Dodecaaluminium trimolybdenum dodecaoxide

Carcinogenicity

Description of key information

Read-across with molybdenum trioxide:
Molybdenum trioxide induced alveolar/bronchiolar carcinoma in rats and mice when administered by inhalation. However, other molybdenum compounds (e.g. molybdenum metal, molybdenum dioxide and various molybdate salts) are not capable of producing this acidic effect because of their chemical composition. Thus the existing classification for carcinogenicity for MoO3 is not read-across to aluminium molybdenum oxide.
Read-across with aluminium compounds:
Various studies with aluminium compounds did not support a carcinogenic effect.

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

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Based on all available information using the analogue approach, the data do not meet the criteria for classification according to Regulation (EC) 1272/2008 or Directive 67/548/EEC, and are therefore conclusive but not sufficient for classification.

Additional information

There are no data available on carcinogenicity for aluminium molybdenum oxide. However, there are reliable data for aluminium and molybdenum compounds considered suitable for read-across using the analogue approach. For identifying hazardous properties of aluminium molybdenum oxide concerning human health effects, the existing forms of the target substance at very acidic and physiological pH conditions are relevant for the risk assessment. As aluminium molybdenum oxide is an inorganic metallic compound, the tendency to hydrolyze is based on its solubility which is highly pH-dependent. At the physiological pH of 7.4, the availability of aluminium is decreased due to the formation of insoluble Al(OH)₃; molybdenum species exist as molybdate anion (MoO₄^2-). At acidic pH conditions (pH < 4), aluminium is predominantly present as Al³⁺, whereas molybdenum species are primarily available in the acidic forms HMoO₄^-or H₂MoO₄. Since the release of aluminium and molybdate species is affected by the biological and pH conditions, the use of data on soluble aluminium and molybdenum compounds is justified for toxicological endpoints representing a worst case scenario. For further details, please refer to the analogue justification attached in section 13 of the technical dossier.

 

Read-across with molybdenum trioxide:

A 2 year carcinogenicity study (NTP, 1997) is available, in which the substance molybdenum trioxide was administered to rats and mice via inhalation at concentrations of 10, 30 or 100 mg/m³. The incidences of alveolar/bronchiolar adenoma or carcinoma (combined) were increased in male rats with a marginally significant positive trend. No increase in the incidences of lung neoplasms occurred in female rats. Exposure of male and female rats to molybdenum trioxide by inhalation resulted in increased incidences of chronic alveolar inflammation, hyaline degeneration of the respiratory epithelium, hyaline degeneration of the olfactory epithelium (females), and squamous metaplasia of the epiglottis.

In male mice, the incidences of alveolar/bronchiolar carcinoma in all exposed groups were significantly greater than that in the control group. Incidences of alveolar/bronchiolar adenoma in female mice in the 30 and 100 mg/m³ groups were significantly greater than that in the control group. Incidences of alveolar/bronchiolar adenoma or carcinoma (combined) in 10 and 30 mg/m³ male mice and in 100 mg/m³ female mice were significantly greater than those in the control groups and exceeded the historical control ranges for 2-year NTP inhalation studies.

Exposure of male and female mice to molybdenum trioxide by inhalation resulted in increased incidences of metaplasia of the alveolar epithelium, histiocyte cellular infiltration (males), hyaline degeneration of the respiratory epithelium, hyaline degeneration of the olfactory epithelium (females), squamous metaplasia of the epiglottis, and hyperplasia of the larynx. Both in rats and mice (male and female), there was no evidence of systemic carcinogenicity. The marginal evidence for carcinogenicity in the lung due to observed localized carcinoma/adenoma (considered by NTP in male rats to be ”equivocal” and in mice designated as “some evidence of carcinogenic activity”) is considered to be an effect which is specific to molybdenum trioxide. The observed localized carcinoma/adenoma are secondary to local lung tissue inflammation, considered to be a result of the acidic reaction of MoO3 in the lung fluids: in aqueous media, MoO3 molecules react with water and release protons according to the following equation: MoO3+ H2O --> MoO4²- + 2 H+.

Based on the effects observed, which are restricted to local effects in the respiratory tract, molybdenum trioxide (MoO3) is classified as Category 2 (H351) according to Regulation (EC) 1272/2008 and R40 (Category 3) according to Directive 67/548/EEC.

A similar effect is plausible only for the substance roasted molybdenite concentrate (RMC), which consists of various forms of molybdenum oxides, with the main constituent being MoO3. Other molybdenum substances (e.g. molybdenum metal, molybdenum dioxide and various molybdate salts) are not capable of producing this acidic effect because of their chemical composition. Thus the existing classification for carcinogenicity for MoO3 is not read-across to aluminium molybdenum oxide.

 

Read-across with aluminium compounds

The studies by Gross et al. (1973) 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 Al₂O₃dust (66% < 1μm) 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. 3.0μm). 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 Al₂O₃particles 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