INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY

    WORLD HEALTH ORGANIZATION



    TOXICOLOGICAL EVALUATION OF SOME
    FOOD COLOURS, EMULSIFIERS, STABILIZERS,
    ANTI-CAKING AGENTS AND CERTAIN
    OTHER SUBSTANCES



    FAO Nutrition Meetings Report Series 
    No. 46A WHO/FOOD ADD/70.36




    The content of this document is the result of the deliberations of the
    Joint FAO/WHO Expert Committee on Food Additives which met in Rome,
    27 May - 4 June 19691





    Food and Agriculture Organization of the United Nations

    World Health Organization



                   
    1 Thirteenth report of the Joint FAO/WHO Expert Committee on Food
    Additives, FAO Nutrition Meetings Report Series, in press;
    Wld Hlth Org. techn.  Rep. Ser., in press.


    QUERCETIN AND QUERCITRON

    Biological Data

    Biochemical aspects

    Twelve hours after oral administration of C14-labelled quercetin to
    rats, 44 per cent. of the radioactivity was still found in the
    intestinal tract and 15.1 per cent. was recovered in respiratory
    carbon dioxide. Small amounts were found in the blood and kidney and
    an appreciable amount in the lungs and in the wall of the
    gastro-intestinal tract. No other organs contained detectable amounts
    of radioactivity. The urine contained about 4 per cent. of the
    administered activity (Petrakis et al., 1959).

    In the urine radioactive phloroglucinolearboxylic acid, phloroglucinol
    and protocatechuic acid could be identified in ether extracts of
    lyophilized stomach and its contents. A fourth radioactive compound
    not identified and a radioactive "quercetin-like" compound were also
    noted. It was not unchanged quercetin. Incubation of quercetin with a
    porcine gastric mucin gave the same results (Kallianos at al., 1959).

    Following intraperitoneal injection of labelled quercetin, then
    probably vanillic acid was found in the urine. Quercetin may possibly
    be degraded in the rat by at least two metabolic pathways, but it was
    found that Protocatechuic acid, phloroglucinolcarboxylic acid and
    phloroglucinol were artefacts arising during the chemical extraction
    procedures (Petrakis et al., 1959; Masri et al., 1959).

    After oral administration of quercetin to rabbits, the following
    substances were found in urine: 3,4-dihydroxyphenylacetic acid,
    3-hydroxyphenylacetic acid and its glucuronide and
    3-methoxy-4-hydroxyphenylacetic acid (Murray et al., 1954; Booth et
    al., 1956). Protocatechuic acid has been found in rat kidney after
    administration of the colour (Douglass & Hogan, 1958).

    Quercetin and other flavonoids are inhibitors of catechol-0-methyl
    transferase. This would account, at least in part, for raised amounts
    of 3, 4-dihydroxyphenylacetic acid in the urine.

    Acute toxicity

                                                                     
    Animal    Route             LD50                Reference
                          per kg body-weight
                                                                     
    rabbit    i.v.        100 mg* (quercetin)           7

    rabbit    i.v.        270 mg* (quercitron)          7
                          given in two doses
                                                                     
    * No toxic signs were seen.

    Short-term studies

    Rat. When 20 or 100 mg of commercial quercetin was given by stomach
    tube to rats as a suspension, either in a single dose or in four daily
    doses of 5 mg or 25 mg respectively, 50 per cent. of the animals
    developed cataracts within ten weeks. No bilateral cataracts were
    observed. Chromatographically pure quercetin did not cause cataracts
    under similar conditions (Nakagawa et al, 1961).

    Long-term studies

    Rat. Seven groups of 10 weanling rats, 5 of each sex, were placed on
    the following diets, 0, 0.25, 0.5 and 1.0 per cent. of quercetin or
    quercitron, for 410 days. No evidence of abnormalities or injury as
    judged by growth, food consumption, blood composition, organ weights
    and histopathological examination could be found (Ambrose et al.,
    1952).

    Comments

    The production of cataracts in rats with commercial quercetin was not
    observed with the chromatographically pure compound and, consequently,
    may be attributable to impurities. However, information on the
    occurrence of toxic impurities in commercial samples of quercetin and
    quercitron is required. The metabolic fate of this colour needs
    elucidation. Adequate long-term studies in a rodent species and a
    two-year study in a non-rodent mammalian species are required.

    EVALUATION

    Not possible on the data available.

    REFERENCES

    Ambrose, A. M., Robbins, D. J. & De Eds, F. (1952) J. Amer. Pharm.
    Ass., 41, 119

    Booth, A. N., Murray, C. W., Jones, F. T. & De Eds, F. (1956) 
    J. Biol. Chem., 223, 251

    Douglass, C.D & Hogan, R. (1958) J. Biol. Chem., 230, 625

    Kallianos, A. G., Petrakis, P. L., Shetlar, M. R. & Wender, S. H.
    (1959) Arch. Biochem., 81, 430

    Masri, M. S., Booth, A.N. & De Eds, F. (1959) Arch. Biochem., 85,
    284

    Murray, C. W., Booth, A. N., De Eds, F. & Jones., F. T. (1954) 
    J. Amer. Pharm. Ass., 43, 361

    Nakagawa, Y., Shetlar, M. R. & Wender, S. H. (1961) Proc. Soc. exp.
    Biol., 108, 401

    Petrakis, P. L., Kallianos, A. G., Wender, S. H. & Shetlar, M. R.
    (1959) Arch. Biochem., 85, 264
    

    See Also:
       Toxicological Abbreviations
       QUERCETIN AND QUERCITRON (JECFA Evaluation)