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    FENITROTHION       JMPR 1977

    Explanation

    Fenitrothion was evaluated by the Joint Meeting in 1969, 1974 and 1976
    (FAO/WHO, 1970, 1975, 1976,). An ADI of 0.005 mg/kg/day was
    recommended in 1974. Because clinical signs were noted in humans at a
    dose of 0.3 mg/kg further observation in humans was desired.

    The Codex Committee on Pesticide Residues, at its 9th Session
    considered the feasibility of applying the limit on citrus fruit
    rather than simply on oranges. It was noted that the data available to
    the Joint Meeting were limited to oranges only and that it would be
    inappropriate to extend the limit to cover all citrus fruits.
    Governments were invited to send data to the Joint Meeting. No
    information was received on this topic, but other additional data on
    both toxicological and residue aspects have become available. They are
    summarized in the following monograph addendum.

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    BIOCHEMICAL ASPECTS

    Further information on absorption, distribution and excretion.

    A metabolism study with special attention to the fate of the phenolic
    moiety was carried out with fenitrothion (> 99.8%) 14C labelled at
    the ring-methyl group.

    Male rats were given a single oral dose of 15 mg/kg of labelled
    fenitrothion and tissue levels were determined 1 and 24 hours p.a.

    At 1 hour p.a. not more than 25% of the applied dose was present in
    the gastro-intestinal tract and significant radio-activity was found
    in the kidneys (11.7 mg/kg fenitrothion equivalents) stomach and
    intestines (5.4), liver (2.6), blood (2.1) and lungs (1.1). In these
    tissues > 80% of the radioactivity represented water soluble
    metabolites, except in the stomach and intestines where 68% was
    fenitrothion. In kidneys additionally a high content of
    3-methyl-4-nitrophenol (MNP) (2.1 mg/kg) was detected; in other
    tissues this amounted to less than 0.2 mg/kg. Fenitrooxon was scarcely
    found with not more than 0.024 mg/kg in the stomach and intestine,
    0.008 mg/kg in the kidneys and less than 0.005 mg/kg in other tissues.
    Some fenitrothion was detected in the fat and pancreas (both 0.5
    mg/kg).

    Twenty-four hours p.a. all tissues contained less than 0.1 mg/kg of
    total 14C, with highest levels in the liver, kidneys, fat and
    stomach and intestine, partly as fenitrothion and partly as
    metabolites. Other tissue levels were lower than 0.005 mg/kg for all
    metabolites.

    The same distribution was observed by autoradiograms of mice and rats,
    shortly and 24 hours after application of 15 mg/kg labelled
    fenitrothion.

    The concentrations of fenitrothion in the blood of rats, rabbits, mice
    and dogs were determined at 1, 3, 9, 24 and 48 hours after oral
    application of 15 mg/kg. A maximum was observed at 1 or 3 hours and
    levels were below 0.01 mg/kg at 24 hours.

    Five male rabbits were fed 0.3 and 10 mg/kg/day fenitrothion for six
    months. Fenitrothion (< 0.005 ppm) and fenitrooxon (< 0.001 ppm)
    were not detectable (< 0.005 and < 0.001 mg/kg respectively) in
    blood and skeletal muscle. In the fat 0.13 mg/kg of the oxygen
    analogue was found.

    After a single oral dose of 15 mg/kg labelled fenitrothion to mice,
    rabbits, dogs and rats the major part (80.-90%) of the
    14C-metabolites were excreted in the urine in 24 hours and 5%, with
    the faeces; the excretion was nearly complete at 48 hours p.a. In rats
    no 14C-metabolites were expired. In the urine 18 metabolites were
    identified with 3-methyl-4-nitrophenol (as the sulphate, free or as
    glucuronide) as the main metabolite in the rodents (50-70%, dogs only
    35%) followed by 0-desmethyl-fenitrothion/-oxon (from 10% in rabbits
    to 55% in dogs). In rabbits and rats small quantities of other
    metabolites were determined with the nitro group reduced to amino
    (total ca. 15%) or with an oxidized ring methyl group (ca. 1%).
    Fenitrothion was not detectable and traces of fenitrooxon (ca. 0.4%)
    were determined in rabbit urine only. About 5% remained unidentified.
    In faeces of rats the same major metabolites as in urine,
    3-methyl-4-nitrophenol (70%) and 0-desmethy-fenitrothion/oxon (20%),
    occurred but also some fenitrothion (10%) was found (Miyamoto et al.,
    1976).

