National Toxicology Program

Selected toxicity information from HSDB, one of the National Library of Medicine's databases. ¹

Names (NTP)

• Saccharin
• 1,1-DIOXIDE-1,2-BENZISOTHIAZOL-3(2H)-ONE (9CI)

Human Toxicity Excerpts

• LARGE DAILY DOSES MAY ... PRODUCE GASTRIC HYPERACIDITY. [Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984., p. II-406]**PEER REVIEWED**
  
• A SURVEY OF BLADDER CANCER PATIENTS & CONTROLS WITHOUT BLADDER CANCER SHOWED THAT IN GENERAL BLADDER CANCER RISK WAS NOT INCREASED BY NONNUTRITIVE SWEETENER SACCHARIN & CYCLAMATE USE. ADJUSTING FOR SMOKING HABITS, OCCUPATION, AGE, RACE, SEX, DIABETES MELLITUS, ETC DID NOT LEAD TO SIGNIFICANT CORRELATIONS BETWEEN THE SWEETENER USE & BLADDER CANCER. [KESSLER II; HEALTH SUGAR SUBSTITUTES PROC ERGOB CONF SUGAR SUBSTITUTES: 85 (1979)]**PEER REVIEWED**
  
• THE RELATION BETWEEN CANCER OF THE LOWER URINARY TRACT & USE OF ARTIFICIAL SWEETENERS CYCLAMATES & SACCHARIN WAS EVALUATED IN A CASE CONTROL STUDY OF 592 PATIENTS, AGED 21 TO 89 YR, WITH LOWER URINARY TRACT CANCER (94% OF WHOM HAD BLADDER TUMORS) & 536 CONTROLS CHOSEN FROM THE GENERAL POPULATION OF THE STUDY AREA. IN THOSE WHO HAD USED SUGAR SUBSTITUTES & DIETETIC BEVERAGES, THE RELATIVE RISK OF LOWER URINARY TRACT CANCER WAS ESTIMATED TO BE 0.9, AS COMPARED WITH ONE IN NONUSERS OF ARTIFICIAL SWEETENERS. AMONG MEN, THE RELATIVE RISK WAS 0.8 IN THOSE WHO HAD USED SUGAR SUBSTITUTES. AMONG WOMEN, THE CORRESPONDING RELATIVE RISKS WERE 1.6 & 1.5. INCREASING FREQUENCY OR DURATION OF USE OF ARTIFICIAL SWEETENERS WAS NOT CONSISTENTLY ASSOCIATED WITH INCREASING RELATIVE RISK. THIS STUDY SUGGESTS THAT, AS A GROUP, USERS OF ARTIFICIAL SWEETENERS HAVE LITTLE OR NO EXCESS RISK OF CANCER OF THE LOWER URINARY TRACT. [MORRISON AS, BURING JE; N ENGL J MED 302 (MAR 6): 537 (1980)]**PEER REVIEWED**
  
• POSITIVE ASSOC BETWEEN USE OF ARTIFICIAL SWEETENERS, PARTICULARLY SACCHARIN, & RISK OF BLADDER CANCER IN MALES WAS OBSERVED IN CASE CONTROL STUDY OF 480 MEN & 152 WOMEN IN 3 PROVINCES IN CANADA. [HOWE GR ET AL; LANCET 2 (SEP 17): 578 (1977)]**PEER REVIEWED**
  
• ... No increase in spontaneous abortions among women taking saccharin. [Shepard, T.H. Catalog of Teratogenic Agents. 5th ed. Baltimore, MD: The Johns Hopkins University Press, 1986., p. 510]**PEER REVIEWED**
  
• ...reported 5 patients in whom oral administration of 0.1 g saccharin caused pruritis and oedematous papules on the trunk and limbs. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V22 151 (1980)]**PEER REVIEWED**
  

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Non-Human Toxicity Excerpts

• GROUPS OF 50 MALE & 50 FEMALE 30-DAY OLD CHARLES-RIVER CD RATS WERE FED EITHER A CONTROL DIET OR A DIET CONTAINING 5% SODIUM SACCHARIN PREPD BY THE MAUMEE PROCESS ... & FREE OF ORTHO-TOLUENESULFONAMIDE. SURVIVAL WAS NOT AFFECTED BY TREATMENT. BLADDER TUMORS (BENIGN & MALIGNANT) WERE OBSERVED IN 1/36 CONTROL MALES & 7/38 MALE RATS FED SACCHARIN WHICH SURVIVED 87 WK OR MORE THE TIME IN WHICH THE FIRST TUMOR WAS OBSERVED ... IN ADDN, 1 TREATED MALE & 2 TREATED FEMALES HAD UROTHELIAL TUMORS OF THE KIDNEY PELVIS & 1 TREATED MALE HAD URETHRAL TUMOR; NO OTHER UROTHELIAL TUMORS WERE OBSERVED IN CONTROLS. /SODIUM SALT/ [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V22 135 (1980)]**PEER REVIEWED**
  
• ADDN OF 0.5% SODIUM SACCHARIN TO THE DIET REDUCED THE GROWTH RATE OF RATS OVER A 38-DAY PERIOD. THE FEEDING OF 0.065 G/KG BODY WT/DAY SODIUM SACCHARIN TO DOGS FOR 11 MO PRODUCED NO TOXIC EFFECTS OTHER THAN OCCASIONAL STOOL SOFTENING. ... ADMIN OF 1% SODIUM SACCHARIN IN DRINKING-WATER &/OR FOOD DECR WT GAIN & CAUSED DEATH IN RATS FED REDUCED FOOD RATIONS. /SODIUM SALT/ [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V22 144 (1980)]**PEER REVIEWED**
  
