Sponsored jointly by FAO and WHO


    The monographs

    Data and recommendations of the joint meeting
    of the FAO Panel of Experts on Pesticide Residues
    in Food and the Environment and the
    WHO Expert Group on Pesticide Residues
    Rome, 24 September - 3 October 1984

    Food and Agriculture Organization of the United Nations
    Rome 1985



         Fenitrothion was evaluated by the Joint Meeting in 1969, 1974,
    1976, 1977, 1979 and 1982. 1/ An ADI of 0 - 0.005 mg/kg bw was
    recommended in 1974 partly supported by studies performed by
    Industrial Bio-Test Laboratories. No independently obtained
    validations, replacement studies or other additional information were
    submitted to the 1982 JMPR concerning these data. Considering the
    absence of adequate mammalian non-rodent toxicity data and an adequate
    teratology study, the ADI was retained as a temporary ADI and reduced
    to 0 - 0.001 mg/kg bw pending receipt of data validation and
    additional data. New studies have been presented and are reviewed in
    this monograph addendum.



    Special Studies on Teratogenicity


         Groups of pregnant ICR-JCL mice (25-27 per group) were orally
    intubated with 0, 20, 70 and 200 mg/kg bw fenitrothion (97.2 percent
    purity) in maize oil from day 7 to 12 of gestation. Eighteen dams in
    each group were sacrificed on day 18 of gestation, foetuses were
    removed by caesarean section and examined for internal and external
    abnormalities, as well as skeletal malformations. The remaining dams
    were allowed to deliver their young naturally at parturition; the
    young mice were then observed for six weeks for growth and
    development. No adverse effects of fenitrothion on maternal body
    weight or physical appearance were noted. No significant differences
    in the reproductive parameters, such as total implantations, dead and
    live foetuses, sex ratio or mean body weight of foetuses, were
    observed between treated and control groups. The anomalies observed in
    the treated groups included cleft palate and open eyelids. However, no
    historical data were provided that permitted an evaluation of the
    significance of these findings. Skeletal variations and ossifications
    were not significantly different between control and test groups. The
    teratogenic potential of fenitrothion to pregnant mice could not be
    determined from this study because the dosing regimen did not cover
    the whole period of organogenesis (Miyamoto et al., 1975).


    1/  See Annex 2 for FAO and WHO documentation.


         Groups of pregnant Sprague-Dawley rats (22-26 dams/group with 24
    control dams) were orally gavaged with 0, 2, 7 and 20 mg/kg bw of
    fenitrothion 97.2 percent purity) in maize oil from day 9 to 14 of
    gestation. Eighteen dams in each group were sacrificed on gestation
    day 20 and foetuses removed by caesarean section. The remaining dams
    were allowed to deliver their young naturally at parturition; the
    young mice were then observed for six weeks for growth and
    development. Foetuses were examined at necropsy for external and
    internal abnormalities as well as skeletal malformations. A slight
    reduction in maternal body weight gain as well as clinical signs of
    toxicity were noted in the high-dose group only. No effects on
    reproductive parameters such as total implantations, incidence of dead
    or resorbed foetuses, foetal sex ratio or foetal birth weight were
    noted between treated and control groups. Although there were no
    apparent compound related skeletal or visceral anomalies, the
    teratogenic potential of fenitrothion to pregnant rats could not be
    determined from this study because the dosing regimen did not cover
    the whole period of organogenesis (Miymoto et al., 1975).

    Special Studies on Short-Term Toxicity


         Groups of purebred beagle dogs (6 males and 6 females per group),
    approximately 3 months old, were administered fenitrothion (purity
    96.8 percent) in the diet at dose levels of 0, 5, 10 and 50 ppm for
    12 months. The dogs were observed for general physical appearance and
    behaviour signs of overt toxicity, moribundity and mortality. Body
    weight and food consumption were determined. Opthalmoscopic and
    physical examinations were also performed. Routine haematological and
    clinical biochemical parameters were determined as well as urinalysis.
    All dogs received a complete post-mortem macroscopic examination and
    selected organs weighed. There was no mortality and no effect on
    appearance or behaviour. Food consumption and body weight gain were
    unaffected by treatment. Clinical analysis showed no treatment-related
    effects on urinalysis, haematological or biochemical parameters,
    except for cholinesterase values. Plasma cholinesterase was
    significantly reduced in both sexes at the high dose level.
    Erythrocyte cholinesterase activity was reduced in high dose males
    only. Brain cholinesterase was unaffected by treatment. There were no
    organ weight changes related to treatment and no macroscopic lesions
    observed. Histopathological examinations were not performed. The
    demonstrated no-effect level is 10 ppm based on plasma and erythrocyte
    cholinesterase depression (Griggs et al., 1984).

    Observations in Humans

         Twelve adult male volunteers were repeatedly given oral doses
    of fenitrothion equal to 0.1 or 0.5 mg/kg bw followed by dermal
    application of 0.1 mg/kg to arms and face. The study lasted nine days.

