INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY
WORLD HEALTH ORGANIZATION
SUMMARY OF TOXICOLOGICAL DATA OF CERTAIN FOOD ADDITIVES
WHO FOOD ADDITIVES SERIES NO. 12
The data contained in this document were examined by the
Joint FAO/WHO Expert Committee on Food Additives*
Geneva, 18-27 April 1977
Food and Agriculture Organization of the United Nations
World Health Organization
* Twenty-first Report of the Joint FAO/WHO Expert Committee on Food
Additives, Geneva, 1977, WHO Technical Report Series No. 617
ALUMINIUM
BIOLOGICAL DATA
BIOCHEMICAL ASPECTS (ABSORPTION)
Due to formation of insoluble aluminiumphosphate (AlPO4) in the
gastrointestinal tract, only a minor amount of orally administered
aluminium-salts is absorbed (Jones, 1938; Kirsner, 1943).
Groups each of 10 mice received a standard diet containing
170 ppm or 355 ppm aluminium (as aluminum sulfate). There was no
significant difference in intake of water, but food intake was
significantly less in the group receiving the higher dose. Aluminum
balance was studied during the last six days of the test. Intake and
faecal excretion of aluminum was significantly higher at the higher
dose whereas urinary excretion and retention of aluminum were not. In
another study, aluminum balance was measured in eight rats on diet
containing 2835 ppm aluminum (as sulfate) for a further eight days.
The increased dose rate of aluminum resulted in a reduction of food
intake (20 to 15 g/rat/day) and a reduction in average body weight.
Aluminum excretion was increased significantly in higher dose group.
About 70% of the dose was excreted in the faeces. Retention was
increased 20 times (Ondreicka et al., 1966).
Two groups of rats were maintained on diets containing 180 ppm or
2835 ppm aluminum (as sulfate for 26 days). Analysis of tissues for
aluminum content, showed significantly increased retention in liver,
brain, testes, blood and femur of rats in the higher test group
(Ondreicka et al., 1966). These balanced studies with mice 25-30%
retention was found (Ondreicka et al., 1966) whereas 10% absorption is
reported after Al treatment in rats (Kortus, 1967).
Men were fed biscuits containing alum phosphate baking powder
(ca 8%) in addition to normal dietary items, and blood and urine
samples collected two, four, six and eight hours after the meal.
Aluminum was frequently found in blood of control men (trace -
0.1 mg/100 ml), and ingestion of the aluminum rich diet caused
occasional slight increase of levels of aluminum in the blood. Urine
of man, before and after ingestion of the aluminum rich diets only
contain small amounts of aluminum (less than 0.5 mgm excreted in 26
hours) (Underhill et al., 1929).
Increased concentrations were found in liver, brain, testes,
femur and blood (Ondreicka et al., 1966), while also increased bone
concentration was observed in uraemic rats (Thurston et al., 1972).
Ingested Al is mainly excreted in faeces, but the urinary Al
concentration is also increased after Al treatment (Ondreicka et al.,
1966).
Influence of aluminum on metabolism of phosphorus
Groups each of 10 mice were maintained on a diet containing
160 ppm or 355 ppm aluminum (as the chloride) for a period of 40 days,
and the phosphorus balance studied during the last six days. At the
high dose level, phosphorus retention was significantly lowered, and
on some days was negative. The concentration of phosphorus in the
liver and femur, was not significantly affected. In another study
eight rats were maintained for eight days on a standard diet, and then
another eight days on the diet plus 2665 ppm aluminum as sulfate.
Addition of aluminum to the diets resulted in decreased food intake
with concomitant lower phosphorus intake, and a reduced excretion of
phosphorus in the urine. However, the excretion of phosphorus in the
faeces was increased (Ondreicka et al., 1966).
Rats were dosed with a single oral dose of aluminum chloride
(188.2 mg/kg body weight), and then with 32P labelled Na2H32PO4.
The distribution of radioactivity was measured in test and control
animals. There was significant decrease in incorporation of 32P into
blood and all tissues examined. Further studies in which rats were
administered aluminum chloride daily (36.5 mg/day) for a period of 52
days, or by a single intragastrtc dose, each treatment being followed
by the i.p. injection of 32P labelled sodium phosphate showed that
where as the specific activity of the soluble phosphorus fractions
isolated from kidney, spleen and liver was not affected by either
chronic or acute intoxication, the incorporation of 32P into
phospholipids, RNA and DNA fractions was significantly decreased. In
another study the influence of chronically administered aluminum
chloride (55 days at 36.5 mg aluminum/day) or acutely administered
aluminum chloride (single oral dose of 223 mg aluminum/kg as the
chloride on day 56 of the study), on the blood serum level of AMP, ADP
and ATP of rat, showed that aluminum chloride caused an increase of
AMP, ADP and a decrease of ATP (Ondreicka et al., 1966).
