Sponsored jointly by FAO and WHO


    Data and recommendations of the joint meeting
    of the FAO Panel of Experts on Pesticide Residues
    in Food and the Environment and the
    WHO Expert Group on Pesticide Residues
    Rome, 23 November - 2 December 1982

    Food and Agriculture Organization of the United Nations
    Rome 1983


    CH3O  O      CH3      O      C2H5
         \"       '       "     /
          P - O - C = C - C - N
         /            '         \
    CH3O              Cl         C2H5


         This pesticide was evaluated toxicologically at the Joint
    Meetings in 1965, 1966, 1968 (FAO/WHO 1965, 1967, 1969)1, and an ADI
    was established at the 1966 Meeting on the basis of no-effect levels
    taken exclusively from data reported by Industrial Bio-Test
    Laboratories (IBT). Additional data have become available and are
    summarized and discussed in this monograph addendum.



    Special Studies on Carcinogenicity


         Groups of 5-week old B6C3F1 mice (10 male and 10 female controls,
    50 males and 50 females/treated group) were fed dietary levels of
    technical phosphamidon at 0, 80 or 160 ppm for 62 weeks (160 ppm-
    group) or 71 weeks (80 ppm-group) in males and 80 weeks in females
    (both treated groups). The male animals were then placed on control
    diet for 28 weeks (160 ppm-group) or 19 weeks (80 ppm-group) and
    female animals, 11 weeks (both treated groups). Pooled controls,
    consisting of 85 male and 85 female control mice from similar
    bioassays of 8 other chemicals and the 10 male and 10 female controls
    concurrent to the present study were used for statistical comparison.
    Moribund animals and terminal survivors at 91 or 92 weeks were
    sacrificed for necropsy and microscopic examination of major tissues
    and all gross lesions. Necropsies were also conducted on all animals
    found dead.

         There was no compound-related effect on mortality. Between 84-92%
    treated males and females, 70% control males and 100% control females
    survived to termination. Generalized tremors, rough hair coats and poor
    physical condition were seen in some males of both treated groups
    after 60 weeks. Dose-related growth depression was apparent in males
    at both 80 and 160 ppm practically throughout the study. Treated


    1  See Annex 2 for WHO and FAO documentation.

    animals exhibited no non-neoplastic lesions that could be associated
    with the compound. Tumour data indicate no significant difference
    between control and treated groups in incidence of any particular type
    of tumour. Under the conditions of the experiment, there was no
    indication of carcinogenicity of phosphamidon in B6C3F1 mice (NCI


         Groups of 5-week old Osborne-Mendel rats (10 male and 10 female
    controls, 50 males and 50 females/treated group) were fed technical
    phosphamidon in their diet at 0, 80 or 160 ppm for 80 weeks and then
    maintained on control diet for additional 30 weeks (males) or 31 weeks
    (females). For statistical comparison, pooled controls were used,
    which consisted of 85 male and 85 female controls from similar
    bioassays of 8 other chemicals and the 10 male and 10 female controls
    from the current study on phosphamidon. Moribund animals and terminal
    survivors at 110 or 111 weeks were sacrificed for necropsy and
    microscopic examination of major tissues and all gross lesions.
    Necropsies were also conducted on all animals found dead.

         Survival was not affected by treatment. Between 50 to 72% males
    and 78 to 90% females of all groups, including the controls, survived
    to the end of the experiment. Growth was depressed in both sexes at
    160 ppm for most of the study. Hyperexcitability and tremors were seen
    in some animals in both treated groups between weeks 6 and 16.
    Histopathologically, except for a seeming increase at 160 ppm in
    incidence of focal cellular changes in the liver and follicular cell
    hyperplasia of the thyroid in males, there were no non-neoplastic
    lesions attributable to the compound. A variety of tumours were
    detected in the treated animals. Such neoplasms, either not dose-
    related or comparable to controls in incidences, were likely to be
    spontaneous in nature. However, tumours of the spleen and thyroid
    seemed to occur more frequently in treated groups than in controls at
    incidences as reported in Table 1.

