Aluminum magnesium vanadium oxide

Endpoint summary

Description of key information

There are no studies available in which the toxicokinetic behaviour of aluminium magnesium vanadium oxide (CAS 170621-28-0) has been investigated.

In accordance with Annex VIII, Column 1, Item 8.8.1, of Regulation (EC) 1907/2006 and with Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2012), assessment of the toxicokinetic behaviour of aluminium magnesium vanadium oxide (CAS 170621-28-0) is conducted to the extent that can be derived from the relevant available information. Available data on the metallic components, i.e. aluminium, magnesium and vanadium in their ionic form, was taken into account as supporting information.

The substance aluminium magnesium vanadium oxide (CAS 170621-28-0) is an inorganic mono-constituent substance with an analytical purity > 85%. It contains ca. 36% oxygen, 26% magnesium, 25% aluminium, 1.5% vanadium. In addition, approx. 10% cerium may be present in the composition of the substance depending on the production process.

The substance is a light yellow powder at 20°C with a melting point of > 1100°C at normal pressure (2011a) and a molecular weight of 86.29 g/mol. No vapour pressure was determined, since the substance has a melting point > 300°C. The water solubility of the substance is < 0.1 mg/L (2011b). Furthermore, the transformation/dissolution test investigating the solubility of the test substance and the concentration of the specific components in aqueous media reveals that the dissolved aluminium was 44.7 µg/L and vanadium was 6 µg/L at the pH of 8 and loading of 1 mg/L. A log Pow value is not available, since the substance is inorganic.

The physicochemical properties of aluminium magnesium vanadium oxide suggests low oral, low inhalation and negligible dermal absorption, and thus low bioavailability. However, the substance is anticipated to release the corresponding metal ions of vanadium, aluminium and magnesium under strong acid conditions as present in the stomach. Whereas absorption of essential major elements like magnesium is relatively high, only poor absorption is reported for aluminium and vandadium, respectively.

Due to the assumed low absorption potential of aluminium magnesium vanadium oxide a low distribution is expected. However, under the strong acid conditions as present in the stomach, the substance is anticipated to release the corresponding metal ions of vanadium, aluminium and magnesium, which are distributed widely after absorption and are mainly accumulated in the bones.

No metabolism is relevant for the substance since it is an inorganic compound, which is not metabolised via physiological pathways. However, after absorption, the release of the ionic forms of aluminium, vanadium and magnesium due to strong acid conditions in the stomach from the parent compound is assumed in a worst case approach. The cations may interact with cell structures and physiological pathways.

Excretion of the parent substance and the unabsorbed ions of the elements are considered to be mainly via the faeces, whereas absorbed vanadium, aluminium and magnesium, preferably in the ionic form, may be primarily excreted via urine.

Additional information

Basic toxicokinetics

There are no studies available in which the toxicokinetic behaviour of aluminium magnesium vanadium oxide (CAS 170621-28-0) has been investigated.

In accordance with Annex VIII, Column 1, Item 8.8.1, of Regulation (EC) 1907/2006 and with Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2012), assessment of the toxicokinetic behaviour of aluminium magnesium vanadium oxide (CAS 170621-28-0) is conducted to the extent that can be derived from the relevant available information. Available data on the metallic components, i.e. aluminium, magnesium and vanadium in their ionic form, was taken into account as supporting information.

The substance aluminium magnesium vanadium oxide (CAS 170621-28-0) is an inorganic mono-constituent substance with an analytical purity > 85%. It contains ca. 36% oxygen, 26% magnesium, 25% aluminium, 1.5% vanadium. In addition, approx. 10% cerium may be present in the composition of the substance depending on the production process.

The substance is a light yellow powder at 20°C with a melting point of > 1100°C at normal pressure (see IUCLID section 4.6)) and a molecular weight of 86.29 g/mol. No vapour pressure was determined, since the substance has a melting point > 300°C. The water solubility of the substance is < 0.1 mg/L (see IUCLID section 4.8). Furthermore, the transformation/dissolution test investigating the solubility of the test substance and the concentration of the specific components in aqueous media reveals that the dissolved aluminium was 44.7 µg/L and vanadium was 6 µg/L at the pH of 8 and loading of 1 mg/L. A log Pow value is not available, since the substance is inorganic.

