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    FENITROTHION

    EXPLANATION

         Fenitrothion was evaluated for acceptable daily intake by the
    Joint Meetings in 1969, 1974, 1977, 1982, 1984 and 1986. The 1969
    monograph (Annex I, FAO/WHO, 1970) was supplemented by addenda
    (Annex I, FAO/WHO 1975b, 1978b, 1983b, 1985c, 1987a). An ADI of
    0.005 mg/kg bw was allocated by the Meeting in 1974. That decision was
    partially based on studies conducted by Industrial Bid-Test
    Laboratories (IBT). In 1982 the Joint Meeting replaced the ADI with a
    Temporary ADI at a lower level (0.001 mg/kg bw). By 1984 a Temporary
    ADI of 0.003 mg/kg bw was allocated. However, the teratogenicity
    studies in mice and rats were considered inadequate because the dosing
    regimen did not cover the whole period of organogenesis. An acceptable
    rat teratology study was evaluated by the 1986 Joint Meeting, which
    allocated an ADI of 0.003 mg/kg bw. Some additional teratology and
    toxicity studies have since been submitted for evaluation by the
    present Joint Meeting, and are summarized in this monograph addendum.

    EVALUATION FOR ACCEPTABLE INTAKE

    BIOLOGICAL DATA

    Toxicological studies

    Special studies on embryotoxicity/teratogenicity

    Rats

         Groups of 20-24 mated female rats (Sprague-Dawley, Crl:CD(SD)BR)
    were given, by daily gavage, doses of 0, 3, 8, or 25 mg/kg bw of
    technical fenitrothion (96.6% purity) in corn oil from day 6 through
    day 15 of gestation. Solutions were freshly prepared each day and
    doses were based on the animal's body weight on day 6 of gestation.

         Animals were observed for clinical signs, body weight and food
    consumption. On day 20 of gestation, the dams were sacrificed and
    examined grossly for abnormalities of the thoracic, abdominal or
    pelvic viscera. The usual teratological parameters were then examined.

         All rats survived to day 20 of gestation. Signs of toxicity
    (tremors, rhinorrea and rough haircoat, etc.) were present in 18
    high-dose animals. A significantly reduced body weight gain was
    evident in the high-dose group from day 11 through day 19 of
    gestation. Food consumption was not significantly altered by any of
    the treatments. The mean numbers of implantations, early and late
    resorptions, live foetuses per litter, mean foetal weight and sex
    ratio were similar in all groups. No dead foetuses were observed.
    Skeletal and visceral variations and malformations were observed in
    both control and treated groups. The majority of visceral variations
    were localized in the kidneys and ureters (i.e., renal papilla reduced
    in size and dilated ureters); the incidence was not dose-related. In
    the high-dose group there was a statistically significant increased
    incidence (3.1%) of foetuses with one full and one rudimentary 13th
    rib. Other skeletal variations included expected degrees of delay in
    ossification of various bones; these did not occur in a dose-related
    pattern. The only skeletal malformation (agnathia) was observed in one
    high-dose foetus. The total number of foetuses with malformations
    (external, visceral and skeletal) was 1, 0, 1 and 1 in control, low-,
    mid- and high-dose groups, respectively. In conclusion, no evidence of
    developmental toxicity was seen under these experimental conditions.

         The NOAEL in this study was determined to be 8 mg/kg bw/day for
    dams (Morseth, 1987).

    Rabbits

         Inseminated female rabbits (HRA:(NZW)SPF) were given, by gavage,
    daily doses of technical fenitrothion (96.6% purity) from day 7
    through day 19 of presumed gestation. Does were randomly divided in 4
    groups (n=16) and administered 0, 3, 10 or 30 mg/kg bw of fenitrothion
    dissolved in corn oil. The doses chosen followed pilot studies in
    which daily oral doses of 100 mg/kg bw caused the death of animals by
    day 3 but daily dose levels up to 20 mg/kg bw to pregnant rabbits did
    not result in maternal or intrauterine toxicity. Solutions were
    prepared fresh weekly and dosing was based on the most recently
    recorded body weight. Animals were observed for clinical signs, body
    weight and food consumption. On day 29 of gestation, all does were
    sacrificed and examined grossly for abnormalities of the thoracic,
    abdominal or pelvic viscera. The usual teratological parameters were
    examined.

         One animal of the control group and one of the mid-dose group
    were anorexic and were found dead on gestation day 8 and 18,
    respectively. Two animals of the low-dose group died following errors
    in gavage technique. Six does of the high-dose group were found dead
    during treatment and three does of the same group aborted or delivered
    prematurely after the end of treatment. During treatment all animals
    of the high-dose group showed reduction in motor activity, ataxia,
    salivation, dyspnea or tremors. These signs were seen only
    sporadically during the post-treatment interval. Animals treated with
    lower doses displayed no clinical abnormality. However some animals in
    all groups were anorexic. Although food consumption was similar in all
    groups, a lower body weight gain was noted for the high-dose group.
    The mean numbers of implantations and live foetuses per litter were
    slightly, not significantly, reduced in the high-dose group. The
    incidence of foetal resorptions, sex ratio and mean foetal body weight
    were similar in all groups.

