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    CAROB (LOCUST) BEAN GUM

    Explanation

         This substance was evaluated for acceptable daily intake for man
    by the Joint FAO/WHO Expert Committee on Food Additives in 1969, 1973
    and 1975 (see Annex, Refs. 19, 32 and 37). Toxicological monographs
    were issued in 1970, 1974 and 1975 (see Annex, Refs. 20, 30 and 38).

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

    Introduction

         Carob bean gum (also called locust bean gum) is the material
    separated and variously refined from the endosperm of the seed of the
    carob tree, Ceratonia siliqua, a large leguminous evergreen that
    is widely cultivated in the Mediterranean area. The carbohydrate
    component of carob bean gum is considered to be a neutral
    galactomannan polymer consisting of a main chain of 1,4-linked
    D-mannose units with a side chain of D-galactose on every fourth or
    fifth unit, attached through 1,6-glycosidic linkages to the
    polymannose chain (LSRO/FASEB, SCOGS-3, 1972).

    BIOLOGICAL DATA

    BIOCHEMICAL ASPECTS

         In a bioavailable calorie assay, groups of 10 male weanling rats
    (Sprague-Dawley) were given 5 g basal diet or basal diet plus 0.5, 1,
    2 g sucrose or 0.5, 1, 2 g gum for 10 days. Comparison of the carcass
    weight gain showed that carob bean gum was not a source of
    bioavailable calories (Robaislek, 1974).

         Fifteen controls and 18 male test rats, after three days on
    normal diet followed by a 12-hour fast, received for two-and-a-half
    days in their diet either 67% cocoa butter with wheat flour or 67%
    cocoa butter with 33% carob bean gum. Glycogen accumulated in the
    liver but far less efficiently than with wheat flour (Krantz et al.,
    1948).

         A digestibility study in groups of five male and five female rats
    (Purdue strain) on a mannose-free diet showed that 85-100% of mannose
    fed as 1% carob bean gum in the diet for 18 hours were excreted in the
    faeces over a total of 30 hours. Some decrease in chain length of
    galactomannan may have occurred, probably through the action of the
    microflora as mammals are not known to possess mannosidase. Liberation
    of galactose units was not determined (Tsay & Whistler, 1975).

         Incubation of solutions or suspensions with human gastric juice,
    duodenal juice plus bile, pancreatic juice and succus entericus with
    or without added rabbit small gut membrane enzymes produced no
    evidence of hydrolysis (Semenza, 1975). Rat large gut microflora
    partially hydrolysed carob bean gum in vitro (Towle & Schranz, 1975)
    after conditioning to 14 carob bean gum in the diet for three weeks.

         Groups each of eight male Holtzman rats were maintained on a
    purified synthetic diet, or the diet plus 1% cholesterol, or the diet
    plus 1% cholesterol plus 10% carob bean gum for 28 days. The increased
    liver cholesterol and liver total lipid induced by cholesterol feeding
    was largely counteracted by concurrent feeding of carob bean gum
    (Ershoff & Wells, 1962).

         Groups each of 12 chicks, one day old, were fed a casein sucrose
    basal diet supplement with 34 cholesterol and either 10, 6, 3, 2, 1.5
    or 1.0% locust bean gum for 27 days. At the end of the test period,
    plasma cholesterol was determined. At the 10% level, there was a 35%
    reduction of plasma cholesterol, no significant effect in body
    weight or food consumption. At the 64 level, there was a moderate
    reduction in cholesterol level. There was a wide variation in the
    hypocholesterolaemic activity of the carob bean gums tested with some
    preparations being totally inactive (Fahrenbach et al., 1966).

         The effect of carob or locust bean gum on nitrogen (N) balance
    and dry matter digestibility was studied in rats. Seventy-two weanling
    male Sprague-Dawley rats were divided into a control and five
    experimental groups of 12 animals each. Various gums including locust
    bean gum were fed at the 10% level in a casein-saccharose-corn starch
    diet. Following a three-day adaptation period, feed remnants, urine
    and faeces were collected during an eight-day balance period. Trypsin
    inhibitory activity was measured in each diet. Carob bean gum caused a
    significant rise in faecal N loss, resulting in a marked reduction of
    apparent protein digestibility from 87.8% in the controls to 75%.
    Urinary N was significantly lower than controls. Faecal dry matter was
    also significantly increased by carob bean gum. There was only slight
    trypsin inhibition caused by carob bean gum (Harmuth-Hoene &
    Schwerdtfeger, 1979).

