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    WORLD HEALTH ORGANIZATION







    Toxicological evaluation of some food colours, thickening
    agents, and certain other substancse



    WHO FOOD ADDITIVES SERIES NO. 8





    The evaluations contained in this publication were prepared
    by the Joint FAO/WHO Expert Committee on Food Additives which
    met in Geneva, 14-23 April 19751



    World Health Organization, Geneva 1975



    1 Nineteenth Report of the Joint FAO/WHO Expert Committee on Food
    Additives, Wld Hlth Org. techn. Rep. Ser., 1975, No. 576;
    FAO Nutrition Meetings Report Series, 1975, No. 55.

    The monographs contained in the present volume are
    also issued by the Food and Agriculture Organization
    of the United Nations, Rome, as
    FAO Nutrition Meetings Report Series, No. 55A



















    ISBN 92 4 166008 2

    (C) FAO and WHO 1975




    MICROCRYSTALLINE CELLULOSE

    Explanation

         This substance was evaluated for acceptable daily intake for man
    by the Joint FAO/WHO Expert Committee on Food Additives (see Annex 1,
    Refs No. 27 and No. 33) in 1971 and 1973.

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

    BIOLOGICAL DATA

    BIOCHEMICAL ASPECTS

         Four rats were fed 14C-labelled microcrystalline cellulose at
    10 and 20% of their diet. No evidence of degradation or digestion was
    noted. Faecal recoveries of radioactivity ranged from 96-104% and were
    complete for all labelled material. No radioactivity appeared in the
    urine (Baker, 1966). One human subject received 150 g of 14C-labelled
    microcrystalline cellulose (47.6 c) in two portions on one day and
    unlabelled 150 g microcrystalline cellulose daily for the subsequent
    10 days. Twenty-four hour faecal and urine collections were examined
    for radioactivity. No radioactivity appeared in the urine or in the
    expired CO2. All administered radioactivity was recovered from the
    faeces within two days (Baker, 1968). Examination of the stools of one
    male and one female patient given 30 g micro-crystalline cellulose as
    dry flour or gel for five-and-one-half weeks showed the presence of
    undegraded material of the same birefringence as the original
    microcrystalline cellulose administered. No significant effects on the
    human gastro-intestinal tract were noted during the administration
    (Tusing et al., 1964).

    TOXICOLOGICAL STUDIES

    Special studies on reproduction

    Rat

         Groups of eight male and 16 female rats were used to produce a P,
    F1a, F1b, F2 and F3 generation after having been fed on diets
    containing 30% of microcrystalline cellulose flour or gel or ordinary
    cellulose as a control. The presence in the diet of such an amount of
    non-nutritious material, which contributed no calories had an adverse
    effect on reproduction. Fertility and numbers of live pups were
    relatively depressed and lactation performance in all three
    generations, as well as survival and the physical condition of the

    pups, were unsatisfactory throughout the study. The new-born pups
    appeared smaller, weak and showed evidence of disturbed motor
    coordination. Liver weights were increased in the group receiving
    microcrystalline cellulose gel in all generations but other organ
    weights showed no consistent patterns. Gross and histopathology
    revealed renal changes similar to those seen in the feeding study in
    females of all generations. Other organs showed no consistent changes.
    No teratological deformities were seen (Anonymous, 1964).

    Special studies on teratogenicity

    Rat

         Seventy-two test rats (Sprague-Dawley CD) divided into eight
    groups were fed a mixture of four types of Elceme in the ratio of
    1:1:1:1. (Elceme is a microcystalline cellulose, and the four types
    are identified by particle size, namely, 1-50  (powder), 1-100 
    (powder), 1-150  (fibrillar), 90-250  (granulate)), in the diet at a
    level of 0, 2.5, 5 or 10% for 10 days, between the sixth and fifteenth
    day of pregnancy. Rats of four test groups were killed on the twenty-
    first day of pregnancy and the following parameters studied: number of
    foetuses and resorption sites, litter size and average weight of rats,
    average weight of foetuses, average backbone length. Foetuses were
    also examined for soft tissue of skeletal defects. The remaining
    groups were allowed to bear young, which were maintained to weaning
    (21 days). The following parameters were studied: litter size, weight
    of pup at days seven and 21, as well as a histological study of the
    offspring. Although there is some suggestion that administration of
    dietary Elceme resulted in a dose dependent increase in resorption
    sites, as well as a change in sex ratio, and possible defects such as
    opaque crystalline lenses, the data has not been presented in a manner
    which permits a meaningful interpretation. However, the authors
    conclude that Elceme is non-teratogenic (Ferch, 1973a).

