PESTICIDE RESIDUES IN FOOD - 1984
Sponsored jointly by FAO and WHO
EVALUATIONS 1984
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
Explanation
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.
EVALUATION FOR ACCEPTABLE DAILY INTAKE
TOXICOLOGICAL STUDIES
Special Studies on Teratogenicity
Mouse
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.
Rat
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
Dogs
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.
COMMENTS
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.
TOXICOLOGICAL EVALUATION
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.
Desirable
Observations in humans.
REFERENCES
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.
(Unpublished)
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:
40-49.
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.