FAO Nutrition Meetings
    Resort Series No. 44A
    WHO/Food Add./68.33


    Geneva, 21-28 August 1967

    The Eleventh Report of the Joint FAO/WHO Expert Committee on Food
    Additives is published as FAO Nutrition Meetings Report Series,
    1967, No. 44; Wld Hlth Org. techn. Rep. Ser., 1968, 383. This
    Report contains general considerations, including the principles
    adopted for the evaluation, and a summary of the results of the
    evaluations of a number of food additives. Additional information,
    such as biological data and a toxicological evaluation, considered at
    that meeting, is to be found in this document.

    Food and Agriculture Organization of the United Nations
    World Health Organization


    Chemical name                 Calcium cyclohexanesulfamate; Calcium

    Empirical formula             C12H24CaN2O6S2.2H2O

    Structural formula


    Molecular weight              432.57

    Definition                    Calcium cyclamate contains not less than
                                  98 per cent. and not more than the
                                  equivalent of 101 per cent.

    Description                   White, odourless crystals or crystalline

    Use                           Non-nutritive sweetener.

    Biological Data

    Biochemical aspects

         The metabolic fate was studied in rats using single oral doses of
    0.46, 0.93 or 1.85 g/kg body-weight. 17-30 per cent. was excreted in
    the urine and 70-80 per cent. in the faeces over 72 hours, absorption
    being slightly less than for the sodium salt (Hwang, 1966). In another
    experiment calcium cyclamate excretion was followed using gas-liquid
    chromatography. At 1 per cent. of the diet 17 per cent. was recovered
    in the urine and 70 per cent. in the faeces; at 5 per cent. of the
    diet, 14 per cent. and 46 per cent.; and at 10 per cent. in the diet,
    15 per cent. and 30 per cent. (Derse & Daun, 1966).

         In the rat, 99 per cent. of the radioactivity excreted in the
    urine following single oral doses (714 and 909 mg/kg) was in the form
    of unchanged cyclamate (Sonders & Miller, 1966).

    Acute toxicity


    Animal     Route      LD50             References
    Mouse      oral       7200             Abbott Laboratories, 1966

               i.v.       570              Abbott Laboratories, 1966

    Rat        s.c.       100              Golberg, 1965

    Rabbit     i.v.       125              Abbott Laboratories, 1966

    Special studies

         The laxative and faecal softening effects were studied in rat,
    mouse, dog and monkey, using 35S-labelled calcium cyclamate. Over 70
    per cent. of the compound remained unabsorbed in the gut, no
    significant systemic effects were noted, and laxative action was due
    to the increased bulk secondary to osmosis as shown by the motility of
    isolated gut. No gross intestinal mucosal changes were noted. The
    laxative dose (ED50) was 2.8 g/kg in the rat (Hwang, 1966). Similar
    results were noted in a repeat study on rats, mice and dogs, these
    being ascribed entirely to osmotic hypertonicity (Taylor et al.,

         Rat. Groups of 10 weanling rats were fed 0, 5 and 10 per cent.
    calcium cyclamate for 22 weeks; 3-day balance studies were done in
    the eighth, fourteenth, twentieth and twenty-second weeks, in which
    chromatographic recoveries from urine and faeces were compared with
    consumption. These recoveries were simultaneously compared with
    isotope recoveries from additional labelled doses of the sodium salt
    administered orally at the beginning of each balance period. Average
    chromatographic recoveries ranged from 76.3 to over 100 per cent.
    Gross, histological and radiological examination of the survivors
    showed no changes attributable to cyclamate (Sonders et al., 1967).

