MONOCROTOPHOS
First draft prepared by
A. Moretto
University of Padua, Padua, Italy
EXPLANATION
Monocrotophos was evaluated by the Joint Meeting in 1972, 1975,
and 1991 (Annex I, references 18, 24, 62). In 1991 the ADI was
changed to 0-0.00005 mg/kg bw, based on a NOAEL of 0.005 mg/kg
bw/day in a two-year study in rats. The Meeting identified (1)
genotoxicity studies, known to exist, with commercial and purified
monocrotophos, and (2) historical control data on the incidence of
brain malformations in rats at the laboratory that performed a
recent teratogenicity study in rats, as being studies which would
provide information valuable in the continued evaluation of the
compound. Information relevant to these issues (new teratogenicity
studies in rats and rabbits) was considered at the present Meeting.
In addition, a human volunteer study that was reviewed at the 1975
Joint Meeting was re-evaluated together with all other available
human data. The results of these studies are summarized in this
monograph addendum.
EVALUATION FOR ACCEPTABLE DAILY INTAKE
Biological data
Biochemical aspects
Absorption, distribution, excretion, and biotransformation
Rats
Wistar albino rats (7/sex) were administered a single oral dose
of 2 mg/kg bw (about 10% of the LD50) of 14C-monocrotophos
(radiochemical purity > 98%) orally via stomach tube. The compound
was dissolved in water and administered in a volume of 2 ml/kg bw.
Trembling, twitching, piloerection, and salivation were evident
0.5 to 3 hours after dosing. There was no mortality. Animals were
sacrificed 96 hours after dosing. Excreta and selected tissues were
analyzed for absorbed radioactivity. Detailed tissue and metabolite
analysis was performed in 5 animals per sex from which greater than
90% recovery of radioactivity was obtained. Excretion profiles did
not differ between males and females. During the first 12 hours,
urinary excretion of radiolabel averaged 77% while 5% was expired as
CO2 and another 1.5% in faeces. At sacrifice (96 hours) the
cumulative excreted label averaged 92% (83% in urine, 3% in faeces,
6% in expired air). Unchanged monocrotophos accounted for 26-33% of
the excreted radioactivity. The metabolite 3-hydroxy-N-methyl
butyramide, formed by hydrolysis of monocrotophos and subsequent
keto group reduction, accounted for 7% of recovered urinary
radioactivity. N-methyl acetoacetamide was also recovered in lesser
amounts. There was no significant accumulation of radioactivity in
tissues. Adipose tissue and liver contained 0.04-0.08 ppm of
monocrotophos equivalents, respectively. Orally administered
monocrotophos is thus readily and almost completely absorbed, and
rapidly excreted in urine either unchanged or as metabolites (Lee,
1987).
Goats
Two dairy goats received 3 consecutive daily doses of
14C-monocrotophos (radiochemical purity > 98.5%) in gelatin
capsules corresponding to 10 ppm in their daily feed ration. The
animals were sacrificed within 24 hours after the final dose.
The elimination of monocrotophos and its metabolites was rapid
via both urine and faeces which accounted for 76 and 56%, and 10 and
17% of the administered radioactivity, respectively. Expired air
was not collected. N-methylacetoacetamide and 3-hydroxy-N-methyl
butyramide, derived from the crotonamide moiety of the parent
compound were recovered in urine. Most of the radioactivity,
however, was present as polar water-soluble products stable to
enzyme, acid and base treatments. Residues in fat, muscle, liver
and kidney were low. Neither monocrotophos nor N-hydroxymethyl
monocrotophos was detected in excreta, milk, liver or kidney (Halls
et al., 1987).
Effects on enzymes and other biochemical parameters
Male albino rats (Wistar strain) were orally given
monocrotophos (98% pure) in distilled water as the vehicle at 9
mg/kg bw on the first day followed by 6 mg/kg bw daily for a period
of 16 days. A control group received distilled water. Biochemical
parameters were determined in subgroups sacrificed on the first day
1 hour after dosing and then 1, 3, 7, 11 and 16 days after dosing.
Brains were removed and the following brain areas dissected:
cerebral cortex, cerebellum, striatum, hippocampus, and medulla.
Activities of AChE and butyrylcholinesterase (BuChE) and ACh content
were determined.
