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    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY

    WORLD HEALTH ORGANIZATION



    SUMMARY OF TOXICOLOGICAL DATA OF CERTAIN FOOD ADDITIVES
    AND CONTAMINANTS



    WHO FOOD ADDITIVES SERIES NO. 13






    The data contained in this document were examined by the
    Joint FAO/WHO Expert Committee on Food Additives*
    Rome, 3-12 April 1978




    Food and Agriculture Organization of the United Nations
    World Health Organization



    * Twenty-second Report of the Joint FAO/WHO Expert Committee on Food
    Additives, Geneva, 1978, WHO Technical Report Series No. 631

    MALTOL

    Explanation

         This compound has been evaluated for acceptable daily intake by
    the Joint FAO/WHO Expert Committee on Food Additives in 1967.

         Since the previous evaluation additional data have become
    available and are summarized below.

    BIOLOGICAL DATA

    BIOCHEMICAL ASPECTS

         No data available.

    Acute toxicity

                                                                        

                             LD50
    Animal        Route      mg/kg bw       References
                                                                        

    Mouse         Oral          550         Dow Chemical Company, 1967

    Rat           Oral        1 410         Dow Chemical Company, 1967

    Guinea-pig
    (male)        Oral        1 410         Dow Chemical Company, 1967

    Rabbit        Oral        1 620         Dow Chemical Company, 1967
    (male)
                                                                        

    Short-term studies

    Rat

         Groups of 15 males and 15 females were fed 0 and 1.0% maltol for
    six months without adverse effect on growth, survival, organ weights,
    haematology and microscopic appearance of major organs (Dow Chemical
    Company, 1967).

    Dog

         Groups of four dogs, not necessarily distributed according to
    sex, were given maltol by capsule at levels of 0, 125, 250 and
    500 mg/kg/day, for 90 days.

         By day 41 all dogs at the 500 mg/kg level had died. Signs of
    death suggested liver damage and red cell destruction, in addition to
    which emesis, ataxia and finally prostration were noted.

         Histological examination revealed pulmonary oedema, pericentral
    and mid-zonal hepatic necrosis, fatty degeneration of the myocardium,
    adrenal cortical and medullary necrosis and testicular degeneration.

         Elevated serum bilirubin was seen in the 500 mg/kg and at 30 days
    in the 250 mg/kg. Histologically the 250 mg/kg showed a moderate
    number of Kupffer cells containing haemosiderin and small amounts of
    intracellular bilirubin. At the 125 mg/kg level only a moderate number
    of haemosiderin-laden Kupffer cells were observed.

         As effects at the lowest level appeared to be marginal, a
    conservative no-effect level could be estimated at 100 mg/kg (Gralla
    et al., 1969).

    Long-term studies

    Mouse

         Groups each of 100 mice (Charles River CDI) equally divided by
    sex were maintained on diets containing maltol at levels of 0, 100,
    200 or 400 ppm for a period of 18 months.

         There were no significant differences in survival between test
    and control groups. The mean body weights of male mice in the 400 ppm
    group were significantly lower than controls. Blood chemistry at
    sacrifice was within normal limits with the exception of plasma urea
    which was significantly elevated in males in the 400 ppm maltol group,
    and a dose-related increase in serum alkaline phosphatase in all
    female test groups. No dose-related haematological changes were
    observed. Ophthalmic observations at 6, 12 and 18 months showed no
    compound-related ocular lesions. At autopsy, the relative organ/body
    weight ratio was similar for test and control animals with the
    exception of the kidney and testes weights of males in the 400 mg/kg
    group, which were significantly lower than controls. Histological
    examination of tissues and organs did not show any compound-related
    lesions except for the testes. Focal testicular atrophy was observed
    in both control and test males, but was most severe in the 400 mg/kg
    group (King et al., 1978a).

    Rat

         A two-year study was carried out in the F1 generation of rats
    (Crl:CD-COB 5 (SD)), derived from parents exposed to diets containing
    maltol at 0, 100, 200 or 400 mg/kg of diet. After weaning the rats
    (groups of 100 equally divided by sex) were maintained on the

    appropriate diets containing maltol. The rats were mated on days 189
    and 245 respectively of the study to provide the F2a and F2b
    generations of a three-generation reproduction study. During the
    course of the study on days 134 and 418 respectively all animals
    showed signs of sialodacryodenitis, a contagious disease of viral
    origin. No deaths occurred from this disease and signs regressed
    within 10 days.

         There were no significant differences in survival between test
    and control animals. Ophthalmic examinations of the high and control
    groups performed at months 12, 18 and 24 showed no compound-related
    eye lesions. Blood chemistry and haematology at sacrifice showed that
    test and control animals were similar and within normal limits with
    the exception of significant increases in K+, Cl-, urea and
    bilirubin in the 400 mg/kg male and female groups, and urea and K+
    in the 200 mg/kg male group. The gross and microscopic examination of
    tissues and organs showed no compound-related lesions, nor was there
    any indication that maltol had an effect upon tumour incidence (King
    et al., 1978b).

    Special studies on reproduction

    Rat

         A three-generation reproduction study was carried out on rats
    (Crl:CD-COB 5 (SD)) using groups of 20 male and 20 female rats for the
    production of each generation. Dosage levels of 0, 100, 200 or
    400 mg/kg of maltol was administered in the diet. During the course of
    the study on day 134 (F1 generation) all animals showed signs of
    sialodacryodenitis, a contagious disease of viral origin. No deaths
    occurred from this disease and signs regressed within 10 days.

         Criteria evaluated were body weight and food consumption of
    parents, fertility index, mating index, gestation index, survival
    index and sex ratio of each generation. At birth all offspring were
    examined for gross morphological abnormalities. Maltol had no effect
    on copulation rate, mating index, fertility index, gestation index and
    length of gestation. The viability index, lactation index, 21-day
    survival index and sex ratios were within normal limits. Differences
    in growth rate of the pups appears to be related to the outbreak of
    sialodacryodenitis in the colony. No specific compound-related
    abnormalities or lesions were reported in the pups (King et al.
    1978b).

    REFERENCES

    Dow Chemical Co. (1967) Unpublished report

    Gralla, E. J., Stebbins, R. B., Coleman, G. L. and Delahunt, C. S.
    (1969) Toxicity studies with ethyl maltol, Toxicol. appl.
    Pharmacol., 15, 604-613

    King, T. O., Reinert, H., Pelé, M. F., Chvedoff, M., Taradach, C.,
    Nachbaur, J., Faccini, J. M., Irisarri, E., Clarke, M. R. and Monro,
    A.M. (1978a) Unpublished data. Research Center, Pfizer, France
    Protocol 75-009. 18-month mouse study with maltol

    King, T. O., Perraud, J., Faccini, J. M., Nachbaur, J. and Monro, A.M.
    (1978b) Unpublished data. Research Center, Pfizer, France Protocol
    74107-Maltol. 3 generation and carcinogenicity study in rats


    See Also:
       Toxicological Abbreviations
       Maltol (FAO Nutrition Meetings Report Series 44a)
       Maltol (WHO Food Additives Series 16)
       MALTOL (JECFA Evaluation)