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    MONOCROTOPHOS

    First draft prepared by Dr. S. Caroldi,
    University of Padua,
    Padua, Italy

    EXPLANATION

         Monocrotophos was previously evaluated by the Joint Meeting in
    1972 (Annex I, 18) when an ADI of 0.0003 mg/kg bw was allocated. 
    Additional data submitted in 1975 (Annex I, 24) with respect to
    mutagenicity testing, biotransformation, and observations on man
    allowed the Meeting to increase the ADI to 0.0006 mg/kg bw.  Since
    then, additional data have been generated, which have been evaluated
    by the 1991 FAO/WHO Joint Meeting.

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    BIOLOGICAL DATA

    Biochemical aspects

    Biotransformation

         Metabolic pathways of monocrotophos in mammals are depicted in
    Fig.1.

    Effects on enzymes and other biochemical parameters

         Thirty male and female (60 controls) Wistar-derived rats
    (5 weeks old at the beginning of the study) were fed monocrotophos (E
    isomer 78.7%) at dietary levels of 0, 0.1, 0.25, 0.5, 2.0 or 8.0 ppm
    for 8 weeks. Ten rats/sex/dose level (20 controls) were sacrificed at
    the end of the 8 week treatment.  Ten rats/sex/dose level (20
    controls) were fed control diet for 5 additional weeks (follow-up
    group) and remaining 10 rats/sex/dose level (20 controls) were
    continued on the same treatment as during the first 8 weeks for 5
    additional weeks;  these rats were killed after 13 weeks.  No clinical
    symptoms or deaths due to treatment with mono-crotophos were observed. 
    Trivial reduction of body weight occurred at 8 ppm in both sexes.  A
    dose-related decrease of plasma, erythrocyte and brain cholinesterase
    activities was measured at all dose levels. Biologically significant
    inhibition of brain cholinesterase activity was observed at 2.0 and
    8.0 ppm monocrotophos.  The level of inhibition was similar in both
    sexes and after 8 or 13 weeks of treatment.  Almost complete recovery
    of both brain and erythrocyte cholinesterase activities, from the
    biological point of view, was detected 5 weeks after the end of
    treatment with the test substance.  No obvious signs of cumulative
    toxicity occurred nor that the observed changes were irreversible
    (Hend & Brown 1981).

    Toxicological studies

    Long-term carcinogenicity studies

    Mice

         Male and female CD mice (5 weeks old at the beginning of the
    study) were offered monocrotophos (E isomer 78.7%) at concentrations
    of 1, 2, 5 or 10 ppm in powdered diet for either 55 (12
    animals/sex/dose), 78 (15 animals/sex/dose) or 104 weeks (50 animals/
    sex/dose).  Control animals were 24, 30 and 100 for the 55, 78 and 104
    week sections, respectively.  The content of trimethyl phosphate was
    below 0.5% and the content of the Z-isomer of monocrotophos was
    approximately 1.5%.  Monocrotophos was incorporated in a nutritionally
    adequate diet; as significant decay was observed at room temperature
    but not at -4 C, diets were prepared and stored at -4 C until used.

