WHO/FOOD ADD./70.38



    Issued jointly by FAO and WHO

    The content of this document is the result of the deliberations of the
    Joint Meeting of the FAO Working Party of Experts and the WHO Expert
    Group on Pesticide Residues, which met in Rome, 8 - 15 December 1969.



    Rome, 1970



    Chemical name

    S-(N-formyl-N-methylcarbamoylmethyl) dimethyl phosphorothiolothionate


    S-(N-formyl-N-methylcarbamoylmethyl) O,O-dimethyl phosphorodithioate,

    Structural formula


    Other relevant chemical properties

    Yellow oil with onion-like odour or white crystalline solid; d420
    1.361; soluble in alcohols, ether, chloroform, ketones, aromatic
    solvents; insoluble in paraffin solvents and water; stable in apolar
    solvents, unstable at alkaline pH. Formothion is available as a 25
    percent and 40 percent emulsifiable concentrate (ingredients other
    than formothion undefined).


    Absorption, distribution and excretion

    Single oral doses of 10 mg/kg body-weight of formothion, labelled with
    carbon14 in the carbamoyl group, were administered by stomach tube to
    male rats. Autoradiographs indicated that the compound was readily
    absorbed from the stomach. Within 30 minutes after giving the dose, a
    high level of radioactivity was found in the liver and kidney,
    although the major activity was still in the stomach. Six hours after
    administration the activity in the stomach area was low; the main
    activity then being in the kidneys, with less activity in the liver,
    intestines, pancreas and thymus. After 24 hours from the time of
    administration of the dose, distinct radioactivity was found only in
    the thymus. The urine was the major source of excretion; it contained
    98-99 percent of the radioactivity compared to the faeces which had
    only 1-2 percent. A total of 51 per cent of the administered

    radioactivity had been excreted in the urine after four hours and 96
    percent after 24 hours. The presence of considerable radioactivity in
    the bile indicated that there was also excretion of the compound and
    its metabolites in the bile. However, because so little radioactivity
    was encountered in the faeces nearly all of these compounds must be
    re-absorbed in the intestine (Klotsche, 1969a).


    Formothion appears to be completely metabolized in male rats. The only
    metabolite found, which is said to be of known structure is termed
    "formothion acid", and this compound is eliminated in the urine more
    rapidly than other polar metabolites of unknown structure.
    ("Formothion acid" to presumably O,O-dimethyl-S-carboxymethyl
    phosphorodithioate or a phosphate analogue of that compound). All
    these metabolites including "formothion acid" contain nearly all the
    administered radioactivity, which indicates that they still contain
    the carboxyl-carbon of the labelled formothion (Klotsche 1969a).

    Although it had been stated that formothion "is converted to
    dimethoate in the animal" (rat) (Carshalton, 1965), no dimethoate has
    been demonstrated in the metabolic studies performed with formothion
    in rats (Klotsche 1969a). However dimethoate has been identified in
    plants treated with formothion (Klotsche 1969b).

    Effect on enzymes and other biochemical parameters

    Experiment in vitro with rat serum cholinesterase have
    demonstrated that formothion has anti-cholinesterase activity
    (Klotsche 1961). For human serum anti-cholinesterase the I50 was
    found to be 1.91 × 10-5 (Zehnder, 1961).

    Special studies on neurotoxicity


    Two groups, each containing three hens were given 100 mg/kg
    body-weight of formothion by intramuscular injection; two more groups
    were given 150 mg/kg. In one of each of the groups the hens were
    protected against the lethal effects of formothion with pralidoxime
    and atropine. All the unprotected and one of the protected hens in the
    150 mg/kg group died from acute poisoning while the other hens
    survived and did not show any clinical symptoms of neurotoxicity
    during an observation period of 22 and 29 days after administration of
    the 100 and 150 mg/kg doses, respectively. A positive control group
    given an unspecified dose of triorthocresyl phosphate (TOCP) displayed
    distinct signs of paralysis (Sandoz, 1964a; Klotsche 1966).

