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 formulaMolecular 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 Abbots Laboratories Bernier, J. J. 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(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