1-Piperazineacetamide, N-(4-aminophenyl)-N,4-dimethyl-

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

6 February - 17 March 2003

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2003

Report date:

2003

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

other: CPMP/SWP/1042/99

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

BIBF 1120/CDBB 213 BS

IUPAC Name:

BIBF 1120/CDBB 213 BS

Details on test material:

- Name of test material (as cited in study report): BIBF 1120/CDBB 213 BS
- Physical state: weak yellow-white solid substance
- Analytical purity: 99.2 % (HPLC)
- Purity test date: 23 january 2003
- Lot/batch No.: 8260050
- Expiration date of the lot/batch: 31 december 2003
- Storage condition of test material: at room temperature in the dark

Test animals

Species:

rat

Strain:

other: CrlGlxBrlHan:WI

Sex:

male/female

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: 0.5% aqueous hydroxyethylcellulose

Duration of treatment / exposure:

BIBF 1120/CDBB 213 BS was given orally by gavage in the morning on 7 days per week,
using a Tuberculin syringe and stomach tube, for 2 weeks. The test substance was
administered as a solution in 0.5% Natrosol 250 HX® (Hydroxyethylcellulose) on a quantity
of 10 mL/kg. The individual dose volume was based on the most recent body weight record.
The test substance was administered to all animals for at least 14 days and until the day
before sacrifice, except for those scheduled for the recovery period.

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

1 mg/kg bw/day (nominal)

Doses / concentrations 2

Dose / conc.:

3 mg/kg bw/day (nominal)

Doses / concentrations 3

Dose / conc.:

10 mg/kg bw/day (nominal)

No. of animals per sex per dose:

1 mg/ml: 14 males/ 14 females
3 mg/ml: 14 males/ 14 females
10 mg/ml: 24 males/ 24 females

Control animals:

yes, concurrent vehicle

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Description (incidence and severity):

None of the animals of the Control and all dose group did show any dose- or test item-related
changes of behavior or clinical findings.
Only in a single animal (No. 453) a clinical finding was observed and recorded (a scabby
hairless area behind the left ear was observed first on Day -5, ameliorated thereafter and
disappeared on Day 8).

Mortality:

no mortality observed

Description (incidence):

No test item-related deaths occurred.
Two accidental deaths were observed. On Day 1 the female No. 261 of the toxicokinetic
satellite group died during narcosis between blood collection times 4 h and 8 h after
administration. This animal was immediately replaced by a spare animal (No. 265), which
completed this satellite group on Day 11. The recovery female No. 469 died during narcosis
for blood collection (clinical pathology) on Day 16.

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

no effects observed

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

no effects observed

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not examined

Effect levels

Dose descriptor:

NOAEL

Effect level:

10 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: highest dose tested

Target system / organ toxicity

Critical effects observed:

no

Applicant's summary and conclusion

Conclusions:

Under the conditions of the present study, daily oral (gavage)administration of
BIBF 1120/CDBB 213 BS to rats over a period of 2 weeks at dose levels up to 10 mg/kg was
associated with no adverse effects.
Hence the highest dose of 10 mg/kg/day was set as NOAEL (No Observed Adverse Effect
Level). At this dose the maximum plasma concentration Cmax of BIBF 1120/CDBB 213 BS
was 1620 and 1690 ng/mL and the systemic exposure (AUC0-24h) was 5440 and
5160 ng·h/mL in males and females, respectively (Day 11; group mean).