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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

    DICHLORVOS

    Chemical name

         O,O-dimethyl 2,2-dichlorovinyl phosphate

    Synonyms

         O,O-dimethyl,-2,2-dichlorovinyl phosphate, dimethyl
    2,2-dichlorovinyl phosphate

    Empirical formula

         C4H7O4PCl2

    Structural formula

    CHEMICAL STRUCTURE 

    Relevant physical or chemical properties

         The molecular weight of dichlorvos is 221 whereas those of the
    other commonly used organo-phosphorus insecticides (e.g. parathion,
    malathion) are in the order of 300. The low molecular weight is
    associated with a relatively high vapour pressure as compared with
    other organic phosphorus compounds but a low vapour pressure as
    compared with compounds generally regarded as fumigants (see Table 1).

         Dichlorvos penetrates closely packed material, such as grain,
    very poorly, but it has exceptional ability to permeate air spaces at
    a distance from the point of application in spite of considerable
    ventilation.

         Dichlorvos hydrolyses rapidly in the presence of moisture. The
    initial breakdown products we considered to be dimethyl phosphoric
    acid and dichloroacetaldehyde. The latter tends to be oxidized on
    exposure to air to dichloroacetic acid. Formulations (and sometimes
    areas treated with dichlorvos) will exhibit a sour or vinegar-like
    odour due to the dichloroacetic acid if hydrolysis has occurred to any
    extent. Dichlorvos itself is odourless at air concentrations
    recommended or normally encountered.

    Use

         Dichlorvos is used to combat flying or other exposed insects in
    buildings and other closed spaces, e.g. control of cigarette beetles
    in tobacco warehouses and control of several species in greenhouses,
    barns, poultry houses, mushroom houses, homes and restaurants and
    other food handling establishments. It is now receiving final inflight
    tests for the control of flies, mosquitos, and other disease vectors
    in aircraft. It has shown promise in the control of malaria mosquitos
    in houses. Its use for the control of pests of crops and of stored
    products is being explored.

    TABLE 1.  MOLECULAR WEIGHT AND VAPOUR PRESSURE OF SELECTED COMPOUNDS

                                                                  
    Compound            Molecular weight      Vapour pressure
                                                 (mm Hg)
                                                                  

    Sarin                    140                           -

    Dichlorvos               221               0.025       at 25C
                                               0.032       at 32.2C

    Parathion                291               0.0000378   at 20C

    Malathion                330               0.00004     at 30C

    Phosphine (PH3)           34          29 200           at 25C

    Cyanide (HCN)             27             760           at 26C

    Carbon tetrachloride     154             100           at 25C

    Tetrachlorethylene       166              18           at 25C
                                                                  

    Residues

         To date, most of the residue data have been produced by employing
    a non-specific cholinesterase inhibition (spectrophotometric) method
    (Giang & Hall, 1951; Giang, Smith & Hall, 1956; USDA, 1965). The
    sensitivity claimed for this method is 0.1 ppm in most of the products
    examined to date, but in tobacco and high fat commodities sensitivity
    is reduced to 0.5 ppm. A tentative method employing microcoulometric
    gas chromotography sensitive to 0.05-0.1 ppm in some vegetables is
    being evaluated (Kiigamagi & Terriere, 1964).

         A negative test by the cholinesterase methods gives some degree
    of assurance that residues are not present. Since one or more degraded
    esters or metabolites of other organic phosphate insecticides are
    commonly found if a positive cholinesterase test results, it is
    necessary to at least employ the two methods described by Getz, 1962a

    and 1962b, for initial identification of residues or degradation
    products.

         A specific insect bioassay, using Drosophila melanogaster has
    been used to detect residues of dichlorvos (Sun & Johnson, 1963). This
    method appears to be interesting due to its specificity.

         To date no reports are available on effects of processing food
    after treatment with dichlorvos (milling, baking, etc.).

