Toxicological evaluation of some food
    additives including anticaking agents,
    antimicrobials, antioxidants, emulsifiers
    and thickening agents


    The evaluations contained in this publication
    were prepared by the Joint FAO/WHO Expert
    Committee on Food Additives which met in Geneva,
    25 June - 4 July 19731

    World Health Organization


    1    Seventeenth Report of the Joint FAO/WHO Expert Committee on
    Food Additives, Wld Hlth Org. techn. Rep. Ser., 1974, No. 539;
    FAO Nutrition Meetings Report Series, 1974, No. 53.



         These compounds have been evaluated for acceptable daily intake
    by the Joint FAO/WHO Expert Committee on Food Additives (see Annex 1,
    Ref. No. 20) in 1969.

         Since the previous evaluation, additional data have become
    available and are summarized and discussed in the following monograph.
    The previously published monograph has been expanded and is reproduced
    in its entirety below.



         Silica, silicic acid and the calcium, magnesium and aluminium
    salts occur ubiquitously in the environment and some have been used
    for many years medically. Food contains various amounts of SiO2, for
    example: potatoes 10.1, milk 2.1, drinking-water 7.1, mineral-water
    22.5, beer 131 gammaSiO2 per g or cm3 (Baumann, 1960).

         Very small amounts of silica are normally present in all body
    tissues but there is no evidence that they play any physiological

         Silicic acid is a normal constituent of the urine, where it is
    found as early as a few days after birth. The amount excreted in the
    urine, which varies considerably according to the diet, is in the
    order of 10 to 30 mg per day (Thomas, 1965). The silica content of
    human tissue varies from 10 to 200 mg/100 g dry weight (spleen 15 mg,
    lung 140 mg) (Anon., 1964). The normal level of silicic acid in human
    blood is below 1 µg SiO2/cm3; the concentration in the corpuscles is
    practically the same as that in the plasma. Silicic acid is present in
    plasma in a molybdate reactive form and is not bound to protein or any
    other substance of high molecular weight. Ingested monomeric silicic
    acid rapidly penetrates the intestinal wall and becomes distributed
    throughout the whole extra-cellular fluid. It enters the blood
    corpuscles at a slower rate (Baumann, 1960).

         Silica dust was administered intragastrically to rabbits and dogs
    leading to a rise in urinary silica output without significant
    variation in blood silica levels. Considerable absorption took place
    with peak excretion in dogs occurring between four to eight hours
    after administration. There appears to be little retention in any
    organ of the body even if animals ingest large amounts of silicates in
    their food. Intragastric 5% silicic acid administered to dogs leads to
    considerable absorption and urinary excretion, peak excretion

    occurring between three to eight hours after dosing. I.v. infusion of
    neutralized sodium silicate (1 mg/ml) in dogs leads to rapid urinary
    elimination of about 50% of the dose (King et al., 1933).

         Rats receiving silica flour, powdered sand or magnesium
    trisilicate orally in large amounts were shown to have crystals of
    these substances in uninflammated myocardium. Entry was via the
    intestinal epithelium (Reimann et al., 1965, 1966). Using
    histochemical techniques lysosomal damage was demonstrated in
    macrophages which had ingested silica particles (Nadler & Goldfischer,

         Administration of 5 g of the siliceous materials listed below in
    20 ml of milk by stomach tube to cats showed the following urinary
    excretion within 120 hours; silicic acid (fresh) 43.3, calcium
    silicate 37.2, magnesium trisilicate 34.1, silicic acid (moist) 29.0,
    SiO2 (quarz) (air sediment very fine) 20.8, magnesium silicates
    (talc) 9.2, diatomaceous earth 8.8 and calcium silico aluminate
    hydrate (kaolin) 7.6 mg SiO2. From this it can be observed that free
    silica is attacked to a variable extent depending on its physical and
    chemical condition. Several silicates are apparently unattacked, as
    nontreated animals excreted an average of 8.6 mg in 120 hours. Some
    complex silicates appear to suffer partial decomposition by the
    hydrochloric acid of the stomach, with partial solution of some of the
    products in the intestine (King & McGeorge, 1938).