Absorption

Absorption is a function of the potential for a substance to diffuse across biological membranes. The most useful parameters providing information on this potential are the molecular weight, the octanol/water partition coefficient (log Pow) value and the water solubility (ECHA, 2014).

Oral

The absorption potential of a substance may also be predicted from oral toxicity studies, assuming that clear treatment-related systemic effects occurred (ECHA, 2014). Studies on the acute oral toxicity of the substance in rats showed no mortality and no systemic effects after single administration of 2000 mg/kg bw (see IUCLID section 7.2.1). Although these data support the assumption that the substance is poorly absorbed, no meaningful information may be derived on the actual amount absorbed.

The potential of a substance to be absorbed in the gastrointestinal (GI) tract may be influenced, e.g. by chemical changes taking place in GI fluids. These changes will alter the physico-chemical characteristics of the substance and hence predictions based upon the physico-chemical characteristics of the parent substance may no longer apply (ECHA, 2014).

Aluminium magnesium vanadium oxide (CAS 170621-28-0) shows a very low solubility in water at pH 8, and thus remains unchanged in the organism under physiological conditions (pH 7.4). However, it is anticipated that the strong acid milieu inside the stomach may facilitate the release of the corresponding free metal ions. Thus, potential absorption of the soluble ions of aluminium, vanadium and magnesium is considered in a worst case scenario.

Although the ionised forms of a substance are not expected to readily diffuse across biological membranes, absorption via the passage through aqueous pores or carriage of ionic species with the passage of water cannot be excluded for small, water-soluble molecules (ECHA, 2014).

Aluminium

Aluminium is known to be only poorly absorbed in humans with an uptake and intestinal absorption rate of ca. 0.1%, reaching maximum absorption of aluminium in the serum within 1.5 – 6 hours after administration (Steinhausen et al., 2004).

However, it has to be considered that bioavailability of aluminium strongly depends on the solubility of the ingested aluminium compound. Bioavailability of different aluminium compounds including 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 was investigated by Atomic Energy of Canada Ltd (2010). 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 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. 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). The highest fractional uptake of 26Al (~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 0.025%), oxide (0.02%) and powdered pot electrolyte (0.042%)) were less bioavailable than the soluble compounds. Moreover, bioavailability of aluminium strongly depends on the presence of dietary constituents which enhance (i.e. carboxylic acid) or inhibit (i.e. phosphate or dissolved silicate) its absorption (ATDSR, 2008).

Magnesium

Absorption of the essential major element magnesium from the human GI tract may vary between ca. 25-75%, depending on the actual amount of magnesium ingested, i.e. low dietary intake results in high absorption, whereas high intake of magnesium rather decreases absorption (FAO/WHO, 2001). Furthermore, absorption of magnesium is dependent on the presence of other nutritional compounds such as dietary fibres and other elements, such as zinc, which may lower magnesium absorption (FAO/WHO, 2001). Generally, magnesium absorption is facilitated by both passive and active transport processes and mostly occurs within the duodenum and ileum (FAO/WHO, 2001).

Vanadium

The toxicologically most relevant compounds of vanadium (V) are those containing the tetravalent (V4+) and pentavalent (V5+) species of the transition metal. Therefore, in the following, data on absorption refer to vanadium compounds with the most critical ionic valences V4+ and V5+.

Several studies in humans indicate that exogenously administered tetra- and pentavalent vanadium compounds are poorly absorbed from the GI tract (NIEHS, 2008). Data indicate that less than 5% of the ingested vanadium is absorbed in humans (WHO, 1996).