The observed signs and symptoms were tremors, sweating (yellow
coloration of the hindquarters), urination, defecation, salivation,
chromodacryorrhea, uncoordinated movements and occasionally gasping.
The rats became tolerant to the acute affects since signs and
symptoms disappeared.
Inhibition of AChE and BuChE activities and elevation of ACh
content were progressive up to day 7 and were followed by a recovery
trend towards normalcy, correlating with the appearance and
disappearance of the cholinergic symptoms. The authors suggested the
possibility of de novo synthesis of cholinesterases resulting in
the development of behavioural tolerance (Swamy et al., 1992).
Toxicological studies
Acute toxicity studies
An acute dermal toxicity study of monocrotophos technical
(77.6% pure) was conducted under semi-occlusive conditions in rats:
the substance was dispersed on the skin and covered with a
gauze-lined dressing fastened to the trunk by an elastic adhesive
bandage. The LD50 was > 2000 mg/kg bw for males and about 2000
mg/kg bw for females. Signs included piloerection, abnormal body
position, exophthalmos, dyspnea, ataxia, body tremors,
chromodacryorrhea, convulsions, trismus, and reduced activity
(Hartmann, 1992).
Short-term toxicity studies
Rats
Monocrotophos technical (77.6% pure) was applied to shaven skin
of rats (Tif:RAI: 5/sex/dose). The compound was applied on gauze
patches under semi-occlusive dressing at dose levels of 0, 0.2, 1,
10 or 100 mg/kg bw/day for 6 hours, 5 days per week for 4 weeks.
Animals were observed daily for clinical signs. Body weight and
food consumption were determined weekly. At termination
haematological and blood chemistry parameters, plasma ChE, RBC AChE
and brain AChE were measured. Animals underwent autopsy with
macroscopic examination and recording on organ weights. Skin,
liver, kidneys, thymus, spleen, thyroid and parathyroids were
microscopically examined. There was no mortality. Clinical signs
consisted of piloerection, dyspnea, and hunched posture in 2 animals
given 10 mg/kg bw/day. In all the animals receiving 100 mg/kg
bw/day these signs were more prominent and additionally, respiratory
murmur, exophthalmos, recumbency, tremor, trismus, and clonic-tonic
cramps were observed. There were no signs of skin irritation.
Slight decrease in body weight and food consumption were noted in
females at 100 mg/kg bw/day during the first week of treatment.
Haematological and blood chemistry parameters were not affected.
Cholinesterase activities in plasma, red blood cells and brain were
decreased at 10 mg/kg bw/day by (males/females) 35/57, 48/19, 25/25%
respectively, and at 100 mg/kg by (males/females) 76/92, 65/21,
61/63%, respectively.
There were no treatment-related changes in organ weights upon
macroscopic examination or in histopathology. The NOAEL in this
study was 1 mg/kg bw/day based on clinical signs and reduction of
plasma ChE, RBC AChE and brain AChE (Hagemann et al., 1992).
Special studies on embryotoxicity and teratogenicity
Rats
Monocrotophos (technical, 77.6% pure) was dissolved in
distilled water and administered by gavage to rats (Sprague-Dawley
Crl: CD[SD]BR, 25 females per group) at doses of 0, 0.1, 0.3, 1 or 2
mg/kg bw/day (no adjustment for purity) once daily during days 6
through 15 of gestation. A control group received an equivalent
volume (10 ml/kg bw/day) of distilled water. The animals were
sacrificed on day 20 post-coitum and necropsied, the fetuses were
removed and examined for external, visceral, and skeletal changes.
The number of pregnant rats (number of rats with live fetuses) was
22(20), 20(20), 23(23), 22(20), 23(22) in control, 0.1, 0.3, 1, and
2 mg/kg bw/day groups, respectively.
There were no mortalities. Clinical signs consisted of
increased startle reflex and tremors in most animals at 2 mg/kg
bw/day. One female receiving 1 mg/kg bw/day also showed tremor.
Body-weight gains were reduced by about 40% at the high dose of 2
mg/kg bw/day during the entire treatment period and by about 30% at
1 mg/kg bw/day between days 6 and 9 post-coitum. Mean food
consumption was reduced by about 25% during the treatment period at
2 mg/kg bw/day. There were no treatment-related necropsy findings.