    Special studies on potentiation


    Single oral doses of formothion were administered jointly to rats with
    the following organophosphorus compounds: diazinon, dimethoate,
    malathion, parathion, phosphamidon and thiometon. There were no
    effects other than additive except for the formothion - dimethoate
    combination where there was some indication of a potentiating effect
    (Klotsche 1969a),

    Special studies on teratogenicity


    Groups of 10 rabbits were given daily doses by stomach tube of 6 and
    30 mg/kg bodyweight of formothion, from the sixth to the eighteenth
    day of pregnancy. Several groups served as controls. Pregnancy rate,
    number of implantations, live and dead foetuses, embryonic and foetal
    deaths and resorptions were comparable in the test and control groups.
    The same was true of the foetal and placental weights and the number
    of malformations of organs and the skeletal systems in the foetuses
    (Klotsche 1969a).

    Acute toxicity

                             LD50 mg/kg
    Animal         Route     body-weight    References

    Mouse (M)      oral        190          Klotsche 1966

    Mouse (F)      oral        195          Klotsche 1966

    Rat (M)        oral        370-400      Klotsche 1966

    Rat (F)        oral        500-540      Klotsche 1966

    Rat (F)        oral        424          Carshalton, 1965

    Rat (M)        i.v.        36           Klotsche 1966

    Guinea-pig     oral        560          Sandoz, 1968

    Rabbit (M)     oral        570          Klotsche 1969a

    Rabbit (M)     i.v.        20           Klotsche 1969a

    Cat (F)        oral        213          Klotsche 1966

    Chicken        i.v.        20           Klotsche 1966

    The symptoms of poisoning were the same as for other
    anti-cholinesterase organophosphorus compounds. In most of the rat
    experiments the onset of symptoms was delayed until 70-90 minutes
    after the oral administration (Carshalton, 1965; Sandoz, 1968).

    Short-term studies


    Three groups of young cocks, each group comprising five birds, were
    fed for three weeks on grain impregnated with approximately 0, 65 and
    330 mg/kg of formothion. In the group that received grain having 330
    mg/kg, weight loss occurred in the first week, probably due to food
    aversion, but the original weight was restored by the end of the test
    period. Haematological examination revealed no abnormalities
    indicative of toxic effects in any group. Serum cholinesterase was
    normal in the group receiving the wheat containing 65 mg/kg but in
    those on the 330 mg/kg level there was a reduction of 30 percent after
    10 days and 40 percent after 21 days compared to the controls (Sandoz,
    1963; Klotsche, 1966).


    Groups of three dogs each comprising two males and one female were
    given doses of 0, 2, 8 mg/kg body-weight of formothion orally in
    gelatine capsules for six months. Another group was given 16 mg/kg for
    three months and then 32 mg/kg for the remaining three months, while a
    further group was given 100 mg/kg for a maximum period of nine weeks.
    There were no deaths in the animals given doses of 32 mg/kg or less,
    but two of the three dogs in the 100 mg/kg group died. These two dogs,
    together with the three controls, one animal in the 2 mg/kg group and
    the three animals in the 32 mg/kg group were submitted to gross and
    histopathological examination at autopsy. In the 100 mg/kg group there
    was a rapid drop in serum cholinesterase, typical symptoms of
    anti-cholinesterase poisoning and weight loss. Decrease in eosinophile
    leucocyte counts and great increase in relative adrenal weights were
    found in the two dogs which died but the surviving dog made rapid
    recovery of weight and serum cholinesterase upon withdrawal of
    formothion. Food intake, haematology, urinalysis and liver function
    tests showed no abnormalities attributable to formothion in the dogs
    given 32 mg/kg or lower. A slight loss of weight was observed at 32
    mg/kg. Weekly determination of serum cholinesterase activity gave
    fluctuating values both in the controls and in the animals given up to
    32 mg/kg (Klotsche, 1966).


    Three groups of pheasants, each containing two male and two females,
    received wheat grain treated with 0, 0.15 or 0.75 percent of
    formothion for three weeks. The decrease in food intake in the group
    on the high level was thought to be largely responsible for a
    considerable loss of weight. The weights in the other groups remained
    constant, or increased slightly. No toxic symptoms were noted and

    haematology showed no pathological changes in any of the animals. The
    activity of serum cholinesterase in the birds on the high strength
    compared with that of the controls, was reduced by about 45 percent.
    The transaminase values were normal, indicating that there was no
    liver damage (Sandoz, 1964b; Klotsche, 1966).