         The total foetal incidence of external malformations (0-2.9%),
    visceral variation (1.2-4.8%), visceral malformations (0-2.4%),
    skeletal malformations (0-7.2%) were not statistically significantly
    different between treated or control groups. No malformation was
    observed in the high-dose group. The total incidence of malformations
    was 2%, 8% and 6% in the control, low- and mid-dose groups,
    respectively; these incidences were not considered significantly
    different. Maternal toxicity was seen in the 30 mg/kg group, without
    effects on foetal growth or development.

         The NOAEL in this study was thus considered to be 10 mg/kg bw/day
    for dams (Morseth et al., 1986).

    Short-term studies

    Dogs

         Groups (6 males and 6 females per group) of purebred beagle dogs
    received a diet containing 0, 5, 10, or 50 ppm of technical
    fenitrothion (96.8% purity), respectively, for 12 months. Although
    this study was previously evaluated by the 1984 Joint Meeting,
    histopathological examinations were not submitted at that time.
    Physical and ophthalmoscopic examinations did not demonstrate any
    effect of the test compound. Haematological and clinical biochemical
    parameters (except for cholinesterase values in the high-dose group),
    urinalysis, body weight and food consumption were not affected by the
    treatment. No organ weight changes nor macroscopical lesions related
    to the treatment were observed.

         Plasma cholinesterase was significantly reduced (35-55% lower
    than pretest values) in both sexes at the high-dose level only.
    Erythrocyte cholinesterase was reduced in high-dose males in 4 of 8
    measurements. Brain cholinesterase was unaffected by any of the
    treatments. Histopathological observations reviewed by the present
    Meeting showed an increased, but not dose-related, incidence of the
    following lesions in treated animals as compared to controls:
    craniopharyngeal pituitary cysts (0/0, 4/6, 2/6 and 3/6 in the 0, 5,
    10 and 50 ppm groups, respectively), lymphocytic infiltrates of
    prostate (3/6 in the high-dose group) and chronic lymphocytic
    thyroiditis (0/6, 1/6, 1/6 and 3/6 in the 0, 5, 10, and 50 ppm groups,
    respectively) in males. Haemorrhages in abdominal lymph nodes (2/6 in
    the mid- and high-dose groups) and lymphoid hyperplasia of mandibular
    lymph nodes (2/6 in the high-dose group) in females were also found.
    All lesions observed are considered to be spontaneous and/or
    incidental in nature.

         The NOAEL in this study was determined to be 50 ppm (Spicer,
    1986).

    COMMENTS

         Although an ADI was allocated for fenitrothion in 1986, the
    Meeting reviewed the additional toxicology studies that had since been
    completed. Additional data confirmed that fenitrothion was not
    teratogenic in rats and rabbits.

         In dogs fenitrothion reduced erythrocyte but not brain acetyl-
    cholinesterase activity at 50 ppm. No other treatment-related
    adverse effects were seen at this dose. Upon re-evaluation of previous
    studies (JMPR 1986) the Meeting utilized available brain acetyl-
    cholinesterase inhibition data in rats and dogs to establish NOAELs
    rather than the plasma cholinesterase data previously used. The
    Meeting also took into account the decreased lactation index noted at
    40 ppm in rats by the 1974 JMPR. The ADI was revised accordingly.

    TOXICOLOGICAL EVALUATION

    LEVEL CAUSING NO TOXICOLOGICAL EFFECT

         Rat:      10 ppm in the diet, equivalent to 0.5 mg/kg bw/day
                   (based on brain acetylcholinesterase inhibition and
                   reproduction)
         Dog:      50 ppm in the diet, equivalent to 1.25 mg/kg bw/day
         Man:      0.08 mg/kg bw/day (highest dose tested).

    ESTIMATE OF ACCEPTABLE DAILY INTAKE FOR MAN

         0-0.005 mg/kg bw

    STUDIES WHICH WILL PROVIDE INFORMATION VALUABLE FOR THE CONTINUED
    EVALUATION OF THE COMPOUND

         Further observations in man.

    REFERENCES

    Morseth, S.L. 1987. Teratology study in rats with Sumithion. Report
    from Hazleton Laboratories America, Inc. submitted by Sumitomo
    Chemical Co., Ltd. to WHO.

    Morseth, S.L., Serabian, S.A., Lichtenberger, J.M., Vargas, K.J.,
    Thakur, A.K. & Burley, P.L. 1986. Teratology study in rabbits with
    Fenitrothion T.G. (Sumithion). Report from Hazleton Laboratories
    America, Inc. submitted by Sumitomo Chemical Co., Ltd. to WHO.

    Spicer, E.J.F. 1986. One year dietary toxicity study in dogs with
    Sumithion technical. Revised report from International Research and
    Development Corporation submitted by Sumitomo Chemical Co., Ltd.
    to WHO.
    


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