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Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2011-09-15 to 2011-10-18
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2011
Report date:
2011

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 425 (Acute Oral Toxicity: Up-and-Down Procedure)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
yes
Test type:
up-and-down procedure
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
METHYL (1R,2R,4S)-2-[HEX-5-EN-1-YL(METHYL)CARBAMOYL]-4-({7-METHOXY-8-METHYL-2-[4-(PROPAN-2-YL)-1,3-THIAZOL-2-YL]QUINOLIN-4-YL}OXY)CYCLOPENTANECARBOXYLATE
EC Number:
922-147-8
Cas Number:
1042695-87-3
Molecular formula:
C32H41N3O5S
IUPAC Name:
METHYL (1R,2R,4S)-2-[HEX-5-EN-1-YL(METHYL)CARBAMOYL]-4-({7-METHOXY-8-METHYL-2-[4-(PROPAN-2-YL)-1,3-THIAZOL-2-YL]QUINOLIN-4-YL}OXY)CYCLOPENTANECARBOXYLATE
Test material form:
solid: particulate/powder
Details on test material:
- Name of test material (as cited in study reports): JNJ-39125593-AAA (T003019)
- Physical state: solid
- Appearance: white powder
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: RT003019PFP201
- Expiration date of the lot/batch: 06 July 2012 (retest date)
- Purity: 98.2 % w/w

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material:
At room temperature (15-25°C) protected from light

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: The test substance formulations were prepared on the day of dosing.

Test animals

Species:
rat
Strain:
other: Crl:CD ‘SD’
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Ltd.
- Age at study initiation: Approximately 8 to 12 weeks
- Weight at study initiation: 194-236 g
- Fasting period before study: Overnight prior to dosing and approximately four hours after dosing.
- Housing: individually, in solid bottomed polycarbonate cages with a stainless steel mesh lid. Each cage contained a quantity of autoclaved wood flake bedding.
- Diet: ad libitum, standard rodent diet (Rat and Mouse No. 1 Maintenance Diet)
- Water: ad libitum, potable water taken from the public supply
- Acclimation period: 5 or 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-23°C
- Humidity (%): 40- 70%
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light):12 /12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: PEG 400, 1.2 eq NaOH 10 N and 0.3 eq HCl 12 N.
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 35, 110 and 300 mg/mL (this does not include the correction factor, the concentrations including the conversion factor were 35.7; 112.2 and 306 mg/mL respectively)
- Justification for choice of vehicle: No data
- Lot/batch no. (if required): No data
- Purity: No data

MAXIMUM DOSE VOLUME APPLIED: 5 mL/kg

DOSAGE PREPARATION: The test item formulations were prepared on the day of dosing.

Rationale for the selection of the starting dose: As no previous toxicological information was available the initial dose level was 175 mg/kg, in compliance with the study guidelines
Doses:
175, 550, 1500 mg/kg
1500 mg/kg was the maximal feasible dose level
No. of animals per sex per dose:
1 female for 175 mg/kg
1 female for 550 mg/kg
3 females for 1500 mg/kg
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Mortality: At least twice daily;
Clinical observations: soon after dosing and at frequent intervals for the remainder of Day 1. On subsequent days, animals were observed once in the morning and again at the end of the experimental day (with the exception of Day 15 - morning only). The nature and severity, where appropriate, of the clinical signs and the time were recorded at each observation;
Body weight: The weight of each rat was recorded on Days 1 (prior to dosing), 8 and 15. Individual body weight changes were calculated.
- Necropsy of survivors performed: yes. All animals were humanely killed on Day 15 by carbon dioxide asphyxiation. Macroscopic evaluation onsisted of opening the cranial, thoracic and abdominal cavities. The macroscopic appearance of all examined organs was recorded.
Statistics:
no data

Results and discussion

Effect levels
Sex:
female
Dose descriptor:
LD50
Effect level:
> 1 500 mg/kg bw
Based on:
test mat.
Mortality:
There were no deaths during the study.
Clinical signs:
There were no clinical signs related to treatment throughout the study.
Body weight:
A low bodyweight gain was observed between Day 8 and 15 for one female dosed at 1500 mg/kg.
Gross pathology:
No abnormalities were noted in any animal at the macroscopic examination at study termination on Day 15.

Applicant's summary and conclusion

Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
The acute median lethal oral dose (LD50) of JNJ-39125593-AAA to rats was > 1500 mg/kg bodyweight. As the unbounded LD50 is situated within the cut-off values for acute oral toxicity category 4 according to the criteria of the CLP Regulation (EC)1272/2008, the test item is classified as such as a conservative approach.