    Effect on treated crop

         No reports are available to indicate whether or not dichlorvos
    combines with food or alters its nutritive value.

    BIOLOGICAL DATA

    Biochemical aspects

         Dichlorvos inhibits cholinesterase activity and thus causes
    parasympathomimetic effects. It requires no metabolic conversion, but
    inhibits the enzyme directly. On the other hand, dichlorvos is broken
    down rapidly in the liver (Tracy, 1960; Tracy et al., 1960). Thus, the
    onset of poisoning is rapid and, if recovery occurs, it is prompt
    (Klotzsche, 1956; Durham et al., 1957; Gaines, 1960; Yamashita, 1962).
    The compound is not stored in the body. It is not excreted in the milk
    of cows or rats even when administered in doses that produce severe
    poisoning (Tracy, 1960; Tracy et al., 1960).

         Both single and repeated large doses cause a reduction in the
    eosinophil count of the peripheral blood of rats that was attributed
    to stress (Klotzsche, 1956).

    Acute toxicity

                                                                  
    Animal           Route     LD50 mg/kg    References
                               body-weight
                                                                  

    Rat              Oral          73        Klotzsche, 1956

    Rat, male        Oral          80        Durham et al., 1957
                                             Gaines, 1960
                                             Mattson et al., 1955

    Rat, female      Oral          56*       Durham et al., 1957
                                             Gaines, 1960
                                             Mattson et al., 1955

    Rat, female      Oral          80**      Durham et al., 1957

    Mouse            Oral         124        Yamashita, 1962

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

    Chick, male      Oral          14.8      Sherman & Ross, 1961
                                                                  

    *  Based on 99% pure material.
    ** Result of 2 tests on a technical preparation (90% pure).

         Rat. Under laboratory conditions it was possible to produce
    concentrations ranging from 31 to 118 g/l in an exposure chamber.
    Under the severest conditions of respiratory exposure, rats showed
    signs of poisoning within 2 hours and died in 4.5 to 17.5 hours
    (Durham et al., 1957).

         Domestic animals. Horses tolerated a single dosage of
    dichlorvos in feed at the rate of 50 mg/kg but showed moderate acute
    poisoning when the insecticide was given by stomach-tube at the rate
    of 25 mg/kg (Jackson et al. 1960). An almost identical dose (27 mg/kg)
    given by stomach-tube caused severe but non-fatal poisoning in a cow
    (Tracy et al. 1960).

         Dichlorvos does not produce either immediate or delayed paralysis
    in hens (Durham et al. 1957).

         Man. Men withstood brief exposure (30-60 minutes) to
    concentrations as high as 6.9 g/l without depression of
    cholinesterase activity or any other observed effect (Durham et al.
    1959; Hayes, 1961). A single exposure for 8 hours at a concentration
    ranging from 0.9 to 3.5 g/l produced slight inhibition of plasma
    cholinesterase activity in man (Witter et al. 1961). Slightly higher
    concentrations or longer periods of exposure, or both, produce
    measurable reduction of both the red cell and plasma enzyme activity
    in men, monkeys and rats (Hayes, 1961).

    Short-term studies

         Rat. Relatively small repeated doses lower the blood
    cholinesterase activity but much larger doses are required to produce
    illness. Thus, Durham et al. (1957) found that a dietary concentration
    of only 50 ppm soon produced detectable lowering of plasm and red cell
    cholinesterase activity in female rats, but a dietary level of 1000
    ppm (about 50 mg/kg/day) was tolerated for 90 days without any
    dimunition of growth or sign of intoxication. Male and female rats
    reproduced as well as controls when maintained on a dietary level of
    100 ppm (T. B. Gaines, unpublished results).

