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Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
No data
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Bioavailability of aluminium compounds including aluminium sulphate studied in rats; study well documented, meets generally accepted scientific principles, acceptable for assessment
Cross-referenceopen allclose all
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2010
Report Date:
2010

Materials and methods

Objective of study:
absorption
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
A bioavailability study is performed to measure the fraction of aluminium that leaves the gastrointestinal tract and enters the bloodstream following the ingestion of aluminium compounds.
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Type:
Constituent
Type:
Constituent
Type:
Constituent
Type:
Constituent
Type:
Constituent
Test material form:
not specified
Details on test material:
- Name of test material (as cited in study report): Aluminium stock solutions containing 26Al as a tracer (Aluminium citrate, aluminium nitrate, aluminium sulphate, aluminium chloride, aluminium metal, aluminium hydroxide, aluminium oxide)
- Source of aluminium-26: 26Al is as a carrier free solution was sourced from the PRIME Laboratory, Purdue University, Indiana, USA.
Radiolabelling:
yes
Remarks:
Al 26 - 26Al is as a carrier free solution was sourced from the PRIME Laboratory, Purdue University, Indiana, USA.

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River (Canada).
- Age at receipt: 6 weeks
- Weight at receipt: Approximately 120 g
- Fasting period before study: Animals were fasted for 24 hours prior to test item administration.
- Housing: Animals were housed two per cage
- Individual metabolism cages: Yes
- Acclimation period:4-6 weeks

ENVIRONMENTAL CONDITIONS
- Temperature: 24 °C
- Humidity: 60%
- Photoperiod: 12 h dark / 12 h light

Administration / exposure

Route of administration:
other: oral: by gastric tube/in honey or intravenous
Vehicle:
other: insoluble powders - either as particulates suspended in water with added 1% carboxymethylcellulose or mixed with honey
Details on exposure:
Administration by gastric tube or honey: All test solutions were administered to the rats via a gastric feeding tube. Insoluble powders were administered either as particulates suspended in water with added 1% carboxymethylcellulose (to maintain a suspension) or added to the back of the rat tongue in honey – which experience has shown ensured that the particles were swallowed.
Administration by intravenous injection: 0.5 mL of aluminium citrate solution containing 0.19ng of 26Al was injected into the saphenous vein of rats under anaesthesia.

VEHICLE:
- Aluminium citrate injection: 1% citrate solution buffered at pH 6.5
- Solution for Ingestion: Aluminium citrate, Aluminium chloride, Aluminium nitrate and Aluminium sulphate
- Test Suspension: Aluminium hydroxide (1% carboxymethylcellulose in water); Aluminium oxide (2% carboxymethylcellulose in water); Aluminium Metal, Powdered pot electrolyte (honey); FD&C Red 40 aluminium lake (with added propylene glycol and 1% carboxymethylcellulose); SALP, KASAL and Sodium aluminium silicate
Duration and frequency of treatment / exposure:
Single administration
Doses / concentrations
Remarks:
Doses / Concentrations:
Administered doses are as follows: 27Al dose per rat (mg); 26Al dose per Rat (ng)
Aluminium citrate injection: 0 mg, 0.19 ng
Aluminium chloride: 50 mg, 1.24 ng
Aluminium nitrate: 50 mg, 1.77 ng
Aluminium sulphate: 50 mg, 2.44 ng
Aluminium citrate: 50 mg, 1.47 ng
Aluminium hydroxide: 17 mg, 12.2 ng
Aluminium oxide: 23 mg, 17.9 ng
Aluminium metal: 6.9 mg, 1.2 ng
Powdered pot electrolyte: 26 mg, 2.40 ng
SALP: 10 mg, 0.46 ng
KASAL: 10 mg, 0.31 ng
Sodium aluminium silicate: 27 mg, 0.60 ng
FD&C Red 40 aluminium lake*: 414 mg, 0.96 ng
*: total mass of product
No. of animals per sex per dose:
12 females for aluminium citrate injection
6 females each for aluminium chloride, aluminium nitrate, aluminium sulphate, aluminium citrate, aluminium hydroxide, aluminium oxide, aluminium metal, powdered pot electrolyte, SALP, KASAL, sodium aluminium silicate and FD&C Red 40 aluminium lake
6 females for control group
Control animals:
other: received water without added 26Al
Positive control:
Not applicable
Details on study design:
Intravenous injection: An initial experiment used 12 rats. This experiment was conducted in order to measure the fraction of bloodstream aluminium (i.e. uptake) that is retained by rats at 7 days post-injection. All rats were injected with an ultra-filtered aluminium citrate solution pH 6.5 prepared from 26Al in 0.02M nitric acid mixed with an equal volume of 2% trisodium citrate. After 7 days the animals were sacrificed and the fraction of the injected aluminium retained in the animal carcasses (less pelts) was determined. The fraction of 26Al intake was then determined by comparing the results for six rats where the short carcass was employed with the results for six carefully prepared entire rats.