Low absorption of vanadium has also been observed in several animal studies (ATSDR, 2012). A study in rats showed that administration of radiolabelled vanadium pentoxide via oral gavage resulted in only 2.6% absorption of radiolabelled vanadium through the GI tract 3 days after exposure (Conklin, 1982). However, also values≤1% for oral absorption of vanadium have been reported (NIEHS, 2008). After repeated exposure, also higher rates of vanadium absorption were observed, as shown by vanadium absorption of 16.5% in rats receiving 100 ppm sodium metavanadate in the diet for 7 days (Adachi et al., 2000). In rats exposed to dietary concentrations of 5 and 25 ppm sodium metavanadate for two weeks, up to 40% of the ingested vanadium was absorbed (Bogden, 1982). The results on absorption of vanadium provide evidence that water-insoluble vanadium compounds such as vanadium pentoxide are rather poorly absorbed from the GI tract in comparison to the water soluble compounds such as sodium metavanadate.

In conclusion, the physicochemical properties of aluminium magnesium vanadium oxide (CAS 170621-28-0) suggest low oral absorption, and thus low systemic bioavailability. However, the substance is anticipated to release the corresponding metal ions of vanadium, aluminium and magnesium under strong acid conditions as present in the stomach. Whereas absorption of essential major elements like magnesium is relatively high, only poor absorption is reported for aluminium and vanadium, respectively.

Dermal

In general, the physical state may already be taken into consideration for a crude estimation of the absorption potential of a substance, which means that dermal uptake of liquids and substances in solution is higher than that of dry particulates, since dry particulates need to dissolve into the surface moisture of the skin before uptake can begin. Molecular weights below 100 g/mol favour dermal uptake, while for those above 500 g/mol the molecule may be too large. Dermal uptake is anticipated to be low, if the water solubility is < 1 mg/L, low to moderate if it is between 1-100 mg/L, and moderate to high if it is between 100-10000 mg/L (ECHA, 2014).

Although the molecular weight of the substance is suggestive of dermal uptake, the physical state in combination with the very low water solubility of the substance is suggestive of very low absorption through the skin.

Apart from the physico-chemical properties, further criteria may apply to assume the dermal absorption potential of the substance.

In general, substances that show skin irritating or corrosive properties may enhance penetration by causing damage to the surface of the skin. Furthermore, if a substance has been identified as a skin sensitiser, then some uptake must have occurred although it may only have been a small fraction of the applied dose (ECHA, 2014).

Furthermore, data on dermal toxicity may indicate whether a substance may be absorbed, if signs of systemic toxicity were clearly attributable to treatment (ECHA, 2014).

Consistent with the data on skin irritation and sensitisation, there is no indication for clinical signs of toxicity and any other treatment-related adverse effects from the acute dermal toxicity study with the substance, resulting in a dermal LD50 > 2000 mg/kg bw in rats (see IUCLID section 7.2.3). Thus, consistent with the data from acute oral toxicity, a low potential for acute toxicity has been demonstrated, although no information on the actual amount of absorbed substance may be derived from these observations.

Moreover, the available data showed that the substance is neither skin irritating nor skin sensitising (see IUCLID section 7.3.1 and 7.4.1). Therefore, no enhanced penetration of the substance due to skin damage is expected.

Overall, taking all available information into consideration, the dermal absorption potential of the substance is expected to be negligible.

Inhalation

In general, particles with aerodynamic diameters below 100 μm have the potential to be inhaled by humans. Particles with aerodynamic diameters below 50 μm may reach the thoracic region and those below 15 μm the alveolar region of the respiratory tract (ECHA, 2014).

Aluminium magnesium vanadium oxide (CAS 170621-28-0) is a powder containing ca. 90% of particles with a particle size smaller than 100 μm, and approximately 70% and 8% of particles are smaller than 47 μm and 16 µm, respectively. Thus, based on the particle size distribution, the substance has the potential to preferably deposit in the thoracic region of the respiratory tract after inhalation.

As for oral absorption, the very low water solubility of the substance is suggestive of low absorption across the respiratory tract. For poorly water-soluble dusts, the rate at which the particles dissolve into the mucus will limit the amount that can be absorbed directly (ECHA, 2014). Such dusts depositing in the tracheo-bronchial region would mainly be cleared from the lungs by the mucocilliary mechanism and swallowed. However a small amount may be taken up by phagocytosis and transported to the blood via the lymphatic system (ECHA, 2014).