Biochemical studies (general)
Rats treated with aluminium chloride (AlCl3) (200 mg Al/kg bw
incorporated in the diet) showed a decrease in glycogen content of
liver and muscle after 18 days exposure. Simultaneously lactic acid
was increased in these organs, like pyruvic acid in the liver and
blood. The co-enzyme A content of the liver was lowered (Kortus,
1967).
Al-salts are reported to interfere with the absorption of glucose
from the GI-tract (Gisselbrecht, 1957).
In vitro studies showed a dose-related inhibition of the
conversion of citric acid to alpha-ketoglutarate (Kratchovil et al.
1967), while the decarboxylation of pyruvic acid was increased by Al
(Langenbeck, 1957). Al-nitrate did not decrease adenylcyclase and
phosphodiesterase activities in rat cerebellum homogenates (Nathanson
and Bloom, 1976).
The oxygen consumption of liver homogenates from Al treated rats
was decreased (Ondreicka et al., 1966).
In vitro studies indicate that there is an activation of
erythrocyte-aminolaevulinic acid dehydratase activity at low
(2 mM-aluminium) concentrations whereas at higher concentrations
(4 mM-aluminium) erythrocyte gamma-aminolaevulinic acid dehydratase
activity was depressed. In vivo studies, with rats injected i.p.
with 150 mg/kg bw aluminium sulfate, indicated that the hepatic
gamma-aminolaevulinic acid dehydratase activity was significantly
greater than controls (Meredith et al., 1974).
TOXICOLOGICAL STUDIES
Special studies on the central nervous system
Recent studies (Crapper and Tomko, 1975) using sensitive
analytical techniques, indicate the cerebral cortical concentrations
(between 4 and 6 µg/g dry weight) are associated with alterations in
cat nervous tissue. Observations from the same laboratory indicate
that the cerebral cortical concentrations in the range of 4-8 µg/g dry
weight are also toxic to rabbit brain (Crapper et al., 1976).
However, in similar studies conducted with two species of rats
they developed neither neurofibrillary degeneration nor progressive
encephalopathies following aluminium applications of up to 10 times
the aluminium dose effective in cats (King et al., 1975).
Special studies on carcinogenicity
Long-term administration of 5 ppm Al in drinking water of mice
(Charles River CD strain, two groups of 38-47 males and females)
increased the number of lymphoma leukaemia tumours in females, but not
the number of animals with tumours (Schroeder and Mitchener, 1975a,
see long-term studies).
A significant increase in tumour incidence was found in male rats
(Long Evans Blu: LE strain, two groups with 19-26 males and females)
after treatment with 5 ppm Al in drinking water during life time
(Schroeder and Mitchener, 1975b).
In eight of 18 rats with subcutaneous implants of Al foil local
sarcomas were observed (O'Gara and Brown, 1967).
No carcinogenic activity was demonstrated in studies using mice,
rats, rabbits and guinea-pigs after administration (intraperitoneal,
intravenous) of Al powder, Al(OH)3, Al2O3, AlPO4 and Al dextran
(Furst, 1969, 1971; Shubik and Hartwell, 1969).
Mutagenicity testing
No DNA damaging capacity was observed in the recombination assay,
using strains of the Bacillus subtilis (Nishioka, 1975).
Reproduction
Ten mice were treated with an average 19.3 mg Al/kg body weight
via drinking water. In the two generations bred, the F1b, F1c, F2a
and F2b litters showed growth impairment when compared with 10
controls receiving 160-180 ppm Al in the diet. No influence on the
number of litters or offspring is reported. No histopathological
abnormalities were observed in liver, spleen and kidneys. Red blood
cell counts did not differ in the first and the last generation
(Ondreieka et al., 1966).
Groups each of 40 mice equally divided by sex were fed diets
containing bread leavened with either yeast, or aluminum phosphate or
alum. The presence of aluminum leavened bread in the diet resulted in
a decreased number of offspring, as well as development of ovarian
lesions (Schaeffer et al., 1928). In another study in which groups of
mice were fed bread with yeast plus 4% physiological saline mixture,
or 13% saline mixture; or bread with alum phosphate baking powder
(4.4% Al plus 4% saline mixture) or bread with alum phosphate powder
(1.3% Al) for a period of four months. The presence of aluminum
treated bread resulted in decreased number of offspring, as well as
increased mortality of offspring during first week of life. Ovaries of
these animals contained a large number of atritic follicles, and were
greatly reduced in size (Schaeffer et al., 1928).
