Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1991-09-18 to 1992-10-07
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Well documented GLP-compliant study performed in methods comparable to OECD Guideline 401. No deviations were recorded.

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 401 (Acute Oral Toxicity)
Deviations:
yes
Remarks:
minor deviation: Animals were only acclimatized for one day.
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder
Details on test material:
- Name of test material (as cited in study report): T001624
- Physical state: solid
- Appearance: white powder
- CAS: 132961-05-8
- Molecular formula: C23H28F2N4O2
- Molecular weight: 430.5 g/mol
Specific details on test material used for the study:
Name of test material: T 1624
- Analytical purity: 99.8% (base titration), 101.6% (acid titration)
- Impurities: 0.22% T 1486, 0.08% unknown, 0.05% R 64766, 0.18% impurity 1, 0.06% impurity 2, 0.07% impurity 5 (0.7% total impurities)
- Lot/batch No.: RT001624 BEA011
- Other:
- Reference number of fabrication: VPIV-545191l.

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Janssen Research Foundation Department of Pharmacology permanent non-inbred laboratory colony
- Age at study initiation: adult
- Weight at study initiation: 234 - 267 g for males, 238 - 262 g for females
- Fasting period before study: starved overnight, but free access to fresh tap water; until four hours after the start of the experiment
- Housing: individually housed in air-conditioned laboratory room
- Diet: no data
- Water: ad libitum
- Acclimation period: The day before the experiment, the animals were transferred to the laboratory room.


ENVIRONMENTAL CONDITIONS
- Temperature: 19.5 to 22 °C
- Humidity: 58 to 62 %
- Air changes: no data
- Photoperiod: 12 hours light / 12 hours dark


IN-LIFE DATES: From: no data To: no data

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: 1% polysorbate 80 in distilled water
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 4.0, 8.0 and 16.0 mg/mL
- Amount of vehicle: 10 mL/kg
- Justification for choice of vehicle: no data
- Lot/batch no.: no data
- Purity: no data

MAXIMUM DOSE VOLUME APPLIED:
10 mL/kg

DOSAGE PREPARATION (if unusual):
Aqueous suspensions of T 1624 were prepared with an ultrasonic sonifier under addition of 1% polysorbate 80, and kept stable with a magnetic stirrer up to the time of treatment. The stability and homogeneity of the suspensions were determined seperately by UV-spectrum analysis.

CLASS METHOD
- Rationale for the selection of the starting dose: not applicable
Doses:
A standard injection volume of 10 mL/kg with 4 different concentrations were given: the solvent, 4.0, 8.0 and 16.0 mg/mL, corresponding to the doses of 0 (control), 40.0, 80.0 and 160 mg/kg, respectively.
No. of animals per sex per dose:
5 males and 5 females
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
- Lethality and gross behavioral observations were made immediately after dosing, periodically during day 1, and at least once daily until the end of the observation period of 14 days.
- Body weights were measured before dosing (day 0) and at days 4, 7, 10 and 14.
- Necropsy of survivors performed: yes
- Other examinations performed: body weights, clinical observations, and gross pathology
Statistics:
Mortality data for days 1, 7 and 14 were analysed by the statistical method of Lewi et al. (1976) and expressed as LD50's with 95% confidence limits in mg/kg body weight. The significance of any difference in body weight evolution between test groups and the vehicle-treated group was assessed by the two-tailed Mann-Whitney U test.

Results and discussion

Effect levelsopen allclose all
Sex:
male
Dose descriptor:
LD50
Effect level:
113 mg/kg bw
95% CL:
75.5 - 170
Sex:
female
Dose descriptor:
LD50
Effect level:
65 mg/kg bw
95% CL:
48 - 88
Sex:
male/female
Dose descriptor:
LD50
Effect level:
85.7 mg/kg bw
95% CL:
64.4 - 114
Mortality:
Four male rats died at the 160 mg/kg dose level, two at one hour and two at six hours post exposure. One male rat died at the 80 mg/kg dose level at 1 hour post exposure. Four female rats died at the 80 mg/kg dose level , two at one hour and two at six hours post exposure. All female rats died at the 160 mg/kg dose level, four one hour and one at three hours post exposure. All deaths occurred within a period of 6 hours after administration of the test substance.
Clinical signs:
Apart from mortality, the following phenomena occurred most frequently: catalepsy, hypotonia, hypothermia, sedation and tremors. All surviving animals became again normal within a period of 2 days after administration of T 1624.
Body weight:
No significant effect on body weight gain was measured.
Gross pathology:
No test substance-related abnormalities were observed. Therefore, no organs were preserved in formalin for histological examination.

Any other information on results incl. tables

Test article: The concentration of the test substance in suspension was determined twice, with a time interval of 5 days between both analyses. The first analysis revealed T1624 concentration of 4.01, 7.97, and 16.8 mg/mL, corresponding to percentages of 100.3, 99.6, and 105.0 of the desired concentrations, indicating that the suspension were correctly prepared. The second analysis indicated that T1624 concentrations to be 4.10, 8.18, and 17.07 mg/mL, corresponding to percentages of 102.2, 102.6, and 101.6 of the initial concentrations, indicating that the suspension were used within their stability period.

Under the conditions of this study, oral administration of T1624 to 5 rats per dose level was lethal in:

- males: 1 animal at 80 mg/kg and 4 at 160 mg/kg

- females: 4 animals at 80 mg/kg and 5 at 16 mg/kg.

Applicant's summary and conclusion

Interpretation of results:
Category 3 based on GHS criteria
Conclusions:
The acute oral LD50 to the test substance was determined to be 113 mg/kg for male rats, 65.0 mg/kg for female rats, and 85.7 mg/kg for both male and female rats. Therefore, the test item is considered as classified as acute oral toxicant category 3.