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    CALCIUM CYCLAMATE, SODIUM CYCLAMATE AND CYCLOHEXYLAMINE

    Explanation

         Calcium cyclamate, sodium cyclamate and cyclohexylamine (CHA)
    were previously evaluated at the Joint Meeting of the FAO/WHO Expert
    Committee on Food Additives in 1967, 1970, 1976, 1977 and 1980 (see
    Annex I, Refs. 14, 22, 40, 43 and 54) and the temporary ADI for
    cyclamate of 4 mg/kg bw was extended pending completion of a
    reproduction study and a conversion study. Since the previous
    evaluation, additional data have become available and are summarized
    in this report. Cyclohexylamine (CHA) is the principal metabolite of
    cyclamate.

    CALCIUM CYCLAMATE AND SODIUM CYCLAMATE

    BIOLOGICAL DATA

    TOXICOLOGICAL STUDIES

    Special studies on mutagenicity

         Groups of 2 men and 2 women consisting of subjects receiving no
    cyclamate, subjects who did not convert cyclamate to cyclohexylamine,
    and those who did convert cyclamate to cyclohexylamine were studied.
    In the groups receiving cyclamate, the subjects were given sodium
    cyclamate 3 times a day for 4 days at total daily doses of 5 g for men
    and 4 g for women. Blood was collected on the first and fifth days of
    the study for chromosome analysis. All chromosome values were within
    normal limits prior to and after treatment (Dick et al., 1974).

         A rat study was conducted. The group distribution, dosages and
    administration routes are presented in the table that follows.

         The cyclohexylamine treated animals were dosed daily for 5 days
    and positive control dosed daily for 2 days. On the day following the
    last dose, animals were killed, femurs removed, and bone marrow cells
    collected for chromosome analysis. There was no apparent increase in
    chromosomal abnormalities in treated, when compared to controls (Dick
    et al., 1974).

         Four groups of mice each containing 150-160 animals were used.
    One group was untreated while the other 3 received by gavage 300 mg/kg
    of methylurea and 15 mg/kg of sodium nitrite. One of the test groups
    received 1.9 g/kg cyclamate in their diet. Treatment continued for
    1 week and then males placed on a normal basal diet for 3 weeks. Each
    male was mated for 4 days with 3 females 1 and 3 weeks after
    treatment. About 13 days after mating, the females were killed and
    scored for dead and living implants. The males of the test groups

    received 0.18% or 3.6% methylurea in their diet for 3 months after
    mating. One of the test groups also received 1.4% sodium cyclamate in
    the diet. At termination, animals were killed and the bladders,
    livers, and lungs were removed for histopathological examination.

         A significant increase of dominant lethals was observed in groups
    treated with sodium nitrite and methylurea but were only slightly
    increased with sodium cyclamate. No histopathological changes in the
    bladder, liver or lungs relating to sodium cyclamate were observed.
    Observed lesions were related to the intake of sodium nitrite and
    methylurea (Aeschbacher et al., 1979).

         Cyclamate and cyclohexylamine were assayed for their mutagenic
    activity using the Ames test with and without microsomal activation.
    Salmonella tester strains TA 1535, TA 100, TA 1537, and TA 98 were
    used. Neither chemical was mutagenic under the conditions of this
    assay (Herbold & Lorke, 1980).

    Special studies on combined reproduction and carcinogenicity

         Groups of 5-7 females were treated orally by gavage with
    cyclamate at doses of 0, 0.2, 1 or 5 g/kg bw on days 14, 17 and 20 of
    pregnancy and observed for life. Complete necropsies were performed.
    All urinary bladders and organs with macroscopic abnormalities were
    examined histologically. There were no treatment-related adverse
    effects. Tumour incidence in treated animals was comparable with
    controls. In particular, no carcinoma of the urinary bladder was
    observed (Schmähl & Habs, 1980).

