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Carcinogenicity

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Description of key information

Chronic toxicity, inhalation, rat:

carcinogenicity: NOAEC >= 75 mg/m³ as aluminium oxide

The weight of evidence does not support a carcinogenic effect from exposure to aluminium oxide. 

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via inhalation route

Link to relevant study records

Referenceopen allclose all

Endpoint:
carcinogenicity, other
Remarks:
dust and Intratracheal injections
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1973
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study with acceptable restrictions
Reason / purpose:
reference to same study
Reason / purpose:
reference to same study
Reason / purpose:
reference to same study
Reason / purpose:
reference to same study
Reason / purpose:
reference to same study
Qualifier:
equivalent or similar to
Guideline:
other: OECD TG 452
Deviations:
yes
Remarks:
: number of animals to low (30 instead of 50 per sex and dose); duration only 1 year instead of 2 years.
GLP compliance:
not specified
Species:
rat
Strain:
not specified
Sex:
not specified
Details on test animals and environmental conditions:
Details on test animals and environmental conditions: no data
It is unclear whether the animals remained in the inhalation chambers even when the exposure was not occurring.
Route of administration:
other: inhalation: dust and Intratracheal injections
Type of inhalation exposure (if applicable):
whole body
Vehicle:
not specified
Remarks on MMAD:
MMAD / GSD: No information was provided on the MMAD and GSD.

Further detail on particle characteristics (e.g. shape):
Particle size by count was provided for the size ranges < 1.0 µm; 1 to 4 µm; and > 4 µm.
(1) British pyro powder
Shape: flake-like
Size: < 1 µm 4.2%, 1 – 4 µm 87.3%, > 4 µm 8.5%
Mean diameter: 2.49 µm
Specific surface area: 10.4 m²/g

(2) US –source atomised particles.
Shape: “spherical”
Size: < 1 µm 1.5%, 1 – 4 µm 95.6%, > 4 µm 2.9%;
Mean diameter: 2.22 µm
Specific surface area: 0.8 m²/g

(3) US-source flake powder
Shape: flake
Size: < 1 µm 0.0%, 1 – 4 µm 28.6%, > 4 µm 71.4%;
Mean diameter: 4.85 µm
Specific surface area: 8.4 m²/g

(4) Negative control: aluminium oxide dust.
Shape: not stated
Size: < 1 µm 66%, 1 – 4 µm 25%, > 4 µm 9%;
Mean diameter: 0.80 µm
Specific surface area: 6.3 m²/g
Details on exposure:
Further details on inhalation exposure:
The chambers were approximately 1.2 m³ in volume. Moisture was removed using anhydrous calcium chloride. 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.

Details on Intratracheal Instillation:
A suspension of the dust in tap water was instilled intratracheally. 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.
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
The air flow through the chambers was monitored with outflowing chamber air forced through 20.3 x 25.4 cm filter (Millipore) filters before ventilation. The filters were used to gravimetrically estimate the average dust concentration in the chamber each day. The data were not reported however.
Duration of treatment / exposure:
Inhalation
According to Table 2 of the article -
Rats in the 50 and 100 mg/m3 chambers were exposed for 6 months. Exposure duration was 12 months for the animals at the lower aluminium powder concentrations of 15 and 30 mg/m3.

The aluminium oxide control rats were exposed to 75 mg/m³ for six months. An additional 30 rats were exposed to 30 mg/m³ of aluminium oxide dust for a year.
Frequency of treatment:
Inhalation:
6 hr/day; 5 days a week
Dose / conc.:
15 mg/m³ air
Remarks:
pyro powder, atomized powder, flake powder
Dose / conc.:
30 mg/m³ air
Remarks:
pyro powder, atomized powder, flake powder
Dose / conc.:
50 mg/m³ air
Remarks:
pyro powder, atomized powder
Dose / conc.:
100 mg/m³ air
Remarks:
pyro powder, atomized powder
Dose / conc.:
30 mg/m³ air
Remarks:
aluminium oxide
Dose / conc.:
75 mg/m³ air
Remarks:
aluminium oxide
No. of animals per sex per dose:
Inhalation:
30 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 were exposed to flake powder at 15 and 30 mg/m³
30 rats were exposed to aluminium oxide dust at 30 and 75 mg/m³

Intratracheal instillation:
15 rats 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.
At the 100mg/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 100mg/m³ dose level for the atomized powder, 15 animals were dosed, 3 were sacrificed at 2 months, 3 at 4 months and 2 at 6 months.

Control animals:
yes
Details on study design:
Control animals:
50 rats were untreated (laboratory controls). Five animals were examined per time point.
Aluminium oxide (numbers and dosing described above) were included as “non-fibrogenic” controls.
For the intratracheal instillation group, 15 rats were included as vehicle controls.

No information was provided on the method used to allocate the animals to groups.
Positive control:
No.
Observations and examinations performed and frequency:
Observations and examinations performed:
No information was provided on observations to monitor animal health but mortality was recorded.

Frequency of the observations and examinations:
For the inhalation exposure, pathological examinations took place at 6, 8, 12 and 18 months into the experiment for the 50 and 100 mg/m³ aluminium powder dose groups and the 70 mg/m³ aluminium oxide dose group (i.e. 0, 2, 6 and 12 months after cessation of exposure). Kills of the lower dose animals took place at 6 and 12 months (0 and 6 months post-exposure).
Sacrifice and pathology:
The method used to sacrifice the animals was not reported in the article.
Histopathological examinations of lung tissue were conducted using sections cut in triplicate and embedded in paraffin blocks. One section was stained with eosin to show aluminium particles, a second section was stained with hematoxylin-eosin, and a third section with PAS or van Gieson. To show cellular components and stromal support structures, the hematoxylin-eosin stained sections were photographed then decolorized and impregnated with silver (Gordon and Sweets method) before another photograph was taken. Aluminium particles were removed prior to this procedure using 10% sodium bisulfite.
Other examinations:
No data.
Statistics:
No data.
Clinical signs:
effects observed, treatment-related
Dermal irritation (if dermal study):
not specified
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
no effects observed
Other effects:
not specified
Details on results:
CLINICAL SIGNS AND MORTALITY
A higher rate than ideal was observed. As high rates were observed in control groups as well as treated groups and appeared to show no relationship to dose, deaths were unlikely to be simply related to the dust exposure. The authors suggest an effect of crowding and low air flow in the chambers. Quantitatively, the mortality results from this study are not reliable. The absence of observations of clinical signs also suggests that caution ought to be used in interpreting the results.

ORGAN WEIGHTS
Lung weights were measured but not reported.

HISTOPATHOLOGY: NON-NEOPLASTIC
ADEQUATE
- alveolar proteinosis was observed after 6 months exposure to 15 mg/m³ in rats.
- foci of fibrosis found for pyro Al powder at 50 mg/m³ exposed for 108 days; killed 6 months later.


