METHAMIDOPHOS
EXPLANATION
Methamidophos was evaluated by the Joint Meeting in 1976, when an
ADI was allocated (Annex 1, FAO/WHO, 1977a). A toxicological monograph
was prepared (Annex 1, FAO/WHO, 1977b). Some relevant toxicological
studies from Industrial Bio-test Laboratories (IBT), supporting the
1976 evaluation, have been found to be invalid.
The compound was re-evaluated in 1982, when some substitute
studies were made available (Annex 1, FAO/WHO, 1983a). A monograph
addendum was prepared (Annex 1, FAO/WHO, 1983b). The 1982 JMPR
allocated a temporary ADI and requested long-term studies, a
carcinogenicity study, and a reproduction study.
The required studies, along with other toxicological studies,
have been submitted and are summarized in this monograph addendum.
Those sections of the 1976 evaluation summarizing invalid IBT studies
have been superseded by the 1982 and 1985 re-evaluations.
EVALUATION FOR ACCEPTABLE DAILY INTAKE
BIOLOGICAL DATA
Biochemical aspects
Absorption, distribution, excretion, and metabolism
Rat
Male and female albino rats were each given orally a single dose
of 32p_ labelled methamidophos at a level of 15 mg/kg b.w. After 24
hours, 77% of the administered radioactive dose was recovered in the
urine.
Identified urinary metabolites were; phosphoric acid, S-methyl
thiophosphoric acid, O,S-dimethyl thiophosphoric acid, O-methyl
phosphoric acid amide, and S-methyl phosphoramidothioic acid.
Unchanged methamidophos and a highly non-polar unidentified metabolite
were detected in the urine (Fakhr et al., 1982).
The tissue distribution and excretion of 14CH3S-methamidophos
was followed in female Sprague-Dawley rats after i.v. injection at a
toxic, but non-lethal, dose (8 mg/kg). Radiolabel was rapidly
distributed to all tissues at approximately equal concentrations. Peak
tissue levels were achieved within 1-10 minutes except in the central
and peripheral nervous system, where peak levels (40 nmol/g) were
found between 20 and 60 minutes, corresponding to peak signs of
toxicity. Within 24 hours of dosing, 47% of the radioactivity was
recovered in the urine and 34% as 14CO2, with < 5% in the faeces
over 7 days (Gray et al., 1982).
Effects on enzymes and other biochemical parameters
Acetylcholinesterase (AChE) inhibition was measured in
erythrocytes, plasma, and various regions of the central nervous
system (CNS) at selected times after i.v. administration of
methamidophos at 8 mg/kg to rats. The degree of Ache inhibition in 3
CNS regions was similar, reaching a minimum activity of 15-20% of
control values at 30-60 minutes, when toxicity was most severe. The
degree of erythrocyte AChE inhibition was less that that of the CNS,
although the time course was similar. Plasma AChE inhibition was more
rapid than that of the CNS or erythrocytes, and reactivation was
slower. When similar concentrations of methamidophos to those found
in vivo were incubated with CNS homogenates, plasma, or erythrocytes
in vitro (3 × 10-3), a similar degree of inhibition occurred over
the same time course. Therefore, the authors concluded that
cholinergic toxicity produced by methamidophos is a result of the
in vivo stability of this compound, which permits its entry into the
nervous system in sufficiently-high concentrations to inhibit AChE
(Gray et al., 1982).
The methylthiophosphorous linkage of methamidophos is cleaved in
the reaction, leading to the inhibition of acethylcholinesterase
(Thompson & Fukuto, 1982).
Special studies on embryotoxicity and teratogenicity
Rat
Groups of 22-26 pregnant female CD rats were administered once
daily, by gavage, methamidophos (technical grade, 70.5% a.i.) at dose
levels of 0, 0.3, 1.0, or 3.0 mg/kg b.w. on days 6 through 15 of
gestation, inclusive.
These dosages were based on preliminary work using dams dosed at
0.5, 1.5, or 4.5 mg/kg b.w. Dams in the 4.5 mg/kg b.w. group aborted
their litters at approximately day 15 of gestation; dams treated at
1.5 mg/kg b.w. carried their litters to day 21. The positive control
group received 350 mg/kg b.w. hydroxyurea on days 9, 10, and 11 of
gestation. Body weights and feed consumption were measured on days 6,
13, and 21 of gestation. On day 21 of gestation, rats were sacrificed
and Caesarean sections were performed. Foetuses were inspected grossly
and were preserved for internal or skeletal examination.
