2H-1-Benzopyran-2-methanol, alpha,alpha'-[[(phenylmethyl)imino]bis(methylene)]bis[6-fluoro-3,4-dihydro-, (alphaR,alpha'R,2R,2'S)-rel-

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2005-04-27 to 2005-08-08

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Guideline study with acceptable restrictions. The test substance purity was not provided.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2005

Report date:

2005

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Deviations:

yes

Remarks:

One animal had to be sacrificed immediately after administration of an incorrect test substance. A replacement animal was treated one week later.

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)

Deviations:

yes

Remarks:

One animal had to be sacrificed immediately after administration of an incorrect test substance. A replacement animal was treated one week later.

GLP compliance:

not specified

Test type:

acute toxic class method

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

2H-1-Benzopyran-2-methanol, alpha,alpha'-[[(phenylmethyl)imino]bis(methylene)]bis[6-fluoro-3,4-dihydro-, (alphaR,alpha'R,2R,2'S)-rel-

EC Number:

618-043-4

Cas Number:

876666-07-8

Molecular formula:

C29H31F2NO4

IUPAC Name:

2H-1-Benzopyran-2-methanol, alpha,alpha'-[[(phenylmethyl)imino]bis(methylene)]bis[6-fluoro-3,4-dihydro-, (alphaR,alpha'R,2R,2'S)-rel-

Test material form:

solid: particulate/powder

Details on test material:

- Name of test material (as cited in study report): JNJ-17303806-AAA (T001586)
- Physical state: solid, powder
- Appearance: white, beige

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: RT001586G1B121
- Expiration date of the lot/batch: 31-12-2005
- Purity test date: unknown

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: unknown
- Solubility and stability of the test substance in the solvent/vehicle: no data
- Reactivity of the test substance with the solvent/vehicle of the cell culture medium: no data

Test animals

Species:

rat

Strain:

other: HanRCC:WIST (SPF)

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: RCC Ltd., Laboratory Animal Services, CH-4414 Fullinsdorf/ Switzerland
- Age at study initiation: 11- 13 weeks
- Weight at study initiation: 166.0 - 200.8 g
- Fasting period before study: 19 hours (access to water was permitted)
- Housing: groups of three in Makron type-4 cages with wire mesh tops and standard softwood bedding
- Diet: pelleted standard Provimi Kliba 3433 rat/mouse maintenance diet ad libitum
- Water: Fullinsdorf community tap water ad libitum
- Acclimation period: 6 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 daytime light period

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: Polyethylene glycol 300 (PEG 300)

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 0.2 g/mL
- Amount of vehicle (if gavage): 10 mL/kg
- Justification for choice of vehicle: The vehicle was chosen after a solubility trial which was performed before the study initiation date.
- Lot/batch no. (if required): 110771224 104041
- Purity: no data


MAXIMUM DOSE VOLUME APPLIED:
- 10 mL/kg body weight


DOSAGE PREPARATION (if unusual):
- The dose formulations were made shortly before each dosing occasion using a magnetic stirrer, a spatula and an Ultra-Turrax (Janke & Kunkel, D-79219 Staufen) as homogenizers. The test substance was weighed into a tared glass beaker on a suitable precision balance and the vehicle added (weight:volume). Homogeneity of the test item in the vehicle was maintained during administration using a magnetic stirrer.

Doses:

2000 mg/kg body weight

No. of animals per sex per dose:

6 animals total

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Mortality/ Viability: Daily during the acclimatization period, during 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.
Body Weights: On test days 1 (prior to administration), 8 and 15
Clinical Signs: Daily during the acclimatization period, during the first 30 minutes and at approximately 1, 2, 3 and 5 hours after administration on test day 1. Once daily during days 2-15. All abnormalities were recorded.
- Necropsy of survivors performed: yes, gross
- Other examinations performed: clinical signs, body weight

Statistics:

No statistical analysis was used.

Results and discussion

Effect levels

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No deaths occurred during the study.

Clinical signs:

other: Slightly ruffled fur was observed in all animals either from the 2-hour reading to test day 6, at the 5-hour examination, from the 5-hour reading to test day 4 or from test day 2 to 4. Eyes tightly closed was seen in five animals from test day 2 to 5 or 6

Gross pathology:

One animal was noted with congestion of the lungs, whereas no macroscopic findings were recorded in the remaining five animals at necropsy.

Other findings:

no data

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

The median lethal dose of T1586 after single oral administration to female rats, observed over a period of 14 days is:
LD50 (female rat): greater than 2000 mg/kg body weight.