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    FENITROTHION          JMPR 1974

    Explanation

         In 1969 the Joint Meeting evaluated fenitrothion in the light of
    the information then available. Recommendations were made for a
    temporary ADI, temporary tolerances on a number of raw agricultural
    commodities and practical residue limits for meat and milk (arising
    from the use of fenitrothion for locust control).

         The Meeting listed seven items of further work or information
    required before the temporary recommendations could be confirmed as no
    longer temporary and before recommendations for additional tolerances
    could be made (FAO/WHO, 1970).

         Since that time a considerable amount of additional research has
    been carried out to provide information and answers to the
    requirements laid down in 1969 and in addition the Meeting had
    available many additional published and unpublished reports relating
    to fenitrothion, its properties, residues, toxicology and analysis.
    This Information has been considered and the following monograph
    addendum has been prepared.

    IDENTITY

    Relevant Chemical Properties

         Because of the many and varied uses to which fenitrothion
    preparations are applied it is important to recognize that the
    performance, toxicity, residues and environmental effects depend
    largely on the quality of the technical product which in turn will
    depend on the method of manufacture and the conditions of storage. In
    response to the requirement of the 1969 Joint Meeting one of the
    largest and most experienced manufacturers of fenitrothion has
    provided information on the impurities in the technical grade
    material. These are given in Table 1 (Sumitomo, 1974). Results of
    analysis of 9 samples of technical fenitrothion are given in Table 2
    (Greenhalgh, 1974a). The importance of the S-methyl isomer, its
    properties, methods of determination and occurrence in technical
    fenitrothion were discussed by Greenhalgh et al. (1974). According to
    these workers the content of the S-methyl isomer varies slightly
    depending upon the method of determination and in the seven samples
    examined ranged from 0.55% to 4.41%. These samples are included in
    Table 2. It must be recognised that the age and storage histories of
    these samples are not known and therefore no conclusion as to the
    relative purity of the original materials may be drawn. The results in
    no way reflect the purity of the technical grade fenitrothion
    presently available from these manufacturers nor do they necessarily
    represent the impurities in commercial formulations, which are often
    stabilised.

         Recently, a GLC method has been developed for the determination
    of the S-methyl isomer in fenitrothion. It is sensitive to 0.1%
    (Kovacicova et al., 1973; Greenhalgh et al., 1974).

         A high speed liquid chromatographic method permits the
    simultaneous monitoring of each of the impurities without clean-up to
    a limit of determination below 0.1% (Marshall et al., 1974).

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    BIOCHEMICAL ASPECTS

    Biotransformation

         Metabolic studies on fenitrothion are described in the 1969
    evaluation (FAO/WHO, 1970). Fenitrothion is metabolised by Bacillus
    subtilis to amino-fenitrothion, desmethyl-aminofenitrothion,
    desmethyl-fenitrothion and dimethyl phosphorothioic acid. Even resting
    cells of the bacteria easily reduced the compound. Fenitrooxon and its
    metabolites were not detected. Amino-fenitrothion is presumed not to
    have biological activity (Anon., sine data, a).

    TABLE 1.  Impurities in technical grade fenitrothion.

    Component                                               Percentage

    active ingredient (by colorimetric method)             95-98
                                                           (95% up)

    O-methyl O,O-di(4-nitro-M-tolyl) phosphorothioate      2-3

    O-methyl S-methyl O-(4-nitro-M-tolyl)
    phosphorothioate                                       0.5-1

    O,O-dimethyl phosphorochloridothioate                  <0.5

    3-methyl-4-nitrophenol                                 <0.2

    toluene                                                <0.1

    water                                                  <0.1

    Effects on enzymes and other biochemical parameters

         Intraperitoneal injections of 25 mg/kg of fenitrothion in mice
    inhibited aminopyrine demethylase and aniline hydroxylase activities
    in the liver by about 50%. Similar effects on drug metabolising enzyme
    activity were observed in female but not male rats. Administration of
    fenitrothion to mice prolonged the hexobarbital sleeping time and also
    suppressed the oxidative metabolism of parathion by their livers in
    vitro. Oxidative drug metabolism by liver was also inhibited by
    addition of fenitrothion (IC50 of 10-5M) to the test system in
    vitro (Uchiyama et al., 1974).



    
    TABLE 2.  Analysis of technical grade fenitrothion 1, 2 (Greenhalgh, 1974).

                                                                                                                               
                                S-Methyl           4-Nitro-                                                      S-Methyl-bis-
    Sample                      fenitrothion       3-methylphenol     Fenitrooxon        Bis-fenitrothion        fenitrothion
                                                                                                                               

    Accothion                   1.63               0.22               <0.1*              0.38                    <0.05*

    Accothion ULV               0.90               0.25               0.44               0.22                    <0.05*

    BASF (Canada Ltd)           4.41               0.10               <0.1*              0.64                    0.14

    Metathion                   2.14               0.16               0.23               <0.01*                  <0.05*

    Metathion CHJZD             3.36               0.36               <0.1*              1.02                    <0.05*

    Novathion                   2.37               0.20               <0.1*              0.54                    0.40

    Sumithion Technical         0.55               0.16               <0.1*              0.48                    <0.05*

    Sumithion E-50              1.26               1.45               <0.1*              <0.01*                  <0.05*

    Sumithion                   <0.05*             <0.004*            <0.1*              1.35                    <0.05*
                                                                                                                               

    1  The history of those samples, date of manufacture and storage conditions are unfortunately
       unknown. As such, these results cannot be taken as an evaluation of each manufacturer's
       product (Marshall and Greenhalgh, 1974).

    2  Determined by high speed liquid chromatography.

    *  Not detected.
    

         Female rats were given single oral doses of 200 mg/kg bw of
    fenitrothion and/or malathion. The level of fenitrothion in the liver
    was decreased in those animals that received both compounds, in
    comparison to those receiving only fenitrothion. However, after an
    initial decrease there was an increased content of fenitrothion in
    blood and muscle of the rats that received malathion as well.
    Fenitrooxon, the toxic metabolite of fenitrothion, increased markedly
    with time in blood and muscle of rats given fenitrothion and malathion
    in combination, in contrast to rats given only fenitrothion, where
    there was a rapid peak and decline in fenitrooxon concentrations.
    Liver fenitrooxon concentrations were not appreciably altered by the
    combined dosage regimen. These studies suggest the possibility for
    potentiation of fenitrothion by malathion, but actual tests for
    potentiation were not conducted (Hladká et al., 1974).

    TOXICOLOGICAL STUDIES

    Special studies on mutagenicity

         Three tests for mutagenicity were performed using microbial
    systems. Using tryptophan auxotrophic mutant and UV repair deficient
    strains of E. coli K 12, cultures were exposed to fenitrothion
    concentrations of 0, 13.2, and 132 µg/ml in a dimethylsulfoxide
    saturated solution. The same concentrations except the 132 µg/ml were
    used with coli-phage lamba 1847 sus E- h+. No mutagenic and radio
    mimetic action was detected (Suzuki et al., 1974).

         Mutagenic activity of fenitrothion was studied in rats given 0,
    10, 40 and 80 ppm of fenitrothion in the diet during a 4-generation
    reproduction study. The study combined the dominant lethal test in a
    single mating (in the course of one week) with P - to F3 generation
    males and females following 200 days of exposure, and at individual
    stages of spermatogenesis with 15 males of F2 and F4 generation in
    each group after an exposure of 100 days and mated each week with 30
    unexposed females for 10 weeks. Chromosome aberrations were analysed
    in the bone marrow of F2 generation males following 200 days of
    exposure, and of F3 generation males following 500 days of exposure
    to a dose of 80 ppm. The results were negative in all tests both in
    relation to dose and generation (Benes et al., 1974a).

    Special studies on neurotoxicity

    Hen

         Groups of adult hens, eight, six and three respectively, were
    orally given single doses of 250, 500 or 1000 mg fenitrothion/kg bw.
    300 mg/kg of TOCP was used as a positive control. Toxic symptoms,
    which lasted 4-10 days occurred in all groups. One half of the hens of
    the middle dosage group and all from the highest fenitrothion group
    died within 24-48 hours post-treatment. No delayed paralysis of the
    legs occurred at any dose group or at any time during the 5-week

    observation period, while all TOCP dosed animals developed paralysis
    within 3 weeks. The sciatic nerves of all the surviving hens given
    fenitrothion were normal.

         A group of 16 hens was given 500 mg fenitrothion/kg and
    immediately after atropine and 2-PAM was given to protect against
    acute anti-cholinesterase effects. None of the surviving hens (12 out
    of 16) showed delayed paralysis during the 21 day observation period.

