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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

    PIPERONYL BUTOXIDE

    Chemical name

           3,4-methylenedioxy-6-propylbenxyl n-butyl diethyleneglycol
    ether

    Synonyms

           Alpha-[2-(2-n-butoxyethoxy)ethoxy]-4,5-methylendioxy-2-
           propyltolune

    or

           6-(propylpiperonyl)-butyl carbityl ether

    or

           (3,4-methylenedioxy-6-propylbenzyl) (butyl diethylene glycol
           ether) ether

    Empirical formula

           C19H30O5 (molecular weight 338)

    Structural formula

    CHEMICAL STRUCTURE 

    Relevant physical and chemical properties

           Piperonyl butoxide is a derivative of piperic acid. Its
    synergistic activity is believed to be due to the presence of the
    methylenedioxy group in the molecular structure. It is synthesized
    from safrole and the butyl ether of diethylene glycol.

           Piperonyl butoxide is quite stable, resistant to hydrolysis,
    oxidation and exposure to sunlight. Strong bases up to 1N
    concentration and weak acids will not affect it, but strong acids will
    destroy it. For a more complete description of the physical and
    chemical characteristics see Negherbon (1959).

    Uses

           Alone, piperonyl butoxide is a compound of only mediocre
    insecticidal power. It acts as an effective synergist to increase the
    toxicity; "knockdown" and persistence of pyrethrins and allethrin. The
    synergist action is so pronounced that the resulting kill of insects
    is much greater than that which can be produced by pyrethrins alone
    (Wachs, 1947; McAlister et al., 1947). It does not synergize or
    potentiate DDT or nicotine. There are some suggestions that piperonyl
    butoxide will potentiate the toxicity of organic phosphate
    insecticides to insects (Robbins et al., 1959). Rotenone, ryanodine
    and benzene hexachloride are activated by piperonyl butoxide but to a
    lesser degree than pyrethrins (Negherbon, 1959).

    Residues

           Residues do result from use on foods, but the information on this
    subject is incomplete.

           In the analysis of residues, extraneous materials extracted from
    natural products develop dark brown to black colours when heated with
    concentrated phosphoric acid. These colours interfere with the residue
    determination by colorimetric end procedure. Each food presents
    different problems in removing interfering substances. Four methods
    have been published by the Association of Official Agricultural
    Chemists. In wheat, pinto beans, Alaska beans hulled rice, oats and
    barley a sensitivity of 20 mmg of piperonyl butoxide of 0.5 ppm can be
    obtained (AOAC, 1960; AOAC, 1963; Munday, 1963).

           A method is reported for flour, grain and oil base materials, but
    details are given only for oil base materials, containing 0.25-0.75
    mg/ml (Jones et al., 1952). A colorimetric method for application to
    fats, waxes and oils is suitable for 50-80 mmg working range (Williams
    & Sweeney, 1956).

    Effect on treated crop

           No information available.

    BIOLOGICAL DATA

    Biochemical aspects

           High oral doses produce haemorrhage into the intestinal tract
    with loss of appetite and prostration (Sarles et al., 1949). It may be
    that these are the effects of local irritation and that the
    hyperexcitability and convulsions produced by large dermal doses
    (Lehman, 1952) are more indicative of the action of the absorbed drug.
    The compound produces liver injury (Sarles et al., 1949; Sarles &
    Vandegrift, 1952), and at least in dogs, and in rats at high dosage
    levels, liver injury was recognized as the cause of death (Sarles &
    Vandegrift, 1952).

           In rats, large subcutaneous doses produce an increased bleeding
    tendency and "rusty" (bloody) urine (Sarles et al., 1949). Massive
    bleeding was found in some animals at autopsy (Sarles & Vandegrift,
    1952).

           Chamberlain (1950) explored the hypothesis that, in insects,
    piperonyl butoxide synergizes pyrethrins by inhibiting lipase
    (esterase), but his results were inconclusive.

           In an experiment in which 87.6% of a large dose given to a dog
    was recovered (chiefly from the faeces), only 0.09% was found in the
    urine (Sarles & Vandegrift, 1952). So far as is known, the
    colorimetric tests used responded to piperonyl butoxide only. Thus,
    the 12% of the dose that was unaccounted for may have been the most
    important part from a toxicological standpoint.

    Acute toxicity

                                                           
    Animal     Route     LD50 mg/kg     References
                         body-weight
                                                           

    Mouse      Oral         4030        Negherbon, 1959

    Rat        Oral      7960-10600     Sarles et al., 1949

    Rat        Oral         13500       Lehman, 1948

    Rabbit     Oral       2650-5300     Sarles et al., 1949

    Cat        Oral        >10600       Sarles et al., 1949

    Dog        Oral         >7950       Sarles et al., 1949
                                                           

           Simultaneous administration of piperonyl butoxide potentiates the
    toxicity of courmaphos (a triphosphate) and its phosphate by a factor
    of 4 to 6 (Robbins et al., 1959).

           There is some evidence that the piperonyl butoxide interferes
    with detoxification of the organo-phosphorus insecticides (Robbins et
    al., 1959). However, apparently no additional toxicity was produced in
    rats when one-sixth as much pyrethrins was added to their diet
    containing piperonyl butoxide at a concentration of 1000 ppm (Sarles &
    Vandegrift, 1952).

    Short-term studies

           Monkey. At comparable dosage, symptomatology was somewhat less
    than that in dogs. Microscopical pathology of the liver in monkeys on
    a dosage of 100 mg/kg/day was comparable to that in dogs receiving 30
    mg/kg/day (a dosage that produced no observed effect in the monkey).