Pre-implantation loss, post-implantation loss, mean number of
fetuses per litter, mean fetal weights and sex ratios were not
affected. External, visceral, and skeletal fetal examination did
not reveal any treatment-related malformations or variations. In
particular, dilatation of lateral cerebral ventricle was observed in
1, 5, and 4 fetuses of the control, 0.1, and 2.0 mg/kg bw/day
groups, respectively.
There was no evidence of embryotoxicity, fetotoxicity, or
teratogenicity at doses up to and including 2 mg/kg bw/day. The
NOAEL for maternal toxicity was 0.3 mg/kg bw/day (Fuchs, 1992).
A new interpretation of the findings in the rat
embryotoxicity/teratogenicity study (Borders et al., 1983)
reviewed by the 1991 Meeting has been submitted for review. The
findings are described in Table 1.
The consultant pathologist thinks now that these findings are
artifacts for the following reasons: a) autolysis of tissues; b)
haemorrhage and encephalocele (separation between meninges and
brain) were due to trauma during processing and shrinkage of
tissues; c) misshaping of brain was a consequence of the above
(Christian, 1992). No historical data were available from the
laboratory where the study was performed.
Rabbits
Artificially inseminated rabbits (New Zeeland white,
Hra:(NZW)SPF, 20 per group) were given Azodrin (technical grade
monocrotophos, purity not reported) by stomach tube on days 6
through 18 of gestation. The dose levels of 0, 0.1, 1, 3, or 6
mg/kg bw/day were administered in aqueous solutions at a volume of 5
ml/kg bw/day; in each dosage group 16, 18, 17, 18, and 19 rabbits
were pregnant, respectively. The rabbits were observed daily and
sacrificed on day 29 of gestation. At termination, the number of
corpora lutea, uterus weight, and numbers of implantations, early
and late resorption, and live and dead fetuses were determined. The
fetuses were sexed, weighed and examined for external, soft tissue
and skeletal alterations.
Table 1. Results of embryotoxicity/teratogenicity study in rats (Borders et al., 1983)
Dose Number of Autolysis Encephalocele Subdural Malpositioning/
fetuses haemorrhage displacement of
the brain
control 1 marked no moderate yes
0.3 mg/kg bw 1 yes yes severe yes
1 yes yes moderate yes
1 marked yes marked yes
l mg/kg bw 1 marked no marked yes
1 moderate yes marked (compression of the
third ventricle)
2 mg/kg bw 1 moderate no marked yes
1 marked yes marked yes
Thirteen does at the high dose and one rabbit at 3 mg/kg bw/day
died. The first mortality occurred after 6 doses and the preceding
symptoms generally included excitatory/depressive signs, diarrhoea,
weight loss and decreased food consumption. Necropsy revealed
gastrointestinal ulceration and/or pulmonary edema. At 6 mg/kg
bw/day hyperpnea, decreased motor activity, salivation, rales,
tremors, impaired or lost righting reflex, constricted pupils and
ataxia were observed in most animals. At 3 mg/kg bw/day, diarrhoea
was observed in some animals. Does given 6 mg/kg bw/day did not
gain weight and had reduced food consumption (-15% as compared to
controls). A slight transient decrease of body-weight gains was
also noted at 3 mg/kg bw/day. Three does given 3 mg/kg bw/day
delivered prematurely. At 6 mg/kg bw/day average numbers of late
resorptions per litter were increased (1.2 ± 2.4 versus 0.1 ± 0.2 in
controls), mean live fetal body weights and maternal uterine weights
were reduced by about 5%. There were no significant differences
among the five groups for average number of corpora lutea,
implantations, litter size, dead fetuses, or early resorptions, and
for fetal sex ratios.
No malformations or reversible developmental changes recorded
at external, soft tissue or skeletal examination were attributed to
treatment. The litter incidence of fetal alterations did not
demonstrate dose-dependent significant differences. It is concluded
that adverse effects on embryo-fetal development occurred at the
dose of 6 mg/kg bw/day, which can be lethal to does. The compound
was not teratogenic when given at doses exceeding the maximum
tolerable level. The NOAEL for maternal toxicity was 1 mg/kg bw/day
(Dearlove, 1987).
Special studies on genotoxicity
The results of genotoxicity studies in addition to those
evaluated by the 1991 Meeting (Annex 1, reference 64) are reported
in Table 2.
