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    PESTICIDE RESIDUES IN FOOD - 1982


    Sponsored jointly by FAO and WHO






    EVALUATIONS 1982





    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

    VAMIDOTHION

    CHEMICAL STRUCTURE 1

    Explanation

         Vamidothion was evaluated for an ADI by the 1973 Joint FAO/WHO
    Meeting (FAO/WHO 1974).1 The data were not adequate for the
    estimation of an acceptable daily intake for man.

         Since the previous evaluation was done, a metabolic study and two
    long-term studies have been provided and are summarized in this
    monograph addendum.

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    BIOCHEMICAL ASPECTS

    Biotransformation

         Data on the metabolic fate of vamidothion have been reviewed by
    Metivier (1974). The proposed metabolic pathway in plants is shown in
    Figure 1. Vamidothion sulphoxide (I) is the main metabolite, whereas
    vamidothion sulphone is formed in very small amounts. Desmethyl
    vamidothion (VIII) has been observed in plants but not in animals. The
    acid (VII) is a hypothetical metabolite observed neither in plants nor
    in animals. Acidic fragments (III, IV, V and VI) are formed in both
    animals and plants.

         Vamidothion sulphoxide appears to be the main metabolite of
    toxicological importance.

              

    1  See Annex 2 for WHO and FAO documentation.

    FIGURE 1

    TOXICOLOGICAL STUDIES

    Special Study for Carcinogenicity

    (See under Long-Term Studies)

    Acute Toxicity

         A summary of results of acute oral toxicity studies on
    Vamidothion and its metabolites is shown in Table 1 (Metivier 1974).

    Table 1.  The Acute Toxicity of Vamidothion and Its Metabolites
                                                                        

                             LD50
    Compounds                (mg/kg)      Species        Sex         Route
                                                                        

    Vamidothion              35           mouse                      oral
    Vamidothion              105          rat            M           oral
    Vamidothion              85           guinea pig                 oral

    Vamidothion sulphoxide   80           mouse                      oral
    Vamidothion sulphoxide   160          rat            M           oral
    Vamidothion sulphoxide   205          guinea pig                 oral

    Vamidothion sulphone     75           mouse          M + F       oral
    Vamidothion sulphone     140          rat            F           oral

    Vamidothion desmethyl    > 10 000     mouse                      oral

    Ac.(VI)NH+4 salt         ca.5 600     mouse                     
    oral

    AC.(III)K+ salt          > 3 000      rat                       
    oral

    Acid (IV                 >2 000       rat            oral
    disodium salt

    Acid (V)                 ca.5 300     mouse          oral
    monoCa++ salt
                                                                        

    Long-Term Studies

    Mouse

         Groups of mice (60 male and 60 female ICR mice/group) were
    administered vamidothion (purity not stated) in the diet for 24 months
    at dosage levels of 0, 0.1, 1, 10 or 100 ppm. Observations were made
    with respect to abnormal symptoms and mortality. At and after 54 weeks
    (12 months), special attention was paid to the occurrence of tumours.
    The animals dying during the experiment were subjected to autopsy for
    investigation on the cause of death. The animals were weighed once a
    week between weeks 1 and 55, and every 2 weeks thereafter. Feed and
    water consumption were determined once a week. Feeding efficiency was
    calculated by dividing the weight increase in males and females of
    each group in weeks 26, 53 and 105 by their feed consumption at the
    respective times. Drug intake was calculated from the average daily
    feed consumption. Haematologic, clinical chemistry and urinalysis
    examinations were carried out on 6 animals of each sex in each
    group in weeks 26 and 53, and on 10 animals of each sex in each
    group in week 110. Major organs were weighed and anatomical and
    histopathological examinations were performed on major tissues and
    organs. Those mice surviving after 110 weeks were sacrificed in week
    112 for pathological examinations.

         There was no remarkable difference in mortality between the
    control and treated groups. Growth, food and water consumption and
    feeding efficiency were similar in the control and any treated group,
    as were urinalysis parameters observed over the course of the study.

         No significant differences between control and treated groups
    were seen in respect to haematological examinations except for i) a
    decrease in the leucocyte count in males and females of the 100 ppm
    group in week 23; ii) a decrease in the leucocyte count in males of
    the 100 ppm group and in females of the 10 ppm and 100 ppm groups in
    week 53. However, haematological examinations in week 100 did not
    reveal any significant changes in male and female of the treated
    groups as compared with those in the control.

         Clinical chemistry values, with the exception of cholinesterase
    activity, were normal, Serum and erythrocyte cholinesterase were
    depressed at dietary levels of 10 ppm, whereas brain cholinesterase
    was depressed only at 100 ppm levels in weeks 26 and 53, but not in
    week 100. The no-effect level with respect to serum and erythrocyte
    cholinesterase was 1 ppm.

         Although slight changes in weights of some organs were recorded
    in weeks 26 and 53, they were neither consistent between males and
    females nor dose related. Thus, it seems unlikely that they were
    related to the toxic effect of administered vamidothion. However,
    measurements of organ weights in week 110 revealed no remarkable
    changes in either absolute organ weights or their ratios to body
    weight.

         Anatomical and histopathological examinations of tissues and
    organs did not reveal any adverse effect attributable to the
    administration of vamidothion.

