Aluminium sodium dioxide

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

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

Adequacy of study:

other information

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP - Guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2010

Report date:

2010

Materials and methods

Objective of study:

toxicokinetics

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 417 (Toxicokinetics)

Deviations:

not applicable

Principles of method if other than guideline:

The objective of this study was to measure the fraction of aluminium that enters the bloodstream of the rat following the ingestion of aluminium citrate; aluminium chloride; aluminium nitrate; aluminium sulphate, aluminium oxide, aluminium hydroxide; finely divided aluminium metal; powdered pot electrolyte; FD&C Red 40 aluminium lake; SALP; Kasal; sodium aluminium silicate. The test materials were prepared using 26Al as a radioactive tracer. The solutions (aluminium citrate; aluminium chloride; aluminium nitrate; aluminium sulphate) and suspensions (aluminium oxide, aluminium hydroxide, SALP; Kasal; sodium aluminium silicate) were administered through feeding tubes. FD&C red 40 aluminium lake, powdered pot electrolyte and aluminium metal were mixed with honey and added to the back of the rat tongue. Control animals received water. The rats were sacrificed 7 days after the administration of the test materials, The 26Al: 27Al ratio was determined by accelerator mass spectrometry (AMS). The amount of 26Al in each sample was then calculated. The fraction of 26Al absorbed was calculated by reference to the 26Al administered and the 26Al fraction retained at 7 days post-injection (determined in the initial experiment with intravenous injection of Al citrate).

GLP compliance:

yes (incl. QA statement)

Test material

Test material information

Constituent 1

Reference substance name:

Aluminum citrate solution Aluminum chloride solution Aluminum nitrate solution Aluminum sulfate solution Aluminum hydroxide suspension Aluminium oxide suspension (α-alumina) Aluminium metal particles Powdered aluminium pot electrolyte suspension Food/pharmaceutical additives: FD&C Red 40 aluminium lake suspension SALP suspension (trisodium aluminium phosphate, Na2Al(PO4)2) Kasal suspension Sodium aluminium silicate suspension

IUPAC Name:

Aluminum citrate solution Aluminum chloride solution Aluminum nitrate solution Aluminum sulfate solution Aluminum hydroxide suspension Aluminium oxide suspension (α-alumina) Aluminium metal particles Powdered aluminium pot electrolyte suspension Food/pharmaceutical additives: FD&C Red 40 aluminium lake suspension SALP suspension (trisodium aluminium phosphate, Na2Al(PO4)2) Kasal suspension Sodium aluminium silicate suspension

Details on test material:

- Name of test material (as cited in study report): Aluminum citrate solution Aluminum chloride solution Aluminum nitrate solution Aluminum sulfate solution Aluminum hydroxide suspension Aluminium oxide suspension (α-alumina) Aluminium metal particles Powdered aluminium pot electrolyte suspension Food/pharmaceutical additives: FD&C Red 40 aluminium lake suspension SALP suspension (trisodium aluminium phosphate, Na2Al(PO4)2) Kasal suspension Sodium aluminium silicate suspension
26Al as a carrier free solution was purchased from the PRIME Laboratory, Purdue University, Indiana, USA.
All test materials were prepared from a 26Al stock solution in dilute HCl.
All water, acids and chemicals used in this study were either Analytical Grade reagents or supplied by collaborators.
The 26Al-labelled oxide, metal and electrolyte were prepared by SINTEF, Trondheim, Norway by electrolysis using 26Al-labelled aluminium hydroxide powder prepared at the Chalk River Laboratories.
The 26Al-labelled aluminium hydroxide powder was also used to prepare the SALP and Kasal (by Innophos), sodium aluminium silicate (by Huber Corporation) and FD&C Red 40 aluminium lake (by Colorcon).
Details on preparation of test materials are provided in the report.
All labelled compounds of commercial products were tested for quality and conformity to the standards by the organisations that produced them or supervised their production at the Chalk River Laboratories.
In case of aluminium citrate, nitrate, sulphate and chloride, ultra-filtered solutions were used.
All other test materials except aluminium metal were used as suspensions.

