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EC number: 231-072-3
CAS number: 7429-90-5
were more numerous among all 3 species than ideal. The % of the animals
dead at 6 months and 12 months are provided in the table below. The
numbers are extracted from Tables 3, 4 and 5 of the publication.
% dead: 6 mos.
% dead: 12 mos.
All three species
developed alveolar proteinosis (AP);
50 and 100 mg/m3exposed
for 6 mths:
Marked AP; but
alveolar walls were generally thin and appeared normal;
spontaneous resolution with little evidence remaining 1.5 years
15 and 30 mg/m3for
Moderate AP from 6
to 12 months followed by gradual clearing. Some AP still present at 24
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
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.
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
clearance of dust:
Dust remained finely
dispersed even within the cytoplasm of macrophages.
50 and 100 mg/m3exposed
for 6 mths: Clearance by 1.5 years post-exposure
15 and 30 mg/m3exposed
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
The laboratory and
the intratracheal injection control did not show evidence of proteinosis.
Pyro and atomized
powder - 100mg/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.
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 ≤24mg/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
Pyro and atomized
powder – ≤12mg/m3
collagenisation of foci at 6 or 12 mths.
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, 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 powdershowed moderate
alveolar proteinosis after 6 months of exposure. Granulomatous
inflammation was observed at 50 mg/m³ after about 3 months of exposure.
Overall, there was no consistent relationship between dose and
severity of response for any of the aluminium powders.The results
showed no clear difference in reaction to the different powders. The
results from this study do not provide evidence to support a progressive
fibrotic response on inhalation exposure to aluminium powder.No
alveolar proteinosis or thickening of alveolar walls was observed in
rats, hamsters or guinea pigs exposed to Al2O3dust (66% < 1μm)
included in the study as a “non-fibrogenic” control.
The reason for the high and variable rates of mortality in this
study is unclear and is a limitation of the study.Several
endpoints specified in the 90-day inhalation toxicity guideline (OECD 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.
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