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.