.beta.-Alanine, N-[[2-[[(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)phenylamino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]-N-2-pyridinyl-, ethyl ester, acetate (1:2)

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

10 September 2003 to 06 September 2005

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2004

Report date:

2005

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:

no

Test material

Test material information

Constituent 1

Reference substance name:

bis(acetic acid); ethyl 3-{1-[1-methyl-2-({[4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl]amino}methyl)-1H-1,3-benzodiazol-5-yl]-N-(pyridin-2-yl)formamido}propanoate

EC Number:

925-312-2

Cas Number:

1184044-93-6

Molecular formula:

C28 H27 N7 O5 x 2 C2 H4 O2

IUPAC Name:

bis(acetic acid); ethyl 3-{1-[1-methyl-2-({[4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)phenyl]amino}methyl)-1H-1,3-benzodiazol-5-yl]-N-(pyridin-2-yl)formamido}propanoate

Test material form:

solid

Test animals

Species:

rat

Strain:

other: CrlGlxBrlHan:WI (SPF quality)

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- males (M) and females (F) CrlGlxBrlHan:WI (SPF quality) strain rats were obtained from Charles River Deutschland GmbH, Sulzfeld, Germany
- The rats were in a body weight range of males 193-207 g, females 134-147 g on Day 1.
- Rats were approximately 8 weeks on Day 1.

CONDITIONS
- Municipal tap drinking water (Stadtwerke Biberach) was always available ad libitum via
drinking bottles.
- The animals were offered pelleted dry food (Kliba No. 3438.0.25, Provimi Kliba SA,
Kaiseraugst, Switzerland). It was available ad libitum, but was withdrawn in the afternoon of
Day -1 until administration. Immediately post administration, free access to food was
allowed again.
- Diet and water are not considered to contain any contaminants which might have
influenced the experimental outcome of this study.
- The animal rooms were designed to permit minimum of 10 air changes per hour. The target temperature and humidity ranges were 22 ± 2°C and 45-75% respectively.
- Light/darkness give a cycle of 12/12 hours, in illumination period from 06:00-18:00 h with average illumination approximately 60 lx (depending on the cage position;
during work in the room the intensity is raised to
approximately 450 lx)

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

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

Details on oral exposure:

Doses were administered by oral gavage (10 mL/kg) at single doses of
200 mg/kg and 2000 mg/kg, respectively, to groups of CrlGlxBrlHan:WI rats, which were
observed for 14 days post administration.

Doses:

200 mg/kg bw (sighting study only), 2000 mg/kg bw

No. of animals per sex per dose:

3 female per 200 mg/kg bw (sighting study)
3 female per 2000 mg/kg bw (main study)
3 male per 2000 mg/kg bw (main study)

Control animals:

no

Details on study design:

Clinical signs were evaluated frequently on the day of administration (Day 1), as well as
once or twice daily thereafter. Body weight was determined one day before administration
(Day -1), and, during the observation period, on Day 1, 2, 8 and 15, respectively.
At the end of the observation period, necropsy was performed on all animals and all gross
macroscopical changes were recorded.

Results and discussion

Effect levels

Sex:

male/female

Dose descriptor:

approximate LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

There were no deaths.

Clinical signs:

other: From about 0.5 h to 3.5 h post administration, piloerection was seen in rats of both genders at all doses. All animals returned to normal during the Day 1 (6.5 h post administration at the latest) and no further abnormal clinical signs were noted througho

Gross pathology:

No necropsy findings were noted.

Applicant's summary and conclusion

Interpretation of results:

other: not classified according to CLP

Conclusions:

Under the conditions of the present study, no mortality in rats was seen subsequent to single oral administration of BIBR 1048 Oxa-Amidin diacetate by gavage at doses of 200 mg/kg and 2000 mg/kg, respectively.
The approximate lethal dose (ALD) for BIBR 1048 Oxa-Amidin diacetate is above 2000 mg/kg for male and female rats.