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




    TOXICOLOGICAL EVALUATION OF SOME
    FLAVOURING SUBSTANCES AND
    NON-NUTRITIVE SWEETENING AGENTS





    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
    1967


    SODIUM CYCLAMATE

    Chemical name                 Sodium cyclohexanesulfamate; Sodium
                                  cyclohexylsulfamate

    Empirical formula             C6H12NNaO3S

    Structural formula

    MOLECULAR STRUCTURE 20

    Molecular weight              201.22

    Definition                    Sodium cyclamate contains not less than
                                  98 per cent. and not more than the
                                  equivalent of 101 per cent.
                                  C6H12NNaO3S.

    Description                   White, odourless crystals or
                                  crystalline powder which in dilute
                                  solution is about 30 times as sweet as
                                  sucrose.

    Use                           Non-nutritive sweetener

    Biological Data

    Biochemical aspects

         Absorption of sodium cyclamate from rat stomach perfused in
    situ amounted to 4 per cent. per hour at pH 1 and nil at pH 3;
    absorption from the small gut occurred at a similar rate of about 4
    per cent. per hour (Kojima et al., 1966b).

         Whole-body autoradiography of the female rat 5 minutes after i.v.
    injection of 100 mg/kg of sodium 14C-cyclamate showed relatively
    uniform tissue distribution, with some concentration in the lungs,
    kidneys, salivary gland and bloodstream; at 7 hours, the radioactivity

    was concentrated in the intestinal contents, the salivary gland and an
    unidentified area of the brain; at 48 hours some activity remained in
    the gastrointestinal contents. In the pregnant rat, little penetration
    into foetal tissue was found at 5 minutes, although the placentas
    showed high concentrations; at 7 hours, maternal tissues except the
    renal medulla and placenta were relatively free of isotope, with most
    of the activity concentrated in the gastrointestinal contents, but the
    foetuses showed high activity, with concentrations in the
    gastrointestinal contents and kidneys. Forty-eight hours after
    injection of the dam, radioactivity in the day-old rat was confined to
    the lower gastrointestinal tract, the kidneys, and perhaps the skin
    (Schechter & Roth, 1967).

         35S-labelled sodium cyclamate was shown to cross the placental
    barrier within 2 hours after i.v. administration in the rat.
    Concentration in foetal tissues declined at a slower rate than that in
    maternal blood (Abbott Laboratories, 1966).

         Seventy-two per cent. of intraperitoneally administered
    35S-labelled sodium cyclamate was excreted unchanged in the urine of
    rats after 5 hours. Single i.p. doses at up to 3.2 g/kg were excreted
    rapidly in 24 hours, while 1.4 g/kg was excreted equally rapidly by
    normal and unilaterally nephrectomized rats (Taylor et al., 1951).

         Repeated oral doses of 80-120 mg/kg for 5 days led to 85 per
    cent. excretion in 5 days and another 3 per cent. in the 4 days
    following the last dose. About 2/3 was excreted in the faeces and the
    remainder in the urine (Taylor et al., 1951). Single oral doses of
    0.5, 1 or 2 g/kg body-weight were excreted to the extent of 30 per
    cent. in urine and 70 per cent. in faeces in 3 days (substantially in
    the first 24 hours). Using 35S-labelled sodium cyclamate in groups of
    4 rats given 2 or 4 g/kg body-weight, after 8 hours 75-80 per cent.
    remained unabsorbed in the gut, 18-25 per cent. was absorbed and
    mostly excreted in the urine and 3-8 per cent. remained in the
    carcass. Feeding rats 1 per cent. sodium cyclamate for 54 days prior
    to an i.p. injection of the substance showed 77 per cent. of the
    injected dose to be excreted in 24 hours, hence no cumulation had
    occurred (Hwang, 1966). When 14C-labelled sodium cyclamate was
    administered orally to rats, 22 per cent. of the activity was excreted
    in the urine, 72 per cent. in the faeces and 0.2 per cent. remained in
    the carcass; 98-99 per cent. of the activity was excreted as cyclamate
    (Miller et al., 1966). However, when sodium cyclamate excretion was
    followed using a gas-liquid chromatography method, at 5 per cent.
    dietary intake only 5 per cent. as recovered in the urine and 19 per
    cent. in the faeces, while at 10 per cent. dietary intakes some 7 per
    cent. appeared in the urine and 18 per cent. in the faeces. No
    explanation for these low recoveries was offered (Derse & Daun, 1966).

