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    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 g/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 g/plate      55%               negative (5)       Simmon et al., 1977
                                                                                     (Azodrin 5)

    Gene mutation (2)           E. coli WP2                   1-10 000 g/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 g/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 g/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 g/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 g/ml           78% ("tech")      positive at        Lin et al., 1987
    in vitro (2)                                                                                       > 200 g/ml

    Chromosome aberration       Chinese hamster ovary cell    9.8-78.1 g/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 g/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 g/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 g/kg bw to 6 male
    volunteers 18-26 years of age.  Monocrotophos was dissolved to a
    concentration of 2 g/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 g/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 g/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.

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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)