LUNG HISTOLOGY
Al-powders:
All three species developed alveolar proteinosis (AP);

Rats:
50 and 100 mg/m³ exposed for 6 mths:
Marked AP; but alveolar walls were generally thin and appeared normal;
AP underwent spontaneous resolution with little evidence remaining 1.5 years post-exposure.
15 and 30 mg/m³ for 12 mths:
Moderate AP from 6 to 12 months followed by gradual clearing. Some AP still present at 24 mths.

Persistent changes:
Small scattered foci of endogenous lipid pneumonitis (granulomatous inflammation) associated with cholesterol crystals that were not surrounded by AP material. These occurred generally not in regions with dust particles. The foci left collagenous scars.
No carcinoma was observed. Lymphoid tumors, reticulum cell and lymphosarcoma noted in both the treated and control groups. Considered spontaneous by authors and numbers were not provided.

Al2O3:
Rats:
Small foci concentrated in respiratory bronchioles and alveolar ducts – consisting of clustered alveoli with swollen macrophages engorged with particles; no thickening of alveolar walls evident; no evidence of AP or pnuemonitis.

Distribution and clearance of dust:
Dust remained finely dispersed even within the cytoplasm of macrophages.
Rats:
50 and 100 mg/m³ exposed for 6 mths: Clearance by 1.5 years post-exposure
15 and 30 mg/m³ exposed for 12 mths: some finely dispersed Al-powder particles were still evident 1 year post-exposure.

There was no dose response evident or noticeable differences in response to the different aluminium powders.

The laboratory and the intratracheal injection control did not show evidence of proteinosis.

Intratracheal Instillation:
Lung histology
Rats:
Pyro and atomized powder - 100 mg/m³
6 mths: numerous large foci of collagenous fibrosis “sharply circumscribed but highly irregular in outline”; some coalesced; no remaining alveolar structure; coarse bundles of collagen; moderate number of plump connective cells; black pigment masses in connective tissue; alveolar tissue between fibrotic foci usually normal.
12mths: collagenous foci with more fibres and fewer connective cells; similar between the different powders; inter-animal variability in response was evident.
Pyro and atomized powder – 12 to ≤ 24 mg/m³
Smaller, more widely separate foci that were highly cellular with only a few collagen fibres; foci were concentrated around the respiratory bronchioles and alveolar ducts.
Pyro and atomized powder – ≤ 12 mg/m³
No significant collagenisation of foci at 6 or 12 mths.
Dose descriptor:
LOAEC
Remarks:
local effects
Effect level:
15 mg/m³ air
Based on:
test mat.
Remarks:
Al powder
Sex:
not specified
Basis for effect level:
histopathology: non-neoplastic
Dose descriptor:
NOAEC
Remarks:
local effects
Effect level:
>= 75 mg/m³ air
Based on:
test mat.
Remarks:
Al2O3 dust
Sex:
not specified
Basis for effect level:
other: no adverse effect observed at the highest dose tested
Critical effects observed:
not specified

Mortality: 

Animal

Dust Type

Dose (mg/m3)

Exposure duration

% dead: 6 mos.

% dead: 12 mos.

Rat

Atomised Al

100

6 mos

0

0

 

Atomised Al

50

6 mos

7

25

 

Atomised Al

30

12 mos

0

28

 

Atomised Al

15

12 mos

0

8

 

Pyro Al

100

6 mos

0

40

 

Pyro Al

50

6 mos

0

20

 

Pyro Al

30

12 mos

0

20

 

Pyro Al

15

12 mos

3

36

 

Flake Al

30

12 mos

0

24

 

Flake Al

15

12 mos

0

32

 

Al2O3

75

6 mos

0

0

 

Al2O3

30

12 mos

0

20

Air control

0

6 mos

0

0

Air control

0

12 mos

0

0

Conclusions:
Intratracheal injection of aluminium powder 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 interspecies 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, 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. There was no dose response evident or a noticeable difference between responses to the different aluminium powders.

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 actual inhalation exposures. All three species developed widespread alveolar proteinosis, rats exhibiting the most severe response. The proteinosis resolved progressively after cessation of exposure. The group of rats exposed for 12 months to 15 mg/m³ of aluminium powder showed moderate alveolar proteinosis after only 6 months of exposure.
Executive summary:

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 Al2O3 content was 16.6% for the British pyro powder, not stated for the flake 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 were exposed to flake powder at 15 and 30 mg/m³, and 30 rats were exposed to aluminium oxide dust at 30 and 75 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 75 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% <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 chronic toxicity guideline (OECD TG 452) 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.

Endpoint:
carcinogenicity, other
Remarks:
inhalation: dust and Intratracheal injections
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1973
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study with acceptable restrictions
Reason / purpose:
reference to same study
Reason / purpose:
reference to same study
Reason / purpose:
reference to same study
Reason / purpose:
reference to same study
Reason / purpose:
reference to same study
Qualifier:
equivalent or similar to
Guideline:
other: OECD TG 452
Deviations:
yes
Remarks:
: number of animals to low (30 instead of 50 per sex and dose); duration only 1 year instead of 2 years.
GLP compliance:
not specified
Species:
hamster
Strain:
not specified
Sex:
not specified
Details on test animals and environmental conditions:
Details on test animals and environmental conditions: no data
It is unclear whether the animals remained in the inhalation chambers even when the exposure was not occurring.
Route of administration:
other: inhalation: dust and Intratracheal injections
Type of inhalation exposure (if applicable):
whole body
Vehicle:
not specified
Remarks on MMAD:
MMAD / GSD: No information was provided on the MMAD and GSD.

Further detail on particle characteristics (e.g. shape):
Particle size by count was provided for the size ranges < 1.0 µm; 1 to 4 µm; and > 4 µm.
(1) British pyro powder
Shape: flake-like
Size: < 1 µm 4.2%, 1 – 4 µm 87.3%, > 4 µm 8.5%
Mean diameter: 2.49 µm
Specific surface area: 10.4 m²/g

(2) US –source atomised particles.
Shape: “spherical”
Size: < 1 µm 1.5%, 1 – 4 µm 95.6%, > 4 µm 2.9%;
Mean diameter: 2.22 µm
Specific surface area: 0.8 m²/g

(3) US-source flake powder
Shape: flake
Size: < 1 µm 0.0%, 1 – 4 µm 28.6%, > 4 µm 71.4%;
Mean diameter: 4.85 µm
Specific surface area: 8.4 m²/g

(4) Negative control: aluminium oxide dust.
Shape: not stated
Size: < 1 µm 66%, 1 – 4 µm 25%, > 4 µm 9%;
Mean diameter: 0.80 µm
Specific surface area: 6.3 m²/g
Details on exposure:
Further details on inhalation exposure:
The chambers were approximately 1.2 m³ in volume. Moisture was removed using anhydrous calcium chloride. 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.