         Carob bean gum has been noted to contain tannins, which depress
    appetite and growth, and trypsin inhibitors, which are also growth
    inhibitory (LSRO/FASEB, SCOGS-3, 1972).

    TOXICOLOGICAL STUDIES

    Special studies on mutagenicity

         Carob (locust) bean gum was evaluated for genetic activity in
    microbial assays with and without the addition of mammalian metabolic

    activation preparations. Indicator organisms used were Saccharomyces
    cerevisiae and Salmonella typhimurium, strains TA-1535, TA-1537
    and TA-1538. Mammalian metabolic activation preparations were from
    mouse (ICR adult), rat (Sprague-Dawley adult) and monkey (Macaca
    mulatta adult). Carob (locust) bean gum did not exhibit genetic
    activity in any of the assays employed (Litton Bionetics, 1975;
    Maxwell & Newell, 1972).

    Special studies on reproduction

         A three-generation reproduction study was carried out in CD
    strain Charles River albino rats. Groups of 10 male and 20 female
    animals were fed a rat chow diet containing 2 or 5% locust bean gum
    (LBG) or 5% alpha cellulose (control). The same doses and animal
    numbers were used throughout the study. In each generation the
    parental animals received the test diet for 11 weeks prior to mating
    and then through mating, gestation and weaning.

         Two or three litters were raised per generation and the second
    litter was used to produce the following generation. Ten males and 10
    females from each treatment group of the F3b generation were selected
    for histopathological examination of 12 major organs and tissues and
    organ weight analysis. All other animals were subject to gross
    necropsy only.

         There were statistically significant decreases in premating body
    weight gain in the F0 females fed 2% LBG and in final body weight in
    the females fed 5% LBG.

         There were the following significant differences in organ weight
    ratios in the F3b 5% LBG group as compared to the controls: smaller
    spleen to brain weight, absolute liver weight, liver to brain weight
    and larger brain to body weight. These differences were ascribed to
    the highly variable values for these parameters in young rats and the
    fact that all the animals may not have been at the same age at
    sacrifice. This factor could have had an effect on organ weight ratios
    in young animals.

         There were no significant treatment-related effects on
    reproductive indices or gross or microscopic pathology (Domanski et
    al., 1980).

    Special studies on teratogenicity

         Teratogenic experiments with four species of animals (rats, mice,
    hamsters and rabbits) did not indicate that the test material was a
    teratogen to mice at 280 m/kg bw and 1300 mg/kg, although 5/21 dams
    died at the latter dose. Up to 1300 mg/kg in rats, up to 1000 mg/kg in
    hamsters and at 196 mg/kg in rabbits no teratological effects were
    seen. At 910 mg/kg in rabbits, most of the pregnant dams died
    (Morgareidge, 1972).

         Carob bean gum was injected via the air cell and yolk or albumen
    route into fertile eggs prior to and after 96 hours of incubation.
    Eggs were candled at 48-hour intervals and dead embryos were examined
    for stage of development and defects. At hatching, all chicks were
    examined for gross defects and samples were taken for gross skeletal
    staining and histopathological examination. Although the authors do
    not state levels of carob bean gum injected, they note anophthalmia,
    phocomelia, micromelia and torticollis occurring with carbob bean gum
    (Naber & Smothers, 1975).