         "Quarz water" (water in which silicic acid had been dissolved as
    a result of contact with quarz powder) given to rats over a prolonged
    period as the only source of liquid intake did not show any SiO2
    storage in tissues (Klösterkotter, 1956).

         In vitro investigations on slices of tissue showed that
    monomeric silicic acid penetrated liver and kidney cells easily,
    whereas spleen and muscle cells were more or less impenetrable
    (Kirsch, 1960).

         Ten gamma monomeric SiO2/cm3 was shown in vitro to damage the
    enzymes of isolated mitochondria in rat liver (Hanger et al., 1963).

         Very small amounts of silica are normally present in all body
    tissues. Recently it was found that silicon meets the criteria for an
    essential trace element in the chick (see short-term studies).


    Special studies on carcinogenicity

         See under long-term studies.

    Special studies on reproduction


         A two-generation reproduction study with the oral administration
    of 100 mg/kg bw per day amorphous silica to rats was conducted
    simultaneously. The parent generation (one male and five females)
    produced five litters with a total of 25 rats. Half a year later one
    male and five females of the first generation were mated; the number
    of animals in the second generation was 21. Neither malformation nor
    any other adverse effects were noted (Mosinger, 1969).

    Acute toxicity

                                   LD50            Reference
         Animal         Route     (mg/kg bw)

         Rat            Oral        3.16           Elsea, 1958a

         The oral LD5 in mice of finely ground silicic acid is >5 g/kg
    bw (Kimmerle, 1968).

         Rabbits receiving 3 mg of silicon in their conjunctival sac
    showed mild irritation for 48 hours (Elsea, 1958a).

         The probable lethal dose of silica (oral) for man is over 15 g/kg
    bw. The probable oral lethal dose of magnesium trisilicate for man is
    over 15 g/kg bw. There is some doubt as to whether large doses cause
    laxation. The probable oral dose for man of sodium silicate lies lower
    at between 0.5 and 5 g/kg and may well be due to its alkalinity
    (Anon., 1964). Data on inhalation toxicity of silica and silicates are
    not relevant to consideration of toxic hazard by the oral route.

    Short-term studies


         Oral administration of 50 mg amorphous silica to rats for three
    months did not cause any toxic effects but no experimental details are
    available (Malten & Zielhuis, 1964). Micronized silica gel was fed to
    four groups of 10 male rats each in their diet at 0%, 0.2%, 1.0% and
    2.5% levels for 28 days. No adverse effects on mortality or abnormal
    gross autopsy findings were discovered. Body weight gain was
    significantly reduced at the 2.5% level and nearly significantly at
    the 1.0% level. No other parameters were examined (Keller, 1958).

         Fifteen male and 15 female rats received daily 50 mg of amorphous
    polymeric silicone dioxide (99.8 SiO2 content of water-free compound)
    by stomach tube for three months. There was no adverse effect on body
    weight gain and mortality. Pathology of organs not enumerated showed
    no abnormalities in comparison with the controls (Kuschinsky, 1955).

         Groups of 15 male and 15 female rats were fed diets containing
    silica at concentrations of 0.0, 1.0, 3.0 and 5.0% for 90 days.
    A fifth positive control group received a diet containing 3.0%
    cosmetic talc. No evidence of systemic toxicity caused by silica was
    found in terms of survival, body weights and food consumption. No
    appreciable deposition of silicon dioxide was seen in the kidney,
    livers, spleen, blood and urine in the animals fed at the 5% level. No
    gross or microscopic pathology attributable to silicon were seen
    (Elsea, 1958b).

         The same compound was fed to 20 male and 20 female rats at a
    concentration of 500 mg/kg bw per day for six months. The same number
    of animals served as the control. After four-and-a-half months five
    females were mated. No adverse effects were noted on mortality, body
    weight gain, haematology (haemoglobin, erythroctye- and leucocyte-
    count) and reproductive performance. Histopathology of stomach,
    intestines, pancreas, liver and kidney of the test group showed no
    significant difference to that of the control group. Litter size,
    birth weight and morphological development of the offspring as well as
    weight gain were normal (Leuschner, 1963).

