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
Special study on embryotoxicity/teratogenicity
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).
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.
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.
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,