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    WHO Pesticide Residues Series, No. 1

    1971 EVALUATIONS OF SOME PESTICIDE RESIDUES IN FOOD

    THE MONOGRAPHS

    The evaluations contained in these monographs were prepared by the
    Joint Meeting of the FAO Working Party of Experts on Pesticide
    Residues and the WHO Expert Committee on Pesticide Residues that met
    in Geneva from 22 to 29 November 1971.1

    World Health Organization

    Geneva

    1972

                     
    1 Pesticide Residues in Food: Report of the 1971 Joint Meeting of
    the FAO Working Party of Experts on Pesticide Residues and the WHO
    Expert Committee on Pesticide Residues, Wld Hlth Org. techn. Rep.
    Ser., No. 502; FAO Agricultural Studies, 1972, No. 88.

    These monographs are also issued by the Food and Agriculture
    Organization of the United Nations, Rome, as document AGP-1971/M/9/1.

    FAO and WHO 1972


    TRICHLORFON

    IDENTITY

    Chemical names

    O,O-dimethyl-(2,2,2-trichloro-1-hydroxyethyl)-phosphonate

    dimethyl 2,2,2-trichloro-1-hydroxyethyl-phosphonate

    Synonyms

    (R)Dipterex           Crop protection

    (R)Dylox              Crop protection and veterinary medicine

    (R)Neguvon            Animal health

    (R)Anthon             Animal health

    (R)Dyvon              Animal health

    (R)Tugon              Control of pests of hygiene

    (R)Metrifonate        Medicine

    (R)Bilarcil           Medicine

    (R)Masoten            Medicine and animal health

    Bayer 2349

    Bay 15 922

    L 13/59

    Structural formula

           O   OH
    CH3O   "   '
         \ "   '
           P - CH - CCl3
          /
    CH3O

    Other information on identity and properties

    Trichlorfon is a white crystalline powder and has a melting point of
    83-84°C. It has a vapour pressure of 7.8 × 10-6 mm Hg at 20°C and
    its volatility is 0.11 mg/m3 at 20°C.

    Its solubility in water is good (at 25°C 15.4 g in 100 ml) and
    increases with rising temperature. It is also readily soluble in low
    alcohols, ketones, aromatic chlorinated hydrocarbons, and dimethyl
    sulfoxide. It is insoluble or only slightly soluble in carbon
    tetrachloride, petroleum ether, ligroin, and cyclohexanone (Bayer,
    1967).

    Trichlorfon is very slowly hydrolyzed in acid media (at pH 1-5 50%
    hydrolysis at 10°C 2400 days, at 20°C 526 days, and at 50°C 11 days).
    In alkaline media it is hydrolyzed more readily (Mühlmann and
    Schroder, 1957). In addition, in alkaline media trichlorfon is
    transformed into dichlorvos (Metcalf et al., 1959).

    Composition of the technical trichlorfon is reported to be (Bayer,
    1971):

    active ingredient                     >98%.

    dichlorvos                            0-0.2%

    chloral                               0-0.05%

    dichloroacetaldehyde                  0-0.03%

    desmethyl trichlorfon
    (by t.l.electrophoresis)              0-0.3%

    H20                                 max. 0.3%

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    Biochemical aspects

    Absorption and distribution

    Trichlorfon is apparently absorbed, distributed, degraded and excreted
    very rapidly in mammals. Robbins et al. (1956) administered
    trichlorfon to a cow (25 mg/kg, oral application) and recovered
    radioactive components in the blood in 0.5 hours after treatment. The
    maximal content was obtained at 1-3 hours after treatment with almost
    no material present at 24 hours. Radioactive components were secreted
    into the milk 6-8 hours after treatment with a maximum occurring 18
    hours after treatment. Traces of radioactive components were evident
    at one week when administered intravenously to cattle (20 mg/kg). The
    radioactive components obtained in blood at one hour were primarily
    (95%) degradation products (Kühnert et al., 1963). Slower absorption
    by intramuscular injection was evident when after six hours following
    administration radioactive components were evident in blood.
    Trichlorfon was present in the milk up to 10 hours after treatment by
    intramuscular injection of 25 mg/kg. Administration to pigs by ip
    injection (25 mg/kg) again showed rapid distribution. Radioactive
    components were evident in blood within 15 minutes with a maxima

    reached within one hour. In 5-7 hours 90% of the radioactivity was
    removed from the blood. Within 30 minutes after treatment radioactive
    components were present in the gut (Schwarz and Dedek, 1965b).

    Schwarz and Dedek (1965a) administered 300 ml and 100 ml of
    32P-labelled trichlorfon to two cows by dermal application. Maximum
    blood concentration of active component was obtained 10-16 hours after
    application, and the levels were 0.45-0.47 ppm with 300 ml and 0.1-0.2
    ppm with 100 ml, respectively. Trace amount was still detected after
    60 hours.

    Secretion of active component into milk was observed, and maximum
    concentration in milk was obtained after 14-18 hours with the level of
    0.45-0.47 ppm in a high dose cow and 0.12-0.13 ppm in a low dose cow.
    Trace amount (less than 0.01 ppm) was found even after seven days with
    high dose.

    Following subcutaneous administration to pigs (25 mg/kg) maximum
    concentration of radioactive components was found in meat in two
    hours. At six hours after treatment 90% of the radioactivity had been
    removed. Dermal application to cattle resulted in milk residues within
    eight hours which were absent at 24 hours following treatment (Leahy,
    1964).

    Trichlorfon solution was poured on the back of cows and the wash was
    scrubbed into the animals coat by brush. Milk was collected at
    two-hourly intervals and residues of trichlorfon were estimated by a
    bioassay method. After treatment with 1 pt of an 8% wash the amount of
    trichlorfon in milk increased to the level of 0.5-0.7 ppm within four
    hours and this level was maintained up to 12 hours. After this time,
    there was a rapid decline. After treatment with 1 or 2 pt of a 4 wash,
    the level of trichlorfon in milk did not exceed 0.4 ppm at any time
    after application, and not more than 0.1 ppm level was obtained after
    six hours. Trace amounts were found after 48-69 hours (less than 0.06
    ppm) (Wickman and Flanagan, 1962). Trichlorfon was administered to 10
    dairy cows at a rate of 60 ml/kg by a "pour on" dressing method. The
    determination of residue in milk, conducted by thin-layer and gas
    chromatography, was found to reach the highest level (0.4 ppm) at six
    hours, after which it declined to a mean of 0.05 ppm at 24 hours and
    of 0.002 ppm at 48 hours (Juszkiewiez, 1970).

    Oral administration to cattle and sheep resulted in meat residues
    within one hour (Behrens, 1959). In 4-6 hours these residues were
    dissipated by 99%. Trichlorfon is rapidly absorbed dermally and
    although relative dermal absorption data are not available there are
    distinct species differences. Sheep apparently absorb trichlorfon
    dermally at a lower rate than cattle (Dedek and Schwarz, 1970),
    Although signs of poisoning were not evident, cholinesterase
    depression was noted when dogs were dipped once into a 1% solution of
    trichlorfon (Bailey, 1956).

    Biotransformation

    Although studied extensively, the metabolism and mode of action of
    trichlorfon remains uncertain. It has been established that
    trichlorfon rearranges via dehydrochlorination to form dichlorvos
    (DDVP, 2,2-dichlorovinyldimethyl phosphate) (Barthel et al., 1955;
    Lorenz et al., 1955; Mattson et al., 1955; Miyamoto, 1961).

    This conversion may occur spontaneously under physiological conditions
    (Miyamoto, 1959) and small quantities of dichlorvos have been isolated
    from biological tissues following trichlorfon treatment (Metcalf et
    al., 1959; Dedek and Lohs, 1970; Schwarz and Dedek, 1965). Apparently
    the conversion of trichlorfon to dichlorvos occurs, to a very minor
    extent, in mammals although in several instances it has not been
    demonstrated (Arthur and Casida, 1958; Hassan and Zayed, 1965; Bull
    and Ridgeway, 1969; Kühnert et al., 1963), Dichlorvos does occur in
    plants (Bull and Ridgeway, 1969) and insects (Metcalf et al., 1959;
    Bull and Ridgeway, 1969). Degradation of trichlorfon apparently
    follows several pathways. The two major reactions include: hydrolysis
    of the methoxyl moiety (Robbins et al., 1956; Bull and Ridgeway, 1969;
    Dedek and Lohs, 1970a) with the methyl group being incorporated by
    alkylation or methyl transfer into proteins in liver and various
    organs (Dedek and Lohs, 1970b) and hydrolysis of the phosphonate (P-C)
    bond (Arthur and Casida, 1957, 1958; Miyamoto, 1961; Hassan et al.,
    1960; Zayed and Hassan, 1965; Hassan and Zayed, 1965; Bull and
    Ridgeway, 1969) yielding trichloroethanol which is subsequently
    conjugated. Miyamoto (1961) has suggested that conjugated metabolites
    from rabbits contain a molecule that has an altered trichloroethyl
    moiety and an intact phosphorus atom. This alteration product has not
    been further defined. In most instances the metabolism in plants and
    animals appears to follow the same route.

    CHEMICAL STRUCTURE 1

    Excretion

    Following acute administration trichlorfon is rapidly eliminated
    primarily via the urine. Following intraperitoneal administration of
    trichlorfon to rats, 71% of the total dose was eliminated in the urine
    in 16 hours (Bull and Ridgeway, 1969). Following oral administration
    to cows, 66% of the dose was eliminated within 12 hours (Robbins et
    al., 1956). Arthur and Casida (1958) demonstrated that the major
    quantity of radioactive components in urine of rats was hydrolysis
    products with less than 1% of the products being extractable by
    organic solvents. Secretion of trichlorfon into milk appears to occur
    rapidly following application (Leahy, 1964; Robbins et al., 1956)
    although this means of elimination is minor and residues are
    eliminated rapidly. It seems apparent that elimination of the toxicant
    is rapid although in one instance Arthur and Casida (1958) treated
    rats with 2000 mg/kg and four hours later found 45% of the
    administered dose in fat. This fat storage was not followed further.
    The delayed recovery of cholinesterase systems in mammals suggests
    that elimination of the toxicant is not complete and small quantities
    of antiesterase agents may remain in the body for prolonged periods
    (possibly in the fat).

    Effect on enzymes and other biochemical parameters

    Trichlorfon is a rapid irreversible inhibitor of cholinesterase.
    Several investigators have reported in vitro values for inhibition
    of this enzyme.