Special studies on skin and eye irritation
A skin irritation test with monocrotophos technical was
performed in 3 New Zeeland white rabbits (Chbb:NZW). The undiluted
test material (500 mg) was placed on gauze patches moistened with
0.5% CMC in 0.1% aqueous polysorbate 80, and applied to a flank of
each animal. The patches were covered by an occlusive dressing
(aluminium foil) and kept in place for 4 hours. Skin reactions were
evaluated 1, 24, 48, and 72 hours and 7 days after removing the
gauze patches.
Table 2. Results of genotoxicity tests on monocrotophos
Test system Test object Concentration Purity Result Reference
Forward mutation test Steptomyces coelicolor spot test not given negative Carere et al., 1978
his A1
Gene mutation S. typhimurium TA100 (1) not given positive Shirasu et al., 1984
Gene mutation (2) S. typhimurium 1-1000 µg/plate 55% negative (3) Simmon et al., 1977
TA100, 1535, 1537, 1538 (Azodrin 5)
Gene mutation (2) S. typhimurium 1-20 mg/plate 55% positive (4) Sandhu et al., 1985
TA100, 98, 1535, 1537, 1538 (Azodrin 5)
Gene mutation (2) S. typhimurium up to 10 mg/plate 55% positive Waters et al., 1982
TA1535, 1537, 1538, 98, (Azodrin 5)
100
Gene mutation (2) E. coli WP2 1-10 000 µg/plate 55% negative (5) Simmon et al., 1977
(Azodrin 5)
Gene mutation (2) E. coli WP2 1-10 000 µg/plate 55% negative Waters et al., 1982
(Azodrin 5)
Gene mutation (2) E. coli WP2 not given 55% negative (6) Sandhu et al., 1985
(Azodrin 5)
Microbial growth S. typhimurium not given 55% positive Waters et al., 1982
inhibition (Azodrin 5) Sandhu et al., 1985
(DNA damage)
Mitotic recombination (2) S. cerevisiae D3 50 mg/ml 55% positive (7) Simmon et al., 1977
(Azodrin 5)
Table 2 (contd)
Test system Test object Concentration Purity Result Reference
Mitotic recombination (2) S. cerevisiae D3 50 mg/ml 55% positive (7) Sandhu et al., 1985
(Azodrin 5)
Mitotic recombination (2) S. cerevisiae D3 not given 55% positive Waters et al., 1982
(Azodrin 5)
Gene mutation S. cerevisiae D7 10-30 mg/ml 55% positive (7) Sandhu et al., 1985
(Azodrin 5)
Gene mutation S. cerevisiae D7 not given 55% positive Waters et al., 1982
(Azodrin 5)
Mitotic recombination S. cerevisiae D7 10-30 mg/ml 55% positive Sandhu et al., 1985
(Azodrin 5)
Gene conversion Aspergillus nidulans 0.25, 0.5 or 1.0 mM not given negative Vallini et al., 1983
Crossing over/ ("commercial positive (8)
Non-disjunction preparation") positive (8)
Chromosome aberrations Vicia faba root tip 1.1, 10, 1000 ppm 55% positive (9) Sandhu et al., 1985
(Azodrin 5)
"Wing mosaic" (10) D. melanogaster 0.5-10 x 10-5% not given positive Tripathy & Patnaik,
("farm 1992
grade")
Sex-linked recessive D. melanogaster 0.5-10 x 10-5% not given positive Tripathy & Patnaik,
lethal tests ("farm 1992
grade")
Recessive lethal D. melanogaster 2-3 ppm 55% negative Valencia, 1981
(sex linked) (Azodrin 5) Sandhu et al., 1985
Table 2 (contd)
Test system Test object Concentration Purity Result Reference
Recessive lethal D. melanogaster not given 55% negative Waters et al., 1982
(sex linked) (Azodrin 5)
Unscheduled DNA Human fibroblast blast cells 10-2-10-7 M 55% positive (weakly) Simmon et al., 1977
synthesis (2) WI-38 (Azodrin 5)
Unscheduled DNA Human fibroblast blast cells 270-2230 µg/ml 55% positive Sandhu et al., 1985
synthesis (2) WI-38 (Azodrin 5)
Unscheduled DNA Human fibroblast blast cells not given 55% positive Waters et al., 1982