Details on Intratracheal Instillation:
A suspension of the dust in tap water was instilled intratracheally. 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.
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
The air flow through the chambers was monitored with outflowing chamber air forced through 20.3 x 25.4 cm filter (Millipore) filters before ventilation. The filters were used to gravimetrically estimate the average dust concentration in the chamber each day. The data were not reported however.
Duration of treatment / exposure:
Inhalation
According to Table 2 of the article -
Rats in the 50 and 100 mg/m3 chambers were exposed for 6 months. Exposure duration was 12 months for the animals at the lower aluminium powder concentrations of 15 and 30 mg/m3.

The aluminium oxide control rats were exposed to 75 mg/m³ for six months. An additional 30 rats were exposed to 30 mg/m³ of aluminium oxide dust for a year.
Frequency of treatment:
Inhalation:
6 hr/day; 5 days a week
Dose / conc.:
50 mg/m³ air
Remarks:
pyro powder, atomized powder
Dose / conc.:
100 mg/m³ air
Remarks:
pyro powder, atomized powder
Dose / conc.:
75 mg/m³ air
Remarks:
aluminium oxide
No. of animals per sex per dose:
Inhalation:
30 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
30 hamsters were exposed to aluminium oxide at 75 mg/m³

Intratracheal instillation:
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.

Control animals:
yes
Details on study design:
Control animals:
25 hamsters were untreated (laboratory controls). Five animals were examined per time point.
Aluminium oxide (numbers and dosing described above) were included as “non-fibrogenic” controls.
For the intratracheal instillation group, 5 hamsters were included as vehicle controls.

No information was provided on the method used to allocate the animals to groups.
Positive control:
No.
Observations and examinations performed and frequency:
Observations and examinations performed:
No information was provided on observations to monitor animal health but mortality was recorded.

Frequency of the observations and examinations:
For the inhalation exposure, pathological examinations took place at 6, 8, 12 and 18 months into the experiment for the 50 and 100 mg/m³ aluminium powder dose groups and the 70 mg/m³ aluminium oxide dose group (i.e. 0, 2, 6 and 12 months after cessation of exposure). Kills of the lower dose animals took place at 6 and 12 months (0 and 6 months post-exposure).
Sacrifice and pathology:
The method used to sacrifice the animals was not reported in the article.
Histopathological examinations of lung tissue were conducted using sections cut in triplicate and embedded in paraffin blocks. One section was stained with eosin to show aluminium particles, a second section was stained with hematoxylin-eosin, and a third section with PAS or van Gieson. To show cellular components and stromal support structures, the hematoxylin-eosin stained sections were photographed then decolorized and impregnated with silver (Gordon and Sweets method) before another photograph was taken. Aluminium particles were removed prior to this procedure using 10% sodium bisulfite.
Statistics:
No data.
Clinical signs:
effects observed, treatment-related
Dermal irritation (if dermal study):
not specified
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
no effects observed
Other effects:
not specified
Details on results:
CLINICAL SIGNS AND MORTALITY
A higher rate than ideal was observed. As high rates were observed in control groups as well as treated groups and appeared to show no relationship to dose, deaths were unlikely to be simply related to the dust exposure. The authors suggest an effect of crowding and low air flow in the chambers. Quantitatively, the mortality results from this study are not reliable. The absence of observations of clinical signs also suggests that caution ought to be used in interpreting the results.

ORGAN WEIGHTS
Lung weights were measured but not reported.

HISTOPATHOLOGY: NON-NEOPLASTIC
ADEQUATE
- foci of fibrosis found for pyro Al powder at 50 mg/m³ exposed for 108 days; killed 6 months later.
- alveolar proteinosis was observed after 2 to 3 months of exposure in two guinea pigs.

LUNG HISTOLOGY
Inhalational series:
Al-powders:
Alveolar proteinosis (AP) was found.

50 and 100 mg/m³ for 6 mths:
Mild AP at the end of exposure. No AP or Al-powder evident 3 mths post-exposure.
Persistent changes: foci of metaplasia of alveolar epithelium – gland-like structures in alveoli opening off respiratory bronchioles and alveolar ducts. These effects are described for treated animals only at the “higher concentration”.
No tumors were observed in the hamster lungs.

Intratracheal Instillation:
Lung histology
Pyro and atomized powder - 12 to ≤ 24mg/m³
Smaller, more widely separate foci that were highly cellular with no collagen fibres; no evidence of inflammatory response; foci were concentrated around the respiratory bronchioles and alveolar ducts; presence of striking metaplasia of the alveolar epithelium giving the tissue a multiglandular appearance.
Pyro and atomized powder – ≤ 12mg/m³
No significant collagenisation of foci at 6 or 12 mths.
Dose descriptor:
LOAEC
Remarks:
local effects
Effect level:
100 mg/m³ air
Based on:
test mat.
Remarks:
Al powder
Sex:
not specified
Basis for effect level:
histopathology: non-neoplastic
Dose descriptor:
NOAEC
Remarks:
local effects
Effect level:
>= 75 mg/m³ air
Based on:
test mat.
Remarks:
Al2O3 dust
Sex:
not specified
Basis for effect level:
other: no adverse effect observed at the highest dose tested
Critical effects observed:
not specified
Conclusions:
Intratracheal injection of aluminium powder 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 interspecies 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, 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. There was no dose response evident or a noticeable difference between responses to the different aluminium powders.

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 actual inhalation exposures. All three species developed widespread alveolar proteinosis, rats exhibiting the most severe response. The proteinosis resolved progressively after cessation of exposure. The group of rats exposed for 12 months to 15 mg/m³ of aluminium powder showed moderate alveolar proteinosis after only 6 months of exposure.
Executive summary:

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 Al2O3 content was 16.6% for the British pyro powder, not stated for the flake 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 were exposed to flake powder at 15 and 30 mg/m³, and 30 rats were exposed to aluminium oxide dust at 30 and 75 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 75 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% <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 chronic toxicity guideline (OECD TG 452) 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.

Endpoint:
carcinogenicity, other
Remarks:
inhalation: dust and Intratracheal injections
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1973
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study with acceptable restrictions
Reason / purpose:
reference to same study
Reason / purpose:
reference to same study
Reason / purpose:
reference to same study
Reason / purpose:
reference to same study
Reason / purpose:
reference to same study
Qualifier:
equivalent or similar to
Guideline:
other: OECD TG 452
Deviations:
yes
Remarks:
: number of animals to low (30 instead of 50 per sex and dose); duration only 1 year instead of 2 years.
GLP compliance:
not specified
Species:
guinea pig
Strain:
not specified
Sex:
not specified
Details on test animals and environmental conditions:
Details on test animals and environmental conditions: no data
It is unclear whether the animals remained in the inhalation chambers even when the exposure was not occurring.
Route of administration:
other: inhalation: dust and Intratracheal injections
Type of inhalation exposure (if applicable):
whole body
Vehicle:
not specified
Remarks on MMAD:
MMAD / GSD: No information was provided on the MMAD and GSD.