                                                                        
    Enzyme source                 I50 (molar)    References
                                                                        
    Commercially purified         3.2 × 10-6     Arthur and Casida, 1957
    Red blood cell (bovine)       3.2 × 10-6     Arthur and Casida, 1957
                                  6.3 × 10-6     Bull and Ridgeway, 1959
    Whole blood (human)           7.9 × 10-5     Arthur and Casida, 1957
    Plasma (human)                1.5 × 10-5     Samir et al., 1966
    Red blood cell (human)        3.4 × 10-6     Rosival et al., 1959
    Serum (human)                 1.3 × 10-7     Rosival et al., 1959
    Brain (rat)                   2.6 × 10-6     Dubois and Cotter, 1955
                                  6.3 × 10-6     Hassan et al., 1965
                                  8.7 × 10-4     Schulemann, 1957
                                                                        

    In vivo, rat cholinesterase activity of brain serum and submaxillary
    gland was maximally inhibited within 15 minutes of Rx by ip injection
    (Dubois and Cotter, 1955). Recovery rates were dependent on the dose
    administered (25, 50 or 75 mg/kg) with 75% of the enzyme recovered
    within four hours at the highest treatment level. At the lowest level,
    activity of cholinesterase was normal within an hour. Cholinesterase
    inhibition in humans apparently recovers at a slower rate than
    demonstrated with rats. Erythrocyte cholinesterase was not recovered
    from two daily doses of 7.5 mg/kg (orally administered) for 38 days
    after treatment. Maximum inhibition was only 50% of pretreatment
    levels (Lebrun and Cerf, 1960). Cholinesterase levels in children
    treated orally for 10 days with 5 or 10 mg/kg returned to normal
    within four weeks.

    Following instramuscular (25 mg/kg) or intravenous (20 mg/kg)
    administration to cattle, calcium levels in the serum were reduced.
    The calcium level returned to normal in three days (Kühnert et al.,
    1963).

    TOXICOLOGICAL STUDIES

    Special studies

    (a)  Carcinogenicity

    Following weekly subcutaneous administration of trichlorfon to rats,
    two of 24 developed local sarcomas after a period of 800 days
    (Pruessmann, 1968). Gibel et al. (1971) observed several incidents of
    forestomach papilloma, liver carcinoma and abdominal sarcoma in rats
    and mice administered trichlorfon (see "short-term studies").

    (b)  Reproduction

    A three generation (two litter per generation) rat reproduction study
    at levels of 0, 100, 300, 1000 and 3000 ppm in the diet resulted in
    adverse effects on reproduction at 1000 ppm and above. At 1000 ppm
    there was evidence of reduced fertility, smaller litters and reduced
    body-weight of pups. At 3000 ppm the pregnancy rate was markedly
    decreased and the pups were smaller and lighter in weight with none
    surviving to weaning. No effects were noted at 300 ppm or below.
    Microscopic examination of the F3b generation indicated no adverse
    effects (Loser, 1969; Spicer and Urwin, 1971).

    (c)  Teratogenesis, mutagenesis

    Daily oral administration of trichlorfon (100 mg/kg for 17 days) to
    lactating rats resulted in no effect on the pups (Rahn, 1963).
    Pregnant rats were administered trichlorfon by continuous inhalation
    for 20 days at concentrations of 0.005, 0.02 and 9 mg/m3. At all
    levels there were external and internal abnormalities in the
    development of embryos, weight differences in organs of the rats,
    weight differences in the embryos, shifts in the level of ascorbic
    acid and nucleic acids in tissues of mothers and foetuses and
    histopathological and histochemical changes in the placenta (Gofmekler
    and Tabakova, 1970). No foetal abnormality or embryotoxic effects were
    observed when trichlorfon was administered orally at 100 mg/kg/day to
    pregnant rats from day six to 15 of gestation (Lorke, 1971).
    Trichlorfon injected into chicken embryo egg sac at seven days after
    fertilization at a dose of 0.0008 of the rat LD50 and examined at 21
    days showed only a slight decrease in embryo viability (Dinerman et
    al., 1970). Dominant lethal tests run with male mice injected with a
    single dose of 0, 50 or 100 mg/kg and mated to untreated females
    resulted in no adverse effects on reproduction or on the young (Arnold
    et al., 1971).

    Except for the one study by inhalation (Gofmekler and Tabakova, 1970),
    trichlorfon does not appear to be a terata-inducing compound nor does
    it induce mutations in rodents.

    (d)  Neurotoxicity

    Subcutaneous administration of trichlorfon to chickens at a single
    dose of 90 mg/kg did not result in ataxic neuropathy (Witter and
    Gaines, 1963). When trichlorfon was fed to hens for 29 weeks at 130
    ppm in the diet, no neurotoxic signs were observed (Ross and Sherman,
    1960). Oral administration of a single dose of 100 mg/kg (with
    atropine and PAM) or dietary levels of up to 5000 ppm for 30 days did
    not result in delayed neurotoxicity. Trichlorfon does not induce
    pathological demyelination or clinical signs of ataxia (Kimmerle and
    Lorke, 1966; Hobik, 1967).

    (e)  Potentiation

    Trichlorfon potentiates the toxicity of azinphos-methyl, EPN and
    malathion but not several other organophosphates and carbamate
    insecticides (Dubois, 1958; Doull et al., 1958; Kimmerle and Lorke,
    1968).

    Intraperitoneal administration of 10 mg/kg to rats resulted in a
    decrease of the malathion detoxifying enzymes in liver and serum
    (Murphy and Dubois, 1958). The effects on the detoxification system
    were transient and were reversed in 24 hours. When rats were fed 100
    ppm trichlorfon in combination with malathion (100 ppm) for two weeks,
    no effects on the detoxifying enzyme were observed (Murphy and Dubois,
    1958). However, when 100 ppm trichlorfon was fed to rats and dogs in
    combination with malathion (1000 ppm), EPN (20 ppm) or azinphos-methyl
    (5 ppm) for six weeks, effects on cholinesterase were noted with EPN
    and malathion but not with azinphos-methyl (Doull et al., 1958). The
    potentiated effects were greatest with EPN, less with malathion and
    absent with azinphos-methyl.

    (f)  Antidotes

    Trichlorfon intoxication in rodents, as with many antiesterase
    organophosphate esters, responds to therapy with atropine and 2 - PAM
    (Wills, 1959; Dubois and Cotter, 1955; Lorke and Kimmerle, 1968).
    2 - PAM was effective in reactivating rabbit cholinesterase and
    reducing mortality in mice (Wills, 1959) and rats (Lorke and Kimmerle,
    1968).

    A recent report on the action of thiamine and pyridoxime as
    therapeutic agents indicates that the antivitamins (oxythiamine and
    desoxypyridoxime) synergize the effects of poisoning. The two vitamins
    when given prior to treatment have shown some beneficial effects
    (Zhdanovich and Vdalov, 1970). There was little effect when given
    after treatment.

    Acute toxicity

                                                                                       

    Animal         Sex          Route        LD50         References
                                             (mg/kg)
                                                                                   

    Mouse          M            oral         660          Vbrovsky et al., 1959
                   M                         950          Schulemann, 1955
                   M&F          ip           500          Dubois and Cotter, 1955
                   M                         650          Vbrovsky et al., 1959
                   F                         575          Vbrovsky et al., 1959
                   M            sc           267          Borgmann and Hunold, 1955
                   F                         320          Borgmann and Hunold, 1955

    Rat            M&F          oral         316-650      Dubois and Cotter, 1955
                                                          Deichman and Lampe, 1955
                                                          Edson and Noakes, 1960
                                                          Schulemann, 1955
                                                          Gaines, 1969
                                                          Hagan, 1958
                                                          Borgmann and Hunold, 1955

                                                                                   

    Animal         Sex          Route        LD50         References
                                             (mg/kg)
                                                                                   

                                se           400          Arthur and Casida, 1958
                                ip           400          Arthur and Casida, 1957
                                             160          Dubois, 1958
                                             225          Dubois and Cotter, 1955
                   M                         160          Murphy and Dubois, 1958
                   M
                   (adult)                   250          Brodeur and Dubois, 1963
                   M
                   (weanling)                190          Brodeur and Dubois, 1963
                   M&F          dermal       2 800        Edson and Noakes, 1960
                                             2 000        Gaines, 1969

    Guinea-pig     M&F          ip           300          Dubois and Cotter, 1955
                                             200          Schulemann, 1955

    Rabbit                      oral         160          Arant et al., 1971
                                dermal       5 000        Deichman and Lampe, 1955

    Chicken                     oral         75-110       Dubois and Doull, 1955
                                                          Kimmerle and Lorke, 1966
                                sc           125          Witter and Gaines, 1963
                                             65           Sherman and Ross, 1959
                                ip           ca. 75       Kimmerle and Lorke, 1966

    Duck
    (1 week old)                oral         105          Dubois and Doull, 1955

    Dog                         oral         420          Deicbman and Lampe, 1955

    Horse                       oral         100          Jackson et al., 1960
                                                                                   
    

    When trichlorfon was administered as a 10% solution to the
    conjunctival sac of rabbits for six days, reversible effects,
    including miosis and vasodilation of the blood vessels of the upper
    lid, were observed (Deichman and Lampe, 1955). Dogs dipped once into a
    1% solution showed no sign of toxicity although cholinesterase was
    depressed (Bailey, 1956). Toxic signs of poisoning are typical of the
    cholinergic response of organophosphate esters. Symptoms include
    twitching, salivation, lacrymation, defaecation, urination, tonic and
    clonic convulsions, prostration, cardiac arrest and respiratory
    failure. The onset of symptoms is rapid as is the recovery following
    sublethal poisoning. Intraperitoneal administration of toxic doses of

    trichlorfon caused the appearance of symptoms in rats and mice in
    about 10 minutes and death or recovery occurred within a few hours.
    Symptoms included scattered muscular fibrillations and body twitches
    which were followed by salivation, lacrymation, defaecation, and
    urination, The severity of the symptoms increased with time and
    included tonic and clonic convulsions, prostration and respiratory
    failure preceded by cardiac arrest.

    Skin irritation was absent when 1:1 mixture of trichlorfon and
    emulsifier was applied to rat and guinea-pig backs daily for four
    weeks (Borgmann and Hunold, 1955). Inhalation studies in a static
    chamber with concentrations of 22 mg/l air caused symptoms of
    cholinergic stimulation but no death. At 8 mg/l no signs of poisoning
    were observed (Borgmann and Hunold, 1955).

    Short-term studies

    Rat

    Rats (five rats per group) were administered trichlorfon
    intraperitoneally at 50, 100 and 150 mg/kg/day for 60 days. Mortality
    was observed at 100 mg/kg/day while at 50 mg/kg/day all animals
    survived (Dubois and Cotter, 1955).

    Rats (13 male and 13 female per group) were fed trichlorfon at dietary
    levels of 0, 20, 100 and 300 ppm for 16 weeks. Significant
    cholinesterase depression was noted at 300 ppm. No effects were
    observed at 100 ppm on growth, behaviour, food consumption or gross
    and microscopic examination of tissues (Doull and Dubois, 1956).