         Two rats given a total of 6.67 g/kg of sodium 14C-cyclamate
    orally over an 8-hour period had total carcass activity levels of 0.33
    per cent. and 0.24 per cent. of this dose after 5 days; recoveries
    from excreta and cage washings were calculated to be 103.25 per cent.
    and 102.59 per cent. of the doses given (Miller et al., 1966).

         About 80 per cent. of a 1000 mg/kg dose of orally administered
    14C-cyclamate was found to be eliminated by the rat in the first 24
    hours, approximately equal amounts appearing in urine and faeces. Only
    unchanged cyclamate was chromatographically identified in the urine.
    0.12 per cent. of the dose was transmitted to litter animals,
    apparently via the milk (Hood et al., 1966).

         Oral sodium cyclamate at 1 per cent. in the diet for one month
    did not alter the BMR of rats (Richards et al., 1951).

         In the rabbit, sodium cyclamate was excreted unchanged in the
    urine to the extent of 80-90 per cent. in 12 hours after i.v., i.p. or
    oral administration (Audrieth & Sveda, 1944).

         Of 600 mg orally administered sodium cyclamate in the dog, 70 per
    cent. was excreted in the urine within 8 hours and 85 per cent. within
    24 hours, while of 100 mg/kg body-weight administered i.v. 92 per
    cent. was excreted. One dog receiving 35S-labelled sodium cyclamate
    i.v. excreted only 0.5 per cent. in the bile and 67 per cent. in the
    urine after 5 hours (Taylor et al., 1951). Three dogs receiving
    0.75-1 g/kg body-weight sodium cyclamate i.g. excreted 21-64 per cent.
    in the urine within 11-17 hours. Cyclamate blood levels were low
    (Hwang, 1966).

         In two dogs given single 14C-labelled doses of 200 and 1000
    mg/kg, severe diarrhoea was seen 9-10 hours later. Total recovery of
    radioactivity from the excreta by the fourth day amounted to about
    97-98 per cent. In the animal given 1000 mg/kg, urinary excretion
    accounted for 27 per cent. of the dose; in this animal, peak
    whole-blood activity levels were found in the first hour after
    administration, with a steady decline to less than 1 per cent. of peak
    by the forty-eighth hour. In the other, the peak whole-blood activity
    level probably occurred during the eighth hour or later, and by 72
    hours was down to 7 per cent. of the highest level measured.
    Ninety-two hours after administration, no activity was detected in the
    skin, eyes, testes, brain, thyroid or skeletal muscle of the low-dose
    dog; total activity in the spleen, liver, lungs, pancreas, heart and
    kidneys was calculated as 0.027 per cent. of the dose administered. In
    a dog given 200 mg/kg 3 times a day for 8 days no activity was
    detected in whole blood 44 hours after the last dose. During the test
    and in the 9 days following, about 40 per cent. of the dose
    administered was recovered from the urine and 54 per cent. from the
    faeces. Nine days after the last dose the activity in the spleen,
    liver, lungs and pancreas totalled 0.005 per cent. of the doses given,
    and activity in a sample of skeletal muscle was about 10 per cent. of
    that found in a biopsy sample taken during the last day of
    administration (Miller et al., 1966; 1967).

         About 80 per cent. of a dose of 1000 mg/kg of 14C-labelled
    cyclamate administered orally in the dog was excreted in the urine in
    24 hours; two apparent metabolites plus unchanged cyclamate were found
    by chromatography of urine samples up to 10 hours after ingestion.
    Only cyclamate and possibly a very similar metabolite were found after

    24-48 hours. No activity was detectable in the bloodstream after 48
    hours. Two dogs were given 200 mg/kg of labelled cyclamate three times
    a day for one week. Between 65 and 97 per cent. of the total dose had
    been excreted by the eighth day after cessation of administration.
    Whole-blood activity levels had dropped to approximately 40 per cent.
    of the dose-cessation levels and tissue levels had dropped to 25 per
    cent. or less of those found in two other dogs given the same regime
    and sacrificed at the end of one week (Hood et al., 1966).

