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EC number: 215-691-6
CAS number: 1344-28-1
Chronic toxicity (OECD 426), oral rat:
NOAEL = 322.5 mg/kg bw/day as aluminium citrate (equivalent to 30 mg
Al/kg bw/day and 113 mg Al oxide/kg bw/day)
supporting, source, RA-A, 18917-91-4, Golub and Keen, 1999:
consistent, dose-response effects on neurobehavioral endpoints
supporting, source, RA-A, 7784-27-2, Columina et al., 2005:
A significant decrease in forelimb grip strength was observed at 100 mg
Al/kg bw/day. No effects in other neuromotor tests were observed.
Additionally, no alterations in open field behaviour or passive
avoidance test were observed.
supporting, source, RA-A, 18917-91-4, Donald et al., 1989:
Pre-weaning (PND 0-21): no effects on neurobehaviour performance;
Post-weaning (PND 21-25): increased foot splay, decreased sensitivity to
heat, and increased fore- and hind limb grip strength in 500 and 1000
mg/kg diet. No consistent effects on negative geotaxis and no effects on
auditory and air-puff startle response were observed.
supporting, source, RA-A, 18917-91-4, Golub et al., 1995:
effects were observed on grip strength and startle response due to
developmental exposure to 500 and 1000 mg Al/kg diet.
There were no studies available in which the neurotoxic properties
of aluminium oxide were investigated.
Information available on aluminium compounds were therefore
considered for this endpoint, 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; ATSDR, 2008). A
detailed rationale and justification for the analogue read-across
approach is provided in the technical dossier (see IUCLID section 13).
A recent combined one-year developmental and chronic neurotoxicity
study with Al-citrate (Alberta Research Council Inc, 2010) may be of
interest for the evaluation of the neurotoxicity of Aluminium hydroxide,
taking into consideration the tenfold lower bioavailability of
Al-hydroxide compared to Al-citrate and excluding effects that can
likely be related to the salt rather than the cation. The study was
conducted according to OECD TG 426 and GLP, and the exposure covered the
period from gestation day 6, lactation and up to 1 year of age of the
offspring. Pregnant Sprague-Dawley dams (n=20 per group) were
administered aqueous solutions via drinking water of 3225 mg/Al
citrate/ kg bw/day (300 mg Al/kg bw/day); 1075 mg/Al citrate/kg bw/day
(100 mg Al/kg bw/day); 322.5 mg/Al citrate/kg bw/day (30 mg Al/kg
bw/day). The highest dose was a saturated solution of Al-citrate. Two
control groups received either a sodium citrate solution (citrate
control with 27.2 g/L, equimolar in citrate to the high dose Al-citrate
group) or plain water (control group). The Al citrate and Na-citrate
were administered to dams ad libitum via drinking water from gestation
day 6 until weaning of offspring. Litter sizes were normalized (4 males
and 4 females) at postnatal day (PND) 4. Weaned offspring were dosed at
the same levels as their dams. Dams were sacrificed at PND 23. At PND 4
1 male and 1 female pup of each litter were allocated to 4 testing
groups: D23-sacrifice group for pre-weaning observations and D23
neuropathology, D64, D120 and D365 postweaning groups for post weaning
observations and neuropathology at the respective days of sacrifice.
Endpoints and observations in the dams included water consumption, body
weight, morbidity and mortality and a Functional Observational Battery
(FOB) (GD 3 and 10, PND 3 and 10). Pups were examined daily for
morbidity and mortality. Additional neurobehavioral tests were performed
at specified intervals and included, T-maze, Morris water maze, auditory
startle, and motor activity. Female pups were monitored from PND26 for
vaginal opening, male pups from day 35 for preputial separation.
Clinical chemical and haematological analysis was performed for each
group on the day of scheduled sacrifice. Al-concentrations were
determined in blood, brain, liver, kidney, bone and spinal cord tissues
by inductively coupled plasma mass spectrometric analysis. Further
metals such as iron, manganese, copper and zinc were also determined.