    Rats (10 male rats per group) were fed trichlorfon at levels of 0. 1,
    5, 25 and 125 ppm for 16 weeks. Cholinesterase depression was minor
    (approximately 30%) at the initial phases of the test (4-8 weeks) and
    slowly rose to near normal values. No effects were noted on food
    consumption, growth or on gross examination of the tissues (Edson and
    Noakes, 1960).

    Cutaneous administration of trichlorfon to mice either alone or mixed
    with "Krotonal" three times per week (alone) for five months or once
    per week ("Krotonal") for six months resulted in a higher incidence of
    pathological abnormalities than the controls. Cutaneous administration
    alone resulted in an incidence of liver necrosis, liver cirrhosis,
    liver carcinoma and forestomach papilloma. With "Krotonal" one case of
    abdominal sarcoma was observed in addition to the other effects
    (Gibel, 1971).

    Dog

    Dogs (two males and two females per group) were fed trichlorfon at
    levels of O, 50, 250, 500 and 1000 ppm in the diet for one year.
    Cholinesterase activity was depressed at 500 and 1000 ppm. At 500 and
    1000 ppm an increased spleen weight with congestion and apparent
    lymphoid atrophy was noted. Males at 1000 ppm exhibited a decrease in

    spermatogenesis and the occurrence of hyperplastic nodules in the
    adrenals. No effects were noted on mortality, growth, food
    consumption, behaviour or gross and microscopic examination of tissues
    other than those mentioned above (Doull et al., 1962a).

    Two dogs were administered 45 mg trichlorfon per kg orally six days
    per week for three months with no cumulative effects noted. The serum
    cholinesterase level was 60% of normal at the conclusion. No mortality
    was observed (Deichman and Lampe, 1955).

    Dogs (one male and one female per group) were fed trichlorfon in the
    diet for 12 weeks at levels of 20, 100, 300 and 500 ppm. The animals
    were maintained on control diets for a further four weeks. Depression
    of erythrocyte and serum cholinesterase activity was noted at 300 ppm
    and above. Trichlorfon at 100 ppm did not affect cholinesterase. No
    effects were noted at any level on the growth, food consumption or
    behaviour of the dogs. Cholinesterase activity returned to normal
    within two weeks of cessation of feeding (Doull and Vaughn, 1958).

    Dogs (one male and one female per group, two males and two females
    served as controls) were fed trichlorfon at levels of 0, 50, 200 and
    500 ppm for 12 weeks in the diet. Plasma and erythrocyte
    cholinesterase activity was depressed at 500 ppm and unaffected at 200
    ppm. Recovery of enzyme activity was complete six weeks after
    trichlorfon feeding stopped (Williams et al., 1959).

    Long-term studies

    Rat

    Rats were administered trichlorfon three times weekly by oral or
    subcutaneous administration for the life of the rats. Higher incidence
    of liver necrosis, liver cirrhosis and forestomach papilloma were
    evident than were described for the control (Gibel et al., 1971).

    Five groups of rats (25 male and 25 female per group; controls
    contained 50 males and 50 females) were fed diets of trichlorfon
    containing 0, 50, 250, 500 and 1000 ppm for a period of two years,
    Male rats at 1000 ppm gained less weight than the control after the
    first two months and failed to regain the weight loss during the
    remaining feeding period. Rats fed 1000 ppm weighed about 15% less
    than the control animals. In male and female rats fed 1000 ppm the
    onset of mortality occurred earlier than in rats from the other groups
    and there was distinct shortening of the survival time in rats fed
    this diet. Apparently 1000 ppm trichlorfon in the diet caused a
    decrease in life span. Rats fed 500 ppm showed a moderate (25%)
    inhibition of serum cholinesterase. No effect was noted on the
    cholinesterase from brain submaxillary gland and erythrocyte at this
    and lower levels. At 1000 ppm all cholinesterase determinations were
    below normal, except for the brain. Gross pathological effects
    resulting from the presence of trichlorfon in the diet included
    mammary gland tumours which occurred in female rats fed 250 ppm (one
    rat), 500 ppm (three rats) and 1000 ppm (two rats). Microscopic

    examinations of the tissues indicated major adverse histological
    findings observed in the mammary glands, gonads and blood vessels of
    the trichlorfon fed animals. Three mammary tumours were observed at
    1000 ppm (an adenocarcinoma, a sarcoma and a fibroma); three were
    observed at 500 ppm (two adenocarcinomas and a fibroadenoma); and one
    was found at 250 ppm (a fibroadenoma). Female rats, fed 500 and 1000
    ppm, exhibited an absence of primary follicules and primative ova; one
    rat fed 250 ppm also lacked follicules and ova. Two of the five rats
    examined at 1000 ppm had tubular androblastomas which were composed of
    epithelial components and stroma. Three of five male rats examined
    from 1000 ppm feeding levels exhibited focal aspermogenesis not
    observed at any other dietary levels. Lesions were observed in the
    middle and small sized arteries of the lung, thymus, pancreas,
    submucosa and adventitia of the gastrointestinal tract and in the
    adrenal glands of several of the animals. The lesions were more common
    in males than in females. The muscular and elastic tissue of the blood
    vessel walls was frequently replaced by fibrous tissues and this was
    associated with a necrotizing inflammation. The gross and microscopic
    examination of the tissues from animals fed the trichlorfon-containing
    diets revealed three pathological effects which appeared to be related
    to the presence of the chemical in the diet. These consisted of an
    increase in the incidence of mammary tumours in the female rats,
    vascular changes and injury to the reproductive systems of both male
    and female animals. The incidence of mammary tumour formation in the
    entire group of rats used in the study (rather than the relatively
    small number of animals used for histological examinations) shows that
    the incidence in the rats fed control diets was 14%, 8% of the rats
    fed 50 ppm, 20% of the rats fed 250 ppm, 21% at 500 ppm and 25% at
    1000 ppm. The comparison of the time for the first tumours to appear
    showed that in control diets 1.7 years, 50 ppm diet 1.6 years, 250 ppm
    1.8 years, 500 ppm 1.5 years, and 1000 ppm 1.1 years. Thus, the total
    frequency and onset of tumour formation appeared to be dose dependent
    (Doull et al., 1962b).

    Rats (25 male and 50 female per group) were fed dietary levels of
    trichlorfon at 0, 100, 200 and 400 ppm for 1.5 years (Doull et al.,
    1965). Serum cholinesterase depression was observed in both males and
    females at 400 ppm. Erythrocyte cholinesterase was depressed in males
    and females at 400 ppm; slightly in males at 200 ppm and very slightly
    depressed in females at 100 ppm. There was a significant mortality in
    the study in the control and experimental groups. The study was
    prematurely concluded at approximately 70 weeks of feeding. At 400 ppm
    the male spleen and liver weights were lighter than the control
    values. At autopsy the major findings occurred in the ovaries and
    mammary glands with slight effects on the lungs. Cystic granular
    ovaries were seen in 40% of the female rats fed 400 ppm; 33% of the
    rats fed 200 ppm; 14% of the rats fed 100 ppm; and 8% of the female
    control rats. Fifteen per cent. of the female rats fed 400 ppm had one
    or more mammary tumours; 11% of the rats fed 200 ppm; and 8% of the
    control had mammary tumours. The induction time for mammary tumours
    was not significantly decreased by increasing dietary concentrations
    of trichlorfon. There were pulmonary abscesses in the lungs of two
    female rats fed 400 ppm and two other female rats from this group

    exhibited exudative pleuritis. Microscopic examination of the tissues
    indicated an absence of primary follicules and primitive ova in four
    of the five rats examined at 400 ppm. This was a significant increase
    from those found at lower levels of feeding. The ovaries from the rats
    fed 400 ppm were atrophic, small in size with nests of luteal or
    granulosa cells, and an increased number of androblasts. Similar but
    less marked changes were found in other groups. A greater frequency of
    simple cysts of the ovaries was observed at 400 ppm than in the
    control group. None of the cysts appeared to be neoplastic.
    Examinations of the mammary tumours indicated that they were benign
    fibro-epithelial tumours. Microscopic appearance of the tumours in the
    trichlorfon fed animals was similar to the tumours seen in the control
    animals. These studies suggest that the addition of trichlorfon to the
    diet may have enhanced some of the aging changes, especially in the
    reproductive tissue.

    Rats (groups of 50 male and 50 female per group, 100 male and female
    were used as controls) were fed trichlorfon at dietary levels of 0,
    50, 250, 500 and 1000 ppm for two years. No effects were observed on
    behaviour, food consumption, weight gain, survival, blood count,
    urinalysis and liver protein content. Slight non-dose dependent
    effects were noted in male and female liver on SDH activity and in
    females on SG-OT activity. Cholinesterase was depressed in both males
    and females at 1000 ppm but not at 500 ppm. The male liver weight was
    significantly increased at 250 and 1000 ppm. An increase in weight was
    observed although it was not statistically significant at 500 ppm.
    There were no other dose-dependent, significant effects on tissue
    weights. Clinical and histological examination of tissues or tumours
    indicated that, of the total of 35 malignant tumours, 15 occurred in
    the control group and only five were found at 1000 ppm dose levels.
    There was no indication of an increased incidence of mammary tumours
    although the total number of mammary tumours observed in the
    trichlorfon fed animals was greater than that found in the controls
    (the percentage of mammary tumour incidence in female rats was:
    control, 9%; 1000 ppm, 8%; 500 ppm, 10%; 250 ppm, 12%; 50 ppm, 18%).
    In the ovaries, cysts were found in 14 of the 33 control animals, and
    at 1000 PPM cysts were found in eight of 20 animals examined. There
    was no evidence of unusual interstitial fibrosis in the trichlorfon
    fed animals. There appeared to be no evidence of acceleration of the
    aging process of the gonads in this experiment. The frequency of
    cystic atrophic ovaries or reduction in spermatogenesis was no
    different in the controls than in the animals treated with 1000 ppm
    trichlorfon in the diet (Lorke and Loser, 1966; Grundmann and Hobik,
    1966).

