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    alpha- and -IONONE

    Explanation

         alpha-ionone was evaluated for the acceptable daily intake for
    man by the Joint FAO/WHO Expert Committee on Food Additives in 1967
    (ADI = 0-0.1 mg/kg) and in 1979, 1980, 1982 (ADI = 0-0.05 mg/kg)
    (Annex I, Ref. 15, 50, 51, 53, and 59).

         Toxicological monographs were issued in 1967 and 1979 (Annex I,
    Ref. 15 and 51).

    BIOLOGICAL DATA

    BIOCHEMICAL ASPECTS

         Following oral administration,  alpha-ionone undergoes
    biochemical oxidation in the rabbit and is excreted in the urine,
    principally, as 5-oxo-cis-tetrahydro-ionone, indicating in vivo
    oxidation of carbon atom 5 in the ionone structure (Prelog & Wursch,
    1951).

    TOXICOLOGICAL STUDIES

    Acute toxicity
                                                         

    Animal    Route     LD50      References
                      mg/kg bw.
                                                         

    Mouse     i.p.      2.277     Sporn et al., 1963
    Mouse     s.c.      2.605     Wenzel & Ross, 1957
    Rat       oral      4.590a    Jenner et al., 1964
                                                         

    a  Test material identified as 60% alpha-ionone and 40% B-ionone.

    Special studies on mutagenicity

         The genotoxicity of a alpha-ionone was studied by a bacterial
    mutation test in the Salmonella/microsome system (with the
    Salmonella typhimurium histidine (-) mutants, TA 98 and TA 100) and
    by a chromosome test in Chinese hamster (CH) cells. In the mutation
    test alpha-ionone (at various dose levels from 0.01 to 50 g/pl) did
    not exhibit significant induction of his + revertants in Salmonella,
    either with or without rat liver microsome metabolic activating
    system. In the chromosome test, alpha-ionone at the concentration of
    25 nM, induced slight chromosome aberrations in the treated CH cells.

    Short-term studies

    Rat

         In a 90-day study on groups of 15 males and 15 females given
    either 0 or 11.5 mg/kg body weight per day, no adverse effects were
    observed (Oser et al., 1965). Another study on groups of 10 males and
    10 females used a mixture of 60 per cent alpha- and 40 per cent
    -ionone at 0, 0.1, 0.25 and 1.0 per cent of the diet for 17 weeks. A
    dose-dependent moderate swelling of liver parenchyma was noted which
    occurred to a very slight degree at the lowest level. No other adverse
    effects were seen (Hagan et al., 1967).

    Rat

         Groups of 10 male and 10 female rats were maintained for 17 weeks
    on diets containing "Ionone Standard" (60% alpha-ionone and 40%
    -ionone) at levels of 0, 1000, 2500, and 10.000 ppm (approximately
    equivalent to 50, 125, and 500 mg/kg body weight). No adverse effects
    were observed on growth, appearance, food intake, haematology, final
    body weight, organ weights or macroscopic appearance of organs of rats
    on all levels of "Ionone Standard" in the diet. However, microscopic
    examination revealed swelling of the hepatic parenchymal cells at
    all dietary levels. This "swelling of parenchymal cells" was
    dose-dependent, being "slight to moderate" at the highest dietary
    level (10.000 ppm), "slight" at the intermediate level (2500 ppm), and
    "very slight" at the lowest level (1000 ppm) (Hagan et al., 1967).

         -ionone was fed to Sprague-Dawley strain rats in the diet at
    levels to provide intakes of approximately 10 or 100 mg/kg body weight
    per day for 90 days. The study consisted of two test groups each of
    fifteen rats of each sex and one control group of thirty rats of each
    sex. Renal function and haematological studies were performed mid-way
    through the treatment period and at the end of the study. The effects
    were limited to the 100 mg/kg groups and were a reduced weight gain,
    and food consumption and serum glucose concentrations, increased water
    intakes and mild renal functional changes. No histological changes
    were evident in the kidneys or livers. It was concluded that the
    no-untoward effect level from this study was 10 mg/kg per day (Ford et
    al., 1983).

    Comments

         Mutagenicity studies carried out with alpha-ionone indicated that
    there were not mutagenic effects on two strains of Salmonella
    typhimurium with and without liver enzyme induction but the compound
    induced light chromosome aberrations. In short-term study on rats with
    alpha-ionone it was shown that the compound does not produce adverse
    effects at dose of 10 mg/kg body weight.

    EVALUATION

    Estimate of acceptable daily intake for man

         0-0.1 mg/kg bw. (group ADI for alpha-ionone and -ionone, singly
    or in combination).

    REFERENCES

    FORD, G.P., BUTLER, W.H., HOOSON, S., GAUNT, I.F., HAWKINS, R.I.
    (1983) The short-term (90-days) toxicity of alpha- and beta-ionones in
    rats. Unpublished report from the British Industrial Biological
    Research Association. Submitted to the World Health Organization by
    the International Organization of the Flavour Industry, Geneva.

    HAGAN, E.C. et al. (1967) Food flavourings and compounds of related
    structure: II. Subacute and chronic toxicity. Food Cosmet. Toxicol.,
    5: 141-157.

    JENNER, P.M. et al. (1964) Food flavourings and compounds of related
    structure: I. Acute and chronic toxicity. Food Cosmet. Toxicol.,
    2: 327-343.

    KASAMAKI, A., TAKAMASHI, H., TSUMURA, N., NIWA, S., FUJITA, T., &
    URASAWA, S. (1982) Genotoxicity of flavouring agents. Mutation Res.,
    105: 387.

    OSER, B.L., CARSON, S., & OSER, M. (1965) Food Cosmet. Toxicol.,
    3: 563.

    PRELOG, V. & WUERSCH, J. (1951) Organ extracts and urine. 21. The
    biochemical oxidation of alpha-ionone in the animal body. Helv.
    Chim. Acta, 34(3): 859-861 (in German).

    SPORN, A. et al. (1963) The toxicity of butyl acetate, methyl
    naphtylketone, and ionone. Igiena (Bucarest), 12(5): 437-446.

    WENZEL, D.G. & ROSS, C.R. (1957) Central stimulating properties of
    some terpenones. J. Am. Pharm. Assoc., 46: 77-82.
    


    See Also:
       Toxicological Abbreviations