Oral ingestion: Seventy-eight rats were then used for the subsequent ingestion study. Each test compound was administered to 6 rats. Test solutions / suspensions were prepared with the aim of administering ~ 1.4 ng of 26Al as citrate, nitrate, chloride and sulphate and >10 ng of 26Al as insoluble particulates and metal. (Note: these levels could not be achieved for the SALP, Kasal, sodium aluminium silicate, and FD&C red 40 aluminium lake and aluminium metal because the production method for these could not be scaled down sufficiently to produce small batch sizes. This resulted in the production of larger batches of test materials that contained much less 26Al/g than planned). These administered amounts were confirmed / adjusted by the analysis of triplicate doses. In addition, six control animals received water without added 26Al. After 7 days the rats were sacrificed and their pelts wetted to minimise dusting. The short carcass samples were ashed in a muffle furnace and white ash was produced. A known amount (typically 10 mg) of stable 27Al was added to each sample. The samples were then dissolved in acid and aluminium extracted by precipitation. Ion sources were prepared and the sample 26Al(ng): 27Al(g) ratio determined using AMS. The amount of 26Al present in each sample was then calculated from this ratio and then corrected to account for the radionuclide discarded with the unanalysed body parts. The fraction of aluminium absorbed was calculated by reference to the amount of 26Al administered and the fractional retention of injected aluminium at 7 days post-intake.
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption)
- Tissues and body fluids sampled: Full rat carcass (excluding the pelt and gastro-intestinal tract (GIT)) and short-carcass samples (which excluded the pelt, GIT, paws, tail and head – all of which were potentially contaminated by 26Al residues present in the bedding from urine and faeces)
- Time and frequency of sampling: Seven days after 26Al administration the control and experimental rats were euthanized (using carbon dioxide gas and cervical dislocation) and samples were collected.
Other:
- Carcass samples were kept in muffle furnace to 500 °C. After 12 hours at this temperature the ash was cooled, dissolved in 8 M nitric acid, dried and then re-ashed at 500 °C to produce a white ash for analysis.
- Measurement of 26A1 Content of Samples: The 26Al content of samples was analysed by using accelerator mass spectrometry (AMS).
- Determination of fractional GIT absorption: The amount of 26Al remaining in test rats at 7 days post-administration (after short-term clearance is completed) of the isotope by injection directly into the bloodstream and by gastric tube into the stomach were compared. The fractional bioavailability of each administered test compound was determined:
Bioavailability =Fraction administered dose in carcass at 7 days (by ingestion) / Fraction administered dose in carcass at 7 days (by injection)

In each case the carcass sample content was determined from the short-carcass sample content by multiplying the latter by a correction factor of 1.7 – derived from the comparison of the full carcass and short carcass results for the rats injected with 26Al-labelled citrate. For each material the mean bioavailability was calculated, ± the standard deviation of the mean (n = 5 or 6).
Statistics:
None