• RABBITS ARE KILLED BY ORAL DOSES OF 8 TO 10 G/KG, PRESUMABLY AS RESULT OF GASTROENTERITIS. [Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984., p. II-406]**PEER REVIEWED**
  
• CHRONIC ADMIN OF SACCHARIN IN DRINKING WATER TO SYRIAN GOLDEN HAMSTERS, UP TO MAX TOLERATED DOSE LEVEL, FAILED TO INDUCE EXCESS OF TUMORS, NOR WERE ANY URINARY BLADDER TUMORS FOUND. [ALTHOFF J ET AL; CANCER LETT 1 (1): 21 (1975)]**PEER REVIEWED**
  
• SUBACUTE TOXICITY WITH SODIUM SACCHARIN WAS EVALUATED BY FEEDING AT DIETARY LEVEL OF 2000 PPM TO BOTH BEAGLE DOGS & ALBINO RATS. DOGS WERE MAINTAINED ON TEST DIETS FOR 16 WK, RATS FOR 13 WK. NO SIGNS OF PHARMACOTOXIC RESPONSE TO THE TEST MATERIAL WAS OBSERVED. /SODIUM SACCHARIN/ [KENNEDY GL JR ET AL; TOXICOLOGY 6 (2): 133 (1976)]**PEER REVIEWED**
  
• MAINLY TESTED AS ITS SODIUM SALT, SACCHARIN HAS BEEN FOUND TO BE WEAKLY MUTAGENIC IN SALMONELLA @ HIGH DOSES, IN DROSOPHILA @ MODERATE DOSES, & IN MICE @ MODERATE TO HIGH DOSES. CMPD IS WEAK CHROMOSOME BREAKER IN ONION ROOT TIPS & IN CHINESE HAMSTER CELLS. FOR MOST OF THESE, & FOR OTHER TEST SYSTEMS AS WELL, A NUMBER OF DOUBTFUL OR NEG RESULTS HAVE BEEN REPORTED. IT IS SUGGESTED THAT THE OBSERVED CONTRAINDICATIONS MIGHT BE RELATED TO THE OCCURRENCE OF VARYING AMT OF IMPURITIES. /SODIUM SACCHARIN/ [KRAMERS PG; MUTAT RES 32 (1): 81 (1975)]**PEER REVIEWED**
  
• IN MALE MICE INJECTED IP WITH 1, 2, OR 4 G SACCHARIN PER KG BODY WT OR RECEIVING DURING A 100 DAY PERIOD 20 G OF SACCHARIN PER LITER OF DRINKING WATER AND TESTED FOR MUTAGENICITY, YIELDED NEG RESULTS. IT IS CONCLUDED THAT THE POS FINDINGS REPORTED IN THE LITERATURE WERE PROBABLY DUE TO THE MUTAGENIC ACTIVITY OF SACCHARIN IMPURITIES. [LEONARD A, LEONARD ED; J ENVIRON PATHOL TOXICOL 2 (4): 1047 (1979)]**PEER REVIEWED**
  
• MALE & FEMALE WISTAR RATS WERE ADMIN SODIUM SACCHARIN FOR LIFE (2 YR) EITHER IN THE DRINKING WATER OR DIET. A CONTROL GROUP RECEIVED SACCHARIN-FREE DIET & DRINKING WATER. MILD UROTHELIAL HYPERPLASIAS DEVELOPED FROM 85 WK IN RATS OF BOTH SEXES RECEIVING SACCHARIN, THE INCIDENCE WAS STATISTICALLY SIGNIFICANT IN BOTH THE BLADDERS & KIDNEYS OF RATS RECEIVING THE HIGHER DOSE IN DIET, BUT IN KIDNEYS ONLY RECEIVING THE LOWER DOSE IN DRINKING WATER. TELANGIECTASIA OF THE VASA RECTA WAS SIGNIFICANT IN RATS OF BOTH SEXES. A VERY LOW INCIDENCE OF BLADDER TUMORS, EXCLUSIVELY IN MALES RECEIVING THE HIGHER DOSE WAS SEEN FROM 95 WK. THE POSSIBILITY THAT SACCHARIN MAY PROMOTE, OR ENHANCE, THE DEVELOPMENT OF LATENT TUMOR CELLS ALREADY PRESENT IS CONSIDERED. /SODIUM SACCHARIN/ [CHOWANIEC J, HICKS RM; BR J CANCER 39 (4): 355 (1979)]**PEER REVIEWED**
  
• NO EFFECTS ON REPRODUCTION WERE OBSERVED IN 20 MICE RECEIVING 194 MG/KG BODY WT SACCHARIN DAILY FOR 180 DAYS. ORAL DOSES OF UP TO 600 MG/KG BODY WT PER DAY SACCHARIN OR ITS SODIUM SALT GIVEN OVER THE TOTAL ORGANOGENESIS PHASE HAVE NOT BEEN FOUND TO INDUCE MALFORMATIONS OR OTHER EMBRYOTOXIC EFFECTS IN MICE, RATS, RABBITS. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V22 145 (1980)]**PEER REVIEWED**
  