    FIGURE 1

    No food was allowed to remain in food hopper for more than 4 days. 
    The actual content of monocrotophos in the diets was checked several
    times throughout the duration of the study and it was always shown to
    be within  10 % of nominal.  The mice were observed daily for general
    health and appearance, body weights and food intake were measured
    weekly.  Every three months groups of 10 mice/sex from the 0 and 10
    ppm dose levels underwent ophthalmoscopic examination. At the
    scheduled times animals were killed and blood samples were taken for
    haematological examinations and cholinesterase  activity
    determinations.  Full necropsies were performed on all animals, major
    organs were weighed and tissues were examined histologically from all
    animals in the 104 week section of the study and from mice fed 0, 5
    and 10 ppm monocrotophos in the 55 and 78 week sections.  Body weight
    and food intake were not affected by treatment with monocrotophos.
    Convulsions were observed in animals in all groups including controls. 
    The overall incidence of convulsions was increased in males from the
    2 ppm dose level and in females from the 1 ppm dose level.  No ocular
    abnormalities related to monocrotophos feeding were detected.  No
    dose-related, biologically significant differences in hematological
    tests were observed.  Mean plasma, erythrocyte and brain
    cholinesterase activities were significantly depressed in all
    treatment groups at all times sampled.  Inhibition was dose-related,
    consistent throughout the duration of the study and no differences
    between sexes were apparent.  In brain after 104 weeks of treatment,
    inhibition was approximately 20%, 30%, 50% and 65% at 1, 2, 5 and 10
    ppm, respectively.  At the end of the study the mortality rate was
    60%,  56%,  60%, 62%, 62% in males and 51%, 50%, 58%, 46% and 54% in
    females at 0, 1, 2, 5, 10 ppm, respectively.  Pathology did not show
    specific lesions attributable to treatment.  Increased incidence of
    pulmonary neoplasms was found in males after 18 months of treatment at
    5 and 10 ppm but this observation was not confirmed at the end of the
    study.  There was no evidence of a treatment-related oncogenic effect
    of monocrotophos up to 10 ppm, the NOAEL for cholinesterase inhibition
    is below 1 ppm (Robinson & Brown 1982).

    Rats

         Male and female Wistar-derived rats (5 weeks old study) were
    offered monocrotophos (E isomer 78.7%) at concentrations of 0.01,
    0.03, 0.1, 1.0 or 10 ppm in powdered diet for either 6 months (8
    animals/sex/dose), 12 months (8 animals/sex/dose), 18 months (19
    animals/sex/dose) and 24 months (50 animals/sex/dose).  Control rats
    were 16, 16, 38 and 100 for the 6, 12, 18 and 24 month sections,
    respectively.  The preparation, storage and presentation of the diets
    were the same as reported in the previous long-term study in mice. 
    The actual content of monocrotophos in the diets was checked several
    times throughout the study and was always shown to be within  10 % of
    nominal.  The rats were observed twice daily (daily on week-ends) for
    general health and appearance throughout the duration of the study.

    Body weights and food intake were measured weekly.  Every three months
    groups of 10 rats/sex from the 0 and 10 ppm groups underwent
    ophthalmoscopic examination.  At 6, 12, 18 and 24 months blood samples
    were taken and urine collected for haematological and clinical
    chemistry examinations, cholinesterase activity determinations and
    urinalysis.  Full necropsies were performed on all animals, major
    organs were weighed and tissues was examined histologically.  Body
    weight was significantly reduced between 5% and 10% in males fed 10
    ppm monocrotophos.  This difference was more apparent during the first
    year of the study and corresponds to lower food intake.  Body weight
    and food intake were not affected by treatment with monocrotophos in
    males up to 1 ppm nor in females at any dose levels.  General health
    and behaviour were not affected by monocrotophos.  No ocular
    abnormalities related  to monocrotophos feeding were detected.  Mean
    plasma, erythrocyte and brain  cholinesterase activities were
    significantly depressed in the 1 and 10 ppm dose groups.  Inhibition
    was dose related (approximately 30-40% and 70-80% at 1 and 10 ppm,
    respectively), consistent throughout the duration of the study and not
    differences between sexes were detectable.  The results of
    haematology, clinical chemistry and urinalysis yielded no consistent
    dose- nor time-related findings throughout the course of the study. 
    At the end of the study, the mortality rate was 24%, 20%, 28%, 30%,
    20%, 32% in males and 49%, 60%, 52%, 56%, 44% and 64% in females at 0,
    0.01, 0.03, 0.1, 1.0 and 10 ppm, respectively.  Organ weight
    variations among groups were of no toxicological relevance.  Pathology
    showed that the incidences of patchy alopecia and ulcerative
    dermatitis of the tail were slightly  higher in the 10 ppm groups of
    both sexes.  Pituitary neoplasm incidence was increased at the end of
    the study in female but not in male rats fed 10 ppm monocrotophos. 
    Because of the high incidence of this type of neoplasm (88% of females
    fed control diet for up to two years versus 96% of females fed 10 ppm
    monocrotophos), this observation was of no biological relevance.  The
    NOAEL for cholinesterase inhibition was 0.1 ppm and there were no
    specific macro- or microscopic lesions and there was no evidence of a
    treatment-related oncogenic effect up to 10 ppm (Robinson  et al.,
    1983).