    Dog

    Dogs (four male and four female per group) were maintained for four
    years on diets containing 0, 50, 200, 800 and 3200 ppm trichlorfon
    (Loser, 1970). Cholinesterase activity in plasma and erythrocytes was
    depressed at 200 ppm. Trichlorfon, at 800 ppm and above, led to an
    increased mortality rate. Increased uric acid and creatinine levels in
    the male dogs at 800 ppm was indicative of kidney damage. Physical
    appearance of the dogs was affected by 800 ppm in the diet. The
    animals had a dull, shaggy coat and appeared weaker and sick.
    Cholinergic symptoms occurred at the highest dose. Mortality was
    evident in dogs fed 3200 ppm and 800 ppm (one male at 800 ppm and two
    females at 800 ppm survived the test). Haematological values showed no
    pathological changes in any group at two years. The activity of the
    serum transaminases (G-OT and G-PT) of the female dogs at 3200 ppm at
    two years was significantly high and regarded as pathological. No
    other effects were noted on liver function activity. The transaminase
    activity in the female dogs surviving the test to four years was
    normal. There were no dose related changes in liver function or blood
    values at four years. Urine examinations on all dogs at two and four
    years showed uric acid and creatinine levels at the 800 ppm dose in
    males and the 3200 ppm dose in the female were increased. There were
    no differences in the clearance tests. Blood sugar and cholesterol
    levels were not affected at 200 ppm. Cholinesterase activity was
    depressed at 200 ppm and the depression was dose dependent. In
    general, the depression of cholinesterase activity was noticeable
    during the earliest parts of the experiment and tended to decrease as
    the experiment progressed until at four years the plasma and
    erythrocyte cholinesterase level were slightly depressed at 200 ppm in
    both male and female with no depression noted at 50 ppm. Comparison of
    the organs weights showed that male dogs at 800 ppm had enlarged
    spleen, smaller adrenals and testis, and the female at 3200 ppm had an
    increased liver weight, enlarged spleen and adrenals and reduced ovary
    size. Based on histological examination of tissues there were no
    changes in morphology which were considered to be significant or
    related to trichlorfon in the diet (Spicer and Payne, 1971).

    Observations in man

    Over 6000 people, most in South Africa and South America, have been
    treated over the past few years for various intestinal and body
    parasites (reviewed by Wegner, 1970). The dosages varied up to 70
    mg/kg/day for periods up to 12 days. The dose of 7.5 mg/kg given 2-4
    times at two week intervals was believed to be the best level as the
    symptoms observed were less severe. Symptoms include cholinesterase
    depression, weakness, nausea, diarrhoea and abdominal pain. Higher
    doses (24 mg/kg) gave more severe symptoms including tachycardia,
    salivation, cholic pain, vomiting, nausea, fatigue, tremors, and
    sweating. The effects were not cumulative and spontaneous recovery in
    all cases was rapid. In a few cases, an indication was given that
    spermatogenesis (size and shape of sperm) might be affected in humans.

    In all cases for treatment of parasites cholinesterase depression was
    evident.

    Namba (1971) reviewing the human data alluded to the observation that
    three persons exposed to trichlorfon showed signs of delayed
    neurotoxicity.

    Various studies on humans have shown two effects: (1) cholinesterase
    depression in all cases which was usually recovered within 30 days of
    the cessation of treatment, and (2) a possible effect on
    spermatogenesis (Wegner, 1970; Hanna et al., 1966; Lebrun and Cerf,
    1960) which included reduced sperm count, seminal fluid volume and a
    decreased motility and viability of the cells in a very limited number
    of cases. Other studies showing no adverse effects include: Davis and
    Bailey, 1969; Abdalla et al., 1965; Abdel-Aal et al., 1970; Beheyet,
    1961. The dose of 7.5 mg/kg given once every two weeks appears to be
    the best available. There is no human no-effect level recorded.

    Comments

    Trichlorfon appears to be rapidly absorbed, distributed, metabolized
    and excreted in animals. The conversion of trichlorfon to dichlorvos
    occurs both in plants and mammals but to only a very minor extent.
    Several long-term studies in rats and dogs are available. In two
    long-term studies in the rat evidence of an increased frequency and/or
    onset of tumour formation (particularly mammary tumours) appeared to
    be dose dependent. A third study in rats did not confirm these
    observations. An incidence of cystic atrophic ovaries and reduced
    spermatogenesis was also observed in two studies and not confirmed in
    the third study, in a three generation rat reproduction study or in a
    dominant lethal test. None of the experiments individually considered
    was by itself indicative of a carcinogenic effect, however the
    cumulative evidence derived from all the experiments considered
    suggests that further investigations of the potential carcinogenicity
    of trichlorfon are required.

    In view of the inconclusive nature of the findings in long-term rat
    studies, only a temporary acceptable daily intake was established for
    trichlorfon.

    TOXICOLOGICAL EVALUATION

    Level causing no toxicological effect

    Rat: 50 ppm in the diet equivalent to 2.5 mg/kg body-weight per day

    Dog: 50 ppm in the diet equivalent to 1.25 mg/kg body-weight per day

    Estimate of temporary acceptable daily intake for man

    0-0.01 mg/kg per day

    RESIDUES IN FOOD AND THEIR EVALUATION

    Use pattern

    Trichlorfon is an insecticide with a broad spectrum of activity. It is
    chiefly effective against Lepidoptera (moths), Diptera (flies),
    and Heteroptera (bugs). In crop protection, trichlorfon is used
    mainly against insect pests in field crops and fruit crops.
    Trichlorfon is also of great importance as a public health pesticide
    and as an animal health product, and is used in medicine as an
    anthelmintic.

    The amount of trichlorfon used in the different sectors of
    application, expressed in percentages, is in the Western world as
    follows:

         45% in field crops (e,g. cereals, rice, maize, cotton, grassland,
         tobacco)

         35% in vegetable crops

         10% in fruit crops (e.g. pome fruit, stone fruit, bush and cane
         fruit, grapes, citrus fruit, olives)

         10% for other uses (e.g. ornamental crops, hygiene, animal
         health)

    Approximately 25 formulations of trichlorfon are sold and registered
    in 83 countries for the control of insect pests of crops and pests of
    hygiene.

    The following formulations are used in agriculture (crop protection):
    50% emulsifiable concentrate, 50%. soluble powder, 80% soluble powder,
    50% wettable powder, 2.5% granular, 5.0% granular, 5.0% dust.

    Pre-harvest treatments

    The recommended application rates and concentrations (in terms of
    active ingredient) for pre-harvest treatments of the major crops are
    as follows:

    Bananas                                  400-600 g/ha

    Beets                                    150-1000 g/ha, or
                                             0.075-0.12% spray

    Cereals (excl. corn and rice)            800-1200 g/ha

    Citrus fruits                            0.12% spray

    Coffee                                   450-550 g/ha, or
                                             0.075-0.12% spray

    Corn                                     400-1500 g/ha

    Cotton                                   400-1500 g/ha

    Currants, gooseberries                   0.075-0.12% spray

    Deciduous fruits (apples, pears,
    cherries, peaches, etc.)                 0.075-0.12% spray

    Grapes                                   0.075-0.12% spray

    Grassland and forage crops               500-2000 g/ha

    Oil palms                                450-1600 g/ha,
                                             or 0.08-0.2% spray

    Olives                                   0.075-0.12% spray

    Potatoes                                 600-1000 g/ha

    Rice                                     800-1200 g/ha

    Sugar cane                               1200-1600 g/ha, or
                                             0.075-0.2% spray

    Tea                                      600-1200 g/ha

    Tobacco                                  600-1200 g/ha

    Vegetables                               150-1200 g/ha, or
                                             0.075-0.12% spray

    For controlling soil-inhabiting cutworms use is made of baits which
    are prepared by mixing 100 g active ingredient (soluble powder), 10 kg
    bran, 500 g sugar in 10 litres of water. The crumbly mess is used to
    treat 1/4-1/2 ha.

    Bait sprays for controlling fruit flies consist of 0.08 or 0.32%
    active ingredient and 0.25 or 0.5 protein hydrolyzate, respectively.

    Post-harvest treatments

    No recommendations.

    Animal treatments

    Trichlorfon is used as an animal health product for the control of
    endoparasites and ectoparasites in/on cattle, sheep, goats, pigs,
    horses, poultry, dogs, cats and fish. Following formulations are used:
    97% soluble powder, 90% soluble powder, 80% soluble powder, 50%
    soluble powder, 6% suspension, 11% solution, 5% injectable solution
    tablets.

    Methods of application are as follows: wash or spray treatment, dip
    treatment, spot-on/pour-on treatment, injection, drench treatment,
    feed mix, pond or immersion treatment.

    Animal health products based on trichlorfon are registered and sold in
    77 countries.

    Spectrum of activity of trichlorfon in animal treatments is given in
    Table 1.

    Trichlorfon is normally applied to the animals at the rate of 25-75
    mg/kg body-weight by various methods.

    The most common method of application is as a wash or spray treatment
    for the control of sucking lice, flies and biting lice. For this
    purpose, the whole of the animal body is washed or sprayed with a
    0.13% solution of Neguvon powder (repeat treatment after five days).

    For the control of warble fly maggots on cattle and Sarcoptes mites
    on pigs, a 2% solution is recommended (repeat treatment after 5-7
    days).

    For the external control of Stephanofilaria in cattle and Habronema
    spp. in horses, use must be made of a 10% solution applied to the
    affected areas.

    The 11% ready-for-use Neguvon solution is used for the control of
    warble fly maggots in cattle, a single application being made by the
    spot-on method. An applicator is supplied with the solution.

    Some of the trichlorfon enters through the skin into the blood system.
    As a result, the effect is enhanced from inside the animal body. The
    systemic action of trichlorfon against warble maggots which wander
    through the body of the host animal until they eventually become
    located beneath the skin of the animal's back, is also produced as a
    result of the compound penetrating through the skin and entering the
    blood system.

    The success of an external treatment can be further increased by a
    simultaneous internal application.

    Internal treatment for the control of endoparasites is made as
    follows:


    
    TABLE 1. SPECTRUM OF ACTIVITY OF TRICHLORFON IN ANIMAL TREATMENTS

                                                                                                                 

                                                Cattle    Sheep/   Pigs     Horses     Poultry     Dogs/     Fish
                                                          Goats                                    Cats
                                                                                                                 

    External application for control of
     ectoparasites:

    Biting lice                                 X         X                 X          X           X
    Sucking lice/fleas                          X         X        X        X                      X
    Sarcoptes mites                             X         X        X        X
    Red avian mite/scaly leg mite                                                      X
    Flies/sheep keds                            X         X        X        X          X
    Warble fly maggots/larvae of
    Dermatobia hominis                          X

    Internal application for control of
     ectoparasites:

    Sarcoptes mites                                                X

    External application for control of
     endoparasites on domestic animals:

    Habronema spp. (summer sores)                                  X
    Stephanofilaria in cattle                   X

    Internal application for control of
     endoparasites:

    Haemonchus spp., Mecistocirrus              X         X
    Oesophagostomum spp.                        X                  X
    Neoascaris vitulorum                        X
    Bunostomum spp./Ostertagia spp./Cooperia
    spp./Trichostrongylus spp.                  X         X

    TABLE 1. (Cont'd.)

                                                                                                                 

                                                Cattle    Sheep/   Pigs     Horses     Poultry     Dogs/     Fish
                                                          Goats                                    Cats
                                                                                                                 

    Oxyguris equi                                                           X
    Stephanofilaria                             X
    Larvae of sheep keds (Oestrus ovis)                   X
    Ascarids                                                       X        X
    Trichuris/Hyostrongylus                                        X
    Gastrophilus spp./Habronema spp.                                        X

    External application for control of
     ectoparasites in fish:

    Argulus/Ergasilus/Lernea/Dactylogyrus/
    Gyrodactylus/Trichodina/different
    fish leeches                                                                                             X
                                                                                                                 
    

    By means of a bottle or drenching gun. For this purpose, it is
    recommended to use a 10% solution, the dose depending upon the
    body-weight of the animal to be treated. The treatment should be
    repeated after 2-3 months, or after an interval of three weeks if
    infestation is severe.

