Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2006-03-07 to 2006-03-30
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2006
Report Date:
2006

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
acute toxic class method
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder
Specific details on test material used for the study:
- Name of test material (as cited in study report): TIC2782 (T002907)
- Substance type: white solid
- Physical state: solid
- Analytical purity: 99.9%
- Lot/batch No.: 00467090 (= Charge 05C0836)
- Expiration date of the lot/batch: 2006-05-04
- Stability of test item: stable under storage conditions
- Stability under test conditions: Unknown in PEG 300
- Storage condition of test material: At room temperature (range of 17-23°C),away from direct sunlight.

Test animals

Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: HanRcc:WIST (SPF) from RCC Ltd., Laboratory Animal Services, CH-4414 Füllinsdorf / Switzerland
- Age when treated: 12 weeks
- Weight at day 1 treatment: 181.9-191.4g
- Fasting period before study: yes, for approximately 18 to 19 hours (access to water was permitted). Food was provided again approximately 3 hours after dosing.
- Housing: Standard laboratory conditions, in groups of three in Makrolon type-4 cages with wire mesh tops and standard softwood bedding
- Diet: ad libitum, Pelleted standard Provimi Kliba 3433 rat/mouse mainte-nance diet
- Water: ad libitum, community tap water from Füllinsdorf
- Acclimation period: 6 days, under laboratory conditions, after health examination. Only animals without any visible signs of illness were used for the study

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3 °C
- Humidity (%): 30-70%
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12
- Other: music during daytime light period

IN-LIFE DATES: 2006-04-14 (group 1); 2006-04-16 (group 2)

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
polyethylene glycol
Remarks:
PEG 300
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 0.2g/mL
- Amount of vehicle (if gavage): 10 mL/kg
- Justification for choice of vehicle: PEG 300 was found to be a suitable vehicle. The vehicle was chosen after a non-GLP solubility trial which was performed before the study initiation date.
- Lot/batch no. (if required): 120471944705164
- Purity: no data

MAXIMUM DOSE VOLUME APPLIED: 10 mL/ KG BODY WEIGHT;

DOSAGE PREPARATION (if unusual): dose levels are in terms of the test item as supplied. The dose formulations were made shortly before each dosing occasion using a magnetic stirrer, a spatula and an Ultra-Turraw as homogenizers. The test item was weighed into a tared glass beaker on a suitable precision balance and the vehicle added (weight:volume). Homogeneity of the test item in the vehicle was maintained during administration using a magnetic stirrer.

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose:
Doses:
Single dosing
2000 mg/kg (2 groups)
No. of animals per sex per dose:
3 females/group
6 females in total
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Moratility / Viability: Daily during the acclimatization period, during the first 30 minutes and at approximately 1, 2, 3 and 5 hours after administration on test day 1 (with the clinical signs) and twice daily during days 2-15. Clinical observations: Daily during the acclimatization period, during the first 30 minutes and at approximately 1, 2, 3 and 5 hours after administration on test day 1. Once daily during days 2-15. All abnormalities were recorded; Body weight: On test days 1 (prior to administration), 8 and 15.
- Necropsy of survivors performed: yes, All surviving animals were killed at the end of the observation period by an intraperitoneal injection of Vetanarcol at a dose of at least 2.0 mL/kg body weight (equivalent to at least 324 mg sodium pentobarbitone/kg body weight) and discarded after macroscopic examina-tions were performed. No organs or tissues were retained.
Statistics:
No statistical analysis was used.

Results and discussion

Effect levels
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No deaths occurred during the study.
Clinical signs:
Slightly ruffled fur was observed in 5 of the treated animals on the day of testing from 30 minutes to 3 hours after dosing or 2−3 hours or 5 hours after dosing. A hunched posture was observed in two of the animals 3 hours after the treatment and persisted in one of the animals at the 5-hour reading. For the remaining days of the study no clinical signs were observed. One of the animals was absent of clinical signs thourhgout the study.
Body weight:
The body weight of the animals was within the range commonly recorded for this strain and age with the exception of animal No. 3 in which a very minor (1.3%) body weight loss was observed during the second week of observation.
Gross pathology:
No macroscopic findings were recorded at necropsy.

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
The median lethal dose of TIC2782 (T002907) after single oral administration to female rats, observed over a period of 14 days is:
LD50 (female rat): greater than 2000 mg/kg body weight. Therefore T002907 is not classified based on CLP Regulation.