    Fenitrothion S-methyl isomer

    Five female rats received a single oral dose of 3.1, 12.5, 50, 100 and
    200 mg/kg S-methyl isomer of fenitrothion (SMF), an impurity. Urinary
    excretion of the metabolite 3-methyl-4-nitrophenol was 65 to 75% of
    the applied dose within 72 hours p.a. with 40 to 60%, within 5 hours
    and less than 1.3% on the 3rd day.

    Cholinesterase inhibition in plasma and erythrocytes was maximal at 6
    hours (60-90%, dose-related) and 48 hours (25-90%) respectively.
    Recovery occurred slowly, depending on the dose, within 3 to 40 days
    (HladkŠ and Krampl, 1975).

    The anticholinesterase activity of SMF in vitro was found to be 2 to
    3 times higher than that of fenitrothion (Rosival et al., 1976).

    TOXICOLOGICAL STUDIES

    Special studies on potentiation

    After one treatment with CC14 the fenitrothion content of rat liver
    was dose-dependant and significantly increased and the compound was
    chemically bound to the oxygenated form of cytochrome P-450.

    An in vitro study with liver homogenates, of rats (incubated in a
    solution containing 0.3 mg/ml fenitrothion) showed a decreased
    fenitrothion-degrading activity of the cytochrome P-450 in rats that
    were pre-treated with 0.5 mg/ml CCI4 (oral).

    The results may indicate that fenitrothion is metabolized by the liver
    enzyme cytochrome P-450 to a toxically active component (Szutowski,
    1975).

    Special studies on teratogenecity

    Fenitrothion was injected into the yolk of chicken eggs at doses of
    0.1 ml of 0.1-30% fenitrothion. Dose levels of 1 and 0.1% produced
    malformations (curled toe, leg weakness and abnormal gait). At the
    high dose levels all the embryos died. There was also a dose-related
    influence on the hatchibility (Paul and Vadlamudi, 1976),

    Special studies on neurotoxicity

    Sixteen hens received orally 500 mg/kg fenitrothion (97.2%) and were
    protected against intoxication by atropine and PAM; this treatment was
    repeated three weeks later. TOTP was used as a positive control. Five
    hens died within two days after the first and none after the second
    treatment; survivors showed symptoms of cholinesterase inhibition. No
    paralysis was observed and histopathological findings in sciatic
    nerves were normal.

    In another test twelve hens received orally 35 mg/kg fenitrooxon (98%)
    and were protected by atropine and PAM, the treatment was repeated
    after three weeks. TOTP served as a positive control. Five hens died
    and none showed paralysis in a three week observation period (Kadota
    et al., 1975a).

    Special studies on ocular toxicity

    Dogs were dosed orally twice weekly with 0.5, 1 and 5 mg/kg
    fenitrothion for 1 year. Myopization was observed 4 months after this
    period.

    The intraocular pressure was elevated at the fourth and ninth month on
    test but recovered four months after the end. No significant changes
    of corneal power and refractive components were observed (Tokoro et
    al., 1976; summary only).

    Rats that received 150 and 300 ppm fenitrothion in feed for 13 and 16
    weeks respectively showed oedema and hyperaemia of the eyelids and
    corneal infiltration or erosion. A decrease in body weight gain and in
    serum cholinesterase was also observed (Fukami, 1976; summary only).

    Acute toxicity

        Fenitrothion

                                                                                         

    species                  route          LD50(mg/kg)         references
                                                                                         

    Hen                      oral.          ca. 500             Kadota et al., 1975a

    Jpn. quail M             oral           115 (80-166)        Kadato & Miyamota,
                                                                1975

    Jpn. quail F             oral           140 (105-186)       Ibid.
                                                                                         
    
    Death occurred within two days; symptoms of cholinesterase, poisoning
    disappeared in ca. eight days.

        Fenitrothion S-methyl isomer

                                                                                       

    species                  route           LD50(mg/kg)        references
                                                                                       

    mouse                    oral            ca. 320            Rosival et al, 1976
    rat (M)                  oral            315                Ibid.
                                                                                       

    Fenitrooxon

                                                                                         

    species                  route           LD50 (mg/kg)       references
                                                                                         

    Hen                      oral            35 (21-57)         Kadota et al., 1975a
                                                                                         
    
    Death occurred within 1 day; symptoms of cholinesterase poisoning, in
    ca. eight days.