Signs of intoxication typical of cholinesterase-inhibiting
compounds were observed only in the rats at 3.0 mg/kg b.w. on days 6-8
to day 20 of gestation. No mortality occurred in any of the groups.
Body weights and feed consumption for rats at 3.0 mg/kg b.w. were
significantly lower than those of the controls from days 13 to 21 of
gestation; body-weight gain (absolute and corrected) was also
significantly reduced.
There were no statistically-significant differences between
control and treated groups with respect to mean values per litter of
implantations, early resorptions (no late resorptions occurred in any
group), or live foetuses.
The mean weights of live foetuses from dams at 3.0 mg/kg b.w.
were significantly lower than those of the controls.
There were no differences between control and treated groups with
respect to the incidence of foetuses with gross internal or skeletal
abnormalities. Increased incidences of abnormal foetuses were observed
in the positive control group.
The no-effect level for maternal and foetal toxicity was
1.0 mg/kg b.w.; that for embryotoxicity and teratogenicity was
3.0 mg/kg b.w. (Hixson, 1984a).
Special studies on reproduction
Groups of CD rats (26/sex/dietary level) were fed diets
containing methamidophos (technical grade, 70.5% purity) at levels of
0, 3, 10, or 33 ppm. After at least 100 days of dosing, the F0 rats
were mated to start a two-generation reproduction study with one set
of F1 litters and 2 sets of F2 litters (F2a and F2b). Because
mating was done on a 2-females-to-l-male basis, only half of the males
in each group were used for mating. The remaining 13 males per group
were continued on treated feed for possible use as replacement
breeders.
Necropsy was performed on F0 and F1 parents and F1a, F2a, and
F2b weaned pups. Tissues processed for histopathology included
reproductive organs from F0 males and females (when available),
reproductive organs from F1 male and female adults, and gross
lesions.
The percent of F0 dams delivering was reduced in all treated
groups, but not in a dose-related pattern. During gestation of F0
dams, feed consumption was comparable among groups, whereas body-
weight gain of the 33-ppm dams was lower than in the controls.
Although there was a trend toward decreased live births in F1 litters
with increasing dose, the differences were not statistically
significant. There was also a trend toward decreased viability
compared with controls during the course of lactation; the difference
was not statistically significant. For F1 pups in the 33-ppm dietary
groups, mean pup weights from lactation day 4 onward and mean litter
weights from lactation day 7 onward were significantly lower than in
controls.
Among F1 parents, rats in the 33-ppm dietary level had body
weights significantly lower than controls throughout the growth
period.
The number of F1 dams delivering litters (as percent of sperm-
positive females) were reduced in the 10-ppm and 33-ppm groups during
production of F2a litters and in all treated groups during production
of F2b litters; in both cases no clear dose-related pattern was
evident. During gestation of F2a and F2b litters, body-weight gains
of dams in the 33-ppm group were lower than in controls and in the
other 2 treated groups, but not statistically-significantly different
from controls.
As with F1 litters, F2a and F2b litters showed a trend toward
decreased live births, decreased lactation indices and decreased
viability indices with increasing dose during lactation; however, the
differences were statistically-significantly different from controls
only on lactation day 14 for the mean number of pups per litter and
the viability index of the 33-ppm F2a group and for the mean number
of pups per litter of the 33-ppm F2b group.
In the 33-ppm group, the F2a mean litter weight was
significantly reduced compared to controls from day 1 onward, and the
mean pup weight was significantly reduced throughout lactation. In the
33-ppm group, the F2b mean litter weight was significantly reduced
compared to controls throughout lactation, but the mean pup weight was
reduced only on lactation day 7.
Sporadic differences from controls in absolute and relative gonad
weights of adults and pups gave no evidence of a dose-related effect.
Gross and microscopic changes were observed in control and test
groups of each generation and were considered unrelated to treatment.
