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    MODIFIED CELLULOSES

         (Ethyl cellulose, ethyl hydroxyethyl cellulose, hydroxypropyl
    cellulose, hydroxypropyl methyl cellulose, methyl cellulose, methyl
    ethyl cellulose, sodium carboxymethyl cellulose).

    1.  EXPLANATION

         Modified celluloses were reviewed at the fifth, seventh, tenth,
    thirteenth, seventeenth, twenty-sixth, twenty-seventh and thirtieth
    meetings of the FAO/WHO Joint Expert Committee on Food Additives.
    (Annex 1, references 5, 7, 13, 19, 32, 59, 62, and 73). At the
    seventeenth meeting a group ADI of 0-25 mg/kg bw was allocated for the
    five previously reviewed modified celluloses which included methyl
    cellulose, methyl ethyl cellulose, hydroxypropyl cellulose,
    hydroxypropyl methyl cellulose, and sodium carboxymethyl cellulose. A
    monograph was prepared discussing these 5 compounds (Annex 1,
    reference 33).

         The use of microcrystalline cellulose was not included in this
    group ADI: no limitation other than that imposed by good manufacturing
    practice was deemed necessary for the use of microcrystalline
    cellulose as an additive (Annex 1, reference 26).

         At the twenty-sixth and twenty-seventh meetings of the committee
    ethyl cellulose and ethyl hydroxyethyl cellulose, respectively, were
    reviewed and added to the group ADI of 0-25 mg/kg bw.  A monograph on
    ethyl hydroxyethyl cellulose was prepared after the thirtieth meeting
    (Annex 1, reference 74).

         Since the previous evaluation, additional data have become
    available and are summarized and discussed in the following monograph.
    The previously published monographs have been incorporated into the
    document below.

    2.  BIOLOGICAL DATA

    ETHYL CELLULOSE

    2.2  Toxicological studies

    2.2.1  Acute toxicity

                                                                 

    Species    Sex    Route      LD50 (mg/kg bw)    Reference

                                                                 

    Rat         ?     Oral            5,000         Moreno, 1977
    Rabbit      ?     Dermal        > 5,000         Moreno, 1977
                                                                 

    2.2.2  Short-term studies

    2.2.2.1  Rats

         No adverse effects were reported in 80 rats fed a diet containing
    1.2% ethyl cellulose, which is equivalent to 182 mg/kg bw/day (Hake &
    Rowe, 1963).

    2.2.3  Long-term/carcinogenicity studies

         No data available.

    2.2.4  Reproduction studies

         No data available.

    ETHYL HYDROXYETHYL CELLULOSE

    2.2  Toxicological studies

    2.2.1  Acute toxicity

                                                                 

    Species    Sex    Route      LD50 (mg/kg bw)    Reference

                                                                    

    Rat         ?     Oral       5,000 - 10,000     Cuthbert, 1975

                                                                    

         The sensitization potential of 4 types of ethyl hydroxyethyl
    celluloses was negative in the guinea pig by Kligman's maximization
    test using positive and negative control groups.

         In albino rabbits, primary skin irritation was evaluated on
    abraded skin using a Draize type of procedure. The ethyl hydroxyethyl
    celluloses produced only very mild irritant reactions, with primary
    indices between 0.75 and 1.0. The control material, sodium
    carboxymethyl cellulose, produced the greatest irritant reactions with
    a resulting index of 1.42 (Cuthbert, 1975).

    2.2.2  Short-term studies

    2.2.2.1  Rats

         Ethyl hydroxyethyl cellulose was administered to Charles River CD
    rats (20 males and 20 females/group) by continuous dietary
    incorporation at dose levels of 0, 250, 1375 or 2500 mg/kg bw/day for
    90 consecutive days. All the animals were observed daily and all signs
    of toxicity or behavioral changes were recorded.  Body weight and food
    consumption were recorded weekly. Ophthalmoscopy and hematology
    analyses were carried out prior to termination. After 90 days of
    treatment the animals were killed and macroscopic examination was
    carried out on all tissues from animals in the control and high-dose
    groups.

         A statistically-significant increase in cumulative food
    consumption was recorded in male rats from the high-dose group
    throughout the study (weeks 1, 4, 8 and 12) and female rats of the
    high-dose group at weeks 4, 8 and 10. The increased food consumption
    was considered to represent compensation for the dietary inclusion of
    the test substance. A corresponding marginal decrease in the
    efficiency of food utilization was noted in rats of this treatment
    group throughout the study.  After adjustment for final body weight,
    a small decrease in liver weight was apparent in male rats of the
    high-dose group in comparison with control values.  No changes in the
    livers of these rats were apparent on histological examination.  In

    all other respects, including general health, body weight,
    ophthalmoscopy, hematology, biochemistry, and macroscopic and
    microscopic pathology, rats receiving ethyl hydroxyethyl cellulose
    were similar to the controls (Elliot  et al., 1985).

    2.2.3  Long-term/carcinogenicity studies

         No data available.

    2.2.4  Reproduction studies

         No data available.

    2.3  Observations in man

         Ethyl hydroxyethyl cellulose was administered in a dose of 1.0 to
    1.5 g, three times a day for at least 2 months, in a study of 85 male
    and female ambulatory patients (age 21-75 yr) with intestinal
    problems. Sixty-eight patients remained on the treatment. X-ray
    contrast media were used to study tablet disintegration in several
    patients. The disintegration time was greater than 20 minutes. Aside
    from minor abdominal discomfort in a few patients, no toxicity was
    noted, and restoration to normal bowel movement was seen (Tomenius,
    1957).

    HYDROXYPROPYL CELLULOSE

    2.1  Biochemical aspects

    2.2.1  Absorption, distribution and excretion

         When 250 or 1,000 mg/kg bw of [14C]hydroxypropyl cellulose was
    administered to rats in a 5% aqueous solution, radioactivity no
    greater than 0.01% of the administered dose was detected in organs,
    urine and expired air.  Recovery of activity in the feces varied from
    98.32 to 102.7%. Hence orally ingested material is not absorbed from
    the gastrointestinal tract of the rat and is excreted quantitatively
    in the feces, principally in the first 48 hours.

         To check on enterohepatic circulation, two additional rats with
    ligated bile ducts were administered 1,000 mg/kg bw of radio-labelled
    material. Bile was collected for 72 hours, but no significant activity
    was found (Industrial Bio-Test Lab., 1964, not validated).

         [14C]hydroxypropylcellulose (12.28% hydroxypropyl group,
    2.74 uCi/mg) was administered to 3 male and 3 female rats of
    Wistar-Imamichi Strain, weighing approximately 250g, at a dose of
    1.3 g/kg bw. Urine and feces were collected for 96 hours, and the
    residual radioactivity was measured in the tissues of the rats after
    sacrifice. The bile duct was cannulated for bile collections.  The
    mean urinary excretion of radioactivity over 96 hours was 2.63% in
    males and 1.50% in females. The mean fecal excretion was 68.7% and
    97.3% in males, and 62.4% and 96.8% in females, over 24 and 96 hrs,
    respectively. Total radioactivity in urine and feces over 96 hrs was
    99.9% in males and 98.3% in females.  Cumulative biliary excretion
    over 24 hrs was .015% for males and .0024% for females (Kitagawa
     et al., 1976a).

         Gel filtration chromatographic patterns of urine were
    inconclusive for identification of the single peak of radioactive
    material. The elution position showed a molecular weight slightly
    higher than glycerol or glucose and it was found at a different
    position than propylene glycol, which was present at a level of less
    than 2% in the administered material. No radioactivity was detectable
    in tissues other than the liver and kidney. The highest radioactivity
    in the liver was 1.5% of the dose in male rats at 12 hrs and 0.026% at
    24 hrs in females (Kitagawa  et al., 1976a).

    2.2  Toxicological studies

    2.2.1  Acute toxicity

                                                                 

    Species   Sex    Route    LD50 (mg/kg bw)    Reference

                                                                 

    Rat        ?     Oral     10,200-15,000      Industrial Bio-
                                                 Test Lab., 1962
                                                 (not validated)
                                                 Kitagawa,  et
                                                  al., 1976b
                                                                 

    2.2.2  Short-term studies

    2.2.2.1  Rats

         Groups of 5 male and 5 female rats received in their diet 0.2%,
    1.0% and 5.0% of hydroxypropyl cellulose for 90 days. Controls
    received unmodified cellulose at the same levels. No differences were
    observed between test and control animals as regards mortality,
    growth, food utilization, urinalysis, hematological indices, organ
    weight, gross pathology and histopathology. At higher dietary levels,
    increased food consumption and decreased food utilization was
    observed, probably due to dietary dilution (Industrial Bio-Test Lab.,
    1963, not validated).

         Groups of 10 male and 10 female young adult Wistar rats were fed
    hydroxypropyl cellulose in 1% gum arabic at doses of 0, 1.5, 3.0, or
    6.0 g/kg bw/day for 30 days and for 6 months. After 30 days, no
    effects were observed on body weight and food consumption, serum
    chemistry, urinalysis, or histopathology.  In females, liver, kidney
    and brain weights were decreased at 3.0 g/kg bw/day, but the decrease
    did not show a consistent dose-response relationship. After 6 months,
    decreased body weight was noted at the high dose level, which was
    statistically significant for females.  No effects related to dosage
    were noted on food consumption, serum chemistry, urinalysis, or
    histopathology. The hemoglobin level of male high- and mid-dose rats
    was reduced. There were sporadic increases or decreases in organ
    weights of a few groups without a dose relationship or associated
    pathological change (Kitigawa  et al., 1976b).

    2.2.2.2  Chickens

         Day-old Arbor Acres chicks were apportioned into groups of 10 and
    fed low-fat, high-fat or high-protein diets containing 2%
    hydroxypropyl cellulose or one of a variety of vegetable gums or other

    polysaccharides for 3 wk. The control diet contained 2% cellulose.
    Growth of chicks on the hydroxypropyl cellulose diet was depressed by
    8% relative to the control diet, but feed intake, nitrogen retention
    and fat absorption were unchanged (Kratzer  et al., 1967).

    2.2.3  Long-term/carcinogenicity studies

         No data available.

    2.2.4  Reproduction studies

         No data available.

