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    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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    See Also:
       Toxicological Abbreviations
       Aluminium (EHC 194, 1997)
       Aluminium (WHO Food Additives Series 24)
       ALUMINIUM (JECFA Evaluation)