         In a test designed to study the influence of cyclamate on
    caloric utilization, groups of 6 male rats were fed 5 g/day basal
    diets supplemented with 0, 1 and 2 g/day of sucrose with and without
    1, 2 and 4 per cent. calcium cyclamate, and 2.33 per cent. sodium
    sulfate (osmotically equivalent to the 4 per cent. cyclamate level)
    for 10 days. A smaller weight gain and mild diarrhoea were seen in the
    4 per cent. cyclamate group. No catharsis was seen in the sodium
    sulfate group. Mild diarrhoea, but without a clear-cut effect on
    weight gain, was again found at the 4 per cent. cyclamate level in a
    further test in which the same animals, redistributed to groups, were
    tested in the same manner with starch instead of sucrose (Frost &
    Main, 1967).

    Short-term studies

         Rat. Calcium cyclamate was fed to groups of rats at 0, 5 and 10
    per cent. of the diet for 8 weeks. Growth rates were reduced despite
    greater food and water intake at both levels, with possible
    histological changes in adrenal and other organs. All faeces were soft
    and moist. Urinalysis and haematology were normal. After 8 weeks half
    the animals were placed on restricted food intake (60 per cent. of 
    ad lib. feeding). Females and males from both series were mated
    twice to produce an F1a and F1b generation. Both filial generations
    showed a dose-related reduction in pup weight. Animals on restricted
    food intake conceived and gestated but could not raise their young
    (Nees & Derse, 1965; 1967).

         Groups of 40 rats were fed 0 and 5 per cent. calcium cyclamate
    for 4 months. Soft faeces without frank diarrhoea, depressed rate of
    weight gain and ceca grossly dilated with fluid were seen in the test
    group. However, appetite was unaffected. Discrete moderate
    histological abnormalities unrelated to length of treatment were seen
    The mucosal architecture was unimpaired except for a rise in crypt
    height; 50 per cent. of test animals showed ballooning of the tips of
    mucosal cells with cytoplasmic vacuolization, while 80 per cent.
    showed oedema of the ileum and enlarged villi without congestion or
    inflammation. The mitotic index did not differ from that of the
    controls, but there was hyperplasia of myenteric ganglion cells and
    other evidence of accelerated cellular replacement.

         Histochemically there was non-specific goblet cell hyperplasia,
    abnormal RNA change but normal fat absorption. Histoenzymatic studies
    showed various qualitative anomalies and alteration in distribution
    particularly depression of ATPase, variable depression of acid and
    alkaline phosphatase, reduced Krebs cycle activity but little
    disturbance of Embden-Meyerhoff pathways. Pentose cycle enzymes were
    increased, indicating a metabolic change induced by enhanced nucleic
    acid synthesis. No definite changes were noted in enzymes involved in
    protein and lipid metabolism (Bernier, 1967).

    Observations in man

          Intravenous doses of 1 g calcium cyclamate were tolerated
    without ill effects (Schoenberger et al., 1953). Oral doses of 5 to 12
    g for 14-21 days had no other effect except soft stools without
    significant effect in frequency of bowel movement (Wisconsin A. R. F.,

         Following administration of a single oral dose of 2 g calcium
    cyclamate (containing 35S-labelled material) to a man, 31.2 per cent.
    was excreted in the urine and 65.5 per cent. in the faeces over 3-4
    days. In another study, 2 volunteers ingested 5 g calcium cyclamate
    daily for 18 days without any adverse effect on metabolism of
    nitrogen, calcium, phosphorus, sodium and potassium. Some 37 per cent.
    of the daily dose was excreted in the urine and 50-61 per cent. in the
    faeces (Schoenberger et al., 1953).

         Urinary excretion was studied by intravenous infusion of a single
    dose of 1 g, followed by oral administration of 5 g/day for 2 weeks
    and a concluding intravenous administration of a 1 g dose. In 2 normal
    subjects, 80 per cent. of the i.v. dose was excreted, whether
    preceding or following the oral course. In 7 nephritics, a mean of 87
    per cent. of the i.v. dose was excreted before the oral course, and 93
    per cent. after. Of the oral doses, mean daily excretion in the normal
    subjects was 31 per cent., and in 3 nephritics it was 13 per cent.
    (Dedmon et al., 1961).