    Special studies on combined reproduction, embryotoxicity,
    teratogenicity and carcinogenicity

         A six-generation experiment with SPF Swiss mice was carried out
    to examine the short-term (reproductive, perinatal, teratogenic) and
    long-term (carcinogenic and toxicological) effects of sodium
    cyclamate, saccharin (as free acid) and cyclohexylamine. The following
    dietary treatments were used:

    (1)  Control

    (2)  2% sodium cyclamate

    (3)  5% sodium cyclamate

    (4)  0.2% saccharin

    (5)  0.5% saccharin

        INCIDENCE OF BONE MARROW CHROMOSOME ABNORMALITIES IN RATS
                                                                                                          

                                                                                  Average %
                                                                                                  
    Expt.  Group   Number    Compound    Dose   Administration   Number of   Gaps and     Reunion     Total
                   of rats                           Route      metaphases    breaks    figures and
                                                                 examined               fragmented
                                                                                        metaphases
                                                                                                          

    I.       1       12      CHA.HCl    50 mg/kg      i.p.         1 200        2.1                    2.1
             2       12      CHA.HCl    50 mg/kg      p.o.         1 200        2.4                    2.4
             3       12      Control                  i.p.         1 200        3.2                    3.2
                             (water)

    II.      1       17      CHA.HCl    68.1 mg/kga   i.p.           850        1.8                    1.8
             2       14      CHA base   50 mg/kg      i.p.           700        1.3                    1.3
             3       12      Control                  i.p.           600        2.8                    2.8
                             (water)
             4       10      TEMb       0.5 mg/kg     i.p.           470        3.0          8.9      11.9
             5        8      METEPAb    20 mg/kg      i.p.           400       12.0         22.0      34.0
                                                                                                          

    a    CHA.HCl was given at 68.1 mg/kg to be equimolar with 50 mg/kg CHA base.

    b    Positive controls were dosed for 2 days; all other groups were dosed for 5 days.

    CHA: cyclohexylamine; CHA.HCl: cyclohexylamine hydrochloride; TEM: triethylenemelamine;
    METEPA: tris-(2-methyl-1-aziridinyl)phosphine oxide
    
    (6)  2% sodium cyclamate + 0.2% saccharin

    (7)  5% sodium cyclamate + 0.5% saccharin

    (8)  0.5% cyclohexylamine

         The P generation consisted of 50 males and 50 females per group.
    Five weeks after the start of the study, 20 females and 10 males per
    group were selected to produce the F1 litter. The litter size was
    inadequate and the remaining 30 females were mated with 15 males to
    produce the F1a' generation. Subsequently, 20 females and 10 males
    were chosen to produce litters for each succeeding generation. The P,
    F3b and F6a generation consisted of 50 males and 50 females and were
    used to study carcinogenicity. The remaining generations consisted of
    10 males and 20 females. Reproduction was studied in generations F1a,
    F2b, F3a, F4a, F5a. Perinatal studies were conducted with the F1a',
    F2b, F4a, and F5b generations. A teratogenic study was undertaken
    with the F6b generation.

         In 5 short-term experiments of the subsequent generations, sodium
    cyclamate and saccharin, or its combinations, did not have any toxic,
    carcinogenic, embryotoxic or teratogenic effect in the dosages used.
    Cyclohexylamine administration led to growth retardation and embryonal
    death, when given in 0.5% concentration in the diet.

         In 3 long-term studies performed with the P generation, the F3b
    and F6a generations only 7 bladder tumours were seen in a total
    number of 2400 animals. The tumours were divided among the different
    groups, including the control groups (Kroes et al., 1977).

    Short-term studies

    Monkey

         Out of 12 monkeys fed 100 mg/kg and 11 monkeys fed 500 mg/kg
    cyclamate 5 days a week for an average of 94 and 95 months, 10 and 9
    respectively survived and did not exhibit any evidence of toxicity.
    Two monkeys at each dose level died. The 2 monkeys at 100 mg/kg died
    within 4 months and necropsy findings showed fatty degeneration of the
    kidney. One of the deaths at 500 mg/kg was accidental, the other died
    after 84 months with necropsy showing vacuolar degeneration of the
    kidney. During the 16-year existence of this colony only 4 monkeys
    have developed spontaneous neoplasms out of a total of 211 control
    monkeys. Three tumours were lymphomas, the fourth a carcinoma of the
    gall bladder (Sieber & Adamson, 1978).

