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    ARABIC GUM (Gum Arabic)

    Explanation

         This substance was last evaluated for acceptable daily intake for
    man by the Joint FAO/WHO Expert Committee on Food Additives in 1969
    (see Annex I, Ref. 19). A toxicological monograph was issued in 1970
    (see Annex I, Ref. 20).

         Additional data have become available and are summarized and
    discussed in the following monograph. The previous monograph has been
    expanded and is reproduced in its entirety below.

    BIOLOGICAL DATA

    BIOLOGICAL ASPECTS

    Absorption and metabolism

         Based on food and caloric intake, arabic gum fed to weanling male
    Sprague-Dawley rats at dietary levels of 0.5 and 2.0 g/day was
    reported to have caloric values of 131% and 110% of corn starch,
    respectively (Nees, 1965).

         Arabic gum is almost completely digested by guinea-pigs (O'Dell
    et al., 1957).

         At dietary levels of less than 10%, arabic gum is fully absorbed
    with a caloric equivalent of 4 calories per gram (Shue et al., 1962).

    Effects on enzymes and other biochemical parameters

         Groups of female ZUR:SIV-Z strain rats, initial body weight
    100-110 g, were gavaged twice daily, 5 days per week for 4 weeks with
    20, 40 or 200 mg/kg of arabic gum as an aqueous suspension. Groups
    of 4 rats were killed at various time intervals and oxidative
    phosphorylation in isolated liver and heart mitochondria was assayed
    as well as mixed function oxidase activity in liver endoplasmic
    reticulum. A dose-dependent uncoupling of oxidative phosphorylation in
    heart and liver mitochondria was reported in the arabic gum groups.
    significant reductions occurred within 2 days to 2 weeks depending on
    the dose. As the feeding of arabic gum continued, liver mitochondria
    isolated from test animals appeared to recover. Recovery did not occur
    in the isolated heart mitochondria at the mid-dosage level. At the
    high-dose level as feeding of test animals continued, there was
    partial recovery in the isolated heart mitochondria followed by
    another decline. The mid- and high-dose levels of arabic gum were
    reported to cause a progressive decline in hepatic mixed function
    oxidase activity, while no effect was noted at the low dose (Bachman
    et al., 1978).

         Another study similar to the preceding one was carried out in
    female rats (ZUR:SIV-Z strain), golden hamsters (ZUR:LAK-Z strain),
    and mice (ZUR;ICR-Z strain). In mice and hamsters, there was an
    initial decrease in hepatic biphenyl hydroxylation; however, enzyme
    activity returned towards control values as the experiment progressed.
    In the rat, biphenyl hydroxylase activity went down and did not
    recover. Hepatic cytochrome b5 and P450 levels were also measured;
    levels of these proteins were not affected by arabic gum dosing in the
    rat. However, cytochrome b5 levels were depressed by the treatment in
    hamsters, while in mice there was a transient decrease in both
    cytochrome P450 and b5 levels (Bachman & Zbinden, 1978).

         Female rats (ZUR:SIV-Z strain) dosed by gavage with 200 mg/kg of
    gum arabic twice daily for 3 or 4 days showed an inhibition of
    phenobarbitol-stimulated aminopyrine demethylation as compared to
    animals not receiving gum arabic (Lutz et al., 1978).

         Groups of 10 Sprague-Dawley rats received 0 or 5% of arabic
    gum in a 0.2% cholesterol-supplemented diet. A tracer dose of
    14C-labelled cholesterol was included in the animals' last meal. The
    animals fed arabic gum had significantly lower absorption of labelled
    cholesterol, although there was no effect on total carcass, serum or
    liver concentrations of cholesterol. However, uptake of 14C-labelled
    cholesterol in liver and carcass was reduced. Arabic gum was
    associated with an increase in total cholesterol biosynthesis (Kelly &
    Tsai, 1978).

