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Toxicological information

Acute Toxicity: oral

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Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2006-03-29 to 2006-05-04
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)
Remarks:
Certificate from the Swiss GLP monitoring authorities.
Test type:
acute toxic class method
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder
Details on test material:
- Name of test material (as cited in study report): JNJ-559728-AAA (T001250)
- Physical state: solid (powder)
- Appearance: White powder
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material:
Janssen Pharmaceutical N.V.; 00443418 RT001250G4a661
- Expiration date of the lot/batch:
Unknown, excluded from statement of compliance
- Purity: 100%

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material:
At room temperature (range of 20 +/- 5 C), light protected
- Stability under test conditions:
Stable under storage conditions
- Solubility and stability of the test substance in the solvent/vehicle:
unknown in Peg 300

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing:
The dose formulations were made shortly before each dosing occassion using a magnetic stirrer, a spatula and an Ultra-Turrax as homogenizers. The test item was weighed into a tared glass beaker on a suitable precision balance and the vehicle added. Homogeneity of the test item in the vehicle was maintained during administration using a magnetic stirrer.

Test animals

Species:
rat
Strain:
other: HanRcc:WIST (SPF)
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: RCC Ltd.., Laboratory Animal Services CH-4414 Fullinsdorf / Switzerland
- Age at study initiation: 12 weeks
- Weight at study initiation: 187.7 - 203.9 grams
- Fasting period before study: no data
- Housing: In groups of three in Makrolon type-4 cages with wire mesh tops and standard softwood bedding ('Lignocel' Schill AG, CH-4132 Muttenz/Switzerland).
- Diet (e.g. ad libitum): Pelleted standard Provimi Kliba 3433 rat/mouse maintenance diet, batch no. 001/06 (Provimi Kliba AG, CH-4303 Kaiseraugst/Switzerland) ad libitum.
- Water (e.g. ad libitum): community tap water from Fullinsdorf ad libitum
- Acclimation period: 6 to 10 days

ENVIRONMENTAL CONDITIONS
- Temperature (deg C): 22 +/- 3 deg C
- Humidity (%): 30-70%
- Air changes (per hr): 10 - 15
- Photoperiod (hrs dark / hrs light): 12/12, with music played during light cycle

IN-LIFE DATES:
From: 2006-04-05 To: 2006-04-19 (1st 300 mg/kg treatment)
From: 2006-04-11 To: 2006-04-11 (2000 mg/kg treatment)
From: 2006-04-20 To: 2006-05-04 (2nd 300 mg/kg treatment)

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): 10 mL/kg body weight
- 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): 120471944705164

MAXIMUM DOSE VOLUME APPLIED:
- 2000 mg/kg-bw

Doses:
300 and 2000 mg/kg bw
No. of animals per sex per dose:
Three females/group, 9 animals total (3 groups)
Control animals:
no
Details on study design:
- Duration of observation period following administration: 15 days
- Frequency of observations and weighing:
Observation: During the acclimatization period, and 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.
Weighing: on days 1 (prior to test), 8, and 15
- Necropsy of survivors performed: yes
Statistics:
No statistical analysis was used.

Results and discussion

Effect levels
Sex:
female
Dose descriptor:
LD50
Effect level:
> 300 - < 2 000 mg/kg bw
Mortality:
All animals tested at a concentration dose of 2000 mg/kg died spontaneously or were killed in extremis for ethical reasons approximately 7.5 hours after treatment. All of the animals treated with 300 mg/kg survived until the end of the study period.
Clinical signs:
Slight to moderate ruffled fur, and slight to moderate sedation with half-closed eyes were noted in all 2000 mg/kg treated animals from the 30-minute to the 5-hour reading. Salivation was also noted in the same animals at the 30-minute and 1-hour reading, whereas hunched posture was noted from the 2- to the 5-hour reading. Slight poor coordination was noted in all animals at the 3- and 5-hour readings. Lacrimation was noted in one animal at the 30-minute and 1-hour reading. The animals walked with a pulled up abdomen at the 2-hour reading. Moderate ruffled fur, salivation, lateral recumbency and deep yellow urine was noted in the two animals just before they were killed in extremis for ethical reasons. Respiratory distress with shaking of the head was also noted in one of them, whereas the second, showed cramps of the back legs at the same reading time.

All animals treated with a concentration of 300 mg/kg showed a slight ruffled fur, between the 30-minute reading and the 5-hour reading and persisted in three animals until test day 3. The animals were slightly sedated between the 30-minute and the 3-hour reading and had half-closed to closed eyes from the 30-minute reading to the 2- or 3-hour reading. Hunched posture was noted in three animals at the 3-hour reading, in two animals at the 5-hour reading and the same clinical signs were again noted in one of them from test days 7 to 9. Slight to moderate poor coordination was noted in three animals on test days 3 and 4, in two animals on test days 2 and 3 and persisted in one of them until test day 9.
Body weight:
The body weight of all animals treated with 300 mg/kg was found diminished (3% to 17%) one week after treatment. The animals recovered the lost weight until the end of the study.
Gross pathology:
At the unscheduled necropsy, one 2000 mg/kg treated animal had collapsed lungs, a stomach with liquid contents and the duodenum and jejunum were filled with yellowish liquid. The other two animals treated at the same dose showed a stomach with yellowish liquid contents and a distended urinary bladder filled with yellowish urine. No macroscopic findings were recorded in the 300 mg/kg treated groups at the scheduled necropsy.

Applicant's summary and conclusion

Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
The median lethal dose of the test substance after single oral administration to female rats, observed over a period of 14 days was: 300 mg/kg < LD50 (female rat) < 2000 mg/kg body weight.