         Groups of 8 hens were given 33.4 or 16.7 mg fenitrothion/kg/day,
    6 days per week for 4 weeks and then observed for another 3 weeks.
    Slight toxic symptoms were seen in both groups during the
    administration and one hen of the highest group died on the 5th day.
    Body weights were decreased in both groups, but the decrease for the
    lower group was transient. No paralysis nor histopathological changes
    in the sciatic nerve or spinal cord were recorded (Kadota et al.,
    1974a).

    Special studies on potentiation

    Rat

         The effects of combinations of fenitrothion with 4 other
    organophosphates were studied in male rats and it was found that only
    the combination with malathion was more than additive and that
    fenitrothion could be considered the "potentiator." The potentiation
    (one half expected LD50) was most pronounced at the combination of
    1:1 (Benes and Cerna, 1970).

    Special studies on reproduction

    Rat

         A three-generation reproduction study in rats was started using
    15 males and 30 females per test-group (20 males + 40 females control)
    at dietary levels of 10, 30 and 150 ppm. After the first filial
    generation (F1a) the study continued using 10 males and 20 females
    per dietary level of 0, 10, 30 and 100 ppm. Fertility, gestation,
    lactation and live birth indices were compared. In the P1 and
    P2-generation animals, 150 and 100 ppm of fenitrothion in the diet
    caused weight reduction in the parental animals as well as in the body
    weights of both sexes at weaning and suppressed lactation indices
    (number of pups weaned divided by the number of pups nursed) through
    all generations. The groups fed the highest dose level also showed a
    higher incidence of cannibalism and/or smallness at weaning whereas
    all litters seemed normal at birth. No dose-related malformations or
    histopathological changes were seen (Rutter and Voelker, 1974b).

         Groups of 10 male and 20 female rats were fed a diet containing
    0, 10, 40 and 80 ppm technical fenitrothion (with maximum 0.5%
    p-nitro-m-cresol) in a 4-generation, 2-litter per generation
    reproduction study. The following parameters were studied: body weight
    and food consumption of the parental animals and indices of fertility,
    gestation, live birth, 24-hour survival, 5-day survival and lactation;
    gross pathology of all pups, organ weights and histopathological
    examination of F4b weanlings; cholinesterase activity in whole blood
    in males of F2a (aged 15 weeks) and in all weanlings of F4b (aged 4
    weeks). Fertility, gestation and live birth indices were normal in all
    groups, whereas the 24-hour and 5-day survival indices were reduced in
    one or both litters of the 80 ppm group in almost all generations. The
    lactation index was reduced in all generations of the 40 and 80 ppm
    groups. The mean litter size was smaller in all but five test litters,
    but the occurrence was without a clear dose-dependence. The lowest
    number of pups was, however, found in six of eight litters in the 80
    ppm group. The mean weight of the pups at birth and at 21 days of age
    was normal whereas the growth of the parental animals was slightly
    decreased in the 80 ppm group. Cholinesterase activity was decreased
    in relation to dose and length of exposure; in the 10 ppm groups the
    decrease was only slight. Organ weights, gross and microscopic
    pathological examinations revealed no abnormalities (Benes et al.,
    1974b).

    Rabbit

         Groups of female albino rabbits were inseminated (gestation day
    0) and on gestation day 6 through 18 inclusive were dosed with 0, 0.3
    or 1 mg fenitrothion/kg/day in gelatine capsules. A positive control
    group given 37.5 mg thalidomide/kg/day was included. The compound had
    no effect on the does nor on the number of implantation sites, early
    or late resorption sites, number of dead or live young or aborted
    foetuses. In the thalidomide group approximately 10 per cent of the
    foetuses showed external malformations, while none were seen in the
    other groups. No effects related to the administration of fenitrothion
    were seen on examination for internal or skeletal deformities (Ladd,
    1971).

    S-methyl isomer of fenitrothion

         The S-methyl isomer of fenitrothion (SMF) occurs as an impurity
    (in the order of 0.5 to 1.5%) of technical fenitrothion. SMF can also
    be formed by thermal isomerization of fenitrothion or by UV
    irradiation-catalyzed isomerization during prolonged storage under
    inappropriate conditions. The acute oral toxicity in rats and mice of
    SMF was approximately twice that of fenitrothion, and the signs of
    poisoning were typical of the muscarinic and nicotinic action of
    acetylcholine seen with anticholinesterase compounds. The in vitro
    anticholinesterase action of SMF was compared with that of
    fenitrothion and its oxygen analogue using human and horse serum and
    fly head cholinesterases. The pI50 values for SMF were: horse serum
    7, human serum 8, and fly head 9; while for fenitrothion the values

    were: human and horse sera 5, fly heads 6. The oxygen analogue of
    fenitrothion was about equal to SMF as a direct cholinesterase
    inhibitor. These results indicate that contamination of fenitrothion
    by SMF can account for much of the anticholinesterase action of
    technical fenitrothion, and that this should be considered if in
    vitro tests are used for anticholinesterase assay purposes. SMF was
    more rapidly degraded than fenitrothion in rats, as shown by measuring
    the rates of excretion of p-nitro-m-cresol. Furthermore, a greater
    proportion of the total dosage of SMF could be accounted for by this
    urinary metabolite. Four groups of 10 male rats each were orally dosed
    with 0, 1, 6 and 12 mg/kg and were mated with untreated female rats
    (20 per group). There were eight sequential matings with a new group
    of females each week. There was slightly greater number of resorptions
    in the treated groups; and although there was not a marked difference
    between the three test groups, the investigators concluded that SMF
    had a low order of mutagenic action (Rosival et al., 1974; Kovacicová
    et al., 1973).

    Acute toxicity

    TABLE 3.  Acute toxicity of fenitrothion

                                                                            

    Animal            Route       LD50 mg/kg bw       References
                                                                            

    Mouse (M)         oral        1030                Miyamoto and Kadota,
                                                      1972

    Mouse (F)         oral        1040                ibid.

    Rat (M)           oral         330                ibid.

    Rat (F)           oral         800                ibid.

    Ringneck
     pheasant         oral        34.5                Fletcher, 1971e

    Mallard duck      oral        2550                Fletcher, 1971f

    Dog               oral        min. lethal
                                  dose 681 mg/kg      Mastalshi, 1971c

    Rat (M)           oral        940                 Benes and Cerna,
                                                      1970

    Rat (F)           oral        600                 ibid.
                                                                            

    TABLE 4a.  Acute toxicity of fenitrothion metabolites - Fenitrooxon.

                                                                            

    Animal            Route       LD50 mg/kg bw       References
                                                                            

    Dog               oral        min. lethal         Mastalski, 1971a
                                  dose = 68.1

    Ringneck
     pheasant         oral        10.6                Fletcher, 1971a

    Mallard duck      oral        12.5                Fletcher, 1971b
                                                                            


    TABLE 4b.  Acute toxicity of fenitrothion metabolites
               - 3-methyl-4-nitrophenol (p-nitro-m-cresol)

                                                                            

    Animal            Route       LD50 mg/kg bw       References
                                                                            

    Dog               oral        min. emetic         Mastalski, 1971b
                                  dose = 680 mg/kg

    Rat (F)           oral        1200                Anonymous, 1971

    Rat (M)           oral        2300                Anonymous, 1971

    Ringneck
     pheasant         oral        4640                Fletcher, 1971c

    Mallard duck      oral        1470                Fletcher, 1971d
                                                                            


    Short-term studies (metabolite)

         Groups of rats (15 males and 15 females) were given 0, 150, 500
    and 1500 ppm of 3-methyl-4-nitrophenol (p-nitro-m-cresol) in the diet
    for 6 months. No dose-dependent changes were found in blood or
    urinalysis, biochemical studies, organ weights or after
    histopathological examination, except a transient excretion of sugar
    in the urine of rats fed 1500 ppm (Anon., sine data, b).

    Short-term studies (fenitrothion)

    Rat

         Groups of 8 male and 8 female rats were fed diets containing 0,
    10, 50 and 250 ppm of fenitrothion for 34 weeks. In another test,
    groups of 16 rats of each sex were fed fenitrothion at 0, 5, 25 and
    125 ppm, for the same period. The feeding of 250 ppm resulted in a
    decrease in body weight gain of the females. In the 125 ppm group a
    lower relative weight of the spleen of both sexes was found. However,
    only the females of the 250 ppm group showed histological changes of
    the liver and spleen. The cholinesterase activities were measured at
    intervals in both plasma and erythrocytes and a dose-dependent
    decrease was found in all test groups, except in plasma from the males
    at 5 ppm. In the females the depression was slight. The activity in
    the brain was decreased only in the 250 ppm groups.(Benes and Cerna,
    1970).