    The apparent difference in the susceptibility of the species may be
    explained by the shorter exposure of the monkey (1 month) compared
    with the dogs (1 year) (Sarles & Vandegrift, 1952).

           Dog. Dogs did not grow as fast as the controls when dosed at
    the rate of 32 mg/kg/day for a year and lost weight when dosed at
    rates of 106 mg/kg/day or higher. Even at 3 mg/kg/day, the dogs showed
    some increase in liver weight and the increase was progressively
    greater at higher dosage rates. The kidneys and adrenals were
    progressively enlarged at dosages of about 100 mg/kg/day and above.
    Microscopical pathology was evident in the liver at dosage rates of
    about 30 mg/kg/day and over. Hepatoma and carcinoma did not occur in
    the dog (Sarles & Vandegrift, 1952).

    Long-term studies

           Rat. In two-year studies, concentrations of piperonyl butoxide
    as high as 1000 ppm caused no decrease in the growth rate of female
    rats; concentrations as low as 100 ppm produced some reduction in the
    growth of males, but the difference was not considered significant. A
    concentration of 10 000 ppm caused a significant reduction in the
    growth rate of both sexes that was accounted for, at least in part, by
    subnormal food consumption (78% of control). A concentration of 25 000
    ppm reduced food consumption to 37% of normal and stunted the animals.
    However, in subacute experiments, anorexia was terminal and therefore
    not the simple effect of unpalatability of the food. A concentration
    of 10 000 ppm caused a distinct increase in mortality in both sexes
    evident in 2 years and a concentration of 25 000 killed about half the
    animals in half a year. Only concentrations of 10 000 ppm or higher
    produced significant increase in the relative weight of the liver and
    kidney. Some degree of liver pathology apparently occurred in all
    groups of rats but was progressively more marked at dietary levels of
    1000 ppm and more. Less marked changes occurred in the kidney and
    adrenal. Benign or malignant tumours occurred in 30% of the test
    animals but the authors claimed that their occurrence was not related
    to piperonyl butoxide. Reproduction was decreased by a dietary level
    of 10 000 ppm and stopped by a concentration of 25 000 ppm (Sarles &
    Vandegrift, 1952).

    Comments on the experimental work reported and evaluation

           Sarles & Vandegrift (1952) made a distinction for the rat 
    between the ill-defined effects of 1000 ppm and the effects of 100 
    ppm, a level which they found to be "nontoxic". Furthermore, dogs 
    showed decreased growth and microscopical pathology of the liver at 
    about 30 mg/kg/day and some increase in liver weight at only 3 
    mg/kg/day.

           The uses of piperonyl butoxide are such that only a small 
    portion of food would be expected to contain any. No report of actual
    residues is available. Although there is no evidence that the 

    presently approved uses of piperonyl butoxide involve any danger there
    is not enough information on the compound to allow the setting of an
    acceptable daily intake figure for human beings.

    Further work considered necessary

           Determination of the nature and amount of the residues reaching
    the consumer.

           A level should be established that causes no significant effect
    during long-term studies in at least 2 species. The question of
    tumorigenicity should be re-explored, especially in rats. Biochemical
    studies should be made on the qualitative and quantitative aspects of
    metabolism of the compound.

    REFERENCES

    AOAC (1960) Official methods of Analysis of the Association of
    Official Agricultural Chemists, ninth ed., Washington

    AOAC (1963) J. Assoc. Offic. Agr. Chem., 46, 145

    Chamberlain, R. H. (1950) Amer. J. Hyg., 52, 153

    Jones, H. A. Ackermann, H. J. & Webster, M. E. (1952) J. Assoc.
    Offic. Agr. Chem., 35, 771

    Lehman, A. J. (1948) Quart. Bull. Assoc. Food and Drug Officials of
    U.S., 12, 82

    Lehman, A. J. (1952) Quart. Bull. Assoc. Food and Drug Officials of
    U.S., 16, 3

    McAlister, L. C. Jones, H. A. & Moore, D. H. (1947) J. econ. Ent.,
    40, 906

    Munday, W. H. (1963) J. Assoc. Offic. Agr. Chem., 46, 244

    Negherbon, W. O. (1959) Handbook of Toxicology, vol. 3, Saunders,
    Philadelphia

    Robbins, W. E., Hopkins, T. L. & Darrow, D. I. (1959) J. econ. Ent.,
    52, 660

    Sarles, M. P., Dove, W. E. & More, D. H. (1949) Amer. J. trop. Med.,
    29, 151

    Sarles, M. P. & Vandegrift, W. B. (1952) Amer. J. trop. Med. Hyg.,
    1, 862

    Wachs, H. (1947) Science, 105, 530

    William H. L. & Sweeney, J. P. (1956) J. Assoc. Offic. Agr. Chem.,
    39, 975
    


    See Also:
       Toxicological Abbreviations
       Piperonyl butoxide (ICSC)
       Piperonyl butoxide (FAO/PL:CP/15)
       Piperonyl butoxide (FAO/PL:1967/M/11/1)
       Piperonyl Butoxide (FAO/PL:1969/M/17/1)
       Piperonyl butoxide (WHO Pesticide Residues Series 2)
       Piperonyl butoxide (Pesticide residues in food: 1992 evaluations Part II Toxicology)
       Piperonyl butoxide (Pesticide residues in food: 1995 evaluations Part II Toxicological & Environmental)
       Piperonyl Butoxide (IARC Summary & Evaluation, Volume 30, 1983)