    In the feed (dry or liquid), mixture with Neguvon powder.

    After oral application, trichlorfon is rapidly resorbed and is
    translocated in the blood stream to the site at which it is required
    to act. Degradation and excretion take place within a few hours.

    The 50% Neguvon injectable formulation is a ready-for-use solution for
    i.m. or s.c. injection, and is used for the control of Haemonchus
    spp., Oesophagostomum spp., and Dermatobia hominis in cattle in
    many countries of the Middle and Far East, Africa and Latin America.

    For some time past, trichlorfon has also been in use as a pond
    treatment and brief dip treatment for the control of ectoparasites in
    fish, and has proved to be most successful. The required dose of the
    80% powder formulation is 2.5 kg per ha of carp and eel ponds which
    have a depth of 50 cm, the dose being raised to 5 kg per ha in 100 cm
    deep ponds; the dosage rates needed for the treatment of trout ponds
    are only half as large.

    The dosage rate for the brief dip treatment for the control of
    Argulus, Dactylogyrus and Gyrodactylus in carps is 2.5 kg per
    100 litres of water, the duration of the dip treatment being five to
    10 minutes.

    In South Africa, trichlorfon is marketed also as a dog shampoo for the
    control of fleas and ticks in dogs and cats, and as a powder
    formulation for the control of fleas in dogs and cats.

    Other uses

    In hygiene trichlorfon is used for the control of flies in stables as
    well as against many other pest species. Baits are used in most
    instances.

    Further, trichlorfon is used on ornamentals, tree nurseries; and
    forestry.

    Residues resulting from supervised trials

    Trials on crops

    The residue data obtained following application of trichlorfon to
    fruit, vegetables and field crops are presented, in extracts, in Table
    2. These data are from papers published in the literature as well as
    from unpublished reports of Chemagro Corporation and Farbenfabriken
    Bayer AG which have been compiled and submitted to the Meeting by
    Bayer (1971). The residue values were determined initially by
    enzymatic procedure (Delta pH method). and in recent years by gas
    chromatography (electron-capture detector, phosphorus detector,
    microcoulometer). Comparative analyses showed good agreement of these
    methods.

    Following application to green plant material, a half-life of about
    1-2 days was obtained for trichlorfon, as shown by residue studies on
    cotton leaves, grass, cabbage, clover, alfalfa and lettuce. Crops
    treated 2-4 weeks before harvest are practically free of residues at
    harvest time (maize, soybeans, rape, flax),

    Following application to bananas, oranges and ground nuts, the bulk of
    the trichlorfon residue is contained in the peel and shells,
    respectively. Within a few days after the application only slight
    residues are to be found in the pulp and nuts, respectively.

    Trials on animals

    On cattle

    The studies of organs showed that following peroral application of
    100 mg of active ingredient per kg, up to 10 ppm of active ingredient
    is present in steak two hours after the application, and that this
    amount decreases to a level of less than 0.1 ppm after 4-6 hours
    (Behrenz, 1959). Following back-line and spray applications, organs
    (liver, kidneys, brain, heart) and steak are practically free of
    residues; in omental fat, on the other hand, maximum active ingredient
    concentrations of 9.2 and 1.9 ppm were found one and seven days,
    respectively, after the application (Adkins, 1966).

    Following administration of trichlorfon to cattle by different routes,
    residue studies were carried out by Chemagro Corporation, Kansas City,
    United States of America, on practically all organs used for human
    diet (meat, fat, liver, heart, kidneys and brain); the determinations
    were made by sensitive gas chromatographic methods (limit of
    determination 0.01-0.1 ppm; Chemagro Report 14.393; 24.808).

    TABLE 2. RESIDUES RESULTING FROM SUPERVISED TRIALS

                                                                            

                                  Dosage active   Pre-harvest    Residue
    Crop                          ingredient      interval       at harvest
                                  kg/ha
                                  (or % spray)    days           ppm
                                                                            

    Alfalfa                       0.6 - 1.1       7              0.04 - 2.0
    Alfalfa, seed hulls           1.7             8              0.2 - 1.6
      "      chaff                1.7             8              0.2 - 0.6
    Apples                        (0.1 - 0.2%)    8 - 30         n.d. - 0.1
    Artichokes, spray             1.1             0 - 12         n.d.
       "        dust              2.8             7 - 14         n.d.
    Bananas, pulp                 0.4 - 0.8       0              n.d. - 0.3
       "     peel                 0.4 - 0.8       0              n.d. - 2.0
    Barley                        1.7             14 - 25        n.d.
    Blackeyed, beans              1.7             14             n.d.
       "       vines              1.7             14             n.d. - 0.9
    Brussel sprouts, spray        1.7             14 - 19        n.d.
       "       "     dust         2.8             14             0.2
    Cabbage                       0.6 - 1.7       15             n.d. - 0.05
    Cauliflower                   1.7             19 - 21        n.d. - 0.15
    Celery, spray                 0.6 - 1.1       5 - 10         0.05 - 0.19
       "    dust                  0.6 - 1.1       5 - 10         0.05 - 0.16
    Cherries                      0.3 - 0.5       3 - 8          0.001 - 0.12
    Clover                        1.1             7 - 8;14       <0.1 - 9.6;
                                                                 <0.1 - 1.4
    Clover, seed head             1.7             14 - 15        <0.1 - 0.7
       "    chaff                 1.7             14 - 15        <0.1 - 0.6
    Corn, kernel                  0.8 - 1.7       30 - 144       n.d.
      "   cobs                    0.8 - 1.7       30 - 144       n.d.
      "   husk                    1.0 - 1.7       30 - 144       n.d.
      "   fodder, forage          1.0 - 1.7       30 - 144       n.d.
    Cotton, seed                  1.1 - 1.7       7 - 10         <0.01 - 0.05
       "    foliage               2.2 - 2.5       7              n.d. - 0.4
    Cowpeas                       1.7             14             n.d.
    Cowpeas, vines                1.7             14             n.d. - 0.9
    Grass, spray                  1.1 - 2.2       12             2 - 5
      "    granular               1.1 - 2.8       12             <1 - 2
    Garden beets                  1.7             14 - 28        n.d.
    Green beans                   1.7             14             n.d.
    Kale                          0.6 - 1.7       6 - 10         n.d. - 0.3
    Lettuce, leaf
      summer appl.                1.1 - 1.7       7              0.1 - 0.2
      winter appl.                1.1 - 1.7       7;14           6.0;3.9
    Lettuce, head
      summer appl.                1.1 - 1.7       7              <0.1 - 0.24
      winter appl.                1.1 - 1.7       7;14           11.1;3.7

    TABLE 2. (Cont'd.)

                                                                            

                                  Dosage active   Pre-harvest    Residue
    Crop                          ingredient      interval       at harvest
                                  kg/ha
                                  (or % spray)    days           ppm
                                                                            

    Lima beans                    1.7             9 - 15         n.d.
      "  vines                    1.7             9 - 15         n.d. - 0.6
    Lin seed                      1.7             14 - 27        n.d.
    Mustard                       1.7             14/15          n.d.
    Oats, grain                   1.1 - 1.7       13/14          n.d. - 1.4
    Oranges, peel, washed         1.1 - 1.7       7              0.1 - 0.21
       "     pulp                 1.1 - 1.7       7              <0.01
    Peaches                       (0.1)           7 - 14         <0.85
    Peanuts, spray
       "     nuts                 1.7 - 2.5       0 - 8          n.d. - 0.1
       "     shells               1.7 - 2.5       0 - 8          0.1 - 2.65
       "     vines                1.7 - 2.5       3 - 8          0.2 - 0.4
    Peanuts, bait
       "     nuts                 1.7 - 2.5       0 - 3          <0.01 - 0.16
       "     shells               1.7 - 2.5       0 - 3          <0.03 - 0.56
       "     vines                1.7 - 2.5       0 - 3          <0.07 - 2.9
    Peppers, spray                1.1 - 1.7       14/15          n.d. - 0.3
       "     dust                 1.2             14             0.4 - 1.1
    Pumpkins                      1.1 - 1.7       13/15          n.d.
    Rape, seed                    0.8 - 1.7       23 - 32        n.d. - 0.1
      "   meal                    1.1 - 1.7       23             n.d.
      "   oil                     1.1 - 1.7       23             n.d.
    Safflower                     2.2             27;33;43       0.6;<0.1;
                                                                 <0.1
    Soybeans, green beans, pods   0.6             0              0.1 - 6.0
       "      vines               0.6             0              0.5 - 8.8
       "      dry beans           0.6             35 - 53        <0.01
       "      dry vines           0.6             35 - 53        <0.08
                                                                 (1 x 0.45)
    Spinach                       0.8 - 1.1       14/15          <0.1 - 1.6
    Strawberries                  0.3 - 1.1       3/4            <0.07
    Sugar beets, roots            0.3 - 1.1       29 - 34        <0.01
      "     "    tops             0.3 - 1.1       29 - 34        <0.05
    Sweet corn, spray
      "     "   husk              1.7 - 2.2       7 - 14         n.d. - 0.6
      "     "   kernel            1.7 - 2.2       7 - 14         n.d.
      "     "   cob               1.7 - 2.2       7 - 14         n.d. - 0.1
      "     "   fodder            1.7 - 2.2       7 - 14         0.2 - 1.1
    Sweet corn, dust
      "     "   husk              2.0             15             2.7 - 9.1
      "     "   kernel, cob       2.0             15             n.d.

    TABLE 2. (Cont'd.)

                                                                            

                                  Dosage active   Pre-harvest    Residue
    Crop                          ingredient      interval       at harvest
                                  kg/ha
                                  (or % spray)    days           ppm
                                                                            

    Sweet corn, granular
      "     "   husk              1.1 - 1.7       14 - 21        n.d. - 8.4
      "     "   kernel            1.1 - 1.7       14 - 21        n.d. - 0.1
      "     "   cob               1.1 - 1.7       14 - 21        n.d. - 0.2
      "     "   fodder            1.1 - 1.7       14 - 21        n.d. - 3.0
    Table beets, roots            1.7             7 - 13         n.d. - 0.2
      "     "    tops             1.7             7 - 13         0.2 - 2.5
    Tea                           1.4 - 1.8       21             <1
    Tobacco, green
       "     spray                1.1 - 1.7       14/15          n.d. - 1.3
       "     dust                 1.0 - 2.5       10/14          n.d.
    Tobacco, cured
       "     spray                1.1 - 1.7       0 - 21         n.d
       "     dust                 1.0 - 2.5       0 - 21         n.d
    Tomatoes                      0.8 - 1.7       7              n.d. - 0.5
    Turnips, roots                                10 - 15        n.d. - 0.09
    Wheat, grain                  1.3 - 1.7       14 - 39        n.d. - 0.25
      "    straw                  1               25 - 39        n.d. - 4.2
      "    flour                  1               25 - 39        <0.05
      "    bread                  1               25 - 39        <0.05
                                                                            


    Following peroral uptake of the active ingredient (12.5 and 20 ppm in
    feed), no trichlorfon residues were detected (<0.1 ppm) in any of the
    examined tissues and organs (brain, heart, kidney, steak, fat) after a
    four week feeding period (Chemagro Report 17.991; 18.884). Following
    external application of the 9 and 16% formulation - single back-line
    application of 25, 50 or 100 mg of active ingredient per kg
    (examination of tissues 21 days after application) and four week mist
    spray application of 1.1 g of active ingredient per animal and day
    (examination of tissues after the final application) - no residues
    were detected in any of the tissues or organs (Chemagro Report 14.412;
    18.495; 26.117).