         Only unchanged sodium cyclamate was identified
    chromatographically in a dog urine sample taken 17 hours after oral
    administration of 200 mg/kg (Sonders, 1967). 35S-labelled cyclamate
    appeared in the milk of lactating dogs partly from blood and partly
    from active secretion but disappeared after 24 hours (Abbott
    Laboratories, 1966).

         In the lactating dog, 4-24 hours after i.v. injection of a 20 mg
    14C-labelled dose, concentrations of cyclamate were found to be
    higher in the milk than in simultaneous blood samples; cyclamate
    appeared in the milk at levels of about 2 µg/ml or less, and
    disappeared from the milk at about the same rate as from the
    bloodstream (Wiegand, 1967).

         Intravenous injection of 35S-labelled sodium cyclamate into
    rats, rabbits and dogs showed that, with the exception of the kidney
    and perhaps the liver, gastrointestinal tract and spleen, there was no
    significant concentration in the various organs examined. Sodium
    cyclamate penetrated into the brain with difficulty but crossed the
    placenta very easily in the rat and was found in the foetus (Taylor et
    al., 1951).

    Cyclohexylamine excretion

         Humans, dogs but not rabbits excrete cyclohexylamine after oral
    doses of 1-3 g of sodium cyclamate. No glucuronates were detected.
    Some 0.7 per cent. of the oral dose is excreted as cyclohexylamine in
    man while in dogs only trace amounts are detected (Kojima &
    Ichibagase, 1966). Rats receiving sodium cyclamate in their diet
    excreted cyclohexylamine in their urine (Leahy et al., 1966). Oral
    administration of 3 g sodium cyclamate on each of 3 days to 5 human
    volunteers resulted in excretion of cyclohexylamine in man,
    representing 0.8 per cent. of the dose administered (Leahy et al.,
    1967). Further extension of the work to 40 volunteers showed 5
    excretors again at 0.8 per cent. of the administered dose while one
    subject excreted 7.5 per cent. of the administered dose as
    cyclohexylamine (Huntingdon Laboratories, 1967).

    Acute toxicity

                                                                       

    Animal     Route     LD50               References
                         (mg/kg 
                         body-weight)
                                                                       

    Mouse      oral      10 000-12 000      Richards et al., 1951
                         11 000             Abbott Laboratories, 1966
                         17 000             Taylor et al., 1967
                         1 525              Mollet, 1966
               i.v.      4 000              Richards et al., 1951
                         4 800              Taylor et al., 1967
               i.p.      10 000-12 000      Fitzhugh et al., 1951
                         7 100              Taylor et al., 1967

    Rat        oral      12 000             Richards et al., 1951
                         17 500             Taylor et al., 1967
               i.v.      3 000-4 000        Richards et al., 1951
                         3 500              Taylor et al., 1967
               i.p.      6 000              Taylor et al., 1967
                                                                       

         Pretreatment of mice dams with 0.5 per cent. sodium cyclamate
    raised the acute i.p. toxicity of the substance in their pups.
    Changing the lipid content of the diet from 6.5 per cent. to 40 per
    cent. increased the i.p. acute toxicity of sodium cyclamate in mice
    (Taylor et al., 1967), Rats consuming up to 8 g/kg body-weight/day of
    sodium cyclamate for 5 days showed no abnormal findings regarding
    haematology, tissue chemistry and histopathology apart from a slight
    decrease in hepatic triglycerides at the 8 g level (Stein et al.,
    1967).

         Diffuse, mild vesiculation of the endoplasmic reticulum
    associated with vacuolization was observed in the liver and kidney of
    monkeys given 4 or 8 g/kg of sodium cyclamate orally and sacrificed 1
    or 48 hours later. No changes in various biochemical values were
    associated with these early morphologic alterations (Stein et al.,
    1967). No ultrastructural changes attributed to cyclamate were found
    in the hepatic cells of two monkeys 48 hours after single doses of
    4000 mg/kg or of one animal 1 hour after an oral dose of 7170 mg/kg
    (Richter et al., 1967).