Moreover, the available data showed that there is no indication for clinical signs of toxicity and any other treatment-related adverse effects from the acute inhalation toxicity study with the substance, resulting in a dermal LC50 > 5 g/m³in rats (see IUCLID section 7.2.2). These also provide further information on the low absorption and bioavailability of this substance via inhalation route. Overall, systemic bioavailability is considered to be low following inhalation exposure to aluminium magnesium vanadium oxide.

Distribution and Accumulation

Distribution of a compound within the body depends on the physico-chemical properties of the substance, especially the molecular weight, the lipophilic character and the water solubility. In general, the smaller the molecule, the wider is the distribution (ECHA, 2014).

As aluminium magnesium vanadium oxide is anticipated to release the corresponding free metal ions under acid conditions in the stomach after ingestion, data on the distribution and accumulation of the relevant ionic forms of aluminium, vanadium and magnesium is considered in a worst case approach.

In general, certain metals and small ions can interact with ions in the matrix of bone, in which they displace the normal constituents of the bone leading to retention of the metal or ion (ECHA, 2014).

Aluminium

Aluminium in the form of Al3+has been shown to accumulate in bones (Jouhanneau et al., 1997).The largest long-term deposition of aluminium occurs in the mineralisation front of bones (Steinhausen et al., 2004, Yokel and McNamara, 2001). The highest tissue concentrations for aluminium were found in the liver, spleen, bone, kidney (Wilhelm et al., 1990) and the brain, which contains lower aluminium concentrations than the other tissues. An equal distribution of aluminium is present within the blood between plasma and cells. Accumulation of about 50% of absorbed aluminium occurs rapidly (within 2 hours) and permanently in the skeleton, which was shown in young rats (Jouhanneau et al., 1997). Furthermore, aluminium is transferred to the offspring through transplacental passage and/or maternal milk (Yumoto et al., 2000).

Magnesium

In the human body, 30-40% of magnesium is located in muscles and soft tissues, 1% is found in extracellular fluid and the remainder (50-60%) is present in the bones (FAO/WHO, 2001). Much of the magnesium in the bone is readily exchangeable with serum, thus representing an important store in the case of magnesium deficiency (FAO/WHO, 2001).

Vanadium

After absorption, vanadium is mainly transported in the plasma, where it is converted to vanadyl (V4+), which forms complexes with iron-containing proteins like transferrin and ferritin (EVM, 2002).

Data from inhalation and oral animals studies showed that absorbed vanadium (tetravalent and pentavalent forms) was mainly distributed to the bone, followed by liver, kidney, and spleen (ICPS, 2001; NIEHS, 2008). Besides these organs, vanadium was also detected in testis after chronic oral administration to rats (Dai et al., 1994). Furthermore, it was demonstrated that vanadium preferably accumulated in bone, testis, kidney and liver of rats, whereas only negligible amounts of vanadium were found in plasma, suggesting a very slow rate of release from the tissues to blood and a high accumulation potential, especially in bones (Dai et al., 1994). Intratracheal installation of radiolabelled penta- and tetravalent vanadium compounds showed that absorption from vanadium via the lung is much higher than via the GI tract, with skeleton, lung, kidney and liver as major targets for vanadium deposition after inhalation (Conklin, 1982).

In addition, there is evidence from studies in pregnant mice that tetravalent vanadium may cross the placental barrier to the foetus (ICPS, 2001; NIEHS, 2008).

In conclusion, the physicochemical properties of aluminium magnesium vanadium oxide (CAS 170621-28-0) suggest low oral absorption, and thus low systemic bioavailability. However, under the strong acid conditions as present in the stomach, the substance is anticipated to release the corresponding metal ions of vanadium, aluminium and magnesium, which are distributed widely after absorption and are mainly accumulated in the bones.

