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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


    VANILLIN

    Chemical name                 4-Hydroxy-3-methoxybenzaldehyde

    Empirical formula             C8H8O3

    Structural formula

    MOLECULAR STRUCTURE 18

    Molecular weight              152.15

    Definition                    Vanillin contains not less than 97 per
                                  cent. and not more than the equivalent
                                  of 103 per cent. C8H8O3.

    Description                   Fine, white to slightly yellow crystals,
                                  usually needle-like, having an odour and
                                  taste suggestive of vanilla. It is
                                  affected by light.

    Biological Data

    Biochemical aspects

         In rabbits, vanillin is metabolized by the following pathway:
    vanillin undergoes rapid conjugation and slow oxidation to conjugated
    vanillic acid, 5 per cent. of which is demethylated to conjugated
    protocatechuic acid, which is then decarboxylated to conjugated
    catechol. Further complete oxidation, opening the aromatic ring
    between C3 and C4, then ensues (Sammons & Williams, 1941). Early
    observers noted conversion to vanillic acid which was mainly excreted
    as free acid or conjugated ethereal sulfate or glucurovanillic acid
    (Preusse, 1880). Later work confirmed that if the rabbit 69 per cent.
    of orally given vanillin is oxidized to 44 per cent. free vanillic
    acid and 25 per cent. conjugated vanillic acid (10 per cent. as
    ethereal sulfate and 15, per cent as p-glucuronide), all excreted in
    the urine. Fourteen per cent. of orally administered vanillin is

    excreted in conjugated form (8 per cent. as ethereal sulfate, 31 per
    cent. as glucuronide), but none as free vanillin. Conjugated vanillic
    acid and conjugated protocatechuic acid are in equilibrium with the
    corresponding free acids which also appear in the urine (Sammons &
    Williams, 1941).

         In man and rat, vanillin is broken down by the liver to vanillic
    acid which is excreted in the urine. Rat and human liver homogenates
    readily convert vanillin to vanillic acid in vitro (Dirscherl &
    Brisse, 1966). Quantitative conversion of dietary vanillin to urinary
    vanillic acid in man has been confirmed. Endogenous vanillic acid
    production and excretion from body catechol amines amounts to <0.5 mg
    per day, compared with the normal contribution from dietary sources of
    about 9 mg/day (Dirscherl & Wirtzfeld, 1964).

    Acute toxicity

                                                                       

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

    Mouse          i.p.      780              Caujolle & Meynier, 1954
                             475              Frazer, 1967

    Rat            oral      1580             Jenner et al., 1964
                             approx. 2800     Hodge & Downs, 1961
                   s.c.      1800(LD)         Deichmann & Kitzmiller, 
                                                1940
                   i.p.      1160             Caujolle et al., 1956

    Guinea-pig     oral      1400             Jenner et al., 1964
                   i.p.      1190             Caujolle et al., 1953

    Dog            i.v.      1320(LD)         Caujolle et al., 1953

    Rabbit         oral      3000(LD)         Deichmann & Kitzmiller, 
                                                1940

    Rat            s.c.      1500             Binet, 1896
                                                                       

    Short-term studies

         Rat. Intragastric administration to rats of 300 mg/kg
    body-weight biweekly for 14 weeks had no deleterious effect. Groups of
    16 rats were fed diets containing vanillin at the rate of 20 mg/kg
    body-weight/day for 18 weeks without any adverse effects while 64
    mg/kg body-weight/day for 10 weeks produced growth depression and
    damage to myocardium, liver, kidney, lung, spleen and stomach. In
    another experiment, 10 male and 10 female rats were fed diets

    containing 0.3, 1.0 and 5.0 per cent. vanillin for 13 weeks. At the
    highest level there was growth depression and enlargement of liver,
    kidney and spleen; mild charges occurred at 1.0 per cent. and none at
    0.3 per cent. (Deichmann & Kitzmiller, 1940). When groups of 5 males
    and 5 females were fed 0, 0.1 and 1.0 per cent. vanillin in their diet
    for 16-28 weeks, there were no adverse effects detectable. Groups of 5
    males were given 0, 2.0 and 5.0 per cent. vanillin in their diet for 1
    year without deleterious effects (Hagan et al., 1967).

    Long-term studies

         Rat. Groups of 12 males and 12 females were fed diets
    containing 0, 0.5, 1.0 and 2.0 per cent. vanillin for 2 years without
    any adverse effects (Hagan et al., 1967).

    Comments

         The metabolic fate of this flavouring is well established in man
    and animals. The short-term studies give conflicting results, but the
    long-term study is used for the evaluation.

    EVALUATION

    Level causing no toxicological effect

         Rat. 2 per cent. (= 20 000 ppm) in the diet, equivalent to 1000
    mg/kg body-weight/day.

    Estimate of acceptable daily intake for man

                                       mg/kg body-weight

         Unconditional acceptance           0-10

    REFERENCES

    Binet, P. (1896) Rev. méd. Suisse rom.,16, 449

    Caujolle, F. & Meynier, D. (1954) C. R. Hebd. Séan. Acad. Sci.,
    238, 2576

    Caujolle, F. Meynier, D. & Forthouat, J. M. (1956) C.R. Hebd. Séan.
    Acad. Sci., 243, 609

    Caujolle, F., Meynier, D. & Moscarella, C. (1953) C.R. Hebd. Séan.
    Acad. Sci., 236, 2549

    Deichmann, W. & Kitzmiller, K. V. (1940) J. amer. Pharm ass. (Sci.
    ed.), 29, 425

    Dirscherl, W. & Brisse, B. (1966) Hoppe-Seyler's Z. physiol. Chem.,
    346, 155

    Dirscherl, W. & Wirtzfeldt, A. (1964) Hoppe-Seyler's Z. physiol.
    Chem., 336 8M1

    Frazer, A. C. (1967) Letter to WHO

    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

    Hodge, H. C. & Downs, W. L. (1961) Toxic. appl. Pharm., 3, 689

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

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

    Preusse, C. (1880) Hoppe-Seyler's Z. physiol. Chem., 4, 213

    Sammons, H. G. & Williams, R. T. (1941) Biochem. J., 35, 1175

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


    See Also:
       Toxicological Abbreviations
       VANILLIN (JECFA Evaluation)
       Vanillin  (SIDS)