    Long-term studies

    Mouse

         Groups of 30 males and 30 females were fed diets containing 0,
    0,7, 1.75, 3.5 or 7.0% sodium cyclamate for 80 weeks. A slight
    reduction in body weight gain was observed in female rats at the 1.75
    and 3.5% cyclamate levels in the diet during the last 6 months of the
    study. Haemoglobin concentrations of both sexes fed 7% cyclamate were
    significantly lower than in the controls at week 80. No apparent
    differences between controls and treated mice with respect to
    mortality, organ weights, incidence of histological changes or tumours
    were noted. The no-effect level in the diet of mice under the
    conditions of this study was 3.5% (approximately 5 g/kg bw per day)
    (Brantom & Gaunt, 1973).

    Rat

         Groups of 50 female rats whose bladders had been instilled with a
    freshly prepared solution containing 2 mg of N-methyl-N-nitrosourea
    (MNU) were fed 0 or 2% sodium cyclamate which was increased to 4%
    after 10 weeks for a period of 21 years. A normal basal diet was given
    to 100 untreated controls. There was no significant effect on body
    weight gain, food or water consumption between groups. Animals that
    survived more than 10 weeks after the administration of MNU exhibited
    a wide range of pathological changes in the urinary tract such as
    necroses, haemorrhages and calcium deposits in the collecting ducts of
    the renal papillae, dysplasia, and focal hyperplasia of the papillary
    and pelvic urothelium. Neoplasms of the urinary tract were observed
    with equal frequency between the MNU treated control and cyclamate
    treated group. No difference in the latency periods of the tumours was
    found between the MNU treated groups (Green et al., 1980).

         Groups of rats untreated and treated with N-methyl-N-nitrosourea
    (a single intravesicular dose of 2 mg) were fed diets containing 0 or
    2 g/kg bw per day of sodium cyclamate for a lifetime or until killed
    because of a palpable tumour. The incidence of bladder tumours was as
    follows:

                                                           

       Treatment       No. of    No. of animals        %
                       animals    with tumours     Incidence
                                                           
    Nil                  98             0              0

    MNU                 124             0              0

    Cyclamate           228             3              1.3

    Cyclamate & MNU      54            31             57.5
                                                           

    Under the conditions of this study, sodium cyclamate was found to
    promote MNU-induced bladder tumours at the applied high dose level.

    OBSERVATIONS IN MAN

         Four groups of 8 men each were administered sodium cyclamate in
    hard gelatin capsules at 0 (sucrose placebo), 5, 10 or 16 g/day for
    213 days. Capsules were taken with regular meals. Blood, urine and
    semen were collected twice prior to commencing study. Samples of blood
    and urine were then collected on days 2 and 8 and weekly thereafter
    while semen was obtained every 2 weeks. Blood was examined for
    glucose, BUN, cholesterol, Na+, K+, protein bound iodine (PBI),
    SGPT, haemoglobin, haematocrit and complete blood count. The
    concentration and motility of sperm in the semen were estimated. Stool
    was collected on days 2, 4, 9 and 11 and on 2 non-consecutive days and
    graded as to consistency. Body weight and blood pressure were
    monitored weekly.

         The only untoward effect observed was softening of the stool
    which occurred in 7/8 men receiving 16 g/day and 2/8 receiving
    10 g/day. All subjects receiving cyclamate excreted cyclohexylamine in
    varying amounts on one or more occasions. The percentage of
    cyclohexylamine that appeared in the urine as free cyclohexylamine
    varied between 0.25 and 75.4% with a mean value of 17.2%. A
    significant increase in the concentration of PBI in the serum was also
    observed. This was shown to be an artifact arising from iodine in the
    colour used in colouring the gelatin capsules (Wills et al., 1981).