         When dichlorvos is given by stomach-tube it is not so well
    tolerated as when the same dosage is absorbed from the diet gradually
    throughout the day. Thus, Tracy et al. (1960) found that female rats

    tolerated doses of 10 and 20 mg/kg but suffered severe, acute
    poisoning when given doses of 30 mg/kg. Even at 30 mg/kg, the rats
    survived and the red cell cholinesterase activity and growth of their
    litters were normal.

         Dog. Dichlorvos given to dogs by capsule at rates equivalent to
    dietary levels of 5 and 15 ppm (0.13 to 0.37 mg/kg/day) produced no
    detectable effect; rates equivalent to 25 ppm and 50 ppm depressed
    brain cholinesterase activity to 88 and 33% of normal, respectively,
    and to some increase in the activity and aggressiveness of the dogs
    (Blucher et al. 1962).

         Monkey. A dermal dose of 50 mg/kg produced cholinergic signs in
    a monkey 20 minutes after administration, and it died after 8 daily
    doses at this rate. Higher dosage rates produced even more rapid onset
    of illness, even though a single dose of 100 mg/kg was not fatal
    (Durham et al. 1957).

         Monkeys tolerated continuous exposure to concentrations ranging
    from 0.1-0.5 g/l for 22 days without a definite change in
    cholinesterase activity. They showed a definite depletion by the 50th
    day of exposure (Durham et al. 1959), but the concentration of the
    insecticide may have exceeded 0.5 g/l sometime between the 22nd and
    50th day (Hayes, 1961).

         Horse. Horses showed mild depression of red cell but not plasma
    cholinesterase activity when exposed continuously to concentrations
    ranging from 0.24 to 1.48 g/l, but they returned to normal in spite
    of continuing exposure (Tracy et al. 1960).

         Man. Men showed no change in cholinesterase activity when
    exposed for 8-10 half-hour intervals, 4 nights per week, for 11 weeks
    to concentrations ranging from 0.07 to 0.66 g/l (average 0.25 g/l).
    They did show a small but statistically significant depression of
    plasm enzyme activity, but not of red cell enzyme activity, when the
    schedule of dosing was maintained but the concentration increased to
    0.40.0.55 g/l (average 0.51 g/l). The other parameters studied,
    including complex reaction time, airway resistance and vision,
    remained normal (Rasmussen et al. 1963). The tolerated inhaled dosage
    averaged 0.5 mg/man/day while the dosage that caused a slight fall of
    plasma cholinesterase, was 1.1 mg/man/day. The compound produced no
    decrease in blood cholinesterase activity and no other indication of
    injury when used for malaria control (Funckes et al. 1963; Gratz et
    al. 1962).

         Experiments on rats show that the liver is highly efficient in
    detoxicating dichlorvos (Gaines, T. B., in preparation) and that the
    compound is absorbed from the gastro-intestinal tract by the blood of
    the hepatic portal system (Laws, E. R., in preparation). Thus, a given
    dose of dichlorvos absorbed after ingestion is less toxic than the
    same dose absorbed in an identical time following inhalation.

    Long-term studies

         No really long-term studies have been made of dichlorvos, nor do
    they appear indicated because of the rapid action and excretion of the
    compound.

    Comments on experimental work reported and evaluation

         Dichlorvos has a greater effect when inhaled than when given by
    mouth. So far the only maximum level causing no significant
    toxicological effect for man has been determined by inhalation
    experiments and is 0.01 mg/kg/day. In dogs, the maximum oral no-effect
    level was 0.37 mg/kg/day. Until more data on oral toxicity to man are
    forthcoming, an acceptable daily intake cannot be established.

    Further work required

    Determination of oral toxicity for man.