Metabolism

No metabolism is relevant for the substance since it is an inorganic compound, which is not metabolised via physiological pathways. However, after absorption, the release of the ionic forms of aluminium, vanadium and magnesium due to strong acid conditions in the stomach from the parent compound is assumed in a worst case approach. The cations may interact with cell structures and physiological pathways.

Aluminium

Aluminium exists in four different forms in the living organisms: as 1) free ions, 2) low-molecular-weight complexes, 3) physically bound macromolecular complexes, and 4) covalently bound macromolecular complexes (Ganrot, 1986). Thus, metabolism of aluminium is determined by its binding affinity to its ligands and finally to their metabolism. In general, aluminium forms low-molecular-weight complexes with amino acids, nucleotides and phosphates as well as with carbohydrates and organic acids. As low-molecular-weight complexes are often chelates, they may be very stable. Furthermore, complexes between aluminium and proteins, polynucleotides, and glycosaminoglycans often represent covalently bound complexes and hence are expected to be metabolically much less active than the smaller, low-molecular-weight complexes.

Magnesium

Magnesium is an essential major element, which is involved in energy metabolism, protein synthesis, RNA and DNA synthesis, and maintenance of the electrical potential of nervous tissues and cell membranes (FAO/WHO, 2001).

Vanadium

In the highly oxygenated blood, vanadate (V5+) is the predominating species of vanadium (ICPS, 2001). In tissues, vanadate is mainly reduced to vanadyl (V4+) due to the physiological pH of the cytosol, but under acid conditions of some cell organelles, oligomers of the vanadate may be formed that may exert higher toxicity compared to monomeric vanadate (NIEHS, 2008). In general, vanadium in tissue may be present in different oxidation states and also undergo redox cycling, depending on the balance between reducing agents (such as reduced glutathione-SH, NADPH, NADH) and oxygen (ATSDR, 2012).

Excretion

In general, characteristics favourable for urinary excretion are low molecular weight, good water solubility and ionisation of the molecule at pH of urine. In contrast, non-absorbed substances that have been ingested are excreted via faeces (ECHA, 2012).

As the absorption potential of aluminium magnesium vanadium oxide (CAS 170621-28-0) from the GI tract is predicted to be very low, most of the substance is expected to be excreted via faeces. However, under the strong acid conditions in the stomach, the ionic forms of aluminium, magnesium and vanadium may be released from the substance and excreted as described in the following sections.

Aluminium

Aluminium is excreted mainly via the faeces, as shown after repeated ingestion of aluminium chloride in mice. In general, unabsorbed aluminium is excreted via the faeces whereas absorbed aluminium is mainly excreted in the urine after years (Steinhausen et al., 2004). Urinary excretion is the also the important route by which systemic aluminium is eliminated from the body (Priest, 2004; Talbot et al., 1995). The filtration of aluminium from the blood into urine occurs in the kidney glomerulus and its efficiency shows a dependency on the chemical species to which the Al is complexed in the blood (Shirley and Lote, 2005).

Magnesium

Excretion of magnesium via urine is mainly dependent on magnesium homeostasis, which is controlled in the kidney by actively reabsorbing magnesium in the loop of Henle in the proximal convoluted tubules (FAO/WHO, 2001).

Vanadium

Absorbed vanadium is mainly excreted via urine, whereas unabsorbed vanadium is eliminated in the faeces (NIEHS, 2008; EVM, 2002; ICPS, 2001). The rate of excretion of absorbed vanadium is rapid, as indicated by the fact that about 40-60% of the administered dose of vanadium is eliminated in the urine within 1-3 days after ingestion (EVM, 2002). However, if vanadium is not absorbed, the major route of excretion was faeces with 59-84% of the ingested dose eliminated (Bogden, 1982; Adachi, 2000).

In conclusion, excretion of the parent substance and the unabsorbed ions of the elements are considered to be mainly via the faeces, whereas absorbed vanadium, aluminium and magnesium, preferably in the ionic form, may be primarily excreted via urine.

 

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