Statistically-significant effects of methamidophos on
reproduction occurred only at the 33-ppm dietary level; thus the no-
effect level in this study was 10 ppm (Hixson, 1984b).
Special studies on carcinogenicity
Mouse
Groups of CD1 albino mice (50 males and 50 females/sex/dietary
level; 10 males and 10 females in the satellite groups) were fed diets
containing methamidophos (70% purity) at levels of 0, 1, 5, or 25 ppm
for 106 weeks.
Mice in the satellite groups were used for haematology
determinations at 6 months and 1 year. Ten mice were randomly selected
among surviving mice for haematology at termination. All mice found
dead or moribund-sacrificed during the study, interim sacrificed at 1
year, and terminal sacrificed were subjected to gross necropsy. The
adrenals, brain with entire brainstem, gonads, heart, kidneys, liver,
lungs, and spleen were weighed. A number of tissues and organs from
all animals were subjected to histopathological examination.
The administration of the test compound had no toxocological
effect on behaviour, occurence of masses, or mortality. Feed
consumption of the controls and those in the 1-ppm and 5-ppm groups
were generally comparable. The 25-ppm females had a fairly consistent
significant decrease in feed consumption after one year. Mean body
weights of male and female mice in the 25-ppm group were significantly
lower than controls in the second half of the study. Haematological
values gave no indication of a treatment-related effect.
Average absolute organ weights were generally comparable between
the control and treated groups, except for lung weights of the 25-ppm
female mice, which were higher than those of the controls, possibly
due to the increased incidence of interstitial pneumonia present in
that group. Relative average weights of adrenals, brain, heart,
kidneys, and lungs of the 25-ppm females and of the brain of the
25-ppm males were significantly higher than those of the controls,
possibly due to significantly-decreased body weights at the 25-ppm
dietary level.
Other than an increase in interstitial pneumonia in the 25-ppm
females and males, the non-neoplastic histopathologic observations
were those of spontaneous lesions of aging mice and were comparable
between dietary levels.
The neoplastic histopathologic observations were naturally-
occurring neoplasms of aging mice. There were no unusual or rare
tumours observed. On the basis of type, site, frequency distribution
by sex, and dietary level, there was no indication of a dose-related
effect. Moreover, there were no dose-related increases in animals with
tumours (either single or multiple), with total tumours, with total
benign tumours, with only single or multiple benign tumours, with at
least one benign tumour, or with both benign and malignant tumours.
There was an increase, interpreted as random, in total malignant
tumours found in female mice fed 1 and 5 ppm, but not 25 ppm,
methamidophos when compared to controls. There was also an increase in
the number of animals with only malignant tumours in female mice fed 5
and 25 ppm methamidophos. These increases in malignant tumours were
interpreted by the author as random, due to: 1) multiple tabulation of
metastatic tumours and malignant lymphomas in 1 animal; 2) the lack of
dose-relationship trends in animals with at least 1 malignant tumour
and animals with both benign and malignant tumours; and 3) there was
no dose-response relationship in the above-mentioned increases. In
summary, there was no evidence of induced oncogenicity for mice
consuming up to and including 25 ppm methamidophos in the diet for 106
weeks.
The no-effect level in this study was 5-ppm, equal to 0.67 mg/kg
b.w./day and 0.78 mg/kg b.w./day for males and females, respectively
(Hayes, 1984a).
Special studies on mutagenicity
See Table 1.
Acute toxicity
See table 2.
When administered to male rats, a combination of 53% cyfluthrin
and 47% methamidophos had a lesser toxic effect (LD50 = 26.0 mg/kg
b.w.) than expected (LD50=17.0 mg/kg b.w., assuming an additive
effect) (Heinmann, 1983),
Short-term studies
Dog
Groups of Beagle dogs (6/sex/dietary level) were fed diets
containing methamidophos (70% purity) at levels of 0, 2, 8, or 32 ppm
for 52 weeks.