         In a similar experiment (see Leuschner, 1963) the same results
    were obtained when feeding a hydrophobic preparation of amorphous
    polymeric SiO2 in which some of the silanol groups on the surface
    reacted with dimethyl-dichlorosilane (98.5% SiO2 content of water-
    free compound) (Leuschner, 1965).

         The compound (see Leuschner, 1965) was also fed to groups of five
    male and five female rats at levels of 0, 500, 1000, 2000 mg/kg bw for
    five weeks. The highest level was raised after 14 days to 4000, after
    28 days to 8000 and after 42 days to 16 000 mg/kg bw. When the level
    was raised to 16 g/kg, all animals lost weight and four animals died.
    Seven days after the level had been raised to 8000 mg/kg, the animals
    did not gain weight normally. At 1000 mg/kg two rats out of 10 showed
    slight changes in the liver epithelia. At higher levels atrophy of the
    liver epithelia, regression of the basophilic structure and glycogen
    content were observed. Histopathology of other organs (not enumerated)
    including the kidney of the animals at all levels showed no
    significant changes compared with the controls (Leuschner, 1964).

         Fifteen rats of each sex were fed one of the four silicon
    compounds (silicon dioxide, aluminum silicate, sodium silicate and
    magnesium trisilicate) for four weeks at the same levels used in the

    dog experiment (see below). Polydipsia, polyuria, and soft stools,
    seen intermittently in a few animals fed magnesium trisilicate or
    sodium silicate, were the only clinical symptoms observed. No
    compound-related lesions were seen in any of the rats (Newberne &
    Wilson, 1970).


         The dermal effects of silica was tested on groups consisting of
    two male and two female rabbits at levels of five and 10 g/kg/day. A
    negative control group received methyl cellulose solution (0.5% w/w)
    and a positive control group received 10 g/kg/day of cosmetic talc.
    Applications were made five days/week for three weeks. No evidence of
    systemic toxicity caused by silica was found in terms of body weight,
    behaviour, silicon content of blood, urine, spleen, liver and kidney.
    No gross or microscopic pathology was seen in the major organs
    examined or in the skin (Elsea, 1958c).


         Pure-bred beagles of both sexes about six months of age were
    fed either silicon dioxide, aluminum silicate, sodium silicate or
    magnesium trisilicate for four weeks. The doses used provided
    approximately equivalent amounts of silicon dioxide as the end product
    (0.8 g/kg/day). Group sizes ranged from six to nine dogs of each sex.
    Polydipsia and polyuria were observed in a few animals fed sodium
    silicate and magnesium trisilicate. All clinical tests on blood and
    urine were within normal limits. However, histopathologic studies
    revealed characteristic renal lesions in all dogs fed sodium silicate
    or magnesium trisilicate but none in the other groups. The lesions
    were visible grossly in all but one animal (Newberne & Wilson, 1970).


         Day-old deutectomized cockerels were kept in a trace element
    controlled environment and fed a synthetic low silicon diet. The diet
    of the test groups was supplemented with sodium metasilicate
    (Na2SiO3œ9H2O) at a level of 100 mg/kg. 114 chickens were in the
    control groups and 114 chickens in the test groups. Growth rates and
    the appearance of the animals were evaluated at two- to three- day
    intervals. The animals were killed at the end of a 25- to 35- day
    period. Gross pathology and histological examinations were carried out
    on the organs of each chick. Differences between the chicks on the
    basal and silicon-supplemented diets were noted after one to two
    weeks. At the twenty-third day of the study the average weight for the
    low silicon group was 76 g compared to a weight of 116 g for the
    supplemented group (p <0.02). The average daily weight gain for the
    control groups was 2.57 g and that of the test groups reached 3.85 g
    (p < 0.01). The animals on the basal diet were smaller and all their

    organs appeared relatively atrophied as compared to the test chickens.
    The leg bones of the deficient birds were shorter, of smaller
    circumference and thinner cortex. The metatarsal bones were relatively
    flexible and the femur and tibia fractured more easily under pressure
    than those of the supplemented group. Thus the effect of silicon on
    skeletal development indicates that it plays an important role in an
    early stage of bone formation (Carlisle, 1972).