         Groups of rats (15 males and 15 females) were fed fenitrothion at
    0, 10, 30 and 150 ppm in the diet for 6 months. Growth, food and water
    consumption, mortality, blood and urinalysis and blood biochemistry,
    except cholinesterase activities, were comparable to the control in
    all groups. The cholinesterase activities of the brain, red cells and
    plasma were depressed in both sexes of the 150 ppm groups, but only in
    the females of the 30 ppm groups and only in plasma of females in the
    10 ppm group.

         Absolute and relative organ weights were within normal limits,
    except for slightly decreased relative weights of the spleen of males
    of the higher dosage groups. No histopathological changes were found
    in the examined organs including the spleen (Anon., 1972).

    Dog

         A toxicity study on the dog was composed of 3 sections: a 90-day
    section for the purpose of range finding utilized an untreated control
    group and three test groups, each consisting of eight purebred beagle
    dogs (four males and four females) (Lindberg et al., 1972); the
    one-year section utilized an untreated control group and two test
    groups, each consisting of eight purebred beagle dogs (four males and
    four females); and the two-year section utilized an untreated control
    group and three test groups, each consisting of twelve purebred beagle
    dogs (six males and six females) (Burtner et al., 1974). The one-year
    and the two-year studies are summarized below:

         As part of a one-year feeding, test groups of 4 male and 4 female
    dogs were fed fenitrothion 0, 5 or 10 ppm in the diet for 90 days and
    cholinesterase activities were determined three times pre-test and on
    days 21, 45 and 90. The activities in the red blood cells were normal
    at all times whereas in the plasma the activities were decreased 20
    and 25% respectively in the two test groups. The 10 ppm group was
    terminated after 90 days and the 5 ppm group continued for a total of

    one year. The same examinations (growth, food intake, mortality, blood
    and urine analysis, organ weights, histopathology and plasma,
    erythrocyte and brain cholinesterase) were performed as for the 90-day
    feeding test. No difference in blood and brain cholinesterase
    activities (maximum inhibition was less than 12%) was found between
    test and control groups (Burtner et al., 1974).

         Groups of dogs (6 males and 6 females) were fed fenitrothion 0,
    30, 100 and 200 ppm in the diet for two years. The same examinations
    were performed as for the 90-day feeding test. The only adverse effect
    was reduction of the cholinesterase activities. Depression of plasma
    cholinesterase activity was apparent in all groups, while erythrocyte
    enzyme activity was unaffected in the 30 ppm group when group averages
    of treated and control animals were compared. Brain activity was
    decreased only after ingestion of 200 ppm (Burtner et al., 1974).

    Cattle, sheep, pigs

         Cattle and sheep were given 3 mg fenitrothion/kg/day for 90 and
    60 days respectively and the cholinesterase activity in the plasma was
    measured. The activity decreased in both species early in the test
    period, but had fully recovered after 30 days. Pigs given a single
    dose of 31 mg/kg showed the typical signs of cholinesterase
    inhibition, but the symptoms disappeared within 48 hours (Anon.,
    1966).

    Long-term studies

    Rat

         Groups of rats (15 males and 15 females) were fed diets
    containing 0, 2.5, 5 and 10 ppm fenitrothion for 92 weeks. The
    cholinesterase activity in the blood was studied and group averages
    between treated and control groups compared after 2, 4, 6, 8, 12, 16,
    20 and 24 weeks. In the 5 ppm group a 20-25% decrease in plasma
    activity of males was seen during the first 16 weeks and a 20-35%
    decrease in the females during 12 weeks. The activity recovered,
    however, during the remaining test period. In the 10 ppm group the
    plasma activity decreased during the first 8 weeks with 30-40% in the
    males and 40-50% in the females. The activity gradually returned to
    normal during the next 8 weeks. The activity of the red blood cells
    was decreased 20-30% in both sexes during the first 6 weeks and then
    fully recovered. Brain activity determined at the end of the test
    period was not affected at any dose level (Kadota et al., 1974b).

         Three groups of rats (50 males and 50 females) were fed
    fenitrothion 10, 30, and 100 ppm in the diet for a period of 104
    weeks. Sixty males and 60 females served as controls. These animals
    were the F1a-generation from the previously mentioned reproduction
    study (Rutter and Voelker, 1974b). Ten rats of each sex and group were
    sacrificed after one year and all the surviving animals at 104 weeks.

    Blood and urinalysis were performed several times during the test
    period. Body weights of the high level males and females were lower
    than the controls from the start of the test and remained so in males
    until after the 52nd week, but at the end of the test no significant
    differences were seen. Food consumption at 52 weeks was lower for the
    middle and high level males, but normal for low level males and all
    the females. In analysis of the mortality data of dosed groups
    compared to controls no difference was found in female animals while
    in males the mortality was significantly higher than the control in
    the lowest dose group. The middle and high dose levels did not show
    any difference from the control mortality. Blood and urine analyses
    were normal except for cholinesterase activity which showed a
    dose-dependent decrease. Significant depression occurred in plasma at
    all 3 dosage levels, but in erythrocyte and brain only at the 100 ppm
    level of both sexes. Statistical analysis of the probabilities of
    tumour incidence (i.e. tumour incidence-adjusted-based on the number
    of animals actually at risk in each group and sex) revealed no
    difference between the control and the 10 ppm or 100 ppm level
    animals. There was a decrease in the probability of only benign
    tumours for the 30 ppm males and an increase of the probability of
    pituitary adenoma incidence for the 30 ppm females, but since this was
    not observed at 100 ppm it did not appear to be dose-related. Absolute
    and relative organ weights and gross and histopathology revealed no
    dose-dependent changes (Rutter and Nelson, 1974a).

    Observations in man

         Adult volunteers were divided into a control group consisting of
    two men and two women and a test group of five men and five women. The
    test period was divided into three parts with increasing dose levels,
    followed by a recovery period. For some of the volunteers, this was
    followed by a fourth test period. The volunteers were given
    fenitrothion orally by gelatine capsules. The daily dose was divided
    in three portions. Dosages were 0.1 mg/kg body weight and 0.3 mg/kg,
    each for 21 days followed by 0.5 mg/kg for 3 days, then 18 days
    recovery and finally 0.2 mg/kg for 21 days. Only 3 persons of the
    control group and 5 of the test group continued after the recovery
    period. Plasma and erythrocyte cholinesterase activity was determined
    5 times prior to the test, 5 times during each of the 21 days test
    periods, 3 times during the recovery period and on day 1 and 3 of the
    short test period. Haematology was performed on the last day of the
    long test and the recovery periods. Two of the persons had a
    significantly depressed plasma cholinesterase activity (10-23%)
    following the dosing with 0.3 mg/kg and the depression was increased
    to 15 and 33% respectively at the 0.5 mg/kg does level. A third person
    showed a 19%, significant, depression at this dose level. The
    erythrocyte cholinesterase activity and the results of haematology
    were within normal limits at all dose levels. Clinical symptoms
    typical of anticholinesterase activity (nausea, abdominal cramps and
    diarrhoea) were observed in approximately half of the dosed persons at
    the 0.3 and 0.5 mg/kg level. No symptoms of cholinesterase inhibition
    were noted with 0.2 mg/kg for 21 days (Garofalo et al., 1972).

    COMMENTS

         Studies of the S-methyl isomer, which occurs as an impurity in
    technical fenitrothion, indicated that it is a much more potent
    anticholinesterase agent but is more rapidly metabolized than the
    parent compound. Acute and short-term studies on a major metabolite in
    plants and animals, 3-methyl-4-nitrophenol (p-nitro-m-cresol),
    indicated a low order of toxicity. Results of studies on delayed
    neurotoxicity of fenitrothion in hens were negative. Results for tests
    for mutagenicity were negative. Results of tests for teratogenesis and
    two reproduction studies in rats indicated no adverse effects at doses
    below those toxic to parents. Short-term studies in rats and dogs
    showed that a depression of plasma cholinesterase was the most
    sensitive indicator of effects and was considerably more sensitive
    than brain cholinesterase inhibition. A 2-year feeding study in rats
    was performed on the F1-animals from one of the reproduction studies.
    Cholinesterase inhibition was the only dose-related effect observed in
    human volunteers given fenitrothion and indicated that a dose of 0.2
    mg/kg bw daily for 3 weeks did not produce inhibition of plasma or
    erythrocyte cholinesterase nor cholinergic symptoms. Studies of tumour
    incidence did not indicate a carcinogenic action. Because clinical
    signs were noted without cholinesterase depression at a dosage of 0.3
    mg/kg, the results of these studies were interpreted with caution in
    estimating the ADI. Nevertheless, since the results of several studies
    in animals have become available, the meeting allocated an ADI.

    TOXICOLOGICAL EVALUATION

    Level causing no toxicological effect

         Rat: 5 ppm in the diet, equivalent to 0.25 mg/kg bw.

         Dog: 5 ppm in the diet, equivalent to 0.125 mg/kg bw.

