1H-Indole-6-carboxylic acid, 2,3-dihydro-3-[[[4-[methyl[2-(4-methyl-1-piperazinyl)acetyl]amino]phenyl]amino]phenylmethylene]-2-oxo-, methyl ester, (3Z)-

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

8 - 10 August 2006

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: The study was conducted in GLP compliance and in accordance with an OECD guideline (see below).

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2008

Report date:

2008

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

GLP compliance:

yes

Test type:

acute toxic class method

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

methyl (3Z)-3-[({4-[N-methyl-2-(4-methylpiperazin-1-yl)acetamido]phenyl}amino)(phenyl)methylidene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylate

EC Number:

922-049-5

Cas Number:

656247-17-5

Molecular formula:

C31H33N5O4

IUPAC Name:

methyl (3Z)-3-[({4-[N-methyl-2-(4-methylpiperazin-1-yl)acetamido]phenyl}amino)(phenyl)methylidene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylate

Details on test material:

Test item: BIBF 1120 BS (intermediate of BIBF 1120 ES)
Appearance: bright yellow solid
Batch number: V12EUN00033
Purity: 100.0 area % (HPLC)
Certificate of analysis: dated 18 July 2006
Stability: confirmed until February 2007
Manufacturer: Boehringer Ingelheim Pharma GmbH & Co. KG, 88397 Biberach/Riss, Germany
Storage conditions: at room temperature, protected from light

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

Species, number of animals: 9 rats, 3 males (M) and 6 females (F)
Strain: Crl:WI(Han), SPF quality
Supplier: Charles River Laboratories, Research Models and Services, Germany GmbH, Sulzfeld, Germany, v
Age (Day 1): approximately 7 weeks
Body weight range (Day 1): males 179 g - 189 g, females 132 g - 148 g

Temperature: 22°C ± 2°C
Relative humidity: 45% - 75%
Light/darkness cycle: 12/12 hours
Illumination period: 06:00 h 18:00 h
Air change: minimum of 10 air changes per hour
Food: pellets ad libitum, food was withdrawn in the afternoon of Day 1 (at about 16:00 h) over night. Immediately post administration, free access to food was allowed again.
Water: tap water ad libitum

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: 0.5% aqueous hydroxyethylcellulose (Natrosol® 250 HX)

Doses:

200 mg/kg bw
2000 mg/kg bw

No. of animals per sex per dose:

3 females per 200 mg/kg bw dose,
each 3 females and 3 males per 2000 mg/kg bw dose

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, macroscopic observations.

Results and discussion

Preliminary study:

none performed

Effect levels

Sex:

male/female

Dose descriptor:

other: ALD (approximate lethal dose)

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

In rats, no mortality was observed subsequent to a single oral administration of 200 mg/kg and 2000 mg/kg, respectively.

Clinical signs:

other: 200 mg/kg (females) No clinical signs were recorded throughout the entire observation period. 2000 mg/kg (males) Piloerection and reduced motor activity were seen on Day 1 (0.25 h to 8.0 h post administration). Male rats returned to normal at Day 2 post

Gross pathology:

No necropsy findings were noted in males and females treated with 200 mg/kg and 2000 mg/kg.

Applicant's summary and conclusion

Interpretation of results:

other: not classified acc. CLP

Conclusions:

Under the conditions of the present study, no mortality was seen in rats subsequent to oral administration of BIBF 1120 BS at doses of 200 mg/kg and 2000 mg/kg, respectively. Thus, the approximate lethal dose (ALD) for BIBF 1120 BS, an intermediate of BIBF 1120 ES, is above 2000 mg/kg.