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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2006-09-13 - 2007-07-04
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study (OECD TG 417) performed under GLP

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2007
Report date:
2007

Materials and methods

Objective of study:
other: ADME
Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 417 (Toxicokinetics)
Version / remarks:
adopted April 1984
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Remarks:
RCC Ltd., Itlingen, Swizerland

Test material

Constituent 1
Test material form:
solid: bulk
Details on test material:
Please refer to "Confidential details on test material".
Radiolabelling:
yes
Remarks:
(14C)

Test animals

Species:
rat
Strain:
Wistar
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: RCC Ltd. Laboratory Animal Services, 4414 Füllinsdorf, Switzerland
- Age at study initiation: about 7 weeks old
- Weight at study initiation: approximately 180 g
- Housing: During acclimatization the animals were kept in groups of 1 -3 rats under conventional hygienic conditions in Makrolon cages with standard soft wood bedding.
- Individual metabolism cages: yes, throughout the experiment
- Diet: free access to certified standard diet
- Water: Tap water was offered ad libitum
- Acclimation period: At least 5 days to the laboratory environment including at least one day to the metabolism cages

ENVIRONMENTAL CONDITIONS
- Temperature: 20.9–21.8 °C (group 1), 20.2-21.0°C (group 2)
- Humidity: 50-67 % (group 1), 55–60 % (group 2)
- Photoperiod (hrs dark / hrs light): 12 hours dark / 12 hours light

IN-LIFE DATES: From: To: 2006-09-13 to 2006-10-05

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: 0.5% carboxymethyl cellulose and 0.4% Tween 80 (v/v) in water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
- Stock solution: [14C] labeled test item (11 mg) was dissolved in chloroform
- A volume of the stock solution containing 10.3 mg [14C] test item (6407 kBq/mg) was added to 389.9 mg unlabeled test item and totally dissolved in volume of 104 mL by addition of chloroform. This procedure yielded to [14C] test item with a final specific radioactivity of 164 kBq/mg (determined by liquid scintillation counting (LSC)). Thereafter the solvent was removed by rotary evaporator. The solid test item was split in two portions of about 200 mg and was placed in two milling bowls. To each milling bowl a volume of 3 mL vehicle was added. The suspension was micronized in a planet micro mill and combined and filled up with CMC solution to a volume of 20 mL, resulting in a concentration of 17.4 mg/mL.

VEHICLE
- Justification for use and choice of vehicle: not specified
- Concentration in vehicle: 17.4 mg/mL
- Amount of vehicle: 5 mL/kg bw

HOMOGENEITY AND STABILITY OF TEST MATERIAL:
- The radiochemical purity of the test item was checked by HPLC at the time of the application.
Duration and frequency of treatment / exposure:
single dose
Doses / concentrations
Remarks:
Doses / Concentrations:
100 mg/kg bw
No. of animals per sex per dose / concentration:
4 male animals group 1 (mass balance)
9 male animals group 2 (blood kinetics)
Control animals:
no
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled:
- group 1: urine, faeces, blood, plasma, liver, fat (renal), carcass, kidneys, muscle, cage wash;
- group 2: blood/plasma
- Time and frequency of sampling:
- group 1: urine and feces at 0-24, 24-48, 48-72 and 72-96 hours, organs, blood, carcass and cage wash after necropsy at 96 hours
- group 2: serial blood at 0.25, 0.5, 1, 2, 3, 4, 8, 24, 36 and 48 hours

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: urine, faeces
- Time and frequency of sampling: 0-24 hours, 24-48 hours
- From how many animals: samples pooled from 4 animals
- Method type(s) for identification: HPLC with UV detection

Results and discussion

Main ADME resultsopen allclose all
Type:
absorption
Results:
The extent of absorption, calculated based on the urinary excretion, accounted for only 0.73 % of the administered dose. Almost the complete dose was excreted unabsorbed with the feces as unchanged parent.
Type:
distribution
Results:
The tissue residues, 96 hours after administration, were very low. The highest conc. was found in abdominal fat accounting for 1.712 μg test item equivalents/g. All other selected tissues and organs revealed conc. below 0.110 μg test item equivalents/g.
Type:
metabolism
Results:
Mostly all of the test item was excreted unabsorbed with the feces as unchanged parent.
Type:
excretion
Results:
Almost the complete dose was excreted unabsorbed with the feces as unchanged parent, accounting for 97.2 % of dose within 48 hours after administration.
Type:
other: kinetics
Results:
Cmax in blood and plasma 1 hour after administration: 2.463 and 4.359 μg test item equivalents/g for blood and plasma, resp. Half-life (8-48 h) of about 13 hours. AUC (0-96 h) were calculated to be 65.2 and 114.3 μg x h/g for blood and plasma, resp.

Any other information on results incl. tables

After oral administration of [14C] test item only a very low amount of radioactivity was absorbed from the gastro intestinal tract and almost the complete dose was excreted unabsorbed as unchanged parent with the feces.

The urinary metabolite pattern investigated exhibited 7 metabolite fractions. However, the major fraction (U7) represented only 0.19 % of the dose. All other fractions were below 0.1 % of the dose.

Applicant's summary and conclusion