    ESTIMATE OF ACCEPTABLE DAILY INTAKE FOR MAN

         0 - 0.005 mg/kg bw.

    RESIDUES IN FOOD AND THEIR EVALUATION

    USE PATTERN

         The wide spectrum of activity against insects and the relatively
    low toxicity towards mammals has resulted in a greatly increased field
    of use against pests of agriculture.

    Pre-harvest treatments

         Many pre-harvest treatments have been approved in 35 different
    countries. The recommended dosages in terms of active ingredient or
    concentration of sprays for the major crops are listed in Table 5.

    TABLE 5.  Recommended dosages in terms of active ingredient or
              concentration of sprays for the major crops.

    Crop                             Recommended dosage

    Rice                            0.3 - 1 kg/ha

                                    3-5 times/season

    Wheat, barley                   0.5 - 1 kg/ha

                                    1-2 times/season

    Pome and stone fruit            0.05 - 0.125%

                                    3-5 times/season

    Grapes                          0.05 - 0.075%

                                    2-3 times/season

    Vegetables                      0.1 - 0.5 kg/ha

                                    2-3 times/season

    Cotton                          0.5 - 2 kg/ha

                                    5-6 times/season

    Coffee                          0.5 - 0.7 kg/ha

                                    2-3 times/season

    Pasture                         0.25 - 0.5 kg/ha

                                    1-3 times/season

    Post-harvest treatments

         Most insects which attack stored products such as rice, wheat,
    barley, oats, maize and oil seeds are susceptible to fenitrothion
    (Green and Tyler, 1965; Kane and Green, 1968; Kashi, 1972). In
    Australia, Brazil, India and Zambia the use of fenitrothion for the
    treatment of grain storage structures and for application to the
    outside of bagged products is approved.

         Fenitrothion is under evaluation by the FAO Working Party of
    Experts on Pest Resistance to Pesticides for stored grain use. The
    Meeting had available extensive data from Australia where many large
    scale trials as well as laboratory experiments have been carried out
    to evaluate fenitrothion for addition to stored grain. The rate of
    admixture effective against the major pests is 8-10 ppm.

    Non-crop uses

         Fenitrothion is extensively used for the control of forest
    insects at the rate of 0.2-0.6 kg/ha. It is also used for the control
    of bark beetles and weevils on logs and timbers at the rate of 1.5-3
    g/m2.

         One of the most important uses for fenitrothion is for the
    control of locusts and grasshoppers where application is made by
    ground equipment and aircraft at the rate of 0.3-0.5 kg/ha. Numerous
    other insect pests of pastures and forage crops are presently being
    controlled with fenitrothion where previously organochlorine
    insecticides were used.

    Other Uses

         Fenitrothion is used extensively for the control of insects of
    public health importance. One of the most extensive uses being the
    control of mosquito vectors of malaria. For uses other than in malaria
    control application is made at rates ranging from 0.2-1 g/m2. For the
    control of the malaria mosquito application is made at the rate of 2
    g/m2 (Sumitomo, 1974).

    RESIDUES RESULTING FROM SUPERVISED TRIALS

         Extensive new data were available from supervised residue trials
    carried out on a wide variety of fruit and vegetable crops in Japan.
    These are presented in Table 6 (Sumitomo, 1974).

         Residue studies carried out on selected crops in Germany are
    given in Table 7 (Bayer, 1972).

    Residues in Rice

         In response to one of the requirements of the 1969 Joint Meeting
    extensive studies have been carried out in Japan to determine the
    residue levels of fenitrothion in the grain of rice following approved
    treatments. Over 120 samples of rice harvested following the
    application of varying rates of fenitrothion (0.5-1 kg/ha) applied at
    varying time intervals before harvest were analysed (Sumitomo, 1974)
    by methods described by Takimoto et al. (1974). The data obtained from
    the different applications are given in Table 6a. The average residue


    
    TABLE 6.  (Part I) Residues resulting from supervised trials in Japan (at intervals of 1-15 days)

                                                                                                                                               

                        Application                        No.
                              Rate, % or                   of          Residue, mg/kg at interval (days) after application
    Crop            No.       kg a.i./ha    Formulation   trials     1             3-4               7                9-11            13-15
                                                                                                                                               

    Onion           1         0.05%           EC          1                        n.d.1                             n.d.

    Potato          3 or 6    0.5 or 0.75     EC          2                        n.d.-0.004        n.d.-0.002                     n.d.
                              kg/ha

    Spanish         1         0.75 kg/ha      EC          1            0.2         0.09              0.008           0.005          0.004
     Paprika

    Japanese Pear   3 or 6    0.04%           WP          2                                          0.06-0.08                      0.02-0.03

    Peer            3 or 5    2.5 kg/ha       WP          2                                          0.01-0.08                      n.d-0.006

    Egg plant       3 or 6    0.75-1.5        EC                                   0.001-0.01        n.d.-0.006                     n.d.-0.002
                              kg/ha

    Peach (pulp)    3 or 6    2 or 2.5        EC          4                        0.07-0.08         0.03-0.07                      0.005-0.015
                              kg/ha

    Peach (peel)    3 or 6    2 kg/ha         EC          2                        2.2-2.9           1.1-1.6                        0.3-0.6

    Peach (peel)    3 or 6    2.5 kg/ha       EC          2                        5-5-6.1           5.5-6.2                        1.8-2.1

    Orange          1         2.25 kg/ha      EC          4                                                          n.d.-0.1

    Grape           3 or 6    1 or 1.25       EC          4                        1.1-2.8           0.5-1.1                        0.1-0.9
                              kg/ha

    Stone-leek      2 or 4    0.57 kg/ha      EC          2          0.006-0.01    0.003-0.005       n.d.-0.001                     n.d.

    Stone-leek      2 or 4    2.86 kg/ha      EC          2          0.09-0.2      0.09-0.2          0.09-0.2                       0.02-0.03

    TABLE 6.  (Part I) (Cont'd.)

                                                                                                                                               

                        Application                        No.
                              Rate, % or                   of          Residue, mg/kg at interval (days) after application
    Crop            No.       kg a.i./ha    Formulation   trials     1             3-4               7                9-11            13-15
                                                                                                                                               

    Strawberry      2 or 4    0.5 kg/ha       EC          2                        0.7-1.1           0-1-0.3         0.06-0.09

    Strawberry      2 or 3    1.0 kg/ha       EC          2                        0.04-0.06         0.02-0.03                      0.005-0.007

    Soybean         2 or 3    0.71 kg/ha      EC          4                        0.02-0.03         0.02-0.05       0.001-0.002    0.001-0.01

    Tomato          3 or 6    1.0 kg/ha       EC          4          0.09-0.2      0.02-0.05

    Tomato          3 or 6    2.5 kg/ha       EC          4          1.3-2.7       0.4-0.9

    Apple           1 or 2    0.04 or 0.05%   WP          3                                          0.2             0.1-0.3        0.03-0.06

    Apple           1 or 3    0-05%           EC          2                                          0.2
                                                                                                                                               

    1  n.d. not detected

    TABLE 6. (Part II) Residues resulting from supervised trials in Japan (at intervals of 21-64 days)

                                                                                                                                               

                   Application                          No.
                          Rate, % or                    of           Residue, mg/kg at interval (days) after application
    Crop        No.       kg a.i./ha     Formulation    trials     21             28-32            34-36            41-49            51-64
                                                                                                                                               

    Onion       1         0.05%          EC             1          n.d.*

    Rice        1         0.75 kg/ha     EC             4                         0.002-0.06       0.002-0.09       0.004-0.06

    Rice        2 or 4    1.2 kg/ha      MG**           4                         n.d.                              n.d.

    Orange      1         2.25 kg/ha     EC             4                         n.d.-0.009

    Soybean     2 or 3    0.71 kg/ha     EC             4                                                           0.002            0.001-0.005

    Apple       3 or 5    0.05%          WP             2                                                                            0.001

    Apple       1 or 3    0.05%          EC             2                         0.04                                               0.002
                                                                                                                                               

    *   n.d. = not detected
    **  MG = micro-granules
    

    TABLE 6a.  Residues of fenitrothion in rice grain following
               standard treatments

                                                                             

                      Days            No. of         Residue of Sumithion
                      after           samples             (mg/kg)
    Formulation       application     analysed     Range             Average
                                                                             

    EC                11-20           14           0.303-0.012       0.109

                      21-40           15           0.154-0.003       0.051

                      41-67           18           0.005-0.001       0.001

    Dusts             11-20            9           0.035-0.001       0.016

                      21-40           22           0.032-0.001       0.003

                      41-67           28           0.003-0.001       0.001

    WP                11-20            4           0.060-0.022       0.036

                      21-40            8           0.059-0.001       0.020

                      41-67            8           0.001             0.001
                                                                             

    level found ranges from negligible (0.001 mg/kg) to 0.1 mg/kg. From
    these data, it is concluded that:

    (1)  regardless of post-treatment period, the residual amount of
         fenitrothion was influenced by formulation. The residue remaining
         after the use of emulsifiable concentrates is higher than that
         from the use of wettable powders which in turn is higher than
         that from the use of dusts.

