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Toxicological information

Basic toxicokinetics

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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: Basic data given

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1994
Report Date:
1994

Materials and methods

Objective of study:
toxicokinetics
Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
Two male volunteers received the following three oral doses of aluminium several weeks apart:
- Al hydroxide (100 mg stable Al3+ ion and 120 Bq of 26Al at pH=7.0) as a suspension in water;
- Al hydroxide (as above) followed by 100 ml of 1% aqueous trisodium citrate, pH=6.5
- 100 mL Al citrate containing 100 mg stable Al3+ ion and 120 Bq of 26Al in 1% aqueous trisodium citrate, pH=6.5
The test materials were administered intragastrically using a paediatric feeding tube inserted via the nose. Blood samples were collected 1, 4 and 24 hours after the administration. Daily output of urine and faeces was collected for 6 days. Faecal samples were analyzed for 26Al using coincidence gamma-counting, and blood and urine samples - using accelerator mass spectrometry (AMS).
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
26Al in carrier-free form was used in this study. A preparation of 26Al in a nitric acid solution was produced and supplied for the study at a concentration of 6.0 kBq/mL.
Preparation of test materials.
For each of the test materials, the mass of stable carrier aluminium was 100 mg. The material was administered as a solution (Al citrate) or a colloidal suspension (aluminium hydroxide) in water. The total volume of the administered solution/suspension was 100 mL.
26Al-labelled aluminium, trisodium citrate complex
The stock solution was prepared by adding 3.572 g of AlCl36H2O (analytical grade) to 400 ml of analytical-grade water to give a concentration of 100 mg Al3+ ion per 100 mL. To this, 400 Bq of 26Al and 4.0 g of analytical grade trisodium citrate were added. The pH of the final solution was 3.5.
26Al-labelled aluminium hydroxide.
The stock suspension was prepared by adding 3.572 g of AlCl3 6H2O (analytical grade) to 400 ml of analytical-grade water, also giving a concentration of 100 mg Al3+ ion per 100 mL. To this, 400 Bq of 26Al was added with stirring to ensure dispersion. 0.1 M sodium hydroxide was added drop-wise until aluminium hydroxide was precipitated as a colloid. The pH of the suspension was 7.0.
Stable citrate was prepared as a 1% solution of analytical-grade trisodium citrate dissolved in analytical-grade water. The pH of the solution of 6.5.
Radiolabelling:
yes
Remarks:
26Al

Test animals

Species:
human
Strain:
not specified
Sex:
male
Details on test animals and environmental conditions:
Study participants:
Source: interested staff members at the Biomedical Research department and individuals who responded to general advertisements (150 potential participants)
Inclusion criteria:
1) Sex: male
2) Age: 20-60 years
3) Health status: no diseases of the heart, liver, kidney, lung, blood, nervous system, gastrointestinal tract, psychiatric disorders based on medical history, physical examinations and laboratory screening.
4) Availability to complete the study
Exclusion criteria:
1) Females
2) History of alcohol or drug abuse
3) Regular use of medications including prescribed drugs and over-the-counter preparations. The latter was aimed primarily at excluding individuals who used aluminium-containing antacids.
Two male volunteers were selected based on these criteria:
- Volunteer A: age 33 years, height 1.94 m, weight 72 kg, estimated blood volume 5.4 L.
- Volunteer B: age 29 years, height 1.76 m, weight 78 kg, estimated blood volume 5.1 L.
Details on the laboratory screening results (hematology, blood biochemistry) are presented in tables 2-4; all parameters were normal.

