PESTICIDE RESIDUES IN FOOD - 1980
Sponsored jointly by FAO and WHO
EVALUATIONS 1980
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, 6-15 October 1980
FENTHION
Explanation
Fenthion was reviewed for an ADI by the Joint Meeting in 1971,
1975, 1977 and 1978 (FAO/WHO, 1972, 1976; FAO, 1978, 1979). A
temporary ADI was estimated to be 0-0.0005 mg/kg bw based on an
extensive series of short-term studies and human exposure data
showing cholinesterase depression to be the most significant
parameter of exposure and effect.
Previous Meetings have expressed concern over the lack of long-term
studies and on the prolonged effects of cholinesterase depression
noted in animals and man. The Meetings have requested long-term
toxicology data and ancillary data to evaluate the safety of food
residues from agricultural use and to assure that an ADI could be
estimated. Additional studies have been received that allow a
complete evaluation of fenthion to be made. For this reason, the
pertinent toxicological data reviewed by previous Meetings and the
new data are all included in this complete monograph.
DATA CONSIDERED FOR DERIVATION OF ACCEPTABLE DAILY INTAKE
BIOCHEMICAL ASPECTS
Absorption, distribution, and excretion
The first studies on mammals (rats) were reported by Brady and
Arthur (1961), who use a 32P-labelled compound. Within a few hours
of applying the compound, large amounts of 32P-activity was found
in the tissues including the bones, evidence that fenthion was
rapidly absorbed, translocated, and degraded by rats. Neither
fenthion nor its oxidative metabolites were stored in tissues even
when rats received daily doses of 10 mg/kg bw by the
intraperitoneal route for 10 consecutive days. At 1.5 hours,
following a single i.p. injection of 200 mg/kg, the following
acetonitrile-soluble residues were observed:
liver 29.5 mg/kg
muscle 9.6 mg/kg
skin 6.1 mg/kg
kidney 16.9 mg/kg
heart 9.6 mg/kg
Most tissues from rats treated orally with 100 mg/kg (single dose)
contained less than 0.01 mg/kg chloroform-soluble residues three
days after treatment. Except for the liver (0.2 mg/kg), the blood,
brain, and fat of these animals contained no detectable
acetonitrile-solution residues. The orally treated animals
eliminated 86% of the activity in the excreta within seven days
after treatment. One to 4% of the activity in urine and faeces was
chloroform-soluble.
As a result of partial starvation, oxidative metabolism in rabbits
was increased, as evidenced by greater concentrations of
fenthion-oxygen analogue in blood. The peak of radioactive
substances in blood of normal rabbits following oral or
subcutaneous administration of 35S fenthion was observed in six to
nine hours following treatment, while in starved rabbits the peak
value was obtained one hour after treatment (Begum, 1968).
Following intraperitoneal administration of 32P-labelled fenthion,
approximately 75% of the administered dose was recovered within
three days in rat urine (60%) and faeces 15%). After oral
administration, 86% of the dose was excreted in urine (45%) and
faeces (40%) with the majority excreted in three days (Brady and
Arthur 1961). Starvation of rabbits had no effect on elimination
of fenthion (or metabolites) following oral or subcutaneous acute
administration (Begum, 1968).
Avrahami and White (1975) treated two lactating dairy cows with 20%
fenthion as a topical spot treatment used for the control of lice
using 32P-labelled fenthion applied at the rate of 9 mg/kg body
weight. Highest residues of total radioactivity in the blood, milk,
urine and faeces appeared between the first and second day after
treatment. The residues were predominantly water-soluble hydrolysis
products of fenthion. The highest daily average level offenthion and
its organosoluble metabolites in the milk from the two cows was
approximately 0.1 mg/kg on the first day after treatment. Of the
total radioactivity applied to each cow, 45-55% was recovered in the
urine, 2-2.5% in the faeces and 1.5-2% in the milk over a period of 4
weeks.
Johnson and Bowman (1972) administered fenthion to lactating dairy
cows at the rate of 25, 50 or 100 mg/kg in the total daily ration for
28 days. Total residues consisting of fenthion, its sulphoxide and
sulphone and the sulphoxide and sulphone of the oxygen analogue in the
milk averaged 0.016, 0.049 and 0.099 mg/kg respectively over the
period. Total residues in faeces consisted of fenthion and its
sulphoxide and averaged from 0.042 to 0.308 mg/kg. Neither fenthion
nor its oxygen analogue was found in urine but totals of the
sulphoxide and sulphone of fenthion and its oxygen analogue averaged
from 0.43 to 1.05 mg/kg. Seven days after feeding was terminated,
residues could not be detected in milk, urine or faeces.