Radiolabelling:

yes

Remarks:

26Al

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River (Canada)
- Age at study initiation: 10-12 weeks at the time of dosing
- Weight at study initiation: approximately 120g
- Fasting period before study: Food was withdrawn 24 hours before the administration
- Housing: The animals were housed two per cage. The bedding material (corncob-derived) was changed daily.
- Individual metabolism cages: yes/no
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 4-6 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24 °C
- Humidity (%): 60%
- Photoperiod (hrs dark / hrs light): 12-hour light/dark cycle

IN-LIFE DATES: From: To:

Administration / exposure

Route of administration:

other: The initial experiment: intravenous injection The main experiment: oral

Vehicle:

water

Details on exposure:

The initial experiment: “0.5 mL of aluminium citrate solution containing 0.19 ng of 26Al was injected into the saphenous vein of twelve rats under anaesthesia.”
The main experiment:
0.5 mL of test solutions (aluminium citrate, aluminium chloride, aluminium nitrate, aluminium sulphate) or suspensions (aluminium oxide, aluminium hydroxide, SALP; Kasal; sodium aluminium silicate) were administered via feeding tubes inserted through the mouth of the anaesthetised animal. The particles of FD&C red 40 aluminium lake, powdered pot electrolyte and aluminium metal were too large to pass though feeding tubes; these particles were mixed with ~0.5 ml of honey and added to the back of the rat tongue. The rats were checked for complete ingestion of the honey and the particles.

Duration and frequency of treatment / exposure:

Single administration.

Doses / concentrations

Remarks:

Doses / Concentrations:
The initial experiment (Al citrate injection):
26Al dose per rat: 0.19 ng
27Al dose per rat: 0 mg

Main experiments
Target doses: ~1.4 ng of 26Al as citrate, nitrate, chloride and sulphate; >10 ng of 26Al as insoluble particulates and metal.

Actual doses
Aluminium chloride
26Al dose per rat: 1.24 ng
27Al dose per rat: 50 mg

Aluminium nitrate
26Al dose per rat: 1.77 ng
27Al dose per rat: 50 mg

Aluminium sulphate
26Al dose per rat: 2.44 ng
27Al dose per rat: 50 mg

Aluminium citrate
26Al dose per rat: 1.47 ng
27Al dose per rat: 50 mg

Aluminium hydroxide
26Al dose per rat: 12.2 ng
27Al dose per rat: 17 mg

Aluminium oxide
26Al dose per rat: 17.9 ng
27Al dose per rat: 23 mg

Aluminium metal
26Al dose per rat: mean 1.2 ng (range 1.282-1.538 ng)
27Al dose per rat: 6.9 mg

Powdered pot electrolyte:
26Al dose per rat: 2.4 ng
27Al dose per rat: 26 mg

SALP
26Al dose per rat: 0.46 ng
27Al dose per rat: 10 mg

KASAL
26Al dose per rat: 0.31 ng
27Al dose per rat: 10 mg

Sodium aluminium silicate
26Al dose per rat: 0.60 ng
27Al dose per rat: 27 mg

FD&C Red 40 aluminium
26Al dose per rat: 0.96 ng
27Al dose per rat: 414 mg (total mass of product)

Control
26Al dose per rat: 0 ng
27Al dose per rat: 0 mg

No. of animals per sex per dose / concentration:

Initial experiment (intravenous injection of Al citrate): 12 female animals
Main experiment (ingestion): 6 female animals per Al compound tested

Control animals:

yes, concurrent vehicle

Positive control reference chemical:

No.