• A HIGHLY PURIFIED PREPN OF SACCHARIN ... CAUSED A SIGNIFICANT, DOSE-RELATED INCR IN CHROMOSOME ABERRATIONS (BREAKS, GAPS, TRANSLOCATIONS & RING FORMATIONS) IN CHINESE HAMSTER OVARY (CHO) CELLS IN THE PRESENCE OF LIVER HOMOGENATE. IT WAS REPORTED ... THAT CHROMATID BREAKS & GAPS WERE ALSO INDUCED IN CHO-K1 CELLS TREATED WITH SODIUM SACCHARIN ... ABERRATIONS HAVE BEEN INDUCED BY SACCHARIN & ITS SODIUM SALT IN OTHER CHINESE CELL LINES. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V22 149 (1980)]**PEER REVIEWED**
  
• ... SACCHARIN THAT IS CLAIMED TO HAVE PRODUCED BLADDER TUMORS CONTAINS O-TOLUENESULFONAMIDE AS IMPURITY. ANOTHER TYPE OF SACCHARIN, MFR BY DIFFERENT PROCESSES NOT CONTAINING THIS IMPURITY, HAS FAILED TO INDUCE TUMORS WHEN FED @ HIGH LEVELS TO RATS. [Searle, C. E. (ed.). Chemical Carcinogens. ACS Monograph 173. Washington, DC: American Chemical Society, 1976., p. 722]**PEER REVIEWED**
  
• Saccharin was tested for mutagenicity in the Salmonella/microsome preincubation assay using the standard protocol approved by the National Toxicology Program. Saccharin was tested at doses of 0.10, 0.33, 1.0, 3.3, and 10 mg/plate in as many as 5 Salmonella typhimurium strains (TA1535, TA1537, TA97, TA98, and TA100) in the presence and absence of rat or hamster liver S-9. Saccharin was negative in these tests and the highest ineffective dose tested in any S. typhimurium strain was 10 mg/plate. [Mortelmans K et al; Environ Mutagen 8: 1-119 (1986)]**PEER REVIEWED**
  
• Male Sprague-Dawley CD rats were exposed to a series (8 to 10) of sequential daily training trials, with 120 min access to a drinking solution containing 0.2% saccharin on half the trials, according to a counterbalanced repeating ABBA design. During the test period, the rats' maintenance chow was replaced by the same chow flavored with 0.8% (by wt) non-nutritive chicken or chocolate flavor. Preference for a flavored food paired with a drinking solution was inferred from a 2-choice test conducted on the day after the last training trial. All rats were given both flavored foods simultaneously. Intake of each was measured after 0.5, 1, 2, 4, and 24 hr. Relative to trials with a different flavored food and only water to drink, food intake was increased by drinking 0.2% saccharin. There was no correlation between the vol of saccharin ingested and the incr in feeding produced by saccharin. [Tordoff MG, Friedman MI; Appetite 12 (1): 1-10 (1989)]**PEER REVIEWED**
  
• Rats were exposed to a series (8 to 10) of sequential daily training trials, with 30 to 120 min access to a drinking solution (0.2% saccharin) on half the trials, according to a counterbalanced repeating ABBA design. During the test period, the rats' maintenance chow was replaced by the same chow flavored with 0.8% (by wt) non-nutritive chicken or chocolate flavor. Learning was unnecessary for the feeding response, as rats that drank saccharin increased food intake whether or not their food contained saccharin contingent flavor cues. However, learning helped support and maintain the response, as rats repeatedly given flavored food together with saccharin to drink later increased intake when given the flavored food without saccharin (ie in extinction). The rewarding or hedonic effects of the immediate or sensory properties of saccharin were not responsible for its effects on feeding, as drinking saccharin before but not after eating flavored food increased food intake and food preference. Furthermore, hungry rats developed an aversion to flavored food paired with saccharin ingestion when the quantity of food was limited. [Tordoff MG, Friedman MI; Appetite 12 (1): 23-36 (1989)]**PEER REVIEWED**
  
• Rats were exposed to a series (8 to 10) of sequential daily training trials, with 30 to 120 min access to a drinking solution (0.2% saccharin) on half the trials, according to a counterbalanced repeating ABBA design. The results show that cephalic phase insulin response could be dissociated from food intake in three ways. (1) Drinking saccharin increased the food intake and food preference of rats with sham surgery or celiac vagotomy, but not hepatic vagotomy; it produced a short lived increase in plasma insulin levels in all three groups, but the insulin response of both the celiac vagotomy and hepatic vagotomy was attenuated relative to the sham surgery group. (2) Rats increased food intake even when a 90 min interval was imposed between drinking saccharin and eating food although insulin and glucose levels returned to normal within 30 min of drinking saccharin. (3) Streptozotocin induced diabetes did not affect the increased feeding response to saccharin. [Tordoff MG, Friedman MI; Appetite 12 (1): 37-56 (1989)]**PEER REVIEWED**
  
• ... Tested pregnant mice with saccharin and found no evidence of teratogenicity. The mice received up to 25 mg/kg daily from the 6th through the 15th day. Cyclamate up to 250 mg/kg was also given without producing fetal changes. Reported no teratogenic effects in the rat fetus when the mother received 25 mg /kg from day 6 through 15 gestation. Also found no teratogenicity in long term studies in mice. In the male offspring of rats maintained on a diet of 7.5% saccharin an increase in bladder neoplasms was found. No increase was found with a diet containing 5% saccharin. [Shepard, T.H. Catalog of Teratogenic Agents. 5th ed. Baltimore, MD: The Johns Hopkins University Press, 1986., p. 510]**PEER REVIEWED**
  