         Data on the examination of animals for tumours did not suggest
    carcinogenic potential (Toyoshima  et al 1975).

    Rat

         Groups of rats (48 male and 48 female Wistar-strain rats/group)
    were administered vamidothion (purity not stated) in the diet for 24
    months at dosage levels of 0, 0.1, 1, 10 and 100 ppm. Observations
    were made with respect to abnormal symptoms and mortality. In and
    after week 54, special attention was paid to the occurrence of
    tumours. The animals dying during the experiment were subjected to
    anatomical and histopathological investigations to determine the cause
    of death. Body weight of both males and females was measured once a
    week until week 53 and every 2 weeks thereafter. Feed and water
    consumption was measured once a week. Feeding efficiency was
    calculated by dividing the weight increase in males and females of
    each group in weeks 26, 53 and 105 by their feed consumption at the
    respective times. Drug intake was calculated from the daily average
    feed consumption. Haematological, clinical chemistry and urinalysis
    examinations were carried out in weeks 26 and 53 (6 animals/sex/group)
    and in week 110 (10 animals/sex/group). Major organs were weighed and
    anatomical and histopathological examinations on major tissues and
    organs were carried out.

         Those rats surviving after 110 weeks were sacrificed in week 112
    for anatomopathological examinations.

         No significant differences between control and test groups were
    observed with respect to toxicological symptoms, mortality, feed
    consumption, water consumption, feeding efficiency, body weight gain
    and haematological and urinalysis parameters. The only difference in
    clinical chemistry values between control and treated groups were
    i) lower GOT activity in females of the 100 ppm group in week 26;
    ii) lower cholesterol level and lower total protein in males of the
    10 ppm group in week 53; iii) depression of serum and erythrocyte
    cholinesterase activities, starting with 10 ppm group; iv) depression
    of brain cholinesterase activity only in males of the 10 ppm and
    100 ppm in week 53. The no-effect level for serum and erythrocyte
    cholinesterase was 1 ppm.

         Anatomical and histopathological examinations of tissues and
    organs did not reveal any adverse effect attributable to the
    administration of vamidothion. Data on the examination of animals
    for tumours did not suggest a carcinogenic potential (Toyoshima
     et al 1975).

    COMMENTS

         Vamidothion was considered by the 1973 JMPR. An ADI was not
    determined. A metabolic study and two long-term studies (mouse, rat)
    were examined by the 1982 JMPR. The metabolic sequence is similar to
    that observed in other organophosphorus compounds and includes both
    oxidative and hydrolytic degradation.

         Two long-term studies failed to reveal adverse effects other than
    moderate plasma and erythrocyte (but not brain) cholinesterase
    inhibition, and demonstrated no oncogenicity,

         However, the Meeting agreed that only a temporary ADI could be
    allocated because of the absence or inadequacy of the multigeneration
    reproduction study, a teratogenicity study, a delayed neurotoxicity
    study and a non-rodent study.

    TOXICOLOGICAL EVALUATION

    Level Causing no Toxicological Effect

         Mouse : 1 ppm in the diet, equivalent to 0.137 mg/kg bw.
         Rat   : 1 ppm in the diet, equivalent to 0.054 mg/kg bw.
         Dog   : 5 ppm in the diet, equivalent to 0.125 mg/kg bw.

    Estimate of a Temporary Acceptable Daily Intake for Man

         0 - 0.0003 mg/kg bw.

    FURTHER WORK OR INFORMATION

    Required (by 1985)

    1.   Teratogenicity studies.

    2.   Multigeneration reproduction studies.

    3.   Delayed neurotoxicity studies.

    4.   A non-rodent (dog) study of adequate duration.

    Desirable

    1.   Mutagenicity tests.

    2.   Observations in humans.

    REFERENCES

    Metivier, J. Vamidothion. Etude du métabolisme. (S.U.C.R:P-D,S.Ph.No.
    1974      17-929). Report from Laboratoires Recherches de la Société
              des Usines Chimiques Rhône-Poulenc submitted to the World
              Health Organization by Rhône-Poulenc, Paris, France.
              (Unpublished)

    Toyoshima, S., Sato, H., Sato, R., Sato, S., Kashima, M. and Motoyama,
    1975a     M. 24-month chronic oral toxicity study with vamidothion in
              mice. Report from Keio University Tokyo, Japan, Sasaki
              Institute, Tokyo, Japan, and Nippon Experimental Medical
              Research Institute, Saitama Pref., Japan, submitted to the
              World Health Organization by Rhône-Poulenc, Paris, France.
              (Unpublished)

    1975b     24-month chronic oral toxicity study with vamidothion in
              rats. Report from Keio University, Tokyo, Japan, Sasaki
              Institute, Tokyo, Japan, and Nippon Experimental Medical
              Research Institute, Saitama Pref., Japan, submitted to the
              World Health Organization by Rhône-Poulenc, Paris, France.
              (Unpublished)


    See Also:
       Toxicological Abbreviations
       Vamidothion (ICSC)
       Vamidothion (WHO Pesticide Residues Series 3)
       Vamidothion (Pesticide residues in food: 1985 evaluations Part II Toxicology)
       Vamidothion (Pesticide residues in food: 1988 evaluations Part II Toxicology)