Table 1. Special studies on mutagenicity with methamidophos
Test Test Range of doses Result Reference
organism substance or concentration
tested
S. typhimurium Methamidophos 0.1-10.0 mg/ No significant Machadao
TA1535, TA1537, technical plate differences of et al.,
TA1538, TA98, (% a.i. not revertants 1982
TAlO0 given) compared to
negative
control.*
Mouse:
Dominant lethal Methamidophos 0, 5, 50, 150 No significant Eisenlord,
assay - 12 technical ppm (not differences et al.,
males/group; (74.3% a.i.) corrected for % indicative of a 1984
8 week mating a.i.), 5-day dominant lethal
cycle, 2 females feeding effect between
to 1 male control and
treated groups.
Mouse in vivo:
Chromosomal Methamidophos 0.6, 2.0, 6.0, No significant Esber, 1983
aberrations technical 9.0, 12.0 mg/ differences in
in bone marrow (74.4% a.i.) kg b.w. by chromosomal
cells (4 M + gavage (as aberrations at 6,
4 F/dose level/ methamidophos) 24, or 48 hrs.
test time) between control and
treated groups.
Table 1. (Con't)
Test Test Range of doses Result Reference
organism substance or concentration
tested
DNA damage:
E. coli (K12) Methamidophos 0.625-10,000 No differences in Herbold,
p3478, DNA (71.2% a.i.) µg/plate the zones of 1983
repair - (not corrected growth inhibition
E. coli W3110 for % a.i.) indicative of DNA
DNA repair + damage.*
* Both with and without S-9 mix
Table 2. Acute toxicity of methamidophos in the rat
Test LD50* LC50*
Sex comp. Route (mg/kg b.w.) (mg/m3) Reference
M Methamidophos Oral 21.0 Duke et al., 1982
(73.1% a.i.)
F Methamidophos Oral 16.2 Duke et al., 1982
(73.1% a.i.)
M Methamidophos inhalation 377 Sangha, 1983
technical 1 hr. exp.
(75.1% a.i.)
F Methamidophos inhalation 241 Sangha, 1983
technical 1 hr. exp.
(75.1% a.i.)
M Methamidophos inhalation 63.2 Sangha, 1984
technical 4 hrs. exp.
(70.5% a.i.)
F Methamidophos inhalation 76.5 Sangha, 1984
technical 4 hrs. exp.
(70.5% a.i.)
* Not corrected for the % of a.i.
Cholinesterase (ChE) activity of plasma and erythrocytes was
determined on all dogs 3 times at weekly intervals prior to initiation
of the study. After initiation, determinations were made twice monthly
for 3 months, then every month and at termination of the study. Brain
cholinesterase activity was determined at termination.
Haematology, blood chemistry, and urinalysis were performed on
all dogs prior to initiation, monthly for 3 months, then every other
month and prior to termination of the study. Gross anatomical
examination was performed on all the dogs sacrificed at termination. A
number of tissues and organs from all animals were subjected to
histopathological examination.
No mortality occurred during the study. Daily observations for
toxicological effects did not reveal treatment-related effects. The
administration of the test compound did not affect feed comsumption or
body weight.
Plasma, erythrocyte, and brain cholinesterase activity of male
and female dogs in the 2-ppm group were not significantly (< 20%)
different from control values at each test period. At 8 and 32 ppm, a
strong dose-related inhibition in cholinesterase activity, that
remained constant throughout the study, was observed, except for the
plasma cholinesterase in the 8-ppm females.
Although statistically-significant differences in haematological,
clinical chemistry, and urinalysis values between control and treated
groups occurred sporadically, there was no evidence of treatment- or
dose-related trends.
Ophthalmological examination did not reveal any effect of
treatment. Absolute and relative organ weights were not affected by
the treatment. Gross necropsy and histopathological examination gave
no indication of a treatment-related effect.
The no-effect level in this study for ChE inhibition was 2 ppm,
equal to 0.06 mg/kg b.w./day for both male and female dogs (Hayes,
1984b).
Long-term studies
Rat
Groups of Fischer 344 rats (50/sex/dietary level, plus 10 reserve
rats and 10 replacement rats/sex/dietary level) were fed diets
containing methamidophos (70% purity) at levels of 0, 2, 6, 18, or
54 ppm for 2 years.
Animals were observed for toxicological effects, abnormalities,
masses (by palpation), and mortality. Feed consumption and body
weights were determined weekly.
