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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

    PHOSPHAMIDON

    Chemical name

          2-chloro-2-(diethyl-carbamoyl)-1-methyl-vinyl-dimethylphosphate;
    dimethyl (1-methyl-2-chloro-2-miethylcarbamoyl-vinyl) phosphate;
    dimethyl diethylamido-1-chlorocrotonyl (2) phosphate.

    Empirical formula

          C10H19O5NCIP

    Structural formula

    CHEMICAL STRUCTURE 

    BIOLOGICAL DATA

           In plants the metabolites of phosphamidon are
    2-chloro-2-ethylcarbamoyl-1-methylvinyl-dimethylphosphate,
    alpha-chloroacetoacetic acid diethylamide, and alpha-chloroacetoacetic
    acid monoethylamide. The first compound is of equal toxicity to
    phosphamidon but the latter two compounds are less toxic after acute
    oral administration (Anliker et al., 1961; Jaques & Bein, 1960).

           Oral administration of 14C-labelled phosphamidon (3 mg/kg
    body-weight) to 3 rats resulted within 24 hours in the excretion of
    90%, and in 72 hours of 95%, of the administered radioactivity in the
    urine, faeces and expired air. The excreted radioactive material
    consisted neither of phosphamidon, des-ethylphosphamidon nor the
    chloroacetoacetamides (Ciba).

           Four rats were fed for 5 days on a diet containing 10 ppm of
    14C-labelled phosphamidon and 2 oxen for 5 days on a diet containing
    20 ppm. Neither phosphamidon nor any of its known metabolites could be
    detected in tissue samples (Ciba). Mammary excretion of
    cholinesterase-inhibitory substances was not found after the feeding
    of 2 cows with grass which had been sprayed with phosphamidon (Ciba).
    In vitro the I50 in 60 minutes for rat brain cholinesterase was
    observed at concentrations 7  10-5 g/ml and for horse serum
    cholinesterase at 5.8  10-7 g/ml phosphamidon (Jaques Bein, 1960).

    Acute toxicity

                                                             
    Animal       Route      LD50 mg/kg    References
                            body-weight
                                                             

    Rat          Oral          17-20      Jaques & Bein, 1960
                                          Klotzsche, 1958

             Subcutaneous       26        Jaques & Bein, 1960

    Mouse        Oral           13        Jaques & Bein, 1960

              Intravenous        6        Jaques & Bein, 1960
                                                             


           The LD50 of the metabolite
    2-chloro-2-ethylcarbamoyl-1-methyl-vinyl-dimethyl-phosphate after oral
    administration in the mouse was 15 mg/kg body-weight, and in the rat
    25 mg/kg body-weight (Jaques & Bein, 1960).

    Short-term studies

           Rat. Three groups each of 5 male rats were given a daily oral
    dose of phosphamidon (83%) in an unnamed emulsifier by stomach-tube.
    All animals survived a dosage of 2.5 mg/kg body-weight for 10 weeks.
    At doses of 5.0 and 10 mg/kg body-weight all the rats died after 1-33
    days. Oral administration of 20% phosphamidon in isopropanol killed
    one of 5 rats during the 10-week period at a dosage of 2.5 mg/kg
    body-weight. At dosages of 5.0 and 10 mg/kg body-weight, all rats died
    within 41 days. Haematological examination showed a reduction of
    lymphocytes and eosinophils, while the number of neutrophils was
    increased (Klotzsche, 1958).

           Four groups of 5 rats each were given 0.3 and 3.0 mg/kg
    body-weight phosphamidon daily by stomach-tube in propylene glycol.
    Rats in the groups receiving 0.3 mg/kg body-weight were killed after
    1, 7, 14 and 21 days for determination of cholinesterase activity in
    serum and brain. No significant inhibition of the serum and brain
    cholinesterase activity was observed. A daily dose of 3 mg/kg
    body-weight did result in 14% reduction of serum cholinesterase
    activity and 12.5% of brain cholinesterase activity after one dose,
    while treatment for 7 days lowered the serum cholinesterase activity
    to 42.5% and the brain cholinesterase activity to 55%. After 14 days'
    treatment, the inhibition was 37% in serum and 67.5% in the brain. One
    group of 5 rats treated for 14 days was left undosed for an additional
    7 days. In this group serum cholinesterase activity was only slightly
    inhibited while the brain cholinesterase activity was still 47.5%
    lower than control values (Jaques & Bein, 1960). Subcutaneous daily
    injections at a dose of 4 mg/kg body-weight were tolerated by 5 rats

    for 21 days. Subcutaneous injections of 10 mg/kg body-weight killed
    all rats within 4 days (Jaques & Bein, 1960).

           The metabolite 2-chloro-2-ethylcarbamoyl-1-methyl-vinyl-
    dimethylphosphate given orally daily to groups of 6 rats in a dose of
    3 mg/kg body-weight killed one rat on the eighth day; a dose of 7.5
    mg/kg body-weight killed all rats within 9 days (Jaques & Bein, 1960).

           Rabbit. In a 21-day experiment 2 of 3 rabbits survived a daily
    oral dose of 3.5 mg/kg body-weight; 7 mg/kg killed 2 of 3 animals
    within 8 days, and 15 mg/kg body-weight all 5 within 7 days.
    Intravenous injections daily for 14 days were survived by 3 rabbits at
    a dose of 3 mg/kg body-weight, while 2 out of 3 died at a dose of 7.5
    mg/kg body-weight (Jaques & Bein, 1960).

    Long-term studies

           No data available.

    Comments on the experimental studies reported

           The studies reported have been carried out exclusively on
    rodents, are of very short duration and comprise small numbers of
    animals.

    EVALUATION

           The toxicological data are considered to be insufficient to
    enable an acceptable daily intake for man to be evaluated.

    Further work required

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

    REFERENCES

    Anliker, R., Beriger, E., Geiger, M., & Schmid, K. (1961) Helv.
    chim. Acta, 44, 162

    CIBA Ltd., Basel. Investigation on the excretion of phosphamidon by
    rats and cattle given single doses or diets containing
    14C-labelled phosphamidon. Unpublished report

    Jaques, R. & Bein, H. J. (1960) Arch. Toxicol., 18, 316

    Klotzsche, C. (1958) Nachr. Deutsch. Pflanzenschutzd., 10, 60
    


    See Also:
       Toxicological Abbreviations
       Phosphamidon (ICSC)
       Phosphamidon (PIM 454)
       Phosphamidon (FAO/PL:CP/15)
       Phosphamidon (FAO/PL:1968/M/9/1)
       Phosphamidon (FAO/PL:1969/M/17/1)
       Phosphamidon (WHO Pesticide Residues Series 2)
       Phosphamidon (WHO Pesticide Residues Series 4)
       Phosphamidon (Pesticide residues in food: 1982 evaluations)
       Phosphamidon (Pesticide residues in food: 1986 evaluations Part II Toxicology)