Biotransformation
Five metabolites were isolated from rat urine and characterized as
fenthion sulphoxide and sulphone, the oxygen analogue of the parent
compound, and its corresponding sulphoxide and sulphone derivatives.
In rabbits, the major urinary metabolites were fenthion-sulphoxide,
fenthion-O-sulphoxide, and sulphone (Begum, 1968). The metabolic
scheme is shown in Figure 1.
FIGURE 1;V080pr16.BMP
Knowles and Arthur (1966) applied fenthion dermally to two dairy cows
each weighing 360 kg at a rate of approximately 13 mg/kg per cow, and
treated two other lactating cows (each weighing 41O kg) by the
intramuscular route with approximately 8.5 mg of fenthion/kg per cow.
In the urine, the peak concentration of radioactive materials occurred
on the first day following either method of treatment. The total
residue of 32P materials from intramuscular treatment decreased from
33 mg/kg at one day to 1.6 mg/kg by 21 days. More than 95% of the
radioactive materials eliminated in the urine consisted of hydrolytic
products. The total 32P materials eliminated in the faeces peaked
two days after both types of treatment. The cumulative percentage of
the administered dose was about 4%. The peak concentration of
acetonitrile-soluble radioactivity occurred one day after
intramuscular treatment and three days after dermal treatment. The
hair of the two cows treated dermally contained about 2000 mg/kg
radioactive fenthion equivalents immediately after treatment.
Chloroform to water partition data indicated that fenthion underwent
little change on the hair to water-soluble components. The
radioactivity in the blood after both types of treatment reached a
peak during the first 24 hours. Between 10% and 38% of the 32P
materials partitioned into chloroform, but no detectable
chloroform-soluble 32P materials were present in the blood at seven
days after either treatment.
Fenthion constituted more than 50% of the non-ionic residues in the
milk for three days after dermal and seven days after i.m. treatment.
In the urine, fenthion accounted for only a small percentage of the
chloroform-soluble radioactivity. More than 50% of the
acetonitrile-soluble radioactive materials in the faeces consisted of
the parent compound. The remainder was accounted for by the other
metabolites, just as in urine. The composition of the hydrolytic
products was also very similar to that found in urine. In the tissues
of the animals slaughtered 14 days after dermal treatment and 21 days
after i.m. treatment, more than 50% of the radioactive
acetonitrile-soluble materials was chromatographed as fenthion, but
oxidation products were also present.
The biotransformation of fenthion in plants is basically similar to
that in animals.
Effects on enzymes and other biochemical parameters
Fenthion and its metabolites are typical organophosphorous
anticholinesterase agents. Typical of this class of agents, the
oxygen analogue is the most potent enzyme inhibitor of all the
metabolites, containing a phosphorous triester configuration (Francis
and Barnes, 1963). The molar I50 fenthion for rat brain
cholinesterase is 1.3 × 10-4M (Dubois and Kinoshita, 1964).
Clinically and biochemically, a prolonged cholinergic effect follows a
single dose (recovery of blood and brain enzyme is very slow) (Brady
and Arthur, 1961). This effect may be as a result of inhibition of
cholinesterase by metabolites that are released at different rates
from storage in the body (Francis and Barnes, 1963), or a possible
potentiation of its own antiesterase effects by selectively inhibiting
enzymes responsible for hydrolysis of the phosphate ester (Brady and
Arthur, 1961). Cholinesterase inhibition cannot be reactivated by
2-PAM, TMB-4 or P-2-S in vivo, indicating that fenthion may
inhibit cholinesterase in a manner different from other
organophosphate esters (Dubois, 1960; Dubois and Kinoshita, 1964;
Francis and Barnes, 1963).
TOXICOLOGICAL STUDIES
Special pharmacological studies
A daily diet containing 300 mg/kg fenthion was given to 8 groups of
Donrya rats: a hare's eye group, a cervial 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 organophosphorous intoxication such as nervousness,
general spasms, diarrhoea, and salivation. Also ophthalmological
symptoms, such as eye-ball protrusion, keratoconus, mammiform cornea,
and cornea turbity were observed. The described pretreatments did not
prevent the ocular symptoms (abstract only) (Kawai et al, 1976).
When fenthion was administered at doses of 0.5 mg/kg orally to rats
and 1-8 mg/kg intravenously to cats, significant inhibition of heart
rate and blood pressure were observed. However, an intravenous dose
of 0.3 mg/kg to cats produced no significant changes in blood
pressure, heart rate, or other physiological parameters (Wills et
al, 1975).