    CYCLOHEXYLAMINE

    BIOLOGICAL DATA

    TOXICOLOGICAL STUDIES

    Special studies on mutagenicity

         Two groups of 20 male mice (30-35 g) received either
    150 mg/kg/day of CHS orally as a 0.6% solution in demineralized water
    or 25 ml water/kg/day on 5 successive days. Males were then mated with
    3 untreated females. Each week 3 other untreated females were placed
    for mating with each male for a total of 8 mating periods. On the
    14th day of gestation the uterus was examined for pro- and post-
    implantation losses. No apparent effect on the mating capacity or
    fertility of the treated males was observed. Pre- and post-
    implantation losses of the treated group were comparable to the
    control. Thus under the conditions of this study there would appear to
    be no dominant lethal effects (Lorke & Machemer, 1974).

         A group of Chinese hamsters, 13 males and 7 females, weighing
    between 30-40 g were given a dose of 200 mg/kg/day of CHA by gavage
    for 3 successive days. Blood samples for lymphocyte culture were taken
    from the orbital plexus prior to and 4 days after treatment. A
    significant increase in structural aberrations of the chromosomes
    (ring chromosome, exchange figures, fragments and breaks) were
    observed. There was no significant increase in aneuploid or polyploid
    cells (Van Went-de Vries et al., 1975).

    Special studies on reproduction

         Two separate studies were conducted. In the first study rats were
    administered orally cyclohexylamine sulfate (CHS) as follows: groups
    of 5 males and 15 females received 22.26 and 44.52 mg/kg/day and 8
    males and 25 females received 89.04 mg/kg/day. A control group of 7
    males and 17 females received distilled water. Survival of progeny at
    birth and 24 hours post-partum was noted. Viable members of each
    litter at 2 days of age were weighed and killed for skeletal visceral
    and chromosomal studies. During the second cycle females were allowed
    to deliver normally and at 2 days post-partum each litter was randomly
    reduced to 8 pups and their body weight gains were measured until
    weaning (21 days). Pups and mothers were then sacrificed. In the
    second study 2 groups of 10 males and 10 females each were
    administered 44.52 or 89.04 mg/kg/day of CHS. A group of 12 males and
    12 females received 178.08 mg/kg/day and a group of 13 males and 13
    females were used as controls. Females showing pregnancy were
    sacrificed after 11-15 days of separation from males. The number of
    viable embryos and resorption sites in the uteri were counted. The
    rats which were discontinued from the breeding studies were bled from
    the abdominal aorta 24, 57, 77, 101 and 119 days after initiation of

    study and within 6 hours of last administered dose. There was no
    detectable effect on body weight gain. Blood analysis for CHS gave
    evidence of its absorption. Male fertility appeared to be impaired.
    However, there was no evidence of adverse effects on female fertility.
    No deleterious effects were noted on embryo viability, litter size,
    litter weight, postnatal viability, weight gain of pups or somatic
    cell chromosomes of pups and dams (Khera et al., 1971).

    Short-term studies

    Rat

         Groups of 100 male weanling Sprague-Dawley rats were randomly
    assigned to 9 treatment groups. Animals were observed for a 1-week
    baseline feeding period followed by a 15-day diet acclimation period
    from which time the animals were fed 0, 50, 100, 200 and 300 mg/kg CHA
    base admixed to basal diet. Four control groups were assigned for
    pair-feeding with each test group. The animals in these control groups
    received an amount of basal diet equal to that consumed by its pair-
    fed partner in the test group during the previous week. The animals
    were fed their respective diets for 90 days. Body weight gain and food
    consumption were recorded weekly. On termination of the study necropsy
    was performed on each animal. Testicular weights were recorded and
    each testis was subjected to histological examination. The body
    weights of the treated groups were found to be significantly less than
    the body weights of the untreated controls. When compared to their
    corresponding pair-fed control the body weights of the treated animals
    were still significantly less except for those receiving 50 mg/kg bw
    of CHA. The mean percentage decrease, however, was only significant
    for the 200 and 300 mg/kg bw groups.