    Short-term studies

    Japanese quail, 60 males and 60 females per group (20 males and 20
    females in the 1.5 ppm group) received 0, 1.5, 5, 15 and 50 ppm
    fenitrothion (97.2%, dissolved in corn-oil in the diet 4 weeks. Every
    two weeks 10 males and 10 females were sacrificed for ChE
    determination in blood and brains respectively. Effects: no animals
    died and no toxic symptoms were seen, nor abnormalities in body weight
    or food consumption. A dose-related decrease of blood ChE activity was
    observed in the females of the 5 ppm group (25%), males and females of
    the 15 ppm (60%) and 50 ppm (85%) groups during the treatment, when on
    the basal diet, recovery occurred within 2 weeks.

    Brain ChE activity was reduced in the females of the 15 ppm group
    (25%) and the males and females of the 50 ppm group (65%) and
    recovered after 4 weeks. In the 50 ppm group the egg-laying rate was
    decreased and recovered after 3 weeks (Kadota and Miyamoto, 1975).

    Short-term studies (metabolites)

    Groups of fifteen male and fifteen female Wistar rats received 0, 5,
    15 and 50 ppm fenitrooxon (99%) respectively in the diet for six
    months. Cholinesterase activity in plasma and brain was dose-related
    and significantly decreased in males and females of the 15 and 50 ppm
    groups; erythrocyte-ChE was significantly decreased in males and
    females of the 50 ppm group. No clear dose dependent changes were
    observed in body weight ratios, food consumption, and biochemical
    parameters or histopathology (Kadota et al., 1975b).

    COMMENTS

    Additional information on absorption, distribution, excretion,
    potentiation, terato-genicity and neurotoxicity was available.

    Fenitrothion is easily absorbed from the gastro-intestinal tract and
    distributed into various tissues. The main metabolites are
    3-methyl-4-nitrophenol and 0-desmethyl-fenitrothion and/or its oxygen
    analogue, which are eliminated rapidly, predominantly by the kidneys.
    Tissue residues are very low. There are some indications that
    fenitrothion induces increased ocular pressure after oral application
    in both dogs and rats. However, this can be expected since it
    depresses cholinesterases. No-effect levels in both rats and dogs were
    demonstrated at 5 ppm in the diet. There are no reasons to alter the
    previously established ADI for humans.

    TOXICOLOGICAL EVALUATION

    Level causing no toxicological effect

         Rat: 5 mg/kg in the diet, equivalent to 0.25  mg/kg bw
         Dog: 5 mg/kg in the diet, equivalent to 0.125 mg/kg bw

    ESTIMATE OF ACCEPTABLE DAILY INTAKE FOR HUMANS

         0.005 mg/kg bw

    RESIDUES IN FOOD AND THEIR EVALUATION

    RESIDUES RESULTING FROM SUPERVISED TRIALS

    Pre-harvest

    The Japanese Science and Technology Agency advised the Meeting that
    extensive trials were carried out between 1973 and 1975 in many
    prefecture of Japan where a variety of fenitrothion formulations were
    applied to rice crops. From 1 to 7 applications were made with
    pre-harvest intervals ranging from 14 to 120 days. Most of the samples
    of hulled rice contained no detectable residues at harvest (limit of
    determination 0.001 mg/kg) but a few contained small residues ranging
    up to a maximum of 0.025 mg/kg.

    Post-harvest

    Having been established for post-harvest use on wheat, studies were
    made into the usefulness and fate of fenitrothion on barley, oats and
    rice and milling products derived therefrom (FAO-WHO 1977). These,
    studies have been extended to include sorghum and further experience
    has confirmed that it is possible and convenient to predict the
    residues of fenitrothion on any raw cereal variety when the
    temperature and relative humidity of the intergrain air is known.

    Following extensive pilot and commercial-scale trials, the Australian
    Wheat Board has treated tons of wheat with fenitrothion at rates
    ranging from 6 to 12 mg/kg depending, on grain temperature, moisture
    content, and anticipated storage period. Following systematic
    monitoring of the fenitrothion content of samples drawn from over 20
    different storage cites each month for over eight months,
    Desmarchelier (1977a) reported that the rate of loss of fenitrothion
    was consistent with predicted values.

    Bengston et al. (1977a) carried out field experiments with grain
    protectant insecticides for the control of malathion-resistant insects
    in stored sorghum in which the level of residues determined by
    analysis and the insecticidal activity was measured by bio-assay using
    10 species of malathion-resistant insects. These workers reported that
    fenitrothion applied at the nominal rate of 12 mg/kg was effective in
    all species except Rhizopertha dominica for more than 12 weeks (test

    still in progress). During the first 24 weeks of storage the residue
    levels were as indicated in Table 1.

