Registration Dossier

Diss Factsheets

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From July 14, 2008 to August 29, 2008
Reliability:
1 (reliable without restriction)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2009

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 425 (Acute Oral Toxicity: Up-and-Down Procedure)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
up-and-down procedure
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
N-methyl-1-(trans-4-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)methanesulfonamide
Cas Number:
1208319-26-9
Molecular formula:
C15H23N5O2S
IUPAC Name:
N-methyl-1-(trans-4-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)methanesulfonamide
Specific details on test material used for the study:
Test material name in the study: PF-03394197-11

Test animals

Species:
rat
Strain:
Crj: CD(SD)
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Rationale for alternative/additional species to rat (if applicable)
- Source: Charles River Laboratories, Portage, Michigan
- Females (if applicable) nulliparous and non-pregnant: [yes/no]
- Rationale for use of males (if applicable)
- Age at study initiation: Approximately 7 weeks
- Weight at study initiation: Female: 184 to 273 g
- Fasting period before study: overnight
- Housing: Individually in stainless steel suspended wire mesh caging
- Historical data:
- Diet (e.g. ad libitum): Block Lab Diet® Certified Rodent Diet #5002, PMI Nutrition International, Inc. Ad libitum, except during designated periods.
- Water (e.g. ad libitum): Automatic watering system, Ad libitum, except during designated periods.
- Acclimation period: 7 to 32 Days
- Microbiological status when known
- Method of randomisation in assigning animals to test and control groups

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17.8 to 26.1°C
- Humidity (%): 30 to 70%
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light): Fluorescent lighting was provided for approximately 12 hours per day.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
methylcellulose
Details on oral exposure:
MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg

DOSAGE PREPARATION (if unusual):
The test article, was used as received from the Sponsor, and a correction
factor of 1.344 was applied to correct for the ratio of molecular weight of the salt to the base
of the test article. Dose preparation was performed by mixing the appropriate amount of test
article, with the appropriate amount of vehicle, to achieve the required nominal concentrations for the limit test, 200 mg/mL, and main tests, 17.5 and 55 mg/mL.

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: limit dose level of 2000 mg/kg
Doses:
2000, 175, 550, 175, 550, 175, and 550 mg/kg
No. of animals per sex per dose:
1 or 3 females
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Observations for morbidity, mortality, injury, and the availability of food and water were conducted twice daily for all animals. Observations for clinical signs were conducted on each surviving animal at 0.5, 2, and 4 hours postdose on the day of dosing, and were continued once daily for no longer than 13 additional days, dependant on survival. Body weights were measured and recorded prior to test article administration on Day 1, and weekly thereafter. Additional body weights were taken for two animals found dead prior to submission to necropsy at dose levels of 2000 mg/kg and 550 mg/kg.
- Necropsy of survivors performed: Necropsy examinations were performed under procedures approved by a veterinary pathologist on all animals found dead, and all surviving animals at the scheduled necropsy. The surviving animals were euthanized by carbon dioxide inhalation, and euthanasia was confirmed by exsanguination via the abdominal vena cava. The animals were examined carefully for external abnormalities including masses. The skin was reflected from a ventral midline incision, and any abnormalities were identified and correlated with antemortem
findings. The abdominal, thoracic, and cranial cavities were examined for abnormalities, and the organs removed, examined, and the tissues and carcasses were discarded.

Results and discussion

Effect levels
Key result
Sex:
female
Dose descriptor:
LD50
Effect level:
310.2 mg/kg bw
Based on:
test mat.
Mortality:
All animals died on Day 2 at 2000 and 550 mg/kg dose level.
Clinical signs:
Impaired limb function, decreased activity, ataxia, slow and difficult breathing, salivation, lacrimation, and partially closed eyelids were observed following the limit dose of 2000 mg/kg, and prior to the animal being found dead. Impaired limb function, decreased activity, ataxia, slow and difficult breathing, prostration, hunched posture, salivation, skin cold to touch, red material around nose, lacrimation, and partially closed eyelids, and decreased feces were all observed in at least one of the three animals dosed at 550 mg/kg. Clinical findings observed following the administration at 550 and 2000 mg/kg were considered to be related to test article administration.
Body weight:
No effect of test article administration was observed on the body weights or body weight gains of the three animals at 175 mg/kg that survived to the scheduled necropsy on Day 15.
Gross pathology:
No test article-related macroscopic observations were made in study animals. Macroscopic observations were usual and/or incidental in rats of this type and age.

Applicant's summary and conclusion

Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
The oral LD50 of the test item when administered to female rats is estimated to be 310.2 mg/kg.
Executive summary:

The acute oral study is performed according to OECD Guideline 425 under GLP. The oral LD50 of the test item when administered to female rats is estimated to be 310.2 mg/kg.