Hafnium tetrachloride

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: no GLP study but enough details are given to conclude on hafnium absorption

Data source

Reference

Reference Type:

publication

Title:

The metabolism of radiohafnium in marmosets and hamsters

Author:

Taylor DM, Siedel A, Doerfel H

Year:

1985

Bibliographic source:

International Journal of Nuclear medecine and biology, 12 (5): 387-391

Materials and methods

Objective of study:

metabolism

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Radiohafnium was administered oraly or subcutaneously to hamsters and intramusscularly for marmosets. Whole body radioactivity measurments and tissues samples scintillation were made.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Hafnium

EC Number:

231-166-4

EC Name:

Hafnium

Cas Number:

7440-58-6

IUPAC Name:

hydrogen fluoride

Test material form:

other: solution

Details on test material:

For Chinese hamsters: 181Hf from Amersham, Buchler, Braunschweig FRG 40 kBq (ca. 1 MBq/kg)
For marmosets: 181Hf-citrate form Amersham, Bh=uchler, Braunschweig FRG 3 kBq (ca. 10 kBq/kg)

Radiolabelling:

yes

Remarks:

181Hf

Test animals

Species:

other: Chinese hamsters and marmosets

Sex:

male/female

Details on test animals or test system and environmental conditions:

Chinese hamsters were bred in the institute for breeding pairs obtained from the Bundesforschungsandstalt für Ernährung, Karlsruhe FRG. They were maintained on a pellet diet, with food and water provided ad libitum.
Marmosets (Callithrex jacchus) came fromthe breeding stock of the Institute of Human Genetics, University of Heidelberg FRG. The animals were between 4 and 9 years old, they were maintained on marmosets pellets and various fresh fruits.

Administration / exposure

Route of administration:

other: hamsters: oral and subcutaneous / marmosets: intramuscular

Vehicle:

not specified

Details on exposure:

Hamsters: radiohafnium was administered orally by placing 10 µL of solution on the back of the tongue or subcutaneously by injection of 0.2 cm3 of solution under the skin of the back.
Marmosets were injected intramusculary into the right thigh with 3 kBq of 181Hf-citrate.

Duration and frequency of treatment / exposure:

One exposure only.

Doses / concentrations

Remarks:

Doses / Concentrations:
For Chinese hamsters: 40 kBq (ca. 1 MBq/kg)
For marmosets: 3 kBq (ca. 10 kBq/kg)

No. of animals per sex per dose / concentration:

marmosets: 2 males and 2 females
hamsters: not mentioned

Control animals:

no

Details on dosing and sampling:

Measurement of radioactivity in marmosets
The in vivo measurements were realised in the human whole body counter. This device consists of four 20 cm dia. x 10 cm thick NaI (Tl) scintillation detectors set up in pairs above and below a stretcher. In order to achieve standard measuring conditions, the animals were counted insteel cages, positioned in the geometrical centre between the detectors and counted for 10 min each. For determination of the 181Hf activity, the predominant 482keV gama peak was evaluated. The measuring device was calibrated with 181Hf standard sources positioned at representative places within the steel cages, this calibration showed the lower detection limit to be about 30Bq 181Hf. The error due to the calibration and the positioning of the animals is about +/- 15 %.
The four marmosets were studied by whole body counting for up to 182 days after injection

Measurement of radioactivity in rats
The measurements of whole body radioactivity in the hamsters were made in a small-animal-whole-body counter consisting of two opposing 13 cm dia. 10 cm thick NaI(Tl) crystal detectors contained in a lead and steel shield.

Each animal was counted first within 30 min of radionucleide injection and at daily or longer intervals thereafter. On each occasion, an aliquot of the injection solution was counted in order to correct for radioactivity decay and small changes in the efficiency of the counter. The initial count on each animal was taken as 100 % for the purpose of calculating the percentage retention at later times.

Measurement of radioactivity in tissue samples
Tissue samples from marmosets and hamsters were assayed by scintillation counting in an automatic gama scintillation counter.

Results and discussion

Main ADME results

Type:

absorption

Results:

oral absorption : between 0.04 and 0.13 % of the ingested dose in Chinese hamsters.

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Absorption was calculated by using a correction factor for excretion based on the whole body retention of 71 % +/- 1 % in 10 rats given 181Hf citrate by sc injection 7 days previously.
Absorption (%) of 135+181Hf from the gastro-intestinal tract of Chinese hamster
- Hf chloride pH6, 1 µg/kg, fasted 18h: between 0.05 and 0.09 % dose +/- 0.01 %
- Hf chloride in 0.2 M HCl (1 µg/kg pH2): 0.13 % +/- 0.01 %
- Hf in "orange juice" (1 µg/kg pH4): 0.05 % +/- 0.01 %
- Hf citrate (1 µg/kg pH 7): 0.09 % +/- 0.01 %

Details on distribution in tissues:

Distribution in tissues: see details in free text field

Details on excretion:

The retention data for the marmosets could be fitted to a two component exponential function
R = 42 exp-0.39t + 66exp-0.0021t
where t is the time after injection in days, and R the amount of 181Hf retained in per cent of the injected dose.

Whole body retention in hamsters was measured in the whole body counter at daily or longer intervals for 28 days at which time the animals were killed and the retention in the various organs and tissues was measured: 4.7 % +/- 0.2 in liver, 0.76 % +/- 0.05 in kidneys, 0.18 % +/- 0.02 in spleen, 3.5 % +/- 0.3 in muscle, 12 % +/- 2 in skin and 25 % +/- 2 in skeleton, total body 62.6 % +/- 2.8.

Metabolite characterisation studies

Metabolites identified:

not measured

Any other information on results incl. tables

During the course of the study, 2 animals (1 male and 1 female marmosets) became ill and had to be humanely killed at 13 and 97 day post injection, the nature of the progressive disease which appeared to involve a fatty degeneration of the liver has not been established.

Distribution of intramuscularly injected 181Hf in the organs of marmosets, values represent percent of dose which was resorbed form injection site until day of sacrifice

day of		liver		femur		kidneys		spleen		lungs
sacrifice	sex	% of dose	% /g	% of dose	% / g	% of dose	% / g	% of dose	% / g	% of dose	% / g
13	male	8.3	0.5	1.1	0.9	4.3	1.9	0.2	0.2	0.3	0.8
97	female	12.1	0.7	0.7	0.7	1.5	0.8	0.2	0.7	0.3	0.2

Applicant's summary and conclusion

Executive summary:

Hf is poorly soluble in water or saline solutions: thus, it is not absorbed efficiently by ingestion. This study, realized with radiohafnium, found an oral absorption ranging between 0.04 and 0.13 % of the ingested dose in Chinese hamsters. It can be absorbed by inhalation only under its aerosol form.

In hamsters, radiohafnium was administered subcutaneously by injection of 0.2 cm³of the solution (40 kBq) under the skin of the back. The radiohafnium organ distribution was skeleton greater than skin greater than liver greater than muscle, at about 7 days post injection.

Four marmosets, 2 females (aged 4 and 8 years) and 2 males (aged 6 and 9 years), exposed to radiohafnium, were also studied. They were injected intramuscularly into the right thigh with 3 kBq. For males and females, sacrificed respectively after 13 and 97 days, the following percentages of doses found in different organs were: in liver,8.3-12.1 % of the dose injected, bones around 1 % measured in the femur; in the kidneys, 1.5-4.3 %; and in a lesser extent in spleen and lung.