Administration / exposure

Route of administration:
oral: unspecified
Vehicle:
water
Details on exposure:
The test materials were administered intragastrically using a paediatric feeding tube inserted via the nose. The solutions were introduced into the feeding tubes from a syringe. A small volume of air was pushed through the tube after completion of the procedure to ensure that any residual fluid was cleared into the stomach. No residues were detected in the tubes or syringes by gamma-ray spectrometry.
Duration and frequency of treatment / exposure:
Day 1: Al hydroxide
Day 21: Al hydroxide followed by 1% aqueous trisodium citrate
Day 49: Al citrate
Doses / concentrations
Remarks:
Doses / Concentrations:
Target doses: 100 mg of stable aluminium carrier and 120 Bq of 26Al
The quantity of administered 26Al was determined by gamma-ray spectrometry of aliquots of the stock solutions prepared for administration. The estimated administered activities and masses of 26Al were:
- 26Al-labelled aluminium hydroxide: 117±1 Bq (1.65 ± 10-7 g)
- 26Al-labelled aluminium trisodium citrate: 112±1 Bq (1.58 ± 10-7 g)
Cumulative 26Al recovery over 6 days after each administration:
an average of 120.7 Bq 26Al was recovered following administration of 26Al-labelled aluminium hydroxide and an average of 122.9 Bq was recovered following administration of 26Al-labelled aluminium citrate. The differences with the estimated intakes were not significant, were consistent with the accuracy of the techniques and were expected to have a negligible effect on calculation of absorbed fraction.
No. of animals per sex per dose:
2
Control animals:
no
Positive control:
No.
Details on study design:
Two healthy male volunteers were selected out of 150 prospective volunteers (interested staff members at the Biomedical Research Department and individuals who responded to general advertisements) based on well-defined selection criteria.
The volunteers received the following three oral doses of 26Al-labelled compounds:
- Day 1: Al hydroxide (100 mg stable Al3+ ion and 120 Bq of 26Al at pH=7.0) as a suspension in water;
- Day 21: Al hydroxide (as above) followed by 100 ml of 1% aqueous trisodium citrate, pH=6.5;
- Day 49: 100 mL Al citrate containing 100 mg stable Al3+ ion and 120 Bq of 26Al in 1% aqueous trisodium citrate, pH=6.5.
The test materials were administered intragastrically using a paediatric feeding tube inserted via the nose.
A venous blood sample (20 ml) was taken from each volunteer on the day before the first dosing. This sample was analyzed for Ca+, PO4-, Mg2+, 25-OH Vitamin D and 1.25-OH Vitamin D at the PMC Ltd (London). A 10-ml blood sample was taken on that day for 26Al determination by AMS. Similar 10-ml blood samples were also taken for 26Al determination on the day prior to each subsequent dosing. In these samples, aluminium residues from previous administrations were determined and used as base-line data.
Blood samples (10 ml) were collected 1 hour (±10 min), 4 hours (±30 min) and 24 hours (±1 hour) after each administration. Persons potentially contaminated with 26Al did not handle the blood samples.
Daily output of urine and faeces was collected for 6 days following each dosing. The times of voiding and the times of each addition to the 24-hour urine sample were recorded. 10 mL of concentrated nitric acid were added to each urine collection bottle as a preservative. Faecal samples were analyzed for 26Al using coincidence gamma-counting, blood and urine samples - using accelerator mass spectrometry (AMS). Ion sources for AMS were prepared at the University of Manchester.
The AMS measurements were performed in Canberra using the tandem Van de Graaf accelerator at the department of Nuclear Physics, Australian National University.
Details on dosing and sampling:
The test materials were administered intragastrically using a paediatric feeding tube inserted via the nose. The solutions were introduced into the feeding tubes from a syringe. A small volume of air was pushed through the tube after completion of the procedure to ensure that any residual fluid was cleared into the stomach. No residues were detected in the tubes or syringes by gamma-ray spectrometry.

Anti-coagulant was added to blood samples, after which they were transferred to the University of Manchester for further processing. After the addition of 1 mg of stable aluminium tracer, the samples were wet ashed with fuming nitric acid to zero carbon content; iron was removed as FeCl3 into di-isopropyl ether; 1 mg calcium was added, and the aluminium precipitated as the phosphate at pH=7.0. Aluminium/calcium phosphate was transferred to ion source and heated at 900 °C in oxygen for 6 hours to produce aluminium oxide.

Urine samples were weighed, acidified and evaporated to dryness under infra-red lamps. The residues were transferred to the Department of Chemistry, University of Manchester, to prepare ion sources for AMS. For preparation of ion sources, the dried residue was dissolved in nitric acid; to this a known quantity (3-5 mg) of stable 27Al yield tracer was added. The resulting solution was divided into two aliquots: one was used for analysis and the other retained for confirmatory analysis if required. To remove aluminium from the solution, calcium was added to the aliquot for analysis, which followed by phosphate precipitation at pH=7. Calcium and boron were removed from the precipitate by solvent extraction. The resulting aluminium nitrate solution was then evaporated onto the sample cavity of the ion source. These were fired at 900 °C in oxygen to produce aluminium oxide.