Haematology and blood chemistry parameters (including
cholinesterase) were determined at initiation, 6, 12, 18, and 24
months. Reserve rats were used for testing at 6 and 12 months, and 10
randomly-selected animals from the experimental groups were used for
testing at 18 and 24 months. Also, plasma, erythrocyte, and brain
cholinesterase inhibition were determined on control and 2-ppm
replacement rats at 1 month. Due to a slight decrease in plasma
cholinesterase activity at 12 months in 2-ppm female reserve rats,
plasma and erythrocyte cholinesterase determinations were made on 10
male and 10 female rats from all dietary levels of chronic-study
animals at 12 and 15 months.
All moribund rats (which were sacrificed), all rats found dead
during the study, and all rats interim-sacrificed at 1 year and at
termination were subjected to gross necropsy. A number of tissues and
organs from all animals were subjected to histopathological
examination.
The animals of the 2- and 6-ppm groups did not differ from the
control animals in behaviour or appearance. Most animals of the 18-
and 54-ppm groups showed, after about 20 weeks from the start of the
study, loose stools, urine staining, rough coats, and skin lesions
(predominantly tail rash) as the most frequently-seen signs. The
number of masses, time of their first observation, and mortality were
not affected by treatment. Mortality in all groups was in the range
2-6% and 18-30% at 78 and 105 weeks, respectively. Feed consumption at
all dietary levels, including the controls, was erratic and no clear
trend was apparent. Decreased body weights were observed in male rats
at 18 and 54 ppm and in female rats at the 54-ppm dietary level.
Although some statistically-significant differences occurred in
haematology and blood chemistry values, there was no evidence of a
dose-related effect.
A strong, dose-related inhibition of plasma, erythrocyte, and
brain cholinesterase activities was observed at each test period in
the 6-, 18-, and 54-ppm groups, compared to the controls. The degree
of inhibition was comparable for both sexes and remained almost
constant throughout the study. The 2-ppm dietary level was the no-
effect level for cholinesterase activity.
Statistically-significant differences were observed in absolute
and relative organ weights for males at 18 and 54 ppm and for females
at 2, 6, 18, and 54 ppm, but they were within the normal range of
untreated mature Fischer 344 rats (historical data for the laboratory
were provided) and no dose-related effect was apparent.
Gross and histopathological findings were comparable between
control and treated groups. The type, site, time of onset, and
incidence of neoplastic changes gave no indication of an oncogenic
effect of methamidophos.
The no-effect level in this study was 2 ppm, based on ChE
inhibition (Hayes, 1984c).
Observations in man
"In workers engaged in the manufacture of methamidophos-
formulated products an occasional temporary inhibition to a minor
degree of cholinesterase activity was observed" (No determinations
presented) (Kollert, 1981).
There have been "no damaging effects on the well-being of the
people engaged with the formulation of methamidophos" (Miksche, 1981).
The clinical and electrophysiological findings in 10 patients
(6 males aged 14-28 years), who developed polyneuropathy after
exposure to the organo-phosphate (OP) insecticide "Tamaron(R)"
(marketed in Sri Lanka) were analysed. The illness is characterized by
2 phases, an initial phase of cholinergic crisis, which responds to
atropine or 2-PAM, and a delayed phase of paralysis of limbs, which
develops 2-4 weeks after poisoning. Paralysis first affects the distal
muscles of the lower limbs, and 2-4 days later the muscles of the hand
and forearm are affected. On examination the affected muscles show
weakness and wasting of varying severity. Four patients seen late in
the course of the disease also had evidence of pyramidal-tract
dysfunction. The late development of pyramidal-tract signs has also
been reported in poisoning due to another OP compound, tricresyl
phosphate.
Electromyography of the distal limb muscles showed evidence of
denervation to varying degrees. Motor nerve conduction was impaired in
the distal segments of the nerves, while conduction in the proximal
segments remained unaffected until the muscles were completely
denervated. Senesory conduction was unaffected.
An unusual feature of the polyneuropathy caused by Tamaron(R) was
the asymmetry of neural involvement. In all patients, the right hand
was affected more than the left hand, clinically as well as
electrophysiologically. The observation that in all the cases the
dominant limb was affected more severely raises the possibility that
factors such as excessive use and fatigueability of muscles has a
bearing on the pathogenesis of the neurophathy in OP poisoning
(Senanayake, 1981; Senayake, 1984).