Details on study design:

The test materials were aluminium citrate; aluminium chloride; aluminium nitrate; aluminium sulphate, aluminium oxide, aluminium hydroxide; finely divided aluminium metal; powdered pot electrolyte; FD&C Red 40 aluminium lake; SALP; Kasal; sodium aluminium silicate. The test materials were prepared using 26Al as a radioactive tracer. Aluminium hydroxide, aluminium oxide, SALP, Kasal, sodium aluminium silicate were suspended in water with added 1% carboxymethylcellulose (to maintain a suspension). The solutions and suspensions were administered through feeding tubes. The particle sizes of FD&C red 40 aluminium lake, powdered pot electrolyte and aluminium metal were too large to pass through feeding tubes; they were mixed with honey and put on the back of the rat tongue.
An initial experiment was conducted to measure the fraction of bloodstream aluminium that is retained by the rats by day 7 post-injection. Twelve rats were injected intravenously with 0.5 ml of aluminium citrate solution containing 0.19ng of 26Al. Six control animals received citrate injections containing no 26Al. The animals were sacrificed on day 7 post-injection. To address issues related to possible contamination of samples by external radionuclide from urine and faeces, in six rats the retained aluminium fraction was determined in short carcasses excluding tissues potentially contaminated by urine and faeces (the pelt, gastrointestinal tract, paws, feet and heads). In the other six rats, the retained aluminium fraction was determined in full carcasses (except pelts). The fraction of 26Al uptake excluded by the analysis of the reduced samples was determined by comparing the results for short carcasses with the results for full carcasses. The resulting correction factor was then used in the main study (ingestion) to determine Al content in the full carcass from the Al content in the short carcass.
In the main (ingestion) study each compound was administered to 6 rats. Six control animals received water. Seven days after the administration, the rats were sacrificed, their short carcasses were ashed in a muffle furnace, and the ash was sent for analysis.
A known amount of stable isotope 27Al was added to each sample, the samples were dissolved in acid, and aluminium was extracted by precipitation. The 26Al: 27Al ratio was determined by accelerator mass spectrometry (AMS). The amount of 26Al in each sample was calculated and corrected to account for the amount discarded with the unanalyzed tissues. The fraction of 26Al absorbed was calculated by reference to the 26Al administered and the 26Al fraction retained at 7 days post-injection (determined in the initial experiment).

Details on dosing and sampling:

Sampling:
The rats were euthanized using carbon dioxide gas and cervical dislocation.
Rigorous measures were used to avoid contamination of samples by external 26Al during dissection: washing prior to dissection; changes of gloves and instruments; removal of gastrointestinal tract to avoid faecal contamination; use of short carcass samples (minus pelt, paws, GI tract, feet and heads).
Samples were ashed in a muffle furnace (gradual increase of temperature to 500 °C; 500 °C for 12 hours). When cool, the ash was dissolved in 8 M nitric acid, dried and re-ashed at 500 °C to produce a “ white ash” for analysis.
Chemical Analyses:
27Al/26Al ratios were determined by AMS at the PRIME Laboratory, Purdue University, Indiana, USA, on aluminium oxide produced from the ashed samples.

The ashed samples were dissolved in acid (50 mL of 5 M nitric acid; few drops of concentrated hydrofluoric acid); a known quantity (10.003 mg) of stable aluminium yield tracer was added to a 10 mL aliquot and the volume adjusted to 20 mL using reverse osmosis water. Calcium was removed by precipitation (2 days) with 2.5 mL of concentrated sulphuric acid. The pH was then adjusted to between 13 and 14 using 5 M sodium hydroxide, left overnight, and then the aluminium was precipitated as aluminium hydroxide by adjusting the pH to between 6 to 9 using 5 M nitric acid. The precipitate was washed with water then heated slowly to 1000 °C to convert the aluminium hydroxide to aluminium oxide. After mixing with silver powder at a ratio of ca. 1:2, the aluminium oxide 27Al/26Al ratios in the samples were determined using AMS (copper cathode; Van de Graaff accelerator).