    REFERENCES

    Blucher, W., Budd, E. R. Dewey, M. L., Eisenlord, G. Hine, C. H.,
    Loquvam, G. L., Powers, M. T. & Riggs, C. W. (1962) Report from the
    Hine Laboratories, San Francisco, California

    Durham, W. F., Gaines, T. B., McCauley, R. H., jr, Sedlak, V. A.,
    Mattson, A. M. & Hayes, W. J., jr (1957) A. M. A. Arch. industr.
    Hlth, 15, 340

    Durham, W. F., Hayes, W. J., jr & Mattson, A. M. (1959) A. M. A.
    Arch. industr. Hlth., 20, 202

    Funckes, A. J., Miller, S. & Hayes. W. J., jr (1963) Bull. Wld Hlth
    Org., 29, 243

    Gaines, T. B. (1960) Toxicol. Appl. Pharmacol., 2, 88

    Gaines, T. B., A technique for studying the net effect of metabolism
    of compounds in the liver on their toxicity (In preparation)

    Gaines, T. B., Effect of dietary DDVP on reproduction in rats and on
    survival of their offspring. Unpublished results

    Getz, M. E. (1962a) J. Ass. Offic. Agr. Chem., 45, 397

    Getz, M. E. (1962b) J. Ass. Offic. Agr. Chem., 45, 393

    Giang, P. A. & Hall, S. A. (1951) Anal. Chem., 23, 1830

    Giang, P. A., Smith, F. F. & Hall, S. A. (1956) J. Agr. Food Chem.,
    4, 621

    Gratz, N. G., Bracha, P. & Carmichael, A. G. (1962) WHO/Vector
    Control/11, 49 pp.

    Hayes, W. J., jr (1961) Bull, Wld Hlth Org., 24, 629

    Jackson, J. B., Drummond, R. O., Buck, W. B. & Hunt, L. M. (1960)
    J. econ. Ent., 53, 602

    Kiigamagi, V. & Terriere, L. C. (1964) Shell Agr. Chem. Div., New York

    Klotzsche, C. (1956) Z. Angew. Zool., 1, 87

    Laws, E. R., jr, The absorption of DDVP (In preparation)

    Mattson, A. M., Spillane, J. T. & Pearce, G. W. (1955) J. Agr. Food
    Chem., 3, 319

    Rasmussen, W. A., Jensen, J. A., Stein, W. J. & Hayes, W. J., jr
    (1963) Aerospace Med., 34, 594

    Sherman, M. & Ross, E. (1961) Toxicol. Appl. Pharmacol., 3, 521

    Sun, Y. P. & Johnson, E. R. (1963) J. Ass. Offic. Agr. Chem., 46,
    524

    Tracy, R. L. (1960) Soap Chem. Spec., 36, 74

    Tracy, R. L., Woodcock, J. G. & Chodroff, S. (1960) J. econ. Ent.,
    53, 593

    USDA. 1965 Method Dr. 5e-62 dated 1 March 1962, rev. Nov. 20 1965.
    Stored Prod. Insect Lab., Agr. Res. Serv., USDA, Savannah, Ga

    Yamashita, K. (1962) Industr. Med. Surg., 31, 170

    Witherup, S., & Schlecht, H. (1962) Report from the Kettering
    Laboratory, University of Cincinnati, Cincinnati, Ohio, 14 pp.

    Witter. R. F., Gaines, T. B., Short, J. G., Sedlak, V. A. & Maddock,
    D. R. (1961) Bull. Wld Hlth Org., 24, 635
    


    See Also:
       Toxicological Abbreviations
       Dichlorvos (EHC 79, 1988)
       Dichlorvos (HSG 18, 1988)
       Dichlorvos (ICSC)
       Dichlorvos (FAO/PL:CP/15)
       Dichlorvos (FAO/PL:1967/M/11/1)
       Dichlorvos (FAO/PL:1969/M/17/1)
       Dichlorvos (AGP:1970/M/12/1)
       Dichlorvos (WHO Pesticide Residues Series 4)
       Dichlorvos (Pesticide residues in food: 1977 evaluations)
       Dichlorvos (Pesticide residues in food: 1993 evaluations Part II Toxicology)
       Dichlorvos (IARC Summary & Evaluation, Volume 53, 1991)