    Special studies

         Laxative and faecal softening effects were studied in rats, mice,
    dogs and monkeys using 35S-labelled compounds. Approximately70 per
    cent. of cyclamate remained unabsorbed in the gut and no significant
    systemic effects were noted. Laxative action as shown by motility of
    isolated gut was ascribed to the increased bulk secondary to osmosis.

    Mice were slightly more susceptible. The laxative dose (ED50) in the
    rat was about 1.9 g/kg body-weight. No gross changes in rat or mouse
    intestinal mucosa were noted (Hwang, 1966). Similar results were noted
    in a repeat study on rats, mice and dogs. Intravenous sodium cyclamate
    in mice did not affect intestinal motility, stool frequency and
    appearance (Taylor et al, 1967).  Sodium cyclamate had no effect on
    the water balance of hypertensive rats with renal disease (Fregley &
    Kier, 1961).

    Short-term studies

         Rat. Groups of 10 weanling rats were fed 0, 1, 5 and 10 per
    cent. sodium cyclamate for 22 weeks. Three-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 doses of the labelled sodium salt
    administered orally at the beginning of each balance period. Average
    chromatographic recoveries ranged from 77.7 to over 100 per cent. and
    isotope recoveries from 91.5 to over 100 per cent. Weight gain was
    adversely affected in the 10 per cent. group. Gross, histological and
    radiological examination of survivors showed no changes (Sonders et
    al., 1967).

         Groups of 10 male and 10 female rats received diets containing 0,
    1, 2 or 3 per cent. of sodium cyclamate for 11 months. No adverse
    effects (apart from occasional lax stools at the 2 per cent. and 3 per
    cent. levels) were noted on growth rate, liver and kidney weight,
    haematology and urinalysis. When rats of corresponding test groups
    were mated, there was no adverse effect on fertility or litter
    characteristics. Of the F1 generation, groups of 3-8 mice and 8
    females were kept on 1, 2 and 3 per cent. sodium cyclamate in their
    diet and again correspondingly mated to give the F2 generation. Pairs
    of corresponding groups continued to receive 0, 1, 2 and 3 per cent.
    in their diet and were remated to produce an F3 generation. No
    adverse effects were seen on conception rate, foetal development and
    litter characteristics (Taylor et al., 1967).

         Guinea-pig. Groups of 7 males received 0.5 or 2 per cent.
    sodium cyclamate in their drinking water for 5 months and controls
    were given 0.3 per cent. saline. Fluid intake was restricted to 30 ml
    per day per animal. There was an apparent increase in mortality at the
    2 per cent. level. There was also a 20 per cent. decrease in
    body-weight at the 2 per cent. level compared with controls. Histology
    of the liver of test animals showed "reduced protoplasm" and
    vacuolization at both dietary levels though less at 0.5 per cent.
    Histology of controls was not reported. Serum lactic dehydrogenase and
    SGOT levels were raised at 2 per cent., but not significantly
    (Hellauer, 1967).

         Dog. Three groups of 2, 4 and 4 dogs received 0, 2 and 4 g/kg
    body-weight of sodium cyclamate i.g. daily for 30 days without
    deleterious effect on body-weight, appearance, marrow picture, hepatic
    function tests, gross autopsy and histology of liver, kidney and
    gastrointestinal tract (Taylor et al., 1967). In another experiment
    dogs were given 0.5 g/kg body-weight sodium cyclamate daily for 11
    months without adverse effect on weight, blood, liver and kidney
    function or urine (Hwang & Richards, 1955). Four groups of 3 dogs
    received 0, or 0.5 g/kg body-weight sodium cyclamate 6 days per week
    i.g. for 11 months. At the tenth month soft stools were seen. No
    adverse effects were seen regarding body-weight, haemoglobin,
    urinalysis and tests of hepatic and renal function, and on gross
    autopsy (Taylor et al., 1967). Groups of 2 dogs were kept on diets
    containing 0, 0.2 or 0.4 per cent. sodium cyclamate daily for 15
    months. All gained weight; haematology and liver and kidney function
    tests were normal; urinalysis did not differ from controls. Gross and
    microscopic examination of the major organs was normal (Richards et
    al., 1951).

