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    ACESULFAME POTASSIUM*

    Explanation

         Acesulfame K was evaluated by the Joint FAO/WHO Expert Committee
    on Food Additives in 1981 (see Annex I, Ref. 57). Some shortcomings
    were apparent in the long-term/carcinogenicity studies in the mouse
    and rat and no ADI for man was allocated. A toxicological monograph
    was prepared (see Annex I, Ref. 58).

         Since that evaluation, additional studies have become available
    and are summarized and discussed in the following monograph addendum.

    BIOLOGICAL DATA

    BIOCHEMICAL ASPECTS

    Absorption, distribution and excretion

         Single oral doses of approximately 15 mg 14C-acesulfame K/kg bw
    were administered to male and female rats which had been pretreated
    with unlabelled Acesulfame K at a level of 300 mg/kg diet for 60 days.
    Control animals without pretreatment were also similarly dosed with
    14C-acesulfame K. In all animals 95.1-98.2% of the dose was recovered
    in urine and cage washings, and 0.95-2.86% in faeces. Total recoveries
    were 96.3-99.2%. Excretion of radioactivity was rapid, 92.6-96.8% of
    the dose being excreted within 24 hours and displayed biphasic
    kinetics. The half-life of the rapid phase was 4-4.5 hours and for the
    slower phase (accounting for <0.5% of the dose) was 109-257 hours.

         No significant differences in route or rate of excretion were
    observed between sexes nor between controls and animals pretreated
    with Acesulfame K for 60 days (Volz & Eckert, 1981).

    Biotransformation

         Separation by TLC of urinary extracts from rats used in the above
    study revealed only one peak which was identical with Acesulfame K. No
    metabolites were detected in control or Acesulfame K-pretreated
    animals (Volz & Eckert, 1981).

              

    *    Monograph addendum.

    TOXICOLOGICAL STUDIES

    Special studies on DNA binding

         After pretreatment for seven days with a diet containing 3%
    Acesulfame K, male rats were given a dose of 250 mg Acesulfame K
    containing 14C-acesulfame K (9.6 x 108 dpm) by oral gavage. After
    eight hours the animals were killed and liver and spleen excised; DNA
    and chromatin protein was isolated from these organs. No radioactivity
    could be detected on any DNA sample. A low level of activity
    (8-11 dpm/mg protein) was associated with chromatin protein and this 
    was claimed to be due to non-covalent interactions of unchanged 
    Acesulfame K (Sagelsdorff et al., 1981).

    Special studies on nitrosation of Acesulfame K

         Acesulfame K was incubated at 37C with excess NaNO2
    (276 mg/100 ml) at pH 3 and pH 1 for one hour and four hours. The
    maximum yield of N-nitroso derivative was 1.4 x 10-3% after four
    hours at pH 1. This was considered to represent a negligible hazard
    in vivo (Eisenbrand, 1982).

    Special studies on the possible reactions of Acesulfame K with food
    constituents

         Acesulfame K (1% aqueous solutions) was heated at 100C with the
    model food constituents, ethanol, sorbitol, glycine, alanine, glutamic
    acid, phenyl alanine or n-butylamine, in acetate buffer at pH 5.
    Analysis by HPLC and UV-spectrometry failed to detect any
    decomposition or interaction products of Acesulfame K in any of the
    model systems (Clauss, 1981).

    Long-term studies

    Rat

         In the previous evaluation, it was observed that some
    shortcomings were apparent in the second long-term feeding study in
    rats, in that only a small proportion of the animals in the control
    and top-dose (3% Acesulfame K) groups were examined histopatho-
    logically in detail. A detailed histopathological examination has now
    been performed on the remaining animals in the control and top-dose
    groups, and on all animals in the lower (0.3% and 1%) dose groups.
    It was concluded that there were no treatment-related histopathological
    changes and, in particular, no evidence of an increase in the incidence
    or alteration of the biological type of the neoplasms diagnosed
    (Newman, 1982).

    Comments

         The absence of mutagenic activity in several in vitro and
    in vivo assays together with negative results in the two-year study
    in rats indicate that Acesulfame K is devoid of mutagenic/carcinogenic
    activity. The earlier mouse carcinogenicity study, though not meeting
    current requirements, was also negative.

    EVALUATION

    Level causing no toxicological effect

         Rat: 3% (30 000 ppm) in the diet, equal to 3-1.5 g/kg bw.
         Dog: 3% (30 000 ppm) in the diet, equal to 900 mg/kg bw.

    Estimate of acceptable daily intake for man

         0-9 mg/kg bw.

    REFERENCES

    Clauss (1981) Model experiments aimed at detecting possible reactions
         of Acesulfame K with constituents of food. Unpublished report
         submitted to WHO by Hoechst A.G.

    Eisenbrand, G. (1982) The nitrosatability of Acesulfame potassium in
         the nitrosamine assay procedure of WHO. Unpublished report
         submitted to WHO by Hoechst A.G.

    Newman, A. J. (1982) Pathology report of the combined chronic toxicity
         and carcinogenicity study with Acesulfame K in rats. Unpublished
         report submitted to WHO by Hoechst A.G.

    Sagelsdorff, P., Lutz, W. K, & Schlatter, Ch. (1981) Research Report
         No. 40182A. Unpublished report submitted to WHO by Hoechst A.G.

    Volz, M. & Eckert (1981) Research Report No. 01-L42-0352-81.
         Unpublished report submitted to WHO by Hoechst A.G.
    


    See Also:
       Toxicological Abbreviations
       Acesulfame Potassium (WHO Food Additives Series 16)
       Acesulfame potassium (WHO Food Additives Series 28)
       ACESULFAME POTASSIUM (JECFA Evaluation)