Special studies on reproduction
Rat
Except for a slight growth depression at the highest level, fenthion
at levels of 0, 3 15 or 75 mg/kg in the diet for three generations
(two litters per generation) produced no adverse effect on rat
reproduction (Loser, 1969). Microscopic examination of the tissues of
the F3b generation did not reveal any significant abnormality (Spicer,
1971).
Mouse
In a five-generation reproduction study (2 litters per generation),
two groups of Charles River CD-1 mice consisting of 14 females, 10
males; and 22 females, 10 males received 0 or 60 mg/kg fenthion,
respectively, in their drinking water. In the parameters studied
(reproductivity performance, lactation, viability, and growth rate of
pups) the principal effect was a significant increase in pup
mortality, especially in the 2nd, 3rd, and 4th generations. The
highest mortality appeared to be in the first postnatal week. No
histopathological changes were noted in the liver or kidney. There
was no evidence of a teratogenic potential (Budreau and Singh, 1973b).
Special studies on teratogenicity
Mouse
Pregnant Charles River CD-1 mice were injected intraperitoneally with
single doses of 40, 80 or 160 mg/kg body weight or with multiple doses
of fenthion at various time periods during organogenesis. Foetuses
were removed by caesarean section on days 16 and 18 and visceral and
skeletal structure examined for abnormalities. The frequency of
resorptions and foetal deaths was not affected. Foetal weights were
reduced significantly. Although the number and type of abnormalities
were increased when compared to the control group, this did not appear
to be dose-related. There was no apparent teratogenic effect,
however, the incidence of resorptions was increased when fenthion was
injected intraperitoneally for three consecutive days (day 9, 10, 11
of gestation) at 20 mg/kg (Budreau and Singh, 1973a).
Rat
Fenthion was administered orally to groups of female rats for one
generation (two litters) at dosage levels of 5 mg/kg body weight or 10
mg/kg body weight from both day 1 through day 7 and day 8 through day
10 of gestation. Some animals were sacrificed on day 21 and foetuses
were removed by caesarean section from these and examined for internal
and external abnormalities. No malformations were observed. The
incidence of resorptions was increased and weight of foetuses reduced.
The second progeny from the remaining females were not affected. In a
further study, rats were given fenthion at a dosage level of 5 mg/kg
body weight from day 1 through day 13 of gestation. There was no
evidence of teratogenesis. However, the incidence of foetal
resorption and abortion was increased. During the lactation period
there was an increased mortality and a decrease in the body weight
gain of the pups. By day 45 postpartum, surviving newborns had
recovered normal weight (Fytizas-Danielidou, 1971).
When preliminary studies indicated that a dose of 100 mg/kg was lethal
to non-pregnant female rats in 2-4 days and that 30 mg/kg induced
toxic signs of poisoning, 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 foetuses,
litter weight, and placental weights were recorded. After gross
examinations were made for skeletal and soft tissue malformations, no
treatment-related teratogenic effects were noted (Machemer, 1978a).
Special studies on mutagenicity
In vivo - mouse
In a dominant lethal assay, 2 groups of 50 male mice (NMRI-strain)
were given a single oral dose of 0 or 25 mg/kg bw. Additionally, a
third group of mice was treated with 10 mg fenthion/kg bw, because 25
mg/kg induced toxic effects in the males (drowsiness, ruffled coat,
and dilated intestines). The compound was given as a 2% aqueous
emulsion.
After injection, each male was caged with an 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 deal implants (sum of deciduomata, the
resorptions, and the dead embryos) were counted.
Except for an increased pre-implantation loss at the dose level of 25
mg/kg bw in the first two mating periods, no other treatment-related
effects on fertility, pre- and post-implantation loss were observed
(Machemer, 1978b).
In vitro - Microorganisms
Fenthion was examined for its mutagenic potential using 3 standard
strains of Salmonella typhimurium (TA-1537, TA-98 and TA-100).
Fenthion was tested in the presence and absence of an S-9 metabolising
enzyme fraction obtained from Aroclor 1254-induced rat liver at
concentrations ranging from 3.15 to 3150 g/plate. Under all
conditions, there was no increase in the level of revertant colonies
above that noted with controls. Both positive and negative acting
chemicals (MMN and benzo [a]pyrene) were used to assure quality
control in the test system. Under this standardised bioassay,
fenthion was not mutagenic (Oesoh, 1977).
Special studies on carcinogenicity
Rat
Groups of rats (50 male and 50 female, F344 strain rats/group, 25 of
each sex were used as controls) were fed fenthion at dietary dosage
levels of 0, 10 or 20 mg/kg for 103 weeks in a carcinogenicity
bioassay. The animals were maintained for 1-2 weeks after the dietary
administration stopped and were then sacrificed for gross and
microscopic examinations.