    (2)  the maximum residue obtained 11-20 days after the final
         application was 0.3 mg/kg. The average residue level was 0.11
         mg/kg in the case of EC formulations. The residue level decreased
         uniformly in the period between final application and harvest.

    (3)  41-67 days after the final application, the residue was on an
         average 0.001 mg/kg in the 54 samples (Sumitomo, 1969).

    These data are in close agreement with the studies (Miyamoto and Sato,
    1965) considered by the 1969 Joint Meeting (FAO/WHO, 1970).

        TABLE 7.  Residue levels in supervised trials - Germany

                                                                                                                                      

                             Rate                         Fenitrothion, mg/kg, after interval (days)
    Crop                     kg/ha          0           1           7           10          14          21          50           90
                                                                                                                                      

    Savoy cabbage            0.4            8.1         1.35        0.05        0.01        0.01

                             0.25           1.6         1.02        0.02        0.01        0.01

    Wine grapes              0.88           9.5                     4.5                     0.8         0.7         0.7

    Must                                                                                                            0.05

    Wine grapes              0.88           8.8                     1.5                     0.27        0.15        0.1

    Must                                                                                                            0.01

    Grapes                   0.625                                                                                              0.01

    Must                                                                                                                        0.01

    Wine                                                                                                                        0.01

    Grapes                                                                                  0.025

    Must                     0.625                                                                                              0.01

    Wine                                                                                                                        0.01

                                                                                                                                      
    
    Miyamoto et al. (1965) studied the fate of 32P-labelled fenitrothion
    applied to field-grown rice plants and found a very rapid decrease in
    fenitrothion deposits.

    3-methyl-4-nitrophenol residues were determined in harvested rice
    grains following the application of fenitrothion. Using the Aich-asahi
    variety, 0.36 mg/kg of 3-methyl-4-nitrophenol was found in rice bran
    and negligible amounts in polished rice. This finding is consistent
    with that reported by Hosokawa, and Miyamoto (1974) using
    14C-labelled fenitrothion applied to apples hanging on the tree.

    Post-harvest treatments

         Green and Tyler (1965) demonstrated that when fenitrothion was
    added to stored barley it gave a much more durable deposit and was
    more effective than over 8 times the quantity of malathion. Dichlorvos
    was relatively transient. In one experiment 0.54 mg/kg fenitrothion
    added to barley declined only slightly, to 0.33 mg/kg, in 19 weeks. At
    the end of the first six weeks the concentration found by analysis was
    substantially the same as that at the time of treatment.

         The Cooper Technical Bureau (1968) reports a series of 10
    large-scale field trials in which fenitrothion was added to bulk wheat
    stored in a variety of silos ranging in size from 6 tons to 6,000
    tons. Details of the application rate and the residue levels found by
    analysis at the beginning and end of the storage period are given in
    Table 8.

         Bengston et al. (1974) report the results of two large-scale
    experiments where fenitrothion was applied to large bulks of wheat at
    two different centres in Australia. Samples were taken in a
    pre-determined pattern from various depths within the bulk of grain at
    regular intervals after treatment. The temperature of the grain
    remained approximately 30°C throughout the storage period. Samples
    drawn at each stage of the experiment were analysed independently by
    five separate laboratories. Bioassays against 16 strains of stored
    product pests were carried out simultaneously on identical samples of
    grain. The results of the chemical analyses are recorded in Table 9.
    By comparison with malathion, fenitrothion deposits remained stable
    over a much longer period and appeared to be less affected by storage
    conditions.

         The Sumitomo Chemical Company (1974) reports interim results of a
    study of the persistence of fenitrothion on stored rice grain.
    Unpolished rice was treated with diluted fenitrothion emulsion to give
    concentrations of 2, 6 and 15 mg/kg of fenitrothion. The rice was
    stored in kraft paper bags at 25°C for periods up to 6 months.
    Moisture content of the grain during the experimental period was
    between 13.1% and 14.1%. Results are given in Table 10.


    
    TABLE 8.  Fenitrothion as a grain protectant, summary of field trials (Australia)

                                                                                                                                               

                                                                                  Residues (mg/kg)
                  Storage                                                              Initial       Final
                                           Duration     Formulation    Application     assay         assay
    State    Capacity and type             (months)     type           rate            (Average)     (Average)    Observations
                                                                                                                                               

    NSW      500-bushel galvanised         10           wmc            2.5             2.0           1.5          Protection maintained
             iron silos                                                5.0             4.1           4.1          throughout trial

    NSW      2,000-bushel galvanized        4           powder         2.5             1.0           0.1          Trial terminated by sale
             iron silos -                                              5.0             2.2           ?            of grain: inconclusive
             'Farm treatment'

    SA       2,000-bushel galvanised        9           powder         2.5             1.3           0.2          Protection maintained;
             iron silos                                                5.0             2.8           0.4          data incomplete

    NSW      7,000-bushel vertical         19           wmc            2.5             2.3           0.7          Protection maintained
             concrete silo bins            10                          2.5             2.3           0.7          throughout; surfaces
                                           19                          5.0             2.2           0.7          dusted with malathion
                                           10                          5.0             2.3           1.2          (20-25 ppm) at 8 months

    NSW      32,000-bushel vertical         7           wmc            6.0             3.2           0.9          Protection maintained
             concrete silo bins                                                        3.2           0.9          throughout
                                            9           wmc            6.0             3.2           1.0
                                                                                       3.8           0.8

    WA       20,000-bushel vertical        10 3/4       wmc            6.0             3.5           0.8          Protection maintained
             concrete silo bins                                                                                   throughout

    NSW      200-bushel silo                6           wmc            6.0             3.4           1.8          Protection failed:
                                                                                                                  Rhizopertha dominica
                                                                                                                  surviving at 3 months,
                                                                                                                  infestation by 6 months

    TABLE 8.  (Cont'd.)

                                                                                                                                               

                                                                                  Residues (mg/kg)
                  Storage                                                              Initial       Final
                                           Duration     Formulation    Application     assay         assay
    State    Capacity and type             (months)     type           rate            (Average)     (Average)    Observations
                                                                                                                                               

    NSW      250,000-bushel bulk           8 1/2        wmc            10.0            4.7           2.2          Protection maintained:
             wheat Depot                                                                                          1 spot infestation could
                                                                                                                  have been fumigated.

    WA       20,000-bushel vertical         8           wmc            6.0             4.1           1.5          Protection maintained.
             concrete silo bin

    WA       47,000-bushel bulk             6           wmc            6.0             2.4           0.8          Final details awaited.
             wheat depot                                                                                          Treated grain, processed
                                                                                                                  and assessed by Aust.
                                                                                                                  Bread Res. Inst., free
                                                                                                                  of taint or odour in
                                                                                                                  flour or bread.
                                                                                                                                               
    

    TABLE 9a.  Fenitrothion residues, mg/kg, in wheat from Site M
               of two trials in Australia. Samples taken at various
               depths analysed by independent laboratories.*

                                                                            

          Sample                              Analyst
               Since
    Depth M.   Treatment     A         B         C         D         Mean
                                                                            

    0.1        1 week        6.0       6.6                           6.3
    1.5                      6.5       7.6                           7.1
    6.0                      7.0       6.6                           6.8
    Mean                     6.5       6.9                           6.7

    0.1        6 weeks       4.9       4.5       4.3       6.3       5.0
    1.5                      4.8       4.7       4.0       3.6       4.1
    6.0                      4.9       4.6       4.0       4.5       4.5
    Mean                     4.9       4.6       4.1       4.6       4.5

    0.1        11 weeks      3.4       4.1       4.7       3.2       3.9
    1.5                      3.6       4.0       4.8       3.0       3.8
    6.0                      3.6       3.7       4.5       2.9       3.7
    Mean                     3.5       3.9       4.7       3.0       3.8

    0.1        16 weeks      3.0       -         -         3.3       3.2
    1.5                      2.8       -         -         3.0       2.9
    6.0                      2.8       -         -         3.1       2.9
    Mean                     2.9       -         -         3.1       3.0

    0.1        22 weeks      3.3       3.1       3.0       3.0       3.1
    1.5                      3.0       3.1       2.0       4.0       3.2
    6.0                      2.4       2.6       2.2       2.8       2.5
    Mean                     2.9       2.9       2.7       3.3       3.0

    0.1        26 weeks      -         2.2       3.4       -
    1.5                      -         2.2       3.0       -
    6.0                      -         1.6       2.1       -
    Mean                     -         2.0       2.8       -
                                                                            

