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    FAO Meeting Report No. PL/1965/10/1
    WHO/Food Add./27.65

    EVALUATION OF THE TOXICITY OF PESTICIDE RESIDUES IN FOOD

    The content of this document is the result of the deliberations of the
    Joint Meeting of the FAO Committee on Pesticides in Agriculture and
    the WHO Expert Committee on Pesticide Residues, which met in Rome,
    15-22 March 19651

    Food and Agriculture Organization of the United Nations
    World Health Organization
    1965

                
    1 Report of the second joint meeting of the FAO Committee on
    Pesticides in Agriculture and the WHO Expert Committee on Pesticide
    Residues, FAO Meeting Report No. PL/1965/10; WHO/Food Add./26.65

    DNOC

    Chemical name

           2-methyl-4,6-dinitrophenol; 2,4-dinitro-6-methylphenol;
    2,4-dinitro-o-cresol; 3,5-dinitro-o-cresol.

    Synonyms

           DNC

    Empirical formula

           C7H6N2O5

    Structural formula

    CHEMICAL STRUCTURE 

    BIOLOGICAL DATA

    Biochemical aspects

           Like other dinitrophenols, DNOC increases the oxidative
    metabolism and heat production by direct cellular reaction. DNOC
    affects enzyme systems by inhibiting the formation of adenosine
    triphosphate and by blocking oxidative phosphorylation.

           In the blood, DNOC combines with the plasm proteins to form
    compounds that persist for variable times depending on the species
    (King & Harvey, 1953). In mammals and plants DNOC is reduced to a
    number of amino compounds (Wessels, 1960).

    Acute toxicity

                                                                     
    Animal             Route       LD50 mg/kg     References
                                   body-weight
                                                                     

    Rat                Oral           26-30       Lehman, 1951
                                                  Negherbon, 1959

    Rat           Intraperitoneal     28.5        Lawford et al., 1954

    Mouse         Intraperitoneal     24-26       Lawford et al., 1954

    Guinea-pig    Intraperitoneal     22.5        Lawford et al., 1954

    Rabbit        Intraperitoneal     23.5        Lawford et al., 1954

    Goat               Oral            100        Negherbon, 1959
                                                                     

    Short-term studies

           Rat. Groups of 5-10 male rats were given diets containing 7.8,
    15.6, 31.2, 62.5, 125, 250, 500 and 1000 ppm DNOC for 105 days.
    Dosages from 7.8 to 31.2 ppm did not affect growth or food
    consumption. Growth and food consumption were slightly increased in
    the 62.5 and 125 ppm groups. Dosages of 125 and 250 ppm killed 60% of
    the rats and growth was inhibited in the survivors on 250 ppm. The
    animals with 500 and 1000 ppm failed to grow and died in 2 or 3 days.
    No histopathological changes were noted in any organ (Ambrose, 1942).

           Groups of 20 male rats were given diets containing 20, 50, 100,
    200, 500 and 1000 ppm DNOC for 6 months. Growth was normal in those on
    20, 50 and 100 ppm; with 200 ppm, growth was decreased but not
    significantly; with 500 ppm there was poor weight gain and with 1000
    ppm half the rats died by the tenth day. The reminder were killed for
    histopathological examination. Slight cloudy swelling of the liver at
    1000 ppm was found (Spencer et al., 1948).

           Duckling. A group of nine ducklings given 0.25% DNOC showed
    bilateral cataracts within 24 hours. This dosage was lethal to all
    ducklings within 2 days (Spencer et al., 1948).

           Man. Two volunteers received 75 mg/day orally for 7 days. In
    one subject, lassitude, headache and malaise occurred on the seventh
    day. In the second no symptoms appeared (Negherbon, 1959).

           Five male volunteers were given daily doses of 75 mg of pure 
    DNOC orally for 5 days. This dose ranged from 0.92 to 1.27 mg/kg
    body-weight per day. The volunteers on the highest dose developed
    symptoms of lassitude, headache and general malaise on the fifth day.
    Doses of the order of 1 mg/kg body-weight resulted in concentrations

    of 15-20 g of DNOC per g of blood after 3-5 days. Symptoms occur when
    the concentration in the blood is of the order of 20 g per g of blood
    (Harvey et al., 1951).

           Bilateral cataracts have occurred from the use of DNOC in the
    treatment of obesity (Bidstrup & Payne, 1951).

    Comments on the experimental studies reported

           Two relatively short studies in rats have indicated that a 
    dosage of 100 ppm of DNOC in the diet is a "no-effect" level. However, 
    human studies have shown that DNOC is more toxic to man than was 
    indicated by these rat studies. Studies with ducks and reports of 
    human use in obesity show that DNOC may produce cataracts.

    EVALUATION

    Estimate of acceptable daily intake for man

           In view of the fact that the maximum no-effect level in the rat
    was established on a six-month experiment only and because of the high
    toxicity of DNOC to man no maximum acceptable daily intake for man can
    be established.

    Further work required

           Chemical composition and toxicity of the plant residues.

    REFERENCES

    Ambrose, A. M. (1942) J. Pharmacol. exp. Ther., 76, 245

    Bidstrup, P. L. & Payne, D. J. H. (1951) Brit. med. J., 2, 16

    Harvey, D. G., Bidstrup, P. L. & Bonnell, J. A. L. (1951) Brit. med.
    J., 2, 13

    King, E. & Harvey, D. G. (1953) Biochem. J., 53, 185 and 196

    Lawford, D. J., King, E. & Harvey, D. S. (1954) J. Pharm.
    Pharmacol., 6, 619-624

    Lehman, A. J. (1951) Quart. Bull. Assoc. Food and Drug Officials
    U.S., 15, 122

    Negherbon, W. O. (1959) Handbook of Toxicology, Philadelphia &
    London, Saunders, vol. III

    Spencer, H. C., Rowe, V. K., Adams, E. M. & Irish, D. D. (1948)
    J. industr. Hyg., 30, 10

    Wessels, J. S. C. (1960) Bioph. Biochem. Acta, 38, 195
    


    See Also:
       Toxicological Abbreviations