Ten isolated cases of acute polyneuropathy seen over 3 years in
Sri Lanka were reported. All 10 developed after poisoning by
formulations of technical grade Tamaron(R), the main ingredient of
which is methamidophos.
A 22-year-old Sinhalese man was admitted to the hospital in an
unconscious state, having ingested about 80 ml of 60% (w/v)
Tamaron(R), in a suicide attempt, a few hours previously. The
diagnosis of organophosphate poisoning was confirmed clinically by the
presence of papillary constriction, muscular fasciculation, and
profuse sweating. The patient was treated with atropine (270 mg in the
first 24 hours), and with furosemide and penicillin. He remained
unconscious for 24 hours, and then recovered gradually over the next 3
days. He was discharged 5 days after admission, with no symptoms
except blurring of vision, which lasted for several days. Ten days
after discharge he had pain with "pins and needles" in the feet,
lasting for 3 days. This was followed by weakness of the feet and, a
day later, by weakness of the hands. At the height of weakness, he had
marked difficulty in walking and using his fingers.
On examination, 1 month after the onset of weakness, he was
unable to move his fingers against resistance and had bilateral
footdrop, with marked weakness of the dorsiflexor muscles and the
evertors of the feet. The muscle power of the knee flexors and the hip
flexors was slightly impaired, but the tone of the proximal muscles
was increased and of a spastic type. The tendon reflexes were
exaggerated, except that the ankle jerks were absent. The plantar
responses were flexor. Sensory testing, including 2-point
discrimination, revealed no abnormalities.
The results of the following investigations were within normal
limits: erythrocyte sedimentation rate; haemoglobin and blood picture;
white-cell count and differential-cell count; fasting blood sugar;
liver-function test; urinalysis for albumin, porphobilinogen, and
urinary sediment; and cerebrospinal-fluid test for sugar, proteins and
cells. Electromyography of the distal muscles of the limbs showed
changes due to denervation, but the motor-conduction velocity in the
fastest-conducting fibers of the peripheral nerves supplying those
muscles was relatively normal. During the 1-month stay in the
hospital, with daily physiotherapy, the patient had a considerable
improvement in muscle power.
The clinical and laboratory findings in the other 9 cases were
similar. Six had ingested the poison in an attempt at suicide. In the
other 3, the exposure had been accidental; one had ingested the poison
while attempting to aspirate the insecticide through a tube from the
spraying machine, another had spilled the poison on his body while
opening the bottle, and another had become intoxicated while spraying
the insecticide. There was good evidence that each of the 10 patients
had used Tamaron(R).
The patients had an acute cholinergic crisis soon after exposure
to the insecticide, with a polyneurophathy developing 2 to 3 weeks
later. Six patients who were followed for 8 weeks or more also had
evidence of pyramidal-tract involvement. Predominant motor paralysis
affecting the distal muscles of the limbs, minimal sensory
abnormalities, and calf pain preceding the onset of weakness are
typical of polyneuropathy caused by organophosphate compounds, as are
the electrophysiologic findings of partial denervation, with surviving
fibres conducting at normal rates and the pyramidal-tract signs noted
during the late stage of illness. All these features and the
circumstantial evidence strongly suggest that the neurologic
abnormalities in these patients were the result of delayed
neurotoxicity caused by an organophosphate contained in the
insecticide labeled "Tamaron(R)".
Polyneuropathy in human beings had not been thought to be
associated with this compound, as it has not produced neurologic
damage in animals. It had been assumed that methamidophos is free of
delayed neurotoxicity. However, the delayed neurotoxicity of some
organophosphate compounds can only be demonstrated experimentally by
using doses well above the short-term mean lethal dose, protecting the
animal from the cholinergic crisis with atropine and oxime
reactivators.