Statistics:

The fractional bioavailability of each administered test compound was determined in the following way:
Bioavailability = Fraction administered dose in carcass at 7 days (by ingestion)/Fraction administered dose in carcass at 7 days (by injection)

To determine the full carcass sample content, the short carcass sample content was multiplied by a correction factor of 1.7 derived from the initial experiment that used injection of Al citrate (see “Preliminary Studies” section below).
For each test material the mean bioavailability ± the standard deviation of the mean was calculated.

Results and discussion

Preliminary studies:

Mortality and general toxicity
No information
Body weights
No information

Food consumption
No information

Water consumption
No information

Correction factor to determine the full carcass sample content from the short carcass sample content
Seven days after the injection of 26Al citrate a mean of 14.6±0.09% of the injected 26Al remained in the full carcass (excluding the pelt and gastrointestinal tract), and a mean of 8.6±0.05% of the injected 26Al remained in the short-carcass. Therefore, for the calculation of absorbed fraction, the results from the short-carcass samples were multiplied by 1.7 before comparing them with the fraction retained in the full rat carcass following injection.

Toxicokinetic / pharmacokinetic studies

Details on absorption:

The mean 26Al/27Al ratio for the 6 control animals that received no 26Al was 5x10E-13. This background level was considered acceptable and was subtracted from subsequent 26Al results prior to calculation of 26Al sample content and absorbed fraction.
Individual results of AMS analysis for each rat are presented in table5 for the soluble Al compounds and in table 6 for the insoluble Al compounds. The mean fractional uptake of 26Al and the standard deviation (presented in table 7 of the report)
Aluminium citrate 0.079±0.0057%
Aluminium chloride 0.054±0.015%
Aluminium nitrate* 0.045±0.013%
Aluminium sulphate 0.21±0.079%
Aluminium hydroxide 0.025±0.041%
Aluminium oxide 0.018±0.038%
Aluminium metal < 0.035%
Powdered Pot Electrolyte* 0.042±0.0036%
SALP <0.047%
Kasal*** <0.03%
Sodium aluminium silicate 0.12±0.011%
FD&C Red 40 aluminium lake 0.093±0.02%
*One outlier result censored;
** “these detection limits are relatively high because an inappropriate estimate of the level of 26Al in the sample (used to determine the quantity of stable 27Al tracer to be added) was made prior to analysis.”
***5 rats only

The highest fractional uptake of 26Al was seen for aluminium sulphate and the lowest for aluminium oxide with a 10-fold difference between these two values. The insoluble compounds (hydroxide, oxide and powdered pot electrolyte) administered as suspensions were less bioavailable than the soluble compounds. The results for D&C Red 40 aluminium lake and for sodium aluminium silicate were closer to the results for soluble salts, which the authors explain by possible release of 26Al from particulates by partial dissolution in the gastrointestinal tract.
The bioavailability of Al metal, SALP and Kasal could not be determined because the amount of 26Al present in the samples was not sufficient to determine the 26Al/27Al ratio. A reanalysis is being conducted. The authors suggest that the bioavailability of aluminium metal particles may be considerably lower than that of soluble aluminium compounds.
The authors compared the results of these analyses with the results of human volunteer studies using 26Al-labelled compounds and found that the results were consistent.

Details on distribution in tissues:

Not studied.

Details on excretion:

Not assessed.

Metabolite characterisation studies

Metabolites identified:

no

Details on metabolites:

Not applicable.

Any other information on results incl. tables

The 7-day interval between the administration of²⁶Al compounds and the AMS measurements was selected “to ensure that all ingested aluminium has been cleared from the GI tract and the phase of rapid excretion of aluminium in urine following its uptake into blood (short-term clearance) has been completed. “

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): other: this study was designed to assess the bioavailability of the substances not the bioaccumulation potential.
“…it can be concluded that the following novel aluminium compounds tested: aluminium nitrate; aluminium chloride; commercial aluminium hydroxide; alumina; powdered pot electrolyte; aluminium metal; SALP, Kasal; sodium aluminium silicate; FD&C red 40 aluminium lake; present no unique biological hazard as a consequence of the bioavailability of their aluminium content. Moreover, the similarities in the data collected confirm the suitability of the rat as an experimental model for metal bioavailability tests that is relevant to the human situation.”