    Two groups, initially comprising 15 male rats per group, were given,
    by stomach tube, doses of 35 mg/kg and 90 mg/kg body-weight of
    formothion. The doses were administered six-times weekly for one month
    and then five times weekly for two months. Only one of the 15 animals
    survived 90 mg/kg while 13 survived 35 mg/kg. Serum cholinesterase
    after three months was 25 percent and 46 percent of normal in the 90
    and 35 mg/kg groups, respectively. No changes due to formothion were
    found upon gross and histopathological examination of the dead or in
    the surviving animals after sacrifice (Klotzsche, 1966; Klotsche,

    Groups of rats, initially comprising 25 male and 25 female animals
    were given by stomach tube 0, 3, 5, 9 and 16 mg/kg body-weight of
    formothion daily for six months. Levels of 3 and 5 mg/kg were
    tolerated without any clinical symptoms, while the rats given 9 mg/kg
    showed slight, and those given 16 mg/kg appreciable symptoms which
    disappeared after four weeks of receiving the compound, indicating
    that a tolerance to the compound developed. A decrease in weight-gain
    for male rats was found in the 9 and 16 mg/kg groups. Haematological
    and urine examination revealed no dose-dependent changes. One rat of
    each sex from each group was sacrificed monthly. Some decrease in
    serum cholinesterase activity was found in the test groups. In the 3
    mg/kg group, though, the activity found from the fourth month and
    onward was comparable to the controls. After six months the
    cholinesterase activity in the 5 mg/kg group was approximately 50
    percent and in the 16 mg/kg group 30 percent of that of the control
    group. The average weights of liver and spleen (10 animals) were not
    different in the test and control groups. Gross and histological
    examinations (two animals from each group) revealed no changes which
    could be attributed to formothion (Klotsche, 1966; Klotsche, 1969a).

    Groups of varying numbers of rats were given formothion percutaneously
    in daily doses of 0, 70 and 140 mg/kg body-weight for three weeks.
    After this time, the surviving animals were sacrificed and these
    animals and those which died during the treatment were subjected to
    autopsy. Gross pathology showed no differences in organ-weights. The
    animals which received 140 mg/kg displayed slight histological changes
    in the liver (fine-droplet fatty infiltration, nuclear pyknosis,
    single cell degeneration) and in the adrenal glands (increased
    plasmavacuolization in the zone fasciculata) (Klotsche and Rüttiman,

    Long-term studies

    No information available.


    Formothion seems to be rapidly and completely metabolized in the rat,
    the only animal from which information on metabolism is available. The
    analogy of this compound with dimethoate, a transformation product in
    plants, was considered but there is no information that such a
    transformation occurs in animals, the only metabolite characterized
    being "formothion acid". Based upon a six-month study in the dog,
    there is a no-effect level of 16 mg/kg body-weight per day. However,
    the rat appears to be a more sensitive animal; an effect of 3 mg/kg
    body-weight produced a depression of serum cholinesterase and a
    no-effect level was not found. There is some indication of a possible
    potentiation of formothion and dimethoate. No information is available
    on long-term studies in animals or observations in man. The
    experimental studies available are considered insufficient for
    establishing an acceptable daily intake for man.



    Formothion is a phosphorus-containing systemic insecticide with
    activity as a contact and stomach poison. It has no ovicidal action.
    It is used on a wide variety of crops (cotton, rice, cereals,
    sugarcane, oil seeds, sugar-beets, citrus, grapes, fruits, vegetables,
    potatoes, tomatoes, coffee, tea, and tobacco) against a wide range of
    sucking pests and a number of biting and chewing insects (aphids,
    fruit flies, olive flies, Mangold flies, white flies, thrips, Jassids,
    mites, scale insects, and mealybugs). Waiting periods between last
    application and harvest are generally one or two weeks, depending on
    country and crop, but may be as much as six weeks. Formothion is
    registered in more than 50 countries in Europe, South America, Africa,
    Asia, and Australia.

    Pre-harvest treatments

    Formothion is usually applied as a 0.1-0.2% spray.

    Post-harvest treatments

    None are known.

    Other uses

    Formothion is applied as a spray on ornamental plants and tobacco.


