Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
21-NOV-2007 to 14-DEC-2007
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2008
Report Date:
2008

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
EU Method B.1 (Acute Toxicity (Oral))
Deviations:
not specified
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
not specified
Qualifier:
according to
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
Deviations:
not specified
GLP compliance:
yes (incl. certificate)
Test type:
acute toxic class method
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid
Details on test material:
White to yellow tan colour
Specific details on test material used for the study:
Identification: CP-902684
Description: Solid; tan
Batch Number: E010005632 or 166-TNN-73
Purity: 98%
Stability of Test Item: Stable under storage conditions.
Expiry Date: 21-MAR-2009
Stability of Test Item Dilution: Unknown in PEG 300; is excluded from the statement of compliance.
Storage Conditions: At room temperature (range of 20 ± 5 °C, provided by RCC), light protected.

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals and environmental conditions:
Animals: Rat, Sprague Dawley (SPF)
Rationale: Recognized by international guidelines as a recommended test system.
Breeder: Charles River Deutschland GmbH, Stolzenseeweg 32-36, D-88353 Kisslegg / Germany
Number of Animals per Group: 3 females
Total Number of Animals: 6 females
Age when treated: 11 weeks
Identification: Unique cage number and corresponding color-coded spots on the tail. The animals were marked at acclimatization start.
Randomization: Selected by hand at time of delivery. No computer generated randomization program.
Acclimatization: Under laboratory conditions, after health examination. Only animals without any visible signs of illness were used for the study.
Room Number: 0105 / RCC Ltd, Füllinsdorf
Conditions: Standard Laboratory Conditions. Air-conditioned with 10-15 air changes per hour, and continuously monitored environment with ranges for room
temperature 22 ± 3 °C and for relative humidity between 30-70 % (values above 70 % during cleaning process possible), automatically controlled light cycle of 12 hours light and 12 hours dark, music during the daytime light period.
Accommodation: In groups of three in Makrolon type-4 cages with wire mesh tops and standard softwood bedding ('Lignocel' Schill AG, CH-4132 Muttenz/Switzerland).

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: PEG 300
Details on oral exposure:
VEHICLE
Identification: Polyethylene glycol 300 (PEG 300)
Description: Colorless viscous liquid
Lot number: 1310049
Source: FLUKA Chemie GmbH, CH-9471 Buchs
Stability of the Vehicle: Stable under storage conditions; expiration date: June, 2009
Concentration in vehicle: The animals received a single dose of the test item by oral gavage administration at 2000 mg/kg. The dosing volume was 10 mL/kg body weight.
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. This formulation trial is excluded from the statement of compliance.

MAXIMUM DOSE VOLUME APPLIED: The dosing volume was 10 mL/kg body weight.
Doses:
2000 mg/kg
No. of animals per sex per dose:
3f/dose
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Body weights- days 1, 8 and 15, observations- first 30 mins, 1, 2, 3, and 5 hours after administration on day 1 and twice daily during days 2-15
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight,organ, pathology, mortality/viability
Statistics:
No statistical analysis was used.

Results and discussion

Effect levels
Key result
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:
No clinical signs were observed during the course of the study.
Body weight:
Three females (nos. 1, 2, 4) lost body weight during the first week after treatment (female no. 1:10.2 %, female no. 2: 0.4 % and female no. 4: 2.6 %) and one fe male did not gain weight during the same time but they recovered until the end of the study. In spite of this body weight loss, the body weight of the animals was within the range commonly recorded for this strain and age.
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 CP-902684 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

Executive summary:

Two groups, each of three female Sprague Dawley (SPF) rats, were treated with CP-902,684 by oral gavage administration at a dosage of 2000 mg/kg body weight. The test item was diluted in vehicle (PEG 300) at a concentration of 0.2 g/mL and administered at a dosing volume of 10 mL/kg.

The animals were examined daily during the acclimatization period and mortality, viability and clinical signs were recorded. All animals were examined for clinical signs within the first 30 minutes and approximately 1, 2, 3 and 5 hours after treatment on day 1 and once daily during test days 2-15. Mortality/viability was recorded at approximately 30 minutes, 1, 2, 3 and 5 hours after administration on test day 1 (with the clinical signs) and twice daily during days 2-15. Body weights were recorded on day 1 (prior to administration) and on days 8 and 15. All animals were necropsied and examined macroscopically.

All animals survived until the end of the study period.

No clinical signs were observed during the course of the study.

Three females (nos. 1, 2, 4) lost body weight during the first week after treatment (female no. 1: 10.2 %, female no. 2: 0.4 % and female no. 4: 2.6 %) and one female did not gain weight during the same time but they recovered until the end of the study. In spite of this body weight loss, the body weight of the animals was within the range commonly recorded for this strain and age.

No macroscopic findings were recorded at necropsy.

The median lethal dose of CP-902684 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