FORMOTHION        JMPR 1973


         Formothion was evaluated by the 1969 Joint Meeting (FAO/WHO,
    1970). Toxicology studies were insufficient for establishing an
    acceptable daily intake. Two-year studies in rats and dogs have been
    completed and this information has been summarized in the present

         By the 1969 Joint Meeting temporary tolerances were recommended
    for strawberries and blackcurrants but residue data on all other crops
    were judged to be insufficient. A number of requirements were laid
    down for further work or information on formothion.

         The 1972 Joint Meeting (FAO/WHO, 1973) clarified a question
    raised at the Sixth Session of the CCPR regarding the identity of the
    compounds covered by the tolerances on strawberries and blackcurrants.
    it was determined that, since the residues at harvest after use of
    formothion were primarily dimethioate and omethoate, the temporary
    tolerances recommended apply to these compounds, expressed as
    dimethioate. It was also noted that tolerances for residues of
    dimethioate in other fruits and vegetables would also apply to
    residues resulting from use of formothion.

         Information on certain of the requirements were received from the
    manufacturer. Czechoslovakia, Australia and New Zealand also responded
    with some information on current agricultural uses and national
    tolerances in those countries.


    Toxicological studies

    Acute toxicity


    Species       Route         LD50          Reference

    Rat           Oral          218           Vorob'yeva and
                                              Lapchenko, 1973

    Mice          Oral          83                  "

    Cat           Oral          310                 "


    Short-term studies

    Rat. Vorob'yeva and Lapehenko (1973) concluded that a daily dose
    level of 0.83 mg/kg was a threshold level based on cholinesterase
    depression. Daily doses above this level disturbed carbohydrate
    metabolism, protein synthesis in the liver and caused changes in the
    liver and heart such as fatty degeneration and dystrophy.

    Dog. Groups of dogs (four male and four female beagle dogs per
    group) were fed formothion in the diet at levels of 0, 40, 160 and 640
    ppm for two years. The animals were between six and eight months of
    age at the beginning of the study. The dogs were fed a standard dry
    diet. Haematological examinations, clinical chemistry analyses and
    urinalysis were perfumed periodically during the course of the study.
    Ophthalmological and behavioural examinations were performed at
    various times. At the conclusion of the study, gross and microscopic
    examination of tissues and organs was performed. All dogs appeared
    normal throughout the study with no changes in weight although there
    was a slight reduction in food intake which appeared to be dependent
    upon the dietary concentration of formothion. There were no apparent
    effects in haematology, urinalysis or clinical chemistry with the
    exception of cholinesterase depression. As was observed with rats, RBC
    cholinesterase was the more sensitive parameter indicative of exposure
    with the level of 160 ppm in the diet and above showing definitive
    inhibition. Brain cholinesterase was unaffected at all dose levels
    while liver cholinesterase was inhibited at 640 ppm in the diet. Gross
    and histological examination of tissues in organs showed no evidence
    of pathological change due to the incorporation of formothion in the
    diet. (Klotzsche and Carpy, 1973)

    Long-term studies

    Rat. Groups of rats (35 male and 35 female Wistar rats per group)
    were fed formothion in the diet at dosage levels of 0, 20, 80 and 320
    ppm for two years. The study started with dose levels of 0, 10, 40 and
    160 plat and after four weeks the doses were increased to 0, 20, 80
    and 320 ppm. The animals were observed daily for mortality and
    behavioural changes body weight and food consumption. Haematological
    examination, chemical chemistry, including cholinesterase activity and
    urinalysis were performed periodically. At the end of the two-year
    period the surviving animals were sacrificed and gross pathology
    performed on tissues and organs. Similar proportion of animals
    survived until the end of the test in all groups. Abnormal behaviour,
    slight tremors or muscle twitches, were observed in single rats at the
    high dose between the third and the twelfth month of the study. Normal
    behaviour was observed during the rest of the study. In the male
    animals there was an impairment of growth which was significant during
    the middle part of the study. This growth reduction appeared to have
    disappeared somewhat during the last months of the study although
    there was a gradual trend towards a reduction in growth as the dietary
    dosage increases. This trend was not noted in females. There was no
    significant difference in food intake in all groups of animals with a

