Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
2018
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2018

Materials and methods

Objective of study:
toxicokinetics
Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 417 (Toxicokinetics)
Version / remarks:
23 July, 2010
Deviations:
no
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Batch No.of test material: 1248-1101
- Expiration date of the lot/batch: 23 Nov 2019
- Purity (radiochemical): > 98 %

RADIOLABELLING INFORMATION (if applicable)
- Radiochemical purity: > 98 %
- Specific activity: 13.2 MBq/mg of AI, 59.6 MBq/mg in acetonitrile
- Locations of the label: phenyl-U-14C

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: freezer
- Solubility and stability of the test substance in the solvent/vehicle: A stability of the test substance in sodium carboxymethyl cellulose in drinking water with a comparable batch of the non-labeled test substance over a period of 7 days stored in the refrigerator is given.

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: In order to achieve the required specific activity, respective aliquots of a solution of the radio-labeled test substance will be taken and the organic solvent will be evaporated to dryness. To the dried residue, respective amounts of non-labeled test substance and the carrier will be added and filled up to the final volume. Due to the possibility to facilitate the structure elucidation of formed metabolites, 13C-test-substance will be added to the test substance preparation with 14C-test-substance for the balance experiments and for the bile excretion experiments. For these experiments, 13C-labeled test substance is mixed with non-labeled test substance in a ratio of 1 : 2 (w : w). In order to achieve the required specific activity, respective amounts of 14C-labeled test substance will be added. Each mixture will be filled up with the carrier to the final volume.
- Final dilution of a dissolved solid, stock liquid or gel: The test substance will be prepared in 0.5 % sodium carbodymethyl cellulose in tap water (CMC). 10 mL/kg bw of test substance preparation will be dosed orally by gavage.
Radiolabelling:
yes

Test animals

Species:
rat
Strain:
Wistar
Remarks:
Crl:WI (Han)
Details on species / strain selection:
Recognized by international guidelines as the recommended test system. Study data have to be interpreted in the context of other data from the same test system.
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, 97633 Sulzfeld, Germany
- Age at study initiation: about 6 - 16 weeks
- Weight at study initiation: about 220 - 380 g prior to dosing
- Housing: During acclimatization and prior to the experiment animals will be housed in groups in polysulfonate cages. During the operation procedure for the bile experiments and multiple dosing of unlabeled test substance for balance experiments, animals are kept individually in Type III polycarbonate cages. During plasmakinetic and tissue distribution experiment animals will be kept individually in polycarbonate cages with steel wire mesh ground; from radio-labeled dosing on animals for the balance experiments will be kept in plastic metabolism cages, except for the two male animals where the exhaled air will be checked and animals in the bile excretion experiments which will be kept individually in all-glass metabolism cages type Metabowl.
- Diet (e.g. ad libitum): Kliba lab diet (mouse ( rat "GLP") either pelleted or meal (depending on the experimental conditions e.g. meal for balance experiments and pellets for plasmakinetics), ad libitum prior to and during the experiment
- Water (e.g. ad libitum): tap water ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24 °C
- Humidity (%): 45 - 65 %
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12 h / 12 h

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Remarks:
0.5 % in tap water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
- Dose 1: 30 mg test substance / mL 0.5 % sodium carboxymethyl cellulose in drinking water (tap water)
- Dose 2: 3 mg test substance / mL 0.5 % sodium carboxymethyl cellulose in drinking water (tap water)

10 mL/kg body weight of a preparation will be administered to rats by gavage.
Duration and frequency of treatment / exposure:
- Experiment 1: 1 oral dose "high dose" with 300 mg/kg bw
- Experiment 2: 1 oral dose "low dose" with 30 mg/kg bw
- Experiment 3: 1 oral dose "high dose" with 300 mg/kg bw
- Experiment 4: 1 oral dose "low dose" with 30 mg/kg bw
- Experiment 5: orally non-labeled once per day for 14 days, radio-labeled once on day 15 "low dose" 30 mg/kg bw
- Experiment 6: 1 oral dose "high dose" with 300 mg/kg bw
- Experiment 7: 1 oral dose "low dose" with 30 mg/kg bw
- Experiment 8: 1 oral dose "high dose" with 300 mg/kg bw
- Experiment 9: 1 oral dose "low dose" with 30 mg/kg bw
Doses / concentrationsopen allclose all
Dose / conc.:
30 mg/kg bw (total dose)
Remarks:
low dose
Dose / conc.:
300 mg/kg bw (total dose)
Remarks:
high dose
No. of animals per sex per dose:
- Experiments 1, 2, 3, 4 and 5: 4
- Experiments 6 and 7: 6
- Experiments 8 and 9: 12
Control animals:
not specified
Details on study design:
- Rationale for animal assignment (if not random): Type and duration of such studies require that animals of similar age are ordered sequentially in batches prior to the experiments. Therefore the conventional randomization and assignment to groups is not possible. Animals will be selected based on health status and to provide a narrow range of body weights (+/- 20 %).
Details on dosing and sampling:
TOXICOKINETIC / PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled (delete / add / specify): urine, faeces, blood, plasma, bile, cage wash
- Time and frequency of sampling: 1, 2, 4, 8, 24, 48, 72, 96, 120, 144, 268 hours (all dose groups)
Statistics:
All relevant data will be presented in appropriate summary tables. Group mean values and standard deviations will be calculated if necessary to aid interpretation. Radioactivity concentrations will be expressed in % of total dose administered. Analysis of kinetic data will be performed based on the group mean values using the PC program system WinNonLin Version 8.0. The results will be evaluated and discussed and individual animal data will be presented in the report.
Parts of balance and tissue distribution experiments will be presented also in µg Eq/g in addition to % of total dose administered as described in the study plan. The results of plasmakinetic experiments will be presented in µg Eq/g only and not as % of total dose administered.

Results and discussion

Main ADME results
Type:
other: ongoing study

Applicant's summary and conclusion