Dodecaaluminium trimolybdenum dodecaoxide

Endpoint summary

Description of key information

Molybdenum compounds: After oral ingestion, molybdenum absorption from the gastrointestinal occurs rapidly and almost completely. Molybdenum levels in blood plasma peak quite early after oral administration. Following inhalation exposure to soluble molybdenum compounds, it can be assumed that systemic absorption after deposition of particles occurs, however, representing a worst case scenario. The dermal absorption of molybdenum is low to negligible. Molybdenum transforms rather quickly to molybdate anions upon dissolution, which represent the physiologically relevant Mo species. The highly soluble molybdate anions are widely distributed in the body: kidneys, liver and bone. No metabolism is expected. The elimination of molybdate anions from plasma is rapid and predominantly via renal excretion (>80%) and only to a lesser extent via faeces (<10%).
Aluminium compounds: Several studies on the pharmacokinetics of aluminium in mammalian species are available. The average fraction of absorbed aluminium is usually < 1%, depending on whether extra aluminium was given and in which form. However, the absorption of water soluble chelates such as aluminium citrate show a higher degree of absorption after oral administration to laboratory animals and man. The mechanism of absorption is fairly complex and not yet fully understood. This is partly due to chemical properties of aluminium, particularly great variability of solubility at different pH values, amphoteric character and formation of various chemical forms depending on pH, the ionic strength and presence of complexing agents. Not all absorbed or parenterally delivered aluminum is excreted in urine. Low glomerular filtration of aluminum reflects that most aluminum in plasma is nonfiltrable because of complexation to proteins, predominantly transferrin. The importance of biliary secretion of aluminum is debatable and the mechanism(s) is poorly understood and appears to be saturable by fairly low oral doses of aluminium.

Additional information

There are no data available on toxicokinetics for aluminium molybdenum oxide. However, there are reliable data for aluminium and molybdenum compounds considered suitable for read-across using the analogue approach.

For identifying hazardous properties of aluminium molybdenum oxide concerning human health effects, the existing forms of the target substance at very acidic and physiological pH conditions are relevant for the risk assessment.As aluminium molybdenum oxide is an inorganic metallic compound, the tendency to hydrolyze is based on its solubility which is highly pH-dependent. At the physiological pH of 7.4, the availability of aluminium is decreased due to the formation of insoluble Al(OH)₃; molybdenum species exist as molybdate anion (MoO₄^2-). At acidic pH conditions (pH < 4), aluminium is predominantly present as Al³⁺, whereas molybdenum species are primarily available in the acidic forms HMoO₄^-or H₂MoO₄. Since the releaseof aluminium and molybdate species is affected by the biological and pH conditions, the use of data on soluble aluminium and molybdenum compounds is justified for toxicological endpoints representing a worst case scenario. For further details, please refer to the analogue justification attached in section 13 of the technical dossier.

Molybdenum compounds

Absorption

Based on numerous published human toxicokinetic studies, the toxicokinetics of molybdenum are well understood. The use of dual stable isotope (⁹⁷Mo,¹⁰⁰Mo) tracers has even allowed the establishment of sophisticated biokinetic models for molybdenum uptake, distribution and elimination. The modeling data indicate a highly efficient homeostatic mechanism over a wide range of intakes, suggesting diffusion rather than active transport as uptake mechanism:

Oral: Molybdenum absorption through the gastrointestinal occurs rapidly and almost completely (approx. 90% when given in water to fasted individuals), with little variation in absorption despite large variations in dose (i.e., between approx. 20-1400 µg/d orally). The absorption from the GI tract is not subject to any “saturation” at these dosages, with 90% at low and 94% at high intake levels. The relative bioavailability of food-bound Mo was 83% compared to “liquid” administration. Molybdenum levels in blood plasma peak quite early after oral administration. The influence of food matrix on intestinal absorption (100% from water by comparison) has been investigated by co-administration with solid food (50% absorption) and black tea (~10% absorption), for example (reference: Data Evaluation, Toxicokinetics, Molybdenum and its inorganic substances, EBRC unpublished report March 2010, EBRC Hannover, Germany).

Inhalation: Relevant animal or human data on inhalation absorption data are not available for molybdenum compounds. Inhalation absorption is a complex issue and cannot be strictly separated from exposure considerations. Due to the structure and nature of the respiratory tract, inhalation and deposition of particles in various regions of the respiratory tract is dependent on particle size characteristics such as size distribution and density, and will vary from species to species. Further, clearance mechanisms may need to be considered. However, as a worst case assumption, one may assume that soluble molybdenum substances are subject to complete systemic absorption after deposition.

Dermal: The dermal absorption of molybdenum is low to negligible, as has been shown in a guideline-conform in-vitro percutaneous absorption study conducted under GLP with the highly soluble substance sodium molybdate dihydrate (Roper, 2009).

Distribution

Upon uptake, the highly soluble molybdate anions are widely distributed in the body. The highest Mo concentrations are found in kidneys, liver and bone. However, there is no apparent accumulation of Mo in animal or human tissues and very little Mo seems to cross the placental barrier (Vyskocil & Viau, 1999).

Metabolism

Molybdenum is not subjected to any metabolism in its true sense: regardless of its original chemical speciation. Molybdenum transforms rather quickly to molybdate anions upon dissolution. In this form, it is available via diet or drinking water, and represents the physiologically relevant Mo species. Once systemically available, molybdenum is stable in the anionic molybdate form and not subject to any changes in speciation or valence.

Excretion

The elimination of molybdenum (in the form of highly soluble molybdate anions) from plasma is rapid and predominantly via renal excretion (>80%) and only to a lesser extent via faeces (<10%), indicating that the uptake of Mo is not regulated at the level of absorption. Neither the variation of Mo dietary intakes in the range 22-1490 µg/d nor an extended depletion/repletion period has been shown to have any statistically significant effect on serum or urinary copper levels, leaving copper absorption and retention largely unaltered (reference: Data Evaluation, Toxicokinetics, Molybdenum and its inorganic substances, EBRC unpublished report March 2010, EBRC Hannover, Germany).

References not cited in the IUCLID:

Vyskocil, A. and Viau, C. (1999) Assessment of molybdenum toxicity in humans, J. Appl.Toxicol. 19(3), 185-92

Data Evaluation, Toxicokinetics, Molybdenum and its inorganic substances, EBRC unpublished report March 2010, EBRC Hannover, Germany

 

Aluminium compounds

The objective of the study from Atomic Energy of Canada Ltd (2010) 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 using ²⁶Al 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 of FD&Cred 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 0.19 ng 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 a white ash was sent for analysis to. At the university, 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 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 the ²⁶Al administered and the ²⁶Al fraction retained at 7 days post-injection (determined in the initial experiment). 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, 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 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. 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.

Reference not cited in the IUCLID:

Greger et al. (1997) Aluminum Exposure and Metabolism. Critical Reviews in Clinical Laboratory Sciences, 34(5):439-474