    Only slight proportions of the parent compound or its metabolites are
    to be found in milk, as shown by a number of studies using
    P32-labelled and unlabelled trichlorfon.

    Following peroral application of 25 mg of active ingredient per kg,
    less than 0.2% of the radioactivity representing the total dose
    administered was secreted in the milk at the end of 144 hours; of
    this, about 10% was unchanged active ingredient and about 23% behaved
    like inorganic phosphorus (Robbins et al., 1956). Following similar
    application of 80 mg of active ingredient per kg, the maximum residue
    at eight hours was 2.5 ppm in the milk samples and at 22 hours
    0.1 ppm; in the following milk samples, the residue levels were below
    the limit of determination of 0.05 ppm (Behrenz, 1961). Following
    spray application of five litres of a 2% active ingredient solution
    and back-line was application of one litre of a 2% solution, the milk
    samples at eight hours were found to contain 0.05-0.25 ppm of active
    ingredient and in the later milk samples no residues were detected
    (Behrenz, 1961).

    Studies by Ackermann et al. (1968) showed that following backline wash
    application of one litre of a 2% trichlorfon solution, the maximum
    residue in the first milk sample at eight hours was 0.2 ppm; the
    residues in the third milk sample at 32 hours were below 0.01 ppm.
    Analyses of these milk samples for dichlorvos showed a maximum content
    of 0.03 ppm in the first sample and 0.01 ppm in the third sample.

    Following a single dermal treatment with 6% suspension, equivalent to
    36 mg of active ingredient per kg, 0.1-0.2 ppm of trichlorfon was
    found to be present within the first eight hours (Leahy, 1964).
    Following application of 1.15 litres of a 2% trichlorfon solution (or
    0.57 litres of a 4% solution) as a dermal wash per animal, the level
    of active ingredient present in the milk did not at any time exceed
    0.4 ppm; milk samples taken later than six hours after the application
    contained about 0.1 ppm of active ingredient (Wickham and Flanagan,
    1962).

    Following pour-on application (of 100 or 300 ml of a 5.7% solution
    (P32-labelled)), the active ingredient concentration in the milk
    reached a peak of 0.13 or 0.47 ppm after 14-18 hours; after four days,
    the content was less than 0.05 ppm, and after seven days it was less
    than 0.01 ppm (Schwarz and Dedek, 1965a).

    Following intravenous and intramuscular injection of 20 and 25 mg of
    P32-labelled active ingredient, radioactive substances were found in
    the milk only at six and 10 hours after the application; dichlorvos
    was not formed in these experiments (Kühnert et al., 1963).

    Chemagro Corporation, Kansas City, United States of America, carried
    out residue studies by gas chromatographic methods following
    application of the active ingredient to dairy cows by different
    routes. The lower limit of determination was 0.003-0.01 ppm (Chemagro
    Report 16.460; 24.808).

    Following peroral uptake of the compound in the feed (12.5, 20, 50,
    150 and 325 ppm) for a period of one or four weeks, no trichlorfon
    residues were found to be present in the milk at the end of the
    feeding period (Chemagro Report 17.440; 18.321; 29.234).

    Following external application of the active ingredient as a single
    pour-on treatment (at 3.7 g/100 kg) or as a single spray treatment
    (at 28 g/animal) or as a four week mist spray treatment (1.1 g per
    animal per day), active ingredient residues of no more than 0.04 and
    0.02 ppm were found in the milk samples taken on the first and second
    day after the application only for those animals which received the
    pour-on treatment (Chemagro Report 17.970; 18.322; 18.521; 21.289).
    The majority of these milk samples were analysed for residues of
    trichloroethanol, a possible metabolite of trichlorfon; however, this
    compound could not be found in any of the examined samples.

    Following a spray treatment of stable walls at a rate of 1 g of active
    ingredient per square metre, no trichlorfon residues were found in the
    milk of the cows kept in the treated stable (Chemagro Report 16.538).

    On pigs

    For the use of trichlorfon for the control of ectoparasites and
    endoparasites in pigs, the degradation and excretion of the active
    ingredient was studied following subcutaneous injection of 25 mg of
    P32-labelled trichlorfon per kg body-weight. The maximum active
    ingredient concentration in blood was reached after 15-60 minutes
    (10-11 ppm) and in the intestinal contents after 20-150 minutes
    (4-5 ppm). After 5-7 hours, the blood and intestinal contents still
    contained about 1 ppm of active ingredient. Dichlorvos was no longer
    detectable in blood 3.5 hours after the application. The trichlorfon
    concentration in meat was always somewhat lower than in the blood; a
    concentration of 5 ppm was found in the meat two hours after the
    injection. The trichlorfon concentration in the meat decreased by a
    power of 10 in each 6-7 hours (Schwarz and Dedek, 1965b, 1966).

    Chemagro Corporation carried out studies using gas chromatographic
    methods (limit of determination 0.01-0.1 ppm residue; Chemagro Report
    14.393; 24.808). After addition of 1500 ppm of active ingredient to
    the drinking water of pigs (the ingested amount was equivalent to a
    single dose of 125 mg of active ingredient per kg body-weight),
    0.02-0.07 ppm of active ingredient was found in the liver and
    0.02-0.05 ppm was found in loin steak four days after the application;
    brain, heart, kidneys and fat samples were free of residues. None of
    the organs contained any trichlorfon residues after seven days
    (Chemagro Report 27.533). Dichlorvos was not detectable in any of the
    examined samples four days after the trichlorfon application (Chemagro
    Report 27.561).

    No trichlorfon residues were detectable in any of the examined organs
    and tissues 14 days after application of the compound in the diet at a
    dose level equivalent to 100 mg/kg body-weight (Chemagro Report
    18.678).

    On sheep

    Following peroral application of 120 mg of trichlorfon per kg
    body-weight, exploratory residue determinations were carried out in
    organs by means of a fly larva test. The residues dropped below the
    limit of determination of 0.1 ppm within 4-6 hours after the
    application (Behrenz, 1959). Following percutaneous application of
    50 mg of the compound per kg body-weight, the concentration in the
    blood reached a level of 1 ppm at which it remained for only a brief
    period. Dichlorvos was detectable only in slight amounts (Dedek and
    Schwarz, 1970).

    Fate of residues

    General comments

    The distribution of trichlorfon residues in organisms is characterized
    by its hydrophilic properties.

    The decomposition of the molecule is brought about both by splitting
    the P-C bond and by hydrolysis of the P-OCH3 bonds (Hassan and
    Zayed, 1965). Furthermore, trichlorfon can be converted to the more
    toxic dichlorvos, O,O-dimethyl-(2,2-dichlorovinyl)-phosphonate.

    In animals

    On account of its hydrophilic properties, trichlorfon is rapidly
    absorbed by the organism, broken down and excreted in the urine.
    Studies with P32-labelled compound on cattle showed that following
    peroral application of dosages ranging from 25-100 mg of active
    ingredient per kg body-weight, 66% of the P32 activity is excreted
    in the urine within 12 hours; of this amount of excreted
    radioactivity, 17% is dimethyl phosphate, 76% is accounted for by a
    metabolite of unknown structure, and 0.26% by unchanged active
    ingredient. After 45 hours, only 0.28% of the P32 activity
    representing the total dose administered is found to be present in the
    urine (Bolle, 1956; Robbins et al., 1956).

    The degradation of the compound in blood proceeds at a very fast rate.
    In cattle, 12 hours after peroral application of 40 mg of active
    ingredient per kg, 0.03%, of the applied P32 activity is present in
    the blood, and 0.003% after 45 hours (Bolle, 1956). The peak of
    radioactivity is attained after two hours (Robbins et al., 1956).
    Following intravenous application, the parent compound is broken down
    by more than 95% after one hour; dichlorvos is found to be present in
    a very low concentration only within the first four minutes (Kühnert
    et al., 1963).

    For further details, see for Biochemical aspects and residues
    resulting from supervised trials: Trials on animals.

    On poultry and eggs

    Gas chromatographic determinations showed that no residues were
    present in giblets, muscle and fat (limit of determination of 0.1 ppm)
    or in the eggs (limit of determination of 0.003 ppm) of poultry which
    had been maintained for four weeks on a diet containing 2.5 and 5 ppm
    of the compound (Chemagro Report 20.945; 21.502).

    In plants

    Studies of the metabolism of trichlorfon in plants were carried out on
    cotton plants.

    The identified metabolites included dimethyl phosphate which accounted
    for up to 70% for the applied trichlorfon dose; only small amounts of
    monomethyl phosphate, O-demethyl trichlorfon, O-demethyl dichlorvos
    and dichlorvos were formed (Hassan et al., 1966; Bull and Ridgway,
    1969). Besides these metabolites, Bull and Ridgway found an
    unidentified metabolite which accounted for a large percentage of the
    applied dose of parent compound; this phosphorus-containing unknown is
    split by ß-glucosidase but not by ß-glucuronidase.

    Chloral and trichloroethanol are stated to be possible degradation
    products (Arthur and Casida, 1957). However, these products could not
    be detected in routine residue studies (Chemagro Corporation,
    unpublished). Earlier studies also revealed that chloral and
    trichloroethanol are metabolized in plants to form
    B-2,2,2-trichloroethanol-gentiobioside (Miller, 1941).

    In micro-organism cultures

    Studies on Penicillium notatum, Fusarium sp. and Aspergillus niger
    showed that approximately half of the applied parent compound is
    transformed within 10 days. The principal metabolite found was
    O-demethyl trichlorfon. A second degradation product formed is
    probably 2,2,2-trichloro-1-hydroxyethyl-phosphonate (Zayed et al.,
    1965).