    TOXICOLOGICAL STUDIES

    Special studies on carcinogenicity

    Mouse

         Groups of 50 male and 50 female B6C3F1 mice were given arabic gum
    in the diet at concentrations of 0, 25 000 or 50 000 ppm (0, 2.5 or
    5.0%) for 103 weeks. The animals were maintained on a control diet for
    an additional 2 weeks prior to sacrifice. No effect of the test
    compound on body weight gain was noted in either sex, although mean
    daily food consumption was reduced in both sexes of the groups
    receiving arabic gum. No effect of the test compound was noted with
    respect to survival, clinical signs, or incidence of gross or
    microscopic non-neoplastic lesions. Hepatocellular adenoma of the
    liver was found in 2/49 controls, 0/50 low-dose and 6/49 high-dose
    females. Hepatocellular carcinomas were found in 1/49 controls, 2/50
    low-dose and 6/50 high-dose females. The number of female mice with
    hepatocellular adenoma, carcinoma or unspecified neoplasm of the liver
    were 4/49, 2/50 and 10/49 in controls, low-dose and high-dose animals,
    respectively. Some high-dose animals had both a hepatocellular adenoma
    and a hepatocellular carcinoma. The historical records at the
    performing laboratory indicate the incidence of control female B6C3F1

    mice with adenomas or carcinomas of the liver has been 56/975 (5.7%)
    with a range of 1/50 to 11/54 (2-20.3%). Male mice given arabic gum
    did not have an increased incidence of liver tumours. The incidence of
    mice with haemangiomas or haemangiosarcomas of the circulatory system
    was not significant in either sex. The conclusion of the study was
    that there was no site at which an increase in tumour incidence could
    be clearly associated with the administration of the chemical
    (National Toxicology Program, 1980).

    Rat

         Groups of 50 male and 50 female Fischer 344 rats were given gum
    arabic in the diet at concentrations of 0, 25 000 or 50 000 ppm
    (0, 2.5 or 5.0%) for 103 weeks. The animals were maintained on the
    control diets for an additional 2 weeks prior to sacrifice. In the
    males, body weights of test and control animals were comparable
    throughout the study, while in the females, weight gain in the test
    animals was slightly less than that of controls. The effect was not
    dose related. As compared to controls, feed intake was reduced in test
    males and test females. No effects of the test compound were reported
    with respect to clinical signs, survival, or incidence of gross or
    microscopic lesions (National Toxicology Program, 1980).

    Special studies on mutagenicity

         Gum arabic did not produce a measurable mutagenic response or
    alteration in the recombination frequency for Saccharomyces
    cerevisiae in either the host-mediated assay or in vitro.
    Similarly, no mutagenicity was reported with gum arabic either in the
    host-mediated assay or in vitro using Salmonella strains G-46 or
    TA-1530.

         Cultures of bone marrow metaphase chromosomes taken from rats
    dosed in vivo with 50 mg or 2.5 g/kg of arabic gum showed an
    increased incidence of chromosomal breaks occurring within 6 hours of
    treatment. Similar effects were found in vitro with human WI-38
    embryonic lung cells.

         Gum arabic was tested using the dominant lethal gene test in
    Sprague-Dawley rats. Males were given 0, 30, 2500 or 5000 mg/kg by
    gavage in a water suspension. A significant increase in dead implants
    was noted in pregnant females mated to males given a single dose of
    5000 mg/kg at the third week of the study. No other significant
    effects were recorded and arabic gum was considered not to be a
    mutagen in this study (Newell & Maxwell, 1972).

         No genetic activity was noted in in vitro mutagenic tests with
    Saccharomyces cerevisiae strain D4 and Salmonella typhimurium
    strains TA-1535, TA-1537 and TA-1538. Both suspension and plate test
    were used, with and without activation. Activation systems were
    prepared from liver, lung, kidney and testes from male mice, rats and
    monkeys (Brusick, 1975).

         Gum arabic was concluded to be not mutagenic based on the sex-
    linked dominant lethal test in Drosophila (Valencia & Abrahamson).

    Special observations on sensitivity

         Sensitivity to arabic gum was found to be a true antigen-antibody
    response in the guinea-pig (Rice, 1955; Silvette et al., 1955).

    Special studies in teratology

         Groups of 21-24 pregnant Wistar-derived rats were dosed by gavage
    on days 6 through 15 of gestation with 0, 16, 75, 350 or 1600 mg/kg of
    arabic gum suspended in corn oil. No compound-related effect was
    observed on nidation, maternal or foetal survival, or on the incidence
    of hard or soft tissue anomalies occurring in the offspring. The
    average foetal weight at birth was slightly depressed in the high-dose
    group.