synthesis (2) WI-38 (Azodrin 5)
Gene mutation (2) Mouse lymphoma cells 50-1200 µg/ml 55% positive Sandhu et al., 1985
L5178Y (Azodrin 5)
Gene mutation Mouse lymphoma cells not given 55% positive Waters et al., 1982
L5178Y (Azodrin 5)
Sister chromatid Chinese hamster ovary cells 125-2000 µg/ml 55% positive Waters et al., 1982
exchange (2) (Azodrin 5)
Sister chromatid Chinese hamster ovary cells not given 55% positive Sandhu et al., 1985
exchange (2) (Azodrin 5)
Chromosome aberration Chinese hamster ovary cell 50-800 µg/ml 78% ("tech") positive at Lin et al., 1987
in vitro (2) > 200 µg/ml
Chromosome aberration Chinese hamster ovary cell 9.8-78.1 µg/ml (11) 35.78% (12) negative Hertner, 1992b
in vitro (2)
Micronucleus in vivo Mouse (male and female 9 mg/kg bw orally (13) 35.78% (12) negative (14) Hertner, 1992a
Tif: MAGf) bone marrow
Table 2 (contd)
Test system Test object Concentration Purity Result Reference
Micronucleus in vivo Mouse bone marrow not given 55% negative Waters et al., 1982
(Azodrin 5)
Micronucleus in vivo Mouse bone marrow not given 55% negative Sandhu et al., 1985
(Azodrin 5)
Micronucleus in vivo Mouse (Swiss inbred male 5 x 1.25, 2,5 or not given negative (15) Bhunya & Behera,
and female) bone marrow 5.0 mg/kg i.p. ("tech") 1988
Chromosome aberration Mesocricetus auratus bone 10.5 mg/kg bw p.o. not given negative (16, 17) Duma et al., 1977
in vivo marrow
Chromosome aberration Mouse (Swiss inbred male 5 x 1.25, 2.5 or not given positive (18) Bhunya & Behera, 1988
in vivo and female) bone marrow 5.0 mg/kg i.p., ("tech")
s.c. or p.o.
Chromosome aberration Rat (male, Wistar) bone 0.5-2 mg/kg not given positive at Adhikeri & Grover,
in vivo marrow bw x 2 i.p. 2 mg/kg bw 1988
Dominant lethal Mouse (ICR/SIM) 15, 30, 60 ppm 55% negative Simmon et al., 1977
in vivo in the diet for (Azodrin 5)
7 weeks
Dominant lethal Mouse (ICR/SIM) 15, 30, 60 ppm 55% negative Waters et al., 1982
in vivo in the diet for (Azodrin 5)
7 days
Dominant lethal Mouse not given 55% negative Sandhu et al., 1985
in vivo (Azodrin 5)
Sperm shape anomaly (19) Mouse (Swiss inbred) 5 x 1.25, 2.5 not given positive Bhunya & Behera,
in vivo or 5.0 mg/kg i.p. ("tech") 1988
Table 2 (contd)
Test system Test object Concentration Purity Result Reference
Sperm shape anomaly (19) Mouse (Swiss inbred male) 5 x 0.18, 0.36, 98% ("tech") positive (15) Kumar & Janardhan,
in vivo 0.72 mg/kg p.o. 1988
(1) Revertant/mole ratio = 0.0064. Scored no. 33 among 44 pesticides (highest ratio = 93.67, lowest 0.00065);
experimental details not given.
(2) Both with and without metabolic activation.
(3) Positive control was 4-o-tolylazo-1-toluidine. Reported negative in the original SRI report,
positive by Waters et al., 1982, and Sandhu et al., 1985.
(4) Only with TA100.
(5) Positive control was AF-2 both with and without metabolic activation.
(6) Positive controls were AF-2 without metablic activation and 2-amino-anthracene with metabolic activation.
(7) Positive control was 2,2,3,4-diepoxybutane.
(8) No dose-response effect.
(9) No dose-response.
(10) Gene mutations, gene conversions or somatic recombinations.
(11) With metabolic activation, 18 or 24 hours incubation time, conc. of 19.5, 39 and 78 µg/ml, positive control:
mitomycin C; without metabolic activation, 3 hours incubation time followed either by 15 hours of 39 hours recovery:
conc. of 9.8, 19.5, and 39 µg/ml positive control: cyclophosphamide.