• ... Studied embryofetotoxicity of possible intermediates or contaminants of commercially prepared saccharin. Administered orally to rats at 0.1% of the diet, O-toluenesulfonamide was devoid of toxicity, O-sulfobenzoic acid increased the number of fetal resorptions sightly, but O-sulfamoylbenzoic acid, and especially NH-4 O-sulfobenzoic acid markedly increased resorptions. [Shepard, T.H. Catalog of Teratogenic Agents. 5th ed. Baltimore, MD: The Johns Hopkins University Press, 1986., p. 510]**PEER REVIEWED**
  
• Six chemicals, diethylhexyl phthalate, ethanol, cyclohexylamine, sodium saccharin, cadmium chloride and triflupromazine, were suggested to be unique germ cell mutagens by the GeneTox Workgroups of the USEPA. If this is a correct classification it would have major consequences when screening for mutagenicity and when labelling genotoxic substances. However, re-evaluation of the GeneTox literature, including some more recent publications, has failed to find substantive evidence that any of these chemicals have been unequivocally established as having unique mutagenic activity in germ cells. For diethylhexyl phthalate, sodium saccharin and triflupromazine the evidence for genotoxic/mutagenic effects is questionable, in both germinal and somatic cells. Ethanol and cadmium chloride showed clastogenic activity, but it was not restricted to germ cells. Both, ethanol and cadmium salts, appear to induce aneuploidy. The unconfirmed clastogenic effect of cyclohexylamine was restricted to rats, but it occurred in both bone marrow and spermatogonia. Therefore, the general observation that rodent germ cell mutagens are also genotoxic in somatic cells in vivo remains valid. /Sodium saccharin/ [Adler ID, Ashby J; Mutat Res 212 (1): 55-66 (1989)]**PEER REVIEWED**
  
• In an attempt to define the role of exposure to sodium saccharin during early life on the subsequent development of bladder tumors, ... /a study was developed to/ compare the responses of male rat pups to exposure to 5% dietary sodium saccharin initiated at parturition with those to exposure initiated at weaning. ... /The study/ also compared the effects of exposure from parturition to sodium saccharin given in a low carbohydrate diet with those of sodium saccharin in rat chow. Sodium saccharin ingestion by the dam was associated with low saccharin concentrations in the pups' urine and had no effect on the cecal or bladder mass in the suckling pups. In the 10 wk after weaning, the rats ingesting sodium saccharin in chow showed decreased weight gain and increases in feed consumption, mass of cecal contents and tissue, urine output, bladder mass, relative water consumption (g water consumed/g feed consumed) and bladder hyperplasia. Except for bladder hyperplasia these effects were generally greater in the rats exposed to sodium saccharin from parturition than in those exposed only from weaning. The animals exposed to sodium saccharin in the low carbohydrate diet had the highest level of urinary saccharin but showed no bladder hyperplasia. /Sodium saccharin/ [Anderson RL et al; Food Chem Toxicol 26 (11-12): 899-907 (1988)]**PEER REVIEWED**
  
• Sodium saccharin, potassium saccharin, calcium saccharin and the free acid when fed to young male rats at a level of about 200 umol/g diet all produced an equivalent increase in the cecal enlargement indicating that this phenomenon was due to the saccharin ion and not the accompanying cation. The sodium and potassium salts caused greater polydipsia and polyuria than the calcium or free acid forms. Simple hyperplasia of the bladder was noted in the rats ingesting the sodium and potassium salts but not in those ingesting the calcium or free acid forms. The difference in urine and bladder response to the salt forms is not attributable to the difference in the total urinary saccharin or the urinary concentration of saccharin. These results suggest that excess water absorption from the lower bowel and the concomitant bladder responses are dependent upon monovalent cation absorption but independent of saccharin absorption. [Anderson RL et al; Food Chem Toxicol 26 (8): 665-9 (1988)]**PEER REVIEWED**
  
• To ascertain whether the bladder mass increase and epithelial hyperplasia induced by 5% dietary sodium saccharin in short-term experiments with rats are caused by increased urinary excretion of indican associated with this treatment, the responses of the urine and bladder induced by 1.5% indole ingestion were compared with those induced by 5% sodium saccharin and 1.5% indole + 5% sodium saccharin. Indole and sodium saccharin, when fed alone, produced equivalent increased in bladder mass and both compounds induced epithelial hyperplasia, but indole ingestion was associated with much greater urinary indican (5 mg/g diet ingested) than was sodium saccharin (0.3 mg/g diet ingested). When indole and sodium saccharin were ingested together, the bladder mass increase was additive, but the epithelial hyperplasia was not exacerbated over that observed with each alone, and the urinary indican was equivalent to that produced by indole alone. These findings suggest that a high level of urinary indican excretion is associated with an increase in bladder mass and epithelial hyperplasia (indole treatment) but indicate that the relatively low urinary indican level obtained by sodium saccharin feeding alone is unlikely to be responsible for the bladder responses noted with this compound. /Sodium saccharin/ [Anderson RL et al; Food Chem Toxicol 27 (12): 777-9 (1989)]**PEER REVIEWED**
  