         Monkey. Monkeys were given 4 g/kg body-weight of sodium
    cyclamate daily for 9 months without significant changes in
    haematology, serum enzymes, urine or gross autopsy findings. Hepatic
    and renal demethylase and desulfurase activities, lysosomal activity
    and mitochondrial oxygen utilization were not affected, but slight
    enlargement of pancreatic islands of Langerhans was noted.
    Electron microscopy revealed some subcellular alterations (Stein et
    al., 1967).

    Teratogenicity studies

         Mouse. Groups of 2-4 mice with control groups of 3 mice were
    given single i.g. doses of sodium cyclamate at various stages of
    pregnancy as follows: 62.5 mg on day 4-5, 125 mg on day 4-5 and 6-7,
    250 mg on day 6-7 and 8-10 and 500 mg on day 6-7 and 8-10. The uteri
    were removed on the eighteenth day, opened and the foetuses assessed
    and absorption sites counted. No abnormalities were detected following
    any administrations on days 8-10 but in all other instances the
    majority of embryos had either been resorbed or appeared dead or
    showed delayed development compared with controls. The foetal LD50
    was calculated to be 180 mg/kg body-weight (Tanaka, 1964a; 1964b).

         In embryotoxicity studies still in progress, groups of 10-14
    female mice, mated at a little over 2 months of age, were given
    intragastric, aqueous doses of 0, 5 and 10 g/kg of sodium cyclamate on
    the eighth day of gestation. On examination of the uteri and foetuses
    on the eighteenth day of gestation, no effect was found (Lorke, 1967).

         Rat. Groups of 20-24 pregnant females were given 50, 100 and
    150 mg/kg body-weight of sodium cyclamate daily from the sixth to the
    fifteenth day of gestation. Three hundred and sixty-three pregnant
    animals served as controls. The dams were autopsied on the
    twenty-first day and the foetuses examined grossly. The number of

    dead, malformed or reported foetuses did not differ from controls
    (Bein et al., 1967).

         Rabbit. Four females were given 1 g/kg body-weight sodium
    cyclamate orally from day 1-18 of gestation. All offspring were normal
    and survival and litter size corresponded with controls (Abbott
    Laboratories, 1966).

         Dog. Groups of 6 dogs (2 male and 4 female) were given 0, 0.45,
    0.9 and 1.35 g/kg of sodium cyclamate for about 6 months. The dogs
    were bred and the offspring after weaning at 8 weeks were placed on
    the same regimen that their respective parents were receiving. After
    20 months there was no adverse effect on the parents. All progeny were
    born normal and have shown no effect of treatment (Abbott
    Laboratories, 1966).

    Long-term studies

         Rat. Groups of 8-20 male and female rats were fed diets
    containing 0, 0.5, 0.1 and 1.0 per cent. sodium cyclamate for 18, 24
    or 30 months. Mating was permitted and the F1 generation kept on the
    same dietary regime. The experiment was carried into the third
    generation at the 0.05 per cent. level. Weight gains, haematology and
    urinalysis were normal. Clinical and pathological studies showed no
    difference from controls as regards major organs. Mortality and tumour
    incidence were similar to those of controls. Normal litters were
    produced (Richards et al., 1951).

         In another experiment groups of 18-24 rats received 0, 0.01, 0.1,
    0.5, 1 and 5 per cent. sodium cyclamate in their diet for 24 months.
    Slight growth depression was noted at 5 per cent. associated with
    marked diarrhoea. Mortality was similar in all groups. Organ weights,
    histopathology of major organs and tumour incidence were no different
    from controls (Fitzhugh et al., 1951).