The pathological investigation includes rain weight and neuropathology.
Statistical analyses were performed using the SAS software release 9.1.
Data collected on dams and pups were analysed separately. All analysis
on pups was performed separately for each sex. Statistical significance
was declared from P ≤ 0.05.
Results: Dams: Eight high dose dams developed diarrhoea. In the
Na-citrate group one dam stopped nursing and the pups were euthanized.
No significant differences between mean body weights of dosed animals
compared to controls were observed during gestation and lactation.
During gestation and lactation low and mid dose group animals consumed
considerably more fluid than controls and high dose group animals. This
is not considered treatment related as there was no dose response. In
all animals the target dose was exceeded during lactation due to the
physiologically increased fluid consumption.
Pups: During the pre-weaning phase weights of mean body weights of
male and females in the sodium citrate and high dose group were
significantly lower than the untreated controls. This suggests a citrate
rather than Al-related effect. No differences between treated and
control animals were observed in the FOB. No other clearly treatment
related effects were observed pre-weaning.
F1-postweaning: General toxicity
No significant differences in body weights throughout the study
were observed between low and mid-dose animals sodium-citrate and
untreated controls. High dose males had significant lower body weights
than controls by PND 84. These animals also had clinical signs. At
necropsy urinary tract lesions were observed in the animals of the high
dose group, most pronounced in the males, hydronephrosis, uretal
dilatation, obstruction and/or presence of calculi. All high dose males
were sacrificed on study day 98. The effect is probably due to
Al-citrate calculi precipitating in the urinary tract at this high dose
level. This effect is related to the citrate salt and cannot be
attributed to the Al-ion. Female high dose animals showed similar
urinary tract lesions, but with a lower incidence and severity. Urinary
tract lesions were also observed in single mid dose males, but also in a
few sodium citrate and control animals. Fluid consumption during the
study was increased in the sodium citrate and Al-citrate groups (in
particular high and mid dose) compared to controls. This is probably due
to the high osmolarity of the dosing solutions. However, the consumed
dose levels decreased in all dose groups during the study. In the
beginning the target dose was considerably exceeded, while versus the
end of the study it was considerably below the target dose. According
to the authors the assigned dose levels still remain valid.
In sodium citrate controls and high dose males and females the
number of days to reach preputial separation or vaginal opening was
longer than in untreated control animals. This may be related to the
lower body weights in these animals at the respective time-point. As the
sodium citrate group showed similar retardation this effect cannot be
allocated to the aluminium cation.
No consistent treatment related effects that could be related to
Al-ion exposure were observed in the FOB. No treatment related effects
on autonomic or sensimotoric function were observed in the study. A weak
association between Al exposure and reduced home cage activity, a very
weak association with excitability, some association with neuromuscular
performance were reported but according to the authors this may also be
related to group differences in body weight, and an association with
physiological function and is thus not considered clearly treatment
related. No treatment related effect on general motor behavior was
observed. No clearly treatment related effect on auditory startle
response was observed. There was no evidence of any treatment related
effect on learning and memory in the Morris Water Maze test and no
clearly treatment related effects in the T-maze test. Hind limb grip
strength and to a lesser extend foot splay were reported to be reduced
compared to controls in high and mid dose male and female animals, more
pronounced in younger than in older rats. However, the observed effects
can be related to the lower body weights of the individual animals
undergoing this test. No details on the individual findings and
historical control data are available. It can therefore not be concluded
with certainty that the observed neuromuscular effects are primary
effects of the treatment and attributable to Al3+. The NOAEL was
reported based on this effect as 30 mgAl/kg bw in a conservative
Haematology: No clinically significant differences in hematology
were observed at the investigation on day 23. In day 64 and 120 females
and day 64 males the high dose group showed slight reduction in
hematocrit (males only), mean hemoglobin and mean corpuscular cell
volume.No such changes were observed in the 364 day group.