    2.2.5  Special studies on teratogenicity

    2.2.5.1  Rats

         Groups of nulliparous female Wistar rats were mated to give 36-37
    pregnant rats per dose group. Hydroxypropyl cellulose was administered
    daily by gavage in 1% gum arabic at dose levels of 0, 200, 1000, or
    5000 mg/kg bw/day between days 7 and 17 post-mating.  On day 21 of
    gestation, 21-24 females were subjected to Cesarean section. Corpora
    lutea, implantations, viable and dead fetuses, and resorbed embryos
    were counted and positions of implantations were observed. All viable
    fetuses were individually weighed and examined for abnormalities. Two
    to three fetuses per group were examined for skeletal abnormalities,
    and the remainder were examined for visceral abnormalities.  Twelve to
    fifteen dams were allowed to deliver spontaneously. Viable pups and
    stillborns were counted, and records taken of body weight, sex, and
    presence of external anomalies. General behavior of pups was observed
    during nursing and individual body weights were recorded at delivery
    and weaning. Times for separation of lower incisors and and separation
    of eyelids were noted. The pups were weaned at the 28th day after
    birth. Each weanling was examined for general behavior and nervous
    reflexes. Skeletal examination was done by soft X-ray. One male and
    one female per group were killed and wet weights of the brain, heart,
    lung, liver, spleen, kidney, thymus, adrenal, testes, epididymis,
    prostate, ovary, pituitary and thyroid were obtained. Remaining
    weanlings were observed for 5 weeks for body weight gain, and at
    maturity for conditioned avoidance response and reproductive ability.

         Both mean litter weight and percent pre-implantation loss were
    significantly increased in the high dose group. The percent of
    skeletal variations was significantly increased for the mid dose only.
    At maturity, the progeny showed no effects on reflex behavior or
    reproductive ability (Kitagawa  et al., 1978a).

    2.2.5.2  Rabbits

         Groups of 11-12 pregnant Himalayan rabbits received oral doses of
    hydroxypropyl cellulose by gavage in 1% gum arabic at levels of 0,
    200, 1000, or 5000 mg/kg bw daily from days 6-18 of pregnancy.
    Cesarean sections were performed on the 29th day of pregnancy and all
    fetuses were examined for skeletal and organ malformations. Up to the
    18th day of study a slight body weight loss was noted in the high dose
    group. A slight decrease in the number of implants, not dose-related,
    was recorded in treatment groups. The resorption rate was
    significantly decreased only in the intermediate dosage group. The
    mean fetal viable weight was not different between groups. The
    pre-implantation loss was significantly increased in the 5000 mg/kg
    bw/day group. The incidence of malformations was comparable to
    historical controls and was not dose-related (Kitagawa  et al.,
    1978b).

    HYDROXYPROPYL METHYL CELLULOSE

    2.1  Biochemical aspects

    2.1.2  Absorption, distribution and excretion

         The disposition of orally administered 500 mg [14C]hydroxypropyl
    methyl cellulose/kg bw (approx. 25 uCi in 3 ml) was examined in 3 male
    and 3 female Sprague-Dawley rats either as a single dose, or as a
    series of 5 consecutive doses. Radioactivity associated with the
    single dose was recovered from the feces (>99%), urine (approx. 1%),
    carcass and tissues (approx. 0.2%), expired air (0.07%), and bile
    (0.05%). The excretory half life from plasma was approximately 2 hr.
    The tissue accumulating the most radioactivity was the
    gastrointestinal tract; 0.53% of the administered dose consisted of
    cellulose units with an average molecular weight < 1000, which was
    thought by the authors to be accounted for entirely (approx. 0.56%
    administered dose) in the urine as methyl ethers of glucose and
    oligomers. Radioactivity recovered after 5 consecutive doses was found
    primarily in the feces (97% in males, 102% in females) with trace
    amounts in the urine (approx. 1.0%) and with no evidence of tissue
    accumulation (Gorzinski  et al., 1986).

         The cecal contents from 2 male Wistar rats were incubated
     in vitro at 37C for 0, 6, 12, 24, and 48 hr in complex medium broth
    with 2 mg/ml of hydroxypropyl methyl cellulose. Total viable bacteria,
    carbohydrate utilization and free reducing-ends were determined.
    Hydroxypropyl methyl cellulose remained almost completely unfermented
    (5% in 48 hr, no further change by 7 days), and there was no increase
    in reducing-ends (i.e., no degradation of the cellulose polymers), or
    in viable bacterial counts compared to the control incubations (Wyatt
     et al., 1988).

    2.2  Toxicological studies

    2.2.1  Acute toxicity

                                                                 

    Species   Sex    Route    LD50 (mg/kg bw)    Reference

                                                                 

    Mouse      ?      i.p.    5,000              Hodge  et al.,
    Rat        F      oral    >1000 mg/kg        1950 CTFA, 1978a
               ?      i.p.    5,000              Hodge  et al.,
                                                 1950
                                                                 

    2.2.2  Short-term studies

    2.2.2.1  Rats

         Groups of 10 male and 10 female weanling rats were fed diets
    containing 0, 2, 10 and 25% hydroxypropyl methyl cellulose, type B,
    for 30 days.  Only in the highest dose were interference with body
    weight gain and diarrhea observed.  There were no histological lesions
    nor were there abnormal findings in urine and blood (Hodge  et al.,
    1950).

          Groups of 10 male and 10 female young rats were fed 0, 1, 3, 10
    and 30% of hydroxypropyl methyl cellulose, type A, for 121 days. Body
    weight gain was markedly retarded at the 30% level, with 50% mortality
    attributed to undernutrition. Only the male rats showed slight body
    weight gain retardation at the 10% dietary level, while the weight
    gain was normal at the lower levels.  Histological examination of
    internal organs revealed no abnormalities in any of the five groups
    (McCollister & Oyen, 1954).

         Groups of 10 male and 10 female young rats were fed diets
    containing 0, 0.3, 1, 10 and 20% of hydroxypropyl methyl cellulose,
    type C, for 90 days. At the 20% level both sexes showed marked
    retardation of body weight gain, with 30% mortality. At the 10% level
    male rats only showed slight but significant weight gain retardation.
    At the lower levels there were no adverse effects. The microscopic
    appearance of tissues was normal at all levels (McCollister  et al.,
    1961).

          Groups of 10 male and 10 female young rats were fed 0, 0.3, 1,
    3, 10 and 20% of hydroxypropyl methyl cellulose, type D, for 84 days.
    No adverse effects were noted with female rats at all levels. Male
    rats showed a definite retardation of body weight gain at 20% level
    and a slight retardation at 10%.  Organ weights and gross and
    microscopic examination revealed no adverse effects (McCollister
     et al., 1961).

         Groups of 10 male and 10 female young rats (unknown strain) were
    fed diets containing 0, 1, 3 and 10% hydroxypropyl methyl cellulose
    (higher viscosity, 31,800 cP) and 0, 1, 3, and 10% hydroxypropyl
    methyl cellulose (lower viscosity, 8,480 cP) for 92 days. No adverse
    effects were observed as judged by mortality, growth, general
    appearance and behavior, body weights, food consumption, hematological
    and serum chemistry analysis, organ weights and gross and histological
    examination (McCollister & Copeland, 1967).

         Groups of 10 male and 10 female Dow-Wistar rats were fed diets
    containing 0, 1, 3 and 10% low viscosity (10 cP) hydroxypropyl methyl
    cellulose for 90 days. Groups of 10 male and 10 female Sprague-Dawley
    rats were fed diets containing 0, 3 and 10% high viscosity (4000 cP)
    hydroxypropyl methyl cellulose for 90 days. No evidence of toxicity

    was observed in either strain of rats as judged by mortality, body
    weights, food consumption, urine and hematological analyses, serum
    chemistry, organ weights and gross and histological examination
    (McCollister  et al., 1973).

         Groups of 15 male and 15 female Sprague-Dawley rats were fed
    diets containing 0, 1 and 5% low viscosity (4.22 cP) hydroxypropyl
    methyl cellulose for 90-91 days. No evidence of toxicity was observed
    in rats as judged by mortality, body weight, food consumption, urine
    and hematology analyses, serum chemistry, organ weights and gross and
    histological examination (Schwetz  et al., 1973).

         Groups of 5 male Wistar rats were fed diets containing either 0
    or 100 g hydroxypropyl methyl cellulose/kg bw for 12 days. The
    hydroxypropyl methyl cellulose diet led to an enlargement of the cecum
    and colon associated with increased contents and tissue weight. The
    density of bacteria in the cecum and colon of animals fed
    hydroxypropyl methyl cellulose was significantly reduced over the
    fibre-free controls. The authors concluded that the cecal and colonic
    hypertrophy is a physical response to the increased content bulk
    (Wyatt  et al., 1988).

    2.2.2.2  Rabbits

         Groups of 6 rabbits were fed diets containing 0, 10 and 25%
    hydroxypropyl methyl cellulose, type B, for 30 days. The group on the
    highest dose maintained, but did not increase, their body weight.
    Normal results were obtained from urine and blood analyses, comparison
    of organ weights and histological examination (Hodge  et al., 1950).

    2.2.2.3  Dogs

         Groups of two dogs were fed for one year 0.1, 0.3, 1.0 and
    3.0 g/kg bw/day of hydroxypropyl methyl cellulose, type B, without
    effect on body and organ weights, urine, blood and microscopic
    appearance of internal organs.  One dog fed 25 g/kg bw/day for 30 days
    suffered no ill effects. Another dog fed 50 g/kg bw/day for 30 days
    exhibited some diarrhea, slight weight loss and slight depression of
    red blood cell count without any histological changes (Hodge
     et al., 1950)

         Groups of 2 male and 2 female beagle dogs were fed diets
    containing 0, 2 and 6% low viscosity (10 cP) hydroxypropyl methyl
    cellulose for 90 days. No evidence of toxicity was observed in dogs as
    judged by mortality, body weight, food consumption, urine and
    hematological analyses, serum chemistry, organ weights and gross and
    histological examination (McCollister  et al., 1973).

         Groups of 4 male and 4 female beagle dogs were fed diets
    containing 0, 1 and 5% low viscosity (4.22 cP) hydroxypropyl methyl
    cellulose for 90-91 days.  No evidence of toxicity was observed in
    dogs as judged by mortality, body weight, food consumption, urine,
    hematology, and serum chemistry analyses, organ weights and gross and
    histological examination (Schwetz  et al., 1973).

    2.2.3  Long-term/carcinogenicity studies

    Rats

         Groups of 50 male and 50 female rats were fed for two years on
    diets containing 0, 1, 5 and 20% of hydroxypropyl methyl cellulose,
    type B. There was a slight  retardation of body weight gain in the
    male group at the highest dose. Mortality ranged from 60 to 84% with
    no significant difference between the groups. Tumour incidence was the
    same in the experimental groups as in controls (Hodge  et al., 1950).

    2.2.4  Reproduction studies

         No data available.

    2.3  Observations in man

         Twenty-five young adults ingested doses ranging from 0.6 to
    8.9 g of hydroxypropyl methyl cellulose, type B, on three separate
    occasions.  Only a mild laxative or constipating effect was noted in
    several cases. About 97% of the dose, determined as methoxy groups,
    was recovered from feces (Knight  et al., 1952).

    METHYL CELLULOSE

    2.1  Biochemical aspects

    2.1.1  Absorption, distribution and excretion

         Methyl cellulose is usually resistant to microbial attack
    (Bargen, 1949). In rats it was not hydrolyzed to cellulose and
    methanol in the intestinal tract and it did not appear to be absorbed
    (Bauer & Lehman, 1951).