The ion sources prepared from the urine and blood samples were analyzed by AMS using the Van de Graaf accelerator at the Department of Nuclear Physics, Australian National University. 26Al content in each sample was determined from measurements of 26Al:27Al ratios.

Fecal samples were weighed, dried, ashed at 500 °C in a muffle furnace to a near-white ash and weighed again. The ash from each sample was analyzed for 26Al using coincidence gamma-counting.
Statistics:
Not required.

Results and discussion

Preliminary studies:
No data.

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Blood
26Al-labelled aluminium hydroxide: no temporal differences between the two volunteers, peak blood concentration of 26Al was observed 4 hours post-administration.

26Al-labelled aluminium citrate or aluminium hydroxide in the presence of citrate: temporal differences were observed between the volunteers (26Al concentrations were highest 1 hour post-exposure in volunteer A but4 hours post-exposure in volunteer B).

Of the three test materials, 26Al given as aluminium citrate was most bioavailable in both volunteers, resulting in the highest time-integrated 24-hour blood 26Al concentrations. The least bioavailable was aluminium hydroxide. Co-administration of the stable citrate solution increased and delayed the uptake of 26Al from the 26Al-labelled aluminium hydroxide (the delay was more evident in subject B). These results suggest that blood aluminium concentrations “reach no convenient and consistent effective plateau and that bioavailability cannot be accurately determined from 26Al or 27Al levels at a single time after administration.” Absorbed fractions of 26Al determined on the basis of calculated blood volumes and blood 26Al concentrations measured 1, 4 or 24 hours post-administration were inconsistent: higher at 4 hours than at 1 hour in some cases and the opposite in others, higher for volunteer A at some time points but higher for volunteer B at other points.
Details on distribution in tissues:
Not studied.
Details on excretion:
Gut retention and faecal excretion
No systematic differences were found between the two volunteers in the mass of faeces voided on each occasion.

The cumulative faecal excretion of 26Al during the 6-day period following administration of each test material was similar in the two volunteers. In both, the faecal excretion of unabsorbed 26Al was virtually complete by 6 days post-administration. There were differences between the volunteers in the pattern of faecal excretion of 26Al: volunteer B retained aluminium for 1-2 days longer than volunteer A, and this was the case following administration of each test material. Therefore, the cumulative gastro-intestinal occupancy of 26Al (expressed as Bq-days) was higher in volunteer B, which creates higher potential for absorption in this volunteer.

Aluminium administered with citrate was retained longer in both volunteers compared to aluminium administered as hydroxide alone.
Urine
There were no significant differences between the volunteers in the weight of collected urine. For all the test materials, 26Al urinary excretion was highest in the first day post-administration and rapidly declined thereafter. The decline was sharpest after administration of 26Al as aluminium citrate. The 26Al urinary excretion was slowest after administration of 26Al-labelled aluminium hydroxide. Co-administration of the citrate increased the levels of 26Al urinary excretion. In volunteer B the excretion was slower than in volunteer A. By day 3 post-administration, cumulative urinary excretion of 26Al reached a plateau for all three Al species (figure 6).

Metabolite characterisation studies

Metabolites identified:
not measured
Details on metabolites:
Not applicable

Any other information on results incl. tables

Toxicokinetic parameters:

Absorbed fractions calculated on the basis of26Al urinary excretion data (assuming 72% excretion of absorbed26Al in urine*):

26Al as aluminium hydroxide                    1.04x10-4 (0.01%)

26Al as aluminium hydroxide with citrate      1.36x10 -3 (0.136%)

26Al as aluminium citrate                         5.23x10-3 (0.523%)

*Based on results of previous studies

The calculated total radiation dose from three administrations was 1.6 µSv, which was 320 times lower than the World Health Organization dose limit of 500 µSv for a category 1 volunteer study.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): other: the study was not designed to assess bioaccumulation potential.
“The results of the present study suggest that in common with other trivalent metals, aluminium is relatively non-bioavailable and that the consumption of either aluminium citrate or aluminium hydroxide in normal quantities is unlikely to result in toxicologically significant body burdens of this metal.”
The kinetics of Al uptake from the gastrointestinal tract is subject to significant inter-individual variability and depends on the aluminium species.
Executive summary:

Two healthy male volunteers received the following three oral doses of26Al-labelled compounds several weeks apart: 1) Al hydroxide (100 mg stable Al3+ion and 120 Bq of26Al at pH=7.0) as a suspension in water; 2) Al hydroxide (as above) followed by 100 ml of 1% aqueous trisodium citrate, pH=6.5; 3) 100 mL Al citrate containing 100 mg stable Al3+ion and 120 Bq of26Al in 1% aqueous trisodium citrate, pH=6.5. The test materials were administered intragastrically using a paediatric feeding tube inserted via the nose.

A venous blood sample (20 ml) was taken from each volunteer on the day before the first dosing. This sample was analyzed for Ca2+, PO42-, Mg2+, 25-OH Vitamin D and 1.25-OH Vitamin D at the PMC Ltd (). A 10-ml blood sample was taken on that day for26Al determination by AMS. Similar 10-ml blood samples were also taken for26Al determination on the day prior to each subsequent dosing. In these samples, aluminium residues from previous administrations were determined and used as base-line data.

Blood samples (10 ml) were collected 1 hour (±10 min), 4 hour (±30 min) and 24 hours (±1 hour) after each administration. Daily output of urine and faeces was collected for 6 days following each dosing. The times of voiding and the times of each addition to the 24-hour urine sample were recorded. Faecal samples were analyzed for26Al using coincidence gamma-counting, blood and urine samples - using accelerator mass spectrometry (AMS).

The cumulative faecal excretion of26Al during the 6-day period following administration of each test material was similar in the two volunteers. In both, the faecal excretion of unabsorbed26Al was virtually complete by 6 days post-administration. There were differences between the volunteers in the pattern of faecal excretion of26Al: volunteer B retained aluminium for 1-2 days longer than volunteer B, and this was the case following administration of each test material. Therefore, the cumulative gastro-intestinal occupancy of26Al (expressed as Bq-days) was higher in volunteer B, which created higher potential for absorption in this volunteer. Aluminium administered with citrate was retained longer in both volunteers compared to aluminium administered as the hydroxide.

After administration of26Al-labelled aluminium hydroxide there were no temporal differences between the two volunteers in blood26Al concentrations, peak blood concentration of26Al was observed 4 hours post-administration. After administration of26Al-labelled aluminium citrate, or aluminium hydroxide in the presence of citrate, temporal differences were observed between the volunteers: blood26Al concentrations were highest 1 hour post-exposure in volunteer A but 4 hours post-exposure in volunteer B. Of the three test materials,26Al given as aluminium citrate was most bioavailable in both volunteers, resulting in the highest time-integrated 24-hour blood26Al concentrations. The least bioavailable was aluminium hydroxide. Co-administration of the stable citrate solution increased and delayed the uptake of 26Al from the26Al-labelled aluminium hydroxide (the delay was more evident in subject B). These results suggest that blood aluminium concentrations “reach no convenient and consistent effective plateau and that bioavailability cannot be accurately determined from26Al or27Al levels at a single time after administration.” Absorbed fractions of26Al determined on the basis of calculated blood volumes and blood26Al concentrations measured 1, 4 or 24 hours post-administration were inconsistent.

For all the test materials,26Al urinary excretion was highest in the first day post-administration and rapidly declined thereafter. The decline was sharpest after administration of26Al as aluminium citrate. The26Al urinary excretion was slowest after administration of26Al-labelled aluminium hydroxide. Co-administration of the citrate increased the levels of26Al urinary excretion. In volunteer B the excretion was slower than in volunteer A. By day 3 post-administration, cumulative urinary excretion of26Al reached plateau for all three Al species Absorbed fractions calculated on the basis of26Al urinary excretion data (assuming 72% excretion of absorbed26Al in urine) were 0.01% for aluminium hydroxide, 0.136% for aluminium hydroxide with citrate and 0.523% for aluminium citrate.

The results of this study suggest that bioavailability of aluminium in the citrate form and more so for the hydroxide form is relatively low and that “consumption of either aluminium citrate or aluminium hydroxide in normal quantities is unlikely to result in toxicologically significant body burdens of this metal.”