    Acute toxicity
                                                                      

                                   LD50
    Animal     Route             (g/kg bw)     Reference
                                                                      

    Mouse      Oral (gavage     13.1 ± 0.65    Maxwell & Newell, 1970
               in corn oil)

    Hamster    Oral (gavage     10.3 ± 0.49    Maxwell & Newell, 1970
               in corn oil)

    Rat        Oral (gavage     13.1 ± 0.75    Food & Drug Research
               in corn oil)                    Laboratories, Inc., 1976

               Oral (gavage        5.00        Maxwell & Newell, 1970
               in corn oil)

    Rabbit     Oral (gavage     9.1 ± 0.39     Maxwell & Newell, 1970
               in corn oil)
                                                                      

    Short-term studies

    Rat

         Groups of 10 males and 10 females were fed in their diet carob
    bean gum at levels of 0, 1, 2 or 5% for 90 days. General condition,
    behaviour, survival, growth, food intake, haematology, blood
    biochemistry and urinalysis showed no treatment-related differences
    between test and control groups at any dietary level except that the
    last glucose level was slightly increased in the 5% group. Gross and
    microscopic examination did not reveal any pathological changes
    attributable to ingestion of the gum. The increase in the relative
    weight of the caecum at the 2% level is not considered to be of
    toxicological importance (Til et al., 1974).

         Groups of newly weaned Sprague-Dawley rats (10 per group) were
    fed a soybean-corn meal diet containing 2% locust (carob) bean gum for
    36 days. Locust bean gum had no effect on the digestibility of the
    diet, nor was there any significant effect on growth (Vohra et al.,
    1979).

    Dog

         Four groups of five male and five female beagles were fed 0, 1, 5
    or 10% of a precooked mixture of carob bean and guar gum (proportions
    unknown) for 30 weeks. Only at the 10% level were hypermotility and
    soft, bulky stools observed, probably of no toxicological
    significance. Also at the 10% level digestibility was reduced. No
    adverse haematological, urinary, gross and histopathological and
    ophthalmological findings were noted (Cox et al., 1974).

    Chicken

         Groups of 20-day-old chickens were fed diets containing 0.25,
    0.52, 12 and 22% carob bean gum for three weeks. Growth depression was
    dose related and marked at the 2% level of intake (Kratzer et al.,
    1967; Vohra & Kratzer, 1964).

         Groups of day-old broiler chickens (seven per group, breed not
    specified) were fed a soybean protein-corn based diet containing 2%
    carob (locust) bean gum for 24 days. The dietary intake of the
    chickens was measured daily for the last week of the experimental
    period; digestibility of the test diet was calculated from the dry
    weights of the feed and excreta. The average body weight of chickens
    and the digestibility of the diet was reduced significantly by the
    inclusion of locust (carob) bean gum in the diet (Vohra et al., 1979).

    Japanese quail

         Groups of day-old Japanese quail (10 per group) were fed a
    soybean-meal-corn based diet containing 2% locust (carob) bean gum
    for either 35 or 37 days. The dietary intake of the quail was measured
    daily for the last week of their experimental period; the
    digestibility of the diet was calculated from the dry weights of the
    feed and excreta. Average body weight and digestibility of the diet
    was significantly reduced by inclusion of locust (carob) bean gum in
    the diet (Vohra et al., 1979).

    Long-term studies

    Mouse

         Groups of 50 male and 50 female B6C3F1 mice were given 0, 25 000
    or 50 000 ppm (0, 2.5 or 5%) carob bean gum in the diet for 103 weeks.
    The surviving animals were then fed a control diet for an additional

    two weeks prior to sacrifice. The mean body weight of the high dose
    male mice was lower than the control during the second year of the
    study. The other dose groups had body weights comparable to their
    respective control groups. No significant compound-related effects
    were noted with respect to survival or gross or microscopic pathology
    except for the possible incidence of alveolar/bronchiolar adenomas in
    male mice. The incidence of this lesion was 7/50 in the control, 17/50
    in the low dose group and 11/50 in the high dose group. The historical
    incidence of this lesion in male mice was 8.1%, although incidences in
    the test laboratory performing the study had ranged upwards of 26%.
    The investigators concluded that "the lack of significant results in
    the high dose group taken together with the relatively high background
    rate of these tumors precludes a clear decision as to the effect of
    locust bean gum at this site. When the incidence of male mice with
    adenomas or carcinomas is analyzed, there is no significant result".
    The report concluded that locust bean gum was not carcinogenic to male
    or female rats or mice under conditions of the test (National
    Toxicology Program, 1980).

    Rat

         Fischer 344 rats in groups of 50 animals/sex were fed 0, 25 000
    or 50 000 ppm (0, 2.5 or 5%) carob bean gum in the diet for 103 weeks;
    the surviving animals were then fed the control diet for an additional
    two or three weeks prior to sacrifice. No compound-related effects
    were noted on body weights, survival, or gross or microscopic lesions.

