FAO Nutrition Meetings 
    Report Series No. 48A 
    WHO/FOOD ADD/70.39




    TOXICOLOGICAL EVALUATION OF SOME
    EXTRACTION SOLVENTS AND CERTAIN 
    OTHER SUBSTANCES




    The content of this document is the 
    result of the deliberations of the Joint 
    FAO/WHO Expert Committee on Food Additives 
    which met in Geneva, 24 June  -2 July 19701




    Food and Agriculture Organization of the United Nations
    World Health Organization


                   

    1 Fourteenth report of the Joint FAO/WHO Expert Committee on Food
    Additives, FAO Nutrition Meetings Report Series in press; Wld Hlth
    Org. techn. Rep. Ser., in press.


    SACCHARIN

         The previous assessment was based on work performed in the 1950s
    and a large number of new studies on saccharin alone are being
    undertaken or are presently in progress. The results of further
    experiments using mixtures of cyclamate and saccharin have now become
    available for evaluation. These should be evaluated when the full data
    have become available.

    Comments

          Calcium and sodium cyclamate have been evaluated previously by
    the Eleventh Joint FAO/WHO Expert Committee on Food Additives in 1967.
    The additional data now reviewed have thrown little further light on
    the exact mechanism of the laxative effect or on the changes observed
    in the cellular and subcellular structures of the gastro-intestinal
    tract. These two problems have been left unanswered at the time of the
    first review. There is now good evidence that a proportion of the
    human population is able to convert cyclamate to cyclohexylamine and
    it is likely that this conversion takes place as a result of the
    activity of the microbial flora of the gut. Recent work has raised the
    problem of mutagenicity of cyclamate as observed under various
    conditions of testing but it is not possible to interpret these
    findings in terms of human risk when taken in isolation. There is some
    doubt whether the observed chromosomal changes are specific to
    cyclamate. More serious are the findings reported in relation to
    bladder carcinoma found after feeding very high doses of
    cyclamate/saccharin mixtures and the more recent reports of the
    production of bladder carcinoma following feeding of cyclamate alone.
    it is difficult to extrapolate these findings to man on the data
    available. Nonetheless, the new information together with the
    previously available evidence on toxicity as well as the discovery of
    the metabolic fate of cyclamate and the toxicity of cyclohexylamine,
    counsels prudence in the future use of cyclamates in food and drink.

         Cyclohexylamine, a known metabolite of cyclamate in some animals
    and man, is itself further metabolized but not all of these
    metabolites have been identified. One long-term study has resulted in
    the production of a single bladder tumour but the number of survivors
    was too small to allow adequate evaluation. Cyclohexylamine may have
    been involved in the appearance of bladder carcinoma following
    ingestion of large doses of cyclamate and cyclamate/saccharin mixture
    by rats.

    Evaluation

     Because of the possible carcinogenic potential of cyclamate in the
    rat, an ADI for this compound cannot be established at the present
    time, and therefore the previously established temporary ADI is now
    withdrawn. The use of cyclamate in the management of diabetes and
    gross obesity was beyond the purview of food additive consideration.

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    See Also:
       Toxicological Abbreviations
       Saccharin (FAO Nutrition Meetings Report Series 44a)
       Saccharin (WHO Food Additives Series 17)
       SACCHARIN (JECFA Evaluation)
       Saccharin  (IARC Summary & Evaluation, Supplement7, 1987)
       Saccharin  (IARC Summary & Evaluation, Volume 22, 1980)