Hexaammonium heptamolybdate

Endpoint summary

Additional information

(I) Introductory remark on read-across:

 

This dossier is one of several dossiers prepared under the auspices of the REACH Molybdenum Consortium (“MoCon”). To avoid unnecessary (animal) testing, a comprehensive grouping and read-across concept has been developed amongst several molybdenum containing substances. This grouping/category approach is described in detail in a separate report, in accordance with the ECHA's "Read-Across Assessment Framework" (RAAF). This document is attached to section 13 in the technical dosser and to the CSR. The following text in this paragraph is therefore applicable to all substances in the category.

 

(II) Comment on the essentiality of molybdenum

Human health risk assessments conventionally focus primarily on the effects of high doses of chemicals, which ultimately may induce toxicity. However, in the case of essential trace elements, harmful effects may also occur at too low intakes due to deficiency. This has implications for risk assessment when the aim of minimising exposure as far as possible may result in recommendations for such low intakes that would lead to deficiency.

It is well established that molybdenum is an essential element for humans, as well as for animals and plants. Molybdenum is a component (co-factor) of enzymes which are essential for life and without molybdenum, organisms cannot function and will show signs of deficiency (see for example a review Mendel and Bittner (2006) and references therein). As for many essential nutrients, recommendations are issued by different organisations in various countries on adequate intake levels, and minimum dietary requirements of molybdenum. For example, the Estimated Average Requirement (EAR) of molybdenum for adults has been established as 34 µg/day, corresponding to ca. 0.5 µg/kg bodyweight/day for a 70-kg adult (FNB, 2001). The National Societies for Nutrition of Germany, Austria and Switzerland (DACH, 2001) have derived an "estimate for adequate intake" of molybdenum as 50-100 µg/day (ca. 0.7. -1.4 µg/kg bw/day), whereas the British Expert Group on Vitamins and Minerals (BEGVM, 2003) has estimated molybdenum requirement in the range 100-300 µg/day (1.4-4.3 µg/kg bw/day).

(III) Basic toxicokinetic data on molybdenum (absorption, distribution, metabolism and excretion)

Absorption

The use of dual stable isotope (⁹⁷Mo,¹⁰⁰Mo) tracers in humans has been developed to a high level of sophistication, thus enabling the establishment of biokinetic models for molybdenum uptake, distribution and elimination. Thus, toxicokinetics of molybdenum in humans are well understood and animal data is therefore not addressed below in great detail.

Oral:

Molybdenum absorption in humans through the gastrointestinal tract occurs rapidly and almost completely (88-93%) when molybdenum (added as ammonium heptamolybdate) was ingested within an aqueous formula that supplemented controlled meals. Little variation in absorption despite large variations in dose, i.e. between approx. 20-1,400 µg/d orally, were observed in these studies (Turnlund et al., 1995). The same group of researchers adapted a compartment model to their experimental data, and the model “closely approximated the highly efficient homeostatic mechanisms of molybdenum metabolism over a wide range of intakes” (Thompson et al., 1996). Giussani et al. (2006) demonstrated that “molybdenum ingested in liquid form was rapidly and totally absorbed...” but that “rates and extent of absorption were lower for composite meals, and also for increasing levels of administration”. Earlier, it has been shown that co-administration of black tea also reduced the bioavailability of molybdenum (Giussani et al., 1998). In addition, oral exposure through food has been investigated for interactions unique to molybdenum: specifically, studies with high-sulfur foods (e.g., soy) have been shown to reduce the oral bioavailability in humans by 37% (Turnlund et al., 1999).

Inhalation:

Relevant animal or human data on inhalation absorption data are not available for molybdenum substances. Inhalation absorption is a complex issue and cannot be strictly separated from exposure considerations. Due to the structure and nature of the respiratory tract, the inhalability and deposition of particles in various regions of the respiratory tract is dependent on particle size characteristics such as size distribution and density. 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 in the respiratory tract. Due to the complexity of this issue it is not further addressed here but considered in more detail elsewhere in the chemical safety assessment of the various molybdenum substances, where appropriate.

Dermal:

The dermal absorption of molybdate 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

Vyskocil and Viau (1999) have summarised information on the distribution of molybdenum in the body as follows: “Once absorbed, molybdenum rapidly appears in the blood and most organs.... The highest molybdenum concentrations are found in the kidneys, liver and bones of most laboratory animals and humans.... There is no apparent bioaccumulation of molybdenum in animal or human tissues. Very little molybdenum seems to cross the placental barrier. ”

Metabolism

Molybdenum is not subject to any metabolism in its true sense: regardless of their original chemical form, dissolved molybdenum substances transform 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

Werner et al. (2000) evaluated the plasma clearance and urinary excretion for molybdenum after injection into five human volunteers: “The data obtained for the plasma clearance... can reasonably be fitted by a two exponential equation. The half times of the fast component range between 4 and 70 minutes and for the slow component between 3 and 30 hours”.    Excretion is predominantly via the kidney (59-94%, increasing with administered dose and only to a lesser extent via faeces (Turnlund et al. 1995).

References:

BEGVM, 2003: British Expert Group on Vitamins and Minerals: Safe Upper Levels for Vitamins and Minerals. Published by Food Standards Agency, May 2003, ISBN 1-904026-11-7.

DACH (2001): Kupfer, Mangan, Chrom, Molybdän. In: Deutsche Gesellschaft für Ernährung, Österreichische Gesellschaft für Ernährung, Schweizerische Gesellschaft für Ernährungsforschung, Schweizerische Vereinigung für Ernährung (Hrsg.): Referenzwerte für die Nährstoffzufuhr, 1. Auflage, 201-208.

FNB, 2001: Dietary reference intakes for vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. Food and Nutrition Board, National Academic Press, Chap. 11, 420-441

Giussani et al.(2006): Rates of intestinal absorption of molybdenum in humans. Appl. Radiation Isotopes 64, 639-644

Mendel, R. and Bittner, F. (2006): Review: Cell biology of molybdenum. Biochimica et Biophysica Acta 1763 (2006) 621–635.

Roper (2009) Disodium Molybdate Dihydrate: The In Vitro Percutaneous Absorption Of Molybdenum Through Human Skin. Unpublished study report for the International Molybdenum Association (IMOA). Test Facility Study No. 782678. Charles River, Tranent, Edinburg, EH33 2NE, United Kingdom

Thompson, K. H.; et al. (1996): Molybdenum metabolism in men with increasing molybdenum intakes: changes in kinetic parameters. J. Appl. Physiol. 81, 1404-1409

Turnlund, J. R.; et al. (1995): Molybdenum absorption, excretion, and retention studied with stable isotopes in young men at five intakes of dietary molybdenum. Am. J. Clin. Nutr. 62, 790-796

Turnlund J. R. et al. (1999): Molybdenum absorption and utilization in humans from soy and kale intrinsically labelled with stable isotopes of molybdenum. Am J Clin Nutr. 1999 Jun;69(6):1217-23.

Vyskocil, A. and Viau, C: Assessment of Molybdenum Toxicity in Humans. J. Appl. Toxicol. 19, 185-192

Werner (2000): Internal biokinetic behaviour of molybdenum in humans studied with stable isotopes as tracers. Isotopes Environ. Health Stud. 36, 123-132