There was no mortality in the study and growth and behaviourial data
were similar to control values. Histopathological studies described a
variety of neoplastic and non-neoplastic lesions common to this strain
of rat. Based on the histopathology and statistical evaluation of the
incidence of tumours, fenthion was not considered to be carcinogenic
to the rat (NCI, 1979).
Mice
Groups of mice (50 male and 50 female, B6C3F1 strain mice/group, 25 of
each sex were used as controls) were fed fenthion in the diet at
dosage levels of 0, 10 or 20 mg/kg for 103 weeks. The animals were
maintained on control diets for up to 1 week after dietary
administration stopped. They were then sacrificed and subjected to
gross and microscopic examinations.
During the first 4 months, no effects were noted on behaviour or
appearance. Clinical signs of poisoning were noted thereafter (it was
not indicated at what dosage levels there were clinical signs of
poisoning). There were no differences in growth over the entire
dosage range for the 103 weeks of study. Survival was not affected by
fenthion.
A variety of neoplasms were reported, the majority of which were not
related to dietary administration of fenthion. It was reported that
sarcomas in male mice (but not females) occurred with a greater
frequency than in controls. The integument was considered to be the
primary site for all primary sarcomas, MOS and fibrosarcomas. In an
incidence of rhabdomyo-sarcoma, the skeletal muscle within
subcutaneous tissue was defined as the site of origin.
Histologically, differentiation was minimal to moderate among the
various fibrosarcomas. The total incidence of skin and subcutaneous
neoplasms (sarcomas) was dose related (controls 0/25; 10 mg/kg - 7/49;
20 mg/kg - 8/48) although the response was slight with respect to any
individual lesion. Spontaneous rhabdosarcomas are rare in mice and
the total incidence is an unusual occurrence. The histopathologic and
statistical evaluation of the data suggested an increased incidence of
sarcoma in male mice that may be related to the dietary presence of
fenthion (MCI, 1979).
The data were reviewed by the Data Evaluation/Risk Assessment Sub
Group of the National Cancer Institute Clearinghouse on Environmental
Carcinogens, who concluded that fenthion was not carcinogenic to rats
or mice under the conditions of the test. Although, because of the
increased incidence of sarcoma of the skin in male mice, fenthion was
suggested to be sarcomagenic in this sex and strain.
Special studies on potentiation
Fenthion potentiates the acute intraperitoneal toxicity of malathion,
dioxathion, and coumaphos in rats. Intraperitoneal administration of
13 other organophosphate or carbamate insecticides did not result in a
greater than additive effect when administered with fenthion (Dubois
and Kinoshita, 1964). Dietary combination of fenthion with coumaphos,
neither of which alone affected cholinesterase when fed to dogs for
six weeks, was found to potentiate the anticholinesterase activity of
serum and red blood cells. Less evident potentiation was observed
when fenthion and malathion were fed and when fenthion was fed in
combination with dioxathion, no potentiation was noted (Doull et al,
1962). Fenthion (2 mg/kg) and malthion (100 mg/kg) resulted in
moderate erythrocyte and serum cholinesterase activity inhibition
(30-40%). When fenthion (2 mg/kg) and dioxathion (3 mg/kg) were fed,
cholinesterase activity was not depressed. When fenthion (2 mg/kg)
and coumaphos (2 mg/kg) were fed to dogs, significant inhibition (75%)
of serum cholinesterase and moderate inhibition (30%) of erythrocyte
cholinesterase was evident. Oral administration to rats of a 75:25
mixture of fenthion and dichlorvos did not result in a greater than
theoretically additive toxicity (Kimmerle, 1967b).
In rats, no synergistic effects on the acute oral toxicity was noted
of fenthion with edifenphos and the active ingredient of Bassa
(2-sec-butylphenyl N-methylcarbamate) (Thyssen, 1977).
Special studies on neurotoxicity
No evidence for delayed neurological disruption in hens was evident
when fenthion was administered orally at a single dose of 25 mg/kg
(Kimmerle, 1965a). When chickens were fed up to 100 mg/kg in the diet
for 30 days, clinical examination of the animals and histological
examination of nerve tissues indicated no demyelinating effect from
fenthion (Kimmerle, 1965b; Dieckmann, 1971).