Further detail on particle characteristics (e.g. shape):
Particle size by count was provided for the size ranges < 1.0 µm; 1 to 4 µm; and > 4 µm.
(1) British pyro powder
Shape: flake-like
Size: < 1 µm 4.2%, 1 – 4 µm 87.3%, > 4 µm 8.5%
Mean diameter: 2.49 µm
Specific surface area: 10.4 m²/g

(2) US –source atomised particles.
Shape: “spherical”
Size: < 1 µm 1.5%, 1 – 4 µm 95.6%, > 4 µm 2.9%;
Mean diameter: 2.22 µm
Specific surface area: 0.8 m²/g

(3) US-source flake powder
Shape: flake
Size: < 1 µm 0.0%, 1 – 4 µm 28.6%, > 4 µm 71.4%;
Mean diameter: 4.85 µm
Specific surface area: 8.4 m²/g

(4) Negative control: aluminium oxide dust.
Shape: not stated
Size: < 1 µm 66%, 1 – 4 µm 25%, > 4 µm 9%;
Mean diameter: 0.80 µm
Specific surface area: 6.3 m²/g
Details on exposure:
Further details on inhalation exposure:
The chambers were approximately 1.2 m³ in volume. Moisture was removed using anhydrous calcium chloride. 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.

Details on Intratracheal Instillation:
A suspension of the dust in tap water was instilled intratracheally. 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.
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
The air flow through the chambers was monitored with outflowing chamber air forced through 20.3 x 25.4 cm filter (Millipore) filters before ventilation. The filters were used to gravimetrically estimate the average dust concentration in the chamber each day. The data were not reported however.
Duration of treatment / exposure:
Inhalation
According to Table 2 of the article -
Rats in the 50 and 100 mg/m3 chambers were exposed for 6 months. Exposure duration was 12 months for the animals at the lower aluminium powder concentrations of 15 and 30 mg/m3.

The aluminium oxide control rats were exposed to 75 mg/m³ for six months. An additional 30 rats were exposed to 30 mg/m³ of aluminium oxide dust for a year.
Frequency of treatment:
Inhalation:
6 hr/day; 5 days a week
Dose / conc.:
15 mg/m³ air
Remarks:
pyro powder, atomized powder, flake powder
Dose / conc.:
30 mg/m³ air
Remarks:
pyro powder, atomized powder, flake powder
Dose / conc.:
30 mg/m³ air
Remarks:
aluminium oxide
No. of animals per sex per dose:
Inhalation:
14 and 26 guinea pigs were exposed to pyro powder at 15 and 30 mg/m³, respectively.
15 and 19 guinea pigs were exposed to atomized powder at 15 and 30 mg/m³, respectively.
21 and 25 guinea pigs were exposed to flake powder at 15 and 30 mg/m³, respectively.
12 guinea pigs were exposed to aluminium oxide at 30 mg/m³.
Control animals:
yes
Details on study design:
Control animals:
12 guinea pigs were untreated (laboratory controls). Five animals were examined per time point.
Aluminium oxide (numbers and dosing described above) were included as “non-fibrogenic” controls.
Positive control:
No.
Observations and examinations performed and frequency:
Observations and examinations performed:
No information was provided on observations to monitor animal health but mortality was recorded.

Frequency of the observations and examinations:
For the inhalation exposure, pathological examinations took place at 6, 8, 12 and 18 months into the experiment for the 50 and 100 mg/m³ aluminium powder dose groups and the 70 mg/m³ aluminium oxide dose group (i.e. 0, 2, 6 and 12 months after cessation of exposure). Kills of the lower dose animals took place at 6 and 12 months (0 and 6 months post-exposure).
Sacrifice and pathology:
The method used to sacrifice the animals was not reported in the article.
Histopathological examinations of lung tissue were conducted using sections cut in triplicate and embedded in paraffin blocks. One section was stained with eosin to show aluminium particles, a second section was stained with hematoxylin-eosin, and a third section with PAS or van Gieson. To show cellular components and stromal support structures, the hematoxylin-eosin stained sections were photographed then decolorized and impregnated with silver (Gordon and Sweets method) before another photograph was taken. Aluminium particles were removed prior to this procedure using 10% sodium bisulfite.
Other examinations:
No data.
Statistics:
No data.
Clinical signs:
effects observed, treatment-related
Dermal irritation (if dermal study):
not specified
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
no effects observed
Other effects:
not specified
Details on results:
CLINICAL SIGNS AND MORTALITY
A higher rate than ideal was observed. As high rates were observed in control groups as well as treated groups and appeared to show no relationship to dose, deaths were unlikely to be simply related to the dust exposure. The authors suggest an effect of crowding and low air flow in the chambers. Quantitatively, the mortality results from this study are not reliable. The absence of observations of clinical signs also suggests that caution ought to be used in interpreting the results.

ORGAN WEIGHTS
Lung weights were measured but not reported.

HISTOPATHOLOGY: NON-NEOPLASTIC
ADEQUATE
- alveolar proteinosis was observed after 2 to 3 months of exposure in two guinea pigs.

HISTOPATHOLOGY: NEOPLASTIC (if applicable)
The authors reported no tumors in the lungs of guinea pigs in the inhalation series.

LUNG HISTOLOGY
Inhalation series:
Al-powders:
All three species developed alveolar proteinosis (AP);
AP that developed was not severe and cleared readily on cessation of exposure. Dust particles were also readily cleared.
Persistent changes: similar to hamsters but altered alveoli contained dust-filled macrophages to a greater extent than hamsters. These effects are observed for treated animals only. Inconsistency between Table 2 and Figure 7 with respect to doses used limit the utility of these results for the extraction of an LOAEC.
No tumors were observed in the guinea pig lungs.
Dose descriptor:
NOAEC
Remarks:
local effects
Effect level:
>= 30 mg/m³ air
Based on:
test mat.
Remarks:
Al2O3 dust
Sex:
not specified
Critical effects observed:
not specified
Conclusions:
Intratracheal injection of aluminium powder 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 interspecies 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, 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. There was no dose response evident or a noticeable difference between responses to the different aluminium powders.

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 actual inhalation exposures. All three species developed widespread alveolar proteinosis, rats exhibiting the most severe response. The proteinosis resolved progressively after cessation of exposure. The group of rats exposed for 12 months to 15 mg/m³ of aluminium powder showed moderate alveolar proteinosis after only 6 months of exposure.
Executive summary:

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 Al2O3 content 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 were exposed 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 15mg/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 TG 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.

Endpoint:
carcinogenicity: inhalation
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1981
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Basic data given.
Qualifier:
no guideline available
GLP compliance:
not specified
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: No data
- Age at study initiation: No data
- Weight at study initiation: No data
- Fasting period before study: No data
- Housing: No data
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: No data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 25 °C
- Humidity (%): 50% ± 10%
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): No data

Route of administration:
inhalation: dust
Type of inhalation exposure (if applicable):
not specified
Vehicle:
not specified
Details on exposure:
The rats were exposed in 1.4 m³ inhalation chambers that could house a total of 40 adult rats or, short-term, 50 young rats. Dust clouds were generated using dispensers (Timbrell, Hyett and Skidmore , Ann. Occup. Hyg., 1968, 11: 273) with modifications after 2 months of exposure (Beckett, Ann. Occup. Hyg., 1975, 18:187) that resulted in an improvement in concentration stability.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Respirable dust concentrations were measured with size-selective gravimetric dust samplers (Casella Type 113A; Dunmore, Hamilton and Smith, 1964). The collected samples were weighed at the end of each day’s exposure and, if necessary, modifications to air flow were made to correct variations.

