Sponsored jointly by FAO and WHO


    The monographs

    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, 24 September - 3 October 1984

    Food and Agriculture Organization of the United Nations
    Rome 1985



         Bendiocarb was evaluated by the Joint Meeting in 1982 at which
    time a temporary ADI was allocated. 1/

         The 1982 JMPR required submission of 1) historical data of total
    lymphoreticular tumours in the CFY strain of rats used in the long-
    term study, and 2) a short-term (28 days) study in dogs to clarify the
    relationship between dietary intake of Bendiocarb and terminal
    erythrocyte and brain cholinesterase activity, using an appropriate
    method for cholinesterase determination. Additional data have been
    submitted and are reviewed in this monograph addendum.

    Corrigenda:  The NOEL for the dog in the 1982 evaluations is
    incorrect. It should be 0.7 mg/kg bw/day.



    Absorption, Distribution and Excretion


         An area on the forearm of each of six male volunteers was exposed
    for 3 h to 14C- Bendiocarb (as an aqueous suspension) at a dosage of
    0.01-0.02 mg/kg bw under occluded conditions in a warm environment and
    non-occluded conditions in a cooler environment. The data indicate
    that Bendiocarb was absorbed (as measured by 14C- urinary excretion)
    more rapidly and to a greater extent (18 percent total urinary
    excretion) under an occlusive dressing than on non-occluded skin
    (6 percent total urinary excretion). The study also showed that
    Bendiocarb was incompletely removed by washing and formed a depot in
    the skin. Some Bendiocarb (generally less than 1 percent of that
    applied) remained on or in the skin 48 h after treatment. The only
    urinary metabolite formed was 2,2-dimethyl-l,3-benzoxodiol-4-ol in
    conjugated forms (Challis, 1982).


    1/  See Annex 2 for FAO and WHO documentation


    Special Study on Carcinogenicity


         Evaluation by trend analysis of historical data on the incidence
    of total lymphoreticular tumours was done in the CFY strain of rats
    used in the long-term study. It demonstrated that the incidences of
    lymphoreticular tumours in treated and untreated groups of each sex
    were not significant, with a calculated chi-square value of 2.45 at
    one degree of freedom. None of the tumour types was observed more than
    twice in one sex at any dose level, indicating the absence of any
    consistent tendency for the recurrence of tumourigenicity in a
    particular organ, and there was no demonstrated decrease in latency.

         There was no evidence that tumours adversely affected survival.
    Moreover, as shown in Tables 1 and 2, the incidence of lymphoreticular
    tumours among untreated control groups in concurrent studies, at the
    same laboratories (Huntingdon Research Centre) and in the same CFY rat
    strain, are comparable to the overall incidences observed among
    treated groups in the present study and, therefore, are not compound-

    Short-term Toxicity


         A series of investigations of the factors influencing assessment
    of effects of Bendiocarb on blood and brain cholinesterase in the dog,
    including controlled alterations of feeding conditions, sampling
    times, sample storage and the analytical method, led to the
    development of an experimental model for monitoring cholinesterase
    effects of Bendiocarb. The principal features of this test system are:

    1.   A 1-h feeding period following overnight fasting recording the
         dose ingested.

    2.   Blood samples within 1.5 h after the end of the feeding period.

    3.   Blood samples rapidly chilled and assayed virtually immediately
         for whole blood cholinesterase.

    4.   Brain samples within 2 h after the end of the feeding period,
         with chilled homogenate prepared and assayed immediately after

    5.   Reference (normal) activity for whole blood obtained from 
         pre-exposure sample and for brain from 24-h recovery sample at
         room temperature.

    6.   Modification of the Ellman analytical technique, adjusting sample
         volume and buffer strength.

        TABLE 1.  Observed Incidence of Lymphoreticular Tumours


    Tumour Type                   Sex                   Dose Level (ppm)
                                                0         2/10      20         200

                       No. Examined/Group       200       100       100        100

    Reticulum cell sarcoma        M             1         1         1          2
                                  F                  0         1          0        0
    Myeloid leukaemia             M             1         0         2          1
                                  F                  1         0          0        0
    Lymphatic leukaemia           M             0         0         1          2
                                  F                  0         0          0        0
    Thymic lymphosarcoma          M             1         2         1          1
                                  F                  0         1          0        0
    Mediastinal lymphosarcoma     M             0         0         0          0
                                  F                  0         1          0        0
    Mast cell leukaemia           M             0         1         0          0
                                  F                  0         0          0        0

    Total L.R. Tumours (%)        M             3         8         10         12
                                  F                  1         6          0        0
                                  M+F           2         7         5          6

    TABLE 2.  Historical Incidence of Lymphoreticular Tumours


    Study              1          2        3         4         5          6        7         8         9

    Males              0/35       2/40     0/48      1/49      0/38       2/38     1/50      1/49      1/49
    %                  0          5        0         2         0          5        2         2         2

    Females            0/50       0/50     1/48      1/50      1/49       1/49     3/50      3/50      1/50
    %                  0          0        2         2         2          2        6         6         2
    These features were developed during successive studies on Bendiocarb.