Acute toxicity
LD50
Animal Sex Route (mg/kg bw) Reference
Mouse M Oral 150 Francis & Barnes, 1963
227 Dubois, 1968
F 190 Francis & Barnes, 1963
225 Dubois, 1968
F i.p. 150 Dubois & Kinoshita, 1964
M 125 Dubois & Kinoshita, 1964
Rat F Oral 245-310 Dubois & Kinoshita, 1964;
Gaines, 1960
615 Francis & Barnes, 1963
M 175-470 Dubois & Kinoshita, 1964;
Klimmer, 1963; Gaines, 1969;
Francis & Barnes, 1963
M&F Inhalation 1197 mg/m3 (1 hour) Thyssen, 1978
M i.p. 325 Dubois & Kinoshita, 1964
F 260 Dubois & Kinoshita, 1964
M 152 Klimmer, 1963
M Dermal 330-650 Gaines, 1969; Klimmer, 1963;
Francis & Barnes, 1963
1680 Mihail, 1978
F 2830 Mihail, 1978
F 330-500 Dubois & Kinoshita, 1964;
Gaines, 1969; Francis &
Barnes, 1963
Mouse F i.p. 200-240 Budreau & Singh, 1973a
Guinea Pig M Oral 1000 Francis & Barnes, 1963
260 Dubois & Kinoshita, 1964
310 Dubois & Kinoshita, 1964
Rabbit M Oral 150-175 Francis & Barnes, 1963
Dermal 150 Klimmer, 1963
Duck Oral 15 Dubois & Doull, 1960
1-2 Keith & Mulla, 1966
Chicken 30 Dubois & Doull, 1960
28 Sherman & Ross, 1961
30-40 Francis & Barnes, 1963
Calf Approx. 40 McGrath, 1961
The signs of poisoning are typical of the central and peripheral
cholinergic effects of organophosphorus esters with a gradual onset of
the symptoms. The symptoms in humans and other animals include
tremors, lacrimation, salivation, vomiting, diarrhoea, and other signs
of cholinergic stimulation.
The rate of absorption through the skin of rabbits is slow. When
fenthion was applied to a cotton plug and placed in a rabbit ear for 4
hours, swelling occurred. When it was left for 24 hours, mortality
resulted (Kimmerle, 1960).
Various solvents used to dissolve fenthion in combination with water
or ethanol had no significant effect on the acute oral LD50
(Kimmerle, 1967a).
Fenthion is an organophosphorus insecticide of intermediate toxicity
to mammals, although it displays considerable differences in its
toxicity to various species, e.g., avian species are very sensitive
(Keith and Mulla, 1966).
Acute Toxicity of the Metabolites
LD50
Compound Oral1 i.p.2 I50(M)3
Fenthion 220 325 >5 × 10-4
Fenthion sulphoxide 125 250 4.5 × 10-5
Fenthion sulphone 125 250 4.7 × 10-4
Fenthion Oxygen analogue 125 26 2.66 × 10-6
Fenthion O-Sulphoxide 50 22 4.8 × 10-5
Fenthion O-Sulphone 30 9 3.2 × 10-5
4-(methylthio)m-cresol 65004
4-methyl(thiosulphoxide)
m-cresol 35004
4-methyl(thiosulphone) 70004
1 Male rats - according to Francis and Barnes, 1963
2 Female rats - according to Dubois and Kinoshita, 1964
3 I50 = Molar concentration resulting in 50% inhibition of human RBC
cholinesterase (Francis and Barnes, 1963)
4 Female rats according to Nelson, 1967
Antidotes
A number of antidotes that are commonly used for organophosphorus
poisoning have been shown to be relatively inactive when used
following fenthion intoxication. Studies with atropine, 2-PAM,
Toxogonin, P-2-S, and TMB-4 (Dubois and Kinoshita, 1964; Francis and
Barnes, 1963; Dubois, 1960 and Lorke and Kimmerle, 1969) administered
alone and in combination showed that these materials did not
successfully alleviate the parasympathomimetic signs of
organophosphate poisoning. When BH-6 (Merck; Darmstadt, Germany) was
administered three to four times in combination with atropine, the
LD50 value increased from 250 to 440 mg/kg (Kimmerle, 1963).
Toxogonin was not effective as a cholinesterase reactivator following
oral intoxication of dogs by fenthion (Hahn and Henschler, 1969).
Short-term studies
Inhalation
Female rats tolerated a daily one-hour inhalation challenge of 0.163
mg/l air for 30 days with cholinesterase depression but no mortality.
At 0.415 mg/l air, all animals were dead within 10 days (Dilley and
Doull, 1961a). Following a standard 4-hour exposure, the LC50 for
fenthion for male and female rats was approximately 1200 and 800
mg/m3. Five consecutive 4-hour exposures resulted in an LC50 for
males of approximately 212 mg/m3 and for females the LC50 was
between 55 and 212 mg/m3 (Thyssen, 1978).