    Other special studies

    Rats, pigs and dogs

         Rats, pigs and dogs were used to study the persorption of
    microcrystalline cellulose. The animals were not fed 12 hours prior to
    oral administration of the test compound. Rats, dogs and pigs were
    given 0.5, 140 and 200 g respectively, of the test compound. Venous
    blood was taken from the animals one to two hours after administration
    of the test compound, and examined for particles. Persorbed particles
    were demonstrated in the blood of all three species. The average
    maximum diameter for persorbed particles was greater for rats than for
    dogs and pigs (Pahlke & Friedrich, 1974).

         Other studies have been carried out to demonstrate the
    relationship between persorbability and size and consistency of
    granules. Using quartz sand, the upper limits for persorbability was
    shown to be 150 . Starch granules must be structurally largely intact
    to possess the property of persorbability. Persorbed starch granules
    may be eliminated in the urine, pulmonary alveoli, peritoneal cavity,
    cerebrospinal fluid, via lactating milk and transplancental
    (Volkheimer et al., 1968).

         In another study dyed plant foods (oatmeal, creamed corn) were
    fed to human subjects, and blood and urine examined for coloured
    fibres. Dyed fibres were shown to be present (Schreiber, 1974).
    Lycopodium spores and pollen grains have also been shown to be
    persorbed by humans (Linskens & Jorde, 1974).

    Acute toxicity

    Rat

         Groups of five male rats received a single oral dose, by stomach
    tube of 10.0, 31.6, 100, 316, 1000 or 3160 mg/kg body weight of a
    suspension of Cellan 300 (refined alpha-cellulose) in distilled water
    or Mazola maize oil. The animals were observed for seven days
    following administration. No differences were observed among the
    groups as regards the average body weight, appearance and behaviour
    compared to normal rats. No abnormal histopathological findings were
    reported in any animals with either formulation. Therefore the acute
    oral LD50 is >3160 mg/kg (Pallotta, 1959).

         Similar single doses of refined alpha-cellulose were given
    intraperitoneally in distilled water suspension to five male rats.
    During seven days observation there were no abnormalities in the rats
    given 316 mg/kg or less. At the 1000 and 3160 mg/kg level there was
    inactivity, laboured respiration and ataxia, 10 minutes after
    administration and at 3160 mg/kg ptosis and sprawling of the limbs.
    These animals appeared normal after 24 hours and for the remainder of
    the observation period. At sacrifice body weights were higher than
    normal and gross autopsy revealed adhesions between the liver,
    diaphragm and peritoneal wall and congestion of the kidneys. Masses
    resembling unabsorbed compound were also observed and these were
    found to a small extent in the mesentary of the animals administered
    316 mg/kg. Histologically all other organs appeared normal. There were
    no mortalities and therefore the acute intraperitoneal LD50 is
    >3160 mg/kg body weight (Pallotta, 1959).

    Short-term studies

    Rat

         Groups of four male rats were kept on diets containing 0.25, 2.5
    or 25% of various edible celluloses for three months. No differences
    were observed among the groups with regard to growth and faecal
    output. Histopathology of the gastro-intestinal tract revealed no
    treatment-related abnormalities (Frey et al., 1928).

         Three groups of five male rats received 0.5% or 10%
    microcrystalline cellulose in their diet for eight weeks. Growth was
    comparable to controls but the 10% group showed slightly lower body
    weights. Haematology, serum chemistry and vitamin B1 levels in blood
    and faeces showed no differences from controls (Anonymous, 1966).