         Investigations on two male adults and one 10-year-old girl showed
    that methyl cellulose passed through the digestive tract practically
    unaltered. When 5-10 g of methyl cellulose were ingested the recovery
    of methoxyl groups from the feces was almost quantitative. Methanol
    formation after the taking of methyl cellulose was not significantly
    different from that observed under normal conditions (Machle  et al.,
    1944).

         It has been stated that methyl cellulose could be partly
    hydrolyzed in the digestive tract to units of lower molecular weight,
    as indicated by a decrease in viscosity. Such intermediate products
    obtained after acid hydrolysis were fed to mice at a dose of 1 g daily
    for 28 days without any demonstrable effect on the growth rate
    (Letzig, 1943).

         There is some evidence for the excretion of methyl cellulose into
    the milk of pregnant rats and this causes transient anemia in suckling
    rats (Baldini, 1958).

         In rats, a one-time dose of 500 mg/kg bw of [14C]methyl
    cellulose (labelled in the methoxyl group, and with a viscosity of
    3300 cP) was excreted in its entirety (102.2%) in the feces within 48
    hours. No radioactivity was detected in the expired air and less than
    0.1% of the original dose of radioactivity was found in the urine,
    selected tissues and remaining carcass. In rats receiving multiple
    doses of labeled methyl cellulose for 5 days, no accumulation of 14C
    activity was observed in the body or in selected tissues (Braun
     et al., 1974).

         When sucrose-based diets containing 8% methyl cellulose of either
    low (25 cP), medium (400 cP) or high (1500 cP) viscosity was fed to
    male rats (Hooded Wistar strain) for 10-11 days, neither food intake
    nor growth were affected by consumption of methyl cellulose.

         Tritium incorporation from i.p.-injected tritiated water into
    fatty acids and cholesterol in the liver was decreased. The authors
    concluded that the decreased hepatic fatty acid synthesis, decreased
    serum glucose and increased glycogen storage observed in treated rats
    could be explained by a slower absorption rate with increasing
    viscosity of the methyl cellulose diets.  No effect of methyl

    cellulose was noted on cholesterol metabolism, and no evidence was
    found to suggest that methyl cellulose is fermented by gut microbial
    flora in the rat (Topping  et al., 1988).

    2.2  Toxicological studies

    2.2.1  Acute toxicity

         LD50 values for methyl cellulose have not been found in the
    literature.  In dogs, single intravenous injections of 40 ml of 0.7 to
    2.8% solutions of methyl cellulose in saline resulted, within 24
    hours, in a moderate anemia and leukopenia and an increased
    sedimentation rate (Hueper, 1944). In rabbits, intravenous injections
    of 10 to 100 mg methyl cellulose/kg bw in a 1% solution had no effect
    on blood pressure or respiration (Wiedersheim  et al., 1953).  In
    man, single oral doses of 5 and 10 g of methyl cellulose were well
    tolerated (Machle  et al., 1944).

         Intravenous injection of a 1% solution of methyl cellulose in
    rabbits induced subintimal deposits of methyl cellulose at arterial
    walls followed by extensive calcification, ossification, cartilage
    formation and lipid deposition (Stehbens & Silver, 1966).

    2.2.2  Short-term studies

    2.2.2.1  Rats

         A group of 10 rats (5 male and 5 female) was fed a diet
    containing 10% methyl cellulose for 95 days. The male rats gained
    weight at the same rate as the controls. The females showed lower food
    intake and slight growth depression.  No abnormalities were found at
    autopsy or on microscopic examination. Weights of the heart, liver,
    spleen and kidney were normal. The stomachs were 15% heavier in the
    experimental group than in the controls (Tainter, 1943).

         Eighty rats received methyl cellulose at the level of 0.8% in the
    diet and 1% in the drinking-water for 8 months. This was equivalent to
    an average total daily intake of 436 mg of methyl cellulose per
    animal. No effect on growth rate was observed in any of the animals.
    Water and food intake were normal. No gross or microscopic
    pathological changes were found post mortem (Deichmann & Witherup,
    1943).

         Groups of 5 female rats were fed diets containing 1.66% and 5%
    methyl cellulose for six months without any adverse effects (Bauer
     et al., 1944).

         Three groups of 10 rats (5 male and 5 female) were given diets
    containing 0.17% (changed after six weeks to 0.5%) and 5% methyl
    cellulose for eight months. No deleterious effect on growth was
    recorded, and macroscopic and microscopic examination of

    representative animals revealed essentially normal tissues. Deposition
    of abnormal material in the tissues was not observed.  Reproduction
    was unimpaired through three generations. Second and third generation
    rats fed a diet containing 5% methyl cellulose for 4 months responded
    normally (Bauer & Lehman, 1951).

         A modified paired feeding experiment was conducted on three
    groups of rats for 90 days; one group received a diet containing 50%
    methyl cellulose, one a diet containing 50% cellulose powder, and one
    the basal diet. Growth depression was seen in the first two groups.
    Subsequent replacement of the methyl cellulose or cellulose diet by
    the basal diet resulted in marked weight gain (Bauer & Lehman, 1951).

         In 28-day experiments with groups of 10 rats, some normal and
    others vitamin-depleted, the oral administration of 50 mg of methyl
    cellulose did not affect the absorption of either 6 g of thiamine or
    3 units of vitamin A per day, as determined by weight gain (Ellingson
    & Massengale, 1952).

         Four intraperitoneal injections over 10 days of a maximal total
    dose of 160 mg of methyl cellulose produced arterial hypertension and
    glumerulo-nephritis in rats given a 1% NaCl solution to drink. In a
    further experiment on rats, methyl cellulose was shown to deposit in
    the renal glomeruli, leading to reduction of filtration and sodium
    accumulation if the latter is given as well. Hypertension and
    glomerular lesions developed (Hall & Hall, 1962).

         Intravenous injections of 1% methyl cellulose were given to rats
    at three-day intervals, which produced splenic enlargement 21 days
    after the last injection. Survival time studies on red cells showed
    that the enlarged spleens destroyed red cells more quickly (Fitch
     et al., 1962).

         Intraperitoneal injections of 2.5% methyl cellulose solution
    twice weekly into adult rats for one to 16 weeks reduced hematocrits
    and increased spleen weights in a dose-dependent manner. Foam
    histiocytes accumulated in the spleen pulp and sinusoids. Electron
    microscopic observations suggested lysosomal ingestion with
    phagolysosome formation (Lawson & Smith, 1968).

         Groups of 10 male and 10 female Sprague-Dawley (Spartan strain)
    rats were fed for 90 days on diets containing methyl cellulose with a
    viscosity of 10 cP (0, 1, 3 and 10%) or a viscosity of 4000 cP (0, 3
    and 10%). Male rats consuming 10% methyl cellulose (viscosity of 10
    cP) exhibited slight reductions in terminal body weight relative to
    controls, but growth was normal in all other 10 cP treatment groups,
    and in all rats consuming the 4000 cP methyl cellulose.  Food
    consumption was significantly elevated (up to 10%) at certain
    treatment levels in rats consuming either of the 2 methyl cellulose
    preparations as described in the following table:

                                                  
                            Food    Consumption
    Viscosity      Dose     Males     Females
                                                  

    10 cP            3%       N          N
                    10%       I          N
    4000 cP          3%       I          N
                    10%       I          I
                                                  

    I = significant increase relative to controls
    N = no significant change relative to controls

    No significant treatment-related effect was observed on other
    toxicological parameters examined in the study, including serum
    chemistry, hematology, urinalyses, organ weights and pathology (gross
    and microscopic). No accumulation of test material in the
    reticuloendothelial system could be detected by histopathologic
    examination (McCollister,  et al., 1973).

    2.2.2.2  Dogs

         Two dogs were fed doses of methyl cellulose increasing from 2 to
    100 g daily for one month without any noticeable effect (Bauer, 1945).

         Solutions containing 0.7 to 2.8% methyl cellulose of different
    molecular weights in 1% NaCl were administered by i.v. injection to 18
    dogs in doses of 40 to 130 ml for 5 days a week.  The maximum total
    dose of 5720 ml was injected within six months. Most of the animals
    died. Hematological reactions and the formation of foam cells were
    observed (Hueper, 1944).

    2.2.3  Long-term/carcinogenicity studies

    2.2.3.1  Rats

         Groups of 30 Sprague-Dawley rats (Spartan strain) of each sex
    were fed diets containing 0, 1% or 5% methyl cellulose of viscosity
    15, 400 or 4000 cP for 2 yr. Gross pathological examinations were
    conducted on terminally ill rats or rats dying during the study, and
    on remaining survivors at termination. During necropsy, sections of
    grossly visible nodules or masses were preserved for histopathological
    examination. There was no indication of increased tumour incidence in
    rats receiving the methyl cellulose diets (McCollister  et al.,
    1973).

         Groups of 20 Sprague-Dawley rats (Spartan strain) of each sex
    were fed chow diets containing 0, 1% or 5% methyl cellulose of
    viscosity 15, 400 or 4000 cP for 2 yr. At termination, gross
    pathologic examinations were performed and blood was sampled (5 rats

    from each sex) for hematologic evaluation (PCV, Hb, and WBC counts)
    and serum chemistry (BUN and AP). Additional groups of rats fed the
    same diets were interim sacrificed at 12 and 18 mos. and subjected to
    either gross pathologic examination (10 rats of each sex) or tested
    for hematology and serum chemistry parameters. During necropsy,
    selected tissues (lungs, heart, liver, kidneys, spleen, and testes)
    were weighed and, with pancreas and adrenals, preserved for
    histopathological evaluation. No treatment-related effect was reported
    on mortality or any other test parameters over the course of the study
    (McCollister  et al., 1973).

         Subcutaneous implantation of 500 mg of methyl cellulose as a
    powder in 25 rats failed to demonstrate carcinogenic properties
    (Hueper, 1959).

    2.2.4  Reproduction studies

         No data available.

    2.2.5  Special studies on teratogenicity

    2.2.5.1  Mice

         Groups of 12-17 pregnant mice were administered daily gavage
    doses of a methyl cellulose suspension in corn oil (70, 153, 330 and
    700 mg/kg bw/day) during days 6-15 of pregnancy. Control groups
    received daily doses of corn oil (negative control) or acetylsalicylic
    acid (110 mg/kg bw, positive control) during the same period of
    pregnancy. On day 17 of pregnancy, dams were subjected to Cesarian
    section and examination of uterine contents. No dose-related effects
    on growth, mortality or incidence of gross lesions were observed in
    treated dams. However, significant reductions in the number of
    implantations, live fetuses, and corpora lutea were observed in high
    dose dams, relative to corn oil controls. No increase in incidence of
    external, visceral and skeletal abnormalities, reduced weight or
    mortality was observed in fetuses from treated dams (Cannon Labs,
    1975).

