Aluminum cobalt oxide

Endpoint summary

Description of key information

Cobalt compounds:
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. 
Aluminium compounds:
Several studies on the pharmacokinetics of aluminium in mammalian species are available. The average fraction of absorbed aluminium is usually below 1% (close to 0.1 to 0.5%), depending on whether extra aluminium was given and in which form. However the absorption of some 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 are 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. 

Additional information

There are no data available on toxicokinetics, metabolism and distribution for cobalt aluminium oxide. However, there are reliable data for various cobalt and aluminium compounds considered suitable for read-across using the analogue approach. For identifying hazardous properties of cobalt aluminium oxide, the existing forms of the target substance at very acidic and physiological pH conditions are relevant for the assessment of human health effects. As cobalt aluminium oxide is a metal-organic salt, which is insoluble in water at pH 6, it is probable that the target substance has also a low degree of solubility at the physiological pH of 7.4. At acidic pH conditions, however, the study of Stopford et al. (2003) showed that water-insoluble cobalt compounds release cobalt ions. Thus, it can be assumed that cobalt aluminium oxide dissociates at acidic pH in the human body resulting in bioavailable cobalt and aluminate ions. Due to the fact that the toxicological effects of cobalt aluminium oxide are mainly caused by exposure to the cobalt ion, the use of data on soluble cobalt compounds is justified for toxicological endpoints as a worst case scenario. In addition, various aluminium compounds are used within the read-across approach. For further details, please refer to the analogue justification attached in section 13 of the technical dossier.

 

Cobalt compounds

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).

Stopford et al. (2003) measured and compared the bioaccessibility of selected cobalt compounds in artificial human tissue fluids and human serum. The authors could show that water-insoluble cobalt compounds (such as cobalt naphthenate and cobalt monoxide) are released at acidic pH conditions in cobalt ions. Cobalt naphthenate was fully soluble in acid fluids (gastric juice (pH 1.5) and lysosomal fluids (pH 4.5)) but had lower degrees of solubility (35 – 45 %) in neutral fluids (pH 7.4: intestinal juice, alveolar fluid, interstitial fluid and serum). Cobalt monoxide was also nearly completely soluble in acid fluids (gastric juice: 100%; lysosomal fluid: 92.4%) but was less than 10% soluble in neutral fluids (intestinal juice, alveolar fluid and interstitial fluid). In serum which is identical to plasma except for the lack of fibrinogen, however the presence or absence of fibrinogen would not be expected to appreciably affect solubility results, cobalt monoxide was about 20% soluble.

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

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

 

Aluminium compounds

The objectives of the study described by Priest (2004)and initially in McAughey et al. (1998) were: the development and validation of a method for the production of transitional alumina aerosol representative of actual worker exposures; determination of the fraction of inhaled aluminium that is transferred directly from the lungs to the blood; and also the fraction that is removed from the lungs, swallowed and excreted in faeces. Two male human subjects were chosen who had no history of cardiac, hepatic, renal, pulmonary, neurological, gastrointestinal, haematological or psychiatric conditions and who were not regularly taking any prescriptions or over-the-counter drugs. The test aerosol was produced using several steps. First, a nebuliser was used to produce a monodisperse distribution of aluminium nitrate solution aerosol containing the ²⁶Al tracer. These droplets were then dried and calcined in an “alumina-tube flow-through furnace” and collected on a PTFE filter. The radiotracer-labelled particles were resuspended in 50% v/v ethanol/water mixture and the suspension nebulised into a chamber (100 L volume). The volunteers, following a breathing pattern of 6 x 1000 mL breaths per minute, were exposed through a system with valves attached to the chamber that separated inhaled and exhaled air for 20 minutes. Re-breathing of exhaled air was used until the last two minutes of the exposure period. During the last two minutes, the particulate matter in the exhaled air was collected for estimation of the deposition efficiency. Post exposure, whole body ²⁶Al was measured using a shielded whole-body monitor. Faecal excretions from the subjects were collected for the two days prior to, and seven days after, the exposure for determination of ²⁶Al. Twenty-four hour faecal samples were also collected at the mid-point of the study and at the end of the study. Venous blood samples were collected at intervals from 1 hour to 82 days after exposure. Daily outputs of urine (bulk 24 hour samples) were collected for six days after the exposure and then at longer intervals until the end of the study (922 days in subject A and 938 days in subject B). The samples were preserved with concentrated nitric acid and, subsequently, the ratio of ²⁶Al:²⁷Al was determined by accelerator mass spectrometry (AMS). The aerodynamic size distribution of the particles was determined using an API Aerosizer time-of-flight instrument and the crystalline structure was examined using X-ray diffraction (XRD). The MMAD from these analyses was 1.2 µm and XRD showed that the test substance consisted of transitional aluminium oxides, some amorphous aluminium oxide, and that α-alumina was absent. McAughey et al. (1998) reported that similar peaks were observed on XRD analysis of a low α-content industrial alumina. Priest (2004) reported a best estimate for the amount of²⁶Al initially inhaled and deposited anywhere in the respiratory tract of 16 ± 5 Bq for one of the subjects and 9 ± 5 Bq for the other. On average, 36% of the initial respiratory deposit was rapidly cleared from the major airways and pharynx within the first 48 hours. After these short-term mechanical removal processes, 9 ± 5 Bq and 4 ± 5 Bq remained (“the initial lung deposit”) in subject A and subject B, respectively. Levels of²⁶Al in the blood collected from the participants were very close to the detection limit of the AMS technique, limiting their reliability. AMS was also required for the determination of ²⁶Al in the faecal samples as the levels were lower than expected. During the first week post-exposure, excretion in faeces, representing the ²⁶Al that was mechanically removed from the respiratory tract and swallowed, was 43.3% of the inhaled amount in subject A, and 28.1% of the inhaled amount in subject B. During the same time period, one subject voided 6.9 Bq in urine and the other 1.5 Bq. The amount of ²⁶Al in urine decreased at rates consistent with half-times of close to 90 days in both subjects. After the initial period, an average of about 0.015% of the initial deposit (0.023% of the initial lung deposit) was eliminated daily in urine, allowing calculation of a half-time for clearance by dissolution processes i.e. transfer to the systemic circulation from the lungs, on the order of 3000 days (8.25 years). Based on these results, mechanical clearance appears to be the main mechanism of particle removal. Measurements of ²⁶Al in urine showed that, by 900 days post-exposure, any excretion of ²⁶Al was below the detection limit of the analytical methods. Integrating the transfer of Al dissolved in the lungs to the blood stream from time zero to infinity indicated that 1.9% of the initial ²⁶Al₂O₃dose deposited in the lungs was ultimately transferred to the systemic circulation. Assuming that 95% of the aluminium that ends up in blood is eliminated through the kidneys then, for every mg of aluminium inhaled, only 500 ng would be retained in the body.

