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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

    MEVINPHOS

    Chemical name

           2-methoxycarbonyl-1-methylvinyl dimethyl phosphate,
    1-carbomethoxy 1-propen-2-yl dimethyl phosphate;
    dimethyl-1-carbomethoxy-1-propenyl-2-phosphate;
    dimethyl-2-methoxycarbomyl-1-methylvinyl-phosphate,
    2-carbomethoxy-1-methylvinyl dimethyl phosphate.

    Synonym

           Phosdrin

    Empirical formula

           C7H13O6P

    Structural formula

    CHEMICAL STRUCTURE 

    BIOLOGICAL DATA

    Biochemical aspects

           The half-line of the alpha-isomer in the plant is approximately
    20 hours, while that of the -isomer is about 48 hours (Casida et al.,
    1956). The principal metabolite is dimethyl phosphate (Casida et al.,
    1956; O'Brien, 1960).

           Mevinphos is hydrolysed to dimethylphosphoric acid by human and
    bovine plasma (Casida et al., 1958). It is rapidly absorbed from the
    intestinal tract and the skin (Casida et al., 1958; Gaines, 1960).
    There is no tendency to accumulate in tissues and excretion takes
    place rapidly as dimethylphosphoric acid in urine. Only hydrolysis
    products were found in the milk from treated cows (Casida et al.,
    1958).

           Mevinphos is a direct cholinesterase-inhibitor. The molar I50 
    of the -isomer, in 60 minutes, is 1.2  10-6 and that of the
    alpha-isomer 1.7  10-8 using human whole blood (Casida, 1955).

    Acute toxicity

                                                                                             
    Animal             Route                           LD50 mg/kg    References
                                                       body-weight
                                                                                         

    Mouse              Oral         propylene glycol     4.3-6.8     Kodama et al., 1954

    Rat, male          Oral         propylene glycol     6.0-6.8     Kodama et al., 1954

    Rat, male          Oral         corn oil and         3.7-6.1     Gaines, 1960
                                      peanut oil                     Kettering Lab., 1957b

    Rat, female   Intraperitoneal   propylene glycol       1.5       Kodama et al., 1954

    Rat           Intraperitoneal                     0.35 (alpha-)  Casida, 1955
                                                       35 (beta-)    Casida, 1955
                                                                                         
    
    Short-term studies

           Rat. Groups, each of 6 female rats, were fed for 60 days on
    diets containing 6.3, 12.5, 50 and 100 ppm of mevinphos. All the
    animals in the 100-ppm group died during the third week. Slight
    tremors were observed at all the lower levels. Weight gain was reduced
    on 50 ppm. No significant histopathological changes were found (Kodama
    et al., 1954). Cholinesterase determinations on plasma, erythrocytes
    and brain all showed inhibition of activity proportional to the dose;
    e.g., in the brain, 90% of the normal value was found at 6.3 ppm, 40%
    at 12.5 ppm And 20% at 50 ppm.

           Groups, each of 12 male and 12 female rats, were fed 25, 50, 100
    and 200 ppm in their diets for 13 weeks. There was a slight increase
    in mortality at 200 ppm and growth depression at the 100- and 200-ppm
    levels. Clinical signs of intoxication were minimal at 25 ppm but
    increased progressively with increasing concentration. Degeneration of
    the epithelial cells lining ducts and acini were found in the
    sub-maxillary, sublingual, parotid, Harderian and lacrimal glands, and
    in the thymus and pancreas, most prominently in the male (Cleveland &
    Treon, 1961).

           Using groups of 30 male and 30 female rats, the same group of
    investigators found inhibition of cholinesterase activity at low-level
    feeding. The diets contained 0.32, 0.8, 2.0 and 5.0 ppm of mevinphos
    and one male and one female were killed daily for determination of
    brain cholinesterase activity during the second, fourth, eighth and
    twelfth week of the experiment. On the basis of statistical analysis
    it was concluded that the decrease in erythrocyte cholinesterase
    activity became significant when the diets of males contained 1.1 ppm
    and that of females 1.3 ppm mevinphos. A concentration in the diet

    greater than 5 ppm was required to cause a significant reduction in
    the cholinesterase activity of the plasm or brain of either sex
    (Kettering Lab., 1957a).

