Cobalt molybdate

Endpoint summary

Description of key information

Oral: After oral ingestion of soluble cobalt substances, absorption from the gastrointestinal tract increases with solubility of the cobalt substance and with iron deficiency of the individual. Studies in laboratory animals indicated increased cobalt levels primarily in liver, as well as in other organs. Orally administered cobalt is primarily eliminated in faeces.  
Inhalation: Following inhalation exposure to soluble cobalt substances, large particles are deposited in the upper respiratory tract where they are subjected to mechanical clearance, including transfer to the gastrointestinal tract. Smaller particles are deposited in the lower respiratory tract where they may be solublised and absorbed, or phagocytosed. Following an initial high rate of faecal clearance, urinary excretion is the primary route of cobalt elimination after inhalation exposure. 

Additional information

There are no toxicokinetic studies available for cobalt molybdenum oxide. However, there are reliable data for soluble cobalt and molybdenum substances considered suitable for read-across using the analogue approach. For identifying hazardous properties of cobalt molybdenum oxide, the existing forms of cobalt molybdenum oxide at very acidic and physiological pH conditions are relevant for risk assessment of human health effects. Cobalt molybdenum oxide is a metal-organic salt, which is highly water soluble (~ 508 mg/L) and nearly completely dissociates in aqueous solutions. As it is expected that cobalt molybdenum oxide is capable of forming ions at very acidic and physiological pH conditions, cobalt cations and molybdate anions will be present and completely bioavailable, same as for other soluble cobalt and molybdenum compounds. Due to the existing cobalt and molybdate ions, data from other soluble cobalt and molybdenum substances are used in the derivation of toxicological endpoints for cobalt molybdenum oxide. For further details refer to the analogue justification.

 

Cobalt substances

Absorption

Oral: The absorption of cobalt salts after oral administration is dependent on their water solubility. Water soluble cobalt salts dissolve directly and have been found to exhibit greater absorption than non-water soluble compounds (Firriolo et al., 1999).

Studies on the absorption of cobalt(II)chloride in human volunteers indicate that the absorption rate from the gastrointestinal tract ranges from 5% to > 20%, depending on the dose and the nutritional status of the individual (Smith et al., 1972; Sorbie et al., 1971). Cobalt absorption was increased among individuals (humans and animals) who were iron deficient (31-71% absorption in iron-deficient subjects, 18-44% in controls) (Valberg et al., 1969; Sorbie et al., 1971). The gastrointestinal absorption is reduced when cobalt is administered after a meal (Midtgard and Binderup, 1994).

Inhalation: Inhalation of cobalt particles results in deposition in the upper and lower respiratory tract (Casarett and Doull, 1986). Particle size is the primary factor determining deposition patterns. Large particles (diameter > 2 µm) deposit in the upper respiratory tract, while smaller particles tend to deposit in the lower respiratory tract, where sedimentation and diffusion can occur. Fractional deposition varies due to particle size, age and breathing patterns of the exposed individuals. Cobalt particles deposited in the respiratory tract can be absorbed into the blood after dissolution, phagocytosed or mechanically transferred to the gastrointestinal tract by mucociliary action and swallowing (Foster et al., 1989).

Dermal: The available data indicate that the in-vivo dermal absorption rate in guinea pigs was in the same range as the in-vitro dermal absorption rate reported for humans (51-86 and 38 nmol/cm²/h, respectively; application of 0.085 M cobalt(II)chloride) (Wahlberg, 1965). Dermal exposure to cobalt(II)chloride may result in significant systemic uptake of cobalt.

Metabolism: The Co²+ cation is not subjected to any metabolism.

Distribution and excretion: The distribution of cobalt after oral administration in rats indicated that cobalt absorbed in the gastrointestinal tract is primarily retained in the liver. But cobalt was also found in the kidneys, heart, stomach, and intestines (Ayala-Fierro et al., 1999).

After inhalation exposure in animals, marked increases of cobalt have been found in the lung. Histological analysis revealed that cobalt particles were localised to macrophages within the bronchial wall or in the interstitium close to the terminal bronchiole. Cobalt has been found also in the liver, kidney, trachea, spleen, bones and heart with the highest level in the liver and kidney (Brune et al., 1980).