    Long-term studies


         Twenty male and 20 female Wistar rats, with starting weights of
    70 g, received daily one feed pellet containing amorphous silica
    (>98.3% SiO2) prior to feeding for two years. The silica content of
    pellets was regularly adjusted in order to ensure a steady consumption
    of 100 mg/kg bw per day. The animals were fed a synthetic diet. At the
    end of two years the survival rates of both male and female rats were
    100%. No adverse effects on behaviour, clinical signs and weight gain
    were noted. The pathologic results of test groups were comparable with
    those of the controls. No evidence of carcinogenic effects was


         A single dose of 50 mg of monomeric silicic acid in 50 cm3
    liquid was tolerated by two volunteers. Higher doses should be taken
    either with more liquid or at intervals of about 20 minutes in order
    to avoid polymerization of silicic acid in the urine (Baumann, 1960).
    A single dose of 2.5 g of amorphous polymeric silicon dioxide to
    volunteers did not significantly raise the SiO2 excretion in the
    urine thus suggesting poor absorption of the compound (Langendorf,

         The mean 24-hour excretion of SiO2 in five male subjects on
    regular diet was 16.2 mg. The value varied widely and was related to
    the amount of SiO2 in the diet. Urinary silica excretion was
    increased in healthy subjects when Mg2Si3O8 n H2O was taken by
    mouth (Page et al., 1941).

         Sixty to 100 g daily for three to four weeks of 12% amorphous
    silicic acid administered orally to patients suffering from gastritis
    or enteritis were tolerated without adverse effects. Only one-
    thousandth of the substance administered was excreted in the urine
    (Sarre, 1953).

         In experiments with two volunteers, it was shown that, after
    ingestion of 50 mg of monomeric silicic acid in 50 cm3 liquid, the
    renal excretion of SiO2 per time unit was not related to the quantity
    of urine excreted in the same time unit. Maximum excretion appeared

    after one to two hours. Even at high concentrations up to more
    than 700 µg SiO2/cm3 urine, the silicic acid was still present
    in a molybdate reactive form. Silicic acid polymerizes above
    100-150 gammaSiO2/cm3. The speed of polymerization is dependent on
    pH and concentration. The experiment was designed so as to exclude
    damage to the urinary tract through precipitation of proteins by
    polymeric silicic acid formed by polymerization of monomeric silicic
    acid at high concentrations. If the urine at concentrations in the
    order of 700 gammaSiO2/cm3 was taken at longer intervals, such as
    two hours, the concentration of monomeric silicic acid was below the
    total SiO2 concentration, thus suggesting that some polymerization
    had taken place. There was indication of storage breakdown of
    reabsorption (Baumann, 1960).

         Oral administration of a single dose of 2.5 g of amorphous
    polymeric silicon dioxide (99.8% SiO2 content of the water-free
    compound) to 12 volunteers caused a slight but statistically
    insignificant increase in the silicon dioxide level of the urine
    (Langendorf et al., 1966).

         Observations in humans indicated that various conditions such as
    lung diseases, chronic diseases and especially growth retardation in
    children were associated with silicon deficiency. Therefore he
    recommended silicon therapy for conditions characterized by under-
    developed and/or damaged mesenchymal tissues (Monceaux, 1973).


         The available data on orally administered silica and silicates,
    including flumed silicon dioxide, appear to substantiate the
    biological inertness of these compounds. Any silicate absorbed is
    excreted by the kidneys without evidence of toxic cumulation in the
    body, except for the reported damage to dog kidney by magnesium
    trisilicate and sodium silicate. Methods for estimating silica in body
    tissues have been greatly improved in recent years making some of the
    earlier data somewhat less valuable. A number of short-term studies in
    two species are available.