Total atmospheric samples were taken from the exposure chambers for 1-hour periods during the exposure. These samples, together with the readings from the Casella dust samplers, were used to estimate the respirable fraction.
Duration of treatment / exposure:
86 weeks for the test fibres; 77 weeks for the positive control
Frequency of treatment:
6 hours a day (frequently extended by 2-3 hours) 5 days a week
Post exposure period:
No data.
Dose / conc.:
2.18 mg/m³ air (nominal)
Remarks:
Saffil
Dose / conc.:
2.45 mg/m³ air (nominal)
Remarks:
"Aged" Saffil
Dose / conc.:
4.57 mg/m³ air (nominal)
Remarks:
UICC chrysotile asbestos
No. of animals per sex per dose:
50 animals per group (25 of each sex)
Control animals:
yes, concurrent no treatment
Details on study design:
Interim killings were performed at 14 weeks (2 animals of each sex per group) and 27 weeks (2 animals of each sex per group) and at 53 weeks (one animal of each sex per group) of the experiment. The other animals were allowed to live until they died, appeared distressed, or until 85% mortality (averaged over all groups) was reached.
Positive control:
Yes. Exposed to a standard reference sample of UICC chrysotile A (Rhodesian) asbestos obtained from the Medical Research Council Pneumoconiosis Research Unit, Llandough Hospital, Penarth, Glamorgan.
Observations and examinations performed and frequency:
Frequency of the observations and examinations:
No information on frequency of health monitoring is provided.
Pathology examination was performed at 14, 27, 53 weeks of the experiment, after animals’ natural death, killing because of distressed condition or at the termination of the experiment when 85% mortality was reached.

Sacrifice and Pathology (methods):
The animals were killed by overexposure to halothane BP
The lungs were removed and inflated with formol saline; the nasal cavity was irrigated with formol salin also. Grossly abnormal tissues and samples of the major organs were fixed in formol sublimate and embedded in paraffin; 5 µm sections were cut and stained with haematoxylin and eosin. A median sections from each lung lobe were also stained and examined.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Other examinations:
The other lung sections were stained with van Gieson’s stain for collagen and by Gordon and Sweet’s method for reticulin.
Statistics:
Statistical analysis was not conducted; the results are presented qualitatively.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
not specified
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
effects observed, treatment-related
Details on results:
Non-neoplastic lesions
Histopathological examination at interim killing
At 14, 27 and 53 weeks lesions characteristic of a low grade pneumonitis were seen in both treated and control animals. The lesions were attributed to respiratory infection.
Generally there was a minimal reaction to both types of alumina fibres; Saffil fibres were seen in alveolar macrophages and in the superficial mediastinal lymph node of one animal killed at 27 weeks; in one animal Saffil fibres were seen in an area of alveolar epithelialization. Other lesions were described as typical of the Alderley Park rat colony and not due to treatment.
Focal necrosis and regeneration of olfactory epithelium was seen nasal cavity tissue of 2 animals exposed to Saffil fibres and in one animal exposed to asbestos.

Histopathological examination at animals’ death or terminal killing
Saffil fibres were seen in the lungs of most rats exposed to Saffil.
The observed effect was limited to pigmented alveolar macrophages.

A minimal alveolar epithelialization was observed in some control animals and in one female exposed to Saffil as manufactured. The number of animals with alveolar epithelialization was slightly higher in rats exposed to aged Saffil; this lesion was minimal in most animals, was more prevalent in females than in males, and was no longer evident after 106 weeks. In the authors’ opinion, this lesion might be at least partly attributable to intercurrent infection. There was no fibrosis in the lungs of the Saffil-treated animals.

In some animals, small numbers of Saffil fibres were seen in nasal passages with evidence of slight irritation of the nasal mucosa with minimal focal necrosis.
Degeneration of olfactory epithelium with replacement by respiratory epithelium seen in all groups was attributed to spontaneous age-related change.

Positive control
In animals exposed to asbestos, a minimal asbestosis was detected at week 14, which progressed to slight asbestosis by week 53 and became more marked as the experiment continued. All animals exposed to asbestos showed asbestosis of some degree.

Neoplasms
No pulmonary tumors (either benign or malignant) were found in the negative control (16 males and 18 females examined), in rats treated with Saffil fibres as manufactured (13 males and 19 females examined) or treated with aged Saffil (19 males and 19 females examined). In the positive control, 2 tumors (1 adenoma and one squamous cell carcinoma) were found among 19 examined male rats, and 7 tumors (4 adenomas, 1 adenocarcinoma and 2 squamous cell carcinomas) among 19 examined female rats. The tumors in the positive control were observed late in the experiment (the first benign tumor at 109 weeks and malignant tumors – at weeks 128 and 129).
Examination for extrapulmonary tumors did not include interim kills. There were no significant group differences in the frequency of extrapulmonary tumors (see table 1).
Dose descriptor:
NOAEL
Remarks:
carcinogenicity
Effect level:
>= 2.45 mg/m³ air (nominal)
Based on:
test mat.
Remarks:
"aged" Saffil
Sex:
male/female
Basis for effect level:
other: no adverse effect observed at the highest dose tested
Critical effects observed:
not specified

Table 1:

 

Number examined

Benign tumors

Malignant tumors

 

male

female

Male

female

male

female

Negative control

19

19

9

21

2

8

Positive control

19

20

10

23

5

6

Saffil as manufactured

13

19

8

20

4

8

“Aged” Saffil

19

20

9

26

3

5

Conclusions:
Exposure to both types of alumina fibres produced minimal pulmonary reaction and no fibrosis. There were no lung tumors in the Saffil treated groups, and no significant group difference in the frequency of extrapulmonary tumors was observed. The authors concluded that “the pulmonary reaction to Saffil fibres observed in this study is…consistent with their classification as biologically inert materials.”
Executive summary:

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.