         Groups of 20-22 pregnant mice were administered daily gavage
    doses of a methyl cellulose suspension in corn oil (0, 16, 74, 345,
    1600 mg/kg bw/day) during days 6-15 of pregnancy. Control groups
    received daily doses of corn oil (negative control) or aspirin
    (150 mg/kg bw, positive control) during the same period of pregnancy.
    On day 17 of pregnancy, dams were subjected to Cesarian section and
    examination of uterine contents.  Methyl cellulose administered at
    levels up to 345 mg/kg bw/day had no effect on nidation or on maternal
    or fetal survival.  However, a significant increase in mortality was
    observed in high dose dams, with a reduced rate of pregnancy in
    survivors. At term, resorption sites were markedly increased in
    number, and live fetuses were significantly reduced in number and
    retarded in maturation and in weight. No evidence of teratogenic

    effects was seen in fetuses from high dose dams or from dams receiving
    lower levels of treatment (Food and Drug Research Laboratories, Inc.,
    1973).

    2.2.5.2  Rats

         Groups of 13-18 pregnant rats were administered daily gavage
    doses of a methyl cellulose suspension in corn oil (120, 260, 550 and
    1200 mg/kg bw/day) during days 6-15 of pregnancy. Control groups
    received daily doses of corn oil (negative control) or acetylsalicylic
    acid (250 mg/kg bw, positive control) during the same period of
    pregnancy. On day 20 of pregnancy, dams were subjected to Cesarian
    section and examination of uterine contents. No dose-related effects
    on growth, mortality or incidence of gross lesions were observed in
    treated dams. The incidences of implantations, live fetuses, corpora
    lutea, dead fetuses and resorptions in treated dams were within the
    normal range. No increase in incidence of external, visceral and
    skeletal abnormalities was observed in fetuses from treated dams, with
    the exception of an increased incidence of extra centers of
    ossification in vertebrae of fetuses from high dose dams. Fetal
    weights were not affected by treatment (Cannon Labs, 1977).

         Groups of 20-25 pregnant rats were administered daily gavage
    doses of a methyl cellulose suspension in corn oil (13, 51, 285, 1320
    mg/kg bw/day) during days 6-15 of pregnancy. Control groups received
    daily doses of corn oil (negative control) or aspirin (150 mg/kg bw,
    positive control) during the same period of pregnancy. On day 20 of
    pregnancy, dams were subjected to Cesarian section and examination of
    uterine contents. No dose-related effects on growth, mortality or
    incidence of gross lesions were observed in treated dams. The
    incidences of implantations, live fetuses, dead fetuses and
    resorptions in treated dams were within the normal range. No increase
    in incidence of external, visceral and skeletal abnormalities was
    observed in fetuses from treated dams, with the exception of an
    increased incidence of extra centers of ossification in vertebrae of
    fetuses from high dose dams, nor were fetal weights affected by
    treatment (Food and Drug Research Laboratories, Inc., 1973).

    2.2.5.3  Hamsters

         Groups of 22-24 pregnant hamsters were administered daily gavage
    doses of a methyl cellulose suspension in corn oil (10, 46, 216, 1000
    mg/kg bw) during days 6-10 of pregnancy. Control groups received daily
    doses of corn oil (negative control) or aspirin (250 mg/kg bw,
    positive control) during the same period of pregnancy. On day 24 of
    pregnancy, dams were subjected to Cesarian section and examination of
    uterine contents. No dose-related effects on growth, mortality or
    incidence of gross lesions were observed in treated dams. The
    incidence of implantations, live fetuses, dead fetuses and resorptions
    in treated dams was within the normal range. No increase in incidence
    of external, visceral and skeletal abnormalities was observed in

    fetuses from treated dams, nor were fetal weights affected by
    treatment (Food and Drug Research Laboratories, Inc., 1973).

    2.2.5.4  Rabbits

         Groups of 10-17 pregnant rabbits were administered daily gavage
    doses of a methyl cellulose suspension in corn oil (7, 32, 148, 685
    mg/kg bw) during days 6-18 of pregnancy. Control groups received daily
    doses of corn oil (negative control) or 6-aminonicotinamide (7 mg/kg
    bw, positive control) during the same period of pregnancy. On day 29
    of pregnancy, dams were subjected to Cesarian section and examination
    of uterine contents. Dams treated at the highest dose level
    experienced increased mortality and a decrease in pregnancy rate in
    survivors, but no dose-related effects on growth or incidence of gross
    lesions were observed. The incidence of corpora lutea, implantations,
    live fetuses, dead fetuses and resorptions in treated dams was within
    the normal range. No increase in incidence of external, visceral and
    skeletal abnormalities was observed in fetuses from treated dams, nor
    were fetal weights affected by treatment (Food and Drug Research
    Laboratories, Inc., 1973).



    
    2.2.5  Special studies on genotoxicity

    Results of genotoxicity assays on methyl cellulose

                                                                                                 

                                             Concentration of
    Test System           Test Object        Methyl cellulose    Results     Reference

                                                                                                 

    Ames test             S.typhimurium      50 g/plate         Negative    Blevins &
    (1)                   TA98, TA100                                        Taylor, 1982
                          TA1535, TA1537,
                          TA1538

    Ames test             S.typhimurium      <70 mg/plate        Negative    Ishidate, Jr.,
    (1)                   TA92, TA94,                                         et al.,
                          TA98, TA100,                                       1984
                          TA1535, TA1537,
                          TA1538

    Host-mediated         S.typhymurium      1 x 4.75, 47.5      Negative    Litton
    assay in rats/        TA1530. G46        & 475 mg/kg bw                  Bionetics,
    reverse mutagenesis                      & 5 x 5000 mg/kg                1974
                                             bw/day

    Host-mediated         S.cerevisiae       1 x 4.75, 47.5      Negative    Litton
    assay in rats/        TA1530, G46        & 475 mg/kg bw                  Bionetics
    mitotic                                  & 5 x 5000 mg/kg                1974
    re-combination                           bw/day

    Chromosomal           Chinese hamster    <4.0 mg/ml          Negative    Ishidate, Jr.,
    Aberration            fibroblast                                          et al.,
                           in vitro                                            1984
                                                                                                 

                                                                                                 

                                             Concentration of
    Test System           Test Object        Methyl cellulose    Results     Reference

                                                                                                 

    Chromosome            Human embryonic    80, 800 & 8000      Negative    Litton
    Aberration            lung cells         g/ml                           Bionetics
    Induction             (WI-38)                                            1974
                           in vitro

    Chromosome            Rat Bone           1 x 4.75, 47.5      Negative    Litton
    Aberration            Marrow cells       475 mg/kg bw                    Bionetics
    Induction              in vivo            & 5 x 5000 mg/kg                1974
                                             bw/day

    Dominant              Male Rats          1 x 4.75, 47.5      Negative    Litton
    Lethal Assay                             475 mg/kg bw                    Bionetics
                                             & 5 x 5000 mg/kg                1974
                                             bw/day
                                                                                                 

    (1)  Both with and without rat liver S-9 fraction.
    

    2.3  Observations in man

         In 3 healthy adults, 5 g of methyl cellulose given twice a day
    for 8 days approximately doubled the volume of the stools and
    increased their frequency slightly (Tainter, 1943).

         There was no evidence of toxicity when 1-6 g of methyl cellulose
    were taken daily as a laxative for 4 to 240 days (maximum 6 g for 240
    days) by 37 patients (Schweig, 1948).

         In another study, doses of 2.5 to 5.25 g of methyl cellulose
    taken orally as a gel in 250 ml of water were mildly constipating
    (Bauer, 1945).

         Patients have been given 2 g of methyl cellulose before meals
    without toxic reactions (Bargen, 1949).

         Two patients given 60-90 ml of a methyl cellulose preparation
    daily for 5 days developed generalized edema, visual disturbances and
    neurological signs which disappeared within 72 hours of cessation of
    intake.  Symptoms were paralleled by sodium and water retention,
    increased serum osmolality and reduced urinary aldosterone excretion
    (Crane  et al., 1969).

         Five adult male volunteers were given 250 mg methyl cellulose/kg
    bw daily, divided into 3 equal portions, over a period of 23
    consecutive days.  The treatment was well tolerated, producing no
    allergic responses or alteration in normal elimination patterns.
    Methyl cellulose, administered as a prehydrated gel, caused increased
    fecal weight (wet and dry basis), but had variable effects on
    intestinal transit time, causing increased transit time in three
    subjects and decreased transit time in the other two. Hematology,
    serum biochemistry and urinalysis parameters remained within normal
    limits. Small, but significant, reductions were observed in fecal
    volatile fatty acids and neutral sterols, but breath hydrogen levels
    were not affected (Eastwood  et al., 1988).

         Fifty healthy adults (44 women and 6 men, 18-70 yr of age) were
    administered  daily doses of bulk laxative containing either a placebo
    or methyl cellulose (4000 cP, 30% substitution, 2 or 4 g) for a 1 wk
    period. All subjects had received placebo for the week preceding
    treatment. In a second phase of the study, 59 adults (56 women, 3 men)
    suffering from constipation were administered daily doses of either
    methyl cellulose (1, 2, or 4 g) or 3.4 g psyllium as a positive
    control for a 1 wk period. All stools generated during the study were
    weighed and analyzed for solids and moisture content. Stool moisture
    content and frequency of bowel movements were increased in normal
    adults consuming 4 g of methyl cellulose, but they were unaffected at
    the 2 g level of exposure relative to the placebo period of the study.
    Stool size was unchanged, and no significant effect on stool
    consistency was noted by the patients.  Constipated adults experienced

    an increase in stool frequency with the psyllium control and with
    methyl cellulose at all dose levels. No significant increase in
    incidence of abdominal discomfort or flatulence was reported (Hamilton
     et al., 1988).

    METHYL ETHYL CELLULOSE

    2.1  Biochemical aspects

    2.1.1  Absorption, distribution and excretion

         After feeding a single dose of 0.6 g of methyl ethyl cellulose in
    the diet of rats some 90% of the dose was recovered from the feces by
    the end of the fourth day. Nearly all alkoxyl groups remained attached
    to the cellulose chain during passage through the gut (Gage, 1962).

    2.2  Toxicological studies

    2.2.1  Acute studies

         No data available.

    2.2.2  Short-term studies

    2.2.2.1  Chicken

         Day-old Arbor Acres chicks were apportioned into groups of 10 and
    fed low-fat, high-fat or high-protein diets containing 2% methyl ethyl
    cellulose or one of a variety of vegetable gums or other
    polysaccharides for 3 wks. Cellulose was used in the control diet.
    Chicks grew normally on the methyl ethyl cellulose diet. Feed intake
    was enhanced by 6% and nitrogen retention was increased by 14%, but
    fat absorption was not significantly changed relative to controls
    (Kratzer,  et al., 1967).

