Cyclopenta[c]cyclopropa[g][1,6]diazacyclotetradecine-12a(1H)-carboxylic acid, 2,3,3a,4,5,6,7,8,9,11a,12,13,14,14a-tetradecahydro-2-[[7-methoxy-8-methyl-2-[4-(1-methylethyl)-2-thiazolyl]-4-quinolinyl]oxy]-5-methyl-4,14-dioxo-, (2R,3aR,10Z,11aS,12aR,14aR)-

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 2010-10-18

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 (incl. QA statement)

Test type:

up-and-down procedure

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

(1R,4R,6S,7Z,15R,17R)-17-({7-methoxy-8-methyl-2-[4-(propan-2-yl)-1,3-thiazol-2-yl]quinolin-4-yl}oxy)-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.0^{4,6}]octadec-7-ene-4-carboxylic acid

EC Number:

618-844-9

Cas Number:

923604-58-4

Molecular formula:

C35H42N4O6S

IUPAC Name:

(1R,4R,6S,7Z,15R,17R)-17-({7-methoxy-8-methyl-2-[4-(propan-2-yl)-1,3-thiazol-2-yl]quinolin-4-yl}oxy)-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.0^{4,6}]octadec-7-ene-4-carboxylic acid

Test material form:

solid: particulate/powder

Details on test material:

- Name of test material (as cited in study report): JNJ-38940642-AAA (T003010)
- Physical state: solid
- Appearance: white powder

Test animals

Species:

rat

Strain:

other: CD (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: 8-12 weeks
- Weight at study initiation: 204-244 g
- Fasting period before study: overnight prior to and approximately four hours after dosing (with the exception of animal B1 which was fed approximately three and a half hours after dosing).
- Housing: individually, in solid bottomed polycarbonate cages with a stainless steel mesh lid, barriered rodent facility kept at a positive pressure
- Diet (e.g. ad libitum): ad libitum, standard rodent diet (Rat and Mouse No. 1 Maintenance Diet)
- Water (e.g. ad libitum): ad libitum, potable water taken from the public supply via polycarbonate bottles fitted with sipper tubes
- Acclimation period: 5-7 days before treatment

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

IN-LIFE DATES: From: 20-09-2011 To: 18-10-2011

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: PEG 400, 1.2 eq NaOH 10N and 0.3 eq HCl 12N

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 35, 110 and 300 mg/mL (max feasible concentration)
- Amount of vehicle (if gavage): 5 mL/kg
- 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 (if unusual): Formulations were stirred before and throughout the dosing procedure

Doses:

175, 550 and 1500 mg/kg

No. of animals per sex per dose:

1 female/group (175 mg/kg, 550 mg/kg)
3 females/group (1500 mg/kg)

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
- mortality: cages of rats were checked at least twice daily for any mortalities
- clinical observations: Animals were observed 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 weight of each rat was recorded on Day 1 (prior to dosing), 8 and 15. Individual weekly bodyweight changes were calculated.
- Necropsy of survivors performed: yes. all animals were humanely killed on day 15 by carbon dioxide asphyxiation
- Other examinations performed: macroscopic examinations: cranial, thoracic and abdominal cavities.

Statistics:

No stastistical analysis was used.

Results and discussion

Effect levels

Key result

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.

Any other information on results incl. tables

The 35 and 110 mg/mL test substance formulations used in this study were found to be within acceptable criteria of concentration verification.

Applicant's summary and conclusion

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

The acute median lethal oral dose (LD50) of JNJ-38940642-AAA to rats was > 1500 mg/kg bodyweight. Based on this unbounded LD50 value, the test item is classified for acute toxicity category 4 according to the criteria of the CLP Regulation (EC)1272/2008 as a worst case scenario.