Aluminum cobalt oxide

Carcinogenicity

Description of key information

Read-across with cobalt compounds:
LOAEC (rat): 0.114 mg Co2+/m³ 
LOAEC (mouse): 0.114 mg Co2+/m³ 
Read-across with aluminium compounds:
There was no evidence of carcinogenicity. 
Based on a worst case scenario, cobalt aluminium oxide is classified as carcinogenic due to data on soluble cobalt compounds.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEC

0.114 mg/m³

Study duration:

chronic

Species:

other: rats and mice

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Based on the analogue approach, the available data on carcinogenicity meet the criteria for classification as Category 1B (H350) according to Regulation (EC) 1272/2008 and as R49 (Category 2) according to Directive 67/548/EEC.

Additional information

There are no data available on carcinogenicity 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

In a 2 year inhalation study, groups of mice and rats were exposed to cobalt(II)sulfate heptahydrate aerosols at concentrations of 0.3, 1, and 3 mg/m³ (calculated as anhydrous salt and equivalent to 0.114, 0.38 and 1.14 mg Co2+/m³) for 6 hours/day and 5 days/week (NTP, 1998).

In mice, mean body weights were increased in all treated females and decreased only in the high-exposed males. Survival was not adversely affected by treatment. The incidences of benign and malignant alveolar/bronchiolar neoplasms were increased in a concentration-dependent manner in male and female mice (significant at high-concentration for males; significant at mid- and high- concentration for females).

Males: 11/50, 14/50, 19/50, and 28/50 for 0, 0.114, 0.38, and 1.14 mg Co2+/m³, respectively

Females: 4/50, 7/50, 13/50, and 18/50 for 0, 0.114, 0.38, and 1.14 mg Co2+/m³, respectively.

In rats, mean body weights and survival were unaffected by treatment. Female rats exhibited a concentration-related increase in the incidence of benign and malignant alveolar/bronchiolar neoplasms (significant at mid- and high-concentration) and of benign and malignant pheochromocytomas of the adrenal medulla (significant at high-concentration). The incidences of benign and malignant alveolar/bronchiolar neoplasms were 0/50, 3/49, 15/50, and 15/50 and of benign and malignant pheochromocytomas 2/48, 1/49, 4/50, and 10/48 for 0, 0.114, 0.38, and 1.14 mg Co2 +/m³, respectively.

There was also a concentration-related increase in incidence of benign and malignant adrenal tumours (pheochromocytomas) in the exposed female rats (significant at high-concentration). The incidences of benign and malignant pheochromocytomas were 2/48, 1/49, 4/50, and 10/48 for 0, 0.114, 0.38, and 1.14 mg Co2 +/m³, respectively.

In males, increased incidence of benign and malignant alveolar/bronchiolar neoplasms was observed (significant at high-concentration), but only a marginally increased incidence of pheochromocytomas of the adrenal medulla. The incidences of benign and malignant alveolar/bronchiolar neoplasms were 1/50, 4/50, 4/48, and 7/50 and of benign and malignant pheochromocytomas were 15/50, 19/50, 25/49, and 20/50 for 0, 0.114, 0.38, and 1.14 mg Co2+/m³, respectively.

Although many of the alveolar/bronchiolar lesions were morphologically similar to those that arise spontaneously, the lesions in rats, unlike those in mice, were predominantly fibrotic, squamous or mixtures of alveolar/bronchiolar epithelium and squamous or fibrous components. Squamous metaplasia of alveolar/bronchiolar epithelium, which is a common response to pulmonary injury, was observed in a number of rats.

The marginally increased incidence of pheochromocytomas in males was considered an uncertain finding because it occurred only in the mid-concentration group and was not supported by increased incidence or severity of hyperplasia. Marginal increases in adrenal medullary tumors may have been exposure related.

In summary, test substance was found to be carcinogenic in mice and rats when administered by inhalation. There was clear evidence of carcinogenicity in male mice, female mice and female rats, based on increased incidences of lung tumors. In addition, female rats had an increased incidence of pheochromocytoma of the adrenal medulla. Some evidence of carcinogenicity in male rats was observed, based on increased incidences of lung tumors at the highest exposure level. No NOAECs were identified, neither for rats nor for mice. The LOAECs for mice and females were determined to be 0.114 mg Co2+/m³. The authors of the NTP study concluded that there was clear evidence of carcinogenicity in male and female mice and female rats and some evidence of carcinogenicity in male rats.