Executive summary:

The objective of this study was to measure the fraction of aluminium that enters the bloodstream of the rat following the ingestion of aluminium citrate, aluminium chloride, aluminium nitrate; aluminium sulphate, aluminium hydroxide, finely divided aluminium metal, powdered pot electrolyte, FD&C Red 40 aluminium lake, SALP, Kasal, sodium aluminium silicate. The test materials were prepared using²⁶Al as a radioactive tracer. Aluminium citrate, aluminium chloride, aluminium nitrate; aluminium sulphate were used as aqueous solutions. Aluminium hydroxide, aluminium oxide, SALP, Kasal, and sodium aluminium silicate were suspended in water with added 1% carboxymethylcellulose (to maintain a suspension). The solutions and suspensions were administered through feeding tubes. The particle sizes ofFD&C red 40 aluminium lake, powdered pot electrolyte and aluminium metalwere too large to pass through feeding tubes; they were mixed with honey and added to the back of the rat tongue.

An initial experiment was conducted to measure the fraction of bloodstream aluminium that is retained by the rats by day 7 post-injection. Twelve rats were injected intravenously with 0.5 ml of aluminium citrate solution containing 0.19ng of²⁶Al. Six control animals received citrate injections containing no²⁶Al. The animals were sacrificed on day 7 post-injection. To address issues related to possible contamination of samples by external radionuclide from urine and faeces, in six rats the retained aluminium fraction was determined in short carcasses excluding tissues potentially contaminated by urine and faeces (the pelt, gastrointestinal tract, paws, feet and heads). In the other six rats, the retained aluminium fraction was determined in full carcasses (except pelts). The fraction of²⁶Al uptake excluded by the analysis of the reduced samples was determined by comparing the results for short carcasses with the results for full carcasses. The resulting correction factor was then used in the main study (ingestion) to determine Al content in the full carcass from the Al content in the short carcass.

In the main (ingestion) study each compound was administered to 6 rats. Six control animals received water. Seven days after the administration, the rats were sacrificed, their short carcasses were ashed in a muffle furnace, and a white ash was sent for analysis to. At the university, a known amount of stable isotope²⁷Al was added to each sample, the samples were dissolved in acid, and aluminium was extracted by precipitation. The²⁶Al:²⁷Al ratio was determined by accelerator mass spectrometry (AMS). The amount of²⁶Al in each sample was calculated and corrected to account for the amount discarded with the unanalyzed tissues. The fraction of²⁶Al absorbed was calculated by reference to the²⁶Al administered and the²⁶Al fraction retained at 7 days post-injection (determined in the initial experiment).

 

The highest fractional uptake of²⁶Al (~0.21%) was seen for aluminium sulphate and the lowest (~0.02%) for aluminium oxide with 10-fold difference between the two values. The insoluble compounds (hydroxide, oxide and powdered pot electrolyte) administered as suspensions were less bioavailable than soluble compounds. The results for D&C Red 40 aluminium lake and for sodium aluminium silicate were closer to the results for soluble salts, which the authors explain by possible release of²⁶Al from particulates by partial dissolution in the gastrointestinal tract. The bioavailability of Al metal, SALP and Kasal could not be determined because the amount of²⁶Al present in the samples was not sufficient to determine the²⁶Al/²⁷Al ratio. A reanalysis is being conducted. The authors suggest that the bioavailability of aluminium metal particles may be considerably lower than that of soluble aluminium compounds.

The authors compared the results of these analyses with the results of human volunteer studies using²⁶Al-labelled compounds and found that the results were consistent. It was concluded that the compounds tested “present no unique biological hazard as a consequence of their bioavailability” and that the rat is a suitable experimental model for studying metal bioavailability relevant to humans.

 

The study was conducted according to the principles of Good Laboratory Practice. The protocol was subjected to internal and external peer review. A Klimisch score 1 was assigned to this study.