         In treated rats both right and left testicular weights were found
    to be significantly less than in the untreated controls. Analysis
    comparing treated to corresponding pair-fed group showed a significant
    difference only at the highest dose group (300 mg/kg bw). The only
    compound-related changes noted at autopsy were in relation to the
    testes of the highest dose group (atrophy, shrinking, soft
    consistency, livid, glassy).

         At termination of the study, 3 cross-sections were prepared from
    both left and right testicle of each rat. Each of these 6 sections
    were evaluated histopathologically. The extent of tubular alteration
    was scored as follows:

    0  - tubular alterations not discernible;

    1+ - up to 5% of tubules within section affected;

    2+ - 6-20% of tubules within section affected;

    3+ - 21-60% of tubules within section affected;

    4+ - 61% or more of tubules within section affected.

    For each rat, the 3 left scores were averaged and the 3 right scores
    averaged to reduce each rat's testicular data to a pair of
    observations. The left and right average scores were analysed
    separately. The average left and right testicular scores for the 2
    highest test groups were significantly higher than the untreated
    control group. When each of the treated groups was compared to its
    pair-fed control, once again, the only treatment groups showing a
    significantly different average testicular score for both left and
    right testis were the 200 and 300 mg/kg groups (Brune & Mohr, 1978).

         Two groups of 15 male rats, 35 days of age, were administered
    CHA as a suspension in corn oil by gavage at dose levels of 0 or
    200 mg/kg/day. Five rats from each group were killed after weeks 4 and
    9 of treatment, the remaining 5 rats/group were maintained untreated
    for 13 weeks. Body weight gain, food and water intake were recorded
    weekly. Serum follicle stimulating hormone (FSH), luteinizing hormone
    (LH) and testosterone levels were determined after 1 day, 4 and 9
    weeks of treatment and after the 13 week withdrawal period. Terminal
    examination included autopsy. Pituitary glands, testes (including
    epididymides), prostate and seminal vesicles were weighed and
    preserved for histological examination. A quantitative assessment of
    spermatogenesis was performed.

         Body weight and food consumption were reduced. FSH levels
    increased and testosterone levels decreased in the treated rats. One
    rat examined after 13 weeks withdrawal of CHA showed bilateral
    testicular atrophy. There were no statistically significant effects on
    the weights of the pituitaries, testes or secondary sex organs of the
    treated animals. Quantitative assessment of testicular spermatogenesis
    showed a significant reduction in the number of late spermatids in the
    treated group both during and after withdrawal periods. After 13 weeks
    withdrawal of CHA, rats were found to have a reduced number of
    spermatocytes and early spermatids (James et al., 1981).

    Dog

         Four sexually mature male Beagle dogs were administered CHA
    suspended in corn oil by gavage. Initially the CHA suspension was
    administered at 75 mg/kg on days 1 and 2, 75 mg/kg twice daily on days
    3 and 4, 150 mg/kg on days 5 and 6 and then 150 mg/kg twice daily on
    subsequent days. After day 9 the dose was reduced to 125 mg/kg twice
    daily to avoid appetite suppression. Two dogs were killed after week
    9 of treatment and the two remaining dogs maintained untreated for
    13 weeks. Body weight gain was recorded weekly. Food and water
    consumption were measured daily. Testicular measurements and semen
    examinations were made prior to and after 2, 4 and 8 weeks of

    treatment and again during withdrawal period. Serum luteinizing
    hormone (LH) and testosterone concentrations were determined prior to
    and after 1, 2, 4 and 8 weeks of treatment and during weeks 4, 8 and
    12 of withdrawal period. At termination full macroscopic examinations
    were performed. Pituitary glands, testes and prostate were weighed and
    preserved for histologic examination. A quantitative assessment of
    spermatogenesis was performed.

