FENTHION JMPR 1978
Explanation
Fenthion was reviewed by the 1971, 1975 and 1977 Meetings
(FAO/WHO 1973b, 1977b, 1978b). A temporary ADI was established and
temporary MRLs were recommended for a range of fruits and
vegetables and attention was drawn to various items on which there
was a need for further work or information. New data received is
evaluated in this monograph addendum.
EVALUATION FOR ACCEPTABLE DAILY INTAKE
TOXICOLOGICAL STUDIES
Special studies
Pharmacological study
A daily diet containing 300 ppm fenthion was given to 8 groups
of Donrya rats: a hare's eye group, a satured eyelid group, a
cervical sympathectomy group, a group given antibiotic eye
ointment, a group given atropine eyedrops and groups given
subcutaneous injections of pralidoxime, atropine and GSH for about
one month. All rats given fenthion showed typical symptoms, of
organophosphorus intoxication such an nervousness, general spasms,
diarrhea, and salivation. Also ophthalmological symptoms, such as
eye-ball protrusion, keratoconus, mammiform cornea and corneal
turbity were observed. The described pretreatments did not prevent
the ocular symptoms (abstract only)(Kawai et al., 1976).
Teratogenicity
Preliminary studies indicated 100 mg/kg was lethal to
non-pregnant female rats in 2-4 days, and that 30 mg/kg induced
toxic symptoms. Therefore four groups of 20 pregnant rats were
dosed orally at 0, 1, 3 or 10 mg/kg/day on days 6-15 of pregnancy.
Day 0 was the day semen was detected). At sacrifice (day 20 of
gestation) implantation rate, numbers of live, dead and resorbed
foetii, litter weight and placental weights were recorded. After
gross examination, approximately 2/3 of the offspring were examined
for skeletal malformations (Alizarin stain), and 1/3 for soft
tissue malformations. No treatment related effects were noted
(Machemer, 1978a).
Mutagenicity
In a dominant lethal assay 2 groups of 50 male mice
(NMRI-strain) were given a single oral dose of 0 or 25, mg
fenthion/kg b.w. Additionally a third group of mice was treated
with 10 mg fenthion/kg b.w., because 25 mg/kg induced toxic effects
in the males (drowsiness, ruffled coat and dilated intestines). The
compound was given in a 2% aqueous cremophor E.L. emulsion.
After injection each male was caged with a untreated virgin
female for a period of 4 days. This procedure was repeated for a
total of 12 matings.
On day 12-16 of gestation the females were sacrificed and the
number of implantations, the live and dead implants (sum of the
deciduomata, the resorptions and the dead embryos) counted.
Except for an increased pre-implanation loss at the dose level
of 25 mg/kg b.w. in the first two mating periods, no other
treatment-related effects on fertility, pre- and post implantation
loss were observed (Machemer, 1978b).
Potentiation
In rats no synergistic effects on the acute oral toxicity was
noticed of fenthion with edinfenphos and the active ingredient of
Bassa. (Thyssen, 1977).
Acute toxicity
In an attempted suicide 0.5 g of 2% fenthion powder was
ingested. The patient felt severe pain in the epigastrium and
abdomen 3 hrs after ingestion, then experienced continued vomiting
and diarrhea. Upon admission to hospital conspicuous reduction of
serum ChE-activity of 0.08 delta pH was observed. She was treated
by repeated injections of P.A.M. and atropine (summary only) (Kanda
and Matsushima, 1976).
Short-term studies
Monkey
In an interim report data are provided on four groups of 5
male and 5 female Rhesus monkeys which received 0, 0.02, 0.07 or
0.2 mg fenthion/kg body weight as a freshly prepared solution in
corn oil, daily by stomach tube for one year. Animals were observed
daily for general appearance, etc., body weight and
ophthalmological examinations were reported monthly, and clinical
chemistry, haematology and urinalysis were performed at 0, 1, 3, 6
and 12 months. Plasma and erythrocyte cholinesterase were measured
at 0, 1, 2, 3 and 4 weeks and thereafter monthly. One monkey/sex
from the 0 and 0.2 mg/kg groups were sacrificed at 7 months, 3
weeks. Brain cholinesterase, organ absolute and relative weights,
gross and histopathology were recorded. The plasma cholinesterase
was depressed in both sexes at 0.2 mg/kg. Plasma cholinesterase
depression occurred at 0.07%, but was inconsistent and minimal. No
adverse effects were noted on any other parameter (Coulston et al.,
1978).
