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Toxicological information

Basic toxicokinetics

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basic toxicokinetics
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2007-11-26 until 2008-05-26
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP - Guideline study

Data source

Reference Type:
study report
Report Date:

Materials and methods

Objective of study:
other: Absorption, distribution and excretion of 14C- Uvinul A Plus in rats at dose level of 100 mg/kg bw.
Test guidelineopen allclose all
according to
OECD Guideline 417 (Toxicokinetics)
according to
EU Method B.36 (Toxicokinetics)
according to
EPA OPPTS 870.7485 (Metabolism and Pharmacokinetics)
according to
other: Japan/ MAFF: Guidelines on the Compiling of Test Results on Toxicity; Tests on In Vivo Fate in Animals, 2001
GLP compliance:
yes (incl. certificate)

Test material

Details on test material:
Labelled test substance:
- Name of test material (as cited in study report): 14C-Uvinul A Plus
- Lot/batch No.: 844-1 101
- Radiochemical purity: 99.5%
- Specific activity: 6.78 MBq /mg
- Stability under test conditions: The stability, homogeneity and correctness of the concentration of the test item preparations as well as the radiochemical purity of 14C-Uvinul A Plus were checked via HPLC.
- Storage condition of test material: At low temperature and in the dark

For producing the test preparation applied in the study, the labelled test substance (detailed above) had to be mixed with the non-labelled test substance (detailed below) in order to reach the required specific activity.

Non- labelled test substance:
- Name of test material (as cited in study report): Uvinul A Plus
- Physical state / appearance: liquid up to solid, yellow
- Analytical purity: 98.7 g / 100 g
- Lot/batch No.: PBG-Charge 00000677LO
- Stability under test conditions: The stability in the vehicle was confirmed analytically. The homogeneity and correctness of the concentrations were also verified analytically.
- Storage condition of test material: Ambient, protection from light

Test animals

Details on test animals and environmental conditions:
- Source: Charles River Laboratories, Sulzfeld Germany
- Age at study initiation: At least about 8 weeks at the date of administration
- Weight at study initiation: Mean weight for the female rats: 235.3 g. Mean weight for the male rats: 328.4 g.
- Housing: During the acclimatization and prior to the experiment in type III Macrolon cages.
During balance experiment in all-glass metabolism cages; type Metabowl (Jencons, Leighton Buzzard, UK).
During the experiment animals were housed individually with the cages being labelled with the project number, animal number, dose and time of first administration.
- Individual metabolism cages: yes
- Diet: Kliba lab diet (mouse/ rat "GLP") either pelleted (e.g . during acclimatization or in steel wire mesh cages) or as meal (e.g. in metabolism cages).
Origin: Provimi Kliba SA, 4303 Kaiseraugst, Switzerland ad libitum prior to and during the experiments.
- Water: Tap water ad libitum

- Temperature (°C): 20- 24°C
- Humidity (%): 30-70%
- Photoperiod (hrs dark / hrs light): Natural day/ light rhythm with additional artificial light as required during working hours.

IN-LIFE DATES: From: 2007-11-26 To: 2007-11-29

Administration / exposure

Route of administration:
oral: gavage
olive oil
Details on exposure:
The requested details in this field are not relavent for the present study (NA- not applicabe)
Duration and frequency of treatment / exposure:
A single oral administration (5mL/ kg bw; 0.5-2 MBq/ animal)
Doses / concentrations
Doses / Concentrations:
Nominal dose level of 100 mg/kg bw.
No. of animals per sex per dose:
24 animals
3 groups, 8 rats in each group (4 females, 4 males)
Group 1: Experiment group (bile duct cannulated at the testing laboratory) - one oral dose of 100 mg/kg bw
Group 2: Same as group 1- Repetition of the experiment
Group 3: Same treatment as in the other 2 groups (animals were delivered with bile duct catheters from the breeding lab) - Confirmation experiment
Control animals:
Positive control:
No positive control
Details on study design:
- Dose selection rationale: 100 mg/kg bw was selected to be applied in this study as it was considered to exert no adverse effects based on a subchronic toxicity study in rats (OECD 408) and it represents a technically appropriate dose for the assessment of the bioavailability of radiolabelled Uvinul A Plus via the oral route.
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: Urine, feces, bile, cage wash
- Time and frequency of sampling: Bile excretion was collected in three-hour time intervals up to 72 hours. Urine and feces were collected in 24 hours intervals up to 72 hours.
- Other: After the experiment, animals were sacrificed and the following tissues were checked for remaining radioactivity: stomach and stomach contents, gut and gut contents, carcass.

Mean values and SD were the only (required) calculated statistical parameters in the study.

Results and discussion

Preliminary studies:
No preliminary studies

Toxicokinetic / pharmacokinetic studies

Details on absorption:
In the present study the bioavailability after single oral administration of 14C-Uvinul A Plus to rats at a dose level of 100 mg/kg bw was examined. The bioavailability was calculated as the sum of radioactivity found within 72 hours in bile (males: 11.28% , females: 19.76% of dose applied), urine (males: 13.79%, females: 22.62% of dose applied), cage wash (recoveries of 0.71% in males and 1.46% in females) and carcass (recoveries of 0.46% in males and 1.26% in females). Altogether the bioavailability was 26% and 45% of the administered dose in male and female rats respectively.
Details on distribution in tissues:
Not determined but radioactivity in the residual carcass was 0.46% in male animals and 1.26% of dose in female animals.
Details on excretion:
Total excretion of radioactivity within 72 hours:
Via bile: 11.28 % of the administered dose for male rats and 19.76 % of the administered dose for female rats.
Via urine: 13.79% of the administered dose for male rats and 22.62 % for female rats.
Via feces: 51.47% of the administered dose for male rats and 32.78% for female rats.
In cage wash: 0.71% (male rats) and 1.46 % (female rats) of the administered dose were recovered.

Metabolite characterisation studies

Metabolites identified:
not measured

Any other information on results incl. tables

The mean total recovery of radioactivity was found to be 79.84% and 88.05% of the applied dose after single oral administration of 100 mg/kg bw Uvinul A Plus to male and female rats, respectively.

Applicant's summary and conclusion