        TABLE 1. Fenitrothion residues on stored sorghum

                                                                                         

                                 Residue (mg/kg) at intervals (weeks) after storage.
                                                                                         

    Site                        1        4       8       12       18      24

    1                           13.4     10.5    10.0    7.9      9.0     8.3
    2                           7.7      7.8     8.6     7.7      5.9     5.6
    3                           16.4     11.5    11.1    9.3      8.8     9.1
    4                           8.2      7.4     10.1    8.5      5.2     4.0
                                                                                         

    
    Desmarchelier (1977b) found that the loss of fenitrothion from
    post-harvest application to wheat, oats, paddy rice and sorghum was a
    second-order process, with rate of loss being proportional, at a fixed
    temperature, to the amount of fenitrothion and the activity of water,
    which was obtained from the equilibrium partial pressure of water
    vapour in the inter-grain space. Figure 1 relates the half-life of the
    deposit of temperature and relative humidity. Tables are published
    elsewhere showing the relative humidity of the inter-grain air
    equilibrium with different varieties of grain of varying moisture
    content.

    It is obvious from these and other studies by the same author (FAO/WHO
    1977) in respect of fenitrothion, pirimiphos-methyl, carbaryl,
    bioresmethrin and other insecticides that the fate of residues of
    grain protectant insectides can be predicted from calculations based
    on several well-defined parameters (Desmarchelier, 1977c). The
    recommended maximum residue limits can therefore be extended to cover
    all raw grains in the confident expectation that the level of the
    initial deposit will decline at a predicted rate dependent only on
    temperature and relative humidity.

    Results of three studies with fenitrothion on barley (Green and Tyler,
    1966; Rengston et al., 1977b and Desmarchelier et al., 1977) were used
    to test the predictions of Desmarchelier (19770) and a high level of
    agreement was found.

    FIGURE 4

    APPRAISAL

    The usefulness of fenitrothion as a grain protectant insecticide and
    the fate of fenitrothion applied to various grains have been evaluated
    in 1974 and 1976. The results of further studies on a variety of
    grains including barley, oats, rice, sorghum and wheat have revealed
    that the rate of decline in residue levels in stored raw cereals can
    be predicted accurately from a knowledge of the temperature, relative
    humidity and residue concentration.

    These data, taken in conjunction with information contained in
    previous monographs, have provided adequate assurance that the maximum
    residue limits already recommended for rice and wheat can be extended
    to embrace all raw cereals, including sorghum.

    Results from extensive commercial-scale trials on sorghum confirm that
    these assumptions are correct. Additional studies following the
    application of fenitrothion to malting barley have confirmed that
    there is no adverse effect from the treatment on the quality of the
    malt produced. Residues in malt and beer are in keeping with
    anticipated values.

    RECOMMENDATIONS

    The previously recommended maximum residue limit for fenitrothion on
    rice and wheat is replaced by a limit at the same level for raw
    cereals. The limit is for the sum of fenitrothion and its oxygen
    analogue, expressed as fenitrothion.

              Commodity      Limit, mg/kg

              raw cereal          10

    FURTHER WORK OR INFORMATION

    DESIRABLE

    1. Further observations in humans.

    2. Information on the level and fate of fenitrothion residues on
    citrus varieties other than oranges.

    REFERENCES

    Bengston, M., Cooper, L.M., Davies, R.A.H., Desmarchelier, J.M., Hart,
    R.J. and Phillips, M. (1977a) Grain Protectants for the Control of
    Malathion-resistant insects in stored sorghum. J. Stored Prod. Res.
    (submitted for publication).

    Bengston, M., Davies, R.A.H., Desmarchelier, J.H., Hart, R.J., Moore,
    B., Murray, W., Phillips, M., Ridley, E., Ripp, E., Scewakowski, C.,
    Snelson J.T., Sticka, R., Wallbank, B. and Wilson, A. (1977b),
    Extensive pilot usage of the grain protectants chlopyrifos-methyl plus
    bioresmethrin, fenitrothion plus d-fenothrin methacrifos and
    primiphos-methyl plus carbaryl (in preparation).

    Desmarchelier, J.M. (CSIRO Division of Entomology, Canberra) (1977a)
    Analysis of fenitrothion 1976-77 Pilot trials. Report to the
    Australian Wheat Board Pest Control Conference (July 1977) (To be
    published)

    Desmarchelier, J.M. (1977b) Loss of fenitrothion on grains in storage.
    J. Stored Prod. Res. (in-press).

