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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


    CITRAL

    Chemical name                 3,7-Dimethyl-2,6-octadienal

    Empirical formula             C10H16O

    Structural formula

    MOLECULAR STRUCTURE 6

    Molecular weight              152.24

    Definition                    Citral contains not less than 95 per
                                  cent. C10H16O.

    Description                   Citral is the principal constituent of
                                  lemongrass oil and Backhousia
                                  citriodora oil. It is usually isolated
                                  from citral-containing oils by chemical
                                  means. It may be prepared synthetically.
                                  The product of commerce is a mixture of
                                  two geometric isomers, a- and -citrals.
                                  Citral is a pale yellow liquid having a
                                  strong lemon like odour.

    Biological Data

    Biochemical aspects

         This aldehyde is probably metabolized to
    1,5-dimethyl-1,5-hexadien-1,6-dicarboxylic acid and
    7-carboxy-3-methylocta-6-enoic acid (Williams, 1959). There is some
    conflicting evidence that this compound may interfere through its
    CH=CH-CHO group with SH groups in the cell.

    Acute toxicity

                                                                       

    Animal       Route        LD50               Reference
                              (mg/kg 
                              body-wegiht)
                                                                       

    Rat          oral         4960               Jenner et al, 1964
                                                                       

         There is an extensive literature on local reactions due to this
    compound, and various pharmacological effects which are not shown
    under normal circumstances.

    Short-term studies

         Rat. In a 12-week feeding study in 15 males and 15 females,
    using mixed citral conpounds there was no adverse effect noticeable at
    50 mg/kg body-weight/day (Oser, 1967). In another study lasting 13
    weeks groups of 10 male and 10 female rats were fed diets containing
    0, 0.1, 0.25 and 1.0 per cent. of citral without any adverse effects
    (Hagen et al., 1967). On the other hand, young rats fed 0.15 mg citral
    daily for 26 days showed reduced body-weight gain in both sexes
    (Shillinger, 1950).

         Rabbit. Oral administration of 2.8 mg/kg body-weight daily for
    3 months reduced body-weight gain, raised fasting blood sugar level
    and prolonged the hyperglycaemic period, produced urobilinuria,
    proteinuria and histological evidence of chronic nephritis
    (Shillinger, 1950).

    Long-term studies

         None available.

    Comment

         The biochemical studies are not conclusive, particularly in
    regard to the local activity of this substance and its pharmacological
    effects under certain circumstances. However, it is possible to
    evaluate this compound on the basis of short-term studies. Because of
    the local action of the compound, it is prudent to employ a safety
    factor of 500.

    EVALUATION

    Level causing no toxicological effect

         Rat: 1 per cent. (= 10 000 ppm) in the diet, equivalent to 500
    mg/kg body-weight/day.

    Estimate of acceptable daily intake for man

                                       mg/kg body-weight

              Conditional acceptance          0-1

    Further work required

         Biochemical and metabolic studies and long-term studies,1  with
    special attention to possible systemic effects on the eyes.

    REFERENCES

    Hagan, E. C., Hansen, W. H., Fitzhugh, O. C., Jenner, F. 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

    Oser, B. L. (1967) Unpublished Report

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

    Williams, R. T. (1959) Detoxication Mechanisms, Second Edition,
    Chapman & Hall, London



                   

    1 When considering the group of flavouring substances citral, 
    citronellol, linalol, linalyl acetate and geranyl acetate, the
    Committee stressed the urgent need to elucidate the metabolic pathways
    which may be common to these widely distributed substances. They found
    it reasonable to require that one or more of these substances should
    be made the subject of long-term studies. Whether this limitation can
    be made and which substances should be chosen may follow from a
    consideration of the biochemical evidence when this becomes available.
    


    See Also:
       Toxicological Abbreviations
       Citral (ICSC)
       CITRAL (JECFA Evaluation)
       Citral  (SIDS)