FENTHION         JMPR 1978


         Fenthion was reviewed by the 1971, 1975 and 1977 Meetings
    (FAO/WHO 1973b, 1977b, 1978b). A temporary ADI was established and
    temporary MRLs were recommended for a range of fruits and
    vegetables and attention was drawn to various items on which there
    was a need for further work or information. New data received is
    evaluated in this monograph addendum.



    Special studies

    Pharmacological study

         A daily diet containing 300 ppm fenthion was given to 8 groups
    of Donrya rats: a hare's eye group, a satured eyelid group, a
    cervical sympathectomy group, a group given antibiotic eye
    ointment, a group given atropine eyedrops and groups given
    subcutaneous injections of pralidoxime, atropine and GSH for about
    one month. All rats given fenthion showed typical symptoms, of
    organophosphorus intoxication such an nervousness, general spasms,
    diarrhea, and salivation. Also ophthalmological symptoms, such as
    eye-ball protrusion, keratoconus, mammiform cornea and corneal
    turbity were observed. The described pretreatments did not prevent
    the ocular symptoms (abstract only)(Kawai et al., 1976).


         Preliminary studies indicated 100 mg/kg was lethal to
    non-pregnant female rats in 2-4 days, and that 30 mg/kg induced
    toxic symptoms. Therefore four groups of 20 pregnant rats were
    dosed orally at 0, 1, 3 or 10 mg/kg/day on days 6-15 of pregnancy.
    Day 0 was the day semen was detected). At sacrifice (day 20 of
    gestation) implantation rate, numbers of live, dead and resorbed
    foetii, litter weight and placental weights were recorded. After
    gross examination, approximately 2/3 of the offspring were examined
    for skeletal malformations (Alizarin stain), and 1/3 for soft
    tissue malformations. No treatment related effects were noted
    (Machemer, 1978a).


         In a dominant lethal assay 2 groups of 50 male mice
    (NMRI-strain) were given a single oral dose of 0 or 25, mg
    fenthion/kg b.w. Additionally a third group of mice was treated
    with 10 mg fenthion/kg b.w., because 25 mg/kg induced toxic effects
    in the males (drowsiness, ruffled coat and dilated intestines). The
    compound was given in a 2% aqueous cremophor E.L. emulsion.

         After injection each male was caged with a untreated virgin
    female for a period of 4 days. This procedure was repeated for a
    total of 12 matings.

         On day 12-16 of gestation the females were sacrificed and the
    number of implantations, the live and dead implants (sum of the
    deciduomata, the resorptions and the dead embryos) counted.

         Except for an increased pre-implanation loss at the dose level
    of 25 mg/kg b.w. in the first two mating periods, no other
    treatment-related effects on fertility, pre- and post implantation
    loss were observed (Machemer, 1978b).


         In rats no synergistic effects on the acute oral toxicity was
    noticed of fenthion with edinfenphos and the active ingredient of
    Bassa. (Thyssen, 1977).

    Acute toxicity

         In an attempted suicide 0.5 g of 2% fenthion powder was
    ingested. The patient felt severe pain in the epigastrium and
    abdomen 3 hrs after ingestion, then experienced continued vomiting
    and diarrhea. Upon admission to hospital conspicuous reduction of
    serum ChE-activity of 0.08 delta pH was observed. She was treated
    by repeated injections of P.A.M. and atropine (summary only) (Kanda
    and Matsushima, 1976).

    Short-term studies


         In an interim report data are provided on four groups of 5
    male and 5 female Rhesus monkeys which received 0, 0.02, 0.07 or
    0.2 mg fenthion/kg body weight as a freshly prepared solution in
    corn oil, daily by stomach tube for one year. Animals were observed
    daily for general appearance, etc., body weight and
    ophthalmological examinations were reported monthly, and clinical
    chemistry, haematology and urinalysis were performed at 0, 1, 3, 6
    and 12 months. Plasma and erythrocyte cholinesterase were measured
    at 0, 1, 2, 3 and 4 weeks and thereafter monthly. One monkey/sex
    from the 0 and 0.2 mg/kg groups were sacrificed at 7 months, 3
    weeks. Brain cholinesterase, organ absolute and relative weights,
    gross and histopathology were recorded. The plasma cholinesterase
    was depressed in both sexes at 0.2 mg/kg. Plasma cholinesterase
    depression occurred at 0.07%, but was inconsistent and minimal. No
    adverse effects were noted on any other parameter (Coulston et al.,

    Long-term studies


         In a 2-year toxicity experiment 50 male and 50 female rats per
    group were fed a diet containing 3, 15 and 75 ppm fenthion. In the
    control group 100 males and 100 females were used.