Pregnant rats were administered 40-200 mg/kg aluminium chloride
intraperitoneally on either gestational days 9, 13, 9-13 or 14-18.
Treatment with 100-200 mg AlCl3/kg caused a dose-related increased
incidence of maternal deaths; doses of 75-200 mg/kg resulted in
extensive liver damage. The incidence of congenital abnormalities
(poor ossification and skeletal defects) was higher in treated animals
(Bennett et al., 1974).
Thirty rats (50-100 g) were used, 20 receiving the synthetic
diet, and the other 10 the synthetic diet plus 0.1% soda alum. Growth
curves were comparable, and breeding tests produced for three
generations, were similar for test and control animals. The progeny of
the rats grew normally (Mackenzie, 1932).
Acute toxicity
LD50 mg/kg References
Salt Species Route body weight
AlCl3 Mouse Oral 3 800 Ondreicka et al., 1966
AlCl3 Rat Oral 3 700 Spector, 1956
Al2(SO4)3 Mouse Oral 6 200 Ondreicka et al., 1966
Al(NO3)3 Mouse i.p. 320* Hart and Adamson, 1971
Al(NO3)3 Rat i.p. 330* Hart and Adamson, 1971
Al(NO3)3 Rat Oral 4 280 Spector, 1956
* Ten daily injections, 30 days ovservation period.
Short-term studies
Rat
Feeding 6-10 mg Al/day to a group of six rats for four weeks
caused an impairment of growth at three and four weeks. Animals
supplemented with 0.1% Na2HPO4 showed a normal rate of growth. No
histological abnormalities were found in liver, kidney and heart, but
rachitic changes were observed in animals not supplemented with
phosphorus. In 3/4 out of nephrectomized rats receiving the same
amounts of Al(OH)3, an increase of Al in bone was found (Thurston et
al., 1972).
Groups of five rats which were normal or had 5/6 nephrectomy
(total one side, 2/3 other side), were administered drinking water
containing 1 or 2% aluminum sulfate. In the case of the nephrectomized
animals, all animals receiving 1% Al2(SO4), died within eight days,
and those at the 2% level within three days. The clinical syndrome
included periorbital bleeding, lethargy and anorexia. None of the
normal rats on the test died during this period, but periorbital
bleeding occurred in 3/5 rats (Berlyne, 1972).
Mice
Groups each of 40 mice equally divided by sex were fed diets
containing bread leavened with aluminum (2.07 or 4.1 g Al/100 g bread)
as aluminum phosphate baking powder for a period of four months. The
groups fed bread leavened with aluminum salt developed serious lesions
of the digestive tract (Schaeffer et al., 1928).
Dog
Groups each of eight beagle dogs, equally divided by sex were fed
diets containing sodium aluminum phosphate, (acidic) at dietary level
of 0.3, 1.0 and 3.0% for 90 days. During this period there were no
significant deviations from normally expected body weight gains.
There were no significant differences in haematologic parameters,
blood chemistry and urine analyses of test groups and controls. At
autopsy, organ weights were similar for test and control animals.
Histopathological examination of tissues did not reveal any compound-
related effects (Industrial BioTest Labs., 1972a). In another study,
groups of dogs were fed the same dietary level of sodium aluminum
phosphate (basic), and parameters described in previous study were
measured. The only compound-related effect observed, was the presence
of unusually large renal concretions in 3/8 of the test animals
(2M, 1F), fed 3% of the test material (Industrial BioTest Labs., 1972b
and c).
Long-term studies
Mouse
No adverse effects on body weight and longevity were observed in
mice (54 males and famales per group, Charles River CD strain)
receiving 0 or 5 ppm Al (as potassium sulfate) during life time
(936 ± 49 days). No details on histopathology are available (Schroeder
and Mitchener, 1975a).
Rat
Two groups of rats (Long Evans, 52 of each sex) received 0 and
5 ppm Al (as potassium sulfate) in drinking water during life time
(1064 ± 20 days). No effects were found on body weight, average heart
weight, glucose, cholesterol and uric acid level in serum, protein and
glucose content and pH of urine. The life span was not affected. The
number of male rats with tumours was significantly increased
(Schroeder and Mitchener, 1975b).
