Registration Dossier

Administrative data

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

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2013
Report Date:
2013

Materials and methods

Objective of study:
toxicokinetics
bioaccessibility
Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 417 (Toxicokinetics)
Qualifier:
according to
Guideline:
EPA OPPTS 870.7485 (Metabolism and Pharmacokinetics)
GLP compliance:
yes (incl. certificate)

Test material

Reference
Name:
Unnamed
Type:
Constituent
Specific details on test material used for the study:
Batch Identification: 724-2102
CAS No.: 76205-19-1
Radiochemical purity: >98 %
Homogeneity: given
Chemical name: 1-(4-chlorophenyl)-1H-pyrazol-3-ol
Radio label: phenyl-U-14C
Specific activity (active ingredient): 8.99 MBq/mg
Storage conditions: keep in refrigerator (approx. +4°C) or cooler

Non-labeled test substance
Batch Identification: L84-174
Purity: 99.6 % (tolerance +- 1.0 %)
Homogeneity: given
Storage stability: expiry date: 01 Apr 2020
Chemical name: 1-(4-chlorophenyl)-1H-pyrazol-3-ol
Physical state /appearance: solid, yellow
Storage conditions: refrigerator

Stability in vehicle: The stability of the radioactive test substance in the vehicle was verified in the experiments by LSC and Radio-HPLC.
Homogeneity and achieved concentrations: The homogeneity and achieved radioactivity concentrations of the test substance preparations
were verified by HPLC and liquid scintillation counting in the experiments.


Radiolabelling:
yes

Test animals

Species:
mouse
Strain:
NMRI
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, 97633 Sulzfeld, Germany
- Weight at study initiation: about 30 – 40 g
- Housing: During acclimatization and prior to the experiment animals were housed individually in Macrolon cages type M III. During the experiments animals were housed individually in steel
wire mesh cages
- Diet (e.g. ad libitum): Kliba lab diet (mouse / rat “GLP”) pelleted, ad libitum prior to and during the experiments
- Water (e.g. ad libitum): drinking water ad libitum
- Acclimation period: at least 8 days before the beginning of the experimental phase

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24°C
- Humidity (%): 30-70%
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:

A stock solution of the radiolabeled test substance in acetone and unlabeled substance were mixed in appropriate amounts. The acetone was evaporated and the mixture was solved in 0.5% CMC in drinking water. 10 mL/kg bw were dosed. The target quantity of radioactivity per animal was about 10 MBq. Therewith, the concentration of the test substance in the test substance preparation and its specific activity was about 100 mg/mL and 27.6 MBq/mL, respectively.
Duration and frequency of treatment / exposure:
frequency of treatment: once; sacrifice 5 hours after dosing
Doses / concentrations
Dose / conc.:
1 000 mg/kg bw (total dose)
No. of animals per sex per dose:
5
Control animals:
yes, concurrent no treatment
Details on study design:
The study was designed to obtain data on kinetics and to demonstrate that the test substance reaches the systemic circulation and the bone marrow.
Details on dosing and sampling:
TOXICOKINETIC / PHARMACOKINETIC STUDY (Absorption, distribution, excretion)

The radioactivity was determined in the following samples:
blood cells, plasma, bone marrow.



Results and discussion

Bioaccessibility

Bioaccessibility testing results:
The mean total radioactive residues (TRR) 5h post dosing were 25.3 μg Eq/g in bone marrow corresponding to 0.001 % of dose. In blood cells mean total radioactive
residues of 7.62 μg Eq/g were found, corresponding to 0.003 % of dose. The mean residues in plasma were 29.83 μg Eq/g corresponding to 0.008 % of dose.

Applicant's summary and conclusion

Conclusions:
The current study demonstrated that radioactive residues of 14C- Pyrazolone are present in the systemic circulation and in bone marrow of mice 5 h after single oral administration of the test substance at a target dose level of 1000 mg/kg bw.