(12) Test conducted with 300 SCW formulation upon specific request on the Philippine government as reported by Ciba-Geigy.
(13) Mice were sacrificed at 16, 24 or 48 hours after dosing.
(14) Positive control: cyclophosphamide (64 mg/kg, route not identified).
(15) No positive control.
(16) A transient decrease of miototic index was reported.
(17) Positive control not included in study design.
(18) Negative chromosome aberration result after oral dose (no statistical significance).
(19) Test not generally accepted as indication of mutagenic potential.
Irritation consisted of grade 1 and 2 ( on a 0-4 point scale)
erythema and edema. The mean values of the recordings at 24, 48 and
72 hours were below 2 in each rabbit for any effect. Skin reactions
recovered by day 7. A transient body-weight loss was noted in 2/3
animals (Hagemann, 1992a).
An eye irritation test with monocrotophos technical (77.6%
pure) was performed in 3 New Zeeland white rabbits (Chbb:NZW).
Irritation reactions were observed 1, 24, 48, and 72 hours, and 7,
10, and 14 days after the application of 100 mg of undiluted test
material into the conjunctival sac. They consisted of grade 1 (0-2
point scale) iris involvement, grade 1 to 2 (0-3 point scale)
redness of conjunctiva, and grade 1 (0-4 point scale) chemosis. The
mean values of the recordings at 24, 48, and 72 hours were below one
for iris lesion, and below two for chemosis or redness in each
rabbit. They recovered completely by day 14. Transient body-weight
loss, miosis, muscular twitching, tremor, trismus, dyspnea, ataxia
and diarrhoea were also observed (Hagemann, 1992b).
Observations in humans
Human volunteer study
Monocrotophos (purity > 99%) was administered daily for 30
consecutive days at dose levels of 0, 3.6 or 5.9 µg/kg bw to 6 male
volunteers 18-26 years of age. Monocrotophos was dissolved to a
concentration of 2 µg/ml in 90% maize oil and 10% acetone and given
orally in gelatin capsules. The control group was given the
capsules containing the excipient only.
Plasma and erythrocyte cholinesterase activities were measured
on days 10, 7, 4, and 0 prior to the exposure phase, twice weekly
during the 30-day exposure and on days 2, 5, 7 and 12 after the
exposure phase. Haematology blood chemistry and urine tests were
performed ten days prior to the exposure phase, at termination of
the exposure phase, and 12 days thereafter.
Each person's cholinesterase enzyme activity was calculated as
a percentage of the mean of his own pretest values. Mean plasma ChE
decreased up to 78% and 72% of pretest values in the low and high-
dose group, respectively, during the treatment. Activities reached a
plateau in about 2 weeks.
Neither group showed a decline of the mean erythrocyte
cholinesterase activities. There were no treatment-related symptoms
and no adverse effects. In a preliminary study, 15 µg/kg bw/day was
administered to a group of 8 persons, which caused a decline of
plasma cholinesterase activity to about 65% of its initial level
after seven days of treatment. After a 3-day pause the same dose
administered again for 4 days resulted in a decline to 49% of the
pretest values. Six other test persons were given 3.6 µg/kg bw/day
for 21 days. The plasma cholinesterase activity fell in about seven
days to 85% of the initial value. Neither dose caused a decline of
erythrocyte cholinesterase activity or clinical signs or symptoms
that could be ascribed to monocrotophos (Verberk, 1972, 1977).
Field monitoring studies
Several studies on occupationally exposed workers have been
conducted (Shell, 1968; Gaeta et al., 1975; Blok et al., 1977;
Ullmann et al., 1979; Kummer & van Sittert, 1985; Castaneda et
al., 1989; van Sittert & Dumas, 1990). All studies were carried
out in countries with hot climates; workers did not usually wear
protective clothing. Plasma cholinesterase, whole blood
cholinesterase or RBC acetylcholinesterase were measured. In 3
cases (Kummer & van Sittert, 1985; Castaneda et al., 1989; van
Sittert & Dumas, 1990) urinary excretion of dimethylphosphates was
also measured. RBC AChE was never found inhibited: in some studies
whole blood ChE was found inhibited in some workers (Gaeta et al.,
1975; Ullmann et al., 1979; Kummer & van Sittert, 1985; Castaneda
et al., 1989; Van Sittert & Dumas, 1990). In most cases, plasma
ChE was inhibited. When urinary excretion of dimethylphosphates was
measured, it was extrapolated that absorption of 1.4 mg of
monocrotophos did not cause inhibition of ChE (Kummer & van Sittert,
1985) whereas absorption of about 20 mg of monocrotophos caused
inhibition of plasma ChE but not of RBC AChE (Castaneda et al.,
1989; Van Sittert & Dumas, 1990). The estimated dose was calculated
assuming that humans, as rats, excrete about 45% of the dose of
monocrotophos as urinary dimethylphosphates.
