Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
other: summary of several experimental results
Adequacy of study:
key study
Study period:
15 January 2008
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
The study represents a summary of physico-chemical, toxicological and eco-toxicological studies that had previously been conducted with the test substance and on that basis concludes assumptions for basic toxicikinetics. However, these data were not derived on an experimental basis.

Data source

Reference
Reference Type:
other company data
Title:
Unnamed
Year:
2008
Report date:
2008

Materials and methods

Objective of study:
other: Assessment of toxicokinetic behaviour

Test material

Constituent 1
Chemical structure
Reference substance name:
-
EC Number:
485-140-4
EC Name:
-
Cas Number:
515815-48-2
Molecular formula:
C33 H30 N4 O2 x HCl
IUPAC Name:
4’-(2-Propyl-4-methyl-6-(1-methylbenzimidazolyl-2-yl)-benzimidazol-1-ylmethyl)biphenyl-2-carbonsäure Hydrochlorid
Test material form:
other: solid
Details on test material:
- Name of test material (as cited in study report): BIBR 277 CL
- Physical state: solid
- Analytical purity: 99.7%
- Purity test date: 26 March 2007
- Lot/batch No.: 70
- Expiration date of the lot/batch: 08 March 2008
- Stability under test conditions: see expiry date
- Storage condition of test material: at room temperature, dark and dry

Results and discussion

Any other information on results incl. tables

The test substance is solid at room temperature with a molecular weight 514.6 + 36.5 g/mol. The substance's boiling point temperature is 298.4°C at normal atmospheric pressure. Vapour pressure was estimated to be 1.24E-17 Pa at 25°C (using Modified Grain Method). The partition coefficient for BIBR 277 SE (log Pow = 3.5) was determined using the High Performance Liquid Chromatography (HPLC) method. The water solubility of the test substance was determined to be 108 mg/L, using the shake-flask method.

BIBR 277 CL is of low volatility, with a relatively high boiling point (>> 150°C) and very low vapour pressure (<< 500 Pa). Based on the log Pow value (1 -4) absorption could potentially occur directly across the respiratory tract epithelium. However, there is practically no exposure through inhalation and thus bioavailability via this route can be excluded.

Based on its molecular weight of 514.6 + 36.5 g/mol, the test substance absorption across the skin is likely to be low, as the molecule is too large, even though water solubility at 108 mg/L and the log Pow value at 3.5 wolud favour absorption. This is supported by the dermal studies, with no toxicity, neither local nor systemic, observed following application of the limit dose (2000 mg/kg bw) in the acute study and absence of irritation or corrosion in the irritation or sensitisation studies using rabbits and guinea pigs.

Administered orally, the test substance is likely to dissolve in the stomach with a water solubility of 108 mg/L. The absorption behaviour of the test substance and BIBR 277 Se is considered to be comparable under the acidic conditions of the stomach. As part of the 28 -day toxicity study with BIBR 277 Se), plasma concentration were measured in male and female rats per dose on day 1, 14 and 28. The compound was fast (median tmax: 1 h) and adequately absorbed after all doses administered. The compounds log Pow value indicates that the test substance is not likely to bioaccumulate should repeat exposures occur. The calculated bioconcentration factor is log bcf = 1.0 (BCF = 10; US EPA Epiwin v.3.12).

Theoretically, when bioavailable test substance is likely to be metabolised and parent compound and degradation products are expected to distribute rapidly throughout the body via systemic circulation. Metabolism may transform BIBR 277 CL into more polar degradation products. Likely pathways are reactions such as cytochrome P-450 -dependent monooxygenase enzyme mediated N-oxidation or oxidative ring opening and cleavage at the carbonamide side-chain. Parent compound and metabolites formed in phase I metabolic reactions may be rendered more polar by phase II metabolic activity in subsequent reactions. The parent compound or possible metabolites may undergo conjugation (e. g. with glutathione), before being excreted in bile and faeces.

It is unlikely that the test substance is metabolised to more reactive (toxic) products. This assumption is supported by results obtained in oral and dermal toxicity and two in vitro tests. In acute and subacute in vivo studies toxicity was low. In an Ames test, a chromosome aberration assay and an in vivo micronucleus test no significant increase in toxicity was noted in the presence of rodent microsomal S9 fraction, when compared to incubation without S9 -fraction. Together, this data indicates that formation of reactive metabolites is rather unlikely.

Based on the substance's structure and physical-chemical properties the test substance is likely to become bioavailable following oral administration. This is supported by substance plasma level measurements following administration. Uptake via the dermal or inhalation route is practically negligible. Once the test substance is bioavailable, the substance and/or its metabolites are expected to rapidly distribute throughout the body. Excretion is likely to occur via bile and via faces.

Applicant's summary and conclusion