         The refinement of cholinesterase monitoring is evidenced by the
    consistency of the effects on cholinesterase activity observed in the
    chronic dog study, i.e. recurrent reductions over the 2-year treatment
    period of whole blood cholinesterase activity at least 30 percent
    below pre-exposure levels in individuals administered 500 ppm
    Bendiocarb in the diet. Previous acute and sub-chronic studies
    demonstrated complete recovery from anticholinesterase effects
    following feeding at dietary levels of 500 or 1000 ppm. Brain
    cholinesterase activity was also similarly decreased after 52 and 104
    weeks of treatment at 500 ppm and complete recovery was observed after
    24 h at room temperature. No consistent effects were detected at 100
    or 20 ppm.

         All animals were fasted overnight at each monitoring stage in
    order to minimize the expected and unavoidable wide variation in the
    amount of diet ingested by individuals in the same group.

         A uniform dose-effect correlation can be demonstrated when the
    amount of Bendiocarb actually ingested in the feeding period is
    considered, with statistically significant reductions in
    cholinesterase activity repeatedly associated with doses greater than
    5 mg/kg. This uniformity of response to a given dose of Bendiocarb can
    also be shown to extend to the degree of effect, with more than 70
    percent of all instances of ingestion of at least 5 mg/kg being
    associated with anticholinesterase activity falling within a narrow
    range that equates to 2-5 percent cholinesterase inhibition per mg/kg
    Bendiocarb dose.

         It is further evident that the individual variation in response
    within and between dose groups observed in both the 16-week and
    chronic dog studies was related to the amount of Bendiocarb ingested
    rather than to the dietary level, given uniform conditions of feeding,
    sampling, analysis, etc. The variability in individual food intake
    during short feeding periods is a consequence of normal daily
    fluctuations in appetite and can produce very different degrees of
    cholinesterase inhibition. Thus, both the daily variation in amount of
    food ingested, as well as the pattern of eating, present limitations
    to the uniformity of response achievable experimentally in dogs.
    However, since blood samples were taken 1.5 h after feeding, and
    considering the rapid reversibility of cholinergic effects from methyl
    carbonates, it was considered adequate to evaluate the inhibitory
    effect on cholinesterase enzymes in the dog. Therefore, the original
    concerns of the 1982 Meeting were alleviated.


         Bendiocarb was evaluated in 1982, at which time a temporary ADI
    was allocated with a request for further information on historical
    data on the incidence of total lymphoreticular tumours in rats in the
    long-term study, and for a short-term study in dogs.

         Historical control data and considerations on the statistical
    analysis of incidences of lymphoreticular tumours provided indications
    that the observed differences among control and treated groups are of
    insufficient extent and consistency to indicate any treatment-related
    effect on tumourgenicity. Furthermore, according to the 1982
    Evaluation, the latency period of these tumours was not modified by
    the treatment.

         The required short-term dog study was not provided. However,
    clarifications made available to the meeting alleviated the concerns
    expressed by the 1982 Meeting with respect to the cholinesterase
    activity determination, and a dog study is no longer required.

         The meeting agreed to estimate a full ADI.


    Level Causing no Toxicological Effect

         Rat: 10 ppm in the diet, equal to 0.38 mg/kg bw

         Dog: 20 ppm in the diet, equal to 0.7 mg/kg bw

    Estimate of Acceptable Daily Intake for Man

         0 - 0.004 mg/kg bw



    1.   Further investigations on the cataractogenic activity of
         Bendiocarb at low dosage levels in rats.

    2.   Observations in humans.


    Challis, J.R.  Dermal absorption of Bendiocarb in man. Report
    1982           Method/12/35 submitted by FBC Limited to WHO,

    See Also:
       Toxicological Abbreviations
       Bendiocarb (Pesticide residues in food: 1982 evaluations)
       Bendiocarb (Pesticide residues in food: 1984 evaluations)