         Groups of 19-21 pregnant CD-1 mice were dosed by gavage on days 6
    through 15 of gestation with 0, 16, 75, 350 or 1600 mg/kg of arabic
    gum suspended in corn oil. No compound-related effect was observed on
    nidation, maternal or foetal survival or on the incidence of hard or
    soft tissue anomalies occurring in the offspring. The average foetal
    weight at birth was slightly depressed in the high-dose group.

         Groups of 19-21 pregnant outbred golden hamsters were dosed by
    gavage on days 6 through 10 of gestation with 0, 16, 75, 350 or
    1600 mg/kg of arabic gum suspended in corn oil. No compound-related
    effect was observed on nidation, maternal or foetal survival or on the
    incidence of hard or soft tissue anomalies occurring in the offspring.

         Groups of 12-14 pregnant Dutch-belted rabbits were dosed by
    gavage with 0, 8, 37, 173 or 800 mg/kg of arabic gum suspended in corn
    oil on days 6 through 18 of gestation. The administration of up to 
    37 mg/kg of the test material as a suspension in anhydrous corn oil 
    had no clear effect on nidation or on maternal or foetal survival. 
    The number and type of abnormalities seen in foetal soft or skeletal
    tissues derived from this group of does did not differ from the number
    occurring spontaneously in the sham-treated controls. However, in 2
    groups of dams dosed at 173 and 800 mg/kg bw respectively, maternal
    toxicity ensued with the loss of a majority of animals in the
    800 mg/kg group. Death was preceded by severe bloody diarrhoea,
    urinary incontinence, with anorexia for 48-72 hours terminally. At

    autopsy no gross pathological findings were seen other than
    haemorrhage in the mucosa of the small intestines. Does which survived
    the highest dose and bore living young to term remained outwardly
    normal, and the offspring were likewise normal in all respects. It was
    concluded that this test substance was not a teratogen in the rabbit
    under the test conditions employed (Morgareidge, 1972).

    Acute toxicity
                                                         
                            LD50
    Animal      Route     (g/kg bw)       Reference
                                                         

    Mouse       Oral        16.0      Morgareidge, 1972

    Rat         Oral        18.0      Morgareidge, 1972

    Hamster     Oral        16.0      Morgareidge, 1972

    Rabbit      Oral         8.0      Morgareidge, 1972
                                                         

    Short-term studies

    Mouse

         Groups of 10 male and 10 female B6C3F1 mice were fed diets
    containing 0, 6300, 12 500, 25 000, 50 000 or 100 000 ppm (0, 0.63,
    1.25, 2.5, 5.0 or 10%) of arabic gum in the diet for 13 weeks. No
    compound-related effects on survival or gross or microscopic pathology
    were noted. Final body weights and feed consumption tended to be
    slightly lower in the dosed animals (National Toxicology Program,
    1980).

    Rat

         Groups of rats were fed 0 or 15% arabic gum in their diet for 62
    days. A cathartic effect was observed, but weight gain, food
    efficiency, haematological findings and organ weights were normal
    (Booth et al., 1963).

         Groups of 10 male and female Fischer 344 rats were fed diets
    containing 0, 6300, 12 500, 25 000, 50 000 or 100 000 ppm (0, 0.63,
    1.25, 2.5, 5.0 or 10%) gum arabic in the diet for 13 weeks. No
    compound-related effects on survival or gross or microscopic pathology
    were noted. Feed consumption was reduced at the 2 highest doses in the
    males, and at all the doses in the females. Final body weights tended
    to be slightly lower in the dosed animals (National Toxicology
    Program, 1980).

    Guinea-pig

         Groups of 10 and 20 guinea-pigs were fed 15% powdered arabic gum
    for 6 weeks. Controls received no bulk food in their diet. Weight gain
    was improved in the test groups (Booth et al., 1949).

    Rabbit

         A group of 4 rabbits was given 20% arabic gum in a casein diet
    for 4 weeks. Weight gain improved significantly in the test groups
    (Hove & Herndon, 1957).

    Dog

         Three dogs were given 32-35 intravenous injections of acacia over
    a period of 76 days at a total cumulative dosage ranging from 15.7 to
    47.7 g/kg. The dog on the largest dose died with an enlarged liver.
    Cause of death, 4 months after its last injection, was not explanable.
    The other two dogs remained in good condition; biopsy showed acacia
    present in their livers 26 months after their last injections (Smalley
    et al., 1945).

