Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2003-08-26 to 2003-09-18
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Well documented GLP compliant study, performed according to OECD guideline 423 and EU method B1 tris. No deviations were recorded.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2003
Report Date:
2003

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
Details on test material:
- Name of test material (as cited in study report): T002251
- Substance type: brown powder
- Physical state: solid
- Analytical purity: 96%
- Purity test date: no data
- Lot/batch No.: 00410155
- Expiration date of the lot/batch: 2004-05-05
- Stability under test conditions: unknown in PEG300
- Storage condition of test material: in the original container, at room temperature (range of 20+/-3°C), away from direct sunlight

Test animals

Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: HanBrl:Wist (SPF) from RDD Ltd., Laboratory Animal Services, CH-4414 Füllinsdorf / Switzerland
- Age when treated: 12 weeks
- Weight at treatment (day 1): 180.8-189.3g
- Fasting period before study: for approx 17 to 18 hours (access to water was permitted). Food was provided again 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 maintenance diet
- Water: ad libitum, community tap water from Füllinsdorf
- Acclimation period: at least 6 days, under laboratory conditions, after health examination. Only animals without 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 the light period

IN-LIFE DATES: From: 2003-09-02 (group 1), 2003-09-04 (group 2)

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
polyethylene glycol
Remarks:
PEG 300
Details on oral exposure:
VEHICLE
- Concentration in vehicle:0.2 g/ml
- Amount of vehicle (if gavage): 10ml/kg bw
- Justification for choice of vehicle: The vehicle was chosen after a non-GLP solubility trial which was performed before the study initiation date.
- Lot/batch no. (if required): 448174/1 21203148
- Purity: not known

MAXIMUM DOSE VOLUME APPLIED: 10ml/kg bw

DOSAGE PREPARATION:
Dose levels are in terms of the test item as supplied by the sponsor. The dose formulations were made shortly before each dosing occasion using a magnetic stirrer as homogenizer. The test item was weighter 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 durig 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: mortality/viability: Daily during acclimatization and twice daily during days 1-15. Weighing: On test days 1 (prior to administration), 8 and 15
- Necropsy of survivors performed: yes
All 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 sodim pentobarbitone/kg body weight) and discarded after macroscopic examinations were performed. No organs or tissues were retained.
- Other examinations performed: clinical signs, body weight,organ weights, histopathology, other:
clinical signs: Daily during acclimatization and at approximately 0, 1, 2, 3 and 5 hours after administration on test day 1. Once daily during days 2-15. All abnormalilties were recorded.
Statistics:
No statistical analyses were 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 occured during the study.
Clinical signs:
Slightly ruffled fur was observed in two animals at the 1- and 2-hour reading and in four animals form the 0-hour to the 5-hour reading and persisted in three animals up to test day 5. Hunched posture was noted in three animals form the 2- or 3-hour to the 5-hour reading. Three animals showed ventral recumbency from the 0-hour to the 1- or 2-hour reading and one animal was seen with slight sedation from the 0-hour to the 3-hour reading.
Body weight:
The body weight of the animals was within the range commonly recorded for this strain and age.
Gross pathology:
No marcoscopic findings were recored at necropsy.

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
The median lethal dose of T002251 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 T002251 is not classified based on CLP regulation.