    slightly higher intake of food in the females at the high dose level.
    It has been suggested that the normal weight gain in the high dosed
    females was a result of the elevated food consumption at this level.
    Increased clinical chemistry values were sporadic throughout the study
    with increases primarily at the end of the study in BUN, SGPT and SAP.
    These increases were not dose dependent. There was no apparent effect
    of formothion on urinalysis. At the conclusion of the study the
    average weight of the spleen in males was significantly decreased at
    all dosage levels. This decrease was not noted in the females. There
    were no histological abnormalities noted in the spleen which coincide
    with the increased weight. There were no other abnormalities noted on
    growth or histological examination of tissues in organs.

         As with other organophosphate esters, cholinesterase was the most
    sensitive indicator of exposure with the red blood cell cholinesterase
    being somewhat more sensitive than the plasma. In both males and
    females there was a slight depression of red blood cell cholinesterase
    at 80 ppm in the diet and a more significant depression at 320 ppm in
    the diet. Plasma cholinesterase depression was observed only at 320
    ppm in the diet. On the basis of cholinesterase depression a marginal
    effect was noted at 80 ppm in the diet with more definitive effects
    being noted at 320 ppm in the diet especially regarding gross and
    spleen weight in males. At 320 ppm in the diet brain cholinesterase
    was significantly depressed with no apparent effect noted at the lower

         On the basis of histological examination there was no evidence
    that formothion given in the diet at levels of up to 640 ppm increased
    the spontaneous tumour incidence in either dogs or rats (Klotzsche and
    Carpy, 1973).


         Two-year studies in rats and dogs, metabolism studies and
    short-term studies in rats were available for consideration by the
    present Meeting. Metabolism in plants has been shown to result in the
    formation of dimethoate and formothion acid O.O dimethyl phosphoryl
    acetic acid. Based on cholinesterase inhibition, no-effect levels of
    20 and 40 ppm on the rat and dog respectively were observed in
    two-year studies. No evidence of carcinogenic potential was observed
    in the rat studies. An ADI for dimethoate was established (FAO/WHO,
    1965) based on human studies, where 0.2 mg/kg bw/day was a noneffect
    level. An ADI for formothion was established based on the studies in
    the rat and the dog and on the experience of human exposure to


    Level causing no toxicological effects

         Rat: 20 ppm in the diet equivalent to 1 mg/kg bw

         Dog: 40 ppm in the diet equivalent to 1 mg/kg bw

    Estimate of acceptable daily intake for man

         0-0.02 mg/kg bw


    Comments on new information

    1.  As far as is known there is only one manufacturer. The technical
    grade contains 95-96% formothion, the remainder being related

    2.  No information was made available on animal metabolism or residues
    in meat and milk; disappearance during storage, processing and
    cooking; or data on residues in commodities moving in inter-state
    commerce or in the total diet. In view of the fact that formothion is
    completely transformed into dimethioate in plants and animals these
    requirements were considered to be no longer necessary.

    3.  GLC method for regulatory purposes

         The 1969 Joint Meeting noted the desirability of a GLC method
    suitable for regulatory purposes. The basic manufacturer (Sandoz) has
    provided an unpublished GLC method (identified CvH 6/70e) with
    thermionic detection which simultaneously determines formothion,
    dimethoate, and omethoate. The method is said to be applicable to the
    determination of formothion residues in plant, material and soil. It
    involves acetonitrile extraction and a florisil/charcoal column
    clean-up. An optional petroleum ether/water and chloroform/water
    partitioning step is included for samples with difficult clean-up
    problems. Detector response varies about three-fold overall between
    the three residue components. Formothion > dimethoate > omethoate,
    with a limit of determination estimated to be about 0.03-0.1ppm for an
    injection equivalent to about 10 mg sample. Recoveries for each
    component at 0.1 and 1.0 ppm fortification levels were satisfactory
    but it was not indicated what the fortified substrate was. The
    multi-residue method of Storherr et. al. (1971) for organophosphorus
    pesticides has been shown, in the meantime, to be applicable for use
    as a regulatory method for dimethoate and omethoate.