Animal data on cobalt elimination indicate that the solubility of the cobalt compound greatly affects the long-term clearance. Soluble cobalt compounds are absorbed into the blood at a faster rate than less soluble compounds and excreted in the urine and faeces (Barnes et al., 1976). Urinary excretion rates seem to correlate with the translocation rate of cobalt from the lungs to blood, whereas faecal excretion rates seem to correlate with mechanical clearance rates of cobalt from the lungs to the gastrointestinal tract (Collier et al., 1989; Patrick et al., 1989). Following an initial high rate of faecal clearance, urinary excretion is the primary route of cobalt elimination after inhalation exposure (Palmes et al., 1959).

After oral administration, faecal elimination is the primary route of excretion. Ayala-Fierro et al. (1999) showed that cobalt(II)chloride was excreted primarily via faeces in rats (70-83% of the administered dose), with urinary excretion for the remainder of the dose. Faecal clearance has been noted to decrease as cobalt particle solubility increases.

Following single intravenous administration of cobalt(II)chloride to rats, 10% of the dose was excreted in faeces indicating biliary excretion and 75% of the dose was excreted in urine 36 hours after administration (Ayala-Fierro et al., 1999).

 

References:

Casarett LJ and Doull J, 1986, The basic science of poisons, 3rd ed. New York , Macmillan Publishing Company, pp. 56-57

Foster PP et al., 1989, An interspecies comparison of the lung clearance of inhaled monodisperse cobalt oxide particles – Part II: Lung clearance of inhaled cobalt oxide in man. Journal of Aerosol Science, 20(2): 189-204

Firriolo JM et al., 1999, Absorption and disposition of cobalt naphthenate in rats after a single oral dose. Journal of Toxicology and Environmental Health A, 58: 383-395

Smith T et al., 1972, Absorption and retention of cobalt in man by whole-body counting. Health Physics, 22: 359-367

Sorbie J et al., 1971, Cobalt excretion test for the assessment of body iron stores. Canadian Medical Association Journal, 104(9): 777-782

Valberg LS et al., 1969, Alteration in cobalt absorption in patients with disorders of iron metabolism. Gastroenterology, 56(2): 241-251

Midtgard U and Binderup ML, 1994, The nordic expert group for criteria documentation of health risks from chemicals. 114. Cobalt and cobalt compounds. Arbete och Hälsa, 39: 1-66

Wahlberg J., 1965, Percutaneous absorption of sodium chromate (51Cr), cobaltous (56Co), and mercuric (203Hg) chlorides through excised human and guinea pig skin. Acta Derm Venerol, 45: 415-426

Brune D et al., 1980, Pulmonary deposition following inhalation of chromium-cobalt grinding dust in rats and distribution in other tissues. Scandinavian Journal of Dental Research, 88: 543-551

Ayala-Fierro F et al., 1999, Disposition, toxicity and intestinal absorption of chloride in male Fischer 344 rats. Journal of Toxicology and Environmental Health A, 56: 571-591

Barnes JE et al., 1976, Cobalt-60 oxide aerosols: Methods of production and short-term retention and distribution kinetics in the beagle dog. Health Physics, 30: 391-398

Collier CG et al., 1989, An interspecies comparison of the lung clearance of inhaled monodisperse cobalt oxide particles – Part V: Lung clearance of inhaled cobalt oxide particles in hamsters, rats and guinea pigs. Journal of Aerosol Science, 20(2): 233-247

Patrick G et al., 1989, An interspecies comparison of the lung clearance of inhaled monodisperse cobalt oxide particles – Part V: Lung clearance of inhaled cobalt oxide particles in SPF Fischer rats. Journal of Aerosol Science, 20(2): 249-255

Palmes ED et al., 1959, Inhalation toxicity of cobalt hydrocarbonyl. American Industrial Hygiene Association Journal, 20: 453-468

 

Molybdenum substances

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:

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