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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: Experiment on biokinetic parameters for ingestion of radionuclides of zirconium in animals using stable tracers. As the substance identification is not entirely clear, the study is given a Klimisch score 3.

Data source

Reference
Reference Type:
publication
Title:
Determination of biokinetic parameters for ingestion of radionuclides of zirconium in animals using stable tracers
Author:
de Bartolo D, Cantone MC, Giussani A, Garlaschelli L, Roth P, Werner E
Year:
2000
Bibliographic source:
Radiation and Environmental Biophysics 39: 53-58

Materials and methods

Objective of study:
other: intestinal absorption, clearance from plasma and exchange with organs
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
A method is developed based on the double stable tracer technique, which allows information to be obtained directly from measurements performed on humans without any associated radiation hazard. The feasibility of the method for investigating the biokinetics of Zr was tested in experiments on rabbits. Isotopically enriched 90Zr and 96Zr oxides were used for the investigations. Three investigations were performed on fasted male rabbits by administering 100 µg of the iv tracer to each rabbit but different oral amounts.
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Isotopically enriched 90Zr and 96 Zr oxides
- Two isotopic solutions were obtained by fusion of the oxides with hydrogen potassium sulphate in ceramic crucibles at 800°C for 3 h (1:25 ZrO2:KHSO4) followed by dissolution of the fusion product in sulphuric acid and dilution with bidistilled water to a final concentration of 0.75 mg/ml and 1 mg/ml, respectively. At pH = 1 the principal component of the solution is expected to be Zr(SO4)2+.
- Supplier of the isotopically enriched Zr oxides: Chemotrade, Düsseldorf, Germany
Radiolabelling:
yes

Test animals

Species:
rabbit
Strain:
not specified
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- The investigations were performed on fasted male rabbits

Administration / exposure

Route of administration:
other: iv injection and oral administration
Vehicle:
other: Two isotopic solutions were obtained as described in section 'Details on test material'
Details on exposure:
Three investigations were performed on fasted male rabbits by administrating 100 µg of the iv tracer to each rabbit but different oral amounts.
Duration and frequency of treatment / exposure:
No data
Doses / concentrations
Remarks:
Doses / Concentrations:
Test 1: Injected tracer: 43.7 µg/kg body weight
Test 1: Oral administration: 1.0 mg/kg body weight
Test 2: Injected tracer: 46.3 µg/kg body weight
Test 2: Oral administration: 2.3 mg/kg body weight
Test 3: Injected tracer: 47.2 µg/kg body weight
Test 3: Oral administration: 3.3 mg/kg body weight
No. of animals per sex per dose:
No data
Control animals:
no
Positive control:
No
Details on study design:
No data
Details on dosing and sampling:
Within the first 6h after administration, about 10 blood samples were withdrawn via a catheter placed in a femoral artery into heparinized syringes and centrifuged. For each sample a volume of 0.8 mL of plasma was then taken up with a micropipette (accuracy better than ± 2%)., and 10 µg of vanadium were added as an internal reference element. Samples of blank plasma matrix with addition of a known quantity of both Zr tracers and of the reference element were also prepared and utilized as standards for the quantitative determination. All samples were dried in an oven at 35°C, pulverized in an agate mortar and then pressed in a die to obtain a compact target of 9 mm diameter and about 0.1 g/cm-2 thickness. They were sealed in appropriate aluminum frames and mounted on a rotating disc placed in an irradation chamber. With this device, up to 39 samples can be simultaneously irradiated under the same beam conditions. The activation experiments were performed using the proton beam of the Philips Cyclotron with a current intensity of 10 µA. Irradiation times lasted about 10h. The de-excitation spectra of the active samples were collected using HPGe detectors and a conventional nuclear spectrometry system. In each sample, the contents of 90Zr and 96Zr were determined on the basis of the intensities of the gamma-lines emitted by 90Nb and 96Nb, respectively. The tracer concentration values were calculated after correction for isotopic impurities.
Statistics:
Best fit curves are obtained using a three-compartiment catenary system, consisting of the small intestine, transfer compartment (plasma) and unquantified tissue pool. Transfer between the compartments and loss to excretion is assumed to be governed by first-order kinetics.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on distribution in tissues:
Results of test 2: The decrease of the concentration of the injected tracer shows the typical pattern of reflux systems. The bi-exponential curve reflects the clearance of the tracer from the plasma to compartment 3 and the reflux into the plasma from this compartment. This assumption appears to be in good agreement with the experimental data. For the oral tracer, the pattern is the result of two competing mechanisms: (1) the absorption into the transfer compartment at the beginning from the GI tract and later, to a lesser extent, reflux from the other organs; and (2) the clearance from plasma. As a consequence, the concentration first increases rapidly, reaching a maximum at about 40 min, then decreases with an asymptotic behaviour similar to that of the injected tracer. Similar patterns were found for the other two tests.

Applicant's summary and conclusion

Conclusions:
The concentration of oral administered Zr tracers first increases rapidly, reaching a maximum at about 40 min, then decreases with an asymptotic behaviour similar to that of the injected tracer.