Following a request from the European Commission, the European Food Safety Authority (EFSA) was asked to evaluate a new study provided by industry that reports on the bioavailability of aluminium from several aluminium-containing compounds in the rat. EFSA was asked whether the scientific data provided by the new study could trigger the revision of the safety evaluation performed by EFSA in 2008, for the different aluminium-based food additives scrutinised in this report (in particular SALP acidic, also known as sodium aluminium phosphate, acidic form or E 541).
Aluminium occurs naturally in the environment, and is the most abundant metallic element in the earth's crust. The naturally occurring stable isotope is 27Al. The isotope 26Al has a long half life but a low natural abundance and is used as a tracer in biological studies. Aluminium is only found in nature as Al3+.
The absorption, distribution and elimination properties of aluminium and several aluminium compounds in humans and experimental animals have been reviewed extensively. The gastrointestinal absorption of aluminium from aluminium compounds is determined to a large extent by its ionic availability in the gut content, and this is mainly related to the prevailing pH, the presence of complexing ligands with which the metal may form absorbable aluminium species and the chemical form of the ingested aluminium compound. It is thought that acid digestion in the stomach would degrade most of the ingested aluminium compounds to yield “free” and soluble Al3+, i.e. hydrated Al3+, part of which may be complexed with mono-, di- and tricarboxylic acids such as citric acid. By passing from the stomach to the intestines the increase in pH results in successive deprotonations and the formation of complexes of aluminium with hydroxide and finally, the formation of insoluble aluminium hydroxide at neutral pH. Therefore, as the pH is neutralised in the duodenum the aluminium ion is gradually converted to aluminium hydroxide and the majority is then expected to precipitate in the intestine, with subsequent faecal excretion, leaving only a minor fraction available for absorption.
Available studies indicate that the oral bioavailability of aluminium in humans and experimental animals from drinking water is approximately 0.3%, whereas the bioavailability of aluminium from food and beverages generally is considered to be lower, about 0.1%. However, considering the available human and animal data, it is likely that the oral absorption of aluminium from food can vary at least 10-fold depending on the chemical forms present in the intestinal tract. The total body burden of aluminium in healthy human subjects has been reported to be approximately 30–50 mg/kg bw. About one-half of the total body aluminium is in the skeleton. Aluminium has also been found in human skin, lower gastrointestinal tract, lymph nodes, adrenals, parathyroid glands, and in most soft tissue organs. In rats accumulation of aluminium after oral exposure was higher in the spleen, liver, bone, and kidneys than in the brain, muscle, heart, or lung. It has also been reported that aluminium can reach the placenta and fetus and to some extent distribute to the milk of lactating mothers.
The main carrier of Al3+ in plasma is the iron binding protein transferrin. Studies have demonstrated that about 90% of the Al3+ in plasma is bound to transferrin and about 10% to citrate. Cellular uptake of aluminium in organs and tissues is relatively slow. Absorbed aluminium is eliminated primarily by the kidneys, presumably as the citrate, and excreted in the urine. Unabsorbed aluminium is excreted in the faeces. Excretion via the bile constitutes a secondary, but minor route. Multiple values ranging from hours to days and years have been reported for the elimination half life of aluminium in humans and animals, suggesting that there are multiple compartments for aluminium storage from which aluminium is eliminated.
The specific aim of the study under consideration was to provide experimental data on the oral bioavailability of a number of aluminium-containing compounds for which there were limited or no data on the toxicokinetic properties. The experimental approach adopted by the authors of the study was to prepare 26Al-labelled compounds with sufficiently high levels of 26Al relative to the stable 27Al isotope to enable the detection of the radiolabel by accelerator mass spectrometry (AMS) in the carcass of the dosed animals. Bioavailability was determined as the ratio of the fraction of radioactivity left in the carcass seven days after oral administration of the 26Al-labelled compound of interest over the fraction of radioactivity left in the carcass seven days after intravenous administration of 26Al-labelled aluminium citrate. Oral administration was as solutions in the case of the citrate, nitrate, sulphate and chloride salts of aluminium. In contrast, aluminium hydroxide, aluminium oxide, the two sodium aluminium phosphates, SALP acidic and SALP basic (KASAL), and sodium aluminium silicate were insoluble, and were administered as suspensions in carboxymethylcellulose. In the case of Allura RedAC aluminium lake (FD&C red 40 aluminium lake), powdered pot electrolyte and aluminium metal, the particles were too large for administration by gastric feeding tube; instead, they were mixed with honey for administration to the back of the rat tongue.