    Observations in man

         After i.v. administration to healthy men of 1 g sodium cyclamate,
    7O-90 per cent. was excreted in the urine within 3 hours and 84-99 per
    cent. within 24 hours. Using 35S-labelled sodium cyclamate i.v. in 3
    patients, the urinary clearance indicated excretion by glomerular
    filtration and tubular secretion. No general metabolic effects were
    noted (Schoenberger et al., 1953). One healthy man was given 300 mg
    sodium cyclamate orally and excreted 79.5 per cent. in the urine over
    7 days, 26 per cent. being excreted in the first 24 hours. Of an oral
    dose of 200 mg sodium cyclamate 77 per cent. was recovered in 3 days
    (Richards et al., 1951). Doses of 1 or 5 g sodium cyclamate were given
    to 3 subjects and 40-48 per cent. was recovered in the urine in 24
    hours (Kojima et al., 1966a). The amounts of cyclamate remaining in
    the body during 2, 5 or 10 g daily administration can be calculated
    for daily excretion rates ranging from 10-90 per cent. For 5 g and 75
    per cent. excretion, the cyclamate residue in the body is 1.67 g
    (Taylor, 1954). Phototoxicity has been reported as an immediate

    reaction to UV radiation (Kennedy et al., 1961). Photo-allergy as a
    delayed reaction to UV radiation has also been noted (Tatsuji &
    Tosbie, 1963).

         Two human subjects were given 14C-labelled doses of 4D mg/kg and
    88 mg/kg. Urine recoveries in 4 days were 51.8 and 73.5 per cent.
    respectively and faecal recoveries were 50.5 and 24.5 per cent.
    Urinary cyclohexylamine accounted for 0.156 and 0.123 per cent. of the
    isotopic material present. Reverse isotope dilution analysis indicated
    that all of the urinary isotope was unchanged cyclamate. Peak plasma
    activity levels were found in the eighth hour and the first hour
    respectively and peak whole-blood levels in the first and sixth hours
    (Sonders & Weigand, 1967).

         Groups of 32 and 30 patients with chronic hepatic or renal
    disease were given 5 and 2 g/day of sodium cyclamate for 6-6.5 months.
    On the basis of clinical chemical studies, cyclamate did not affect
    the patient's progress (Zöllner & Schneller, 1967).

    Comments

         Although this substance has been studied extensively in animals
    and man, there are certain lacunae such as the exact mechanism of the
    laxative effect, bearing in mind the changes observed in cellular and
    subcellular structures in histoenzymatic studies, the influence on the
    foetus in view of the easy transplacental passage and the significance
    of the appearance of the metabolite cyclohexylamine in the urine of
    man. The teratogenic effects which have only been seen in some studies
    in mice may well be related to physical and environmental factors
    rather than inherent teratogenic potential of sodium cyclamate.
    Long-term experiments have only been conducted in one species and
    further feeding studies in a second species are needed. The possible
    nutritional aspect of prolonged unrestricted use of cyclamate may
    require consideration.

    EVALUATION

         In view of the extensive studies in animal and man and widespread
    use in some countries, on the one hand, and the gaps in information
    about certain biological effects on the other, a temporary acceptable
    daily intake is allocated with some further work specified below.

    Level causing no significant toxicological effect

         Man: 12 000 mg per day, equivalent to 200 mg/kg/day (soft
    stools and more frequent bowel movements were observed in some
    subjects).

    Estimate of acceptable daily intake for man

                                  mg/kg body-weight

        Temporary acceptance           0-50

    Further work required within 3 years

    (1) Investigation into the metabolism to cyclohexylamine and other
    possible metabolites and full toxicological evaluation of these
    metabolites including any possible human genetic aspects.

    (2) Investigation into the exact mechanism of the laxative effect
    including any possible enteropathic cellular and subcellular changes.

    (3) Lifespan studies in a second species including observations on
    reproduction and development of several filial generations.

