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    WORLD HEALTH ORGANIZATION

    WHO Food Additives Series 1972, No. 1




    TOXICOLOGICAL EVALUATION OF SOME 
    ENZYMES, MODIFIED STARCHES AND 
    CERTAIN OTHER SUBSTANCES




    The evaluations contained in this publication were prepared by the
    Joint FAO/WHO Expert Committee on Food Additives which met in Rome,
    16-24 June 19711





    World Health Organization

    Geneva

    1972





                   

    1 Fifteenth Report of the Joint FAO/WHO Expert Committee on Food
    Additives, Wld Hlth Org. techn. Rep. Ser., 1972, No. 488; FAO
    Nutrition Meetings Report Series, 1972, No. 50.

    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. 50A

    (c) FAO and WHO 1972


    MICROCRYSTALLINE CELLULOSE

    Biological data

    Biochemical aspects

    Four rats were fed 14C-labelled microcrystalline cellulose at 10 and
    20 per cent. of their diet.  No evidence of degradation or digestion
    was noted.  Faecal recoveries of radioactivity ranged from 96-104 per
    cent. 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 µc) in two portions
    on one day and 150 g unlabelled micro crystalline cellulose daily for
    the subsequent 10 days.  Twenty-four hour faecal and urine collections
    were examined for radio activity.  No radioactivity appeared in the
    urine or in the expired CO2.  All administered radioactivity was
    recovered from the faeces within 2 days. (Baker, 1968.)  Examination
    of the stools of 1 male and 1 female patient given 30 g
    microcrystalline cellulose as dry flour or gel for 5-1/2 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).

    Acute toxicity

                                                                     

                                   mg/kg 
    Animal   Sex     Route      body-weight    Reference
                                                                     

    Rat      male    oral         >3160        Hazleton Labs., 1959
    Rat      male    i.p.         >3160        "    "   "

                                                                     

    Short-term studies

    Rat

    Groups of 4 male rats were kept on diets containing 0.25, 2.5 or 25
    per cent. 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 5 male rats received 0, 5 or 10 per cent.
    microcrystalline cellulose in their diet for 8 weeks.  Growth was
    comparable to the controls but the 10 per cent. group showed slightly
    lower body-weights.  Haematology, serum chemistry and vitamin B,
    levels in blood and faeces showed no differences from the controls
    (Yoshitoshi Internal Seminar, 1966).

    Long-term studies

    Rat

    Three groups of 50 male and 50 female rats received in their diet for
    72 weeks either 30 per cent. 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 proximal renal tubules in
    females on microcrystalline cellulose but all other organs appeared
    unremarkable.  Tumour incidence did not differ between the groups
    (Hazleton Laboratories, 1963).

    Reproduction studies

    Rat

    Groups of 8 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 per cent. 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
    co-ordination.  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 (Hazleton
    Laboratories, 1964).

    Observation in man

    A number of clinical studies using refined cellulose as roughage in
    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 3 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 8 female volunteers supplemented their normal diet with
    30 g microcrystalline cellulose per day either as dry powder or gel
    (15 per cent. aqueous) for 6 weeks followed by 2 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 increased 5-8
    times during the test period.  Microscopy revealed the presence of
    microcrystalline cellulose (Hazleton Laboratories, 1962).

    In another study 8 healthy males received 30 g microcrystalline
    cellulose daily as supplement to their diet for 15 days.  D-zylose
    absorption varied between pre-test, 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 B,
    during microcrystalline cellulose ingestion showed no difference from
    control periods (Yoshitoshi Internal Seminar, 1966).

    Comments

    The animal and human studies including the use of radio-labelled
    material show complete absence of digestion or absorption.
    Microcrystalline cellulose is structurally very close to naturally
    occurring cellulose.  Doses up to 30 g per day appear to be tolerated
    therapeutically as bulk laxative.  The adverse effects reported in the
    long-term studies are probably attributable to the inadequacies of a
    diet containing a large amount of indigestible material.

    EVALUATION

    Acceptable daily intake for man

    No limit.*

    REFERENCES

    Baker, E. M. (1966) Unpublished report of F.M.C. Corporation

    Baker, E. M. (1968) Unpublished report of F.M.C. Corporation


                   

    * Except for good manufacturing practice.

    Frey, J. W., Harding, E. R. & Helmbold, T. R. (1928) Med. J. Rec.,
    June, 585

    Hazleton Laboratories Inc. (1959) Unpublished report submitted by
    American Viscose Corporation

    Hazleton Laboratories Inc. (1962) Unpublished report submitted by
    American Viscose Corporation

    Hazleton Laboratories Inc. (1963) Unpublished report submitted by
    American Viscose Corporation

    Hazleton Laboratories Inc. (1964) Unpublished report submitted by
    American Viscose Corporation

    Tusing, T. W., Paynter, O. E. & Battista, O. A. (1964) Agric. Fd.
    Chem., 12, 284

    Yoshitoshi Internal Seminar (1966) Unpublished report submitted by
    Asaki Chemical Industry Co. Ltd.

    


    See Also:
       Toxicological Abbreviations
       Microcrystalline cellulose (WHO Food Additives Series 5)
       Microcrystalline cellulose (WHO Food Additives Series 40)
       MICROCRYSTALLINE CELLULOSE (JECFA Evaluation)