         The rats were weighed weekly during the first 26 weeks and
    thereafter at 14-day intervals. Food consumption was recorded
    weekly. Clinical chemistry was performed on 5 male and 5 female
    rats per group at intervals of 1, 3, 6 and 12 months, and on 10
    males and females at the end of the experiment. The clinical
    chemistry included hematology, liver- and kidney function tests,
    urinalysis, blood sugar and serum cholesterol determinations.
    Plasma and erythrocyte cholinesterase activities were determined
    after 1, 2, 4, 8, 13, 26, 52, 78 and 105 weeks. Brain
    cholinesterase activity was not measured. At the end of the
    experiment the rats were examined macroscopically, the organs
    weighed and studied microscopically.

         3 and 15 ppm fenthion did not affect the physical appearance,
    behaviour, growth and survival rate. The male rats of the 75 ppm
    group had a significantly lower body weight. A tendency toward
    increased mortality was observed in the 75 ppm group in both sexes.
    Hematology, blood chemistry, urinalysis gross macroscopy and
    histopathology revealed no compound related effects.

         Dietary concentrations of 15 and 75 ppm fenthion caused
    dose-dependent depression of plasma and erythrocyte cholinesterase
    activity. At 3 ppm cholinesterase activity was only slightly
    depressed in the plasma of the females. A no-effect level of 3 ppm
    fenthion diet is stated (Bombard and Loser, 1977).


         A prospective study was carried out on 150 cases of
    anticholinesterase insecticide poisoning to observe the influence
    of the type of insecticide used on the clinical picture and
    prognosis. Of the 150 cases, 32 had consumed fenthion, 48
    fenitrothion and 50 malathion. Twenty did not know exactly which
    agent was consumed. Paralytic signs were significantly more
    frequent with fenthion than with malathion or fenitrothion (being
    81.2%, 30% and 23% resp.). These signs occurred later with fenthion
    and lasted longer. Death occurred significantly more often with
    fenthion (the mortality rate being with fenthion 35.5%0 with
    malathion 4% and with fenitrothion 2.1%). Pulmonary oedema was
    commonest with malathion and not encountered with Fenthion. The
    cholinesterase depression was most marked with fenthion reaching 0
    in 18 of the 27 cases studied (Wadia et al., 1977).


         The additional data requested by the 1971 and the 1975 Joint
    Meetings have been partially met, a long-term rodent study having
    been submitted. Cholinesterase inhibition is the most sensitive
    criterium. No tumorogenic activity was noted. A long-term nonrodent
    study is underway, as indicated by the interim report on a monkey
    study. In addition, special studies in pharmacology, mutagenicity
    and teratology have been received.

         Whilst the data reviewed do not increase the concerns relating
    to fenthion, the continued absence of some previously requested
    studies precludes the allocation of a firm ADI. However, the data
    do permit an extension of the existing temporary ADI.


    Level causing no toxicological effect:

         Rat: 3 ppm in the diet, equivalent to 0.15 mg/kg b.w.

         Dog: 2 ppm in the diet, equivalent to 0.05 mg/kg b.w.

         Monkey: 0.07 mg/kg b.w. by gavage daily

    Estimate of temporary acceptable daily intake for man:

         0 - 0.0005 mg/kg b.w.



         Submissions received from Australia and Japan confirmed (see
    FAO/WHO 1972b) that fenthion is currently used on a wide range of
    fruits and vegetables, and for the control of insect vectors of
    farm animals and of pests of public health importance.

         Use patterns in Japan on rice and potatoes are summarized in
    Table 1.