The Tamaron(R) sold in Sri Lanka is formulated locally; it
contains methamidophos as a 60% (w/v) solution in ethylene glycol
monomethyl ether, with an added dispersing agent (5%). The trace of
material remaining in the bottle from 1 of the above cases was
identified as a typical formulation of Tamaron(R), which, besides
methamidophos, normally contains small amounts of several related
compounds as impurities (principally an isomer and the N-methyl
analogue of methamidophos). Preliminary studies were performed on 2
samples of Tamaron(R) purchased in Sri Lanka, and compared with
results with a purer sample of methamidophos (95% pure). The
formulated material, which contained impurities similar to the ones in
the sample analysed after poisoning, was much more potent in acute
toxicity tests than an equivalent amount of methamidophos dissolved in
water. However, the high potency did not appear to be due to any of
the several impurities that have been identified. It is probably due
to alterations in the pharmacokinetics of methamidophos caused by the
solvent. The solvent may increase absorption or it may prolong the
circulation life of the agent. When either pure or impure
methamidophos was administered to hens at about twice the unprotected
median-lethal dose, 50% inhibition of the target protein involved in
initiation of neuropathy (commonly called neurotoxic esterase) was
found. Thus, although no neuropathic response has ever been observed
in hens given any formulation of methamidophos, the results of the
target-protein assays deliver a clear warning (Senanayake & Johnson,
1982).
COMMENTS
Pharmacokinetic and metabolism studies indicate that
methamidophos is rapidly absorbed, distributed, metabolized and
excreted, mainly via urine as acid metabolites and through the expired
air as CO2.
In addition to the rabbit study evaluated in 1982, a no-effect
level for embryotoxic/teratogenic effects was established in a rat
study. A no-effect level was also found from data for reproductive
effects.
Methamidophos was found to be non-mutagenic in bacterial and
in vivo assays. There were no indications of oncogenicity in a mouse
oncogenicity study or in a rat chronic toxicity/oncogenicity study. A
new 1-year dog study confirms the NOEL used for the derivation of the
1982 temporary ADI.
Methamidophos caused delayed polyneuropathy in man following
excessive exposure. However, maximum tolerated doses in hens failed to
cause delayed neuropathy.
The toxicology monograph prepared by the present meeting
supersedes the monograph prepared in 1976.
TOXICOLOGICAL EVALUATION
LEVEL CAUSING NO TOXICOLOGICAL EFFECT
Rat: 2 ppm in the diet, equal to 0.1 mg/kg b.w.
Dog: 2 ppm in the diet, equal to 0.06 mg/kg b.w.
ESTIMATE OF ACCEPTABLE DAILY INTAKE FOR MAN
0 - 0.0006 mg/kg b.w.
FURTHER WORK OR INFORMATION DESIRED
Observations in man
REFERENCES
Duke, C.E., Cisson, C.M., & Wong, Z.A. The efficacy of atropine
(1982) sulfate and pralidoxime chloride (2-PAM) as antidotes for
acute oral toxicity of Monitor(R) technical (SX-1244) in
rats. Unpublished report No. SOCAL 1678 from Environmental
Health and Toxicology, Chevron. Submitted to WHO by Bayer
F.R.G.
Eisenlord, G.H., Canver, J.H., & Wong, Z.A. Dominant lethal study of
(1984) methamidophos technical in mice. Unpublished report No SOCAL
1783 from Environmental Health and Toxicology, Chevron.
Submitted to WHO by Bayer F.R.G.
Esber, H.J. In vivo cytogenetics study in mice - methamidophos
(1983) technical (SX-1244). Unpublished report MRI-176-CCC-82-56
from EC&G/Mason Research Institute, Massachussets, USA.
Submitted to WHO by Bayer F.R.G.
Fakhr, I.M.I., Abdel-Hamid, F.M. & Afifi, L.M. In vivo metabolism of
(1982) 32P-Tamaron(R) in the rat. Isotope Rad. Res, 14, 49-55.
Gray, A.J., Thompson, C.M., & Fukuto, T.R. Distribution and excretion
(1982) of (14CH3S)-methamidophos after intravenous administration
of a toxic dose and the relationship with anticholinesterase
activity. Pest. Biochem. Physiol., 18, 28-37.
Hayes, R.H. Oncogenicity study of methamidophos technical (Monitor(R))
(1984a) in mice. Unpublished report No. 80-332-01 from Environmental
Health Research, Mobay Chemical Corporation. Submitted to
WHO by Bayer F.R.G.