Available studies on the carcinogenicity of cobalt in humans are based on occupational exposure to cobalt, often in the presence of carbides such as tungsten carbide. Due to co-exposure with other substances, the data were insufficient to conclude on the carcinogenic potential of elemental cobalt alone. Based on inadequate evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in experimental animals (NTP, 1998), soluble cobalt(II)salts are classified as Category 1B (H350) according to Regulation (EC) 1272/2008 and as R49 (Category 2) according to Directive 67/548/EEC.

 

Aluminium compounds

The studies by Gross et al. (1973) (Klimisch Score = 2) and Pigott et al. (1981) do not support a carcinogenic effect for aluminium metal and aluminium oxide.

Gross et al. (1973) exposed rats, guinea pigs and hamsters to three different aluminium powders (British pyro powder, a US-flake powder, and a US-source atomized powder with approximately spherical particles) and also aluminium oxide dust, included as a negative “non-fibrogenic control”. The Al₂O₃content was 16.6% for the British pyro powder, not stated for theflake powder and 2.9% for the atomized powder. The doses administered by inhalation ranged from 15 to 100 mg/m³, 6 hours per day, 5 days per week for either 6 or 12 months. Thirty rats were exposed to pyro powder at each 15, 30, 50 and 100 mg/m³, 30 rats were exposed to atomized metal powder at each 15, 30, 50 and 100 mg/m³, 30 rats wereexposed to flake powder at 15 and 30 mg/m³, and 30 rats were exposed to aluminium oxide dust at 30 and 70 mg/m³. Five rats were sacrificed per time point (6, 8, 12 and 18 months). Thirty hamsters were exposed to pyro powder at 50 and 100 mg/m³, 30 hamsters were exposed to atomized powder at 50 and 100 mg/m³, and 30 hamsters were exposed to aluminium oxide at 70 mg/m³. Between 15 and 25 guinea pigs were exposed to each of the aluminium powders at 15 and 30 mg/m³. Twelve guinea pigs were exposed to aluminium oxide dust at 30 mg/m³. The chambers were approximately 1.2 m³ in volume, moisture was removed using anhydrous calcium chloride and powders were dispersed through the chambers by means of a dust-feed mechanism (Wright). Air flow was limited to 10 litres/min to attain high dust concentrations. 

The dusts, suspended in tap water, were also administered by intratracheal instillation to different groups of animals. Concentrations were used such that 1mL of the suspension contained the required dose. Injections were performed under anaesthetic (ether) using an illuminated laryngeal speculum to facilitate the introduction of the 18-gauge, blunt needle. A tap water “vehicle” control group was included. For intratracheal instillation, 15 rats and 15 hamsters were allocated to each dose for the pyro, atomized and flaked powders. With the exception of the highest dose level, 1 to 5 animals were sacrificed at 6 months and 7 to 10 animals at 12 months post-exposure. At the 100 mg/m³ dose level for the pyro powder, 15 animals were dosed, 4 were sacrificed at 2 months, 4 at 4 months and 7 at 6 months. At the 100 mg/m³ dose level for the atomized powder, 15 animals were dosed, 3 animals were sacrificed at 2 months, 3 animals at 4 months and 2 animals at 6 months.

Mortality was reported but no data on clinical signs, body weight, or organ weights was provided. Histopathological examinations of the lungs were conducted on sections cut in triplicate from lung tissue stained with either eosin alone to show aluminium particles, hematoxylin-eosin,or PAS/ van Gieson. To show cellular components and stromal support structures, the hematoxylin-eosin stained sections were examined before and after decolorization and impregnation with silver (Gordon and Sweets method).

Intratracheal injection of the aluminium powders caused nodular pulmonary fibrosis in the lungs of the rats only at the highest dose administered (100 mg).A fibrotic response was not observed in hamsters indicating inter-species differences in response. 12 mg of dust administered intratracheally did not lead to collagen production in rats or hamsters. The response of hamster and guinea pigs lungs differed from rats. At higher concentrations (i.e. 100 mg/m³ for hamsters, unclear for guinea pigs), hamster and guinea pig lungs developed metaplastic foci of alveolar epithelium that persisted beyond the resolution of alveolar proteinosis and clearance of the dust particles. 

Progressive fibrosis was not observed in rats on inhalation exposure to the powders indicating that the intratracheal instillation mode of test compound delivery may lead to artifacts not representative of physiologically relevant exposures. There was no dose response evident or a noticeable difference between responses to the different aluminium powders. All three species developed widespread alveolar proteinosis, rats exhibiting the most severe response. However, alveolar walls appeared thin and normal. The proteinosis resolved progressively after cessation of exposure. Small scattered foci of endogenous lipid pneumonitis (granulomatous inflammation) developed associated with cholesterol crystals that were not surrounded by alveolar proteinaceous material. These effects generally occurred in regions not associated with dust particles and left small collagenous scars. The group of rats exposed for 12 months to 15 mg/m³ of aluminium powder showed moderate alveolar proteinosis after 6 months of exposure. Granulomatous inflammation was observed at 50 mg/m³ after about 3 months of exposure.