    Desmarchelier, J.M. (1977c) Loss of bioresmethrin, carbaryl,
    d-fenothrin etc. on grain in (manuscripts of papers being prepared for
    publication).

    Desmarchelier, J.M., Bengston, M., Connell, M., Phillips, M., Ridley,
    E., Snelson, J.T., Sticka, R. and Wilson, A. (1977) Extensive pilot
    usage of the grain protectant combinations fenitrothion plus
    bioresmethrin and primiphos-methyl plus bioresmethrin (in
    preparation).

    Fukami Y. (1976) The ocular injurious level of organic phosphates in
    rats. Jpn. J, Clin. Ophthalmol., 30, 841-848.

    Green, A.A. and Tyler, P.S. (1966) A field comparison of malathion,
    dichlorvos and fenitrothion for the control of Oryzaepholus
    surenamensis infesting stored barley. J. Stored Prod. Research, I,
    197.

    HladkŠ, A. and Krampl, V. (1975) Effect of S-methylfenitrothion on the
    activity of cholinesterase and on the excretion of its metabolites in
    rats. Int. Arch. Occup. Environ. Hlth., 36, 67-73.

    Kadota, T., Okuno, Y, and Miyamoto, J. (1975a) Acute oral toxicity and
    delayed neurotoxicity of 5 organophosphorus compounds, salithion,
    cyanox, surecide, sumithion and sumiaxon in adult hens. Botyu-Kagaki
    (Sci. Pest. Contr.), 40, 49-53.

    Kadota T. and Miyamoto, J. (1975) Acute and sub-acute toxicity of
    sumithion in japanese quails, Botyu-Kagaku (Sci. Pest. Contr.), 40,
    54-58.

    Yiyamoto, J., Mihara, K. and Hosokawa, S. (1976) Comparative
    metabolism of m-methyl-14C-sumithion in several species of mammals
    in vivo. J. Pesticide Sci., 1, 9-21.

    Paul, B.S. and Vadlamudi, V.P. (1976) Teratogenic studies of
    fenitrothion on white leghorn chick embryos. Bull, of Environ.
    Contamination and Toxic., 15, 223-229.

    Rosival, L., Vargova, M., SzokolayovŠ J., Cerey, K., HladkŠ, A.,
    BŠtora, V., KovacicovŠ, J. and Truchlik, S. (1976) Contribution to the
    toxic action of S-Methyl fenitrothion. Pest. Biochem. and Physiol.,
    6, 280.286.

    Szutowski, M.M. (1975) Effect of carbontetrachloride on activation and
    detoxification of organophosphorus insecticides in the rat. Toxical.
    Appl. Pharmacol., 33, 350-355.

    Tokoro T., Suzuki, K., Hayashi, K. and Otsuka, J. (1976) Development
    of myopia induced by organic phosphorous pesticide (sumithion) in
    beagle dogs. J. Jpn. Ophthalmol. Soc., 80, 51-53.

    FAO/WHO (1970) 1969 evaluations of some pesticide residues in food.
    FAO/PL:1969/M/17/1; WHO/Food Add./70.38.

    FAO/WHO (1975) 1974 evaluations of some pesticide residues in food.
    AGP:1974/M/11; WHO Pesticide Residues Series No. 4.

    FAO/WHO (1976) 1975 evaluations of some pesticide residues in food.
    AGP:1975/m/13; WHO Pesticide Residues Series No. 5.

    FAO/WHO (1977) 1976 evaluations of some pesticide residues in food.
    AGP:1976/M/14.
    


    See Also:
       Toxicological Abbreviations
       Fenitrothion (EHC 133, 1992)
       Fenitrothion (HSG 65, 1991)
       Fenitrothion (ICSC)
       Fenitrothion (FAO/PL:1969/M/17/1)
       Fenitrothion (WHO Pesticide Residues Series 4)
       Fenitrothion (Pesticide residues in food: 1976 evaluations)
       Fenitrothion (Pesticide residues in food: 1979 evaluations)
       Fenitrothion (Pesticide residues in food: 1982 evaluations)
       Fenitrothion (Pesticide residues in food: 1983 evaluations)
       Fenitrothion (Pesticide residues in food: 1984 evaluations)
       Fenitrothion (Pesticide residues in food: 1986 evaluations Part II Toxicology)
       Fenitrothion (Pesticide residues in food: 1988 evaluations Part II Toxicology)
       Fenitrothion (JMPR Evaluations 2000 Part II Toxicological)