    2.2.3  Long-term/carcinogenicity studies

    2.2.3.1  Mice

         Groups of 50 male and 50 female mice were fed 0, 0.1 and 1% of
    methyl ethyl cellulose for two years. Body weight was slightly reduced
    in both sexes at the 1% level in the latter part of the test period.
    There was no difference between the groups in survival, tumour
    incidence, blood picture and gross and microscopic appearance of
    internal organs (Imperial Chemical Industries, 1966).

    2.2.3.2  Rats

         Groups of 50 male and 50 female rats were fed 0, 0.1 and 1% of
    methyl ethyl cellulose for 2 years. Body weight was reduced in males
    at the 1% level in the latter part of the test period. There was no
    difference between the groups in survival, tumour incidence, blood
    picture and gross and microscopic appearance of internal organs
    (Imperial Chemical Industries, 1966).

    2.2.4  Reproduction studies

         No data available.

    SODIUM CARBOXYMETHYL CELLULOSE

    2.1  Biochemical aspects

    2.1.1  Absorption, distribution and excretion

         Sodium carboxymethyl cellulose (CMC) is readily hydrolyzed by
    micro-organisms (Reese  et al., 1950).  Diastase and cellulases are
    stated to bring about the breakdown of this compound (Letzig, 1943).
    Pepsin and pancreatin, separately or in combination, do not attack the
    substance (Massatsch & Steudel, 1941).

         In 5 rats fed 5 g of CMC collectively, approximately 90% of the
    dose was recovered in the feces (Shelanski & Clark, 1948).

         Experiments on 6 rats during 4 periods of 10 days each showed
    that CMC given in the diet at levels of 5%, 10% and 14% was reclaimed
    quantitatively in the feces (Ziegelmayer  et al., 1951).

         [14C]-labelled CMC, containing up to 0.34% radioactive sodium
    glycolate, was given orally to 2 groups of 5 male rats each in a dose
    of 400 mg. No detectable activity (less than 0.02% of the dose) was
    found in the livers and kidneys and about 0.14% of the administered
    radioactivity was found in the 48-hour urine samples.  This amount,
    however, could be accounted for by the free radioactive glycolate
    present in the test compound (Wiebe  et al., 1962).

         Only about 50% of the intake of CMC could be recovered from the
    feces of two rabbits on diets containing 4.76% and 9% CMC. Two dogs
    received 10 g of CMC for one day and 20 g daily for the following 5
    days. The total doses were recovered quantitatively in the feces
    (Ziegelmayer  et al., 1951).

         Two human adults were given 30 g of CMC by mouth daily for 4 days
    and a third was given 20 g/day. About 90% of the compound was
    recovered from the feces (Ziegelmayer  et al., 1951).

    2.2  Toxicological studies

    2.2.1  Acute toxicity

                                                                            

    Species       Route     LD50(mg/kg bw)      Reference

                                                                        

    Rat           oral      15,000-27,000      Shelanski & Clark, 1948
                                               CTFA, 1977
                                               CTFA, 1978a,b
                                               CTFA, 1980

    Guinea-pig    oral      16,000             Shelanski & Clark, 1948
                                                                        
    
         Rats, guinea-pigs and rabbits showed no symptoms after
    administration by stomach tube of 300 mg/kg bw in three divided doses
    (Rowe  et al., 1944).

          Six rats given an intravenous injection of 1 ml of a 1.6%
    solution of CMC showed the presence of particles localized in cells of
    the reticulo-endothelial system 48 hours later (Jasmin & Bois, 1961).

          Four dogs given an i.v. injection of 40 ml of 0.25% CMC in 1%
    sodium chloride solution reacted with a transitory leukopenia (Hueper,
    1945).

    2.2.2  Short-term studies

    2.2.2.1  Rats

         Ten rats received 300 to 500 mg of CMC daily for two months
    without any adverse effect (Werle, 1941).

         Ten male and 15 female rats were fed a diet containing 5% CMC for
    201 to 250 days. Judged by growth rate, mortality, organ weights and
    the results of histopathological examination of the liver, kidney,
    spleen, pancreas, adrenal gland, testis and gastrointestinal tract,
    there were no significant differences between the treated and the
    control groups (Rowe  et al., 1944).

         Another group of 10 rats received a diet containing 20% of CMC
    for 63 days. Slight growth retardation and a laxative effect were
    observed.  Organ weights and both gross and microscopic pathological
    examination revealed no abnormalities (Rowe  et al., 1944).

         Two groups of 100 rats received 500 and 1000 mg/kg bw/day of CMC
    mixed in their diets for six months.  No adverse effects were observed
    in any of the experimental animals as determined by growth rate,
    fertility and examination of the blood, urine and main tissues
    (Shelanski & Clark, 1948).

         Six rats were fed 14% of CMC in the diet for five weeks without
    demonstrable deleterious effect (Ziegelmayer  et al., 1951).

         Ten rats given subcutaneous injections of CMC showed mast-cell-
    like elements within the adrenal medulla.  Changes in the
    adrenocortical cells and the presence of granules in the adrenal-vein
    were noted occasionally (Selye, 1955).

         Rodents (12 animals per group) were maintained for 21 days on a
    high-protein diet containing 0 or 15% sodium CMC of 10 viscosity
    grades (35-4500 cP) or 4 other vegetable gums. Animals were weighed on
    alternate days. Body weight gain for one sample of CMC exceeded that
    of controls and body weight gains for two CMC samples were less than
    that of controls.  Average fecal water content (measured as %) was
    increased in all CMC-fed animals from 1.9-3.0 fold, and average filled
    cecal weight (g/kg bw) was increased 1.5-3.3 fold relative to
    controls. It was noted that there was a tendency for CMC samples of
    low molecular weight to produce high fecal wet weights.  Measuring the
    viscosities of completely hydrated samples of CMC indicated that CMC
    can have large or narrow molecular weight distributions.  It was
    suggested that different molecular weight distributions in samples of
    CMC may produce different physiologic or dietary responses to CMC
    (Anderson, 1986).

    2.2.2.2  Guinea-pigs

         Two groups of 100 animals were fed CMC for six months at levels
    of 500 and 1000 mg/kg bw/day mixed in the diet. No signs of toxicity
    were observed.

         Two groups of 20 guinea-pigs received CMC in their diet at rates
    of 500 and 1000 mg/kg bw/day for one year. As judged by weight gain,
    gross and histopathological examination, no adverse effects were noted
    (Shelanski & Clark, 1948).

    2.2.2.3  Rabbits

         Three rabbits were fed CMC at levels of 4.8% and 9% in their diet
    for two periods of 15 days without any detectable toxic effects 
    (Ziegelmayer  et al., 1951).

    2.2.2.4  Dogs

         Two dogs were given daily doses of CMC (0.3-0.4 g/kg bw) in water
    by mouth for two months without adverse effects (Werle, 1941).

          Groups of 10 dogs were fed CMC in the diet at levels of 500 and
    1000 mg/kg bw/day for six months. Growth rate was the same in all
    groups.  Six animals from each group were examined post mortem.
    Histologically, the stomach, intestines, spleen, kidney, heart, lung
    and pancreas in treated animals were no different from those of
    controls (Shelanski & Clark, 1948).

         Five dogs received intravenous injections of 0.25% CMC in 1%
    sodium chloride solution in doses increasing from 40 ml to 150 ml for
    a maximum of three months. There were no gross pathological changes.
    Histopathological studies revealed uptake of CMC in the
    reticuloendothelial cells in the aorta (Hueper, 1945).

    2.2.2.5  Chickens

         Groups of 20 one-day-old chicks were maintained on diets
    containing 0 or 2% sodium CMC for 20 days. Addition of sodium CMC to
    the diet resulted in decreased growth rate (Vohra & Kratzer, 1964).

    2.2.3  Long-term/carcinogenicity studies

    2.2.3.1  Mice

         Groups of 50 male and 50 female mice were maintained for up to
    100 weeks on  ad libitum diets containing 0, 0.1 and 1% of sodium
    CMC. There was no apparent difference in mortality and tumour
    incidence between the groups (Imperial Chemical Industries, 1966).

         Groups of 50 male and 50 female B6C3F1 mice were used as vehicle-
    controls in a carcinogenicity study of selenium sulfide, and received
    50 mg/kg bw of CMC by gavage, 5 days per week for 103 weeks. Untreated
    mice served as controls. Test animals were observed twice daily and
    examined weekly for clinical signs and the presence of palpable
    lesions. Mean body weights were recorded every two weeks for the first
    12 weeks, then monthly for the remaining 93 weeks. Animals that were
    moribund and those that survived to the end of the study were
    necropsied.  Gross and microscopic examinations were performed on
    major organs and all gross lesions.  CMC-gavaged animals had
    approximately the same or fewer neoplasms than untreated control
    animals (NCI, 1979).

    2.2.3.2  Rats

         Groups of 25 rats, divided about equally by sex, were placed for
    two years on diets containing CMC in concentrations providing 100, 500
    and 1000 mg/kg bw daily. Three generations of litters were produced
    and kept on the same diet as their parents. According to growth rates,
    monthly urine and blood examinations, fertility, and histopathological
    examination of the main organs there were no differences between the
    test rats and the controls. No neoplasms were found in any of the
    experimental animals (Shelanski & Clark, 1948).

         Groups of 50 male and 50 female rats were maintained for up to
    two years on  ad libitum diets containing 0, 0.1 and 1% of sodium
    CMC. No difference in mortality and tumour incidence was apparent
    between the groups (McElligot & Hurst, 1968).

         Thirty rats were given weekly injections of 1 ml of a 2% aqueous
    solution of CMC subcutaneously.  After 73 weeks, 43% of the animals
    showed tumour s at the site of injection, characterized as
    fibrosarcomas of moderate malignancy (Lusky & Nelson, 1957).

         Twenty rats were given subcutaneous injections once a week of 2%
    aqueous solution of CMC.  In 4 animals, tumours developed at the site
    of injection within 13 to 16 months.  Two of the neoplasms were
    fibromas and two fibrosarcomas (Jasmin, 1961).

         Fifty F344 rats of each sex served as the vehicle control for a
    carcinogenicity study of selenium sulfide, and received 5 mg/kg bw of
    CMC by gavage five days per week for 103 weeks. Untreated rats served
    as controls. Test animals were observed twice daily and examined
    weekly for clinical signs and the presence of palpable lesions. Mean
    body weights were recorded every two weeks for the first 12 weeks,
    then monthly for the remaining 93 weeks. Animals that were moribund
    and those that survived to the end of the study were necropsied. 
    Gross and microscopic examinations were performed on major organs and
    all gross lesions.  Eighty percent of CMC-fed male rats and 76% of
    CMC-fed female rats survived until the end of the study. These
    percentages were similar to those for untreated rats.  CMC-gavaged
    animals had approximately the same or fewer neoplasms than untreated
    control animals (NCI, 1979).

    2.2.4  Reproduction studies

         No data available.