    Man

         Nine patients with nephrotic oedema received 1-6 intravenous
    injections of acacia over periods up to 8 weeks, with total doses
    ranging from 80 to 325 g. There were no signs or symptoms of liver
    enlargement, and no other complications. Five of these patients
    excreted in the urine 5.5-38% of a single dose during periods ranging
    from 10 to 30 days, respectively (Johnson & Newman, 1945).

    OBSERVATIONS IN MAN

         Sensitivity reactions have been reported in man, e.g., asthma in
    printers (Brown & Crepea, 1947; Bohner et al., 1941; Sprague, 1942;
    Fowler, 1952).

         Occupational exposure to arabic gum has been associated with
    rhinitis and asthma in sensitive individuals (Cuthbert, 1973).

         Sensitivity to arabic gum as a tablet additive has been reported
    in some kidney transplant patients. Hypersensitivity manifested as
    itching, and rash with fever and arthralgia was also reported in
    individual patients (Rubinger et al. 1978). Sensitivity of some
    individuals to gum arabic in food has also been reported (Gelfand,
    1949).

    Comments

         Metabolic studies are limited, but it has been demonstrated that
    in the rat this gum is completely metabolized when it comprises less
    than 10% of the diet. Mitochondrial preparations isolated from the
    liver or hearts of rats maintained on diets containing arabic gum
    showed a dose- and time-dependent uncoupling of oxidative
    phosphorylation. Hepatic mixed function oxidase activity was also
    depressed. Changes were also reported in hepatic cytochrome b5 and
    P450 levels in the liver of test animals maintained on diets
    containing arabic gum. The significance of these effects is not known,
    since inclusion of arabic gum in the diet of test animals at levels
    that cause these effects does not cause a reduction in weight gain,
    which would be expected if uncoupling of oxidative phosphorylation
    occurred.

         Teratology studies were negative in rats, mice, hamsters and
    rabbits, although maternal toxicity was observed at very high dose
    levels in the rabbit.

         Mutagenic studies in a number of systems, including host-mediated
    assay, the Ames test, Saccharomyces cerevisiae, dominant lethal test
    and Drosophila, were negative. Lifetime feeding studies in the rat and
    mouse at 5% of the diet showed no significant adverse effects.

    EVALUATION

    Estimate of acceptable daily intake for man

    Not specified.*

              

    *    The statement "ADI not specified" means that, on the basis of the
         available data (toxicological, biochemical, and other), the total
         daily intake of the substance, arising from its use or uses at the
         levels necessary to achieve the desired effect and from its
         acceptable background in food, does not, in the opinion of the
         Committee, represent a hazard to health. For this reason, and for
         the reasons stated in individual evaluations, the establishment of
         an acceptable daily intake (ADI) in mg/kg bw is not deemed
         necessary.

    REFERENCES

    Bachman, E. et al. (1978) Biochemical effects of gum arabic gum,
         tragacanth, methylcellulose and carboxymethylcellulose in the rat
         heart and liver, Pharmacol., 17, 39-49

    Bachman, E. & Zbinden, G. (1978) Biochemical effects of chronically
         administered suspended agents on mitochondrial metabolism and
         hepatic mixed function oxidases in rat, mice and hamster, Arch.
         Toxicol. Suppl., 1, 183-187

    Bohner, C. B., Sheldon, J. M. & Trenis, J. W. (1941) Sensitivity of
         gum acacia with a report of ten cases of asthma in printers,
         J. Allergy, 12, 290

    Booth, A. N., Elvehjem, C. A. & Hart, E. B. (1949) The importance of
         bulk in the nutrition of the guinea pig, J. Nutr., 37, 263

    Booth, A. N., Hendrickson, A. P. & De Eds, F. (1963) Physiologic
         effects of three microbial polysaccharides on rats, Toxicol.
         Appl. Pharmacol., 5, 478

    Brown, E. B. & Crepea, S. B. (1947) Allergy (asthma) to ingested gum
         tragacanth - a case report, J. Allergy, 18, 214