Endpoint:
carcinogenicity: inhalation
Type of information:
other: Epi observational
Adequacy of study:
weight of evidence
Study period:
1995-1996
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Basic data given.
Qualifier:
no guideline available
GLP compliance:
no
Species:
other: human
Strain:
not specified
Sex:
male
Details on test animals and environmental conditions:
Not applicable.
Route of administration:
inhalation
Type of inhalation exposure (if applicable):
other: Not applicable.
Vehicle:
other: Not applicable.
Details on exposure:
TYPE OF EXPOSURE MEASUREMENT: Personal sampling:

Individual cumulative exposures to bauxite and alumina were calculated as described below:
Time-weighted average monitoring data for inhalable dust were received from the company. Air sampling before 1998 was performed with a closed-face 37 mm cassette for total dust (NIOSH N-0500) which could underestimate the inhalable fraction. After 1998, the Institute of Medicine inhalable sampling head was used. The annual arithmetic mean was calculated for each combination of site, department, job and task. Tasks for which there were no monitoring data were assigned a proportion of value from a similar monitored task (from 5 to 100%, determined by a hygienist). Values were also extrapolated to years for which no measurements were available. A value of half the limit of detection was assigned to tasks with no monitoring data and considered to have very low exposure. For workers who quit before 1986 work histories were available only at the job level. For all workers, a job-exposure matrix was developed from the TEM by weighting tasks performed in each job using task weighting factors from the 1995-1996 interviews. It was assumed that workers with no interview data after the 1995/1996 survey remained in their last reported jobs until employment termination or until the study termination.
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No data
Duration of treatment / exposure:
Not applicable.
Frequency of treatment:
Not applicable.
Post exposure period:
Not applicable.
Dose / conc.:
5.7 other: mg/m³-years
Remarks:
bauxite; median cumulative exposure among the bauxite-exposed workers
Dose / conc.:
13.4 other: mg/m³-years
Remarks:
bauxite; mean cumulative exposure among the bauxite-exposed workers
Dose / conc.:
187 other: mg/m³-years
Remarks:
bauxite, maximum cumulative exposure among the bauxite-exposed workers
Dose / conc.:
2.8 other: mg/m³-years
Remarks:
alumina; median cumulative exposure among the alumina-exposed workers
Dose / conc.:
14.5 other: mg/m³-years
Remarks:
alumina; mean cumulative exposure among the alumina-exposed workers
Dose / conc.:
210 other: mg/m³-years
Remarks:
alumina; maximum cumulative exposure among the alumina-exposed workers
No. of animals per sex per dose:
Total number of subjects in the study: 5770
Details on study design:
Type of population: Occupational

HYPOTHESIS TESTED (if cohort or case control study):
The objective of this study was “to examine the associations between alumina and bauxite dust exposure and cancer incidence and circulatory and respiratory disease mortality among bauxite miners and alumina refinery workers.”

STUDY PERIOD: 1983-2002

SETTING: Four bauxite mines and three alumina refineries in Western Australia

STUDY POPULATION & SAMPLE
- Inclusion criteria: Male workers hired on or after 1 January 1983, for whom work history information was available (n=5770). Fifty eight subjects were excluded because of unavailable job history information.
- Total number of subjects in the study: 5770
- Sex/age/race: male. Mean age at study entry 32 years (SD 10.5 years), maximum age at study entry – 64 years.
Mean duration of employment – 14.1 years (SD 8.7 years), maximum – 40 years. The study population included smokers and non-smokers (further detail is provided in the results section).

COMPARISON POPULATION
- Type: Control or reference group:
- Details: unexposed workers within the cohort

METHOD OF DATA COLLECTION
Interview / Record review / Work history / other: national mortality and national and state cancer incidence registries
- Details of data collection:
Work histories and smoking information for cohort members whose employment ended before 1995 were abstracted from company records. Work histories and smoking information for all other cohort members were collected at interviews during a 1995-1996 survey and later during the follow-up period. Mortality and cancer incidence information was obtained by linkage with national mortality and national and state cancer incidence registries for the period 1983-2002.
HEALTH EFFECTS STUDIED
- Disease(s):
Cancer incidence based on linkage with national and state cancer incidence registries
- Mortality:
Mortality from non-malignant respiratory diseases and from circulatory diseases (cardiovascular and cerebrovascular) based on linkage with the national mortality registry
FOLLOW-UP: 1983-2002

Exposure assessment: Estimated and Measured:
A task-exposure matrix (TEM) was developed as described by Benke et al., 2001 (Appl Occup Environ Hyg. 16:149-153) and Fritschi et al., 2001 (J Occup Health, 43: 231-237)
Positive control:
Not applicable.
Observations and examinations performed and frequency:
Not applicable.
Sacrifice and pathology:
Not applicable.
Other examinations:
Not applicable.
Statistics:
Relative risks for each exposure category compared to the unexposed category were calculated using Poisson regression with categorical covariates for age, calendar year (5-year intervals were used when the number of cases was sufficient) and smoking (see above). Exposure-response relationships were examined for endpoints for which there were at least 6 exposed cases and the risk in ever exposed was elevated compared to never exposed. Exposure categories were disease-specific and were based on distribution of exposure of cases applying cut-offs at the 33.3 and 66.6 percentiles. Tests for trend were performed by setting the ordinal exposure variable (0-3) to a continuous variable.
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
not examined
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
no effects observed
Details on results:
EXPOSURE LEVELS
- Arithmetic mean:
Cumulative bauxite exposure for exposed workers (57%): 13.4 mg/m3-years
Cumulative alumina exposure for exposed workers (41%): 14.5 mg/m3-years
- Median: (for those exposed)
Cumulative bauxite exposure for exposed workers (57%): 5.7 mg/m3-years
Cumulative alumina exposure for exposed workers (41%): 2.8 mg/m3-years
- Other:
Maximum cumulative bauxite exposure for exposed workers (57%): 187 mg/m3-years
Maximum cumulative alumina exposure for exposed workers (41%): 210 mg/m3-years
Cumulative exposures to bauxite and alumina were not correlated; 32% had never been exposed to either dust, 16% had been exposed to both dusts.
FOLLOW-UP
A total of 93,420 person-years of follow-up; mean duration of follow-up 16.2 years (SD 4.8 years), maximum – 20 years.

RESULTS
Bauxite
Exposed vs. unexposed: non-significantly increased mortality from cerebrovascular diseases (RR=2.1; 95% CI 0.5-8.1; n=10) and from non-malignant respiratory diseases (RR=5.8; 95% CI 0.7-48; n=7). No increase in mortality from cardiovascular diseases (RR=0.9; 95% CI 0.6-1.4) was observed.
No exposure-response relationship was found for cerebrovascular disease mortality. There was a monotonic increasing trend in mortality from non-malignant respiratory diseases with increasing exposure category (see tables below). The 7 respiratory disease deaths included chronic obstructive pulmonary disease, asbestosis, unspecified bronchopneumonia, other interstitial pulmonary disease with fibrosis.

No significant association with bauxite exposure was observed for incidence of any cancer. A non-significant increase was observed for stomach cancer (RR=1.7; 95% CI 0.3-9.3; n=6) and brain cancer (RR=2.1; 95% CI 0.4-11; n=7). Because of the small number of cases, the exposure-response relationship was not examined for these cancers.
Exposure to alumina
Exposed vs. unexposed: A significantly increased mortality from cerebrovascular diseases (RR=3.8; 95% CI 1.1-13) was observed. No significant increase was observed for mortality from cardiovascular diseases (RR=1.1; 95% CI 0.7-1.8) or from non-malignant respiratory diseases (RR=0.9; 95% CI 0.2-4.5)
A significant (non-monotonic) trend was observed for mortality from cerebrovascular diseases and a suggestive trend (p=0.1) for mortality from all circulatory diseases (see tables below).