    In soil

    Trichlorfon is not used for the control of soil pests. Studies
    conducted by Chemagro Corporation have shown, however, that after
    addition of 10 ppm of trichlorfon to soil, the residue level drops
    below the limit of determination within 15-112 days depending upon the
    soil type. Trichlorfon has a very low stability in soil; residues of
    trichlorfon in runoff water from sandy loam, silt loam and high
    organic silt loam soils showed a relatively low tendency to move
    (Chemagro Report 28.937). After addition of 0.25 ppm of trichlorfon to

    pond water, no residues are to be found in the mud (Chemagro Report
    21.313).

    In food processing

    The published data on trichlorfon residues have generally been
    obtained in studies of non-processed plant and animal products. When
    these products are processed for the human diet, the trichlorfon
    residue level is considerably reduced by such processing procedures as
    boiling and sterilization.

    In spinach, the residues which have an original level of 2.0 ppm in
    the treated plants are reduced by bleaching (five minutes at 100°C) to
    a concentration of 0.03 ppm and by further sterilization (100 minutes
    at 115°C) to a level of 0.01 ppm. In dwarf beans, the residue level is
    reduced from 1.22 ppm to 0.06 ppm and 0.05 ppm, respectively. In peas,
    which had an original residue level of 0.21 ppm, no more residues were
    detectable after bleaching and sterilization (Dormale et al., 1959).

    Tomatoes were treated with 10 ppm of the compound and then canned
    according to standard commercial procedure. The heat treatment
    destroyed 80% of the compound (Chemagro Report 9012). Safflower seed
    containing 0.9 ppm of the compound was processed into meal, crude oil
    and refined oil. None of the three processed products contained
    detectable residues (Chemagro Report 11.255).

    Meat of sheep which ware slaughtered one hour after receiving a
    peroral application of 120 mg/kg contained 1-10 ppm of the compound;
    after the meat had been boiled for one hour, it contained no
    detectable residue (Behrenz, 1959).

    In beef which was immersed in a trichlorfon solution to prevent fly
    maggot infestation, the residue level of the compound was reduced by
    thorough washing from 0.77 ppm to 0.58 ppm. After one hour's boiling,
    the residue level in the meat and in the broth was less than 0.1 ppm
    (Börger and Maier-Bode, 1967).

    Evidence of residues in food in commerce or at consumption

    No data were submitted for consideration.

    Methods of residue analysis

    Many colorimetric, thin-layer chromatographic and gas chromatographic
    methods for the determination of trichlorfon residues are described in
    the literature. Some of the methods permit simultaneous determination
    of trichlorfon and its possible metabolites, e.g. trichloroethanol and
    dichlorvos. However, formation of trichloroethanol was not established
    in any of the residue studies undertaken.

    Trichlorfon can be extracted from plant material with chloroform
    (Zadrozinska, 1966), acetone/hexane (Anderson et al., 1966), ethyl
    acetate (Cernà, 1963; Watts et al., 1969) or diluted acetic acid
    (Sissons and Telling, 1970). For clean-up, the extract residue is
    transferred to water; after separating the plant constituents with
    petroleum ether or heptane, the parent compound is extracted with
    chloroform or diethyl ether (Zadrozinska, 1966; Anderson et al.,
    1966). For determination of the compound by the cholinesterase
    inhibition technique, extraction with water will suffice (Reynolds
    et al., 1960; Chemagro Report 2412; 3581). Column chromatographic
    clean-up of the plant extract is possible on charcoal (Watts et al.,
    1969) or on aluminium oxide (Sissons and Telling, 1970). If plant
    material with a high water content is involved, the compound can be
    separated from the plant constituents by dialysis of the macerate in
    diluted sulfuric acid, and extracted from the diffusate with diethyl
    ether (Anderson et al., 1966; Chemagro Report 8839; 21811).

    Trichlorfon can be extracted from animal tissues with acetonitrile
    (Beck and Sherman, 1968; Anderson et al., 1966; Chemagro Report
    14393), chloroform (Ackermann et al., 1969; Chemagro Report 24808) or
    acetone (Chemagro Report 24808). For further clean-up, the extract
    residue is transferred to water, fat portions are separated with
    heptane, and the parent compound is extracted from the aqueous phase
    with diethyl ether (Chemagro Report 14393; Anderson et al., 1966),

    In milk, trichlorfon (after removal of fat by centrifuging and
    separation of protein by precipitation) is determined either directly
    by bioassay (Wickham and Flanagan, 1962) or (after extraction with
    chloroform) by thin-layer chromatography, together with possibly
    formed dichlorvos (Ackermann et al., 1968). For gas chromatographic
    determination of trichlorfon, the milk is extracted with acetone and
    benzene. In this method, trichloroethanol is co-determined as a
    possible metabolite (Chemagro Report 16460).

    Enzymatic determination

    Giang and Hall (1951) developed a method for the enzymatic
    determination of organic phosphorus insecticides (Delta pH method).
    For the determination of trichlorfon residues, the parent compound is
    converted to dichlorvos which is a strong cholinesterase inhibitor
    (Reynolds et al., 1960; Chemagro Report 2412; 3581), The lower limit
    of determination is approximately 0.01 ppm trichlorfon. The method is
    unspecific.

    Bioassays

    Bioassays with mosquito larvae (Aedes aegypti) have been employed
    for determining residues of trichlorfon in milk (Behrenz, 1961;
    Wickham and Flanagan, 1962). Börger and Maier-Bode (1967) used
    Daphnia magna as the test species for determining residues of
    trichlorfon in meat. The limit of determination is approximately 0.05
    ppm. The method is unspecific.

    Thin-layer chromatography

    Trichlorfon residues in plants and in animal tissues can be determined
    by thin-layer chromatography on silica gel or aluminium oxide plates
    sprayed with silver nitrate. The lower limit of determination is
    0.25-0.5 ppm of trichlorfon in apples (Zadrozinska, 1966) and
    0.2-0.5 µg in animal tissue extracts (Beck and Sherman, 1968). Smaller
    amounts of trichlorfon and dichlorvos can be determined by the
    cholinesterase inhibition technique (Ackermann et al., 1968, 1969).

    Agar-diffusion method

    The agar-diffusion method described by Sandi (1962) was modified for
    routine determination of trichlorfon. A residue level of 0.1 ppm can
    be determined in milk; however, it is not possible to separate
    trichlorfon from dichlorvos (Ackermann et al., 1968).

    Colorimetry

    A colorimetric micro method for determining trichlorfon residues is
    based on the determination of chloroform (which is separated from the
    trichlorfon by pyrolysis at 550°C) with pyridine and sodium hydroxide
    (Fujiwara reaction). This method was used for determining trichlorfon
    residues in olive oil (Allessandrini and Lanforti, 1957) and in fruit
    and lettuce (Cernà, 1963). The limit of determination is approximately
    1 ppm in olive oil and 10 µg in plant material.

    Trichlorfon residues can be determined colorimetrically also by a
    total phosphorus procedure in plant material (Sissons and Telling,
    1970) and in milk (Leahy, 1964); the lower limit of determination is
    0.1-0.2 ppm.

    Gas chromatography

    Trichlorfon residues can be determined with a high degree of
    sensitivity and specificity by gas chromatography. The intact molecule
    is not determined by this method but instead the cleavage products
    chloral or dimethyl phosphite which form upon pyrolytic cleavage of
    trichlorfon in the injection port of the gas chromatograph. Chloral is
    detected with the electron-capture detector (Anderson et al., 1966);
    trichloroethanol can be simultaneously determined as a theoretically
    possible metabolite. Chloral can also be determined with the Dohmann
    microcoulometric gas chromatograph (Chemagro Report 8839). The
    clean-up of extracts is simpler when trichlorfon is detected with a
    phosphorus-specific detector, e.g. a modified flame ionization
    detector (thermionic detector) (Chemagro Report 21811, 24808). The
    limits of determination of these gas chromatographic methods depend
    upon the material being analysed and the clean-up procedure used.
    However, they are usually very low, e.g. 0.01-0.1 ppm with an
    electron-capture detector and 0.003-0.06 ppm with the phosphorus
    detector.

    Studies on 30 different phosphorus-containing pesticides registered
    for use in different crops show that only phosphamidon interferes with
    the gas chromatographic determination of trichlorfon with the
    phosphorus detector (Chemagro Report 21811, 27471, 29411). By using a
    different column, this interference can be avoided (Chemagro Report
    26335).

    Parallel residue analyses of treated plant material showed agreement
    of residue values obtained by the cholinesterase inhibition technique
    and by gas chromatography. Determination by the cholinesterase
    inhibition technique produces slightly higher residue values, which is
    probably due to the presence of slight traces of dichlorvos (Chemagro
    Report 9733).

    For routine determination of trichlorfon residues, gas chromatography
    is the most suitable method. The compound can be detected with a
    microcoulometer, an electron-capture detector or a phosphorus-specific
    detector, e.g. a thermionic or flame photometric detector.

    Examples of national tolerances and safety intervals

                                                                            

    Country             Crop                          Tolerance      Safety
                                                      ppm            interval
                                                                     days
                                                                            

    Argentina           Bananas                       0.2 (provisional)
                        Bananas (peeled)              0
    Australia           General                                      2
                        Fruits, grains, vegetables    2.0
    Austria             General                                      14
                        Cucumbers, tomatoes,
                        peppers                                      4
    Belgium             General                                      10
                        Fruits, vegetables,
                        excl. potatoes                0.5
    Brazil              Vegetables                    0.5            7
                        Fruits and field crops        0.5            10
                        Meat and milk                 0.001
    Bulgaria            General                                      14
    Canada              Alfalfa                                      14
                        Rape                                         21
                        Corn                                         40
                        Sugar beets                                  14
                        Sugar beets, tops                            28
                        Tobacco                                      3
                        Beans                                        14
                        Cabbage, cauliflower,
                        Brussels sprouts                             21

                                                                            

    Country             Crop                          Tolerance      Safety
                                                      ppm            interval
                                                                     days
                                                                            

                        Carrots, rutabagas,
                        salsify, turnips                             28
                        Collards, kale, lettuce,
                        spinach                                      28
                        Peppers                                      21
                        Table beets                                  28
                        Tomatoes                                     21
                        Artichokes, bananas,          NR
                        beans, beef cattle,           NR
                        beets, Brussels               NR
                        sprouts, cabbage,             NR
                        carrots, cauliflower,         NR
                        collards, corn, kale,         NR
                        lettuce, peppers, rape        NR
                        seed, rutabagas,              NR
                        salsify, spinach,             NR
                        sugar beets, tomatoes,        NR
                        turnips                       NR
    Finland             General                                      14
    France              General                                      7
    German Democratic   Fruits, root vegetables,
    Republic            leafy vegetables,
                        cabbages, legumes,
                        fruit-producing
                        vegetables (tomatoes,
                        cucumbers)                    1.0
                        Meat, fish, animal and
                        vegetable fats, eggs,
                        milk, baby foods              0
                        Field crops, fruits                          10
                        Cherries                                     5
                        Vegetables                                   7
                        Special crops                                14
                        Crops used for the
                        production of baby foods,
                        drugs and health foods                       30
    German Federal      Fruits, field crops,
    Republic            incl. fodder crops                           10
                        Vegetables                                   7
                        Application under glass:
                        general                                      10
                        Leafy vegetables,
                        fruit-producing vegetables,
                        root vegetables,

