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    Toxicological evaluation of some food
    additives including anticaking agents,
    antimicrobials, antioxidants, emulsifiers
    and thickening agents



    WHO FOOD ADDITIVES SERIES NO. 5







    The evaluations contained in this publication
    were prepared by the Joint FAO/WHO Expert
    Committee on Food Additives which met in Geneva,
    25 June - 4 July 19731

    World Health Organization
    Geneva
    1974

              

    1    Seventeenth Report of the Joint FAO/WHO Expert Committee on
    Food Additives, Wld Hlth Org. techn. Rep. Ser., 1974, No. 539;
    FAO Nutrition Meetings Report Series, 1974, No. 53.

    MICROCRYSTALLINE CELLULOSE

    Explanation

         This substance has been evaluated for acceptable daily intake by
    the Joint FAO/WHO Expert Committee on Food Additives (see Annex 1,
    Ref. No. 27) in 1971.

         The previously published monograph has been revised and is
    reproduced in its 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 to 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 µc) in two portions on
    one day and 150 g unlabelled 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 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
    gastrointestinal 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 (Hazelton Laboratories, 1964).

    Acute toxicity
                                                                        

    Animal    Sex       Route     mg/kg bw       Reference
                                                                        

    Rat       male      oral      > 3160         Hazelton Labs., 1959

    Rat       male      i.p.      > 3160         Hazelton Labs., 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 gastrointestinal 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 diets for eight weeks. Growth was
    comparable to the controls but the 10% groups showed slightly lower
    body weights. Haematology, serum chemistry and vitamin B1 levels in
    blood and faeces showed no differences from the controls (Yoshitoshi
    Internal Semina, 1966).

    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 proximal renal tubules in females on microcrystalline
    cellulose but all other organs appeared unremarkable. Tumour incidence
    did not differ between the groups (Hazelton Laboratories, 1963).

    OBSERVATIONS 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 three months. The only effect
    noted was an increase in bowel movements but no diarrhoea or other
    gastrointestinal 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 fulness 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 five to
    eight times during the test period. Microscopy revealed the presence
    of microcrystalline cellulose (Hazelton Laboratories, 1962).

         In another study eight healthy males received 30 g micro-
    crystalline 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 1131-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 (Yoshitoshi Internal
    Seminar, 1966).

    Comments:

         The animal and human studies, including the use of radio-labelled
    material, show a virtually complete absence of digestion or
    absorption. 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 considered to be attributable to the
    inadequacies of a diet containing a large amount of indigestible
    material.

    EVALUATION

    Estimate of acceptable daily intake for man

         Not limited.*

    REFERENCES

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

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

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

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

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

    Hazelton Laboratories Inc. (1963) Unpublished report submitted by
         American Viscose CorporaTion

    Hazelton 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 relevant paragraph in the seventeenth report, pages 10-11.


    See Also:
       Toxicological Abbreviations
       Microcrystalline cellulose (WHO Food Additives Series 1)
       Microcrystalline cellulose (WHO Food Additives Series 40)
       MICROCRYSTALLINE CELLULOSE (JECFA Evaluation)