    2.2.5  Special studies on cecal microflora

         Groups of 6 male Sprague Dawley rats with conventional gut
    microflora were fed a purified diet containing 0 or 5% of CMC for 4
    weeks.  After 4 weeks, the rats were killed by cervical dislocation
    and the ceca removed; cecal contents from each animal were removed and
    maintained under anaerobic conditions for analysis of gut microflora
    and measurement of enzyme activities.  CMC decreased the final body
    weight of the rats by 9% compared to the control group.  The weight of
    the cecal wall was significantly increased as was the weight of cecal
    contents. Feeding CMC to rats significantly increased the total
    bacterial population of the cecum. No attempt was made to analyze the
    species composition of the microflora. Feeding CMC to rats also
    significantly increased  in vitro activity of bacterial azoreductase,
    beta-glucosidase, beta-glucuronidase, nitrate reductase, and urease.
    The greatest effect on for urease activity (elevated 5.3 fold) and
    beta-glucosidase activity (elevated 8.2 fold).  The authors suggested

    that the fact that feeding CMC increased the total activity of all
    enzymes studied may indicate that the beta-1,4-glucose backbone of CMC
    was susceptible to attack by the intestinal bacteria (Mallett
     et al., 1984).

         Groups of 5 male Wistar rats were fed a fiber-free synthetic diet
    containing 0 or 10% CMC, hydroxypropyl methyl cellulose, or
    carboxymethyl guar for 12 days. At termination, rats were anesthetized
    and killed by cervical dislocation; cecum and ascending colon were
    removed. All diets supplemented with non-digestible polysaccharides
    led to a visible enlargement of the cecum, which was associated with
    increased wet weight of contents and of tissue. The enlargement in the
    CMC-supplemented group was particularly marked, with an almost 8-fold
    increase in weight of cecal contents and a doubling of tissue weight. 
    Animals fed the CMC-supplemented diet had diarrhea (profuse unformed
    stools) from the 2nd day of feeding, and the total output of fecal
    material was significantly increased.

         CMC did not significantly increase the density of bacteria in the
    cecum and colon, but because of the increased cecal mass the absolute
    number of bacteria per cecum was elevated. The aerobic flora of the
    fiber-free controls was composed primarily of  Streptococcus spp.,
    but aerobic bacteria found in cecal and colonic contents of rats fed
    CMC were almost entirely  E.coli. No enterotoxin activity was
    detected in the  E.coli strains isolated from CMC-fed rats with
    diarrhoea, and serotyping showed that the strains belonged to groups
    that are not commonly associated with diarrhea in man.

         A substantial amount of unfermented CMC was present in the
    intestinal contents of rats fed the CMC-supplemented diet, and the
    proportion of CMC increased distally. The CMC appeared not to have
    been hydrolyzed to shorter chain lengths, as no increase in reducing
    ends could be demonstrated compared with animals maintained on the
    control diet.  CMC also was poorly fermented by cecal and colonic
    bacteria  in vitro. In addition, rats fed the CMC-supplemented diet
    had significantly lower short-chain fatty acid concentrations in the
    cecum.  The authors concluded that enlargement of the rat cecum in
    response to dietary non-digestible polysaccharides such as CMC can
    occur when the polysaccharide is resistant to fermentation (Wyatt
     et al., 1988).


    
    2.2.6  Special studies on genotoxicity

    Results of genotoxicity assays on CMC

                                                                                            

                                             Concentration
    Test System           Test Object           of CMC           Results     Reference

                                                                                            

    Ames test             S.typhimurium      5.0% Na CMC         Negative    Litton
    (1,3)                 TA1535,TA1537                                      Bionetics
                          TA1538                                             1975

    Ames test             S.typhimutrium     2.5, 5.0 & 10%      Negative    Litton
    (l,4)                 TA1535,TA1537      Na CMC                          Bionetics
                          TA1538                                             1975

    Ames test             S.typhimurium      0.5, 1, 10, 100,    Negative    Litton
    (2,3)                 TA98,TA100,        1000, 2500 & 5000               Bionetics
                          TA1535,TA1537      g Na CMC/plate                 1980
                          TA1538

    Ames test             S.typhimurium      <2.5 mg Na          Negative    Ishidate,
    (2,3)                 TA92,TA94,TA98,    Na CMC                          Jr.  et al.
                          TA100,TA1535,                                      1984
                          TA1537

    Recombinogenicity     S.cerevisiae       0.25, 0.50, 1.00%   Negative    Litton
                          D4 - ade           Na CMC                          Bionetics
                          D4 - try                                           1975
                                                                                            

                                                                                            

                                             Concentration
    Test System           Test Object           of CMC           Results     Reference

                                                                                            

    Chromosome            Chinese Hamster    <2.8 mg Na          Negative    Ishidate,
    Aberration            fibroblasts        Na CMC/ml                       Jr.  et al.
                                                                             1984
                                                                                            

    (1)  Both with and without rat, mouse or monkey liver, lung or testes
         S-9 fraction
    (2)  Both with and without rat liver S-9 fraction
    (3)  Plate incorporation assay
    (4)  Suspension assay
    


    2.2.7  Special studies on teratogenicity

    2.2.7.1  Mice

         Sodium CMC (0, 16, 74, 345, 1600 mg/kg bw/day) was administered
    as a corn oil solution by gavage to groups of 19-24 pregnant mice
    (Albino CD-1 outbred females) from days 6-15 of gestation. A positive
    control group of 24 pregnant mice received 150 mg aspirin/kg bw/day.
    All pregnant females survived until the end of the study.  No effects
    were observed on nidation or on maternal or fetal survival.  The
    number of abnormalities seen in either soft or skeletal tissues of the
    test groups did not differ from the number occurring spontaneously in
    sham-treated controls (Food and Drug Research Laboratories, 1975).

    2.2.7.2  Rats

         Sodium CMC (0, 16, 74, 345, 1600 mg/kg bw/day) was administered
    as a corn oil solution by gavage to groups of 19-22 pregnant rats
    (Wistar-derived) from days 6-15 of gestation. Nineteen pregnant rats
    (positive control group) were dosed with 250 mg aspirin/kg bw/day. All
    pregnant females survived until the end of the study.  No effects were
    observed on nidation or on maternal or fetal survival. The number of
    abnormalities seen in either soft or skeletal tissues of the test
    groups did not differ from the number occurring spontaneously in
    sham-treated controls (Food and Drug Research Laboratories, 1975).

         Twenty male rats (albino, Sprague-Dawley-derived) were treated at
    least 60 days and 40 female rats were treated at least 14 days before
    mating and during a 6-day mating period with 200 mg/kg bw/day by
    gavage; 20 male and 40 female rats were maintained under identical
    conditions but were not dosed with CMC (controls) For one half of the
    females, treatment was continued until sacrifice on day 14 of
    gestation; for the remaining half of the females, treatment continued
    until weaning of the progeny (day 28 after birth).

         No reactions to treatment with CMC were noted in the parents. 
    Average body weights were comparable throughout the experiment
    (however, the body weight gain for males treated with CMC was less
    than the body weight gain for control males at 7 of the 10 weighings).
    No difference was observed in mating efficiency or pregnancy rate. The
    mean numbers of corpora lutea and implantation sites, as well as the
    ratios of corpora lutea to implantation sites, were comparable in both
    the CMC-treated and control groups. The rate of resorptions was not
    significantly increased in the CMC-treated group. In both groups of
    rats, the normal pregnancy duration was maintained (21-22 days) and no
    disturbances of parturition were noted. No significant difference was
    noted in litter size and sex ratio between the CMC-treated and control
    groups.

         The body weight gain of the pups was comparable for both groups. 
    No abnormal nesting behavior (nursing, suckling, and creeping) was
    noted, and eye opening and pinna detachment followed the normal course
    in both groups.  Results of behavioral tests (which included righting
    reflex, photophobotaxis, cliff avoidance, palmar grasp ability,
    negative geotaxis, and exploratory locomotion pattern in a cylindrical
    cage, direct pupillary reflex, and hearing ability by startle
    response), were comparable in test and control offspring  (Fritz &
    Becker, 1981).

    2.3  Observations in man

         Daily oral doses of 20 to 30 g of Na CMC for seven days were well
    tolerated by 3 human subjects (Ziegelmayer  et al., 1951).

         Eleven patients received 10 g of Na CMC daily for six months
    without complaint, but in seven further cases the dose had to be
    reduced owing to abdominal discomfort. No hematological changes were
    observed (Brick, 1952).

         Adult patients have been treated for more than a year with daily
    oral doses of 2-6 g of CMC as a laxative and there were no ill effects
    (Brick, 1949; Fittipoldi & Davis, 1948; Schultz, 1949).

         Skin tests on 100 men and 100 women demonstrated that sodium CMC
    is not a primary irritant or a sensitizer (Shelanski & Clark, 1948).

         Twelve men (26-62 years of age; mean age of 38) weighing from
    77.5 to 111.5 kg (mean weight 88.7 kg) consumed a basal diet
    containing four refined fibers (cellulose, CMC, locust bean gum, or
    karaya gum) at a level of 0.75 g fiber/100 calories (19.1 to
    26.0 g/day). Each of the four fibers were fed for 4 weeks in a
    randomized rotation pattern throughout the study, so that each fiber
    was followed by every other fiber. The basal diet contained 14.6% of
    calories as protein, 35% of calories as fat (641 mg cholesterol), and
    50.4% of calories as carbohydrate, with a relatively low amount of
    endogenous fiber. Caloric intake ranged from 2550 to 3600 kcal/day. At
    the end of each 4-week dietary period, fasting plasma cholesterol
    (HDL, LDL, and VLDL), serum total cholesterol, triglycerides, and free
    fatty acids were determined. At the end of 4 weeks, total serum
    cholesterol had dropped significantly (from 196 mg/dl base line, to
    164 mg/dl after CMC) and plasma LDL decreased significantly (from
    131 mg/dl to 107 mg/dl). No statistically significant changes were
    observed in triglycerides, free fatty acids, VLDL, or HDL levels. The
    HDL/(VLDL+LDL) ratio after consuming CMC-supplemented diets for 4
    weeks was significantly higher than the ratios after consumption of
    the basal diet alone or of the cellulose-supplemented basal diet
    (Behall  et al., 1984).

         Five healthy men (24-58 yrs of age, weighing 73-84 kg each)
    consumed 15 g CMC daily (5 g CMC, 3 times a day) for 23 days following
    a 7-day control period.  Results of a diet inquiry for the 1st and 4th
    weeks of the experiment showed no differences in individual intakes of
    protein, fat, carbohydrate, sugar, alcohol, and fiber. CMC was well
    tolerated by all subjects and no adverse effects were observed. CMC
    had no effect on plasma biochemistry, urinalysis, glucose tolerance,
    serum cholesterol, triglyceride and phospholipids, breath hydrogen and
    methane concentrations. The average intestinal transit time decreased.
    Fecal wet and dry weights increased substantially when CMC was added
    to the basal diet. Mean fecal bile acid levels and fecal fat content
    increased.  The mean excretion of neutral sterols decreased from 48 to
    29 umol sterols/g dry weight of feces (Anderson  et al., 1986;
    Anderson, 1986).