• Three methods used to detect proliferative changes in the rat urothelium, light microscopy, scanning electron microscopy, and autoradiography, were compared for their sensitivity in detecting changes produced by administration of sodium saccharin. Weanling male F344 rats were fed sodium saccharin as 0, 3, 5, or 7.5% of the diet, and the bladders were evaluated after 4, 7 and 10 wks of feeding. Light microscopic changes and increase in labeling index were seen at all time points in rats fed 7.5% sodium saccharin, but not at the lower doses. A slight increase in labeling index was also observed at 10 wks in the 5.0% /group/. Scanning electron microsopic changes were evident as early as 4 wks with increasing severity at the 3, 5, and 7.5% doses. This study demonstrates that the hyperplastic response of the urothelium to sodium saccharin administration varies with dose and time, and that observation by scanning electron microscopy is the most sensitive of the three methods evaluated for detecting these changes. /Sodium saccharin/ [Cohen SM et al; Scanning Microsc 4 (1): 135-42 (1990)]**PEER REVIEWED**
  
• Sodium saccharin has been reported to promote the development of urinary bladder tumors in rats following low doses of several carcinogens. To evaluate the generality of this effect between species, an initiation-promotion study was conducted in mice. Weanling female BALB/c mice were initiated with 200 ppm dietary 2-acetylaminofluorene for 90 days. Following a 2 week period of control diet, saccharin was administered at 0, 0.1, 0.5 1.0, and 5.0% in the diet for the remainder of the 132 week study. An elevated incidence of persistent bladder transitional cell hyperplasia and a low incidence of urothelial and hepatocellular tumors indicated that these organs achieved an adequate dose of the initiator. However, sodium saccharin dosing did not result in an increased incidence of tumors in either the bladder or liver and is therefore not considered to be a promoter of carcinogenesis at these sites in the mouse. Furthermore, sodium saccharin exhibited a modest inhibitory effect on the rate of development of lymphomas in both initiated and noninitiated animals. Interspecies difference in the bladder tumorigenic effect of sodium saccharin and their association with differences in urinary tract physiology are discussed. /Sodium saccharin/ [Frederick CB et al; Fundam Appl Toxicol 12 (2): 346-57 (1989)]**PEER REVIEWED**
  
• Since both sodium L-ascorbate and sodium saccharin promote two-stage bladder carcinogenesis in rats, synergism of the two chemicals was investigated with special reference to the role of urinary pH and sodium+ concentration. Male F344 rats were given 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine in the drinking water for 4 wk and then treated with basal diet containing 5% sodium saccharin, 5% sodium L-ascorbate, 5% sodium saccharin plus 5% sodium L-ascorbate, 5% L-ascorbic acid, 5% sodium saccharin plus 5% L-ascorbic acid, or no added chemical for 32 wk. Treatment with sodium saccharin or sodium L-ascorbate alone significantly increased the induction of neoplastic and preneoplastic lesions of the bladder. Sodium saccharin plus sodium L-ascorbate also induced these bladder lesions significantly when compared with the controls, and the number of lesions was greater than the sum of the lesions in the group treated with sodium saccharin alone or sodium L-ascorbate alone. In contrast, the induction of carcinomas and papillomas in rats treated with sodium saccharin plus sodium L-ascorbate produced an elevation of urinary pH and sodium+ concentrations, although the increases were not different from those in rats fed sodium saccharin or sodium L-ascorbate alone. Sodium saccharin plus L-ascorbic acid, however, did not cause elevation of urinary pH, although it increased urinary sodium+ concentration. Thus, the bladder carcinogenesis promotion by sodium saccharin was synergized by sodium L-ascorbate and inhibited by L-ascorbic acid. This modulation was associated with changes of urinary pH and Na+ concentration. /Sodium saccharin/ [Fukushima S et al; Cancer Res 50 (14): 4195-8 (1990)]**PEER REVIEWED**
  
• When male rats of certain strains are fed a diet with 3% or more sodium saccharin, their urinary bladders developed epithelial hyperplasia and a greater incidence of tumors. Since the daily dose of saccharin is high, a link between tumor formation and the disruption of urothelial physiologic and biochemical processes has been sought. ... Male and female Sprague-Dawley rats were fed a saccharin free or 7.5% sodium saccharin diet for 1 month. Excised bladders were mounted in flux chambers and exposed to Krebs-Ringer bicarbonate solution or urine. Bioelectric properties and (22)Na, (36)Cl, and (14)C mannitol or (3)H mannitol undirectional fluxes were measured by conventional techniques. No differences were noted between bladders from male and female animals or between sodium saccharin-fed animals and animals fed the saccharin-free diet. When both surfaces of the epithelium were exposed to Krebs-Ringer bicarbonate solution, transepithelial dc conductance fell over 4 hr to 50% of the initial value. Conductance averaged 1.4 ms/sq cm. Transepithelial potential difference was usually lumen negative and averaged 0.7 mV. Unidirectional permeability coefficients for (36)Cl, (22)Na, and radiomannitol were symmetric, proportional to conductance, and followed a rank order compatible with unrestricted passive diffusion. Exposure of the bladder lumen to urine from animals fed saccharin-free or sodium saccharin diet hyperpolarized the transepithelial potential difference by more than 5 mV and raised conductance nearly threefold. Permeability coefficients remained symmetric and compatible with passive diffusion. Exposure of the lumen to solutions with the potassium+, sodium+, and chlorine concentrations and osmolality of urine simulated the conductance and potential difference effects of urine. ... /Results suggest/ that sodium saccharin feeding or urine with saccharin does not uniquely affect the permeability of the excised preparation. Small hydrophilic solutes appear to cross bladder epithilium through paracellular channels which increase in aggregate area during exposure of the lumen to urine. The hyperpolarization induced by lumenal urine is the consequence of the transepithelial potassium+ gradient. /Sodium saccharin/ [Gatzy JT et al; Toxicol Appl Pharmacol 100 (3): 424-39 (1989)]**PEER REVIEWED**
  