Clinical chemistry: while a number of borderline statistically
significant changes were observed, such as globuline levels, alkaline
phosphatase and glucose in the high dose group little or no biological
significance is associated with them. Elevated creatinine and urea
levels in Day 64 males are consistent with the renal toxicity observed
in these animals.
Organ weights: Brain weights did not differ among the groups, with
two exceptions in the day 64 group males brain weights were
significantly lower than controls. In the 120 day female high dose group
brain weights were also significantly lower than controls. These
findings were not reproduced at the other sacrifice times. Brains to
body weight ratios were not significantly different and the lower brain
weights can be attributed to the body weight.
Pathology: The main pathology findings were the renal lesions with
precipitates in the urinary tract and secondary lesions such as
hydronephrosis and uretal dilatation in particular in the high dose
group males and to a lesser extend females. Fluid colonic content was
also observed in some high dose animals, in particular males. According
to the authors the test item clearly precipitated in the urinary tract
causing stone formation and blockage and resulted in fluid colonic
content. No other macroscopic effects were observed in other organs.
Histopathology: No treatment related histopahological effects were
observed in the nervous system at any time point.
Aluminium concentrations in different organs were dose related.
Tissue concentrations were highest in blood, and then in decreasing
order brainstem, femur, spinal cord, cerebellum, liver cerebral cortex.
A conservative NOAEL of 322 mg Al-citrate/kg bw corresponding to
30 mg Al/kg bw for neuromuscular effects was derived from this study
(with a bioavailability correction this would correspond to ca. 300 mg
Al from Al(OH)3).
The most important effects were however related to a precipitation
of the citrate in the kidneys and urinary tract and this effect is not
related to the Al3+ ion. The effects on grip strength and foor splay
observed can also not be attributed unequivocally to Al-exposure as they
may have been secondary to the general toxicity and body weight
differences between treated and control animals undergoing this test.
Neurobehavioral effects as reported by e.g. Thorne et al., 1986 could
not be confirmed in this study.
In another study, groups of female rats were exposed to 0, 50, or
100 mg Al/kg bw/day as aluminium nitrate nonahydrate in drinking water
(Colomina et al., 2005). In order to increase aluminium absorption,
citric acid (710, 355, and 710 mg/kg bw/day in the control, 50, and 100
mg/kg bw/day groups, respectively) was added to the drinking water. The
adult rats were exposed to aluminium nitrate nonahydrate for 15 days
prior to mating and during gestation and lactation periods. After
weaning, the pups were exposed to the same doses as the mothers from PND
21 through 68. Besides aluminium nitrate nonahydrate exposure, some
animals in each group underwent restraint stress, which consisted in
placing the rats for 2 hours/day in cylindrical holders on gestation
days 6-20. A battery of neurobehavioral tests was conducted on the
offspring: righting reflex (PNDs 4, 5, 6), negative geotaxis (PNDs 7, 8,
9), forelimb grip strength (PNDs 10-13), open field activity (PND 30),
passive avoidance (PND 35), and water maze (only tested at 53 mg/kg/day
on PND 60). The rats were sacrificed on PND 68.
In the dams exposed to aluminium nitrate nonahydrate, no
significant alterations in body weight, food consumption, or water
consumption were observed during gestation. The authors stated that
decreases in water and food consumption were observed during the
lactation period in the rats exposed to 100 mg Al/kg bw/day, but these
data were not shown and maternal body weight during lactation was not
mentioned. No significant effects in the number of litters, number of
foetuses per litter, viability index, or lactation index were observed.
In addition, no differences in days at pinna detachment or eye opening
were observed. Age at incisor eruption was significantly higher in males
exposed to 50 mg Al/kg/day, but not in males exposed to 100 mg Al/kg/day
or in females. A significant delay in age at testes descent was observed
at 100 mg Al/kg/day and vagina opening was delayed at 50 and 100 mg
Al/kg/day. A decrease in forelimb grip strength was observed at 100 mg
Al/kg/day. No effects in other neuromotor tests were observed.