    Brusick, E. (1975) Mutagenic evaluation of compound FDA 71-15, gum
         arabic. Unpublished. Litton Bionetics, Inc. Contract, 32 pp.
         Contract No. 223-74-2104. Submitted to the World Health
         Organization by the US Food and Drug Administration

    Cuthbert, O. D. (1973) Investigation into an outbreak of rhinitis and
         asthma in a printing works, Ann. Occup. Hyg., 16, 203

    Fowler, P. B. S. (1952) Printer's asthma, Lancet, 2, 755

    Gelfand, H. H. (1949) The vegetable gums by ingestion in the etiology
         of allergic disorders, J. Allergy, 20, 311-321

    Hove, E. L. & Herndon, F. J. (1957) Growth of rabbits on purified
         diets, J. Nutr., 63, 193

    Johnson, J. B. & Newman, L. H. (1945) Intravenous injection of acacia,
         Arch. Intern. Med., 76, 167

    Kelly, J. & Tsai, A. (1978) Effects of pectin, gum arabic and agar on
         cholesterol absorption, synthesis and turnover in rats,
         J. Nutr., 108, 630-639

    Lutz, W. K., Braudle, E. & Zbinden, G. (1978) Effect of gum arabic on
         aminopyrine demethylation in rats, Experientia, 34, 1609-1610

    Newell, G. W. & Maxwell, W. A. (1972) Study of mutagenic effects of
         gum arabic. Unpublished. Standard Research Institute, pp. 31.
         Contract No. FDA 71-267. Submitted to the World Health
         Organization by the US Food and Drug Administration

    Morgareidge, K. (1972a) Acute toxicity studies on gum arabic.
         Unpublished. Food and Drug Research Laboratories, Inc. Contract
         No. FDA 71-260. Submitted to the World Health Organization by the
         US Food and Drug Administration

    Morgareidge, K. (1972b) Teratologic evaluation of FDA 71-15 (gum
         arabic). Unpublished. Food and Drug Research Laboratories, Inc.
         Contract No. FDA 71-260. Submitted to the World Health
         Organization by the US Food and Drug Administration

    National Toxicology Program (1980) Carcinogenesis bioassay of gum
         arabic. Unpublished. National Toxicology Program, Research
         Triangle Park, North Carolina, pp. 134. Submitted to the World
         Health Organization by the US Food and Drug Administration

    Nees, P. W. (1965) Hallmark pure gum arabic No. 1 U.S.P. - evaluation
         of caloric content. Unpublished. In: Wisconsin Alumni Foundation,
         Madison, Wisconsin, pp. 3, (Assay Report No. 4121036. Submitted
         to the World Health Organization by the US Food and Drug
         Administration

    O'Dell, B. L. et al. (1957) Diet composition and mineral balance in
         guinea pigs, J. Nutr., 63, 65

    Rice, C. E. (1955) An investigation of some of the factors determining
         the decrease in complement activity in anaphylactic shock,
         J. Immunol., 75, 85-95

    Rubinger, D., Friedlander, M. & Superstine, E. (1978) Hypersensitivity
         to tablet additives transplant recipients on prednisone,
         Lancet, 2, 689

    Silvette, M., Swinford, O., Jr & Tull, L. (1955) Observations on
         acacia as an immunizing, sensitizing anaphylactogenic and
         desensitizing antigen, J. Allergy, 26, 509-518

    Shue, G. M., Douglass, C. D. & Friedman, L. (1962) Nutritional studies
         of complex carbohydrates, Fed. Proc., 21(2), 91

    Smalley, R. E. et al. (1945) Effect of intravenously administered
         solution of acacia on animals, Arch. Intern. Med., 76, 39

    Sprague, P. H. (1942) Bronchial asthma due to sensitivity to gum
         acacia, Canad. Med. Ass. J., 47, 253

    Valencia, R. & Abrahamson, S. (undated) Drosophila sex-linked
         recessive lethal test on gum arabic. Unpublished. Contract No.
         FDA 223-77-2119, pp. 4. Dept. of Zoology, University of
         Wisconsin. Submitted to the World Health Organization by the US
         Food and Drug Administration
    


    See Also:
       Toxicological Abbreviations
       Arabic gum  (FAO Nutrition Meetings Report Series 46a)
       Arabic gum (WHO Food Additives Series 5)