The results of the analysis of the control (untreated) animals presented in the study under consideration showed that the mean background 26Al:27Al ratio was 5 x 10-13. Seven days after 26Al citrate injection (iv), the ratio was approximately 500 times higher. This represented only 8.6% of the injected dose. The 26Al:27Al ratios in the oral dosing study were much lower, being only 1.5- to 15-fold higher than the mean background 26Al:27Al ratio obtained from control (untreated) animals. For the soluble aluminium citrate, chloride, nitrate and sulphate salts, the fraction absorbed ranged from 0.045 to 0.21% of the dose. In the case of the following aluminium compounds administered as suspension, aluminium hydroxide, aluminium oxide, Allura Red AC aluminium lake (FD&C red 40 aluminium lake) and sodium aluminium silicate, the percentage of the aluminium dose absorbed ranged from 0.018 to 0.12%. However, the measured 26Al:27Al ratios for the two sodium aluminium phosphates, SALP acidic and SALP basic (KASAL), and aluminium metal were below the limit of detection by AMS.
EFSA notes that the measurements of the remaining quantity were made on day 7 following the administration. The authors argued that this extended time span ensures that all ingested aluminium had been cleared from the gastrointestinal tract and the phase of rapid excretion of aluminium in urine following its uptake into blood (short-term clearance) had been complete. However, the limitation of their approach is that less than 10% of the bioavailable dose remains in the experimental animals after administration of the compounds. Also, the authors of the study assumed that the single time point 26Al:27Al ratio measurements accurately reflect the toxicokinetics of aluminium.
In the case of aluminium metal and the two sodium aluminium phosphate forms, SALP acidic and SALP basic (KASAL), the AMS measurements were below the experimental limit of detection. The authors of the study acknowledged that for SALP and SALP basic (KASAL), this was due to the low level of 26Al that was incorporated into the test product relative to the 27Al levels. While this makes it impossible to derive bioavailability data, from the limits of detection provided by the authors, the bioavailability of aluminium metal and SALP basic (KASAL) can be estimated to be <0.015% and <0.024% for SALP acidic. However, in the case of aluminium metal, the conclusion that its bioavailability is <0.015% is only valid if assuming that the size of the aluminium metal particles had no impact on its absorption.
The oral bioavailability of aluminium in humans and experimental animals from drinking water is approximately 0.3%, whereas the bioavailability of aluminium from food and beverages generally is considered to be lower, about 0.1%. The results presented in the study discussed in this Statement not only confirm these findings but also extend them to several aluminium-containing food additives authorised in the EU that had not previously been assessed for their bioavailability. The bioavailability of aluminium from SALP, acidic, which could not be determined due to the technical reasons outlined above, has recently been studied in the rat using SALP acidic incorporated in a biscuit and SALP basic (KASAL) in cheese. The latter study found the bioavailability aluminium from biscuit and cheese to be around 0.1% and 0.1-0.3%, respectively.
Overall, the study under consideration concludes that the oral bioavailability of twelve different aluminium-containing compounds, including the food additives aluminium sulphate, Allura Red AC aluminium lake (FD&C red 40 aluminium lake) and sodium aluminium silicate, ranges from 0.02 to 0.21%, and thus falls within the overall 10-fold range of previously reported bioavailability values. Therefore, the study does not provide any additional information on the bioavailability of aluminium from aluminium-containing compounds that could modify the conclusions reached in 2008 by the Panel on Food Additives, Flavourings, Processing Aids and Food Contact Materials. Therefore, EFSA concludes that this study does not give reason to reconsider the previous safety evaluation of aluminium-based food additives authorised in the European Union performed by EFSA in 2008.