Hayes, R.H. One-year feeding study of methamidophos (Monitor(R)) in
(1984b) dogs. Unpublished report No. 81-174-01 from Environmental
Health Research, Mobay Chemical Corporation. Submitted to
WHO by Bayer F.R.G.
Hayes, R.H. Chronic feeding/oncogenicity study of methamidophos
(1984c) (Monitor(R)) to rats. Unpublished report No. 81-271-01 from
Environmental Health Research, Mobay Chemical Corporation.
Submitted to WHO by Bayer F.R.G.
Heimann, K.G. FCR 1272 & SRA 5172 (c.n. cyfluthrin (proposed) and
(1983) methamidophos)/study for combination toxicity. Unpublished
report No. 12003 from Institute of Toxicology, Bayer AG.
Submitted to WHO by Bayer F.R.G.
Herbold, B. SRA 5172 (methamidophos)/pol test on E. coli to evaluate
(1983) for DNA damage. Unpublished report No. 12318 from Institute
of Toxicology, Bayer AG. Submitted to WHO by Bayer F.R.G.
Hixon, E.J. Embryotoxic and teratogenic effects of methamidophos
(1984a) (Monitor(R)) in rats. Unpublished report No. 82-611-01 from
Environmental Health Research, Mobay Chemical Corporation.
Submitted to WHO by Bayer F.R.G.
Hixon, E.J. Effects of methamidophos (Monitor(R)) on reproduction in
(1984b) rats. Unpublished report No. 82-671-01 from Environmental
Health Research, Mobay Chemical Corporation. Submitted to
WHO by Bayer F.R.G.
Kollert, W. BBA - requirement/effects on humans. Unpublished internal
(1981) letter, June 5, from Medical Department, Bayer AG. Submitted
to WHO by Bayer F.R.G.
Machadao, M.L., Parker, J.A., & Wong, Z.A. Salmonella/mammalian
(1982) microsome mutagenicity test (Ames test) with Monitor(R)
technical. Unpublished report SOCAL 1711 from Environmental
Health & Toxicology, Chevron. Submitted to WHO by Bayer
F.R.G.
Miksche, L. Effect on humans/internal experiences. Unpublished
(1981) internal letter, June 12, from Medical Department, Bayer AG.
Submitted to WHO by Bayer F.R.G.
Sangha, G.K. Acute inhalation toxicity study with technical
(1983) methamidophos (Monitor(R)) in rats. Unpublished report No.
80-041-12 from Environmental Health Research, Mobay Chemical
Corporation. Submitted to WHO by Bayer F.R.G.
Sangha, G.K. Acute inhalation toxicity study with technical
(1984) methamidophos (Monitor(R)) in rats. Unpublished report No.
80-041-02 from Environmental Health Research, Mobay Chemical
Corporation. Submitted to WHO by Bayer F.R.G.
Senanayake, N. Clinical and electrophysiological features of
(1981) polyneuropathy produced by a new organophosphate compound.
Proc. Sri Lanka Assoc. Advance. Sci., 37, 5-6.
Senanayake, N. Pesticide induced neuropathy in Sri Lanka: A clinical
(1984) epidemiological and electrophysiological study. Proc. Sri
Lanka Assoc. Advance. Sci., 40, 16-17.
Senanayake, N. & Johnson, M.K. Acute polyneuropathy after poisoning by
(1982) a new organophosphate insecticide. New Engl. J. Med.,
306, 115-157.
Thompson, C.M. & Fukuto, T.R. Mechanism of cholinesterase inhibition
(1982) by Methamidophos. J. Agr. Food Chem., 30, 282-284.
See Also:
Toxicological Abbreviations
Methamidophos (HSG 79, 1993)
Methamidophos (ICSC)
Methamidophos (JMPR Evaluations 2002 Part II Toxicological)
Methamidophos (Pesticide residues in food: 1976 evaluations)
Methamidophos (Pesticide residues in food: 1979 evaluations)
Methamidophos (Pesticide residues in food: 1981 evaluations)
Methamidophos (Pesticide residues in food: 1982 evaluations)
Methamidophos (Pesticide residues in food: 1984 evaluations)
Methamidophos (Pesticide residues in food: 1990 evaluations Toxicology)