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 0.19ng of²⁶Al. 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 of ²⁶Al in each sample was calculated and corrected to account for the amount discarded with the unanalyzed tissues. 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).

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.

The study from Schlesinger (2000) examined the pattern of alumina accumulation and retention in the lungs, and its translocation to other organs in Sprague-Dawley rats that received weekly intratracheal instillation of alumina (MMAD = 1.2 µm) at a dose of 1 mg alumina/kg body weight for 20 weeks and were followed for 19 weeks post-exposure. Control animals received concurrent intratracheal instillation of vehicle (0.9% sodium chloride). No information is provided on environmental conditions and animal health monitoring. The rats’ diet contained 290 ppm aluminium. Contribution from Al in the diet was taken into account by means of determining baseline Al levels in the tissues of control rats. Tissue samples (lung, brain, bone, kidney, liver spleen) were taken 1 week following 1, 5, 10 and 15 instillations and weekly beginning 1 week after the last instillation. Two exposed and two control rats were sacrificed at each time point. Blood and urine were not collected. Standard flame atomic absorption spectroscopy (AAS) was used for Al determination in lung tissue and a more sensitive graphite furnace AAS technique – for Al determination in other tissues. The possibility of external Al contamination was reduced by acid-washing of beakers and centrifuge tubes. The analytical procedure was validated using two National Institute of Standards and Technology (NIST) standards. Analysis of covariance was used to test for time trends in the accumulation or clearance of Al and for differences between the exposed and the control rats.

There was a significant difference between the exposed and the control animals in time trends of lung Al burden (p < 0.01). Al burden in the lung of the control animals remained virtually unchanged during the experiment. Al burden in the lung of the exposed animals significantly increased during the exposure period (the estimated increase was 32.855 µg Al/g lung per week, significantly greater than zero). There was no statistically significant clearance of Al from the lung of the exposed animals after exposure termination. The (non-significant) negative slope for the post-exposure period suggests that Al was removed from the lung at a rate of 2.6 µg per gram lung tissue per week. The estimated removal of Al from the lung during the entire post-exposure period was 47 µg/g lung tissue, i.e ~9% of the lung burden at the end of exposure). There was no evidence of translocation of alumina from the lung to extrapulmonary tissues: no significant time trends in Al burdens in any examined organ of the exposed animals, and no significant difference between the groups. This suggests that any alumina that was transferred from the lungs to the systemic circulation was likely small in amount and effectively removed from the blood by renal clearance avoiding any build up in extrapulmonary tissues. However, as Al levels in blood and urine were not measured, the actual amount of systemic absorption cannot be estimated. 

The non-guideline study from Rollin (1991) was designed to establish if a deposition of Al in body organs occurred as a result of inhalation exposure to low concentrations of aluminium oxide (0.56 ± 0.17 mg Al/m³), similar to levels found in Al foundries. Eight young adult femalewhite rabbits were exposed via inhalation to Al₂O₃ eight hours a day, five days a week for 5 months. Eight animals served as controls. Every 2 weeks, 2 ml of blood were drawn from an ear vein of each rabbit and Al serum concentrations were determined. All animals were sacrificed at one time point after exposure termination. Al concentrations in the lung, brain, liver, kidney, heart and bone (sternum) were determined by atomic absorption spectrometry. The concentrations of Al in serum were only slightly raised; cyclic changes occurred with an average period of~53 days with a steady slow increase. The increase in Al lung concentration was~160-fold and highly significant (P < 0.005) compared to the control. There was evidence for transfer of Al to the brain (~2.5-fold increase compared to the control, P < 0.005) and, to a lesser extent, to the bone (~1.2-fold increase, P < 0.02). Concentration in the liver became detectable after exposure. The increase in Al concentration in the kidney was not significant, and the concentration in the heart muscle decreased compared to the control. Because tissue Al concentrations were determined only at one time point immediately after exposure, the dynamic of Al accumulation, Al clearance and retention could not be evaluated. Limited information is provided on the methods. In particular, there is no information on the particle size and shape of the test item.