VOL.: 73 (1999) (p. 517)
Saccharin
Chem. Abstr. No.:
Chem. Abstr. Name: 1,2-Benzisothiazol-3(2H)-one, 1,1-dioxide
Sodium saccharin
Chem. Abstr. No.:
Chem. Abstr. Name: 1,2-Benzisothiazol-3(2H)-one, 1,1-dioxide, sodium salt
Calcium saccharin
Chem. Abstr. No.:
Chem. Abstr. Name: 1,2-Benzisothiazol-3(2H)-one, 1,1-dioxide, calcium salt
5.1 Exposure data
Saccharin and its salts have been used as sweeteners for nearly a century. Saccharin (acid form), sodium saccharin and calcium saccharin are widely used as non-caloric table-top sweeteners, in beverages and foods, in personal care products and in a variety of non-food applications. The average daily dietary intake is generally less than 1 mg/kg bw.
5.2 Human carcinogenicity data
Case–control studies of the carcinogenicity of artificial sweeteners have been reported only for the urinary bladder or lower urinary tract. Most of the studies were published between 1975 and 1985, so that any association would be to sweeteners that were on the market over 25 years ago. The studies varied widely in the detail with which information on the source and nature of artificial sweeteners was identified, collected and presented. The terms used in the various studies include ‘table-top’, ‘dietetic beverages’, ‘saccharin’ and ‘artificial sweeteners’ with no further characterization; only the salts of saccharin are used in these ways. Eight of the studies considered were hospital-based, which raises uncertainty about the representativeness of the controls’ consumption of artificial sweeteners in relation to the general population. The results of the population-based studies must also be viewed with caution, owing to the sizable proportion of non-respondents, which might reflect the occurrence of health-related conditions associated with the use of replacements for sugar.
A statistically significant relative risk in the order of 1.6 for the association between use of artificial sweeteners (and saccharin salts as such) and bladder cancer and a dose–response relationship between intake and odds ratio were found for men but not for women in an early study in Canada. In subsequent population-based studies, including a study of several thousand people in the United States, estimates for the entire population of each study did not confirm the existence of an assocation. In some studies, estimates of the strength of the association between consumption of sweeteners and bladder cancer differed between smokers and non-smokers, but the direction of the difference and its distribution between the sexes was inconsistent over the studies.
In spite of the fact that three studies showed high, statistically significant relative risks for small subsets of consumers of very large amounts of artificial sweeteners, the finding was limited to men in one study and to women in the other two. In addition, no consistent pattern of dose–response relationship between use of artificial sweeteners and cancers of the urinary bladder or lower urinary tract is apparent in the available literature.
5.3 Animal carcinogenicity data
Sodium saccharin was tested by oral administration in numerous experiments in rats and mice and in a few studies in hamsters, guinea-pigs and monkeys.
Sodium saccharin produced urinary bladder tumours in male rats in four two-generation studies, in one study in male rats in which administration commenced at birth and in one study commencing at 30 days of age. Sodium saccharin was not carcinogenic for the urinary bladder in several one-generation studies in male and female rats or in mice.
Saccharin (acid form) did not produce tumours in one study in male and female mice, in one study in male rats or in one study in female rats. Calcium saccharin did not produce tumours in one study in male rats.
A few studies with sodium saccharin in hamsters and guinea-pigs also showed no induction of bladder tumours but were considered inadequate. In one long-term (up to 23 years) study in monkeys in which oral administration of sodium saccharin was begun shortly after birth, no bladder tumours were observed, but a relatively low dose (25 mg/kg bw) and relatively few animals were used.
Sodium saccharin has been studied in numerous experiments in adult rats involving administration concurrently or, more frequently, sequentially with other chemicals or treatments. Enhanced bladder tumorigenesis has been observed after prior treatment with known urinary bladder carcinogens. In one study, saccharin (acid form) did not significantly enhance the incidence of bladder carcinogenesis, while calcium saccharin produced a marginal increase.
Thus, the only organ affected by sodium saccharin is the urinary bladder and only in rats exposed for periods including pre- and/or postnatal periods and/or when exposure was begun by 30 days of age.