Long-term studies
Rat
In a 2-year toxicity experiment 50 male and 50 female rats per
group were fed a diet containing 3, 15 and 75 ppm fenthion. In the
control group 100 males and 100 females were used.
The rats were weighed weekly during the first 26 weeks and
thereafter at 14-day intervals. Food consumption was recorded
weekly. Clinical chemistry was performed on 5 male and 5 female
rats per group at intervals of 1, 3, 6 and 12 months, and on 10
males and females at the end of the experiment. The clinical
chemistry included hematology, liver- and kidney function tests,
urinalysis, blood sugar and serum cholesterol determinations.
Plasma and erythrocyte cholinesterase activities were determined
after 1, 2, 4, 8, 13, 26, 52, 78 and 105 weeks. Brain
cholinesterase activity was not measured. At the end of the
experiment the rats were examined macroscopically, the organs
weighed and studied microscopically.
3 and 15 ppm fenthion did not affect the physical appearance,
behaviour, growth and survival rate. The male rats of the 75 ppm
group had a significantly lower body weight. A tendency toward
increased mortality was observed in the 75 ppm group in both sexes.
Hematology, blood chemistry, urinalysis gross macroscopy and
histopathology revealed no compound related effects.
Dietary concentrations of 15 and 75 ppm fenthion caused
dose-dependent depression of plasma and erythrocyte cholinesterase
activity. At 3 ppm cholinesterase activity was only slightly
depressed in the plasma of the females. A no-effect level of 3 ppm
fenthion diet is stated (Bombard and Loser, 1977).
OBSERVATIONS IN MAN
A prospective study was carried out on 150 cases of
anticholinesterase insecticide poisoning to observe the influence
of the type of insecticide used on the clinical picture and
prognosis. Of the 150 cases, 32 had consumed fenthion, 48
fenitrothion and 50 malathion. Twenty did not know exactly which
agent was consumed. Paralytic signs were significantly more
frequent with fenthion than with malathion or fenitrothion (being
81.2%, 30% and 23% resp.). These signs occurred later with fenthion
and lasted longer. Death occurred significantly more often with
fenthion (the mortality rate being with fenthion 35.5%0 with
malathion 4% and with fenitrothion 2.1%). Pulmonary oedema was
commonest with malathion and not encountered with Fenthion. The
cholinesterase depression was most marked with fenthion reaching 0
in 18 of the 27 cases studied (Wadia et al., 1977).
Comments
The additional data requested by the 1971 and the 1975 Joint
Meetings have been partially met, a long-term rodent study having
been submitted. Cholinesterase inhibition is the most sensitive
criterium. No tumorogenic activity was noted. A long-term nonrodent
study is underway, as indicated by the interim report on a monkey
study. In addition, special studies in pharmacology, mutagenicity
and teratology have been received.
Whilst the data reviewed do not increase the concerns relating
to fenthion, the continued absence of some previously requested
studies precludes the allocation of a firm ADI. However, the data
do permit an extension of the existing temporary ADI.
TOXICOLOGICAL EVALUATION
Level causing no toxicological effect:
Rat: 3 ppm in the diet, equivalent to 0.15 mg/kg b.w.
Dog: 2 ppm in the diet, equivalent to 0.05 mg/kg b.w.
Monkey: 0.07 mg/kg b.w. by gavage daily
Estimate of temporary acceptable daily intake for man:
0 - 0.0005 mg/kg b.w.
RESIDUES IN FOOD AND THEIR EVALUATION
USE PATTERN
Submissions received from Australia and Japan confirmed (see
FAO/WHO 1972b) that fenthion is currently used on a wide range of
fruits and vegetables, and for the control of insect vectors of
farm animals and of pests of public health importance.