           Dog. Groups of 4 dogs were fed 0.3, 1,0, 2.5, 5.0, 75 and 200
    ppm in their diets for 14 weeks. All the animals in the 200-ppm group
    died. The dogs on 75 ppm level showed mild clinical signs of
    intoxication and failed to gain weight. At autopsy, pathological
    lesions of the exocrine glands were seen. The groups on the lower
    levels behaved similarly to the control group as regards weight gain
    and post-mortem examination. Determinations of cholinesterase
    activities showed that 0.3 and 1.0 ppm had no effect on erythrocyte or
    plasma cholinesterase activity. 2.5 ppm lowered erythrocyte
    cholinesterase activity to 80%, 5 ppm to 70% of normal values. On 5
    ppm plasm cholinesterase activity was 90% of normal and brain
    cholinesterase activity was not affected by 0.3-5.0 ppm in the diet
    (Cleveland & Treon, 1961; Kettering Lab., 1957c).

           Five dogs fed 1 ppm mevinphos for 6 weeks together with either 
    1 ppm parathion, 2 ppm demeton, 5 ppm methylparathion, 20 ppm EPN or 
    100 ppm malathion, showed no significant inhibition of cholinesterase
    activity of the plasma or the erythrocytes. Feeding experiments on 32
    female dogs with combinations of the above-mentioned organophosphates
    in the stated concentrations did not show evidence of potentiation
    when mevinphos was fed in combination with any of the compounds for 6
    weeks (Kettering Lab., 1961).

           Cattle. Twelve bull calves 1.5 to 4 weeks of age, divided into
    groups of 3, were fed mevinphos in a milk diet at concentrations
    equivalent to 0.02, 0.2 and 2.0 mg/kg body-weight per day for 3 weeks.
    Cholinesterase determinations on whole blood revealed a progressive
    decrease in enzyme activity. At 0.02 mg/kg body-weight activity
    dropped to 75% of normal, at 0.2 mg/kg body-weight to 40% and at 2
    mg/kg body-weight to below 5%. Only the group on 2 mg/kg body-weight
    showed signs of intoxication. During an additional 4-week period the
    cholinesterase activities returned almost to normal (Casida et al.,
    1958).

           Twelve lactating dairy cows in groups of 3 were given mevinphos
    in capsules at the rate of 0.026, 0.13 and 0.52 mg/kg body-weight per
    day for 12 weeks. The two highest doses depressed the rate of weight
    gain but there was no evident effect on milk production or milk-fat
    content. Signs of intoxication were not observed and no gross
    pathological lesions were found. Erythrocyte cholinesterase activity
    was not significantly lowered by 0.026 mg/kg body-weight per day. 0.13
    mg/kg body-weight per day gradually decreased the activity to about
    30% and 0.52 mg/kg body-weight per day to below 20% of the initial
    value (Casida et al., 1958).

    Long-term studies

           No data available.

    Comments on experimental studies reported and evaluation

           From the present data a no-effect level in the dog would appear
    to be 1 ppm, in the rat 0.8 ppm and in young calves <0.2 ppm. The
    short duration of these studies, in view of the progressive decrease
    in cholinesterase activity after minimal daily oral doses, makes it
    impossible to determine an acceptable daily intake for man.

    Further work required

           Chemical composition and toxicity of the residues. Observations
    on the effect in man. Reproduction studies in the rat.

    REFERENCES

    Casida, J. E. (1955) Science, 122, 597

    Casida, J. E. et al. (1956) J. Agr. Food Chem. 4, 236

    Casida, J. E., Gatterdam, P. E., Knaak, J. B., Lance, R. D. &
    Niedermeier, R. P. (1958) J. Agr. Food Chem., 6, 658

    Cleveland, F. P. & Treon, J. F. (1961) J. Agr. Food Chem., 9, 484

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

    Kettering Laboratory, Cincinnati, Ohio (1957a) Unpublished report,
    15 March

    Kettering Laboratory, Cincinnati, Ohio (1957b) Unpublished report,
    22 March

    Kettering Laboratory, Cincinnati, Ohio (1957c) Unpublished report,
    19 June

    Kettering Laboratory, Cincinnati, Ohio (1961) Unpublished report, 28
    September

    Kodama, J. K. et al. (1954) Arch. industr. Hyg., 9, 45

    O'Brien, R. D. (1960) Toxic Phosphorus Esters, Academic Press, New
    York
    


    See Also:
       Toxicological Abbreviations
       Mevinphos (WHO Pesticide Residues Series 2)
       Mevinphos (Pesticide residues in food: 1996 evaluations Part II Toxicological)
       Mevinphos (Pesticide residues in food: 1997 evaluations Part II Toxicological & Environmental)