    In pears

         A single application of fenthion at 250 g/100l resulted in
    0.08-0.21 mg/kg residues 7 days after treatment. This decreased to
    less than 0.02 mg/kg 14 days after application (Table 2) (Race,

        TABLE 1. Use pattern of fenthion in Japan


    Crop           Formulation         Application         Use: permitted        No. of
                                       method              period                applications

                   Emulsible           seed                before seeding
                   concentrate         immersion

                                       spraying            up to 30 days
                                                           before harvest

                   Wettable            spraying            up to 30 days
                   powder                                  before harvest

    Rice           ULV                 spraying do         up to 30 days
                   concentrate         not dilute)         before harvest        6

                   Dust                seed dressing       before seeding

                                       dusting             up to 14 days
                                                           before harvest

                   Granule             dusting             up to 14 days
                                                           before harvest

                   concentrate         dusting             up to 7 days
                                                           before harvest        -

    Potato         Wettable

    TABLE 2. Residues of fenthion in pears, raspberries, strawberries and radishes in Norway


    Crop                Application rate,    Number of      Period between       Residues,
                        g/ha or g/100l       treatments     final treatment      mg/kg
                                                            and harvest

    Pears               250 g/100l               1                 7             0.08-0.21
                                                                  14             < 0.02
                                                                  21             < 0.02
                                                                  28             < 0.02
                                                                  35             < 0.02

    Raspberries         250 g/100l               2                 1             2.9 - 3.3
                                                                   5             0.14-0.18
                                                                   8             0.05-0.06
                                                                  16             < 0.02

    Strawberries        50 g per 1000 m row      1               24-30           <0.05

    Radishes            200 g/ha                 1               15-16           <0.06
                                                                 20-22           <0.06

                        400 g/ha                 1                16             <0.06
                                                                 20-22           <0.06
    In raspberries

         Two applications at 250 g/100l resulted in residues of 2.9-3.3
    mg/kg 1 day after the last application. They declined rapidly to
    0.14-0.18 mg/kg after 5 days and 0.05-0.06 mg/kg after 8 days. After
    16 days, the residues were below the detection limit of 0.02 mg/kg
    (Norway, Table 2).

    In strawberries

         A single application of 50 g per 1000 m row gave residues below
    0.05 mg/kg 25-30 days after application (Norway, Table 2).

    In radishes

         Application at 200 and 400 g/100l gave residues below 0.06 mg/kg,
    15-22 days after application (Norway, Table 2).

    In rice

         In Japan, application at 0.5-1.0 kg ai/ha under normal
    cultivation or with a preharvest interval generally above 25 days gave
    residues below detection limits in hulled rice (Table 3). In a study
    with fenthion applied as a dust 4 days before harvest, the residue in
    hulled rice was still below the limit of detection of 0.001 mg/kg.
    With good agricultural practice, therefore, the residues in hulled
    rice would not exceed the MRL.

    In potatoes

         In 1974, multiple applications as dust and emulsifiable
    concentrate at 0.5-2.0 kg ai/ha gave residues below the detection
    limit. Two applications at 0.5 kg ai/ha with harvesting 7 days after
    last application gave residues below 0.01 mg/kg (Table 3).


         In a market basket study in Australia in 1970, fenthion residues
    were not determined specifically but the total organophosphorus (OF)
    residues found did not exceed 0.5 mg/kg. Some 240 samples were
    examined and only 32 contained any OF residues, of which only 3
    exceeded 0.2 mg/kg. Traces of fenthion have been detected occasionally
    in dairy products monitored routinely in a continuous national
    residues survey programme. For example, in a 12 month period
    (1977-78), 3 of 335 samples of dairy produce contained fenthion
    residues in the range 0.1-0.2 mg/kg.

        TABLE 3. Residues of fenthion in rice and potatoes (Japan 1978)


    Crop           Origin      Year     Formulation     Rate           No       Pre-harvest      Residue
                                                        (kg ai/ha)              (days)           (mg/kg)

    Rice           Hokkaido    1974     Dust            0.6            4        45               <0.008
    (hulled)                                            0.6            2        48               <0.008
                   Nigata                               0.6            1        83               <0.002
                   Ibaragi                              0.6            6        14               <0.004
                   Ishikawa                             0.6            2        24, 25           <0.01
                   Shiga                                0.8            2        30               <0.01
                   Shimane                              0.8            3        25, 60           <0.004

                   Aichi       1975                     0.6            1        73               <0.01
                   Shiga                                0.8            2        46               <0.003
                   Wakayama             E.C.            0.5-0.9        1-6      51, 68           <0.005
                   Kochi                Dust            0.8            3        4                <0.001