Exposure by inhalation daily for nine days, six hours per day at 210
mg/m3 (initial concentration in a static inhalation chamber),
resulted in signs of poisoning, but no mortality in cats, guinea pigs,
rabbits, and rats. Cholinesterase, which was severely depressed,
recovered in three weeks (Klimmer, 1963). Fenthion exhibits a
relatively low degree of acute mammalian toxicity. In only one
instance was a sex difference in susceptibility noted, and this is in
contrast to the generally noted resistance of males to other
phosphorothioates (Dubois and Kinoshita, 1964).
Duck
Mallard ducks fed 25 mg/kg of fenthion in the diet for six weeks
became emaciated and could not fly or walk; after two days on normal
food, recovery was evident. A dietary level of 5 mg/kg produced no
adverse clinical reaction (Keith and Mulla, 1966).
Rat
Dermal administration of fenthion at 14.5 and 25 mg/kg for 60 days to
rats resulted in 40% mortality in the higher-dosed group and no
mortality in the lower-dosed group. However, blood cholinesterase
levels were depressed to about 20% of normal at the lower treatment
level (Dubois, 1961). Cholinesterase was depressed and mortality was
absent when fenthion was applied to rats dermally for 12 days at 2.9
mg/kg (Dubois and Puchala, 1960).
Rats tolerated daily intraperitoneal administration of 10 mg/kg
fenthion for 60 days with no mortality. At 20 mg/kg, 80% of the
treated animals died within 20 days (Dubois and Kinoshita, 1964).
Mortality (12 dead of 30 rate tested) occurred following daily oral
administration of approximately 25 mg/kg (1/10 LD50) for 75 days (6
days per week). Signs of poisoning were transient, disappearing
shortly after dosing (Klimmer, 1963).
In a preliminary study, male rats were orally administered fenthion
five days a week for 13 weeks at a dose of 30 mg/kg/day. Mortality
occurred in approximately 30% of the rats over the course of the
experiment and cholinesterase activity was depressed between 80-90% of
normal. At the conclusion of the experiment, cholinesterase recovery
was very slow, up to 40 days (Kimmerle, 1961).
Rats (22 male and 22 female per group) were fed dietary levels of
fenthion at 0.25, 0.50, 2.5 or 5.0 mg/kg/day for three months.
Cholinesterase activity depression was evident at 0.5 mg/kg/ day in
red blood cells, serum, liver, and heart at all testing intervals. At
the lowest feeding level (0.25 mg/kg), the inhibition (approximately
10-20%) did not progressively increase with time, indicating lack of
cumulative effects. Mortality in females was evident at 5.0 mg/kg.
The animals died manifesting muscarinic and nicotinic effects.
Body-weight gain was reduced in males at 0.25 mg/kg and above, while
in females it was evident only at 2.5 mg/kg. Behaviourial effects
were noted (piloerection) at 0.5 mg/kg and above (especially in
females).
This effect decreased with time and disappeared by week 7. Organ
weights were all distinctly lower than the controls, but as the body
weight was also reduced, the organ-to-body-weight ratio did not appear
to be affected. Histological examination showed the testes to have
reduced spermatogenesis and atrophic prostate glands were noted at the
highest feeding levels (2.5 and 5.0 mg/kg). The ovary was not
affected (Shimamoto and Hattori, 1969).
Rats (six groups of 12 male and 12 female) were fed for 16 weeks on
diets containing 0, 2, 3, 5, 25, or 100 mg/kg. Cholinesterase
depression was evident at 25 mg/kg and absent at 5 mg/kg. No adverse
effects were noted in food consumption, weight gain, or gross and
microscopic examination of tissues (Doull et al, 1961).
Rats (six groups of 25 male and 25 female) were fed for one year on
diets containing 0, 2, 3, 5, 25 or 100 mg/kg of fenthion. There was
no evidence of significant changes in growth rate, food consumption,
general appearance, and gross or microscopic examination of tissues.
Survival of male rats at 25 mg/kg was slightly depressed.
Cholinesterase examinations indicated depression at the 5 mg/kg level
and above, with 3 mg/kg showing no adverse enzyme effects. A mild
extramedullary haematopoiesis was observed in controls and all dosage
levels, and haemosideresis was evident in the spleen of the rats at
100 mg/kg levels (Doull et al, 1963a).
Dog
Groups of dogs (4 male and 4 female beagle dogs/group) were fed
fenthion in the diet for two years at dosage levels of 0, 3, or 10
mg/kg. A high dose group received 30 mg/kg for 64 weeks, 50 mg/kg for
2 weeks (weeks 65 to 67) and 60 mg/kg for the remainder of the study
(weeks 68 to 104).
