Aluminum sodium oxide

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:

other information

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable, well documented publication which meets basic scientific principles

Data source

Reference

Reference Type:

publication

Title:

Investigation of the aluminium biokinetics in humans: a 26Al tracer study.

Author:

Steinhausen, C. et al.

Year:

2004

Bibliographic source:

Food and Chemical Toxicology 42: 363-371

Materials and methods

Objective of study:

toxicokinetics

Principles of method if other than guideline:

Aluminium absorption, distribution, speciation and excretion in six healthy volunteers and in two patients with chronic renal failure were investigated following administration of a single oral or i.v. dose of 26Al.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Aluminium chloride

EC Number:

231-208-1

EC Name:

Aluminium chloride

Cas Number:

7446-70-0

Molecular formula:

AlCl3

IUPAC Name:

aluminum trichloride

Details on test material:

- Name of test material (as cited in study report): AlCl3
- Analytical purity: no data

Radiolabelling:

yes

Remarks:

26Al

Test animals

Species:

human

Strain:

not specified

Sex:

male

Details on test animals or test system and environmental conditions:

Eight male human individuals were investigated in the present study, six healthy volunteers and two patients with chronic renal failure (chronic glomerulonephritis in both cases).

Administration / exposure

Route of administration:

other: single oral dose and i.v. dose

Vehicle:

not specified

Details on exposure:

A single oral dose of 26Al was administered to three volunteers and to two patients, an i.v. dose was administered to three volunteers.

Duration and frequency of treatment / exposure:

single treatment

Doses / concentrations

Remarks:

Doses / Concentrations:
The oral dose consisted of 100 ng 26Al together with 100 μg 27Al given as the chemical compound AlCl3.
The i.v. dose was 1 ng 26Al together with 20 μg 27Al given also as AlCl3.

No. of animals per sex per dose / concentration:

not applicable

Control animals:

no

Details on dosing and sampling:

PHARMACOKINETIC STUDY (Absorption, distribution, speciation, excretion)
- Tissues and body fluids sampled: urine, blood
- Time and frequency of sampling: Blood samples were taken in intervals between 5 minutes and 512 days after administration. Daily urine samples were collected for 24 hours and pooled, over time periods of up to 9 days.
- Other: For the speciation measurements, blood samples were taken after 5 min., 20 min., 1 h, 4 h and 24 h after i.v. administration.

Results and discussion

Preliminary studies:

no data

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Oral administration to healthy volunteers:
The numbers of 26Al atoms in serum reach their maximum values between 1.5 and 6 h after administration with about 2.5 x 10-4, 1.3 x 10-4, 4 x 10-4 relative to the administered dose for the volunteers.
Oral administration to patients with chronic renal failure:
The numbers of 26Al atoms in the blood plasma reach their maximum values with about 1.4 x 10-4 relative to the administered dose 4 h after administration.
Intravenous administration to healthy volunteers:
Fifteen minutes after administration the amount of 26Al atoms has decreased to about 40% of the administered dose for both volunteers.

Details on distribution in tissues:

no data

Details on excretion:

Oral administration to healthy volunteers:
In the urine collected, about 7 x 10-4 and 1.4 x 10-3 26Al atoms relative to the administered dose are measured after 4 and 9 days. The experimentalaluminium clearances were obtained to be in the range from 2.2 to 17 mL/min for the healthy volunteers compared to creatinine clearances in the range between 120 and 150 mL/min. The number of 26Al atoms in the accumulated urine of the first 4 days is obtained to be about 1.4 x 10-4 relative tothe administered dose.
Oral administration to patients with chronic renal failure:
In the accumulated urine, about 5 x 10-4 and 3 x 10-4 26Al atoms relative to the administered dose are measured after 5 and 7 days. The experimental aluminium clearances were obtained to be 4.0 and 3.5 mL/min compared with the creatinine clearances of 38 and 32 mL/min, respectively.
Intravenous administration to healthy volunteers:
In the accumulated urine, about 28 and 25% of the i.v. administered 26Al atoms were measured after 5 days. Analysing the urine data, it is evident thatafter 5 days the majority of 26Al atoms is still stored in the body. The experimental aluminium clearances were obtained to be 3.1 and 2.2 mL/min compared to the creatinine clearances of 143 and 122 mL/min, respectively.

Metabolite characterisation studies

Metabolites identified:

not measured

Any other information on results incl. tables

The simulations show that the p.o. dose of 26Al stored in the bones is about 3% of that one of the i.v. dose. The i.v. blood plasma concentration of 26Al is found to be one million times larger than the p.o. concentration immediately after i.v. administration, and 30 times larger after years after i.v. administration.

The fast decrease in the plasma concentration after minutes for i.v. administration is due to the distribution to the interstitial fluid with a short time constant. The 26Al plasma concentration after years is caused by the reverse transport from the bones into the plasma. The transport to and from the peripheral compartments (liver and spleen, muscles, bones) and excretion determine the time dependence over the whole investigated time period.

The largest long-term deposition of aluminium occurs in the bones.

After years, all 26Al taken up is excreted via the urine. As seen from the long-term measurements of 26Al in the accumulated urine and as obtained from the simulations, the uptake factor of 26Al after oral application, about 99.9% of 26Al are excreted by the intestinal tract as faeces.

26Al in the accumulated urine is lower for patients with chronic renal failure due to the reduced function of the kidneys compared with healthy volunteers. This means that more 26Al is stored in the body of patients with chronic renal failure than in healthy volunteers.

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): bioaccumulation potential cannot be judged based on study results