         Groups of 50 male and 50 female Charles River strain albino rats
    were fed diets containing 5% alpha cellulose (control) or 2 or 5%
    carob bean gum (CBG) for 24 months. There was an interim sacrifice of
    10 animals/sex/dose carried out at 12 months.

         Significantly greater body weights in the 2% CBG females were
    observed at weeks 11, 94, 95, 96, 97, 98, 99 and 100 of the study and
    at week 13 in the 5% CBG females. Numerous significant differences in
    food consumption were observed during the study, but these were
    ascribed to the spillage of the control diet. Inclusion of alpha
    cellulose in the diet was said to result in physical characteristics
    which made spillage control very difficult.

         The following significant differences with respect to haematology
    measurements were noted: decrease in reticulocyte count in 5% CBG
    females at six months; decrease in haemoglobin concentration in 2% CBG
    female rats at six months; and increase in segmented neutrophils and
    decrease in lymphocytes in 2% male rats at six months.

         A statistically significant reduction in absolute thyroid weight
    was noted in the 2% and 5% male CBG groups at the interim sacrifice. A
    significant reduction in absolute brain weight was cited in the 5% CBG
    females at the final sacrifice.

         No significant treatment-related effects on gross or microscopic
    pathology were reported (Carlson & Domanski, 1980).

    OBSERVATIONS IN MAN

         A clinical study of a commercial preparation of carob bean grain
    as a laxative in doses of "two heaping teaspoonfuls" in 56 patients,
    some of whom took the preparation regularly for two years, resulted in
    no untoward effects related to the gastrointestinal tract, and no
    allergenic reaction (Holbrook, 1951).

         Eight infants between the ages of two-and-a-half to five months
    were fed meals of sugared milk or sugared milk plus a 1% powder
    extract from carob bean. Addition of the carob supplement did not
    alter the duration of the gastrointestinal transit time of the meal.
    Physiological aerophagy was markedly suppressed by the supplement
    (Rivier, 1952).

    Comments

         In vitro tests with human enzyme preparations show little
    utilization by the gut. Carob bean gum was not teratogenic in several
    mammalian species although it did produce terata in the chick embryo
    assay. The available short-term studies in the rat and dog showed no
    evidence of adverse effects at the 5% level. The effects noted in
    feeding trials are those expected of a non-metabolized polymeric
    substance acting as a bulking agent. In the previous evaluation, it
    was noted that the following studies were not available for
    evaluation: long-term, reproduction, teratogenicity and mutagenicity.
    The new data submitted showed that carob bean gum did not cause any
    significant compound-related effects in a three-generation
    reproduction study. It was not mutagenic in microbial systems, with
    and without activation. In lifetime feeding studies in the rat and
    mouse, carob bean gum was not carcinogenic.

    EVALUATION

    ADI 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

    Carlson, W. & Domanski, J. (1980) Two year chronic oral toxicity study
         with locust bean gum in albino rats. Unpublished study.
         Industrial Bio-Test Laboratories, Inc.

    Cox, G. E., Baily, D. E. & Morgareidge, K. (1974) Subacute feeding in
         dogs with a pre-cooked gum blend. Unpublished report from the
         Food and Drugs Laboratories, Inc., submitted to the World Health
         Organization by Hercules BV

    Domanski, J., Carlson, W. & Frawley, J. (1980) Three generation
         reproduction study on locust bean gum in albino rats. Unpublished
         study

    Ershoff, B. H. & Wells, A. G. (1962) Effects of gum guar, locust bean
         gum and carrageenan on liver cholesterol of cholesterol-fed rats,
         Proc. Soc. Exp. Biol. Med., 110 (3), 580-582

    Fahrenbach, M. J., Riccardi, B. A. & Grant, W. E. (1966)
         Hypocholesterolemic activity of mucilaginous polysaccharides in
         White Leghorn cockerels, Proc. Soc. Exp. Biol. Med., 13 (2),
         321-326

    Food & Drug Research Laboratories, Inc. (1972) Teratologic evaluation
         of FDA 71-14. Teratologic evaluation of carob bean (locust) gum.
         Submitted under Contract No. FDA 71-260. Maspeth, N.Y.