• The tumor-promoting activities of sodium cyclamate and sodium saccharin were investigated in an assay based on the induction of epithelial foci exhibiting enhanced growth potential in a rat bladder explant culture system. An initiating, non-focus- inducing dose was defined for the carcinogen N-methyl-N-nitrosourea to make promotion studies possible. Saccharin induced epithelial foci when added to cultures pretreated with an initiating dose of N-methyl-N-nitrosourea, and also increased the incidence of foci in cultures treated with transforming doses of N-methyl-N-nitrosourea. Cyclamate was found to induce a high incidence of foci when added to cultures by itself. When N-methyl-N-nitrosourea and cyclamate treatments were combined, an additive effect could be detected. These results indicate that both cyclamate and saccharin can contribute to epithelial transformation in this system. /Sodium saccharin/ [Nicholson LJ, Jani H; Int J Cancer 42 (2): 295-8 (1988)]**PEER REVIEWED**
  
• Aqueous salt solutions containing sodium chloride, potassium chloride, magnesium chloride, sodium sulfate, calcium chloride, ammonium chloride, or sodium saccharin are mutagenic in yeast when logarithmic growth of cells is interrupted by exposure to a 0.5-2.0 M salt solution. Stationary-phase cells are not mutated by this treatment. When placed in an enriched medium with the salt, the stationary-phase cells grow after a prolonged lag period. The compounds tested (sodium chloride, potassium chloride, and sodium saccharin), under conditions in which growth in medium can take place exhibit an antimutagenic response as measured by the compartmentalization test. The antimutagenic action of salt solutions in yeast is concentration-dependent. Unlike the mutagenic action of these compounds, which approximates an osmolality-dependent response, the antimutagenic action seems to be correlated with toxicity as measured by growth rate reduction at increasing concentrations of the compounds. For example, sodium saccharin and sodium chloride exhibit almost identical osmolalities; however, 0.3 M sodium saccharin reduces the growth rate much more than does 0.3 M sodium chloride. At these same molar concentrations, the spontaneous mutation rate for histidine prototrophy is, for the control, 6.2x10-8 mutations/cell/generation, 3.5x10-8 with 0.3 M sodium chloride, and 1.7x10-8 with 0.3 M sodium saccharin. /Sodium saccharin/ [Parker KR, von Borstel RC; Basic Life Science 52: 367-71 (1990)]**PEER REVIEWED**
  
• Saccharin, administered to male albino rats at a dose of 65 mg/kg body weight/day (weak dose) for a total period of 39 weeks resulted in a distinct decrease in the hepatic alkaline phosphatase (AkP, 86%), lactate dehydrogenase (LDH, 28%) and glutamate pyruvate transaminase (GPT, 67%) activities. The glutamate oxaloacetate transaminase (GOT) activity, however, increased 3.05 fold after 26 weeks of saccharin administration. The urea content showed 3.26% fold increase during the first 13 weeks of saccharin administration, which normalized subsequently. The cholesterol content and DNA content increased 7.7 fold and 2.6 fold after 26 weeks of saccharin administration. The soluble protein and RNA content, on the other hand, decreased 63% and 35% during the first 26 weeks of saccharin administration. After strong dose (260 mg/kg body wt/day) administration, various biochemical parameters followed the same pattern as for the weak dose, except for the extent of damage and for the DNA content, which decreased significantly when compared to weak dose experiment. Both concentrations of saccharin caused hypertrophy of hepatic cell, its nucleus and nucleoli in addition to excessive vacuolation. The number of nuclei/cell remained unaltered, whereas number of nucleoli/nucleus increased significantly after saccharin intoxication. [Shakoori AR et al; Pakistan Journal of Zoology 27 (1): 1-13 (1995)]**PEER REVIEWED**
  
• ... While exposure to rodents during only the adult phase provided qualitatively similar results, early neonatal exposure typically provided slightly higher incidences of tumors, and decreased latency to tumor onset in certain scientific studies. In a series of studies recently performed by the NIEHS with three known animal carcinogens, neonatal or adult exposure produced similar tumors in similar tissues. The food additive saccharin, which shows bladder tumors, and eugenol reliably produced tumors only with neonatal exposure. Implications for carcinogenicity testing of food additives are discussed in light of these experimental findings. [Hattan DG; International Journal of Toxicology 17 (3): 337-53 (1998)]**PEER REVIEWED**
  
• The tumor suppressor gene p53 encodes a nuclear phosphoprotein which is critical for cell cycle control and prevention of uncontrolled cell proliferation that can lead to cancer. Previous studies have shown that cells respond to DNA damage by increasing their levels of p53, which then acts to prevent replication of damaged DNA. ... The epigenetic (non-DNA-reactive) carcinogens azathioprine and saccharin, as well as two substances generally considered to be non-carcinogens, dimethylsulfoxide and benzethonium chloride, had no effect on p53 protein levels of treated cells. Measurement of the cytotoxic effects of each of these chemicals led to the conclusion that p53 protein induction is not a general, non-specific consequence of the cytotoxic effect of these genotoxins. [Yang J, Duerksen-Hughes P; Carcinogenesis 19 (6): 1117-25 (1998)]**PEER REVIEWED**
  