Acute intoxications
Several cases have been reported (Simson et al., 1969; Brown,
1973; Philips, 1978; EPA, 1980; Senanayake & Karalliede, 1987;
Skillman, 1987). An estimate of the ingested dose was never
available. None of the subjects surviving the acute phase has been
reported to develop delayed polyneuropathy. Two subjects developed
the intermediate syndrome which lasted for about two weeks
(Senanayake & Karalliede, 1987).
COMMENTS
Monocrotophos is rapidly excreted without evidence of
significant accumulation in the body.
In a new teratogenicity study in rats, no evidence of
teratogenicity or embryo/fetotoxicity was observed at any doses
tested (up to 2 mg/kg bw/day by gavage). Malformations of the brain
were not observed. The NOAEL for maternal toxicity was 0.3 mg/kg
bw/day.
Upon re-evaluation of the teratogenicity study in rats reviewed
by the 1991 Joint Meeting and of additional information provided,
the Meeting concluded that the previously described brain
malformations were artifacts due to incorrect tissue sampling and
handling. This conclusion is also supported by the lack of a clear
dose-response and by the new negative teratogenicity study.
In a teratogenicity study in rabbits, monocrotophos was not
teratogenic at doses up to 6 mg/kg bw/day, which was lethal to the
mothers. Embryo/fetotoxicity was observed at this dose. The NOAEL
for maternal toxicity was found to be 1 mg/kg bw/day.
Commercial formulations containing monocrotophos are genotoxic
in vitro. In addition, in vivo results suggest that these
formulations may cause chromosomal damage and sperm abnormalities in
rodents. High purity monocrotophos has not been adequately tested
for genotoxicity.
Carcinogenicity studies in mice and rats evaluated by the 1991
Joint Meeting were negative.
In a human volunteer (6 males) study, an oral dose of 0.0059
mg/kg bw/day for 30 days caused up to 28% plasma cholinesterase
depression without erythrocyte cholinesterase depression.
The Meeting allocated an ADI of 0-0.0006 mg/kg bw on the basis
of the 30-day human volunteer study with a NOAEL of 0.006 mg/kg
bw/day based on absence of erythrocyte cholinesterase inhibition,
using a 10-fold safety factor.
TOXICOLOGICAL EVALUATION
Level causing no toxicological effect
Mouse: < 1 ppm in the diet, equivalent to < 0.15 mg/kg
bw/day (two-year study) (1991 JMPR)
Rat: 0.1 ppm in the diet, equivalent to 0.005 mg/kg bw/day
(two-year study) (1991 JMPR)
Human: 0.006 mg/kg bw/day (30-day study)
Estimate of acceptable daily intake for humans
0-0.0006 mg/kg bw
Studies which will provide information valuable in the continued
evaluation of the compound
Further observations in humans.
Genotoxicity studies with high-purity monocrotophos.
REFERENCES
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systemic pesticides: in vivo chromosomal aberrations in bone
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Bhunya, S.P. & Behera, B.C. (1988) Mutagenicity assay of an
organophosphorus pesticide, monocrotophos in mammalian in vivo
test system. Cytologia, 53: 801-807.
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See Also:
Toxicological Abbreviations
Monocrotophos (HSG 80, 1993)
Monocrotophos (ICSC)
Monocrotophos (WHO Pesticide Residues Series 2)
Monocrotophos (WHO Pesticide Residues Series 5)
Monocrotophos (Pesticide residues in food: 1991 evaluations Part II Toxicology)
Monocrotophos (Pesticide residues in food: 1995 evaluations Part II Toxicological & Environmental)