         Body weight gain and food consumption were reduced during
    treatment; however, both returned to normal during the withdrawal
    period. Serum LH and testosterone concentrations were not affected.
    Sperm count was decreased and a significantly increased percentage of
    abnormal spermatozoa was observed, both parameters returning to normal
    after a 12-week withdrawal period. Weights of pituitary glands, testes
    and secondary sex organs of treated rats were not affected. CHA
    administration caused a reduction in the counts of spermatocytes and
    early and later spermatids after 9 weeks of treatment. These counts
    exhibited remarkable improvement at the end of the recovery period
    (James et al., 1981).

    Long-term studies

    Mouse

         Groups of 48 male and 50 female weanling mice were fed diets
    containing 0, 300, 1000 or 3000 ppm (0, 0.03, 0.1 or 0.3%)
    cyclohexylamine hydrochloride for 80 weeks. There were no apparent
    adverse effects on general health, behaviour, body weight gain, food
    or water consumption, haematology or in the incidence of tumours.
    However, there was a slight increase in some minor histological
    changes of the liver at 3000 ppm (0.3%). The no-effect level of
    CHA.HCl was found to be 1000 ppm (0.1%) (Hardy et al., 1976).

    Rat

         Groups of 48 males and 48 females were fed a diet containing 0,
    600, 2000 or 6000 ppm (0, 0.06, 0.2 or 0.6%) cyclohexylamine
    hydrochloride (CHA.HCl) for 104 weeks. A dose-related decrease in body
    weight gain, food consumption, and water intake was observed.
    Haemoglobin concentration of females given 6000 ppm (0.6%) CHA.HCl was
    reduced during the first 52 weeks of the study. There were, however,
    no apparent effects later in the study or in the males. Total
    leucocyte count was reduced in males after 104 weeks. Blood urea (BUN)
    concentrations were significantly reduced in males at all dose levels
    while serum albumin concentrations were increased at the 2 higher dose
    levels. At 6000 ppm (0.6%) CHA.HCl, rats produced a more dilute urine.
    The relative organ weights of liver, spleen, and kidneys in males fed
    the diet containing 6000 ppm (0.6%) CHA.HCl were lower than the
    control values and the relative weight of the thyroids in females was
    reduced at 2000 and 6000 ppm (0.2% and 0.6%) CHA.HCl. There was no
    indication of a tumorigenic effect at any treatment level.

         Testicular changes, such as atrophy of the tubules with few
    spermatids, were noted in rats given 2000 or 6000 ppm (0.2 or 0.6%)
    CHA.HCl. The changes, other than histological effects observed in the
    testes, were considered explicable in terms of the changes resulting
    from a lowered body weight gain and reduced food consumption. The
    no-effect level was 600 ppm (0.06%) on the basis of effects on the
    testes (Gaunt et al., 1976).

    Comments

         The evaluation of recent studies permitted the change in the
    previously established ADI. The temporary status of the ADI maintained
    at the twenty-fourth meeting of the Joint Committee in 1980 is removed
    and the ADI increased.

    EVALUATION

    Level causing no toxicological effect

    Rat: 100 mg/kg bw in the diet.

    Estimate of acceptable daily intake for man*

    0-11 mg/kg bw as calcium and sodium salts, expressed as cyclamic acid.

              

    *    Calculation of ADI

    (1)  approximately 37% cyclamate absorbed. 63% available for
         conversion to CHA by intestinal flora. Absorbed cyclamate is not
         metabolized.

    (2)  human conversion rate of cyclamate to cyclohexylamine - 30%.

