Registration Dossier

Toxicological information

Carcinogenicity

Currently viewing:

Administrative data

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 for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to same study
Qualifier:
equivalent or similar to guideline
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 or test system 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 for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to same study
Qualifier:
equivalent or similar to guideline
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 or test system 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 for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to same study
Qualifier:
equivalent or similar to guideline
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 or test system 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:
read-across from supporting substance (structural analogue or surrogate)
Remarks:
Summary of available data used for the endpoint assessment of the target substance
Adequacy of study:
weight of evidence
Justification for type of information:
Refer to analogue justification provided in IUCLID section 13.
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Dose descriptor:
NOAEC
Remarks:
carcinogenicity
Effect level:
>= 2.45 mg/m³ air (nominal)
Based on:
test mat.
Remarks:
"aged" Saffil
Sex:
not specified
Basis for effect level:
other: no adverse effect observed at the highest dose tested
Remarks on result:
other: woe, source, RA-A, 7429-90-5, Pigott et al., 1981
Critical effects observed:
not specified
Conclusions:
Exposure to the source substance (CAS 7429-90-5) did not increase incidences of neoplastic findings. Applying the read-across approach, a similar response are expected for the target substance (CAS 1344-28-1).
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

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.

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.