    Reproduction studies

    Rats

         In a 1-litter 2-generation reproduction study, groups of 13 male
    and 26 female Wistar rats approximately 5 weeks old received
    monocrotophos (E isomer 78.7%) admixed in the diet at 0, 0.1, 1, 3 or
    10 ppm. The preparation, storage and presentation of the diets was the
    same as previously reported in long-term studies in mice and rats. 
    The actual content of monocrotophos in the diets was checked several
    times throughout the duration of the study and was always shown to be
    within  10 % of nominal.  Rats were maintained on their respective
    diets for at least 15 weeks,  then each male rat was allocated to two
    females of the same treatment group.  The F1 generation was culled

    to the same number of rats as in F0 and animals were exposed to the
    appropriate test diet for 18 weeks before being bred to produce F2
    generation. Body weights were recorded monthly for adult rats in the
    pre-mating phase and at 1,  4, 7, 14 and 21 days of age for F1 and
    F2 pups.  Mating performance, fertility, litter size and viability
    were recorded.  Pathology was performed on F0 and F1 adults, on
    selected F1 and F2 pups.  Sperm head counts were made on the testes
    of F0 and F1 adult rats.  Significantly lower body weights (6-9%
    reduction) were recorded in male but not in female rats fed 10 ppm
    monocrotophos for both F0 and F1 generations.  No treatment-related
    toxic effects were observed in the F0 and F1 adults during the
    pre-mating phase.  Faecal pellets produced by F0 and F1 rats fed 10
    ppm monocrotophos were smaller and darker than dose produced by
    controls.  There were no monocrotophos-related effects on sperm head
    counts of the F0 or F1 parent rats.  Mating performance, fertility
    index and gestation index were not different among F0 groups.  At 10
    ppm the F1 male mating index was lower and fewer litters were
    produced compared to controls.  The gestation lengths of F0 and F1
    females at 10 ppm dose level were significantly greater than those of
    controls. Mean litter size, viability index and lactation index were
    significantly reduced at 10 ppm for both F1 and F2 generations. 
    Viability index in the F2 generation was reduced also at 3 ppm. Mean
    pup weights were lower at 10 ppm for both F1 and F2 generations and
    at 3 ppm for the F2 generation.  There were three total litter losses
    at 10 ppm of the F1 and F2 generations and one litter loss of the
    F2 generation at 3 ppm, probably due to lactation deficiency as
    suggested by poor mammary development observed in dams.  Higher kidney
    and liver weights were observed for F2 female weanlings at 3 and 10
    ppm.  These finding were not related to any histopathological
    abnormalities.  No pathological changes of any tissues (excluding poor
    mammary development mentioned above) could be related to monocrotophos
    exposure.  One ppm was the NOAEL in this reproduction study (Dix &
    Thorpe, 1981).