    Residues of formothion, after normal application (0.1-0.2% spray),
    generally decrease to less than 1 ppm after 10 days. Persistence of
    residues depends on type of crop and environmental factors (rainfall,
    temperature). Residues are usually formothion and dimethoate
    (O,O-dimethyl S-(N-methylcarbamoylmethyl) phosphorodithioate), the
    latter being formed by loss of the N-formyl group. (Dimethoate was
    evaluated by FAO/WHO in 1967). The oxygen analogue of dimethoate,
    dimethoxon, may also form.

    In trials on fruits and vegetables, residues often diminish to 0.1 ppm
    or less in 14 days. In some instances (sugar-beets and potatoes) no
    residues were found after treatment. In typical trials following
    normal practice, the maximum residues found are listed in the
    following table:

        Typical maximum residues found following normal application

                                                           Maximum residues
                                                           when sampled,
                          Spray             Day            respectively, ppma/
    Crop                  application       sampled        Formothion         Dimethoate

    Sugar-beets           0.2%              0,7,10         nd,nd,nd           nd,nd,nd

    Cherriesb/            0.2%              0,14,21        0.4,nd,nd          1.6,0.3,0.1

    Tomatoes              0.15%             0,29           0.2,nd             0.4,0.06

    Grapes                0.15%             0,56           0.8,nd             0.8,0.05

    Plums                 0.15%             0,16           0.6,<0.05          0.15,<0.05

    Coffee leavesc/       0.5%(2X)          1/4,14,28      61,nd,nd           53,7,0.6

    Strawberries          0.2%              0,14,21        0.2,nd,nd          0.4,0.3,0.1

    Potatoes              0.2%              3,7            nd,nd              nd,nd

    Apples                0.2%              1,7            0.25,nd            0.25,0.1

    Black currants        0.2%              0,7            0.6,nd             1.2,1.6d/

    Snap beans            0.2%              0.5,7          tr,nd              0.75,0.35

    Wheat                 700 cc/ha         7,14,21        nd,nd,nd           0.12,0.23,0.11

    Sugarcane plant       ca. 0.3 kg/ha     30             nd                 nd

    Typical maximum residues found following normal application (continued)

                                                           Maximum residues
                                                           when sampled,
                          Spray             Day            respectively, ppma/
    Crop                  application       sampled        Formothion         Dimethoate

    Olives                0.12% (2X)        10,20          nd,nd              nd,nd

    Olive oil             0.12%             10,20          nd,nd              nd,nd

      peel                0.12%             15,29          0,17,0.31          1.30,1.70
      pulp                0.12%             15,29          nd,nd              tr,tr
      whole fruit         0.12%             15,29          0.12,nd            0.55,0.18

      peel                0.12%             15,29,96       0.35,0.14,tr       2.10,1.20,0.22
      pulp                0.12%             15,29,96       nd,nd,nd           0.14,tr,nd
      whole fruit         0.12%             15,29,96       tr,0.08,tr         0.49,0.27,tr
      leaves              0.12%             96             nd                 0.63

    Cole crops            0.2%              60-105         nd                 nd

    a/ tr - trace; nd - none detected. Fingings of more than 0.1 ppm dimethoxon are
       given in footnotes.
    b/ Up to 0.35 ppm dimethoxon found in other trials. Oxon generally less than
       0.1 ppm at 21 days.
    c/ Deliberate overdose to study degradation. Test conducted in greenhouse.
    d/ 0.2 ppm dimethoxon

    According to Sandoz (Anon., 1969) the active residues after treatment
    of plants with formothion are formothion, dimethoate, and dimethoxon.
    The data of Table I indicate that formothion has usually degraded to
    dimethoate almost completely after seven days with the exception of
    residues on the peel of oranges and grapefruits, on which 0.17 and
    0.35 ppm residues of formothion were found after 15 days.

    A recent study on the metabolism of 32P-labelled dimethoate is of
    interest because dimethoate is the principal persistent residue of
    formothion. It was applied to bean plants four ways, and the only
    significant residue besides dimethoate was the oxygen analogue (Lucier
    and Menzer, 1968).

    Information on the fate of residues in mammals is scanty. However
    14C-labelled formothion administered orally to the rat was completely
    metabolized, and elimination was essentially complete in 24 hours; the

    only metabolite of well known structure is said to be formothion acid
    (Anon., 1969); presumably this is the thiocarboxy derivative

        CH3O  S
            \ "

    which is also a metabolite of dimethoate in mammals (FAO/WHO, 1968).