No significant association with alumina exposure was observed for incidence of any cancer. Non-significant increase was observed for stomach cancer (RR=5.2; 95% CI 0.9-29). Because the number of cases was small, exposure-response relationship for stomach cancer was not examined.
Critical effects observed:
not specified

Table 1: Exposure to bauxite and mortality form cerebrovascular diseases

Unexposed

Low

Medium

High

P value for trend

Exposure categories

0.27

0 mg/m3-years

>0-0.71 mg/m3-years

0.71-16.5 mg/m3-years

>16.5 mg/m3-years

Number of deaths

3

2

3

2

Relative risks (95% CI) adjusted for age, calendar year and smoking

1

2.5 (0.4-15)

2.2 (0.4-11)

2.4 (0.4-15)

Table 2: Exposure to bauxite and mortality from non-malignant respiratory diseases

Unexposed

Low

Medium

High

P value for trend

Exposure categories

0.1

0

>0-16.0 mg/m3-years

16.0-48.3 mg/m3-years

>48.3 mg/m3-years

Number of deaths

1

2

2

2

Relative risks (95% CI) adjusted for age, calendar year and smoking

0.4 (0.0-4.0)

1

2.6 (0.3-20)

6.4 (0.8-53)

Table 3: Exposure to alumina and mortality from all circulatory diseases

Unexposed

Low

Medium

High

P value for trend

Exposure categories

0.11

0

>0-2.31 mg/m3-years

2.31-13.2 mg/m3-years

>13.2 mg/m3-years

Number of deaths

51

9

10

9

Relative risks (95% CI) adjusted for age, calendar year and smoking

1

0.8 (0.4-1.6)

1.7 (0.9-3.4)

1.6 (0.8-3.3)

Table 4: Exposure to alumina and mortality from cerebrovascular diseases

Unexposed

Low

Medium

High

P value for trend

Exposure categories

0.04

0

>0-6.05 mg/m3-years

6.05-11.7 mg/m3-years

>11.7 mg/m3-years

Number of deaths

4

2

2

2

Relative risks (95% CI) adjusted for age, calendar year and smoking

1

2.7 (0.5-15)

8.7 (1.5-49)

4.2 (0.7-21)

Strengths and limitations:

Strengths: rigorous exposure assessment

Limitations:

The associations are based on very small numbers of deaths.

Causes of death as determined from an administrative database may be of limited validity.

Possible residual confounding by smoking

Conclusions:
There was statistical evidence for an association between mortality from non-malignant respiratory diseases and exposure to bauxite, and between mortality from cerebrovascular diseases and exposure to alumina. These associations were based on small numbers of cases and may reflect chance findings. Neither bauxite nor alumina exposure was associated with increased cancer risk.
Executive summary:

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, anofdevice 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.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
75 mg/m³
Study duration:
chronic
Species:
rat
Quality of whole database:
The available information comprises adequate, reliable (Klimisch score 2) studies from reference substances with similar structure and intrinsic properties. Read-across is justified based on the presence of a common metal ion, or ion complex including a hydrated metal ion, and following from this a similar chemical behaviour (refer to endpoint discussion for further details).
The available information as a whole is sufficient to fulfil the standard information requirements set out in Annex VIII-IX, 8.6, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.

Carcinogenicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Systemic Effect

Human studies

Systemic carcinogenic effects from exposure specifically to aluminium have not been investigated in epidemiological studies.One study (Friesen et al., 2009; chapter 7.10.2) that investigated associations between alumina dust exposure and cancer incidence did not find evidence of an increase in risk of any cancer. The study was based on relatively few cases observed during a short follow-up period, and only crude adjustment for smoking was done. Although aluminium production has been classified by IARC as Group 1 (Carcinogenic to humans), the ATSDR (2008) states that “It is important to emphasize that the potential risk of cancer in the aluminium production industry is probably due to the presence of known carcinogens (e.g., PAHs) in the workplace and is not due to aluminium or its compounds.” The evidence from epidemiological studies does not support a carcinogenic effect.  

 

Animal studies

Available animal studies do not provide evidence supporting a systemic carcinogenic effect of the target compounds. 

 

Human studies

Local (Respiratory organs)

Local carcinogenic effects from exposure specifically to aluminium have not been investigated in epidemiological studies.

 

One study that examined associations between exposure to alumina dust and cancer incidence (Friesen et al., 2009; chapter 7.10.2) provides no evidence of an increase in the risk of cancers in the respiratory organs. The study was based on relatively few cases observed during a short follow-up period, and only crude adjustment for smoking was done. The available evidence from epidemiological studies does not support a carcinogenic effect.

Additional human study 

Pan et al. (2011) investigated residential proximity to Al smelters in Canada and risk of female breast cancer in a population-based case-control study using data collected by the National Enhanced Cancer Surveillance System (NECSS). The study was based on individual data collected from 21,020 Canadians with one of 19 types of cancers and 5039 population controls aged 20 to 76 years collected between 1994 and 1997 in 8 of the 10 Canadian provinces (Alberta, British Columbia, Manitoba, Newfoundland, Nova Scotia, Ontario, Prince Edward Island, and Saskatchewan). The protocol was approved by the respective ethics review board of each province and the analyses were based on 2343 incident cases of breast cancer (863 premenopausal and 1480 postmenopausal) and 2467 female controls from all eight provinces. Breast cancer cases were identified by the population-based provincial cancer registries and all cases were verified by pathology reports. Breast cancer was defined as C50 according to the International Classification of Diseases for Oncology, Second Edition. Questionnaires were sent to 3013 cases and 2982 cases were contacted. Completed questionnaires were received from 2362 cases, representing 78.4% of cases. Questionnaires were also mailed to 3847 women without diagnosis of cancer and these women were selected as potential controls using a random sample stratified by age group. In total, 2492 women completed and returned the questionnaire (representing 64.8% of the ascertained controls). The provincial registries collected data by self-administered questionnaires designed to retrieve data on cancer risk and included information on education, average family income over the last 5 years, marital status, ethnic group, height, weight, physical activity, alcohol consumption, diet and vitamin and mineral supplements for the past 20 years. Questionnaires also gathered smoking history, menstrual and reproductive history (including menopausal status), a lifetime residential history and employment history, the distance between a residence and an industrial source and number of years of proximity. Assessment included food consumption frequency and pattern and portion size for each of 69 foods consumed 2 years before interview. Distance to an industrial source was estimated using the locations and years of production for Al smelters and 9 other major industry types: copper smelters and refineries, lead smelters, nickel smelters and refineries, zinc smelters and refineries, petroleum refineries, paper mills, pulp mills, steel mills, and thermal power plants. The risk of breast cancer associated with residential proximity to Al industrial facilities was estimated based on odds ratios and corresponding 95% confidence intervals using unconditional logistic regression with the software package SAS (version 9; SAS Institute, Inc, Cary, NC). Variables of interest were distance and years of residence near an industrial facility. The variable “distance” was categorized as more than 3.2 km (>2 miles), 0.8 to 3.2 km (0.5 to 2 miles), and more than 0.8 km (0.5 mile). The change-in-point estimate approach was used to assess potential confounding factors: age, educational level, family income, alcohol consumption, smoking, body mass index, total calorie intake, recreational physical activity level, menopausal status, and number of live births. The final multivariate models were adjusted for age (years, continuous), province of residence, education (years, continuous), number of live births (none, 1, 2, 3, and ≥4), age at menarche (years, continuous), alcohol consumption (servings per week, continuous), pack-years of smoking (continuous), total caloric intake (kilocalories per week, continuous), and employment in the specific industry under consideration (yes and no). For postmenopausal women, the models were also adjusted for body mass index and recreational physical activity. To evaluate the trends for all models of categorized data, the different categories were treated as a single ordinal variable.