Use patterns in Japan on rice and potatoes are summarized in
Table 1.
RESIDUES RESULTING FROM SUPERVISED TRIALS
In pears
A single application of fenthion at 250 g/100l resulted in
0.08-0.21 mg/kg residues 7 days after treatment. This decreased to
less than 0.02 mg/kg 14 days after application (Table 2) (Race,
1978).
TABLE 1. Use pattern of fenthion in Japan
Crop Formulation Application Use: permitted No. of
method period applications
allowed
Emulsible seed before seeding
concentrate immersion
spraying up to 30 days
before harvest
Wettable spraying up to 30 days
powder before harvest
Rice ULV spraying do up to 30 days
concentrate not dilute) before harvest 6
Dust seed dressing before seeding
dusting up to 14 days
before harvest
Granule dusting up to 14 days
before harvest
Microgranule
Emulsible
concentrate dusting up to 7 days
before harvest -
Potato Wettable
powder
TABLE 2. Residues of fenthion in pears, raspberries, strawberries and radishes in Norway
Crop Application rate, Number of Period between Residues,
g/ha or g/100l treatments final treatment mg/kg
and harvest
(days)
Pears 250 g/100l 1 7 0.08-0.21
14 < 0.02
21 < 0.02
28 < 0.02
35 < 0.02
Raspberries 250 g/100l 2 1 2.9 - 3.3
5 0.14-0.18
8 0.05-0.06
16 < 0.02
Strawberries 50 g per 1000 m row 1 24-30 <0.05
Radishes 200 g/ha 1 15-16 <0.06
20-22 <0.06
400 g/ha 1 16 <0.06
20-22 <0.06
In raspberries
Two applications at 250 g/100l resulted in residues of 2.9-3.3
mg/kg 1 day after the last application. They declined rapidly to
0.14-0.18 mg/kg after 5 days and 0.05-0.06 mg/kg after 8 days. After
16 days, the residues were below the detection limit of 0.02 mg/kg
(Norway, Table 2).
In strawberries
A single application of 50 g per 1000 m row gave residues below
0.05 mg/kg 25-30 days after application (Norway, Table 2).
In radishes
Application at 200 and 400 g/100l gave residues below 0.06 mg/kg,
15-22 days after application (Norway, Table 2).
In rice
In Japan, application at 0.5-1.0 kg ai/ha under normal
cultivation or with a preharvest interval generally above 25 days gave
residues below detection limits in hulled rice (Table 3). In a study
with fenthion applied as a dust 4 days before harvest, the residue in
hulled rice was still below the limit of detection of 0.001 mg/kg.
With good agricultural practice, therefore, the residues in hulled
rice would not exceed the MRL.
In potatoes
In 1974, multiple applications as dust and emulsifiable
concentrate at 0.5-2.0 kg ai/ha gave residues below the detection
limit. Two applications at 0.5 kg ai/ha with harvesting 7 days after
last application gave residues below 0.01 mg/kg (Table 3).
RESIDUES IN FOOD IN COMMERCE OR AT CONSUMPTION
In a market basket study in Australia in 1970, fenthion residues
were not determined specifically but the total organophosphorus (OF)
residues found did not exceed 0.5 mg/kg. Some 240 samples were
examined and only 32 contained any OF residues, of which only 3
exceeded 0.2 mg/kg. Traces of fenthion have been detected occasionally
in dairy products monitored routinely in a continuous national
residues survey programme. For example, in a 12 month period
(1977-78), 3 of 335 samples of dairy produce contained fenthion
residues in the range 0.1-0.2 mg/kg.