    Harmuth-Hoene, A. & Schwerdtfeger, E. (1979) Effect of indigestible
         polysaccharides on protein digestibility and nitrogen retention
         in growing rats, Nut. Metab., 23, 399-407

    Holbrook, A. A. (1951) The behaviour of carob bean in the
         gastrointestinal tract of man, Amer. J. Dig. Dis., 18, 24-28

    Krantz, J. C., jr, Carr, C. J. & De Farson, C. B. (1948) Guar poly-
         saccharide as a precursor of glycogen, J. Amer. Diet Ass.,
         24, 212

    Kratzer, F. H., Rajaguru, R.W.A.S.B. & Vohra, P. (1967) The effect
         of polysaccharides on energy utilization, nitrogen retention and
         fat absorption in chickens, Poultry Sci., 48, 1489-1493

    Litton Bionetics, Inc. (1975) FDA Project No. 2468, Food and Drug
         Administration Contract No. 223-74-2104. Evaluation of test
         compound locust bean gum, FDA 71-14

    LRSO/FASEB (1972) Evaluation of the health aspects of carob bean gum
         as a food - SCOGS-3. Prepared for Bureau of Foods, US Food and
         Drug Administration Contract No. FDA 72-85

    Maxwell, W. A. & Newell, G. W. (1972) Study of the mutagenic effects
         of FDA-71-14 (locust bean gum). Unpublished report from the
         Stanford Research Institute, submitted to the World Health
         Organization by Hercules BV

    Morgareidge, K. (1972) Teratological evaluation of FDA-71-14 (locust
         bean gum). Unpublished report from the Food & Drug Research
         Laboratories, Inc., submitted to the World Health Organization by
         Hercules BV

    Naber, E. C. & Smothers, S. E. (1975) Patterns of toxicity and
         teratogenicity in the chick embryo resulting from the
         administration of certain nutrients and food additives, Poultry
         Sci., 54 (5), 1806

    National Toxicology Program (1980) Carcinogenesis bioassay of locust
         bean gum. DHHS publication No. (NIH) 81-1777 

    Rivier, C. (1952) Recherches sur le mode d'action du Nestargel,
         Schweiz. Mediz., 82, 256

    Robaislek, E. (1974) Bioavailable calorie assay of guar gum.
         Unpublished report from WARF Institute, Inc., submitted to the
         World Health Organization by the Institut Européen des Industries
         de la Gomme de Caroube

    Semenza, G. (1975) Report on the possible digestion of locust bean gum
         in the stomach and/or in the small intestine in an in vitro
         study. Unpublished report from the Eidgenossische Technische
         Hochschule Zurich, submitted to the World Health Organization by
         the Institut Européen des Industries de la Gomme de Caroube

    Til, H. P., Spanjers, M. Th. & de Groot, A. P. (1974) Sub-chronic
         toxicity study with locust bean gum in rats. Unpublished report
         from Centraal Instituut voor Voedingsonderzoek TNO, submitted to
         the World Health Organization by Hercules BV and the Institut
         Européen des Industries de la Gomme de Caroube

    Towle, G. A. & Schranz, R. E. (1975) The action of rat microflora on
         carob bean gum solutions in vitro. Unpublished report from the
         Hercules Research Center, submitted to the World Health
         Organization by Hercules Incorporated

    Tsay, L. B. & Whistler, R. L. (1975) Digestibility of galactomannans.
         Unpublished report submitted to the World Health Organization by
         Professor H. Neukom, Chairman of the Technical Committee of the
         Institut Européen des Industries de la Gomme de Caroube

    Vohra, P. & Kratzer, F. H. (1964) Growth inhibitory effects of certain
         polysaccharides for chickens, Poultry Sci., 43, 1164-1170

    Vohra, P., Shariff, G. & Kratzer, F. H. (1979) Growth inhibitory
         effect of some gums and pectin for Tribolium castaneum larvae,
         chickens and Japanese quail, Nutr. Rep. Internat'l, 19 (4),
         463-469
    


    See Also:
       Toxicological Abbreviations