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    FENITROTHION

    EXPLANATION

         Fenitrothion has been evaluated for acceptable daily intake by
    the Joint Meetings in 1969, 1974, 1977, 1982, and 1984 (Annex 1,
    FAO/WHO, 1970a, 1975a, 1978a, 1983a, and 1985b). A toxicological
    monograph was prepared by the Joint Meeting in 1969 (Annex 1, FAO/WHO,
    1970b) and monograph addenda were published after the Joint Meetings
    in 1974, 1977, 1982, and 1984 (Annex 1, FAO/WHO, 1975b, 1978b, 1983b,
    and 1985c). In 1974 the Meeting allocated an ADI of 0.005 mg/kg b.w.,
    which was partially based on studies conducted by Industrial Bio-Test
    Laboratories (IBT). Replacement studies, independently-obtained
    validations, or other additional data had not been submitted for
    evaluation by the Joint Meeting in 1982, so at that time the ADI was
    replaced with a temporary ADI at a lower level (0.001 mg/kg b.w.). In
    1984 most of the required data were supplied and evaluated by the
    Joint Meeting, which extended the temporary ADI at a higher level
    (0.003 mg/kg b.w.). Two teratogenicity studies in mice and rats,
    however, were considered unsatisfactory, and so an acceptable rat
    teratology study was required. This teratology study has been
    submitted for evaluation by the present Joint Meeting, and it is
    summarized in this monograph addendum.

    EVALUATION FOR ACCEPTABLE INTAKE

    BIOLOGICAL DATA

    Toxicological studies

    Special study on embryotoxicity/teratogenicity

    Rat

         Groups of 20 mated female rats (Wistar strain, 12 weeks old) were
    given fenitrothion (97.6% pure compound; 0.1% 3-methyl-4-nitrophenol)
    in sunflower oil by gavage at single daily doses of 0, 2, 8, 16, or
    24 mg/kg b.w. from days 6 through 16 of presumed (positive sperm
    smear) gestation. On day 20 of gestation the rats were sacrificed and
    the number of viable and dead fetuses, resorptions, implantations, and
    corpora lutea were recorded. Fetuses were subjected to external and
    internal (skeletal and soft tissue) examination.

         Clinical signs of maternal toxicity (tremors and chromoda-
    cryorrea) were observed in 19/20 dams of the group receiving
    24 mg/kg b.w./day. In this group, 11/20 dams died between days 10 and
    16 of gestation. Statistically-significant decreases in body-weight
    gain during both the treatment period and the entire gestation period
    were noted in rats receiving 16 and 24 mg/kg b.w./day, as compared to
    controls. Food consumption was significantly decreased in the
    high-dose group during the treatment period, as compared to controls.
    Embryotoxicity was observed in rats at the highest dose, in which
    there were an increased total number of resorptions, a statistically-
    significant reduction in the mean number of live fetuses, and a
    statistically-significant reduction in the mean weight of placenta as
    compared to controls. An increased number of resorptions was also
    present at 2, 8, and 16 mg/kg b.w./day as compared to controls, but
    these differences were not statistically significant. There was
    apparently no significant difference between treated and control
    groups in fertility index, gestation index, and litter size. Sex
    ratio (number of male fetuses/number of female fetuses) and mean
    fetal body weight were lower in fetuses of the high-dose group than
    in controls, but the differences were apparently not statistically
    significant. A number of skeletal variations and malformations were
    observed in both control and treated groups. These included: fifth
    and sixth ribs fused and tibial aplasia in 1 fetus at 2 mg/kg
    b.w./day and irregular shape of ossification centers in sternebrae in
    5 fetuses at 8 mg/kg b.w./day, in 4 fetuses at 24 mg/kg b.w./day,
    and in 1 control fetus. The authors of the study concluded that
    "under the conditions of this study, fenitrothion was judged to be
    non-teratogenic at levels up to and including 24 mg/kg b.w./day when
    administered orally by gavage to rats during days 6 through 15 of
    gestation" (Benes & Tejnorvoa, 1986).

    COMMENTS

         The teratogenicity study in the rat required by the 1984 JMPR has
    been submitted and evaluated. In this study fenitrothion was not found
    to be teratogenic. At doses exceeding 8 mg/kg b.w./day, fenitrothion
    was maternally toxic and embryotoxic.

    TOXICOLOGICAL EVALUATION

    LEVEL CAUSING NO TOXICOLOGICAL EFFECT

         Rat:    5 ppm in the diet, equivalent to 0.25 mg/kg b.w./day
         Dog:    10 ppm in the diet, equivalent to 0.3 mg/kg b.w./day

    ESTIMATE OF ACCEPTABLE DAILY INTAKE FOR MAN

         0 - 0.003 mg/kg b.w.

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

         1.   Observations in man.
         2.   Submission of ongoing teratogenicity studies.

    REFERENCE

    Benes, V. & Tejnorova, I. Fenitrothion: Teratogenicity study in rats.
    1986      Unpublished report from Institute of Hygiene and
              Epidemiology, Prague, Czechoslovakia. Submitted to WHO by
              Institute of Hygiene and Epidemiology, Prague,
              Czechoslovakia.
    


    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: 1988 evaluations Part II Toxicology)
       Fenitrothion (JMPR Evaluations 2000 Part II Toxicological)