    3.  COMMENTS

         Since the previous evaluation, additional data have become
    available. These data include studies in rats on cecal enlargement and
    changes in cecal flora, teratology and development, as well as
     in vitro mutagenicity studies on methyl cellulose and carboxymethyl
    cellulose.

         These studies confirmed the conclusion of the earlier meetings of
    the Committee that modified celluloses have a low toxicity.

         Long-term/carcinogenicity studies on hydroxypropyl methyl
    cellulose, methyl cellulose, methyl ethyl cellulose, and sodium
    carboxymethyl cellulose in rats and mice are available.  No evidence
    of mutagenicity or carcinogenicity has been observed.  Reproduction
    and teratology studies with hydroxypropyl cellulose, methyl cellulose,
    and sodium carboxymethyl cellulose have been performed in mice, rats
    and rabbits.  The consumption of these modified celluloses did not
    interfere with the reproductive process, and no embrytoxic or
    developmental effects were observed.

         A new substantial body of human data was available investigating
    the laxative effects of modified celluloses which occurs in some
    subjects at levels as low as 5 g/person/day.  At higher doses diarrhea
    has been reported in some subjects, but in others constipation
    developed.  Studies in humans did not exceed the addition of 30
    g/person/day.  An intake of 30 g/day has been recommended as the upper
    safe level of dietary fiber in general (NRC, 1989).

    4.  EVALUATION

    Estimate of acceptable daily intake

         ADI "not specified".  The ability to produce laxation should be
    taken into account when using these substances as food additives.  See
    p.78 for the definition of "ADI not specified".

    5.  REFERENCES

    ANDERSON, D.M.W., EASTWOOD, M.A. & BRYDON, W.G. (1986).  The dietary 
    effects of sodium carboxymethylcellulose in man.  Food Hydrocolloids
    1, 37-44.

    ANDERSON, D.M.W. (1986).  Some dietary effects of the ingestion of
    sodium carboxymethylcellulose by man and rodents.  Unpublished Report
    from University of Edinburgh. Submitted to WHO by Organisation des
    Fabricants Cellulosiques Alimentaires (OFCA).

    BALDINI, M. (1958).  Proc. 6th Int. Congr. Int. Soc. Haematol., New
    York, GR & STR.

    BARGEN, J.A. (1949).  A method of improving function of the bowel: the
    use of methylcellulose.  Gastroenterology 13, 4, 275-278.

    BAUER, R.O. (1945).  Methyl cellulose: its laxative action and effects
    of chronic feeding on growth and reproduction.  Fed. Proc. 4, 112.

    BAUER, R.O. & LEHMAN, A.J. (1951).  Chronic toxicity studies on methyl
    cellulose in rats.  J.Amer.Pharm.Assoc.,Sci.Ed. 40, 257-260.

    BAUER, R.O., LEHMAN, A.J. & YONKMAN, F.F. (1944).  Chronic toxicity of
    an alkyl ether of cellulose, methyl cellulose.  Fed.Proc. 3, 65-66.

    BEHALL, K.M., LEE, K.H. & MOSER, P.B. (1984).  Blood lipids and
    lipoproteins in adult men fed four refined fibers.  Am.J.Clin.
     Nutrition, 39, 209-214.

    BLEVINS, R.D. & TAYLOR, D.E. (1982).  Mutagenicity screening of
    twenty-five cosmetic ingredients with the Salmonella/microsome test. 
     J.Environ.Sci. Health, A17, 217-239.

    BRAUN, W.H., RAMSEY, J.C. & GEHRING, P.J. (1974).  The lack of
    significant absorption of methylcellulose, viscosity 3300 cp. from the
    gastrointestinal tract following single and multiple oral doses to the
    rat.  Fd.Cosm.Toxicol. 12, 373-376.

    BRICK, J.B. (1949).  Experiences with sodium carboxymethylcellulose as
    an antacid.  Amer.J.Dig.Dis. 16, 315-319.

    BRICK, J.B. (1952).  Effect of sodium carboxymethylcellulose on the
    blood cells.  Amer.J.Dig.Dis. 19, 248-250.

    CANNON LABS (1975).  Investigation of teratogenic and toxic potential
    of Methocel in mice.  Unpublished Report by Cannon Labs, Inc.,
    Reading, Pennsylvania.  Submitted to WHO by the U.S. Food and Drug
    Administration.

    CANNON LABS (1977).  Investigation of teratogenic and toxic potential
    of Methocel in rats.  Unpublished Report by Cannon Labs, Inc.,
    Reading, Pennsylvania.  Submitted to WHO by the U.S. Food and Drug
    Administration.

    CRANE, M.G., HARRIS, J.J., HERBER, R., SHANKEL, S. & SPECHT, N.(1969). 
    Excessive fluid retention related to cellulose ingestion - studies on
    two patients.   Metabolism 18, 945-960.

    CTFA - Cosmetics, Toiletries and Fragrance Association (1977).  Acute
    oral rat study on CG* (2-20-69).  Unpublished Report by  CTFA. 
    Abstract submitted to WHO by OFCA (Organisation des Fabricants de
    Produits Cellulosiques Alimentaires).

    CTFA - Cosmetics, Toiletries and Fragrance Association (1978a).  Acute
    oral rat study on HPMC (2/20/87).  Unpublished Report by CTFA.
    Abstract submitted to WHO by OFCA (Organisation des Fabricants de 
    Produits Cellulosiques Alimentaires).

    CTFA - Cosmetics, Toiletries and Fragrance Association (1978b).  Acute
    oral rat study on CG* (2-20-65).  Unpublished Report by CTFA.
    Abstract submitted to WHO by OFCA (Organisation des Fabricants de 
    Produits Cellulosiques Alimentaires).

    CTFA - Cosmetics, Toiletries and Fragrance Association (1980).  Acute
    oral rat study on CG* (2/20-57).  Unpublished Report by CTFA.
    Abstract submitted to WHO by OFCA (Organisation des Fabricants de 
    Produits Cellulosiques Alimentaires).

    CUTHBERT, J.A. (1975).  Report on the safety testing of four
    modocolls.  Unpublished Report (Project # 403428) by Inveresk. Res.
    Internat., Musselburgh, Scotland.  Submitted to WHO by OFCA
    (Organisation des Fabricants de Produits Cellulosiques Alimentaires).

    DEICHMANN, W. & WITHERUP, S. (1943).  Observations on the ingestion of
    methyl cellulose and ethyl cellulose by rats.  J.Lab.Clin.Med. 28,
    1725-1727.

    EASTWOOD, M.A., BRYDON, W.G. & ANDERSON, D.M.W. (1988).  The dietary
    effects of methyl cellulose in man.  Unpublished Report submitted to
    WHO by OFCA (Organisation des Fabricants de Produits Cellulosiques
    Alimentaires).

    ELLINGSON, R.C. & MASSENGALE, O.N. (1952).  Proc.Soc.Exp.Biol. (N.Y.)
    79, 92.

    ELLIOT, P.H., SMITH, P.A., STREET, A.E., GIBSON, W.A., BEGG, S.E.,
    OTTER, J.M.  & SHILLAM, K.W.G. (1985).  The effects of continuous
    dietary administration of ethylhydroxyethyl cellulose to rats for
    ninety days.  Unpublished Report from Huntingdon Research Centre,
    Huntingdon, England. Submitted to WHO by Huntingdon Research Centre.

    FITCH, F.W., ROWLEY, D.A. & BYE, I.J. (1962).   Arch.Path., 74, 397.

    FITTIPOLDI, J. & DAVIS, F.L. (1948).  Gastroenterology, 10, 667.

    FOOD & DRUG RESEARCH LABORATORIES, Inc. (1973).  Teratologic
    evaluation of FDA 71-51 (Methocel).  Unpublished Report by FDRL,
    Waverly, New York.  Submitted to WHO by the U.S. Food and Drug
    Administration.

    FOOD & DRUG RESEARCH LABORATORIES Inc. (1975).  Teratologic evaluation
    of FDA 73-69, sodium carboxymethylcellulose in mice and rats. 
    Unpublished Report by FDRL, Waverly, New York. Submitted to WHO by the
    U.S. Food and Drug Administration.

    FRITZ, H. & BECKER, H. (1981).  The suitability of carboxymethyl
    cellulose as a vehicle in reproductive studies.
     Arzneim.Forsch./Drug.Res. 31, 813-815.

    GAGE, J.C. (1962).  Unpublished report to WHO.

    GORZINSKI, S.J., TAKAHASHI, I.T. & HURST, G.H. (1986).  The fate of
    ultralow viscosity 14C-hydroxypropylmethylcellulose in rats
    following gavage adminis-tration.  Drug and Chem.Toxicol. 9, 83-100.

    HAKE, C.L. & ROWE, V.K. (1963).  Ethers. In Industrial Hygiene and
    Toxicology, Ed. Patty, F.A., Vol II, p.1717.  Interscience Publishers,
    New York.

    HALL, C.E. & HALL, O. (1962).  Dependency of macromolecular
    hypertension induced by methyl cellulose upon sodium chloride excess.
     Texas Reports Biol.  Med. 20, 587-598.

    HAMILTON, J.W., WAGNER, J., BURDICK, B.B. & BASS, P. (1988).  Clinical
    evaluation of methylcellulose as a bulk laxative.  Dig.Dis.Sci. 33,
    993-998.

    HODGE, C., MAYNARD, E.A., WILT, W.G., BLANCHET, H.J. & HYATT, R.E.
    (1950).  Chronic oral toxicity of a high gel point methyl cellulose
    (Methocel HG) in  rats and dogs.  J.Pharmacol.Exp.Ther. 99, 112-117.

    HUEPER W.C. (1944).  Reactions of the blood and organs of dogs after
    intravenous injections of solutions of methyl celluloses of graded
    molecular weights.   Amer.J.Path. 20, 737-771.

    HUEPER, W.C. (1945).  Experimental studies in cardiovascular
    pathology, XI.  Thesaurosis and atheromatosis produced in dogs by the
    repeated intravenous injection of solutions of sodium cellulose
    glycollate.  Am.J.Pathol. 21, 1021-1029.

    HUEPER, W.C. (1959).  Carcinogenic studies on water-soluble and
    insoluble macromolecules.  Arch.Path. 67, 589-617.

    IMPERIAL CHEMICAL INDUSTRIES (1961).  Methylethylcellulose as an
    emulsifying, aerating and foaming agent in foods.  Unpublished Report
    by ICI, Ayrshire, Scotland.  Submitted to WHO by OFCA (Organisation
    des Fabricants de Produits  Cellulosiques Alimentaires).