• In studies primarily designed to evaluate the effects of saccharin and silicate on the urinary bladders of rodents, hemorrhage of the glandular stomach was observed in high incidence. It occurred in young rats with high doses of saccharin (7.5% sodium saccharin; 6.3% acid saccharin), with no difference between male and female F344 rats fed during ages 5 to 15 weeks, no difference between sodium saccharin and acid saccharin, and was reversible, even with continued saccharin administration. Sodium silicate (0.38, 1.13, 2.26% of the diet) had no influence on gastric hemorrhage. Iron deficiency anemia has been observed in young rats fed high dietary levels of saccharin, and the present results suggest that gastric hemorrhage contributes to its etiology. [Okamura T et al; Toxicology Letters 74 (2): 129-40 (1994)]**PEER REVIEWED**
  
• The incidence of sodium saccharin (NaS)-associated bladder tumors in male rats increases when exposure to high doses begins in utero or at birth compared with treatment after weaning. The present experiment evaluated the effect of sodium saccharin exposure on selected physiological parameters in young second generation rats. 6-wk-old male and female Sprague-Dawley rats were placed on either a diet supplemented with 7.5% sodium saccharin or an untreated diet, and mated 4-6 wk later. Treatment was continued through lactation and the offspring were weaned on to the same diet. Body weights were significantly depressed in sodium saccharin-treated litters by 4 days after birth, and were 35% lower than controls by 30 days when the animals were killed. sodium saccharin treatment of the offspring was associated with an increase in faecal moisture content and caecal content weight, changes in several urinary analytes, a 50% increase in serum cholesterol a 10-fold increase in serum triglycerides and decreases in serum and hepatic vitamins. In addition, sodium saccharin-treated dams and pups were anaemic. Relatively few differences between males and females were noted, but significant inter-litter differences existed. The numerous physiological changes indicate that 7.5% dietary sodium saccharin exceeds the maximum tolerated dose for weanling rats. [Garland EM et al; Food Chem Toxicol 29 (10): 657-67 (1991)]**PEER REVIEWED**
  
• A previous study in our laboratory demonstrated that 30-day-old Sprague-Dawley rats exposed to 7.5% sodium saccharin (NaS) since conception differ from untreated rats in several physiological parameters. In the present study, to determine the dose response of the changes associated with sodium saccharin treatment, animals were evaluated at 30 days post-birth, after treatment with dietary levels of 0, 1, 3 or 7.5% sodium saccharin since conception. Most physiological consequences of sodium saccharin treatment in the weanling rat, including anaemia and reductions in serum folate and vitamin A concentrations, were dose dependent. Serum vitamin E, cholesterol and triglyceride concentrations were decreased at the two lower doses of sodium saccharin but were significantly increased with 7.5% sodium saccharin. The no-effect level (NOEL) was similar for physiological effects and for bladder tumor production in two-generation studies (1% sodium saccharin in the diet). The reversibility of the effects of 7.5% sodium saccharin was examined in 90-day-old rats. The increases in lipids and vitamin E were reversible. Although values for hematological parameters and serum vitamin A remained significantly reduced at 90 days, changes were less severe than at 30 days. Histological examinations revealed that the effects of 7.5% dietary sodium saccharin on the bladder were negligible, indicating that the physiological changes observed in the young rat are probably not directly related to the production of bladder tumors. [Garland EM et al; Food Chem Toxicol 29 (10): 669-79 (1991)]**PEER REVIEWED**
  
• The present paper describes the possible clastogenic activity of the following synthetic sugar substitutes, such as cyclamate in daily doses of 11 and 110 mg/kg, saccharin, 5 and 50 mg/kg, acesulfam, 15 and 150 mg/kg, sucralose, 15 and 150 mg/kg, aspartame, 40 and 400 mg/kg, orally given to C57Bl/6 mice during 5 days. No clastogenic activity was found in the compounds tested. [Durnev AD et al; Vapor Med Khim 41 (4): 31-3 (1995)]**PEER REVIEWED**
  

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Human Toxicity Values

• None found

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Non-Human Toxicity Values

• LD50 Mouse oral 17 g/kg [Lewis, R.J. Sax's Dangerous Properties of Industrial Materials. 9th ed. Volumes 1-3. New York, NY: Van Nostrand Reinhold, 1996., p. 348]**PEER REVIEWED**
  

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Absorption, Distribution and Excretion

• TRANSPLACENTAL TRANSFER OF ... (14)C-SACCHARIN ADMIN BY IV INFUSION TO RHESUS MONKEYS IN LATE PREGNANCY, WAS RAPID, BUT SLIGHT. (14)C WAS CLEARED MORE SLOWLY FROM FETAL THAN FROM MATERNAL BLOOD, & WAS DISTRIBUTED IN ALL FETAL TISSUES EXAMINED ... WAS ONLY BIOTRANSFORMED TO LIMITED EXTENT & WAS RAPIDLY EXCRETED ... . [The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 2: A Review of the Literature Published Between 1970 and 1971. London: The Chemical Society, 1972., p. 150]**PEER REVIEWED**
  
