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EC number: 231-072-3
CAS number: 7429-90-5
Key Studies for Dose Descriptor
Gross et al. (1973) and Pauluhn (2009a) were chosen as the most
relevant and adequate studies to consider as possibly key for derivation
of a DNEL for aluminium metal dust and powder under repeated exposure
(inhalation, local effect). Both studies, however, have limitations. The
Gross et al. (1973) study only assessed histopathology and did not
measure more sensitive endpoints such as inflammatory markers in BALF.
Pauluhn (2009a) exposed rats to manufactured nanoparticulate materials
which, although agglomerated (MMAD=0.6 and 1.7 µm) may exhibit different
retention kinetics in the lung than the larger particle sizes more
typical of worker exposures. Gross et al. (1973), which employed test
materials particularly relevant to the exposure scenarios specified by
the client, has been chosen as the key study.
The LOAEC from Gross et al. (1973), a chronic study, is 50 mg/m³
for a critical effect of granulomatous inflammation, lipid pneumonitis
and collagenous scars. These effects represent a cholesterol granuloma,
a rare occurrence in humans (Green et al., 2007), but a progression in
the overload-associated alveolar lipoproteinosis response typical of
Additional support comes from the study by Thomson et al. (1986).
Although this study used an acute exposure (4 hours) and stearine-coated
Al flake-powder, the authors observed no effects on BALF fluid cell
counts or biochemistry during 6 months follow-up of rats exposed to 10
mg Al/m³. At the 10 mg Al/m³ level, the average of three separate
samples had an average geometric particle size of 3.28±2.25 μm. At 50 mg
Al/m³, a persistent increase in polymorphonuclear neutrophils was
observed.No adverse pulmonary physiological responses (compliance,
resistance or tidal volume) were observed at 1000 mg Al/m³. 10 mg Al/m³
is an acute exposure NOAEC from this study based on a sensititve
endpoint (BALF cell counts and cytology).
Key Study: Gross et al. (1973)
Dose Descriptor: 50 mg/m³, LOAEC
Test Animal: Rat
Test substance: aluminium powders - mean particle size diameters:
2.49, 2.22 and 4.85 μm
Doses used: 0, 15, 30, 50, 100 mg/m³
Duration of exposure in the experiment: 6 months (for 50 and 100
mg/m³) and 12 months; 6 hours per day, 5 days per week; follow-up to 30
Effects observed: lipid pneumonitis, granulomatous inflammation;
collagenous scars but fibrosis was not evident.
Mode of Action: Based on the weight of evidence, the target
substances behave as low cytotoxic, poorly soluble particulates (PSPs).
From a risk assessment perspective based on studies in rats, two
possible thresholds can be envisioned for pulmonary toxic effects on
chronic exposure to ‘nuisance” PSPs:
1) a dosimetric threshold to avoid overloading
macrophages and leading to a persistent inflammatory response;
2) a mechanistic threshold greater than the dosimetric
threshold that occurs when anti-inflammatory responses are overwhelmed
and effects may progress to fibrosis (Oberdorster, 2002).
For a persistent inflammatory response potentially leading to
fibrosis, the mode of action for aluminium oxide (dust), aluminium
hydroxide and aluminium powder (uncoated) in the respirable and
inhalable size range is threshold and related to volumetric overloading
Calculation of DNEL long-term,worker according to the ECHA
guidance (ECHA guidance, Chapter R8, p27):
Modification of starting point to correct for differences in
inhalation volume between the rats and lightly active humans –
LOAEC (corrected) = LOAEC * 6.7m³ (8h)/10m³ (8h)
= 50 * 6.7/10
= 33.5 mg/m³; corrected starting point
Allometric scaling is not necessary as the mode of action is a
portal-of-entry effect (overload) and adjustment for inhalatory volume
has been carried out to modify the starting point; scientific evidence
suggests rats are at greater susceptibility to overload than humans
(Oberdorster, 1995; Pauluhn, 2010), therefore a factor o f
2.5 for remaining effects was not considered appropriate.
Eurometaux has adopted the ECETOC (2010) approach for intraspecies
and interspecies assessment factors. Therefore, the client indicated
that this value should be inserted here As inorganic metal compounds ar
not metabolized by the usual metabolic systems and furthetmore the
effects are related to unspecifc particle effects, the intraspecies
factor can be reasonable reduced to 3.
Duration of exposure: 1 (The duration of exposure was adequate.)