There was no mortality in the study and all dogs appeared healthy over
the course of the study. When the high-dose level was increased from
30 to 60 mg/kg, faecal changes were noted, although diarrhoea was not
observed. Food consumption was normal except for those animals at the
60 mg/kg level, where at some time intervals, all the food was not
consumed at each meal. There were no ophthalmological changes, and
most clinical blood chemistry, haematology, and urinalyses parameters
were unaffected by fenthion. Cholinesterase depression in both
plasma, erythrocyte, and brain was observed. Plasma cholinesterase
was the most sensitive parameter, being depressed at dietary
concentrations of 10 mg/kg and above. Erythrocyte cholinesterase was
depressed in males at 10 mg/kg and in females in the high dose group
only. Brain cholinesterase of both males and females was depressed,
only at the highest concentration tested. There were no remarkable
observations associated with gross or microscopic examinations of
tissues and organs. A no-effect level in this study was 3 mg/kg,
equal to a dietary intake of 0.09 mg/kg body weight for fenthion
(Hoffmann and Weischer, 1975).
Dog
Dogs (four groups of two males and two females per group) were fed
fenthion at 0, 2, 5 or 50 mg/kg for 12 weeks. Growth was not affected
at any dietary level. Erythrocyte cholinesterase activity was
depressed at 50 mg/kg while serum cholinesterase was depressed at 5
mg/kg and above. Little, if any, depression of the serum
cholinesterase was evident before five weeks, after which it
progressively decreased to about 40% inhibition (Doull et al, 1961).
Dogs (four groups of two males and two females) were fed fenthion at
0, 2, 5, or 50 mg/kg in the diet for one year. There was no effect of
fenthion on food consumption or growth over the test interval.
Erythrocyte and serum cholinesterase were significantly depressed at
50 mg/kg with the serum also depressed at 5 mg/kg. An increase in the
weight of the spleen, which was not dose dependant, was evident in all
of the treated animals.
Microscopic examinations of the tissues showed splenic congestion and
some decrease in the cellularity of the red pulp was evident at all
dose levels fed. Extramedullary haematopoiesis and haemosideresis was
also observed in the spleen. Microscopic examination of other tissues
did not reveal any significant changes (Doull et al, 1963b).
Monkey
Four groups of 5 male and 5 female rhesus monkeys 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 and body weight and
ophthalmological examinations were reported monthly. Clinical
chemistry, haematology, and urinalyses were performed at 0, 1, 3, 6
and 12 months. Plasma and erythrocyte cholinesterase activity was
measured at 0, 1, 2, 3, and 4 weeks and thereafter monthly. One
monkey/sex from the 0 and 0.2 mg/kg groups was sacrificed at 7 months,
3 weeks. Brain cholinesterase, absolute and relative organ weights,
and gross and histopathology analyses were reported. The plasma
cholinesterase was depressed in both sexes at 0.2 mg/kg. Plasma
cholinesterase depression occurred at 0.07 mg/kg, 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 0, 3, 15, or 75 mg/kg 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: haematology,
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.
Fenthion at 3 and 15 mg/kg did not affect the physical appearance,
behaviour, growth, and survival rate. The male rats of the 75 mg/kg
group had a significantly lower body weight. A tendency toward
increased mortality was observed in the 75 mg/kg group in both sexes.
Haematology, blood chemistry, urinalysis, and gross and microscopic
pathology revealed no compound-related effects.
Dietary concentrations of 15 and 75 mg/kg fenthion caused
dose-dependant depression of plasma and erythrocyte cholinesterase
activity. At 3 mg/kg, cholinesterase activity was only slightly
depressed in the plasma of the females. A no-effect level for
fenthion in this study is 3 mg/kg (Bomhard and Loser, 1977).