    *  Amount applied equivalent to 6 ppm on weight of wheat
       (Approximately 1000 tonnes)

    TABLE 9b.  Fenitrothion residues, mg/kg, in wheat from Site W
               of two trials in Australia. Samples taken at various
               depths analysed by independent laboratories.*

                                                                            

          Sample                              Analyst
               Since
    Depth M.   Treatment     A         B         C         D         Mean
                                                                            

    0.1        2 weeks       4.8       4.5       4.0       4.2       4.3
    1.5                      4.4       4.1       -         4.6       4.4
    6.0                      4.8       5.0       4.2       5.6       5.0
    Mean                     4.7       4.5       -         4.8       4.7

    0.1        8 weeks       4.5       4.5       5.8       5.5       5.0
    1.5                      3.6       3.8       4.9       4.1       4.0
    6.0                      3.8       4.3       5.3       4.8       4.5
    Mean                     4.0       4.2       5.3       4.9       4.5

    0.1        13 weeks                4.5       6.1       8.0       6.2
    1.5                                4.6       5.4       7.4       5.8
    6.0                                5.0       6.5       4.1       5.2
    Mean                               4.7       6.0       6.5       5.7
                                                                            

    TRIAL TERMINATED BECAUSE OF INFESTATION WITH RHIZOPERTHA DOMINICA.

    
    TABLE 10.  Residue of fenitrothion in/on unpolished and polished
               rice and rice bran

                                                                                                

                    Treatment     Fenitrothion, mg/kg, after storing period (months)
                      dose,
    Commodity         mg/kg       Initial      1            2            3            6
                                                                                                

    Unpolished       2            1.03         0.83         0.79         0.78         0.68
    rice
                     6            3.92         2.82         2.68         2.44         2.18

                    15            9.38         6.54         6.09         5.85         5.45

                    control       <0.01        <0.01        <0.01        <0.01        0.01

    Polished Rice    2            0.13         0.12         0.11         0.09         0.09

                     6            0.44         0.32         0.29         0.25         0.26

                    15            1.02         0.83         0.67         0.58         0.58

                    control       <0.01        <0.01        <0.01        <0.01        <0.01

    Rice Bran        2            8.31         6.41         5.31         4.63         4.46

                     6            27.2         19.5         18.1         17.5         13.1

                    15            65.0         48.1         41.0         41.6         34.8

                    control       0.07         0.13         0.02         0.02         0.02
                                                                                                
    
         Although recovery studies indicated that close to 100% of a
    measured amount of fenitrothion would be recovered from treated rice
    grains, analysis of the samples prepared in the above experiment
    recovered only from 43-53% of the amount of fenitrothion applied.
    Irrespective of the amount applied (2, 6 and 15 ppm) the amount of
    fenitrothion recoverable by analysis at the end of 6 months was only
    about half that recovered immediately following treatment. The
    greatest decline occurred in the first month and thereafter the
    residues appeared to decline relatively slowly.

    FATE OF RESIDUES

    General Comments

         Since the previous evaluation (FAO/WHO, 1970) some new
    experimental work concerning the fate of residues has been reported.
    The behaviour of fenitrothion in the environmental system, like that
    of other pesticides which contain a nitrophenol moiety, is determined
    by its readiness to form an aminophenol moiety by reduction of the
    nitro group as well as by its transformation by hydrolysis. The
    reduced compound has been found in polluted water, soil, animals,
    plants and even following photodecomposition (Sumitomo, 1974).

    In animals

         Orally administered 32P-labelled fenitrothion was readily
    absorbed from the digestive tract of guinea pigs or rats and the major
    portion of the radioactivity was excreted in the urine. Neither
    fenitrothion nor fenitrooxon was detected and desmethyl fenitrothion,
    dimethyl phosphorothionate and dimethyl phosphate were eliminated in
    the urine (Miyamoto et al., 1963). Following intravenous injection of
    radioactive 32P-fenitrothion into guinea pigs and rats fenitrothion
    rapidly disappeared from the blood. Fenitrothion and fenitrooxon were
    found in tissues and their amounts decreased rapidly. The desmethyl
    compound and the dimethyl esters mentioned above were found mostly in
    the liver and kidneys (Miyamoto, 1964).

         Details of metabolic studies in animals are given in the 1969
    monograph (FAO/WHO, 1970) where an outline of the degradation pathway
    is shown. Excretion of metabolic products is rapid and chiefly in the
    form of 3-methyl-4-nitrophenol, the fenitrothion hydrolysis product
    (Hladka and Nosil, 1967).

         Thirty calves (1-1.5 years, average weight 243 kg) confined on a
    pasture sprayed with 375 g/ha, of fenitrothion (11.8 mg/kg initial
    residue on the grass) were periodically sacrificed and muscle and
    omental fat were analysed. On the first day residues in the meat and
    fat were about 0.01 mg/kg. No residue of fenitrothion was found in the
    meat from the third day onwards and only 0.004-0.007 mg/kg was found
    in the fat on the third day. These amounts decreased almost to control
    levels by the seventh day (Anonymous, 1968; Miyamoto and Sato, 1969).

         Lactating dairy cows were fed 50 ppm of fenitrothion in the feed
    (dry basis) for 29 days. No residue of fenitrothion, fenitrooxon, or
    the cresol appeared in the milk. A maximum of 0.006 mg/kg of
    amino-fenitrothion was found (Bowman, 1969).

         Silage prepared from corn treated with 1, 2 and 3 kg/ha of
    fenitrothion was fed to lactating Jersey cows for 8 weeks. Although
    traces (0.001-0.005 mg/kg) of amino-fenitrothion were found in the
    milk of cows fed the 3 kg/ha silage, no residues (less than 0.001
    mg/kg) were found in the milk of cows consuming silage treated at
    lower levels (Leuck et al., 1971). The urine contained total

    metabolites averaging from 0.53-5.1 mg/kg but these consisted mostly
    of amino-fenitrothion and about 0.1 mg/kg or less of the parent
    insecticide and its cresol. Although faeces of the cows contained low
    levels of residue (0.04-0.18 mg/kg, mainly as the amino compound)
    neither blood cholinesterase depreciation nor any abnormality of
    general health or milk production were noted.

         Jersey cows were fed on diets spiked with 0, 25, 50 and 100 ppm
    of fenitrothion for 28 days. Consumption of diets containing
    fenitrothion did not depress feed intake, milk production or blood
    cholinesterase activity. Milk, urine, and faeces from cows fed as much
    as 100 ppm dietary fenitrothion contained neither fenitrothion, its
    oxygen analogue, nor its cresol; but the amino analogue of
    fenitrothion in milk, urine and faeces of cows fed the 25, 50 and 100
    ppm diets averaged 0.002-0.17, 4.64-35.6, and 0.19-1.80 mg/kg
    respectively. Seven days after feeding the diets containing
    fenitrothion was terminated, residues could not be detected in milk,
    urine, or faeces from any cows (Johnson and Bowman, 1972).

    In plants

         Apples hanging on the tree were dipped in a 0.1% emulsion of 14C
    labelled fenitrothion and maintained under natural weather conditions.
    The half-life of the parent compound in and on fruit was found to
    range between 1 and 3 days, and fenitrooxon, fenitrothion S-isomer,
    p-nitrocresol and desmethylfenitrothion were found.
    p-nitrocresol-ß-glucoside was also found and it was concluded
    that the absorbed fenitrothion was gradually hydrolysed to
    p-nitrocresol in the tissues and that it was conjugated with glucose
    (Hosokawa and Miyamoto, 1974).

         Coastal bermuda grass and corn treated with an emulsifiable
    concentrate of fenitrothion at 1, 2 and 3 kg/ha and sampled at 0, 1,
    7, 14, 21 and 28 days post-treatment were analysed for residues of the
    parent compound, its oxygen analogue and its cresol. The residues of
    the parent compound diminished rapidly, those of the O-analogue were
    low (none were detected in the 21 and 28 day samples), and those of
    the cresol were highest in the 1 and 7-day samples. The total residue
    on both crops diminished to less than 1 mg/kg in 28 days. In contrast,
    residues of the parent compound and its O-analogue in corn ensiled in
    glass jars were relatively stable and diminished at a much lower rate,
    and the residues of the cresol increased significantly (Leuck and
    Bowman, 1969).

    In water

         Fenitrothion was found to be very stable under sterile acidic
    conditions at 37°C, while under alkaline conditions it was hydrolysed
    rapidly with a half-life of three days at pH 11 and less than 24 hours
    at pH 13, forming only 3-methyl-4-nitrocresol. Other decomposition
    products were hardly observed at these alkaline pH's, while under
    neutral and acidic conditions trace amounts (at most 2% of the initial
    radio-activity) of unidentified compounds were formed (Miyamoto,
    1974).
    
