Cobalt(2+) hydrogen citrate

Endpoint summary

Description of key information

Oral: After oral ingestion of soluble cobalt (II) salts, absorption from the gastrointestinal tract increases with solubility of the cobalt compound 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 (II) salts, 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 data available on toxicokinetics for cobalt hydrogen citrate. However, there are reliable data for soluble cobalt compounds considered suitable for read-across using the analogue approach.

Cobalt hydrogen citrate is a metal-organic compound, which is water soluble and nearly completely dissociates in aqueous solutions. For identifying hazardous properties of cobalt hydrogen citrate concerning human health effects, the existing forms of the target chemical at physiological and very acidic pH conditions (e. g. in the stomach) are relevant for risk assessment. For cobalt hydrogen citrate, it can be assumed that cobalt cations are released under biological conditions that are considered to be toxicologically relevant. Furthermore it is anticipated that the cobalt cation released by the parent compound is the determining factor for toxicological effects, same as for other soluble cobalt compounds. Therefore, data originating from soluble cobalt compounds can be used in the derivation of toxicological endpoints for cobalt hydrogen citrate. For further details, please refer to the analogue justification attached in section 13 of the technical dossier.

Absorption

Oral: The absorption of cobalt (II) 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 dichloride in human volunteers indicated 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 Cobalt 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 not cited in the IUCLID

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