5.4 Other relevant data
Studies in humans and rodents reveal that, after absorption, saccharin and sodium saccharin are excreted unchanged in the urine. Excretion occurs relatively rapidly with no evidence of accumulation. The strong nucleophilic character of the saccharin anion and the lack of metabolism are consistent with the lack of DNA reactivity. The urinary concentration of the saccharin anion is similar, regardless of the form administered.
Sodium saccharin has been shown to enhance urothelial cell proliferation in rats, primarily in males, resulting in hyperplasia. This regenerative cell proliferation follows urothelial cytotoxic effects. Administration of saccharin (acid form) does not produce these effects in rats. Sodium saccharin at doses that enhance cell proliferation in rats does not do so in other species, including mice, hamsters and guinea-pigs. Hyperplasia was not produced in non-human primates, although the dose used in this study was lower than that used in the studies in rodents.
The cytotoxicity has been shown to result from formation of a calcium phosphate-containing precipitate in rat urine after administration of high doses of sodium saccharin or a variety of other sodium salts. A combination of factors in urine composition appears to be critical for formation of the precipitate, including a pH of 6.5 or greater, high urinary concentrations of calcium phosphate and protein and high urinary osmolality. This combination of critical factors appears to be unique to the rat and is consistent with the species-specific urothelial proliferative and tumorigenic effects in rats.
Saccharin, generally as the sodium salt, has been tested for developmental and reproductive toxicity in mice, rats, hamsters and rabbits. The effects have generally been limited to reductions in body weights at high dietary concentrations. With the exception of a test in Drosophila larvae, no effects have been reported in a variety of short-term assays to screen for teratogenicity in vivo and in vitro.
Saccharin (acid form) was not genotoxic in human or rodent cells in vitro. It weakly induced DNA single-strand breaks in rat hepatocyte cultures. It induced aneuploidy in yeast but was not mutagenic to bacteria.
Sodium saccharin induced dominant lethality in three of seven studies in mice in vivo; it did not induce heritable translocations, chromosomal aberrations in spermatocytes or embryos or altered sperm morphology in rodents in vivo. Negative or conflicting results were obtained in most studies of chromosomal damage in bone marrow, somatic mutation and sister chromatid exchange in rodents in vivo. Sodium saccharin was mutagenic in host-mediated and body fluid assays and caused DNA single-strand breaks in hepatic and renal cells of mice; however, bile from rats exposed to sodium saccharin was not mutagenic. Sodium saccharin did not cause DNA damage and did not bind covalently to DNA of rat liver or bladder. It induced genotoxic effects in human and rodent cells and in Drosophila and yeast. It was not mutagenic to bacteria.
The positive results for genotoxicity found with sodium saccharin in mammalian cells in vitro have been hypothesized to result from increased osmolality (i.e. nonspecific ionic effects). This hypothesis would appear to explain some but not all of the findings of sister chromatid exchange, chromosomal aberrations and gene mutations in vitro. The few positive results seen in mice treated with sodium saccharin in vivo would not be readily explained by ionic influences.
Impurities in the test materials could explain the positive results obtained in some studies in mice treated with high doses of sodium saccharin. It is notable that no data are available on the genetic effects of saccharin or its salts in rats; however, the available evidence indicates no binding of sodium saccharin to DNA in rat bladder or liver. Overall, the results of tests for genotoxicity do not support a mechanism for the induction of urothelial-cell tumours in rats involving direct interaction of sodium saccharin with DNA.
5.5 Evaluation
There is inadequate evidence in humans for the carcinogenicity of saccharin salts used as sweeteners.
There is sufficient evidence in experimental animals for the carcinogenicity of sodium saccharin.
There is inadequate evidence in experimental animals for the carcinogenicity of saccharin (acid form) and calcium saccharin.
Overall evaluation
In making its evaluation, the Working Group concluded that sodium saccharin produces urothelial bladder tumours in rats by a non-DNA-reactive mechanism that involves the formation of a urinary calcium phosphate-containing precipitate, cytotoxicity and enhanced cell proliferation. This mechanism is not relevant to humans because of critical interspecies differences in urine composition.
Saccharin and its salts are not classifiable as to their carcinogenicity to humans (Group 3).
For definition of the italicized terms, see Preamble Evaluation.
Previous evaluations: Vol. 22 (1980); Suppl. 7 (1987)
Synonyms
Saccharin
Calcium saccharin
[Names in brackets are for formerly manufactured products]
See Also:
Toxicological Abbreviations