         A study of cyclamate ingestion was carried out in 164 children,
    aged 3-16 years, in four weight classes of 15-45 lbs., 45-75 lbs.,
    75-105 lbs. and 105-135 lbs., with arbitrarily assigned body weights
    of 30, 60, 90 and 120 lbs. for individuals within these classes, for
    the purpose of administration of daily doses. These classes were
    further subdivided into three groups of 15-16 children each. These
    groups received 0, 1 and 1.5 g/30 lbs. body-weight/ day for 12 weeks.
    After a rest period of two weeks the groups were redistributed to the
    same dosages for another 12 weeks.

         The compound was administered as artificially sweetened
    carbonated soft drinks, and, in the higher weight classes, in capsule
    supplements, whereas the 0 g/30 lbs. group received sugar-sweetened
    soft drinks only. Soft stools, but no diarrhoea, were seen in some of
    the children. No effect was noted in physical examinations, nor in
    peripheral blood picture, examination of urine, and laboratory
    parameters of liver function (Freese et al., 1967).

         Ten healthy males were given 5 g/day in aqueous solution for 5
    days, removed from the regimen for 7 days, then returned to 5 g/day
    for another 5 days. Slightly increased water excretion in urine and
    faeces but no change in serum sodium and potassium, BUN and serum
    alkaline phosphatase activity were found. Blood cell counts were
    unchanged (Berndt & Calandra, 1965).

         Groups of 28 male volunteers took 5-7 g/day of calcium cyclamate
    for 21 days, or 7-12 g/day for 14 days, without significant change in
    blood cell counts or composition of the urine. One man experienced a
    significant increase in the frequency of bowel movements at 7 g/day;
    12 g/day produced questionably significant increases in 4 of 28. Bulk
    and softness of stools was increased at 10-12 g/day but the group mean
    of frequency of bowel movements was not affected at this level
    (NAS-NRC, 1955).

         Six male volunteers received 5 g calcium cyclamate daily in
    divided doses for 7-1/2 months. No unusual symptoms were reported
    except increased bulk and mushiness of stools without increase in
    number of bowel movements. No adverse effects were noted in
    haemopoietic, cardiovascular, renal or hepatic systems (Schoenberger
    et al., 1953).

         Thirty adult males ingested 1.8-6.42 g/day in dietetic foods, by
    capsule and in soft drinks, for 48 weeks without apparent effect on
    renal, hepatic or thyroid functions or on peripheral blood picture
    (Radding, 1967).

         Forty-two diabetic outpatients kept daily records of their
    voluntary cyclamate intake for 6-9 months: the cumulative daily
    averages of intake for the period ranged from 209 to 3107 mg/day. No
    changes in bowel habits or gastrointestinal signs or symptoms were
    noted. At six months, the group average results of blood cell counts,
    examination of urine, determination of blood urea nitrogen and liver
    function tests, except serum alkaline phosphatase, were not different
    from base-line determinations. Mean serum alkaline phosphatase
    activity was lowered, and mean fasting blood sugar was slightly
    increased (Stern, 1967).

         Twenty-one patients with chronic renal disease took up to 5.3
    g/cay of calcium cyclamate by capsule for 6 months without any
    alteration in their clinical courses attributable to cyclamate. Of the
    original 29 persons started on the regimen, one stopped taking
    cyclamate after the first month because of diarrhoea (Kark, 1967).

         Seventeen patients with functional gastrointestinal disease took
    4-5 g/day by capsule for 6-10 weeks. Of the original group of 20, one
    stopped the regimen after 3 weeks because of exacerbation of a
    pre-existing dermatitis, and another stopped after 5 days because of
    diarrhoea. No other adverse effects were noted (Batterman, 1966).


         See Sodium Cyclamate


         See Sodium Cyclamate


         See Sodium Cyclamate

    See Also:
       Toxicological Abbreviations