    Evidence of residues in food in commerce or at consumption

    No definite data available. However, the statement is made that
    residues are rapidly degraded by high temperature, especially by


    A residue method for formothion should determine the parent
    insecticide and the two metabolites, dimethoate and dimethoxon.

    The method utilized to obtain almost all the data of this report
    requires a thorough cleanup of the plant extract (several column
    chromatographies and binary solvent partitions) followed by paper
    chromatography with formamide as the immobile phase (Faderl, 1962).
    Recoveries are 70-80% for formothion, 85-95% for dimethoate and 70-80%
    for dimethoxon. Sensitivities are 0.04-0.06 ppm. Determinations are
    semi-quantitative (± 25%) below 3 ppm. A thin-layer chromatographic
    procedure is also described but it does not appear to have any
    significant advantage over the paper procedure (Anon., 1969). The
    paper chromatographic method, although acceptable, is not the method
    of choice today.

    Since formothion is usually converted to dimethoate within a week and
    the waiting interval after treatment is at least one week, only
    dimethoate (and possibly dimethoxon) is likely to remain at harvest.
    Methods for the analysis of dimethoate (and dimethoxon) already cited
    (FAO/WHO, 1968) should therefore be useful for formothion and perhaps
    directly applicable. An international interlaboratory study on methods
    for dimethoate residues in crops has recommended a colorimetric
    procedure devised by Frehse (Joint Dimethoate Residues Panel, 1968).

    Use of a gas chromatographic method with flame-photometric or
    thermionic detection should give improved accuracy, sensitivity,
    specificity, and reliability in analyzing for residues of formothion
    and its metabolites. Such a method will be more rapid and less subject
    to error because little or no cleanup is needed. As part of method
    development an exhaustive extraction (e.g. Soxhlet) should be used to
    check on completeness of extraction (Bowman et al., 1968). Gas
    chromatographic methods for qualitative detection of both formothion
    and dimethoate have appeared (Askew et al., 1969; Ruzicka et al.,

    1967; Ebing, 1968). A gas chromatographic procedure for multiresidue
    detection and analysis of organophosphorus pesticides is likely to
    prove suitable, and such a procedure should be established.


                                (ppm)                    Withholding
    Country          (Various fruits and vegetables)     period (weeks)

    Belgium                       -                           2

    Denmark                       -                           1

    E.E.C.                        0.6 (proposed)              -

    France                        -                           1

    Germany (Fed. Rep.)           0.6*                        2

    Great Britain                 -                           1

    Netherlands                   0.5                         2

    Sweden                        -                           3 (proposed)

    Switzerland                   0.3                         6**

    *  0.5 ppm dimethoate + 0.1 ppm formothion
    ** For cherry flies, 3 weeks


    Formothion is a phosphorus-containing systemic insecticide used on a
    wide variety of crops in many countries to control many sucking pests
    and some biting and chewing insects. It is usually applied as a
    0.1-0.2 percent spray prepared from a 25 or 40 percent emulsifiable
    concentrate (ingredients other than formothion undefined). Residues
    are generally 0.3-0.5 ppm or less after one or two weeks and at
    harvest usually consist of dimethoate (to which it degrades) and
    occasionally traces of dimethoxon.

    Information on mammalian metabolism is scanty. However, if the residue
    at harvest is dimethoate and its oxon, the information on dimethoate
    already on record (FAC/WHO 1968) should suffice.

    Formothion and dimethoate should be considered together since their
    significant residues appear to be identical at harvest; that is, the
    effect of applying dimethoate and formothion will be additive.

    No data are available on residues in meat and milk, in total diets, in
    foods in commerce, or in cooked or processed foods.

    A sensitive and reliable analytical method in needed for regulatory
    purposes. A gas chromatographic analysis with a flame photometric or
    thermionic detector in suggested. Specificity is high and sensitivity
    is usually 0.01 ppm or better. Methods of this kind have been
    published and should be evaluated.



                          Pre-harvest         Tolerance
         Crop           interval, days           ppm

    Strawberries              14                 0.3

    Blackcurrants              7                 2.0

    Insufficient data were available on which to base recommendations for
    grapes, wheat and citrus fruit.


