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

Acute Toxicity: oral

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 guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 425 (Acute Oral Toxicity: Up-and-Down Procedure)

Deviations:

no

Test guideline 2

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

Test material information

Constituent 1

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)cyclopentane-1-carboxylate

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)cyclopentane-1-carboxylate

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:

other: There were no clinical signs related to treatment throughout the study.

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.