Data from 2343 breast cancer cases (863 premenopausal cases and 1480 postmenopausal cases) and 2467 controls (835 premenopausal controls, 1604 postmenopausal controls, and the menopausal status unknown for 28 controls) were available for final analysis. The premenopausal women, compared with controls, were older, had slightly higher family income, started menstruation at an earlier age, and had longer years of menstruation. The postmenopausal women were slightly younger, had higher education, consumed more alcohol and tobacco, had higher body mass index, started menstruation at an earlier age and had fewer live births and longer years of menstruation compared with controls. The results indicated no elevated risk of breast cancer among premenopausal and postmenopausal women living 0.8 to 3.2 km of aluminium smelters.After adjustment for age, province of residence, education, smoking pack years, alcohol consumption, number of live births, age at menarche, total energy intake, and employment in the industry under consideration, the odds ratios were not statistically significant for premenopausal breast cancer women living near aluminium smelters compared to the control group [0.8 to 3.2 km, 8 breast cancer patients and 13 control participants; OR - 0.52 (0.21 - 1.31)] and those living < 0.8 km from smelters [2 breast cancer patients and 1 control participant; OR = 2.08 (0.18-23.72). For postmenopausal breast cancer patients, the adjusted for age, province of residence, education, smoking pack years, alcohol consumption, number of live births, age at menarche, total energy intake, and employment in the industry under consideration, the odds ratios were not statistically significant for women living near aluminium smelters compared to the control [0.8 to 3.2 km, 19 breast cancer patients and 14 control participants; OR = 1.06 (0.50-2.23)] and living less than 0.8 km from aluminium smelters [ 6 breast cancer patients and 6 control participant; OR = 0.97 (0.27 - 3.41). For both pre- and postmenopausal breast cancer patients, the adjusted for age, province of residence, education, smoking pack years, alcohol consumption, body mass index, recreational physical activity, number of live births, age at menarche, menopausal status, total energy intake, and employment in the industry under consideration odds ratios were not statistically significant for women living near aluminium smelters compared to the control [0.8 to 3.2 km, 27 breast cancer patients and 27 control participants; OR = 0.84 (0.48 - 1.49)] and living less than 0.8 km from aluminium smelters [8 breast cancer patients and 7 control participant; OR = 1.10 (0.37-3.25).

Pan et al. (2011) attempted to identify possible associations between breast cancer risk with residential proximity to steel mills, pulp mills, petroleum refineries, and thermal power plants. Among strengths of this population-based study are the relatively large sample size and the length of time that participants had lived near Al smelters and other industrial plants. A number of potential confounders were controlled, including employment in the specific industry under consideration. However, this study has a number of limitations: no information on the particular age of women when they resided near a plant, information was not available for all patients on their family history of breast cancer, benign breast disease or their use of the oral contraceptives or estrogen replacements. No Al exposure measurements or indeed exposure measurements for any other airborne materials were provided for cases and controls inasmuch as mere proximity to a potential source does not necessarily mean that the person had been exposed to materials that may arise from operations at that site. A Reliability Score 3 was assigned.

Cantone et al. (2011) investigated relationships between the inhaled Al and other metal (manganese, nickel, zinc, arsenic, lead, iron) particulates and the expression of the cancer-promoting gene histone 3 lysine 4 dimethylation (H3K4me2) and histone 3 lysine 9 acetylation (H3K9ac) activity in peripheral blood leucocytes of 63 steel workers exposed to metal-rich particulate matter (PM). Detailed information on lifestyle, smoking, drug use, medical conditions, body mass index (BMI), education, and residential history was obtained through a self-administered questionnaire. Records from the factory administrative files were used to extract information on occupational history. Metals (aluminum, manganese, nickel, zinc, arsenic, lead, iron) and PM with aerodynamic diameters ≤ 10μm and ≤ 1μm (PM10 and PM1, respectively) were measured in working areas. Concentrations of individual metals in PM10 were measured by inductively coupled plasma mass spectrometry using the total quant method. Personal exposure was calculated as the average level of metals and PM in the work area weighted by the time spent in each area. Cumulative exposure was estimated as the product of the time-weighted levels of metals and PM during the study by the years of employment in the plant. Workers participating in the study were on average 44.0 years old (with a range 27 – 55 years) and 40% (n = 25) were current smokers.The average workplace air level of inhalable Al was 8.50 ± 18.07 mg/m³ with the maximum individual exposure level of the 84.07 mg/m³ and minimum of the 0.4 mg/m³ with a difference in the individual exposure level more than 200 times. No statistically significant associations were observed between the activity of H3K4me2 and H3K9ac and airborne levels of Al either for personal or cumulative exposure. In spite of the study limitations (limited number of participants, lack of control group, possible exposure misclassification and selection biases, lack of complete exposure measurements, limited endpoints studied), the results suggest that long-term exposure to inhalable Al failed to cause changes at the genomic levels of histone modifications in blood leukocytes of the exposed workers. In addition, reported findings provide evidence for low genotoxic potential of inhaled Al particulate. A Reliability Score 3 was assigned.

 

Animal studies

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 control. The Al2O3 content 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 were exposed to flake powder at 15 and 30 mg/m³, and 30 rats were exposed to aluminium oxide dust at 30 and 75 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 75 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% < 1μm) included in the study as a 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 TG 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.

 

In-vitro studies and Mechanism of Action

The results from in-vitro studies indicate that aluminium oxide has low cytotoxicity. 

Overall, the current weight of evidence does not support an association between inhalation exposure to aluminium metal/aluminium oxide and cancers in the respiratory organs. The weight of evidence also does not support a systemic carcinogenic effect from exposure to aluminium metal and aluminium oxide.

Justification for classification or non-classification

Based on the weight of evidence approach for carcinogenicity no classification is required for aluminium oxide according to DSD (67/548/EEC) or CLP (1272/2008/EC) classification criteria.