                   Gumma       1976     E.C.            1              4        29               <0.02
                                                        1              5        29               <0.02
                   Ehime                Granule         1              1        57               <0.003
                                        Dust            0.8            1        39               <0.007
                                                        0.9            2        36

    Potatoes       Hokkaido    1974     Dust            2              5        21               <0.008
                                        E.C.            0.5            4        27               <0.008
                   Gumma                                0.5            2        7                <0.01


         Data on residues in pears, raspberries, strawberries, and
    radishes provided by Norway supported the MRLs established previously
    and data from Japan show that if good agricultural practice is
    followed it is unlikely that the MRLs set for hulled rice and potatoes
    will be exceeded.

         Fenthion was only occasionally detected in the national residue
    monitoring programme in Australia. No new data were received on the
    effects of processing or cooking on residues of fenthion.


         No changes to the existing temporary MRLs are recommended.


    Required (1980)

    1.   Additional report on the on-going non-human primate study.
         Adequate long-term feeding studies in a non-rodent mammalian

    2.   Investigations on the mechanism of long-lasting cholinesterase
         inhibition, as previously requested.


    1.   Information on the effect of processing and cooking on fenthion
         residues in fruits and vegetables.


    Australia Report from the Codex Contact Point, Australia on uses
    (1978)         of fenthion.

    Bomhard, E. and Loser, E. Chronic toxicity study on rats. Rep. nr.
    (1977)         6769 from Institut für Toxikologie, Bayer A.G.
                   Unpublished report submitted by Bayer A.G.

    Coulston, F., Rosenblum, I. and Ford, W. A safety evaluation of
    (1978)         fenthion in Rhesus monkeys (Macaca mulatta). A twelve
                   month interim report from Albany Medical College of
                   Union University, Albany, (N.Y.).

    Japan Report from the Codex Contact Point, Japan on fenthion in rice
    (1978)         and potatoes.

    Kanda, M. and Matsushima, S. A case of acute fenthion poisoning.
    (1974)         Annual Rep. Jpn. Inst. Rural. Med. 3: 50-53

    Kawai, M., Tojo, K., Miyazawa, S., Maruta, H., Naito, M.
    (1976)         Experimental studies on the effects of organophosphorus
                   compounds on the eyes. Natl. Defense Med. J. 23 no.
                   1: 1-10 (abstract).

    Machemer, L. S 1752 (Fenthion, Lebaycid-Wirkstoff) Untersuchungen auf
    (1978a)        embryotoxische und teratogene Wirkungen an Ratten nach
                   oraler Verabreihung, Rep. nr. 7580, from Institut für
                   Toxikologie, Bayer A.G. Unpublished report submitted by
                   Bayer A.G.

    Machemer, L. S 1752 (Fenthion, Lebaycid active ingredient). Dominant
    (1978b)        Lethal study on male mice to test for mutagenic
                   effects. Rep. nr. 7449 from Institut für Toxikologie,
                   Bayer A.G. Unpublished report submitted by Bayer A.G.

    Race, J. Report from the Codex Contact Point, Norway on fenthion
    (1978)         uses on pears, raspberries, strawberries and radishes.

    Thyssen, J. Untersuchungen zur Kombinationstoxizität von
    (1977)         Edifenphos, Fenthion und Bassa-Wirkrtoff. Report nr.
                   7176 from Institut für Toxikologie, Bayer A.G.
                   Unpublished report submitted by Bayer A.G.

    Wadia, R.S., Bhirud, R.H., Gulavani, A.V. and Amin, R.B.
    (1977)         Neurological manifestations of three organophosphate
                   poisons. Indian J. Med. Res. 66 446-468.

    See Also:
       Toxicological Abbreviations
       Fenamiphos (ICSC)
       Fenamiphos (WHO Pesticide Residues Series 4)
       Fenamiphos (Pesticide residues in food: 1977 evaluations)
       Fenamiphos (Pesticide residues in food: 1980 evaluations)
       Fenamiphos (Pesticide residues in food: 1985 evaluations Part II Toxicology)
       Fenamiphos (Pesticide residues in food: 1987 evaluations Part II Toxicology)
       Fenamiphos (Pesticide residues in food: 1997 evaluations Part II Toxicological & Environmental)
       Fenamiphos (JMPR Evaluations 2002 Part II Toxicological)