    Use patterns

    TABLE 1
                                     Treatment       PHI        National
    Country            Crop          rate (ai)       (days)     tolerance

    Czechoslovakia     Fruits        0.05%           28         0.1a

                       Cherries      0.05%           18         0.5a

    TABLE 1 (Cont'd.)
                                     Treatment       PHI        National
    Country            Crop          rate (ai)       (days)     tolerance

                       Oats          250g/ha         21         -

    New Zealand        Lettuce                    )
                       Brassicas                  )
                       Potatoes                   )
                                     6.4 oz/acre  )  14         1
                       Carrots                    )
                       Celery                     )

    Australia          Citrus                                   -
                       tree fruits

                       Grapes                        14         -
    a Proposed national tolerances as dimethioate.

    Residue data on crops from supervised trials

         Additional data from trials on citrus, small grains and their
    straws, lettuce and radish are available. No formothion was found at
    any time under the conditions of the test on samples other than
    citrus. Dimethoate and omethoate were found on the leafy vegetable and
    root parts for two to three weeks. No residues were detected in grain
    at any time. A summary of the data on grains, lettuce and radishes are
    shown in Table 2.

         The data on citrus from supervised trials in Israel show that
    residues of formothion per se are present for as long as 62 days and
    that these might approximate 0.2 ppm at harvest under good
    agricultural practices (fifteen-day pre-harvest interval). Residues of
    dimethoate and omethoate (total) at the same interval after treatment
    averaged 0.62 ppm (max. 1.25 ppm), well within the tolerance
    recommended for dimethoate residues in citrus at the 1967 Meeting (2
    ppm). On the basis of these data a tolerance of 0.2 ppm formothion
    would be appropriate.

    Fate of residues

    In plants

         A new 14C metabolism study for formothion on bean plants has
    become available (Sauer, 1972). In general, it confirms previous

    information on the fate of formothion residues, i.e. rapid
    transformation to dimethoate, omethoate and O,O-dimethyl
    dithiohosphoryl acetic acid. Further metabolic products are
    O,O-dimethyl dithiophosphoric acid; and bis
    (O,O-dimethyl-thiophosphoryl) disulfide.

         The formothion was labelled in two positions, as was dimethoate,
    which was studied for comparison purposes. The study reinforces
    conclusions of the 1972 Joint Meeting that the residues arising from
    the use of either formothion or dimethoate, are in fact, identical.

    In soil and water

         An unpublished report (Sandoz, 1969) on degradation in soil and a
    similar report on fate in water (Sandoz, 1972) were also made
    available. Degradation in both soil and water was rapid. The rate of
    degradation in water increased with pH.

        TABLE 2
                                         Maximum residues at end of interval
    Crop          Dosage   interval      Formothion   Dimethoate   Dimethoxon
                  % ai     (days)                     (ppm)

    Grain       0.5      59            nda          nd           nd

      straw       0.5      73            nd           nd           nd

      lettuce     0.05     7             nd           3.3          0.70
                           14            nd           0.12         0.12
                           21            nd           0.01         0.03

    Radish        0.07     0             nd           5.9          0.06
    (roots)                1             nd           5.1          0.06
                           3             nd           0.17         0.02
                           7             nd           0.03         0.01
                           14            nd           0.01         0.01
      Grain       0.05     56            nd           nd           nd

      straw       0.05     56            nd           nd           nd

      plant       0.05     0             nd           1.2          nd
                           7             nd           0.04         0.03
                           14            nd           nd           nd
                           28            nd           nd           nd

    a nd = non-detected

         Temporary tolerances were recommended by the 1969 Joint Meeting
    for strawberries and blackcurrants with the stipulation that certain
    additional information on residue chemistry be required and that
    certain other information would be desirable. The basic manufacturer
    has responded directly to two of the requirements as indicated below.
    Response to the other requirements was limited to statements that
    information available on dimethoate residues fulfils the requirements
    for formothion.

         The Sixth Session of the Codex Committee on Pesticide Residues
    requested clarification as to whether the 1969 tolerances applied to
    formothion or to the primary metabolite dimethoate. The 1972 JMPR
    clarified the recommended formothion tolerance as applying to residues
    of dimethoate and omethoate resulting from the use of formothion. It
    was also noted by the 1972 Meeting that the previously recommended
    tolerances for dimethoate on citrus, tree fruits, tomatoes, peppers,
    and vegetables would apply to residues resulting from use of

         The working party was informed that Sandez Ltd is at present the
    only manufacturer. That company has furnished statements of
    composition for two BC formulations which permits a calculation that
    the technical product contains 95-96% formothion.

