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    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY

    WORLD HEALTH ORGANIZATION



    TOXICOLOGICAL EVALUATION OF SOME
    FOOD COLOURS, ENZYMES, FLAVOUR
    ENHANCERS, THICKENING AGENTS, AND
    CERTAIN FOOD ADDITIVES



    WHO FOOD ADDITIVES SERIES 6







    The evaluations contained in this publication were prepared by the
    Joint FAO/WHO Expert Committee on Food Additives which met in Rome,
    4-13 June 19741


    World Health Organization     Geneva     1975






              

    1  Eighteenth Report of the Joint FAO/WHO Expert Committee on
    Food Additives, Wld Hlth Org. techn. Rep. Ser., 1974, No. 557.
    FAO Nutrition Meetings Report Series, 1974, No. 54.

    XANTHAM GUM

    BIOLOGICAL DATA

    BIOCHEMICAL ASPECTS

         The caloric availability and digestibility indicated that xantham
    gum is not utilized by the body and the conclusion was substantiated
    by finding that practically all of the gum fed during a seven-day
    period could be accounted for in the faeces (Booth et al., 1963).

         When 14C-labelled xantham gum prepared by fermentation of
    uniformly labelled glucose with xanthomonas campestris was fed to rats
    at a level of 2% (50 mg in total) in the diet a maximum of 15% of the
    label was metabolized to carbon dioxide in 100 hours. In vitro tests
    showed that the acetate content was labile at gastric pH. Acetate and
    pyruvate accounted for only 9.8% of the label in the gum used. The
    finding that 15% of the label was metabolized to carbon dioxide
    indicated that the hexoses were used to a certain extent also. No
    accumulation in tissues were found and the observed metabolism of
    labelled material and distribution of 14C in tissues was that
    expected from feeding a simple 14C-labelled molecule such as acetate
    or a hexose. Analysis of faecal material showed no accumulation of the
    five polysaccharide constituents, except acetate. Some 98% of the
    radioactivity in the faeces could be attributed to unchanged or only
    slightly modified polysaccharide. In vitro tests indicated that
    nonenzymatic hydrolysis and the action of faecal-microorganisms is
    responsible for the initial breakdown of polysaccharide in vivo
    (Gumbmann, sine data).

    TOXICOLOGICAL STUDIES

    Special studies on reproduction

    Rat

         A three-generation reproduction study was carried out using
    groups of 10 male and 20 female rats in the first generation and
    20 male and 20 female rats in subsequent generations. Dosage levels
    of 0, 0.25 and 0.5 g/kg/day were administered in the diet. Criteria
    evaluated were survival, body weights, general appearance, behaviour,
    the number of litters produced, numbers of live births and
    stillbirths, physical condition of young, weight of young at birth and
    weaning and the survival of young. Females that had fewer than two
    litters were examined to determine whether there was foetal
    resorption. Malformations in offspring were recorded and gross and
    micropathological examinations made on the offspring of the second and
    third generations. No adverse effects attributable to xantham gum were
    found in this study (Woodard et al., 1973).

    Acute toxicity
                                                                        

    Animal    Route     LD50         References
                        (mg/kg bw)
                                                                        

    Mouse     oral      > 1 000        Booth et al., 1963

              i.p.      >  50          Booth et al., 1963

              i.v.      100-250        Hendrickson & Booth (sine data)

    Rat       oral      >45 000        Jackson et al., (sine data I)

    Dog       oral      >20 000        Jackson et al., (sine data II)
                                                                        

         Daily application of a 1% solution for 15 days to rat skin
    produced no signs of irritation. Daily application of a 1% solution
    for five days to rabbit conjunctiva produced no signs of irritation.
    Intradermal challenge tests in guinea-pigs did not produce evidence of
    sensitization (Hendrickson & Booth (sine data)).

    Short-term studies

    Rat

         A study was carried out on an unspecified number of rats fed on
    diets containing 7.5% or 10% xantha gum for 99-110 days. No untoward
    effects were observed in extensive investigations on these animals
    (Booth et al., 1963).

         In a 91-day feeding study a reduced rate of weight gain was found
    in groups of rats receiving 7.5% or 15% of xantham gum in the diet.
    Diets containing 3% or 6% gum did not reduce weight gain. No
    significant alterations in haemoglobin, red and white cell counts, and
    organ weights were observed in these rats. Histological examination of
    tissues from rats at the 15% level showed no pathological effects. At
    the highest dosage level the animals produced abnormally large faecal
    pellets but diarrhoea did not occur. A paired-feeding test was used to
    compare the growth of rats ingesting a diet containing 7.5% xantham
    gum and comparable rats restricted to the same intake of control diet.
    No difference in weight gains was found at the end of 18 days,
    indicating the absence of a growth-inhibiting factor (Booth et al.,
    1963).