Results and discussion

Preliminary studies:
Not applicable

Bioaccessibility

Bioaccessibility testing results:
- The results of the analysis of the six rats that received 26Al are shown in Table 7.1.1/1. It can be seen that the mean 26Al: 27Al ratio was 5.0 x 10^-13. This is ratio is about 500 times lower than that measured in the carcasses of rats that received aluminium citrate injections and about 7 times lower than the ratios measured following the administration of 26Al-labelled compounds. This background level is acceptable and was subtracted from all subsequent 26Al results prior to the calculation of 26Al sample content and absorbed fraction.
- At 7 days after injection 14.6% of the injected 26Al remained in the full rat carcass. In contrast only 8.6% of the injected 26Al remained in the short carcass samples that were used for the remainder of the study. It follows that a correction factor of 1.7 was used to estimate retention at 1 week for all experimental samples that employed the short carcass sample.
- AMS results of the analysis of administered doses showed that the mean amounts of 26Al administered were 1.6 ng for aluminium citrate, 1.1 ng for aluminium chloride, 1.9 ng for aluminium nitrate, 2.4 ng for aluminium sulphate, 12.2 ng for aluminium hydroxide, 17.9 ng for aluminium oxide, 1.3 - 1.5 ng for the aluminium metal, 2.4 ng for the powdered pot electrolyte, 0.46 ng for the SALP, 0.31 ng for the Kasal, 0.51 ng for the sodium aluminium silicate and 0.96 ng for the FD&C red 40 aluminium lake.
- Estimates of GI tract bioavailability were possible for all of the test materials except the aluminium metal, SALP and Kasal. In these cases the amount of 26Al present in the samples was insufficient to determine the 26Al: 27Al ratio. A reanalysis is expected. The calculated fractional uptake of 26Al for all the aluminium solutions was similar and ranged from a high uptake of 0.002 for aluminium sulphate to a low uptake of 0.0006 for aluminium chloride. The fractional uptake of 26Al administered as insoluble particulates was lower: 0.0003 for aluminium hydroxide; 0.0002 for aluminium oxide and 0.0003 for the 26Al administered as powdered pot electrolyte; 0.001 for the sodium aluminium silicate; 0.0009 for the FD&C red 40 aluminium lake. The results for aluminium metal, SALP and Kasal were <0.0003, <0.001 and <0.001, respectively.

Any other information on results incl. tables

Table 7.1.1/2: Mean measured fractional uptake of aluminium following gastric administration of 26Al – labelled compounds

 

Compound

Mean Fraction

SD

Upper 95% CI

Lower 95% CI

Aluminium Citrate

7.9 x 10-4

5.7 x 10-5

9.0 x 10-4

6.7 x 10-4

Aluminium Chloride

5.4 x 10-4

1.5 x 10-4

8.3 x 10-4

2.5 x 10 -4

Aluminium Nitrate*

4.5 x 10-4

1.3 x 10-4

7.0 x 10-4

2.0 x 10-4

Aluminium Sulphate

2.1x 10-3

7.9 x 10-4

3.7 x 10-3

5.6 x 10-4

Aluminium Hydroxide

2.5 x 10-4

4.1 x 10-4

1.1 x 10-3

-5.7 x 10-4

Aluminium Oxide

1.8 x 10-4

3.8 x 10-4

9.4 x 10-4

-5.9 x 10-4

Aluminium Metal

<6.0 x 10-4

 

 

 

Powdered Pot Electrolyte*

4.2 x 10-4

3.6 x 10-5

1.2 x 10-3

-3.1 x 10-4

SALP

<5.8 x 10-4

 

 

 

Kasal**

<7.7 x 10-4

 

 

 

Sodium Aluminium Silicate

1.2 x 10-3

1.1 x 10-4

1.5 x 10-3

1.0 x 10-3

FD&C Red 40 aluminium lake

9.3 x 10-4

2.0 x 10-4

1.3 x 10-3

5.4 x 10-4

*One outlier result censored **5 rats only The results of the present study in the rat confirm this expectation with the measured bioavailability decreasing in the order: aluminium sulphate (2.1 x 10-3); sodium aluminium silicate (1.2 x 10-3); FD&C red 40 aluminium lake (9.3 x 10-4); aluminium citrate (7.9 x 10-4); aluminium chloride (5.4 x 10-4); aluminium nitrate (4.5 x 10-4); aluminium in powdered pot electrolyte (4.2 x 10-4); aluminium hydroxide (2.5 x 10-4); aluminium oxide (1.8 x 10-4). The results for aluminium metal, SALP and Kasal were below the detection limit under the AMS conditions employed (<1.0 x 10-4, <5.8 x 10-4, and < 7.7 x 10-4, respectively), but are being reanalysed using different AMS conditions. Given the level of uncertainty in the mean (average SD ~13% of mean) bioavailability the ranked values given above should be treated with caution. However, it can be safely concluded that under the experimental conditions employed: the most bioavailable species was aluminium administered as aluminium sulphate: other soluble species, sodium aluminium silicate and FD&C red 40 aluminium lake have a similar bioavailability – within the range 5 x 10 -4 to 1 x 10-3; insoluble species were less bioavailable than soluble species with a bioavailability of about 2 x 10-4.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): bioaccumulation potential cannot be judged based on study results
Under the experimental conditions, the most bioavailable aluminium compound was aluminium sulphate with an oral absorption rate of 0.21%.
Executive summary:

A study was performed to determine the bioavailability of Aluminium compounds in Sprague-Dawley rats. Initially 12 rats intravenously injected with aluminium citrate (0.19 ng 26Al) and after 7 days the animals were sacrificed and the fraction of the injected aluminium retained in the animal carcasses was determined. Subsequent to intravenous injection study, the following substances (as 27Al dose per rat (mg) and 26Al dose per Rat (ng), respectively) were administered to 6 rats of each by oral administration:

Aluminium chloride: 50 mg, 1.24 ng; Aluminium nitrate: 50 mg, 1.77 ng; Aluminium sulphate: 50 mg, 2.44 ng; Aluminium citrate: 50 mg, 1.47 ng; Aluminium hydroxide: 17 mg, 12.2 ng; Aluminium oxide: 23 mg, 17.9 ng; Aluminium metal: 6.9 mg, 1.2 ng; Powdered pot electrolyte: 26 mg, 2.40 ng; SALP: 10 mg, 0.46 ng; KASAL: 10 mg, 0.31 ng; Sodium aluminium silicate: 27 mg, 0.60 ng; FD&C Red 40 aluminium lake*: 414 mg, 0.96 ng

Control rats received water without added 26Al. After 7 days the animals were sacrificed and the fraction of the injected aluminium retained in the animal carcasses was determined. The 26Al content of samples was analysed by using accelerator mass spectrometry (AMS). The fraction of aluminium absorbed was calculated by reference to the amount of 26Al administered and the fractional retention of injected aluminium at 7 days post-intake.

At 7 days after injection 14.6% of the injected 26Al remained in the full rat carcass. In contrast only 8.6% of the injected 26Al remained in the short carcass samples that were used for the remainder of the study.  AMS results of the analysis of administered doses showed that the mean amounts of 26Al administered were 1.6 ng for aluminium citrate, 1.1 ng for aluminium chloride, 1.9 ng for aluminium nitrate, 2.4 ng for aluminium sulphate, 12.2 ng for aluminium hydroxide, 17.9 ng for aluminium oxide, 1.3 - 1.5 ng for the aluminium metal, 2.4 ng for the powdered pot electrolyte, 0.46 ng for the SALP, 0.31 ng for the Kasal, 0.51 ng for the sodium aluminium silicate and 0.96 ng for the FD&C red 40 aluminium lake.

 

Estimates of GI tract bioavailability were possible for all of the test materials except the aluminium metal, SALP and Kasal. The calculated fractional uptake of 26Al for all the aluminium solutions was similar and ranged from a high uptake of 0.002 for aluminium sulphate to a low uptake of 0.0006 for aluminium chloride. The fractional uptake of 26Al administered as insoluble particulates was lower: 0.0003 for aluminium hydroxide; 0.0002 for aluminium oxide and 0.0003 for the 26Al administered as powdered pot electrolyte; 0.001 for the sodium aluminium silicate; 0.0009 for the FD&C red 40 aluminium lake. The results for aluminium metal, SALP and Kasal were <0.0003, <0.001 and <0.001, respectively. It can be seen that highest fractional uptake 2.1 x 10 -3 (0.21%) was found following the ingestion of 26Al-labelled aluminium sulphate and the lowest uptake followed the administration of the aluminium oxide – 1.8 x 10-4 (0.02%). The results show that the compounds administered as suspensions (hydroxide, oxide, metal and powdered pot electrolyte) were less bioavailable than the soluble compounds (citrate, chloride, nitrate and sulphate).

 

Under the experimental conditions, the most bioavailable aluminium compound was aluminium sulphate with an oral absorption rate of 0.21%.