    There was no evidence of dermal irritation and no apparent differences
    in cholinesterase activity observed (Shelanski et al., 1977).

         Fenitrothion was measured in the serum of nine workers, engaged
    in the spraying of a wettable powder formulation, for three
    consecutive days. No material was identified in the serum samples and
    neither cholinesterase nor glutamic oxalacetic transaminase or
    glutamic pyruvic transaminase activities were adversely affected by
    exposure (Usutani et al., 1978).

         During a 30-day spraying operation of fenitrothion in south Iran
    for malaria control, a group of 28 pest control operators and 925
    inhabitants were monitored with respect to clinical observations and
    cholinesterase activity. Mild clinical symptoms (e.g. nausea,
    dizziness) were observed in 8/20 spray operators, who also
    demonstrated depressed whole blood cholinesterase activity. Among the
    inhabitants very mild complaints, namely dizziness and nausea, were
    reported (Motabar et al., 1973).

         A large-scale spray operation was monitored by WHO in Kisumu,
    Kenya, involving 35-40 spray operators who used fenitrothion 5 h per
    day, five days per week intermittently for two years. Numerous
    clinical parameters were measured in exposed operators and matched
    controls. Clinical examination of operators and control subjects did
    not reveal any significant difference between the groups. In a similar
    indoor village-scale trial of fenitrothion, used in Central Java for
    four weeks (involving 978 houses), there were no complaints or
    clinical symptoms of organophosphorus toxicity among the spray
    operators or the inhabitants of the sprayed area. However,
    cholinesterase activity, determined by the tintometric method, was
    reduced in 4/12 spraymen to 40-60 percent of the pre-exposure values
    after the third week of spraying.


         Fenitrothion was last evaluated in 1982 when, in view of the
    absence of 1) replacement studies for those performed previously by
    Industrial Bio-Test Laboratories (IBT), (2) adequate mammalian
    non-rodent toxicology data and (3) an adequate teratology study, the
    ADI was replaced by a temporary ADI. Most of the additional data
    required have now been supplied and evaluated.

         Teratogenicity studies in the mouse and rat showed no embryotoxic
    or teratogenic effects at doses up to 20 mg/kg in rats and 200 mg/kg
    in mice, but these studies were considered unsatisfactory as dosing
    did not cover the whole period of organogenesis. The previously
    evaluated rabbit teratology study was validated.

         A one-year toxicity study in dogs showed changes in
    cholinesterase activities as the only toxic manifestations; plasma
    cholinesterase was depressed in both sexes at 50 ppm, erythrocyte
    cholinesterase was slightly depressed only in males and the no-effect
    level was 10 ppm.

         Further observations of occupationally exposed humans showed no
    skin irritation, no tendency to accumulation and no evidence of liver
    damage or other toxicity, except slight nausea and decreased plasma
    cholinesterase activities. In addition, WHO has undertaken extensive
    monitoring over a period of two years of spray operators applying
    fenitrothion indoors; except for mild inhibition of whole blood
    cholinesterase activity and slight alterations of some other
    biochemical and haemotological parameters, there were no significant
    adverse effects.

         As some information on teratology was available from two three-
    generation studies, the temporary ADI was extended at a higher level.


    Level Causing no Toxicological Effect

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

    Dog: 10 ppm in the diet, equivalent to 0.3 mg/kg/ bw

    Estimate of Temporary Acceptable Daily Intake for Man

    0 - 0.003 mg/kg/ bw

    Further Work or Information Required (by 1986)

    An acceptable rat teratology study.


    Observations in humans.


    Griggs, L.M.P., Jefferson, N.D., Blair, N., Kopplin, J.R., Richter,
    1984      W.S., Spicer, E.J.F. One-year dietary toxicity study in
              dogs. Report from International Research and Development
              Corporation submitted by Sumitomo Chemical Co., Ltd. to WHO

    Miyamoto, J., Kohda, H. & Kadota, T. Teratogenic studies with
    1975      Sumithion in ICR-JCL mice and Sprague Dawley rats. Report
              submitted by Sumitomo Chemical Co., Ltd. to WHO.

    Motabar, M., Sanai, G.H. & Heidari, A.A. Toxicological evaluation of
    1973      Sumithion (OMS-43) on operators and inhabitants in the
              Mamasani area Southern Iran. Iranian J. Pharm. Health, 2:

    Shelanski, M.V., Levenson, T. & Karras, C. Report from Product
    1977      Investigations Inc. submitted by Sumitomo Chemical Co., Ltd.
              to WHO. (Unpublished)

    Usutani, S., Nishiyama, K., Sato, I., Matsuura, K. & Sawada, Y.
    1978      Studies on the amount of exposure to pesticides and blood
              levels or organophosphorus pesticides of farmers engaging in
              joint control works over apple orchards. J. Jap. Assoc.
              Rural Med., 27: 79-88.

    See Also:
       Toxicological Abbreviations