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


    PIPERONAL

    Synonyms                      Heliotropine; Piperonyl aldehyde

    Chemical name                 Piperonal

    Empirical formula             C8H6O3

    Structural formula

    

    Molecular weight              150.14

    Definition                    Piperonal contains not less than 99 per
                                  cent. C8H6O3.

    Description                   Piperonal is found in oils of Spirea
                                  ulmaria L., Doriphora sassafras
                                  Endl., and other oils. It is prepared by
                                  oxidation of isosafrole. It is a white
                                  crystalline substance with a sweet
                                  floral odour resembling heliotrope and
                                  free from safrole by-odour.

    Biological Data

    Biochemical aspects

         This is probably metabolized to piperonylic acid. The glycine
    conjugate of piperonylic acid has been isolated from human urine
    (Heffter, 1895).

    Acute toxicity

                                                                       

    Animal       Route       LD50                References
                             (mg/kg 
                             body-weight)
                                                                       

    Mouse        i.p.        >500                Patty, 1963

    Rat          oral        2700                Jenner et al., 1964

                 i.p.        1500-1700           Binet, 1896
                                                                       

         Intragastric administration of 900 mg/kg body-weight per day to 3
    male and 3 female rats for 4 days produced slight gross liver damage
    in some animals (Taylor et. al., 1964). When rats were given 13-115 mg
    Piperonal perorally for 5-9 days, fatty infiltration of the liver
    parenchymal cells was noted (Shillinger, 1950). Ten grams have been
    ingested by man without any adverse effect (Von Oettingen, 1949).

    Short-term studies

         Rat. A 12-week feeding study on 15 males and 15-females, using
    mixed aldehydes, produced no adverse effect at 14.2 mg/kg
    body-weight/day (Oser, 1967). In another study, groups of 5 male and 5
    female rats were fed diets containing 0 and 1.0 per cent. piperonal
    for 15 weeks, and 0.1 per cent. for 28 weeks. No adverse effects were
    noted on body-weight gain, haematology, organ weights of major organs
    and histology of major tissues (Hagan et al., 1965; Hagan et al.,
    1967).

    Long-term studies

         Rat. Groups of 20 male and 20 female rats were fed on diets
    containing 0, 0.1 and 0.5 per cent. piperonal for 2 years without any
    specific adverse effect (Baer & Griepentrog, 1967).

    Comments

         The long-term study in rats compensates for the scanty
    information on the metabolic fate of this compound, and the evaluation
    is based on this. Further metabolic studies are desirable.

    EVALUATION

    Level causing no toxicological effect

         Rat. 0.5 per cent. (= 5000 ppm) in the diet, equivalent to 250
    mg/kg body-weight/day.

    Estimate of acceptable daily intake for man

                                       mg/kg body-weight

         Unconditional acceptance           0-2.5

    REFERENCES

    Baer, F. & Griepentrog, F. (1967) Unpublished report

    Binet, P. (1896) Rev. Med. Suisse, 16, 449

    Hagan, E. C., Jenner, P. M., Jones, W. I., Fitzhugh, O. G., Long, E.
    C., Brouwer, J. G. & Webb, W. K. (1965) Toxic. appl. Pharm., 7, 18

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

    Heffter, A. (1895) Arch. exp. Pathol. Pharmacol., 35, 342

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

    Oser, B. L. (1967) Unpublished report

    Patty, F. A. (1963) Industrial Hygiene and Toxicology Vol. II.
    Interscience

    Shillinger, J. I. (1950) Gig. i. San., 3, 37

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

    Von Oettingen, W. F. (1949) Nat. Inst. Health Bull., No. 190, 342
    

    See Also:
       Toxicological Abbreviations
       PIPERONAL (JECFA Evaluation)