TABLE 3. Residues of fenthion in rice and potatoes (Japan 1978)
Application
Crop Origin Year Formulation Rate No Pre-harvest Residue
(kg ai/ha) (days) (mg/kg)
Rice Hokkaido 1974 Dust 0.6 4 45 <0.008
(hulled) 0.6 2 48 <0.008
Nigata 0.6 1 83 <0.002
Ibaragi 0.6 6 14 <0.004
Ishikawa 0.6 2 24, 25 <0.01
Shiga 0.8 2 30 <0.01
Shimane 0.8 3 25, 60 <0.004
Aichi 1975 0.6 1 73 <0.01
Shiga 0.8 2 46 <0.003
Wakayama E.C. 0.5-0.9 1-6 51, 68 <0.005
Kochi Dust 0.8 3 4 <0.001
Gumma 1976 E.C. 1 4 29 <0.02
1 5 29 <0.02
Ehime Granule 1 1 57 <0.003
Dust 0.8 1 39 <0.007
0.9 2 36
Potatoes Hokkaido 1974 Dust 2 5 21 <0.008
E.C. 0.5 4 27 <0.008
Gumma 0.5 2 7 <0.01
APPRAISAL
Data on residues in pears, raspberries, strawberries, and
radishes provided by Norway supported the MRLs established previously
and data from Japan show that if good agricultural practice is
followed it is unlikely that the MRLs set for hulled rice and potatoes
will be exceeded.
Fenthion was only occasionally detected in the national residue
monitoring programme in Australia. No new data were received on the
effects of processing or cooking on residues of fenthion.
RECOMMENDATIONS
No changes to the existing temporary MRLs are recommended.
FURTHER WORK OR INFORMATION
Required (1980)
1. Additional report on the on-going non-human primate study.
Adequate long-term feeding studies in a non-rodent mammalian
species.
2. Investigations on the mechanism of long-lasting cholinesterase
inhibition, as previously requested.
Desirable
1. Information on the effect of processing and cooking on fenthion
residues in fruits and vegetables.
REFERENCES
Australia Report from the Codex Contact Point, Australia on uses
(1978) of fenthion.
Bomhard, E. and Loser, E. Chronic toxicity study on rats. Rep. nr.
(1977) 6769 from Institut für Toxikologie, Bayer A.G.
Unpublished report submitted by Bayer A.G.
Coulston, F., Rosenblum, I. and Ford, W. A safety evaluation of
(1978) fenthion in Rhesus monkeys (Macaca mulatta). A twelve
month interim report from Albany Medical College of
Union University, Albany, (N.Y.).
Japan Report from the Codex Contact Point, Japan on fenthion in rice
(1978) and potatoes.
Kanda, M. and Matsushima, S. A case of acute fenthion poisoning.
(1974) Annual Rep. Jpn. Inst. Rural. Med. 3: 50-53
(abstract).
Kawai, M., Tojo, K., Miyazawa, S., Maruta, H., Naito, M.
(1976) Experimental studies on the effects of organophosphorus
compounds on the eyes. Natl. Defense Med. J. 23 no.
1: 1-10 (abstract).
Machemer, L. S 1752 (Fenthion, Lebaycid-Wirkstoff) Untersuchungen auf
(1978a) embryotoxische und teratogene Wirkungen an Ratten nach
oraler Verabreihung, Rep. nr. 7580, from Institut für
Toxikologie, Bayer A.G. Unpublished report submitted by
Bayer A.G.
Machemer, L. S 1752 (Fenthion, Lebaycid active ingredient). Dominant
(1978b) Lethal study on male mice to test for mutagenic
effects. Rep. nr. 7449 from Institut für Toxikologie,
Bayer A.G. Unpublished report submitted by Bayer A.G.
Race, J. Report from the Codex Contact Point, Norway on fenthion
(1978) uses on pears, raspberries, strawberries and radishes.
Thyssen, J. Untersuchungen zur Kombinationstoxizität von
(1977) Edifenphos, Fenthion und Bassa-Wirkrtoff. Report nr.
7176 from Institut für Toxikologie, Bayer A.G.
Unpublished report submitted by Bayer A.G.
Wadia, R.S., Bhirud, R.H., Gulavani, A.V. and Amin, R.B.
(1977) Neurological manifestations of three organophosphate
poisons. Indian J. Med. Res. 66 446-468.