         The fate of fenitrothion in river water with sediment was
    demonstrated by using actual river water containing 2.5, 5 and 10 mg/l
    of fenitrothion. The half-life was approximately 50 hours in aerated
    samples and 30-40 hours in non-aerated samples where decomposition was
    accelerated by anaerobic bacteria (Zitko et al., 1974).

    In soil

         Decomposition and leaching of fenitrothion in 4 different types
    of soil were studied under laboratory conditions (Miyamoto, 1974a).
    Carbon-14 labelled fenitrothion at 10 ppm was added to two kinds of
    silty loam, sandy loam and sand, and kept at 25°C in the dark under
    upland or submerged conditions. Under upland conditions fenitrothion
    was decomposed with a half-life of 12-28 days depending on the type of
    soil. The major decomposition products were 3-methyl-4-nitrophenol and
    carbon dioxide. 3-methyl-4-nitrophenol, formed during the early period
    of the incubation, amounted to 10-20% while the amount of carbon
    dioxide reached approximately 40% after 60 day incubation in the silty
    loam and the sandy soil.

         Under submerged conditions decomposition of fenitrothion was even
    more rapid than in upland conditions and amino-fenitrothion, the major
    metabolite, was produced quite rapidly; in the silty and sandy loam
    50-70% of the fenitrothion was converted to amino-fenitrothion in
    approximately 10 days. Since fenitrothion was stable in sterilised
    soil, micro-organisms might play a major role in the decomposition,
    fungi being likely to be more active than bacteria. In the leaching
    study, fenitrothion and its radioactive decomposition products were
    not significantly eluted from 3 types of soil and remained at or near
    the top. Only in sand with low organic matter and clay content, were
    these compounds loosely bound to the soil allowing them to migrate
    easily with moving water.

    In storage and processing

         Fenitrothion applied to unpolished rice (post-harvest application
    for grain protection) at rates of 2, 6 and 15 mg/kg resulted in 0.68,
    2.18 and 5.45 mg/kg respectively remaining after 6 months of storage
    at 25°C. At the highest dosage rate, 15 mg/kg applied to rice grain
    decreased to 6.54, 5.85 and 5.45 mg/kg, after 1, 3 and 6 months
    storage respectively. Details of the distribution of fenitrothion
    residues on unpolished and polished rice and rice bran are given in
    Table 10 (Sumitomo, 1974).

         Bengston et al. (1974) as part of an extensive evaluation of
    grain protectants in Australia, submitted grain which had been treated
    with fenitrothion 13 and 26 weeks previously to a laboratory scale
    milling and baking trial. The distribution of fenitrothion residues in
    the raw grain, milled grain products and bread is given in Table 11.
    It will be noted that there is a minor discrepancy between the results
    of 2 participating laboratories, one of which reports no residues in
    bread, the other reporting residues at the limit of determination.


    
    TABLE 11.  Fate of fenitrothion residues in wheat subjected to milling and baking1

                                                                                                            

                                                              Fenitrothion, mg/kg
                                             Wheat W                                       Wheat M
    Stage of                 Laboratory A                 Laboratory B                   Laboratory B
    Processing          1        2        Mean        1        2        Mean        1        2        Mean
                                                                                                            

    Whole grain         4.0      3.9      4.0         4.2      4.0      4.1         3.0      3.1      3.0

    Cleaned grain       3.2      3.2      3.2         -        -        -           -        -        - 

    Bran                9.4      11.3     10.4        8.0      8.6      8.3         8.2      8.0      8.1

    Shorts (pollard)    8.0      7.6      7.8         6.1      6.1      6.1         6.2      5.8      6.0

    Flour               0.44     0.47     0.5         0.35     0.3      0.3         0.66     0.68     0.6

    Bread               0.11     0.11     0.1         ND2      ND       ND          T3      T        T
                                                      <0.2     <0.2                 (0.1)    (0.1)    (0.1)
                                                                                                            

    1  From wheat in trials referred to in Table 9.

    2  ND = not detected.

    3  T = trace.
    

    Photodecomposition

         An extensive study of the fate of fenitrothion under the
    influence of ultra-violet light has been performed by Ohkawa et al.
    (1974). Irradiation of fenitrothion in various solutions with UV light
    in air resulted in rapid photodecomposition, depending upon the
    solvent used, and the following compounds were produced:

         carboxy-fenitrothion (the main decomposition product),
         fenitrooxon, carboxy-fenitrooxon, 3-methyl-4-nitrophenol,
         3-carboxy-4-nitrophenol and parathion-methyl.

    Irradiation with UV light in nitrogen produced none of these products,
    but a trace amount of fenitrothion S-isomer was found in aqueous
    methanol. When fenitrothion was exposed to sunlight in water solution,
    carboxy-fenitrothion was the main decomposition product and
    fenitrooxon, 3-methyl-4-nitrophenol, 3-carboxy-4-nitrophenol and
    fenitrothion S-isomer were also detected. When fenitrothion deposits
    on silica gel chromatoplates were exposed to sunlight or UV light,
    carboxy-fenitrothion and fenitrooxon were the major decomposition
    products. Carboxy-fenitrooxon, 3-methyl-4-nitrophenol and
    4-carboxy-4-nitrophenol were also obtained. When 14C-fenitrothion was
    applied to surfaces the radio-carbon was more rapidly lost from the
    leaf surfaces of bean plants than from silica gel chromatoplates, but
    the same products in almost the same proportions were found on both
    surfaces. Two major products, carboxy-fenitrothion and fenitrooxon,
    and 3-methyl-4-nitrophenol were further degraded into more polar
    products, and finally into polymeric humic acids. Certain carbamate
    and pyrethroid insecticides slightly accelerated the
    photodecomposition of fenitrothion.

    METHODS OF RESIDUE ANALYSIS

         Despite the large number of methods for the analysis of
    fenitrothion, it was not until 1969 that a method capable of analysing
    for fenitrothion, fenitrooxon and the cresol was reported (Bowman and
    Beroza, 1969). This method has now been extended to include
    S-methyl-fenitrothion (Hallett et al., 1974). Although fenitrothion
    can be readily separated from fenitrooxon and S-methyl-fenitrothion by
    GLC it is more convenient and accurate to separate the phosphate
    esters by column chromatography prior to GLC analysis (Bowman and
    Beroza, 1969).

         The solvent and the technique used to extract fenitrothion from
    tissues are determined by the nature of the material to be analysed.
    Materials with a high water content such as fruit and some vegetables
    are blended with polar solvents: acetonitrile (McLeod et al., 1969;
    Watts et al., 1969); acetone (Mollhoff, 1968) or methanol (Sumitomo,
    1974). For materials containing both fat and water, e.g. milk and
    meat, combinations of polar and non-polar solvents have been used:
    methanol/acetronitrile (Miyamoto et al., 1967), chloroform/methanol

    (Bowman and Beroza, 1969). For dry materials, e.g. rice and grain,
    benzene has been used (Sumitomo, 1974). Non-polar solvents like hexane
    are also used for materials with a high fat content, e.g. omental fat
    (Miyamoto and Sato, 1969).

         Gas-liquid chromatography is generally the method of choice for
    the quantitation of fenitrothion and its metabolites. Although some
    analyses for fenitrothion have been carried out using an electron
    capture (EC) detector (Dawson et al., 1964; Kahazawa and Kawahara,
    1966), current methods invariably use selective phosphorus detectors.

         The sensitivity of the alkali flame ionization detector (AFID) to
    phosphorus compounds is generally greater than that of the flame
    photometric detector (FPD) by a factor 10-30. On the other hand, the
    precision of the results obtained with an FPD is usually better.
    Bowman and Beroza (1969) used the FPD whilst Miyamoto and Sato (1969)
    and Hallett et al. (1974) have used the AFID. The response of
    fenitrothion was found to be greater by a factor of 3 than that of
    fenitrooxon and S-methyl-fenitrothion with an AFID. The least
    detectable amounts are 8.6 x 10-13 g/sec for fenitrothion, 2.9 x 10-12
    g/sec for fenitrooxon and 2.5 x 10-12 g/sec for S-methyl-fenitrothion
    (Greenhalgh et al., 1974). The difference in sensitivity was
    attributed partly to peak shape and partly to combustion conditions in
    the flame. Although the sensitivity of detection of aminofenitrothion
    with the AFID and the FPD is comparable to that of fenitrothion, it is
    some 250 times less for an EC detector (Greenhalgh, 1974b).

         Greenhalgh (1974a) reviews the information on various columns and
    packing materials and as reported separately Greenhalgh (1974b) has
    shown the advantage of using 4% SE-30/6% QF-1 on Chromosorb W. This
    column readily resolves amino-fenitrothion, fenitrothion, fenitrooxon
    and S-methyl-fenitrothion in that order. It is free from interference
    from parathion and parathion-methyl.