         It was indicated in the report that statistical analyses showed a
    significant increase in combined incidence of spleen haemangioma and
    haemangiosarcoma at 160 ppm and a significant dose-related trend with
    respect to the combined incidence of splenic tumours in male rats when
    compared to pooled controls. The comparison with concurrent controls
    was not significant. Background incidence in the testing laboratory of
    such splenic tumours in untreated male Osborne-Mendel rats was
    reported as 6/240(3%), with incidences in individual groups as high as
    3/9 (33%) and 2/9 (22%). No tumours of the spleen occurred in
    females of the current study. As for thyroid tumours, there was a
    statistically significant dose-related trend for the combined
    incidence of C-cell adenoma and carcinoma in female rats when compared
    to pooled controls. Incidences of these tumours in the female treated
    groups were also significantly higher than in the pooled controls.

        Table 1.  Tumour Incidence in Rats Treated with Phosphamidon

                                                 Males                                        Females
                                  0              80ppm          160 ppm       0               80ppm          160 ppm


    Haemangioma                                  1/50(2)
    Haemangiosaracoma             1/7(14)1       2/50(4)        5/49(10)
    Haemartoma                                   1/50(2)


    Follicular cell carcinoma                                   1/47(2)       0/10            1/50(2)
    C-cell adenoma                               7/48(15)       5/47(11)      0/10            8/50(16)       7/46(15)
    C-cell carcinoma              1/8(13)                                     0/10            1/50(2)        1/46(2)

    1  The numerator denotes the number of animals with the lesion and the denominator the number of animals with
       the specific tissue examined microscopially. Figure in parentheses indicates incidence in %.
        However, according to the historical records of the testing
    laboratory, incidence of the particular thyroid tumours in untreated
    females of Osborne-Mendel strain was 16/235(7%), with incidences in
    individual control groups as high as 3/9(33%) and 3/10 (30%). In males
    the incidence of thyroid tumours was not statistically significant.
    The conclusion was made that "the data obtained in this bioassay with
    Osborne-Mendel rats are insufficient to allow the interpretation that
    technical-grade phosphamidon is carcinogenic in this species".
    Following a review of the report on the current carcinogenic study of
    phosphamidon, members of the Data Evaluation/Risk Assessment Subgroup
    of the Clearinghouse on Environmental Carcinogens in the United States
    were of the opinion that "the results from the assay should be
    considered to be equivocal and, therefore, no conclusion drawn on the
    carcinogenicity of phosphamidon" (NCI 1979).


         Phosphamidon was last reviewed by the 1968 JMPR. Additional data
    now available included two carcinogenicity studies in rodents, one of
    which (mice) was negative, and the other (rat) was inconclusive. It
    was noted that no data on delayed neurotoxic potential had ever been

         An ADI was established at the 1966 Meeting on the basis of the
    no-effect levels taken exclusively from IBT data, which have been
    found to be invalid. The Meeting was informed that a number of
    essential replacement studies had been commissioned. The Meeting
    decided to change the ADI to a temporary status and requested that the
    studies be submitted at the earliest possible date.


    Level Causing no Toxicological Effect

         Rat : 2 ppm in the diet, equivalent to 0.1 mg/kg bw

         Dog : 0.5 mg/kg bw/day

    Estimate of Temporary Acceptable Daily Intake for Man

         0 - 0.001 mg/kg bw


    Required (by 1985)

    1.   The following replacement or new studies:

         a. 2-year rat study;
         b. 12-month dog study;
         c. 2-generation reproduction study in rats;
         d. Teratology studies in rats and rabbits;
         e. Mutagenic studies.

    2.  An appropriate delayed neurotoxicity study.


         Further toxicity studies on the metabolites of phosphamidon.


    NCI Bioassay of phosphamidon for possible carcinogenicity, National
    1979      Cancer Institute, Carcinogenesis Technical Report Series No.
              16, D.H.E.W. Publication No.(NIH)79-816. Report of a study
              performed at Gulf South Research Institute, Louisiana and
              prepared at Tracor Jitco, Inc., under the direction of NCI.

    See Also:
       Toxicological Abbreviations
       Phosphamidon (ICSC)
       Phosphamidon (PIM 454)
       Phosphamidon (FAO Meeting Report PL/1965/10/1)
       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: 1986 evaluations Part II Toxicology)