         Talc and magnesium silicate are specified free from asbestos-like
    particles. This stipulation is made while acknowledging the fact that
    existing methods for estimating asbestos-like particles in talc and
    magnesium silicate are not yet fully adequate.


    Estimate of acceptable daily intake for man

    (a)  Silicon dioxide and certain silicates except magnesium silicate
    and talc:

         Not limited.*

    (b)  Magnesium silicate and talc:

         Temporarily not limited.*


         Required by June 1976.

    (1)  For magnesium silicate studies to elucidate the reported kidney
    damage in dogs. Long-term feeding studies on talc demonstrated to be
    free from asbestos-like particles.

    (2)  A satisfactory method for estimating asbestos-like particles in
    talc and magnesium silicate.


    Anonymous (1964) Unilever Research Laboratory, Report No. CH 64888,
         dated 21 October 1964

    Baumann, H. (1960) Hoppe-Seylers, Z. physiol. Chemie., 320, 11

    Carlisle, E. M. (1972) Silicon: an essential element for the chick,
         Science, 178, 619

    Elsea, J. R. (1958a) Unpublished report, January 8, from Hazleton
         Laboratories, Inc.

    Elsea, J. R. (1958b) Unpublished report, July 11, from Hazleton
         Laboratories, Inc.

    Elsea, J. R. (1958c) Unpublished report, May 6, from Hazleton
         Laboratories, Inc.

    Hanger, R., Kirsch, K. & Standinger, Hj. (1963) Beitr. Silikose
         Forsch. S-Bd Grundfragen Silikoseforsch Bd, 5, 69


    *    See relevant paragraph in the seventeenth report (pages 10-11).

    Keller, J. G. (1958) Unpublished report to W. R. Grace & Co.

    Kimmerle (1968) Unpublished report submitted by Bayer

    King, E. J., Stantial, H. & Dolan, M. (1933) Biochem. J., 27, 1002

    King, E. J. & McGeorge, M. (1938) Biochem. J., 32, 426

    Kirsch, K. (1960) Beitr. Silikose-Forsch. S-Bd. Grundfragen der
         Silikoseforsch., 4, 33

    Klosterkötter (1956) Diskussionsbemerkung, Beitr. Silikose-Forsch. S
         Bd. Grundfragen Silikoseforsch. Bd., 2, 348

    Kuschinsky, G. (1955) Unpublished summary report submitted by Degussa

    Langendorf, H. von & Lang, K. (1966) Zeitschrift für Ernührungswis
         senschaft, 8, 27

    Leuschner, F. (1963) Unpublished report submitted by Degussa

    Leuschner, F. (1964) Unpublished report submitted by Degussa

    Leuschner, F. (1965) Unpublished report submitted by Degussa

    Malten, K. E. & Zielhuis, R. L. (1964) Industrial toxicology and
         dermatology in the production and processing of plastics,
         Elsevier, p. 204

    Monceaux, R. H. (1973) La silice, problème biologique médical et
         social de grande actualité, Unpublished report submitted by
         Degussa, Paris

    Mosinger, M. (1969) Unpublished report submitted by Degussa

    Nadler, S. & Goldfischer, S. (1970) J. Histochem. Cytochem., 18, 368

    Newberne, P. & Wilson, R. B. (1970) Proc. Natl. Acad. Sci., 65, 872

    Page, R. C., Hefner, R. R. & Frey, A. (1941) Amer. J. Digest. Dis., 8,

    Reimann, H. A., Imbriglia, J. E. & Ducanes, Th. (1965) Proc. Soc. exp.
         Biol. Med., 119, 9

    Reimann, H. A., Imbriglia, J. E. & Ducanes, Th. (1966) Amer. J.
         Cardiol., 17, 269

    Sarre, H. (1953) Unpublished summary report submitted by Degussa

    Thomas, K. (1965) Dtsch. Zeitschr. f. Verdauungs- u. Stoffwechsel
         Krankheiten, 25, 260

    See Also:
       Toxicological Abbreviations