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    FAO Nutrition Meetings
    Resort Series No. 44A
    WHO/Food Add./68.33




    TOXICOLOGICAL EVALUATION OF SOME
    FLAVOURING SUBSTANCES AND
    NON-NUTRITIVE SWEETENING AGENTS





    Geneva, 21-28 August 1967



    The Eleventh Report of the Joint FAO/WHO Expert Committee on Food
    Additives is published as FAO Nutrition Meetings Report Series,
    1967, No. 44; Wld Hlth Org. techn. Rep. Ser., 1968, 383. This
    Report contains general considerations, including the principles
    adopted for the evaluation, and a summary of the results of the
    evaluations of a number of food additives. Additional information,
    such as biological data and a toxicological evaluation, considered at
    that meeting, is to be found in this document.


    Food and Agriculture Organization of the United Nations
    World Health Organization
    1967

    trans-ANETHOLE

    Chemical name             trans-p-Propenylanisole

    Empirical formula         C10H12O

    Structural formula

    MOLECULAR STRUCTURE 1

    Molecular weight          148.21

    Description               Anethole is prepared from anise oil and
                              other sources, or it is prepared
                              synthetically. It is a colourless or faintly
                              yellow liquid at or above 23°. It has a
                              sweet taste and a characteristic anise-like
                              odour. It is affected by light.

    Limit of cis-isomer       Not more than 1 per cent. (by gas-liquid
                              chromatography).

    Biological Data

    Biochemical Aspects

         This ether is probably metabolized to anisic acid (Kühling &
    Giacosa, 1890).

    Acute toxicity

                                                                                            

    Animal        Route              LD50                 Reference
                                 (mg/kg body-weight)
                                                        
                            trans-isomer     cis-isomer
                                                                                        

    Mouse         oral      5000             -            Boissier et al.,1967

    Mouse         oral      3050             -            Jenner et al., 1964
    Mouse         i.p.      1410              95          Caujolle & Meynier, 1958
    Mouse         i.p.       650             135          Boissier et al., 1967
    Rat           oral      3200             -            Boissier et al., 1967
    Rat           oral      2940             150          Shelansky & Gabriel, 1958
    Rat           oral      2090             -            Jenner et al., 1964
    Rat           i.p.       -                67          Caujolle & Meynier, 1958
    Rat           i.p.       900              93          Boissier et al., 1967
    Guinea-pig    oral      2167             -            Jenner et al., 1964
                                                                                        
    
         Feeding 3 male and 3 female rats 700 mg/kg body-weight/day
    intragastrically for 4 days produced slight gross changes in the liver
    (Taylor et al., 1964).

    Short-term studies

    Trans-isomer

         Rat. Groups of 5 males and 5 females were fed dietary levels of
    0, 1000, 3000, 10 000 and 30 000 ppm of trans-isomer for 90 days.
    There was no survival past 20 days at the highest level, and survival
    was affected at the 10 000 ppm level. Depressed food consumption and
    body-weight gain, in proportion to the level fed, were found at 3000
    ppm and above. No examination was made of animals dying during the
    study, but post-study gross and microscopic examination of major
    organs of survivors disclosed hepatocellular oedema, degeneration and
    regeneration, in proportion to the level fed, at, 3000 ppm and above.
    No effect was seen at 1000 ppm. There were no differences between the
    groups in periodic examinations of blood and urine (Kay & Calandra,
    1959).

         Groups of 5 male and 5 female rats were fed diets containing 0,
    0.25 and 1.0 per cent. of anethole. The group in the highest level was
    sacrificed after 15 weeks and showed slight hydropic changes of
    hepatic cells in males only, while the group on the lowest level was
    kept for 1 year without any evidence of adverse effects (Hagan et al.,
    1967).

    Cis-isomer

         Rat. Groups of 5 males and 5 females were fed dietary levels of
    0, 10, 30, 100, 300, 1000 and 3000 ppm of cis-isomer for 90 days.
    Survival was affected and food consumption and body-weight gain were
    depressed at the highest level. No examination was made of animals
    dying during the study, but post-study gross and microscopic
    examination of major organs of survivors disclosed hepatocellular
    oedema, degeneration and regeneration, in proportion to the level fed,
    at 300 ppm and above. No effect was seen at 100 ppm. There were no
    differences between the groups in periodic examination of blood and
    urine (Kay & Calandbra, 1959).

    Long-term studies

         No data available.

    Comments

         This ether is probably metabolized to anisic acid. The available
    information is scanty and toxicity appears to be dependent on
    stereoisomeric configuration. The short-term studies can be used for
    evaluation. Further metabolic investigation and long-term studies are
    essential.

    EVALUATION

    Level causing no toxicological effect

         Rat: 2500 ppm in the diet, equivalent to 125 mg/kg
    body-weight/day.

    Estimate of acceptable daily intake for man

                                            mg/kg body-weight

              Conditional acceptance            0-1.25

    Further work required

         Biochemical, metabolic and long-term studies on the
    trans-stereoisomer with emphasis on the effect on the liver.

    REFERENCES

    Boissier, J. R., Simon, P. & LaBourhis, B. (1967) Thérapie, 22,
    309 

    Canjolle, F. & Meynier, D. (1958) Compt. Rend., 246, 1465

    Hagan, E. C., Hansen, W. H., Fitzhugh, O. G., Jenner, P. M., Jones, W.
    I., Taylor, J. M., Long, E. L., Nelson, A. A. & Brouwer, J. B. (1967)
    Fd Cosmet. Toxicol., 5(2), 141

    Jenner, P. M., Hagan, E. C., Taylor, J. M., Cook, E. L. & Fitzhugh, O.
    G. (1964) Fd Cosmet. Toxicol., 2, 327

    Kay, J. H. & Calandra, J. C. (1959) Unpublished report submitted by
    Hercules Powder Company, Inc.

    Kühling, O. & Giacosa, P. (1890) Ann. chim. Farm., 11, 304

    Taylor, J. M., Jenner, P. M. & Jones, W. I. (1964) Toxicol. appl.
    Pharmacol.,6, 378
    


    See Also:
       Toxicological Abbreviations
       Anethole, trans- (WHO Food Additives Series 42)