Dose response extrapolation: 3 (Based on a LOAEC)
Adequacy of database: 1
No fibrosis was observed in the study by Gross et al. (1973); the
study did not assess more sensitive inflammatory endpoints such as
biochemical markers in BALF; the relevance of the critical effect to the
human lung is unclear, however, as it is consistent with a rat lung
overload response. Considering the human, animal and in-vitro data as a
whole, an assessment factor of 1 for database adequacy is considered
Total assessment factor = 9
Calculated DNEL long-term, worker = 33.5/9 = 3.72 mg Al/m³,
respirable, 8 hour TWA.
Key Study for Dose Descriptor
The long-term consumer DNEL for systemic effects is based on a
chronic 1-year oral study with the read-across substance aluminium
citrate (ToxTest, TEH-113, 2010). The GLP study was designed “to develop
data on the potential functional and morphological hazards to the
nervous system that may arise from pre-and post-natal exposure to
aluminium citrate”. In terms of hazard assessment of toxic effects,
available data on the toxicity to reproduction/development of other
aluminium compounds was taken into account by read-across following
a structural analogue approach, since the pathways leading to toxic
outcomes are likely to be dominated by the chemistry and biochemistry of
the aluminium ion (Al3+) (Krewski et al., 2007). The oral NOAEL for
female and male rats was found to be 30 mg/kg bw/day. However, this was
already a conservative assumption as the effects observed could have
been secondary to kidney toxicity based on a crystallization of
Al-citrate in the kidneys after chronic exposure and/or reduced body
weight and not Al-related.
Key Study: Developmental and One-Year Chronic Neurotoxicity Study
of Aluminium Citrate in Rats. ToxTest, Alberta Research Council Inc.
Project No. TEH-113.
Dose Descriptor: NOAEL - 30 mg Al/kg bw/day
Test substance: aluminium citrate
Doses used: 30, 100 and 300 mg Al/kg bw/day
Duration of exposure in the experiment: Pregnant females were
exposed to Al-citrate from GD6 to GD21 and from PND 1 to PND 21. Pups
were exposed to Al-citrate in utero and with maternal milk from PND 1 to
PND 21, 64, 120 or 364.
Effects observed: A deficit in footsplay- and hind-limb grip
strength in the mid-dose group, supported by evidence of dose response
for this endpoint after chronic exposure.
Ratio of bioavailability between test and target substance: Priest
(2010): Ratios of the whole body fractional uptake for Al-citrate
(0.079%) to the whole body fractional uptakes of Al metal (<0.015%).
Calculation of DNEL long-term, systemic, general population
according to the ECHA guidance (ECHA guidance, Chapter R8, p27):
Modification of starting point, to adjust ratios of the whole body
fractional uptake for Al-citrate (0.079%) to the whole body fractional
uptakes of Al metal (<0.015%).
NOAEL (corrected) = NOAEL * 5.27
= 158.00 mg Al/kg bw/day; corrected starting point
4 for allometric scaling (rats to humans) [ECHA default, 2008].
Due to the fact that inorganic metal compounds are not metabolized by
liver enzymes a toxicokinetic factor is not adequate for the
extrapolation. In addition the NOAEL was already conservative because it
is possible that the effects observed are not related to the Aluminium
ion, but secondary to kidney effects in the rats due to crystallistion
of Al critrate and/or lower body weight. The allometric factor is
therefore already conservative and no additional factor is needed.
Due to the fact that inorganic metal compounds are not subject to
metabolism, differences in enzyme activities between individuals do not
need to be considered and the intraspecies factor for the general
population can be reduced to 5. Furthermore ECETOC (2010) provided
evidence that a factor of 5 is in most cases sufficiently conservative.
Duration of exposure: 1 (The study exposed the animals until they
were 1 year of age.) Dose response extrapolation: 1 (Based on a NOAEL
Adequacy of database: 1
Evidence for differences in toxicokinetics of Al when complexed
with citrate (Jouhanneau et al., 1997); uncertainty as to the critical
period of exposure and lack of information on food consumption in the
ToxTest-TEH-113 study. Conservative assumption on the NOAEL as the
effects may well be secondary to general toxicity based on
crystallization of Al-citrate in the kidneys and not related to
Total assessment factor = 20
Calculated DNELlong-term, systemic, general population= 158.00/20
= 7.9 mg Al/kg bw/day.
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