    REQUIRED (before an acceptable daily intake for the parent
              compound can be established)

    1. Short-term studies in a non-rodent mammalian species with
       cholinesterase determination.

    2. Long-term studies in rats.

    3. Information on ingredients in technical products produced by
       several manufacturers.

    4. Data on animal metabolism and residues in meat and milk of animals
       consuming agricultural products treated in accordance with good
       agricultural practice.

    5. Data on disappearance of residues during storage, processing and

    6. Data on residue levels in raw agricultural commodities moving in
       commerce and in total diet studies.


    1. Metabolic studies in non-rodent mammalian species.

    2. Observations in man.

    3. Evaluation of a gas chromatographic method for residue analysis and
       for regulatory purposes.


    Anon. (1969) Formothion. An organophosphorus systemic insecticide. 
    Submitted by the Swiss delegation to the Codex Committee on Pesticide

    Askew, J., Ruzicka, J.H. and Wheals, B.B. (1969) A general method for
    the determination of organophosphorus pesticide residues in river
    waters and effluents by gas, thin-layer and gel chromatography.
    Analyst 94, 275-83

    Bowman, M.C., Leuck, D.B. and Beroza, M. (1968) Procedures for 
    extracting residues of phosphorus insecticides and metabolites 
    from field-treated crops. J. Agr. Food Chem. 16, 796-802

    Carshalton. (1965) WHO insecticide evaluation and testing programme. 
    Stage I. Toxicity report. OMS 968. Unpub. Rept. from the Toxicology
    Research Unit, Carshalton

    Ebing, W. (1968) Gaschromatischer Rückstandnachweis von 47
    phosphorhaltigen Insektizid-Wirketoffen nach einer Einheitverfahren.
    Pflanzenschutz-Berichte 38, 1-22

    Faderl, N. (1962) Methode zur Bestimmung von Mikromengen organischer
    Phosphorinsektizide. Mitt. Geb. Lebensmittelunters. Hyg. 53,

    FAO/WHO. (1968) 1967 evaluations of some pesticide residues in food.
    FAO/PL:1967/M/11/1; WHO/Food Add. 68.30.

    Joint Dimethoate Residues Panel. (1968) The determination of dimethoate
    residues in fruits and vegetables; report. Analyst 93, 756-66

    Klotsche, C. (1961) Formothion, ein neuer systemicher 
    phosphorsaureester geringerer Giftigkeit. Mitt. Lebensmitt. Hyg., 
    52; 340-9

    Klotsche, C. and Rüttiman, G. (1965) Subacute dermal toxicity of 
    Anthio (containing 24% of formothion as active ingredient). Unpub.
    Rept. produced and submitted by Sandoz, Ltd., Basle

    Klotsche, C. (1966) Toxikologische Untersuchungen mit dem 
    systemischen phosphorsaureester Formothion. Int. Arch. Gewerbepath.
    Gewerbehyg. 22.246-61

    Klotsche, C. (1969a) Formothion. An organophosphorus insecticide.
    Unpub. Rept. on animal toxicology submitted by Sandoz, Ltd., Basle

    Klotsche, C. (1969b) Formothion. An organophosphorus insecticide.
    Unpub. Rept. on residues in plants submitted by Sandoz, Ltd., Basle

    Lucier, G.W. and Menzer, R.E. (1968) Metabolism of dimethoate in 
    bean plants in relation to its mode of application. J. Agr. Food
    Chem. 16, 936-45

    Ruzicka, J., Thomson, J. and Wheals, B.B. (1967) The 
    gas-chromatographic examination of organophosphorus pesticides and 
    their oxidation products. J. Chromatogr. 30, 92-9

    Sandoz. (1963) Toxicity of Anthio to birds. Unpub. Rept. produced 
    and submitted by Sandoz, Ltd., Basle

    Sandoz. (1964a) Neurotoxicity of Anthio. Unpub. Rept. produced and 
    submitted by Sandoz, Ltd., Basle

    Sandoz. (1964b) Toxicity of Anthio to birds (pheasants) Unpub. 
    Rept. produced and submitted by Sandoz, Ltd., Basle

    Sandoz. (1968) Formothion. Unpub. summary report produced and 
    submitted by Sandoz, Ltd., Basle

    Zehnder, K. (1961) Personal communication cited by Klotsche, 1961

    See Also:
       Toxicological Abbreviations
       Formothion (WHO Pesticide Residues Series 2)
       Formothion (WHO Pesticide Residues Series 3)