• ... SACCHARIN IS RAPIDLY EXCRETED UNCHANGED: ALMOST ENTIRELY IN URINE OF TREATED GUINEA PIGS, & 70% IN URINE, 30% IN FECES OF TREATED RATS. [The Chemical Society. Foreign Compound Metabolism in Mammals Volume 3. London: The Chemical Society, 1975., p. 349]**PEER REVIEWED**
  
• IN 3 VOLUNTEERS, 85-92% OF DOSES OF 1 G 3(14)C-SACCHARIN ADMIN ORALLY FOR 21 DAYS WAS EXCRETED UNCHANGED IN THE URINE WITHIN 24 HR; NO METABOLITES WERE FOUND. WITHIN 48 HR, 92.3% OF A DOSE OF 500 MG (14)C-SACCHARIN WAS EXCRETED IN THE URINE & 5.8% IN THE FECES. [IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Man. Geneva: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT. (Multivolume work)., p. V22 151 (1980)]**PEER REVIEWED**
  
• TISSUE LEVELS, INCLUDING BLADDER, KIDNEY, & LIVER, OF SACCHARIN WERE DETERMINED IN RATS DURING TWO-GENERATION FEEDING STUDIES. [SWEATMAN TW, RENWICK AG; TOXICOL APPL PHARMACOL 62 (3): 465 (1982)]**PEER REVIEWED**
  
• THE KINETICS OF DIETARY SACCHARIN WERE DETERMINED IN 6 HEALTHY WOMEN WHO USED SACCHARIN CONTAINING PRODUCTS IN THEIR DIET & WERE ASKED TO TAKE DIVIDED EQUAL DOSES OF SACCHARIN EVERY 6 HR TO MAINTAIN THEIR AVERAGE DAILY INTAKE (100-300 MG) FOR 3 DAYS. AT THE END OF THIS PERIOD, EACH SUBJECT TOOK A SINGLE DOSE THAT WAS EQUAL TO ONE DIVIDED DOSE. SACCHARIN CONCN IN PLASMA & URINE SAMPLES WERE USED TO ASSESS THE KINETIC PROFILE. SACCHARIN ABSORPTION WAS RAPID WITH MAXIMUM CONCN IN PLASMA IN 0.5-1.0 HR. MAXIMUM PLASMA CONCN & AREAS UNDER THE PLASMA CONCN-TIME CURVES WERE PROPORTIONAL TO DOSE. RENAL CLEARANCE EXCEEDED GLOMERULAR FILTRATION RATE IN ALL CASES & APPROXIMATED RENAL PLASMA FLOW WHEN CORRECTED FOR THE SACCHARIN FREE FRACTION IN PLASMA. MEAN ELIMINATION T/2 WAS 7.5 HR & MEAN APPARENT VOLUME OF DISTRIBUTION WAS 264 LITERS. THE KINETIC PARAMETERS INDICATE THAT SACCHARIN IS DISTRIBUTED AS A FUNCTION OF LEAN RATHER THAN TOTAL BODY MASS; THIS OBSERVATION SUGGESTS THAT THERE MAY BE ONE OR MORE HIGH RETENTION COMPARTMENTS FOR SACCHARIN. [COLBURN WA ET AL; CLIN PHARMACOL THER 30 (OCT): 558 (1981)]**PEER REVIEWED**
  

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Metabolism/Metabolites

• ... 3-(14)C-SACCHARIN WAS EXCRETED UNCHANGED, MAINLY IN THE URINE (85-92% IN 24 HR) BY ADULT HUMAN SUBJECTS, BOTH BEFORE & AFTER TAKING 1 G OF SACCHARIN DAILY FOR 21 DAYS; NO METABOLITE OF SACCHARIN WAS FOUND. THESE RESULTS WERE AMPLY CONFIRMED IN ANIMAL EXPERIMENTS, IN WHICH ORALLY ADMIN (14)C-SACCHARIN WAS EXCRETED ENTIRELY UNCHANGED BY RATS ON A NORMAL DIET & BY RATS ON A DIET CONTAINING 1% & 5% OF SACCHARIN FOR UP TO 12 MO. 80-90% OF THE DOSE WAS EXCRETED IN THE URINE, 10-20% IN THE FECES; NO (14)CO2 WAS FOUND IN THE EXHALED AIR, & NO (14)CO3(2-) OR 2-SULFAMOYLBENZOIC ACID IN THE URINE. [The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 5: A Review of the Literature Published during 1976 and 1977. London: The Chemical Society, 1979., p. 419]**PEER REVIEWED**
  
• YIELDS IN MONKEYS SULFAMOYLBENZOIC ACID & O-SULFOBENZOIC ACID. /FROM TABLE/ [Goodwin, B.L. Handbook of Intermediary Metabolism of Aromatic Compounds. New York: Wiley, 1976., p. S-1]**PEER REVIEWED**
  
• EXPOSURE OF MALE CHARLES RIVER CDI RATS TO 5% SACCHARIN DIET IN UTERO & THROUGHOUT WEANING, DID NOT INDUCE DETECTABLE METABOLISM. NO METABOLITES WERE DETECTED IN URINE OF NORMAL RATS GIVEN TRACER DOSE. PRETREATMENT WITH 3-METHYLCHOLANTHRENE DID NOT INDUCE SACCHARIN METABOLISM. [SWEATMAN TW, RENWICK AG; SCIENCE 205 (4410): 1019 (1979)]**PEER REVIEWED**
  

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TSCA Test Submissions

• None found

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Footnotes

¹ Source: the National Library of Medicine's Hazardous Substance Database, 10/28/2007.