         A mixture of four types of Elceme (in the ratio of 1:1:1:1)
    was fed to groups of Wistar rats for 30 days at a dietary level of
    50%, and for 90 days at a dietary level of 10% (Elceme is a
    microcrystalline cellulose, and the four types are identified by
    particle size, namely, 1-50  (powder), 1-100  (powder), 1-150 
    (fibrillar), 90-250  (granulate)). All test animals were observed for
    food intake and weight gain. For animals in the 10% group urinalysis,
    haematologic tests and serum biochemical tests were carried out at
    weeks six and 13 of the test. A complete autopsy including
    histopathology was carried out at the end of the study. Animals in the
    50% level were subjected to a persorption test, and the last day of
    the study, by addition of a cellulose staining dye (Remal, Wine-red)
    to the food of the test animals at a level equivalent to 5% of the
    Elceme. The animals were sacrificed 24 hours after administration of
    the diet, and a careful histological examination was made of the
    gastro-intestinal tract, spleen, liver, kidney and heart for stained
    particles.

         Animals in 10% level gained significantly less weight than those
    in the control group; the marked decrease commenced in the third or
    fourth week of the study. Food intake was similar in test and control
    group. Urinalysis, haematologic values and biochemical values for test
    and control groups were similar for test and control group 1. At
    autopsy some of the rats on the test died had distended stomachs which
    often contained considerable amounts of the test diet. The absolute
    liver and kidney weight and the ratio of the weight of these organs to
    brain weight was increased in test animals when compared with control
    animals. No compound related pathology was reported. Animals in the
    50% group, showed considerable less weight gain than control animals
    in spite of a marked increase in food consumption. No persorption of
    dyed fibres was observed (Ferch, 1973).

    Long-term studies

    Rat

         Three groups of 50 male and 50 female rats received in their diet
    for 72 weeks either 30% ordinary cellulose or dry microcrystalline
    cellulose or microcrystalline cellulose gel. Appearance and behaviour
    was comparable in all groups. No adverse effects were noted. The body
    weights of males given microcrystalline cellulose gel were higher than
    those of the controls. Food efficiency, survival and haematology were
    comparable in all groups. The liver and kidney weights of males
    receiving microcrystalline cellulose gel were higher than the
    controls. Gross and histopathology showed some dystrophic
    calcification of renal tubules in females on microcrystalline
    cellulose but all other organs appeared unremarkable. Tumour incidence
    did not differ between the groups (Anonymous, 1963).

    OBSERVATIONS IN MAN

         A number of clinical studies using refined cellulose as roughage
    in the human diet for the treatment of constipation showed no
    deleterious effects. Groups of 18 children received regular amounts of
    edible cellulose instead of normal cereal for three months. The only
    effect noted was an increase in bowel movements but no diarrhoea or
    other gastro-intestinal disturbances were seen (Frey et al., 1928).

         Eight male and eight female volunteers supplemented their normal
    diet with 30 g microcrystalline cellulose per day either as dry powder
    or gel (15% aqueous) for six weeks followed by two weeks without
    supplementation. No adverse findings were reported regarding
    acceptance or body weight but most subjects complained of fullness and
    mild constipation. Haematology was normal in all subjects. Biochemical
    blood values showed no differences between treatment and control
    periods, nor was there evidence of liver or kidney function
    disturbance. Urinalysis produced normal findings. The faecal flora
    remained unchanged. The cellulose content of faeces increase five to
    eight times during the test period. Microscopy revealed the presence
    of microcrystalline cellulose (Anonymous, 1962).

         In another study eight healthy males received 30 g
    microcrystalline cellulose daily as supplement to their diet for
    15 days. D-xylose absorption varied between pretest, test and post-
    test periods being lower during microcrystalline cellulose ingestion.
    The absorption of I131 triolein was unaffected by microcrystalline
    cellulose ingestion. No change was noted in the faecal flora nor was
    there any significant effect on blood chemistry during ingestion of
    microcrystalline cellulose. Examination of urine, blood and faecal
    levels of vitamin B1 during microcrystalline cellulose ingestion
    showed no difference from control periods (Anonymous, 1966).