Overall, there was no consistent relationship between dose and severity of response for any of the aluminium powders. The results showed no clear difference in reaction to the different powders. The results from this study do not provide evidence to support a progressive fibrotic response on inhalation exposure to aluminium powder. No alveolar proteinosis or thickening of alveolar walls was observed in rats, hamsters or guinea pigs exposed to Al₂O₃ dust (66% < 1 μm) included in the study as a “non-fibrogenic” control. 

The reason for the high and variable rates of mortality in this study is unclear and is a limitation of the study. Several endpoints specified in the 90-day inhalation toxicity guideline (OECD 413) were not assessed, particularly body and organ weights. The study design and animal husbandry were not described in sufficient detail. Considering reliability for use in the hazard identification, a Klimisch Score of 2 is appropriate for the lung pathology results and a Score of 3 for the mortality results.

Pigott et al. (1981) reported no evidence of fibrosis in a repeated dose inhalation study that administered alumina fibres (Saffil) at levels between 2 and 3 mg/m³ for 86 weeks. The respirable fraction of the particulates was 30 - 40% and the median diameter ca. 3.0 μm). The only pulmonary response observed was the occurrence of pigmented alveolar macrophages. The authors reported qualitatively that a minimal alveolar epithelialization was seen in control animals but that the numbers were slightly higher in rats dosed with aged Saffil.There were no lung tumors in the Saffil treated animals, and no significant group difference in the frequency of extrapulmonary tumors was observed.

One study of ultrafine Al₂O₃ particles administered by intratracheal instillation to rats was identified. Induction of lung tumours was observed. The results from this study lack relevance to actual human exposures due to the mode of administration and the high doses administered.

Due to the high doses applied and the high dose rate, rat-specific effects due to lung overload are likely. 

The available evidence from animal studies does not support a carcinogenic effect specific to aluminium oxide and aluminium metal in humans.

Friesen et al. (2009) investigated the associations between alumina and bauxite dust exposure and circulatory disease mortality, respiratory disease mortality and cancer incidence in a cohort of employees from four bauxite mines and three alumina refineries in. These individuals were employed on or after Jan 1, 1983. For employees employed before the survey in 1995-1996, work history and smoking status were obtained from company records. Outcomes were determined by linkage with the national mortality database and the national and state cancer incidence registries. Cumulative exposure to inhalable bauxite and alumina were estimated using a task-exposure matrix for those employed in 1995/6. A less detailed job-exposure matrix was required for subjects who left employment before 1996. Before 1998, total dust was measured using a NIOSH cassette subsequently found to underestimate the inhalable fraction. Post-1998, an of device was used. The study cohort had a mean age of 32 years (10.5, sd, standard deviation) at entry, a mean duration of employment of 14.1 years, a mean person-year (PY) contribution of 16.2 years (4.8, sd) providing a total of 93,420 PYs of follow-up. A greater percentage of the bauxite-exposed workers were either current (29% v 24%) or former (29% v 25%) smokers compared to the unexposed group while alumina-exposed workers and unexposed workers did not differ with respect to smoking status. The median, mean and maximum cumulative exposures to bauxite among the bauxite-exposed workers were 5.7, 13.4, and 187 mg/m³-yr, respectively. The median, mean and maximum cumulative exposures to alumina among the alumina-exposed workers were 2.8, 14.5, and 210 mg/m³-yr, respectively. Exposure categories used in the analyses were defined based on the tertiles in the few cases. The relative risk of death from non-malignant respiratory disease showed a significant trend (7 deaths; p < 0.01) with cumulative bauxite exposure with adjustment for age, calendar year and smoking. The deaths were due to chronic obstructive pulmonary disease, asbestosis, unspecified bronchopneumonia and interstitial pulmonary disease with fibrosis. Cumulative alumina exposures showed a marginally significant trend with mortality from cerebrovascular disease (10 deaths; p=0.04). No notable associations or trends were observed for cancer outcomes. The analyses in this study were based on only a few cases accrued during the relatively short follow-up and adjustment for smoking was done using only a crude categorical variable. Further follow-up and accrual of more cases will be required to determine the validity of the reported trends.

Carcinogenicity: via inhalation route (target organ): respiratory: lung