    IMPERIAL CHEMICAL INDUSTRIES (1966).  Food Additive Petition to the
    U.S. Food and Drug Administration. Sodium Carboxymethyl ethylcellulose
    as an emulsifying, aerating and foaming agent in foods.  Unpublished
    Report.

    INDUSTRIAL BIO-TEST LABORATORIES (1962).  Hydroxypropyl Cellulose.
    Unpublished Report submitted to WHO by Hercules Powder Co.

    INDUSTRIAL BIO-TEST LABORATORIES (1963).  Hydroxypropyl Cellulose.
    Unpublished Report submitted to WHO by Hercules Powder Co.

    INDUSTRIAL BIO-TEST LABORATORIES (1964).  Hydroxypropyl Cellulose.
    Unpublished Report submitted to WHO by Hercules Powder Co.

    ISHIDATE Jr., M., SOFUNI, T., JUSHIKAWA, K., HAYASHI, M., NOHMI, T.,
    SAWADA, M. & MATSUOKA, A. (1984).  Primary mutagenicity screening of
    food additives currently used in Japan.  Fd.Cosmet.Toxicol. 22,
    623-638.

    JASMIN, G. (1961).  Carcinogenic action of carboxymethyl cellulose.
     Rev.Can.  Biol. 20, 701-707.

    JASMIN, G. & BOIS, P. (1961).  Storage and tissue disposal of
    carboxymethyl cellulose injected into rats.  Rev.Can.Biol. 20,
    819-822.

    KITAGAWA, H., TOKUNAGA, T., EBIHARA, S., KAWANA, H., & SATOH, T.
    (1970). Acute Toxicities of Hydroxypropyl Cellulose in Mice and Rats.
     Pharmacometrics, 4, 1013-1015.

    KITAGAWA H., SAITO, H., YOKOSHIMA, T., NANBO, T., USHIODA, K., UEDA,
    T. &  OYABU, S. (1976a).  Absorption, distribution and metabolism of
    14C-Hydroproxy-propyl cellulose of low substitution.  Oyo Yakuri 12,
    33-9.

    KITAGAWA, H., YANO, H., SAITO, H. & FUKUDA, Y. (1976b).  Acute
    subacute and chronic toxicities of hydroxypropyl cellulose of low
    substitution in rats.  Oyo Yakuri 12, 41-66.

    KITAGAWA, H., SATOH, T., SAITO, H., KATOH, M., MAKITA, T. & HASHIMOTO,
    Y.  (1978a).  Teratological study  of hydroxypropylcellulose of low 
    substitution (L-HPC) in rats.  Oyo Yakuri 16, 271-298.

    KITAGAWA, H., SATOH, T., SAITO, H., KATOH, M., MAKITA, T. & HASHIMOTO,
    Y. (1978b).  Teratological study of hydroxypropylcellulose of low
    substitution (L-HPC) in rabbits.  Oyo Yakuri, 16, 259-269.

    KNIGHT Jr., H.F., HODGE, H.C., SAMSEL, E.P., DELAP, R.E. &
    McCOLLISTER, D.D.  (1952).  Studies on single oral doses of a high gel
    point methylcellulose.   Am.Pharmaceut.Assoc. 49, 427-429.

    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. 46, 1489-1493.

    LAWSON, N.S. & SMITH, E.B. (1968). Splenic ultrastructure in rats
    treated  with methylcellulose.  Arch.Path. 85, 179-188.

    LETZIG, E. (1943).  Digestibility and innocuousness of water-soluble
    cellulose derivatives.  Z.Untersuch.Lebensmitt. 85, 401-413.

    LITTON BIONETICS, Inc. (1974).  Mutagenic evaluation of compound, FDA
    71-51, Methocel.  Unpublished Report by Litton Bionetics, Kensington,
    Maryland.  Submitted to WHO by the U.S. Food and Drug Administration.

    LITTON BIONETICS, Inc. (1975).  Mutagenic evaluation of compound FDA
    73-69.  Sodium carboxymethylcellulose gum, low viscosity.  Unpublished
    Report by Litton Bionetics, Kensington, Maryland.  Submitted to WHO by
    the U.S. Food and Drug Administration.

    LITTON BIONETICS, Inc. (1980).  Mutagenicity evaluation of sodium-CMC,
    purified grade, in the Ames Salmonella/microsome plate test. 
    Unpublished Report by Litton Bionetics, Kensington, Maryland. 
    Submitted to WHO by the U.S. Food and Drug Administration.

    LUSKY, L.M. & NELSON, A.A. (1957).  Fibrosarcomas induced by multiple
    subcutaneous injections of carboxymethylcellulose (CMC),
    polyvinylpyrrolidone (PVP), and polyoxyethylene sorbitan monostearate
    (Tween 60).  Fed.Proc. 16, 318.

    MACHLE, W., HEYROTH, F.F. & WINTHERUP, S. (1944).  The fate of methyl
    cellulose in the human digestive tract.  J.Biol.Chem. 153, 551-559.

    MALLETT, A.K., WISE, A. & ROWLAND, I.R. (1984).  Hydrocolloid food
    additives and rat caecal microbial enzyme activities.  Fd.Chem.Toxic.
    22, 415-418.

    MASSATSCH, C. & STEUDEL, H. (1941).  Behavior of "Fondin" in
    metabolism.   Z.Untersuch Lebensmitt. 82, 249-252.

    McCOLLISTER, D.D. & COPELAND, J.R. (1967).  Results of 92 day dietary
    feeding studies of hydroxypropyl methylcelluloses NC-1214 and
    NC-1214.5 in rats. Un-published Report by Biochemical Research
    Laboratory, Dow Chemical Company. Sub-mitted to WHO by Dow Chemical
    Company, Midland, Michigan.

    McCOLLISTER, D.D. & OYEN, F. (1954).  Dietary feeding of a new methyl
    cellulose preparation to rats.  J.Amer.Pharm.Assoc.Sci.Ed. 43,
    664-666.

    McCOLLISTER, D.D., OYEN, F. & GREMINGER, G.K. (1961).  Dietary feeding
    of propylene glycol ethers of methylcellulose to rats.  J.Pharm.Sci.
    50, 615-620.

    McCOLLISTER, S.B., KOCIBA, R.J. & McCOLLISTER, D.D. (1973).  Dietary
    feeding studies of methylcellulose and hydroxypropylmethyl cellulose
    in rats and dogs.   Fd.Cosmet.Toxicol. 11, 943-953.

    McELLIGOTT, T.F. & HURST, E.W. (1968).  Long-term feeding studies of
    methylethylcellulose (Edifas A) and sodium carboxymethylcellulose
    (Edifas B) in rats and mice.  Fd.Cosmet.Toxicol. 6, 449-460.

    MORENO, O.M. (1977).  Unpublished Report to RIFM, 20 October.

    NCI - National Institute of Health, Bethesda, Maryland, USA (1979).
    Bioassay of selenium sulfide for possible carcinogenicity. 
    Unpublished Report submitted to WHO by OFCA (Organisation des
    Fabricants de Produits Cellulosiques Alimentaires).

    NRC - National Research Council, Washington, D.C., USA. (1989). 
    Report on Nutrition and Health.  Submitted to WHO by the U.S. Food and
    Drug Administration.

    REESE, E.T., SIU, R.H. & LEVINSON, H.S. (1950).  The biological
    degradation of soluble cellulose derivatives and its relationship to
    the mechanism of cellulose hydrolysis.  J.Bact. 59, 485-497.

    ROWE, V.K., SPENCER, H.C., ADAMS, E.M. & IRISH, D.D. (1944).  Response
    of laboratory animals to cellulose glycolic acid and its sodium and
    aluminum salts.  Food Res. 9, 175-182.

    SCHULTZ, J. (1949).  Carboxymethyl cellulose as a colloid laxative.
     Amer.J.  Dig.Dis. 16, 319-322.

    SCHWEIG, K. (1948).  The use of methyl cellulose as a bulk laxative.
     N.Y.St.  J.Med. 48, 1822-1823.

    SCHWETZ, B.A., HUMISTON, L.G., KOCIBA, R.J. & JERSEY, G.C. (1973). 
    Results of subchronic toxicity studies on HCl-tailored hydroxypropyl-
    methyl cellulose in rats and dogs.  Polym.Repr.Am.Chem.Soc.,
     Div.Polym.Chem. 17, 6-11.

    SELYE, H. (1955).  Changes in adrenal medulla following treatment with
    an ACTH-preparation containing carboxymethylcellulose.
     Proc.Soc.Exp.Biol.(N.Y.) 90, 670-672.

    SHELANSKI, H.A. & CLARK, A.M. (1948).  Physiological action of sodium 
    carboxymethylcellulose on laboratory animals and humans.  Food Res.
    13, 29-35.

    STEHBENS, W.E. & SILVER, D. (1966).  Arterial lesions induced by
    methyl cellulose.  Amer.J.Path. 48, 483-501.

    TAINTER, M.L. (1943).  Methyl cellulose as a colloid laxative.
     Proc.Soc.Exp.  Biol.(N.Y.) 54, 77-79.

    TOMENIUS, J. (1957).  Ethylhydroxyethylcellulose (Etulos).
     Am.J.Digest.  Diseases 2, 508-517.

    TOPPING, D.L., OAKENFULL, D., TRIMBLE, F.P. & ILLMAN, R.J. (1988).  A
    viscous fibre (methylcellulose) lowers blood glucose and plasma
    triacylglycerols and increases liver glycogen independently of
    volatile fatty acid production in the rat.  Brit.J.Nutr. 59, 21-30.

    VOHRA, P. & KRATZER, F.H. (1964).  Growth inhibitory effect of certain 
    polysaccharides for chickens.  Poultry Sci. 43, 1164-1170.

    WERLE E. (1941).  The harmlessness of sodium cellulose glycolate,
    known as a dilating substance, when fed to rats and dogs.  Chemiker-
     Zeitung 65, 320-321.

    WIEBE, A.K.  et al. (1962).  Unpublished report to the Hercules
    Powder Co.

    WIEDERSHEIM, M., HERTLEIN, W., HUSEMANN, E. & LOTTERLE, R. (1953).
    Pharmacology of soluble polysaccharides and polysaccharide
    derivatives.  Naunyn-Schmiedeberg's Arch.Exp.Path.Pharmak. 217,
    107-129.

    WYATT, G.M., HORN, N., GEE, J.M. & JOHNSON, I.T. (1988).  Intestinal
    microflora and gastrointestinal adaptation in the rat in response to
    non-digestible dietary polysaccharides.  Brit.J.Nutr. 60, 197-207.

    ZIEGELMAYER, W., COLUMBUS, A., KLAUSCH, W. & WIESKE, R. (1951). 
    Effect of carboxymethylcellulose on digestion in rats, man and
    rabbits.   Arch. f. Tierernahrung  2, 33-52.


    See Also:
       Toxicological Abbreviations
       Modified celluloses (WHO Food Additives Series 5)
       MODIFIED CELLULOSES (JECFA Evaluation)