    Comments:

         The human studies including the use of radiolabelled
    microcrystalline cellulose show complete absence of digestion or
    absorption. Doses up to 30 g per day appear to be tolerated
    therapeutically as a bulk laxative. While long-term animal studies
    reported for microcrystalline cellulose do not permit the
    establishment of a no-effect level, the adverse effects produced are
    probably attributable to the inadequacies of a diet containing a large
    amount of indigestible, non-absorbable, non-caloric material. Detailed
    studies on the persorption of particulate matter suggest that
    infinitesimally small amounts of ingested microcystalline cellulose
    may be absorbed, in a manner similar to other naturally occurring
    plant particulate matter, e.g. cellulosic material. However, any
    persorbed microcystalline cellulose is likely to be excreted in the
    urine or bile as has been observed with other particulate matter, and
    is not likely to accumulate in hazardous amounts in tissues and
    organs. The general inertness of this material strongly suggests that
    microcrystalline cellulose is biologically similar to other cellulose
    derivatives which have already been considered by Joint FAO/WHO Expert
    Committees on Food Additives and for which ADIs have been established
    on the basis of long-term studies in several animal species.

    EVALUATION

         Acceptable daily intake not specified.*

    REFERENCES

    Anonymous (1962) Microcystalline cellulose; oral administration -
         Human. Unpublished report from Hazleton Labs, Inc. submitted to
         the World Health Organization by FMC Corporation

    Anonymous (1963) Long-term nutritional balance study - Rats.
         Unpublished report from Hazleton Labs, Inc. submitted to the
         World Health Organization by FMC Corporation

    Anonymous (1964) Microcystalline cellulose: reproduction study - Rats.
         Unpublished report from Hazleton Labs, Inc. submitted to the
         World Health Organization by FMC Corporation

              

    *    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.

    Anonymous (1966) Effect of ingestion of avicel-contained foods on
         living organisms. Unpublished report from Yoshitoshi Internal
         Seminar submitted to the World Health Organization by Asahi
         Chemical Industry Co., Ltd.

    Baker, E. M. (1966) Microcystalline cellulose: oral administration -
         Rats. Unpublished report from Fitzsimmons General Hospital
         submitted to the World Health Organization by FMC Corporation

    Baker, E. M. (1968) Microcrystalline cellulose: oral administration -
         Humans. Unpublished report from Fitzsimmons General Hospital
         submitted to the World Health Organization by FMC Corporation

    Frey, J. W., Harding, E. R. & Helmbold, T. R. (1928) Dietetic
         investigations of edible pure cellulose, Med. J. Record, 127,
         585-589

    Ferch, H. (1973a) Innocuity of Elceme(R). Part I, Pharm. Ind., 35, (9),
         578-583

    Ferch, H. (1973b) Innocuity of Elceme(R). Part II, Pharm. Ind., 35,
         (9), 658-661

    Linskens, H. F. & Jorde, W. (1974) Persorption of lycopodium spores.
         and pollen grains, Naturwissenschaften, 61, 35

    Pahlke, G. & Friedrich, R. (1974) Persorption of microcystalline
         cellulose, Naturwissenschaften, 61, 35

    Pallotta, A. J. (1959) Acute oral administration - Rats; and acute
         intraperitoneal administration - Rats, of microcrystalline
         cellulose. Unpublished report from Hazleton Labs, Inc. submitted
         to the World Health Organization by FMC Corporation

    Schreiber, G. (1974) Ingested dyed cellulose in the blood and urine
         of man, Arch. environ. Health, 29, 39

    Tusing, T. W., Paynter, O. E. & Battista, O. A. (1964) Birefringence
         of plant fibrous cellulose and microcrystalline cellulose in
         human stools freezer-stored immediately after evacuation,
         Agric. Fd. Chem., 12, (3), 284-287

    Volkheimer, G., Schultz, F. H., Lehmann, H., Aurich, I., Hubner, R.,
         Hubner, M., Hallmayer, A., Munch, H., Opperman, H. & Strauch,
         S. (1968) Primary portal transport of persorbed starch granules
         from the intestinal wall, Medicine Experimentalis, 18,
         103-108


    See Also:
       Toxicological Abbreviations