Additionally, no alterations in open field behaviour or passive
avoidance test were observed. In the water maze test, latency to find
the hidden platform was decreased in the 50 mg Al/kg/day group on test
day 2, but not on days 1 or 3; no significant alteration in time in the
target quadrant was found.
The overall effects indicated a maternal NOAEL of 100 mg Al/kg
bw/day as aluminium nitrate nonahydrate.
An offspring NOAEL could not be identified. Based on decreased
forelimb grip strength and delay in vagina opening the offspring LOAEL
was considered to be 50 mg Al/kg bw/day as aluminium nitrate nonahydrate.
However, due to the lack of body weight data during crucial periods of
development , the effects observed cannot unequivocally be attributed to
the Al exposure.
In general, weight of evidence would suggest that oral exposure to
aluminium is not associated with marked signs of neurotoxicity in
animals. Studies involving exposure to high aluminium doses have not
noted significant increases in the incidence of overt signs of
neurotoxicity (Donald et al. 1989; Golub et al. 1992). Only in one
study, an overt sign of toxicity reported was an increase in cage mate
aggression in male mice exposed to 200 mg Al/kg bw/day from gestation
day 1 through postnatal day 170 (Golub et al. 1995).
Decreases in forelimb and/or hindlimb grip strength have been
observed in mice exposed to 100 mg Al/kg bw/day for over 2 years (Golub
et al. 2000). In contrast, no alterations in grip strength were observed
in mouse dams exposed to 330 mg Al/kg bw/day (Donald et al. 1989) as
aluminium lactate in the diet on gestation day 1 through lactation day
21 or in mice exposed to 200 mg Al/kg bw/day on gestation day 1 through
postnatal day 170 (Golub et al. 1995). No significant alterations have
been observed for negative geotaxis in mouse dams exposed to 330 mg
Al/kg bw/day as aluminium lactate in diet on gestation day 1 through
lactation day 21 (Donald et al. 1989). A decrease in total spontaneous
activity, vertical activity (rearing), and horizontal activity were
observed in mice exposed to 130 mg Al/kg bw/day for 6 weeks (Golub et
al. 1989). Exposure to lower doses of aluminium lactate or aluminium
nitrate (with added citric acid) has not been associated with decreases
in motor activity. No alterations in motor activity (as assessed in open
field tests) were found in rats exposed to 100 mg Al/kg bw/day for 1 or
2 years (Roig et al. 2006). Similarly, no alterations in total activity
or horizontal activity were observed in mice exposed to 100 mg Al/kg
bw/day as aluminium lactate in the diet during gestation, lactation, and
postnatally until 2 years of age (Golub et al. 2000). However, the
investigators noted that the automated activity monitor used in this
study did not detect vertical movement of the older rats and that their
previous study (Golub et al. 1989) found that vertical movement was more
sensitive than horizontal movement. Another chronic-duration study (Roig
et al. 2006) found no significant alterations in the total distance
travelled or the total number of rearings in rats exposed to 100 mg
Al/kg bw/day as aluminium nitrate in drinking water (citric acid added)
from gestation day 1 through 2 years of age.
Changes in thermal sensitivity was not observed in mouse dams
exposed 330 mg Al/kg bw/day as aluminium lactate in the diet on
gestation day 1 through lactation day 21 (Donald et al. 1989). No
changes in startle responsiveness were observed in mice exposed to 250
or 330 mg Al/kg bw/day as aluminium lactate in the diet on gestation day
1 through lactation day 21 (Donald et al. 1989; Golub et al. 1992a).
In a low quality study, no significant alterations in performance
on the water maze test were found in rats exposed to 100 mg Al/kg bw/day
as aluminium nitrate in the drinking water for a chronic duration (Roig
et al. 2006).
Overall, there is no consistent evidence for neurotoxicity of
Al-compounds after repeated exposure. In particular the substances of
low bioavailability, such as Al-metal, Al2O3 and Al(OH)3 are unlikely to
cause neurotoxic effects because of their limited bioavailability. No
classification is required according to DSD (67/548/EEC) or CLP
(1272/2008/EC) classification criteria.
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