Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
August 3, 2001 to September 4, 2001
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2001
Report Date:
2001

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
yes
Remarks:
dose level of 200 mg/kg tested instead of 300 mg/kg according to the guideline
Qualifier:
according to
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Deviations:
yes
Remarks:
dose level of 200 mg/kg tested instead of 300 mg/kg according to the guideline
GLP compliance:
yes
Remarks:
in compliance with the Swiss Ordinance relating to GLP, adopted February 2nd, 2000 (RS 813.016.5), and based on the OECD Principles of GLP, revised in 1997 and adopted November 26th, 1997 by decision of the OECD Council (C(97)186/Final)
Test type:
acute toxic class method
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder
Remarks:
migrated information: powder
Details on test material:
- Name of test material (as cited in study report): T002113
- Substance type: powder
- Physical state: solid
- Analytical purity: 92.9 %
- Impurities (identity and concentrations): no data
- Purity test date: no data
- Lot/batch No.: RT002113G3A231
- Expiration date of the lot/batch: December 1st, 2001 (retest date)
- Storage condition of test material: at room temperature (range of 20 +/- 3 °C), away from direct sunlight
- Stability of test item: stable under storage conditions
- Stability of test item in vehicle: 2 hours, the concentration, homogeneity, and stability of T002113 in the vehicle was determined (seee further)

Test animals

Species:
rat
Strain:
other: HanBrl: WIST (SPF)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: 9 rats (3 males and 6 females) , RCC Ltd, Biotechnology and Animal Breeding Division, CH-4414 Füllinsdorf, Switzerland
- Age when treated: approx. 8 weeks for males, 10 weeks for females
- Weight at day 1 of treatment: 185.3 - 198.3 g for males, 168.3 - 180.9 g for females
- Fasting period before study: 16 to 20 hours before treatment until approximately 3 hours after dosing , access to water was permitted
- Housing: in groups of three per sex in Makrolon type-4 cages with wire mesh tops and standardized softwood bedding ('Lignocel' Schill AG, CH-4132 Muttenz/Switzerland)
- Diet (e.g. ad libitum): ad libitum, pelleted standard Provimi Kliba 3433 rat maintenance diet, batch no. 72/01 (Provimi Kliba AG, CH-4303 Kaiseraugst/Switzerland). Results of analyses for contaminants are achieved at RCC Ltd, Itingen.
- Water (e.g. ad libitum): ad libitum, community tap water from Itingen. Results of bacteriological, chemical and contaminant analyses are achieved at RCC Ltd, Itingen
- Acclimation period: 7 days (under laboratory conditions, after health examination): 3-9 aug 2001 (females, 2000 mg/kg), 8-14 aug 2001 (males, 200 mg/kg), 14-20 aug 2001 (females, 200 mg/kg)

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3°C
- Humidity (%): 30-70 %
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12 hrs dark/12 hrs fluorescent light (light period between 6.00 and 18.00), music during light period

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: bi-distilled water
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 20 mg/ml and 200 mg/ml
- Amount of vehicle (if gavage): no data
- Justification for choice of vehicle: The vehicle was chosen after a non-GLP solubility trial performed before experimental starting date.
- Lot/batch no. (if required): no data
- Purity: no data

MAXIMUM DOSE VOLUME APPLIED: 10 ml/kg body weight

DOSAGE PREPARATION (if unusual): The test item was weighed into a tared glass beaker on a suitable precision balance and the vehicle added (weightvolume). The mixtures were prepared using a magnetic stirrer. Homogeneity of the test item in the vehicle was maintained during administration using a magnetic stirrer.

Doses:
200 mg/kg body weight (females) and 2000 mg/kg body weight (males and females)
No. of animals per sex per dose:
2 x 3 (except only 3 females at a dose of 2000 mg/kg)
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: mortality and viability daily during acclimatization and twice daily during days 1-15. Body weights on test days 1 (pre-administration), 8 and 15. Clinical signs daily during acclimatization and at least four times on test day 1 after the test item administration. Once daily during days 2-15.
- Necropsy of deaths: animals which died spontaneously during the observation period were necropsied as soon as they are found dead and any abnormalities recorded.
- Necropsy of survivors performed: yes, all surviving animals were killed at the end of the observation period by an intraperitoneal injection of NARCOREN (Rhone Merieux GmbH, 0-88471 Laupheim) at a dose of at least 2.0 ml/kg body weight (equivalent to at least 320 mg sodium pentobarbitone/kg body weight)
- Macroscopic examinations at necropsy. No organs or tissues were retained
Statistics:
No statistical analysis was used.

Results and discussion

Effect levels
Sex:
female
Dose descriptor:
LD50
Effect level:
> 200 - < 2 000 mg/kg bw
Based on:
test mat.
Mortality:
All females at 2000 mg/kg died approx. 15 minutes after the test item application.
5/5 at 2000 mg/kg (females), 0/5 at 200 mg/kg (males and females)
Clinical signs:
Moderate tremor and lateral recumbency was noted before spontaneous death occurred (females at 2000 mg/kg).
In female no. 8 at 200 mg/kg moderate tremor and lateral recumbency was evident 2 minutes after the test item application. Slightly ruffled fur, hunched posture, slight sedation and dyspnea were noted in female no. 8 on test day one. All other surviving animals were without clinical signs.
Body weight:
The body weight of the animals was within the range commonly recorded for this strain and age.
Gross pathology:
No macroscopic findings were observed at necropsy.

Applicant's summary and conclusion

Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
The median lethal dose of T002113 after single oral administration to rats of both sexes, observed over a period of 14 days is:
200 mg/kg body weight < LD5O (RAT) < 2000 mg/kg body weight