         A thermionic - GLC method capable of measuring simultaneously
    formothion, dimethoate, and omethoate was submitted by Sandoz. It is
    as yet unpublished. Dimethoate and omethoate are also detected by a
    multi-residue method for organophosphate pesticides, suitable for
    regulatory purposes.

         The requested information on animal metabolism and residues in
    meat or milk; disappearance in storage, processing, and cooking; and
    occurrence in commodities in commerce and total diet studies were not
    directly provided but in view of the recommendation of the 1969
    Meeting that the residues following the use of formothion are
    dimethoate and omethoate (except for citrus), it would appear
    unnecessary to pursue these requirements further.

         Information has been made available to FAO on new national
    tolerances and approved uses on certain fruits, vegetables, and grains
    In Australia, New Zealand and Czechoslovakia. There are no adequate
    data from supervised trials corresponding to these uses. In any event
    the interpretation that dimethoate tolerances apply to residues
    arising from the use of formothion would obviate the need to extend
    the present tolerances to specific crops which are covered by
    tolerances for dimethoate and omethoate.

         Citrus presents an exception to the pattern of terminal residues
    resulting from the use of formothion. Formothion residues per se
    exist for considerable periods after treatment of citrus. Data
    indicate that a tolerance of 0.2 ppm for the parent compound would be
    necessary under good agricultural practices including a pre-harvest
    interval of 15 days.


         The following tolerance is recommended for formothion per se
         Tolerance      ppm            Interval on which
                                       are based (days)
         Citrus         0.2            15

         The residue should be measured and expressed as formothion.
    Residues of dimethoate and omethoate occurring simultaneously should
    be determined separately and expressed as dimethoate.

         The previously recommended tolerances for residues of dimethoate
    and omethoate from use of formothion on strawberries and blackcurrants
    are also recognized under the heading dimetboate along with
    recommended tolerances for dimethoate and omethoate residues on
    citrus, tree fruits, tomatoes, peppers, and vegetables resulting from
    the use of either dimethoate or formothion.



    1.  A survey of current uses of both formothion and dimethoate on
    crops on which either pesticide may be used with a view to making
    recommendations for common tolerances.

    2.  Additional studies to show whether the residues of formothion per
    se will occur on crops, particularly olives.


    FAO/WHO. (1965b) Evaluation of the toxicity of pesticide residues in
    food. FAO Meeting Report, No. PL/1965/10/1; WHO/Food Add./27.65

    FAO/WHO. (1970) 1969 Evaluations of some pesticide residues in food.
    FAO/PL: 1969/M/17/1, WHO/FOOD ADD./70.38

    FAO/WHO. (1973) 1972 Evaluation of some pesticide residues in food
    AGP: 1972/M/9/1, WHO Pesticide Residues Series, No. 2

    Klotzsche, C. and Carpy, S. (1973) Formothion, two-year feeding study
    in rats and dogs. Unpublished report from Sandoz Chemical Company

    Sandoz. (1969) Formothion degradation in soil. Report CvH 9/69, 
    unpublished report of Sandoz Agrochemical Research, Basle, Switzerland

    Sandoz. (1972) The behaviour of formothion in water at different pH
    values. Unpublished report of Sandoz Agrochemical Research, Basle,

    Sauer, H.H. (1972) Fate of formothion on bean plants in the
    greenhouse. J. Agr. Food Chem.,.20, No. 3, 578-583

    Storherr, R.W., Ott, P. and Watts, R.R. (1971) A general method for
    organophosphorus pesticide in non-fatty foods. J.A.O.A.C., 54:

    Vorob'yeva, N.M. and Lapehenko, V.S. (1973) Toksikologicheskaya 
    Kharakteristika Novogo Pesticida Antio. Farmakol. Toksikol. 6: 104-7


    See Also:
       Toxicological Abbreviations
       Formothion (FAO/PL:1969/M/17/1)
       Formothion (WHO Pesticide Residues Series 2)