         Although it is possible to separate fenitrothion and its polar
    metabolites by GLC, separation can also be achieved using liquid
    column chromatography. Bowman and Beroza (1969) used de-activated
    silica gel (20% H2O) to clean up extracts of corn and Bermuda grass
    and at the same time separate fenitrothion, its cresol and
    fenitrooxon. Activated Florisil has also been used to clean up
    fenitrothion, with a recovery of 97% on elution with ether/benzene,
    1:2 (Beckman and Garber, 1969). It has also been used to clean up
    grain extracts containing fenitrothion (Horler, 1966). Bowman and
    Beroza (1969) reported that alumina decomposed the fenitrothion.

         A more detailed study has been carried out on the recovery of
    fenitrothion and fenitrooxon at the 1.6 g level using silica gel,
    Florisil and carbon columns (Hallett et al., 1974). All three columns
    gave a 95-100% recovery of fenitrothion, which was eluted with
    benzene. Further elution with acetone/benzene, 3:1, gave fenitrooxon.
    The recovery of the fenitrooxon was, however, dependent on the
    activity of the column as shown in Table 12.

    TABLE 12.  Recovery of fenitrooxon

          % Water                  % Recovered
         in packing         Florisil          Silica gel

         0                 0                 100

         5                 50-58             100

         10                100               100

         15                100               64-66

         25                100               64-69

         The cresol was not studied because it did not interfere when
    using specific phosphorus GLC detectors. The carbon column also gave
    good recoveries of both fenitrothion and fenitrooxon (Watts et al.,
    1969). This column is very useful for highly pigmented extracts but is
    inconvenient to prepare.

         The recoveries quoted for fenitrothion in Table 6 differ from the
    results of Bowman and Beroza, (1969). This can be attributed to the
    absence of large amounts of sodium sulphate and a different elution
    pattern. It has since been found that Florisil will decompose
    S-methyl-fenitrothion to some extent. Silica gel (2% H2O) is now
    Preferred. A 95-100% recovery of fenitrothion, fenitrooxon and
    S-methyl-fenitrothion is achieved at the 1 µg level. The S-methyl
    isomer is eluted in the acetone fraction with the fenitrooxon.

         Takimoto and Miyamoto (1974) have assembled the results of
    extensive experience in the determination of fenitrothion residues
    into a set of detailed procedures for handling a wide range of
    different substrates. A series of extraction and clean-up procedures
    are laid down for each different situation. Quantitation is attained
    by GLC methods using the flame thermionic detector (FTD). For most
    substrates the limit of determination is 0.005 mg/kg but according to
    the authors it is often easy to determine fenitrothion at a level as
    low as 0.001 mg/kg or even less.

         Krehn (1973) has prepared an extensive review which includes
    detailed information on residue analysis, confirmatory tests, cleanup
    and quantitation.

    NATIONAL TOLERANCES REPORTED TO THE MEETING

         The following national tolerances were reported to the meeting.

    TABLE 13.  National tolerances reported to the Meeting

                                                                             
                                                                 Tolerance
    Count               Crop                                     mg/kg
                                                                             

    Australia           apples, cherries, grapes,                0.5
                        lettuce

                        red cabbage, tea (green)                 0.3

                        tomatoes                                 0.2

                        cocoa                                    0.1

                        milk and milk products                   0.05*
                        (fat basis)

                        meat and fat of meat                     0.03*

    Czechoslovakia      fruits, vegetables                       0.5

    Germany (Federal    vegetables                               0.4
    Republic of)

    Holland             cereals, fruits                          0.5

    Japan               rice, soybeans, persimmon,               0.2
                        pear, apple, mandarin,
                        orange, peach, grapes,
                        strawberries, pumpkin,
                        cucumber, onion, tomato,
                        egg plant, green pepper,
                        lettuce, tea

    Poland              fruits, vegetables                       0.4
                                                                             

    APPRAISAL

         The 1969 Joint Meeting after reviewing the available information
    on fenitrothion specified that further work or information was
    required on residue levels in commodities moving in commerce, on
    disappearance during storage, on residue decline in rice, on
    persistence of residues in stored grains, on occurrence of
    4-nitro-3-methyl phenol, and on the quality of technical fenitrothion.
    Evaluation of gas-chromatographic methods for regulatory purposes was
    desirable.

         The Meeting received considerable information on all these
    questions with the exception of residues in commodities moving in
    commerce. There was additional information on other uses, extensive
    new data on the chemical, physical and biological properties of
    fenitrothion and extensive information on new residue studies. While
    new uses have been developed these have mainly been an extension to
    other crops, the rate of application remaining similar to that
    referred to in the 1969 Meeting.

         There is a potential demand for fenitrothion as a grain
    protectant and extensive data are available on the performance and
    fate of fenitrothion in wheat and rice and in milled products from
    these grains. The usefulness of fenitrothion for this purpose is
    highlighted by the worldwide development of insect strains resistant
    to malathion.

         Results from the analysis of many different grades of technical
    fenitrothion were considered by the Meeting and the significance of
    the various components has been studied in relation to the fate of
    fenitrothion in the environment in general and in many separate
    aspects.

         It was recognized that the residues on fruits, vegetables, forage
    crops and pasture resulting from approved uses of fenitrothion were
    relatively low and that their level declined rapidly with a half-life
    of 1 to 2 days. There is no tendency for fenitrothion or its
    metabolites to accumulate in animal tissues or foods of animal origin
    following approved uses on pasture or forage crops or from feeding of
    food-processing wastes.

         The many methods of residue analysis have been examined and
    reviewed by numerous authors. It is generally accepted that the method
    of Bowman and Beroza (1969) is suitable for regulatory purposes,
    particularly as it is capable of analysing for the parent fenitrothion
    together with fenitrooxon and the residual cresol. Takimoto and
    Miyamoto (1974) have documented procedures for dealing with many
    substrates with corresponding extraction and clean-up procedures.
    Quantitation is attained by GLC methods using flame thermionic and
    electron capture detectors. The limit of determination is reported to
    be 0.005 mg/kg in many substrates.

    RECOMMENDATIONS

    TOLERANCES

         The following tolerances, which revise recommendations made in
    1969, are recommended. The maximum residue limits include the parent
    fenitrothion and the oxygen analogue fenitrooxon expressed as
    fenitrothion (mg/kg).

    Crop                                                  mg/kg

    Wheat bran                                            20

    Wheat                                                 10

    Wheat flour (wholemeal)                                5

    Peaches                                                2

    Wheat flour (white)                                    1

    Apples, cabbage, red cabbage, cherries, grapes,
    lettuce, peas, rice (in husk), strawberries, tea
    (green, dry), tomatoes                                 0.5

    Leeks, oranges, radishes, bread (white)                0.2

    Cauliflower, cocoa beans, egg plant, pears,
    peppers, rice (polished), soybeans (dry)               0.1

    Cucumbers, meat, fat of meat, milk, milk
    products, onions, potatoes                             0.05*

    * At or about the limit of determination


    FURTHER WORK OR INFORMATION

    DESIRABLE

    1.   Further observations in man.

    2.   Results from studies now in hand on the effect of cooking on
         fenitrothion residues in rice.

    3.   Further studies to determine the fate of residues during the
         cooking of other cereal products from wheat and rye.

    4.   Information on the level and fate of residues following
         post-harvest use on oats, barley and rye.

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    Rutter, H.A. and Voelker, R.W. (1974b) Three-generation reproduction
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    Sumitomo Chemical Co. Ltd. (1974) Fenitrothion data submission for
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    Chemical Co., Ltd. (Unpublished)

    Suzuki, H., Miyamoto, J. and Oka, A. (1974) Mutagenicity and
    radiomimeticity screening of Sumithion. Report submitted by Sumitomo
    Chemical Co.Ltd. (Unpublished)

    Takimoto, Y. and Miyamoto, J. (1974) Analysis of Sumithion residues.
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    Uchiyama, M., Yoshida, T., Homma, K. and Hongo, T. (1974) Inhibition
    of hepatic drug-metabolizing enzymes by thiophosphate insecticides and
    its toxicological evaluation. Report submitted to WHO. (Unpublished)

    Watts, R.R., Storherr, R.W., Pardue, J.R., and Osgodd, T. (1969)
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    Board of Canada, Technical Report No. 458.
    


    See Also:
       Toxicological Abbreviations
       Fenitrothion (EHC 133, 1992)
       Fenitrothion (HSG 65, 1991)
       Fenitrothion (ICSC)
       Fenitrothion (FAO/PL:1969/M/17/1)
       Fenitrothion (Pesticide residues in food: 1976 evaluations)
       Fenitrothion (Pesticide residues in food: 1977 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)