    (3)  mol wt. cyclamate        = 2
         mol wt. cyclohexylamine

    (4)  no-effect level for cyclohexylamine = 100 mg/kg bw

    (5)  no-effect level for cyclamate

         x =   100 × 2    =  200   =  1058
              0.63 × 0.3    0.189

    (6)  ADI for cyclamate =      NOEL      = 1058  =  10.6 mg/kg
                             Safety factor    100      bw per day

    REFERENCES

    Aeschbacher, H. U. et al. (1979) Effect of simultaneous administration
         of saccharin or cyclamate and nitrosamide (MNU) on bladder
         epithelium and the dominant lethal test, Toxicology Letters,
         3, 273

    Brantom, P. G. & Gaunt, I. F. (1973) Long-term toxicity of sodium
         cyclamate in mice, Fd. Cosmet Toxicol., 11, 735-746

    Brune, H. & Mohr, U. (1978) Establishment of the no-effect dosage of
         cyclohexylamine hydrochloride in male Sprague-Dawley rats with
         respect to growth and testicular atrophy. Unpublished report from
         Abbott Laboratories, Ltd.

    Dick, C. E. et al. (1974) Cyclamate and cyclohexylamine: Lack of
         effect on the chromosomes of man and rats in vivo, Mutation
         Res., 26, 199-203

    Gaunt, I. F. et al. (1976) Long-term toxicity of cyclohexylamine
         hydrochloride in the rat, Fd. Cosmet. Toxicol., 14, 255-267

    Green, U. et al. (1980) Syncarcinogenic action of saccharin or sodium
         cyclamate in the induction of bladder tumours in MNU-pretreated
         rats, Fd. Cosmet. Toxicol., 18, 575-580

    Hardy, J. et al. (1976) Long-term toxicity of cyclohexylamine
         hydrochloride in mice, Fd. Cosmet. Toxicol., 14, 269-276

    Herbold, B. A. & Lorke, D. (1980) On the mutagenicity of artificial
         sweeteners and their main impurities examined in the Salmonella/
         microsome test, Mutation Res., 74, 155-156

    Hicks, R. M., Wakefield, J. St J. & Chowaniec, J. (1975) Evaluation of
         a new model to detect bladder carcinogen or co-carcinogens,
         results obtained with saccharin, cyclamate and cyclophosphamide,
         Chem.-Biol. Interactions, 11, 225-233

    James, R. W., Heywood, R. & Crook, D. (1981) Testicular responses of
         rats and dogs to cyclohexylamine overdosage, Fd. Cosmet.
         Toxicol., 19, 291-296

    Khera, K. S. et al. (1971) Reproduction study in rats orally treated
         with cyclohexylamine sulfate, Toxicol. Appl. Pharmacol., 18,
         263-268

    Kroes, R., Peters, P. W. J., Berkvens, Johanna M., Verschuuren, H. G.,
         De Vries, Th. & Van Esch, G. J. (1977) Long-term toxicity and
         reproduction study (including a teratogenicity study) with
         cyclamate, saccharin and cyclohexamine, Toxicol., 8, 285-300

    Lorke, D. & Machemer, L. (1974) Investigation of cyclohexylamine
         sulfate for dominant lethal effects in the mouse, Toxicol.,
         2, 231-237

    Schmähl, D. & Habs, M. (1980) Absence of carcinogenic response to
         cyclamate and saccharin in Sprague-Dawley rats, Drug Res.,
         30, 1905-1906

    Sieber, S. M. & Adamson, R. H. (1978) Long-term studies on the
         potential carcinogenicity of artificial sweeteners in non-human
         primates. Proc. ERGOB Conf. Health and sugar substitutes, Geneva,
         266 pp.

    Van Went-de Vries, G. F. et al. (1975) In vivo chromosome damaging
         effect of cyclohexylamine in the Chinese hamster, Fd. Cosmet.
         Toxicol., 13, 415-418

    Wills, J. H., Serrone, D. M. & Coulston, F. (1981) A 7-month study of
         ingestion of sodium cyclamate by human volunteers, Regulatory
         Toxicol. Pharmacol., 1, 163-176
    


    See Also:
       Toxicological Abbreviations