    Special studies on delayed neurotoxicity

    Hens

         Fourteen adult Warren Studdler laying hens were treated orally
    with monocrotophos 60% w/v in acetone on two separate occasions 3
    weeks apart.  Monocrotophos was administered in gelatin capsules to
    supply 6.7 mg/kg of monocrotophos (equivalent to LD50 in domestic
    fowl).  Hens were protected against cholinergic toxicity with atropine
    sulphate (17.4 mg/kg i.m.) and pralidoxime chloride (50 mg/kg i.m.). 
    Positive controls received tri-O-tolyl phosphate (0.5 ml/kg
    undiluted, p.o.), negative controls did not received any treatment. 
    Nine out of 14 birds died of acute cholinergic symptoms within 4 days
    of the first or second monocrotophos dose; the five animals which
    survived both monocrotophos doses did not develop clinical nor
    histopathological signs of delayed neurotoxicity.  Positive controls

    gave the expected positive clinical and histopathological responses
    (Owen  et al., 1978).

         Groups of 10 adult hens (COFAL/Marek) were dosed by gavage with
    technical monocrotophos (containing 77.4% of the active E-isomer of
    monocrot-ophos, 0.43% trimethyl phosphate) at concentrations of 0,
    0.03, 0.1, 0.3 mg/kg for 96 days.  A positive control group received
    tri-orthocresol phosphate (TOCP) at 7.5 mg/kg  p.o. Because of lack of
    neurotoxic symptoms both the highest monocrotophos dose and TOCP dose
    were increased on day 79 to 0.5 mg/kg and 10 mg/kg, respectively. 
    Monocrotophos was dissolved in acetone and pipetted into gelatin
    capsules half-filled with feed; the acetone was allowed to evaporate
    at room temperature.  Stability of the test compound under these
    conditions was confirmed by analytical tests.  Plasma cholinesterase
    activity was reduced in all groups, including the TOCP group.  This
    reduction was dose-related and at the highest dose level ranged
    between 11.8% after the first dose and 46.9% after the final dose.  No
    changes in erythrocyte cholinesterase activity and no clinical signs
    of the cholinergic type were observed.  Body weights and egg-laying
    performance were not consistently affected throughout the duration of
    the study.  Some of the hens dosed with TOCP showed clinical (3 out of
    10 birds) and histopathological (7 out of 10 birds) signs of delayed
    neuropathy after raising the TOCP dose to 10 mg/kg.  None of the
    monocrotophos-treated hens developed delayed neuropathy. 
    Mono-crotophos is devoid of neurotoxic potential under the conditions
    of the study.  However, the short-term study was performed at doses
    too low at which neither acute cholinergic nor delayed neurotoxic
    effects could have been detectable (Becci & Parent, 1981).

    Special studies on embryotoxicity and teratogenicity

    Rats

         Twenty-six female Charles River Crl:CD (SD) BR albino rats were
    treated with technical monocrotophos at concentrations of 0, 0.3, 1.0,
    or 2.0 mg/kg/day orally by gavage (5 ml/kg, dissolved in distilled
    water) on days 6 to 15 of gestation.  The test chemical was supplied
    by Shell Chemical Company which also performed characterization,
    stability and chemical analysis of dosage formulations.  The
    concentrations of all samples before and after dosing were within 
    10% of the nominal concentrations.  A single female rat dosed with 2.0
    mg/kg died on gestation day 15, it had a diffuse, red-black crusted
    exudate around both eyes and a thinned glandular stomach which lacked
    mucosal convolutions.  The remaining females survived up to the final
    sacrifice.  Mean body weights (from gestation day 12) and carcass
    weights were significantly reduced in animals dosed at 1.0 and 2.0
    mg/kg bw.  Carcass weights were also reduced at 0.3 mg/kg.  No 
    significant differences were noted for the gravid uterus weights. 
    Muscle tremors and/or twitchings, listlessness, salivation, urine