Groups each of 24 rats were maintained on diets containing SAS
powder (a mixture of sodium aluminum sulfate and calcium acid
phosphate) at dietary levels equivalent to approximately 0, 0.15%,
1.8% or 0.44%.* Some of the test animals were bred for seven
successive generations. The SAS had no effect on reproductive
performances as measured by number of offsprings, average birth
* SAS baking powders contain ca. 20% sodium aluminum sulfate. Thus
diet contained 400, 33 and 98 ppm aluminum respectively.
weight, average weaning weight and number weaned. Histopathologic
examination of kidneys of rats that survived 21 months on the diet did
not reveal any significant changes (Lymann and Scott, 1930).
OBSERVATIONS IN MAN
Estimates of the daily intake vary between 10 and 100 mg/person
(Sorenson et al., 1974).
The Al concentration in human tissues from different geographic
regions was found to be widely scattered, and probably reflected the
geochemical environment of the individuals and of locally grown food
products (Tipton and Cook, 1965).
In healthy human tissues from the United Kingdom the Al
concentration was usually below 0.5 µg/g wet weight, but higher levels
were observed in liver (2.6 µg/g), lung (18.2 µg/g), lymph nodes
(32.5 µg/g) and bone (73.4 µg/g of ash) (Hamilton et al., 1972).
In two subjects the intake was found to be 18 and 22 mg/day
during a 30-day period. Excretion took place mainly via faeces
(respectively 17 and 45 mg/day): 1 mg was found in 24-hour urine. The
mean balances were 0 and -24 mg/day (Tipton et al., 1966).
The Al concentration in muscle, bone and brain of patients
maintained on a phosphorus binding Al gel for at least two years was
respectively 14.8, 95.5 and 6.5 µg/g dry weight is 1.2, 2.4 and
2.2 µg/g dry weight in control subjects. Patients on dialysis, who
died of a neurologic syndrome of unknown cause (dialysis
encephalopathy syndrome) had brain grey matter concentrations of
25 mg Al/kg dry weight, while in controls 2.2 mg/kg was measured
(Alfrey et al., 1976).
Al levels in some regions of the brain of patients, who suffered
from the Alzheimer's disease were in the range of 6-12 µg/g dry
weight (control: < 2.7 µg/g dry weight). Involvement of Al in the
pathogenesis of the Alzheimer's disease is suggested (Crapper et al.,
1973).
The aluminium content of brain in Alzheimer's disease, in which
the diagnosis was based on histological appearances, revealed an
elevated (0.4-107.0 µg/g) aluminiam content (Crapper et al., 1976).
The brain of an aluminium ball mill worker with progressive
encephalopathy accompanied by dementia and convulsions was found to
contain 5 ppm Al (wet weight) which is 20 times the normal
concentration (McLaughlin et al., 1962).
Oral administration of Al(OH)3 in doses of 15-40 mg Al/kg body
weight daily to patients under dialysis is effective in lowering the
predialysis Ca-P product. Systematic use of Al(OH)3 over nearly four
years in more than 70 patients did not result in the appearance of a
particular clinical picture suggesting intoxications and was
compatible with a survival rate of more than 85% after three years.
The development of metastatic calciferations was prevented, and
existing non-vascular and in a few cases vascular metestatic
calciferations disappeared (Verberckmoes, 1972).
Raised serum Al levels were found in about 1/3 of non-dialysed
patients with advanced renal failure receiving 45 g Al resin/day or
more or 3-6 g Al(OH)3/day for 7-14 days (Berlyne et al., 1970).
Eight patients with chronic renal failure were given 1.5-3.4 g Al
(as Al(OH)3)/day for 20-37 days. In all patients there was a decrease
in plasma phosphorus. The balance became more negative in four and
less positive in one, remained unchanged in two and became positive in
one. Patients absorbed 100-568 mg Al daily. Al administration may
decrease parathyroid over-activity since in three patients a
normalization of serum parathyroid hormone is found when serum Ca is
increased and serum phosphorus is lowered (Clarkson et al., 1972).
Occurrence and daily intakes
Aluminum occurs naturally in foods, the amount found in plants
being generally higher than that in animal foods. In the case of
plants the level of aluminum present is related to local soil and
atmospheric conditions (Truffert, 1950; Campbell et al., 1957).
Estimates of the daily intake of aluminium ranges in the
published literature from 1.53 to 160 mg/person/day (Sorensen et al.,
1974). Tipton (1966) analysed in the diet and excretion of two
subjects for 30 days and found that the mean balances were 0.000g
and -0.024 g. This reaffirms earlier results (Campbell, 1957) that
excessive intake and absorption by a normal individual is followed by
prolonged excretion of the excess, following a reduction in intake.
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