registration Dossier

Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
14 June 1991 to 16 July 1991
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:
no
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): T-5333
- Lot/batch no.: 629
- Storage condition of test material: Test article was 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., Porage MI.
- Age at study initiation: about 5 weeks old
- Weight at study initiation: 144.2 to 195.5 g
- Housing: Individually except during 7 day acclimation period
- Diet (e.g. ad libitum): ad libitum Certified Rodent Chow #5002 meal (Purina Mills, Inc.)
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 7 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 25
- Humidity (%): 30 to 70
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From 14 June 1991 to 16 July 1991

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
Test article was dosed as received form the sponsor.
Duration of treatment / exposure:
32 days
Frequency of treatment:
once daily
Doses / concentrations
Remarks:
Doses / Concentrations:

Basis:
actual ingested
No. of animals per sex per dose:
20 male, 20 female
Control animals:
yes
Details on study design:
- Dose selection rationale: Low toxicity expected
- Rationale for animal assignment (if not random): Random

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Observed twice daily (a.m. and p.m.)
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Observed twice daily for mortality and moribundity and predose and apporximately 1.5 hours postdose for obvious indications of a toxic effect. At least once weekly, each animal was removed from its cage and examined.
BODY WEIGHT: Yes
- Time schedule for examinations: Recorded prior to randomization, on the first day of treatment, and weekly thereafter.
WATER CONSUMPTION AND COMPOUND INTAKE: No data
OPHTHALMOSCOPIC EXAMINATION: No data
HAEMATOLOGY: Yes
- Time schedule for collection of blood: Evaluated during week 5.
- Anaesthetic used for blood collection: Yes (ketamine)
- Animals fasted: Yes
- How many animals: All animals
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Week 5
- Animals fasted: Yes
- How many animals: All animals
URINALYSIS: No data
NEUROBEHAVIOURAL EXAMINATION: No data
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
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):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Details on results:
BODY WEIGHT AND WEIGHT GAIN: Weights and weight gains in the test groups were not significatly different than the control group
CLINICAL CHEMISTRY: No abnormal findings
NEUROBEHAVIOUR: No abnormal behaviors observed
ORGAN WEIGHTS: No abnormal organ-to-body weight percentages observed
GROSS PATHOLOGY: No effects observed

Effect levels

Key result
Dose descriptor:
NOEL
Effect level:
> 2 000 mg/kg bw (total dose)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
mortality
body weight and weight gain
haematology
clinical biochemistry
organ weights and organ / body weight ratios
gross pathology
histopathology: non-neoplastic
other: There were no test article related clinical observations or changes in body weights or food consumption noted for males or females. Oral administration of the test article had no effect on clinical pathology or anatomical pathology.

Target system / organ toxicity

Key result
Critical effects observed:
no
System:
other: There were no test article related clinical observations or changes in body weights or food consumption noted for males or females. Oral administration of the test article had no effect on clinical pathology or anatomical pathology.

Applicant's summary and conclusion

Conclusions:
Based on the results of this study, the no-observable-effect level for the test article in male and female rats was greater than 2000 mg/kg.
Executive summary:

A 4 week oral toxicity study was conducted on the test article utilizing rats. 20 male and 20 female Crl:CDBR VAF/Plus rats were assigned at random to one control group and three treated groups (five/sex/group). The control group was given 0.9% sodium chloride at 1 mL/kg body weight. The test groups received 200, 1000, and 2000 mg/kg body weight at a volume of 0.104, 0.520, and 1.04 mL/kg respectively. The animals received their respective doses daily (A.M.) for a total of 32 days. Rats were observed twice daily (A.M. and P.M.) for mortality and moribundity and pre-dose and approximately 1.5 hours post-dose for obvious indications of a toxic effect. 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. All animals were examined macroscopically and selected tissues were weighed and preserved. Tissues from all animals in the control and high-dose groups were sectioned, stained, and examined microscopically. There were no test article related clinical observations or changes in body weights or food consumption noted for males or females. Oral administration of the test article had no effect on clinical pathology or anatomical pathology. Based on the results of this study, the no-observable-effect level/no-observable-adverse-effect level for the test article in male and female rats was greater than 2000 mg/kg as described in the study report. In the absence of any adverse findings, it can also be considered that the NOAEL is > 2000 mg/kg.