    Dog

         Four groups of two male and two female young adult beagle dogs
    were fed for two weeks on diets providing 0, 1 or 2 g/kg bw/day of
    xantham gum or 2 g/kg/day of cellulose powder. Persistent diarrhoea
    occurred in dogs receiving the 2 g/kg/day xantham gum and occasional
    diarrhoea in those receiving 1 g/kg/day. All dogs, including controls,
    lost weight but the weight loss was most marked in animals receiving
    xantham gum. The red blood cell count, haemoglobin concentration and
    serum cholesterol were lowered and the relative adrenal weight
    increased in dogs receiving 2 g/kg/day xantham gum. These effects were
    considered to be due to the persistent diarrhoea in this group. Liver
    and kidney function tests indicated no disturbance in the function of
    these organs. Extensive gross and histopathological examination failed
    to detect lesions which could be attributed to ingestion of the gum
    (Robbins et al., 1964).

         Groups of three male and three female beagle dogs were fed on
    diets supplying 0, 0.25 and 0.5 g/kg bw/day of xantham gum for 12
    weeks. Animals receiving the 0.5 g/kg level had softer stools than
    normal but no diarrhoea. Growth was slightly retarded in the males and
    the serum cholesterol level was lowered in both sexes of the group
    receiving 0.5 g/kg/day. No other untoward effects were seen. The no-
    untoward-effect-level in this test was considered to be 0.25 g/kg/day
    (Research report, 1964).

         Xantham gum was administered in the diet at levels supplying 0,
    0.25, 0.37 and 1.0 g/kg bw/day to groups of four male and four female
    beagle dogs for 107 weeks. No effects attributable to administration
    of gum were seen in the treated animals with regard to survival, food
    intake, body weight gain, ECG, blood pressure, heart rate, body
    temperature, and ophthalmic and neurological examinations. The
    haemoglobin, total and differential white cell counts, coagulation and
    prothrombin times, thrombocyte counts, serum alkaline phosphates,
    blood urea nitrogen, blood glucose, SGOT and SPGT were the same in
    control and treated animals. Urine pH, glucose and sediment contents
    were comparable with controls but there was a dose related increase in
    urine SG and a more frequent appearance of urinary albumin in dogs
    consuming 1.0 g/kg/day of gum. Stool consistency was normal at the
    0.37 g/kg level but loose at the top dosage level. The weight of
    faeces showed a dose-related increase, as would be expected from
    feeding a non-absorbed hydrophilic gum at high dosage levels. The
    increased urinary SG is consistent with physiological adjustment for
    the extra water excreted in the faeces. Examination of the appearance
    and weights of organs and histopathological examinations failed to
    detect any untoward effects of treatment with xantham gum at any
    dosage level (Woodard et al., 1973).

    Long-term studies

    Rat

         Groups of 30 male and 30 female rats were fed on diets for 104
    weeks supplying 0, 0.25, 0.5 or 1.0 g/kg bw/day of xantham gum. No
    abnormalities which could be attributed to ingestion of these
    experimental diets were found with regard to survival, body weight
    gain, food consumption, behaviour and appearance. Ophthalmic and
    haematologic examination yielded normal results. Analysis of blood for
    glucose, SGOT and prothrombin time showed no abnormalities in test
    groups. Organ weights were within normal limits and no lesions
    attributable to xantham gum were found on gross and histopathological
    examination (Woodard, 1973).

    Comments:

         Studies indicate that this polymeric material is poorly absorbed.
    It is partially degraded at gastric pH and probably also by intestinal
    organisms in the rat. Molecules, or parts of the molecule which are
    absorbed, are metabolized by normal energy-forming pathways. There is
    no evidence of accumulation of the substance in tissues. At high
    dosage levels it causes diarrhoea in dogs which was considered not
    unusual for a hydrophilic gum. The possibility of this effect
    occurring in man has been considered but use as food additive
    according to general principles should preclude this. An adequate two-
    year test in rats failed to show any carcinogenicity attributable to
    the material. The reproduction study on rats revealed no untoward
    effects.

    EVALUATION

    Level causing no toxicological effect

         Rat: 1000 mg/kg bw

    Estimate of acceptable daily intake for man

         0-10 mg/kg bw

    REFERENCES

    Booth, A. N., Hendrickson, A. P. & DeEds, F. (1963) Toxicol. appl.
         Pharmacol., 5, 478

    Gumbmann, M. R., Research Report "Metabolism of 14C Polysaccharide
         B-1459 by the Rat", Western Regional Research Laboratory, Albany,
         California

    Hendrickson, A. P. & Booth, A. N., Research Report "Supplementary
         acute toxicological studies of polysaccharide B-1459", Western
         Regional Research Laboratory, Albany, California

    Jackson, N. N., Woodard, M. W. & Woodard, G., Research Report "Xantham
         gum, acute oral toxicity to rats", Woodard Research Corporation

    Jackson, N. N., Woodard, M. W. & Woodard, G., Research Report "Xanthan
         gum, acute oral toxicity to dogs", Woodard Research Corporation

    Research Report (1964) "Safety evaluation of polysaccharide B-1459
         (xanthan gum) in laboratory animals - effects of feeding to dogs"
         Western Regional Research Laboratory, Albany, California

    Robbins, D. J., Moulton, J. E. & Booth, A. N. (1964) Food. Cosmet.
         Toxicol., 2, 545

    Technical bulletin on Keltral, Kelco Co., San Diego, California,
         United States of America

    Woodard, G. et al. (1973) Toxicol. appl., Pharmacol., 24, 30


    See Also:
       Toxicological Abbreviations