    soaked fur and crusty eyes were observed in females dosed with 2.0
    mg/kg, mainly within 4 hours of administration of the test substance. 
    Pathological examination at final sacrifice did not show abnormalities
    which could be related to monocrotophos administration.  There were no
    statistically significant differences noted in the mean numbers of
    corpora lutea, implantation sites, resorption sites, nor viable
    fetuses in treated animals.  Reproductive percentages calculated for
    the treated dams were comparable to those of the control group.  Mean
    body weight and crown-rump length data obtained for the 2.0 mg/kg
    fetuses were significantly lower than those of the control fetuses. 
    Mean percent of runt fetuses per litter was increased in 1.0 and 2.0
    mg/kg  groups.  The percentage of fetuses with non-ossified
    sternebra(e) was increased in litters of the 2.0 mg/kg group. The
    incidence (58.4%) was approximately doubled in comparison with control
    group and with the other groups at lower mono-crotophos dose levels
    but within the range of previous historical data (4.7% to 82.1%). 
    Malformed and/or misshapen brain (malformed brain with subdural
    haemorrhage/encephalocoele) was observed in 1, 3, 2 and 2 fetuses at
    0, 0.3, 1, 2 mg monocrotophos/kg, respectively.  This malformation is
    uncommon in Sprague-Dawley rats; it appeared to be a progression of
    the same type of lesion which differed only in the degree of severity. 
    These brain malformations may suggest a teratogenic effect of
    monocrotophos in rats (Borders  et al., 1983).


        Table 1.  Results of genotoxicity assays on monocrotophos

                                                                                                                                              

    Test system              Test object           Concentration of          Purity        Results            Reference
                                                   test substance
                                                                                                                                              

    In vitro

    Reversion assay (1)      S. typhimurium        0-10 000 g/plate         Not given     Positive with      Moriya et al. (1983)
                             TA98, TA100,          dissolved in DMSO                       TA100 and
                             TA1535, TA1537,                                               WP2hcr (2)
                             TA1538
                             E. coli WP2hcr

    Reversion assay (1)      S. typhimurium        10-8000 g/0.1 ml         78.4%         Slight positive    Hool & Arni (1986)
                             TA98, TA100,          dissolved in acetone                    with TA100
                             TA102, TA1535,                                                (3)
                             TA1538

    L5178Y Tk +/-            Mouse lymphoma        50-1200 g/ml             58.4%         Positive           Jotz et al. (1980)
    mutation assay (1)       cells                 dissolved in DMSO                       (4)

    Sister chromatid         Human lymphoid        0-2 g/ml in absolute     Not given     Positive           Sobti et al. (1982)
    exchange assay           cells (LAZ-007)       ethyl alcohol                           (5)

    Sister chromatid         Human lymphocytes     0.1-0.8 g/8 ml           36%           Positive           Rupa et al. (1988)
    exchange assay                                 culture x 24, 48,                       (6)
                                                   72 hr dissolved
                                                   in DMSO

    Sister chromatid         Chinese hamster       CHO: 25-400 g/ml         78%           Positive           Wang et al. (1987)
    exchange assay (1)       ovary cells,          RTE: 12.5-100 g/ml                     (7)
                             Rat tracheal          dissolved in DMSO
                             epithelial cells
                                                                                                                                              

    Table 1 (contd).

                                                                                                                                              

    Test system              Test object           Concentration of          Purity        Results            Reference
                                                   test substance
                                                                                                                                              

    Reverse mutation         Saccharomyces         0.1-3% dissolved in       58.4%         Positive           Mortelmans et al. (1980)
    mitotic recombination    cerevisiae D7         DMSO                                    (8)
    gene conversion (1)

    Chromosome               Human lymphocytes     0.01 g/ml x 24, 48,      36%           Positive           Rupa et al. (1988)
    aberrations                                    72 hr dissolved in                      (6)
                                                   DMSO

    Chromosome               Human lymphocytes     10-4 - 10-9 M x 50 h      69%           Positive           Vaidya et al. (1982)
    aberrations                                    in distilled water                      (9)

    Mitotic                  Saccharomyces         5%                        55%           Positive           Simmon et al. (1977)
    recombination (1)        cerevisiae D3                                                   (10)