    REFERENCES

    Abbott Laboratories (1966) Review of cyclamates

    Audrieth, I. F. &, Sveda, M. (1944) J. Org. Chem., 9, 89

    Batterman, R. C. (1966) Unpublished report submitted by Abbott
    Laboratories

    Bein, H. J,, Fritz, H., Hess, R. & Loustalot, P. (1967) Unpublished
    report submitted by CIBA

    Berndt, C. W. & Calandra, J. C. (1965) Unpublished report submitted by
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    Bernier, J. J. (1967) Unpublished report

    Dedmon, R. E., Ryan, W. G. & Kark, R. M. (1961) Unpublished report
    submitted by Abbott Laboratories

    Derse, P. H. & Daun  R. J. (1966) J. Ass. Off. Agr. Chem., 49, 1090

    Fitzhugh, O. G, Nelson, A. A. & Frawley, J. P. (1951) J. Amer. 
    Pharm. Ass.,  Sci Ed., 40, 583

    Freese, H. B., Jenike, T. S. & Rubenkoenig, H. L. (1967) Unpublished
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    Fregley, M. J. & Kier, L. B. (1966) Tox. Appl. Pharm., 9, 124

    Frost, D. V. & Main, B. T. Unpublished report submitted by Abbott
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    GoLberg, L. (1965) Unpublished report

    Hellauer, H. (1967) Unpublished report

    Hood, S. L., Somaini, S. M., Zink, V. R. & Bogner, R. L. (1966)
    Unpublished report submitted by Abbott Laboratories

    Huntingdon Research Centre (1967) Unpublished report

    Hwang, K. (1966) Arch. int. Pharmacodyn., 163, 302

    Hwang, K. & Richards, R. K. (1955) Unpublished report

    Kark, R. M. Unpublished report submitted by Abbott Laboratories 1967

    Kennedy, B., O'Quinn, S., Perret, W. J., Tilley, J. C. & Hennington,
    V. M. (1961) J. Louis. State Med. 113, 365

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    Miller, J. P., Michael Crawford, L. E., Sonders, R. C. & Cardinal, E.
    V. (1966) Biochem, biophys. Res. Comm., 25, 153

    Miller, J. P., Michael Crawford, L. E. & Netwal, J. C. (1967)
    Unpublished report submitted by Abbott Laboratories

    Mollet, M. (1966) Unpublished report submitted by Abbott Laboratories

    National Academy of Sciences - National Research Council (1955) 
    The Safety of Artificial Sweeteners for Use in Foods, Publication
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    Nees, P. O. & Derse, P. H. (1965) Nature (Lond.), 208, 81

    Nees, P. O. & Derse, P. H. (1967) Nature (Lond.), 211, 1191

    Radding, R. S. Unpublished report submitted by Abbott Laboratories
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    Richards, R. K., Taylor, J. D., O'Brien, J. L. & Duescher, H. O.
    (1951) J. Amer. Pharm. Ass., Sci. Ed., 40, 1

    Richter, W. R., Stein, R. J., Rdzok, E. J. & Moize, S. M. (1967)
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    Schoenberger,. J. A., Rix, D. M., Sakamoto, A., Taylor, J. D. & Kark,
    R. M. (1953) Amer. J. Med. Sci.,  225, 551

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    Abbott Laboratories

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    Laboratories

    Sonders, R. C. & Wiegand, R. G. (1967) Unpublished report submitted by
    Abbott Laboratories

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    report submitted by Abbott Laboratories

    Stein, A. A., Serrone, D. M. & Coulston, F. (1967) Tox. Appl.
    Pharm., 10, 381

    Stern, S. B. (1967) Unpublished report submitted by Abbott
    Laboratories

    Tanaka, R. (1964a) Jap. J. Publ. Health, 11, 909

    Tanaka, R. (1964b) J. Iwate Med. Ass., 16, 330

    Tatsuji, K. & Tosbie, A. (1963) Med. Cult,  5, 796

    Taylor, J. D. (1954) Unpublished report

    Taylor, J. D., Richards, R. K. & Davis, J. C. (1951) Proc  Soc. Exp.
    Biol. Med., 78, 530

    Taylor, J. D., Richards, R. K., Wiegand, R. G. & Weinberg, M. S.
    (1967) Fd Cosmet. Toxicol.,

    Tremolieres, J., Krebs, M. & Pedron, A. (1967) Unpublished report
    submitted by Abbott Laboratories

    Wisconsin Alumni Research Foundation (1965) Unpublished report

    Zöllner, N. & Schnelle, K. (1967) Arzneim.-Forsch. (Drug Res.) 17,
    1568
    


    See Also:
       Toxicological Abbreviations