OBSERVATIONS IN MAN
Fenthion has been widely used in many parts of the world for control
of household pests, mosquitoes, etc. Cholinesterase studies conducted
on individuals in areas treated by the World Health Organization for
malaria eradication have shown that very slight plasma cholinesterase
depression occurs when exaggerated spray schedules were followed. The
plasma cholinesterase levels were depressed for up to six weeks after
spraying (Elliot and Barnes 1963). It was also evident that the
children in the population (less than seven years old) were more
susceptible to the anticholinesterase effects (Taylor, 1963). A man
who ingested two ounces of a fenthion formulation (Entex(R)) recovered
from severe organophosphorous poisoning after being in critical
condition for the first six days after poisoning. Recovery was slow,
lasting up to 30 days. 22 days after poisoning, the cholinesterase
activity was still depressed (Pickering, 1966). In humans, the signs
of poisoning appear rapidly, beginning with blurred vision, unsteady
gait, and slurred speech. After 72 hours of emergency treatment
following an unknown quantity of fenthion, a man suffered extreme
respiratory difficulty necessitating artificial ventilation and
endotracheal intubation. The patient began to recover only after 11
days of treatment, which included atropine, PAM, and toxogonin (Dean
et al, 1967). In another case, 45 minutes after ingestion of 30 ml
of a fenthion formulation a man was in a comatose state with pale
skin, cyanotic mucous membranes, slow regular heart beat, no
peripheral blood pressure, and no reactions to pain or light
stimulation on the pupils. Recovery took six days (von Clarmann and
Geldmacher-von-Mallinkrodt, 1966).
The potential dermal and respiratory exposure to fenthion during field
application by hand gun power spray equipment, back-pack hand pressure
sprayer, and hand granular dispersal for mosquito control was studied
over two work seasons (Fytizas-Danielidou, 1971). Human workers
exposed to 3.6-12.3 mg/h (dermal) or <0.02-0.09 mg/h (inhalation),
equivalent to 0.5-1.5 mg/kg/day (dermal) and 0.01-0.05 mg/kg/day
(inhalation), showed a decrease in plasma, but not erythrocyte
cholinesterase activity (Wolfe et al, 1974).
A 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 what agent was consumed. Paralytic signs were significantly
more frequent with fenthion than with malthion or fenitrothion (being
81.2%, 30% and 23% respectively). These signs occurred later with
fenthion and lasted longer. Death occurred significantly more often
with fenthion (the mortality rate being with fenthion 35.5%, with
malathion 4%, and with fenitrothion 2.1%). Pulmonary oedema was most
common with malathion and not encountered with fenthion. The
cholinesterase activity was most marked with fenthion reaching 0 in 18
of the 27 cases studied (Wadia, et al, 1977).
A group of male volunteers were administered fenthion orally for
periods of time up to 4 weeks at dosage levels of 0, 0.04 or 0.07
mg/kg body weight. There were no effects reported on physical signs
or symptoms, haematology, or urinalysis parameters. With the
exception of a slight plasma cholinesterase depression noted at the
high dosage level, no effects were noted on the various clinical
chemistry parameters (Griffin et al, 1979).
EVALUATION
COMMENTS
The meeting reviewed new data requested by previous meetings and
considered all of the available information on fenthion.
Fenthion, an organophosphorus insecticide, is rapidly absorbed,
metabolised and excreted. Fenthion does not accumulate in the body.
In most instances, those metabolites that remain fully esterified are
more toxic than the parent compound. Fenthion and its biologically
active metabolites are anticholinesterase agents and the signs and
symptoms of poisoning are typical of the cholinergic response. The
signs of intoxication from a single oral dose develop slowly and
persist for a considerable time. Although there is no explanation for
the long-lasting cholinesterase depression, slow appearance and
disappearance of cholinergic signs and lack of appropriate antidote,
these are of minimal concern in establishing an ADI. It would however
be of interest to have such information, which could be of high value
in cases of acute poisoning. The cholinergic signs of poisoning are
not readily alleviated by atropine or by the common oxime
reactivators.
Fenthion is not mutagenic in mammalian or microbial test systems. It
is not carcinogenic, or teratogenic and does not affect reproduction
in rodents. Fenthion does not induce delayed neurotoxicity in hens
nor is it potentiated by other cholinergic chemicals.
In extended short-term studies with rats, dogs and monkeys, and in a
long-term rat study, there were no indications of adverse effects
other than cholinesterase depression. Studies of humans exposed
occupationally or through malaria-control programmes, as well as of
volunteers ingesting a standardised dose, do not indicate any short-
or long-term adverse effects except plasma depression and acute
cholinergic response.
From the available data no-effect levels in rat, dog and a monkey were
noted.
Observations in humans provide additional assurance of the safety of
the residue level in food.
Maximum level causing no toxicological effect
Rat: 3 mg/kg in the diet equivalent to 0.15 mg/kg bw/day.
Dog: 3 mg/kg in the diet equivalent to 0.09 mg/kg bw/day.
Monkey: 0.07 mg/kg bw/day
Man: 0.02 mg/kg bw/day
Estimate of acceptable daily intake for man
0-0.001 mg/kg bw
FURTHER WORK AND INFORMATION
Desirable
Studies to elucidate the mechanism of the long-lasting cholinesterase
inhibition noted in human studies as well as in animal bioassays.
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