                                                                            

    Country             Crop                          Tolerance      Safety
                                                      ppm            interval
                                                                     days
                                                                            

                        legumes, fruits incl.
                        grapes                        0.5

    Great Britain       General                                      2
    Hungary             Animal products               0
    Israel              Fruits incl. grapes,
                        clover, alfalfa,
                        sub-tropical trees, sugar
                        beets, fodder crops                          7
                        Maize                                        30
                        Tomatoes, cucumbers,
                        cucurbits, cabbage,
                        radish, lettuce,
                        spinach, beans, other
                        vegetables                                   10
                        Peppers, eggplants,
                        strawberries, cauliflower,
                        artichokes                                   14
    Morocco             General                                      7
                        Olives                                       30
    Netherlands         General                       0.5
                        General, field-grown                         10
                        Spinach, field-grown                         4
                        General (under glass
                        from 1 March - 1 Nov.)                       17
    New Zealand         Tomatoes (canned)                            1
                        Other crops                                  14
    Poland              Fruits, legumes (not
                        vegetables), root
                        crops and other field
                        crops                                        14
                        Vegetables                                   10
    Portugal            General                                      7
                        Industrial tomatoes                          4
    South Africa        Maize, wheat, citrus
                        fruits, apples, pears,
                        apricots, peaches,
                        sub-tropical crops                           10
                        Cucurbits                                    7
                        Alfalfa                                      2
                        Tomatoes                                     3
                        General                       2.0
    Soviet Union        General                       1.0
    Spain               General                                      10

                                                                            

    Country             Crop                          Tolerance      Safety
                                                      ppm            interval
                                                                     days
                                                                            

    Sweden              General                                      14
    Switzerland         General                                      21
                        Vegetables                                   14
                        Beets                                        42
                        Vegetables, legumes,
                        fruits incl. grapes           0.5
    United States of    See USDA Summary of
    America             Registered Agricultural
                        Pesticide Chemical Uses
    Yugoslavia          General                       0.5
                        Fruits, vegetables,
                        field crops                                  14
                                                                            


    Appraisal

    Trichlorfon is an organophosphorus insecticide which is especially
    used on crops against a variety of insects (moths, flies, bugs, etc.).
    It is also widely used against ecto- and endoparasites of animals, in
    public health and as an anthelmintic in medicine.

    It is used on a wide variety of field and pasture crops with
    application rates of 150-2000 g/ha, normally 500-1200 g/ha, or as
    0.075-0.2% sprays. As an animal health product, it is normally applied
    at a rate of 25-75 mg/kg body-weight externally as wash or spray and
    spot-on treatment and internally by mouth and by injection. In public
    health it is used against flies and other pests commonly in the form
    of baits. Other uses are on ornamentals, in tree nurseries, and in
    forestry.

    Residue data for evaluation are satisfactory.

    The behaviour of trichlorfon is characterized by its hydrophilic
    properties. Its decomposition is brought about by splitting the P-C
    bond and by hydrolysis of the P-OCH3 bonds. In addition, in tissues
    it can be converted in trace amounts to dichlorvos. Products of more
    advanced degradation have also been found and characterized. In food
    processing, trichlorfon residues are substantially disappearing.

    As a result of use of trichlorfon, residues may occur in animal feed.
    When the applications are made in accordance with good agricultural
    practice the residues are considered to be no hazard to the animal
    health and no detectable contamination of the foods derived from these
    animals is to be expected.

    There are a number of methods of residue analysis available. For
    regulatory purposes highly specific and sensitive gas chromatographic
    methods with detection limits of less than 0.01-0.1 ppm have been
    developed.

    Due to the insignificant magnitude of dichlorvos and to the low
    toxicity of other degradation products, recommendations for tolerances
    of trichlorfon residues are made in terms of the parent compound.

    Since the direct application of trichlorfon to the domestic animals
    may result, although for a short limited period of time, in residues
    of varying magnitude in milk, meat, and fat, it is necessary, in
    accordance with the local needs of animal health, to set limitations
    of use, e.g. type of formulation, route of application, dosage,
    condition of the animals, and safety interval from treatment to use of
    animal products for human food. The recommendations for trichlorfon
    residues in animal products are made, because the use of insecticides
    is necessary in animal health, application of trichlorfon according to
    good agricultural practice will cause no health hazards to animals,
    and, by adjusting properly the conditions of use, milk, meat, organs,
    and fat can be obtained from the treated animals practically free from
    the trichlorfon residues. Additional safeguard of the consumer against
    the residues is the degradation of trichlorfon in storage, processing
    and cooking of the animal products before they are consumed.

    RECOMMENDATIONS FOR TOLERANCES, TEMPORARY TOLERANCES OR PRACTICAL
    RESIDUE LIMITS

    Temporary tolerances

    The following recommendations are made for temporary tolerances:

                                                              

                                    Period from
    Crop                            treatment        Tolerance
                                    to analysis      (ppm)
                                    (days)
                                                              

    Cereals:
    Barley                          21               0.1
    Maize                           30               0.1
    Wheat                           30               0.2

    Fruits:
    Apples                          14               0.1
    Bananas, pulp                   0                0.2
    Cherries                        7                0.1
    Oranges, pulp                   7                0.1
    Peaches                         14               0.2
    Strawberries                    4                0.1

    (continued)
                                                              

                                    Period from
    Crop                            treatment        Tolerance
                                    to analysis      (ppm)
                                    (days)
                                                              

    Vegetables:
    Artichokes                      7                0.1
    Blackeyed, beans                14               0.1
    Brussels sprouts                14               0.2
    Cabbage                         14               0.1
    Cauliflower                     21               0.2
    Cowpeas                         14               0.1
    Green beans                     14               0.1
    Kale                            14               0.2
    Lima beans                      14               0.1
    Mustard, leaf                   14               0.1
    Peppers                         14               1
    Pumpkins                        14               0.1
    Sweet corn, kernels and cobs    14               0.2
    Tomatoes                        14               0.1
    Celery                          14               0.2
    Sugar beets                     30               0.05
    Beets                           14               0.2
    Turnips                         14               0.1

    Oil seeds:
    Cotton seed                     14               0.1
    Flax seed                       14               0.1
    Lin seed                        30               0.1
    Safflower seed                  45               0.1
    Soybeans, dry                   45               0.1

    Nuts:
    Peanuts, shelled                7                0.1

    Animal products:
    Meat, fat and by-products
    of cattle and pigs              14               0.1
    Whole milk                      2                0.05
                                                              


    Further work or information

    Required before 30 June 1975

    1.   A two-generation carcinogenicity study to elucidate the possible
         increase in the incidence of tumours including those of the
         mammary gland.

    2.   More information on residues on oats.

    3.   More information on residues on lettuce and spinach under various
         conditions (including greenhouses).

    Desirable

    1.   Elucidation of the effect on spermatogenesis.

    2.   Information on residues occurring in food in commerce and in
         total diet studies.

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    Chemagro-Report (Chemagro Corporation, Kansas City, USA)

    2412      Tentative method for microestimation of Dipterex residues by
              the Cholinesterase inhibition technique

    3581      The determination of Dylox residues by the Cholinesterase
              inhibition technique

    8839      The microcoulometric determination of Dylox residues in
              plant material

    9012      The effect of canning on Dylox residues in tomatoes

    9733      A comparison of Dylox residue results obtained by the
              Cholinesterase inhibition procedure (Report 3581) and the
              vapor phase chromatographic procedure (Report 8839)

    11 255    The effect of processing on Dylox residues in Safflower

    14 393    Determination of Neguvon, Chloral hydrate and
              trichlorethanol residues in animal tissues by electron
              capture gas chromatography

    14 412    Trichlorfon residues in cattle tissues (Backline application
              with 8 and 16% pour-on)

    16 460    Determination of Trichlorfon, Chloral hydrate and
              trichlorethanol residues in milk by electron capture gas
              chromatography

    16 538    Trichlorfon residues in milk (barn spray prepared with S.P.)

    17 440    Trichlorfon residues in milk (in feed prepared)

    17 970    Trichlorfon residues in cattle milk (mist spray with 1%
              Co-Ral - 2% Trichlorfon combination)

    17 991    Trichlorfon residues in cattle tissues (in feed prepared)

    18 321    Trichlorfon residues in cattle milk (in feed prepared with
              technical standard)

    18 322    Trichlorfon residues in milk (spray prepared with 80%
              soluble powder)

    18 495    Trichlorfon residues in cattle tissues (mist spray with 1%
              Co-Ral - 2% Trichlorfon combination)

    18 521    Trichlorfon residues in milk (pour-on with 8% formulation)

    18 678    Trichlorfon residues in swine tissues (in feed with 90%
              soluble powder)

    18 884    Trichlorfon residues in cattle tissues (in feed prepared
              with technical standard)

    20 945    Trichlorfon residues in poultry tissues (in feed prepared
              with Dylox 80% S.P.)

    21 289    Trichlorfon residues in milk (mist spray prepared with 1%
              Co-Ral - 2% Trichlorfon combination)

    21 313    Trichlorfon residues in mud (spray on surface with 50% S.P.)

    21 502    Trichlorfon residues in eggs (in feed prepared with 80%
              S.P.)

    21 811    Determination of residues of Trichlorfon in Alfalfa by
              thermionic emission gas chromatography

    24 808    Determination of residues of Trichlorfon in bovine animal
              tissues by thermionic emission gas chromatography

    26 117    Trichlorfon residues in cattle tissues (Backline application
              using 8% pour-on)

    26 334    A confirmatory gas chromatographic procedure for Trichlorfon
              residue analysis

    27 471    An interference study for Trichlorfon residue determination
              on Alfalfa and Clover

    27 533    Trichlorfon residues in swine tissues (drinking water
              treated with Neguvon)

    27 561    DDVP-residues in swine tissues (drinking water treated with
              Neguvon)

    28 937    Trichlorfon residues in runoff water from soils

    29 234    Trichlorfon residues in milk (Bolus-capsules fortified with
              Dylox 80% S.P.)

    29 411    An interference study for the residue method for Trichlorfon
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    See Also:
       Toxicological Abbreviations
       Trichlorfon (EHC 132, 1992)
       Trichlorfon (HSG 66, 1991)
       Trichlorfon (JECFA Food Additives Series 51)
       Trichlorfon (WHO Food Additives Series 45)
       TRICHLORFON (JECFA Evaluation)
       Trichlorfon (WHO Pesticide Residues Series 5)
       Trichlorfon (Pesticide residues in food: 1978 evaluations)
       Trichlorfon (IARC Summary & Evaluation, Volume 30, 1983)