    DNA-repair               Human fibroblast      0.0001-10 mM              55%           Positive           Simmon et al. (1977)
    (UDS) (1)                cells (WI-38)                                                 (11)

    In vivo

    Chromosome study         Chinese hamster       1.4, 2.8, 5.6 mg/kg       78.4%         Negative           Strasser & Arni (1986)
    (bone marrow)                                  in distilled water                      (11)
                                                   administered orally
                                                   twice 24 h apart

    Chromosome study         Swiss mouse           1, 1.5, 2 mg/kg           69%           Positive           Vaidya et al. (1982)
    (bone marrow)                                  administered i.p.                       (8)
                                                   twice 24 h apart
                                                   in distilled water
                                                                                                                                              

    Table 1 (contd).

                                                                                                                                              

    Test system              Test object           Concentration of          Purity        Results            Reference
                                                   test substance
                                                                                                                                              

    Nucleus anomaly test     Chinese hamster       1.4, 2.8, 5.6 mg/kg       78.4%         Negative           Strasser et al. (1986)
    (bone marrow)                                  in distilled water                      (12)
                                                   administered orally
                                                   twice 24 h apart

    Micronucleus test        Swiss mouse           2, 4, 8 mg/kg i.p.        Not given     Negative           Kirkhart et al. (1980)
    (bone marrow)                                  administered twice                      (13)
                                                   24 h apart

    Micronucleus test        Swiss mouse           1, 1.5, 2 mg/kg i.p.      69%           Positive           Vaidya et al. (1982)
    (bone marrow)                                  administered twice                      (8)
                                                   24 h apart

    Chromosome study         Rat                   0.5, 1, 2 mg/kg in        Not given     Equivocal          Adhikari & Grover (1988)
    (bone marrow)                                  DMSO administered                       (15)
                                                   i.p. twice 24 h
                                                   apart

    Dominant lethal          Mouse                 15, 30, 60 mg/kg of       55%           Negative           Simmon et al. (1977)
                                                   diet x 7 weeks                          (16)
                                                                                                                                              
    

    Special studies on genotoxicity

    (1)  Both with and without metabolic activation

    (2)  Part of a study in which 228 pesticides were tested for
         mutagenicity in bacterial reversion-assay systems

    (3)  The study was repeated three times at similar doses giving
         similar results.  Positive control without activation:
         Daunorubicin HCl, 5-10 g/0.1 ml; 4-nitroquinoline-N-oxide,
         0.125-0.250 g/0.1 ml; mitomycin-c, 0.5-1 g/0.1 ml; sodium
         azide, 2.5-5 g/0.1 ml; aminoacridine hydrochloride, 50-100
         g/0.1 ml gave expected positive responses. Positive control with
         activation: 2- aminoanthracene, 5-20 g/0.1 ml; cyclophosphamide,
         250 g/0.1 ml gave the expected positive responses.

    (4)  Positive control without activation: ethylmethane sulfonate, 500
         g/ml gave expected positive response.  Positive control with
         metabolic activation: 3-methylcholantrene, 5 g/ml gave expected
         positive response.  The test substance gave positive response  at
         200 g/ml and above and at 840 g/ml and above with and without
         metabolic activation, respectively.

    (5)  Monocrotophos was tested without metabolic activation.  A
         dose-related statistically significant increase of sister
         chromatid exchange frequency was observed.

    (6)  Positive control not run.

    (7)  Monochrotophos was positive for sister chromatid exchange
         inductions in both CHO and RTE.

    (8)  Positive control with and without metabolic activation:
         1,2,3,4-diepoxybutane, 0.013% gave expected positive response.
         Monochrotophos induced mitotic crossing-over, gene conversion,
         and reverse mutation, with and without metabolic activation.

    (9)  Positive control not run.

    (10) Positive control: 1,2,3,4,-diepoxybutane, 0.1% gave expected
         positive response.

    (11) Positive control without metabolic activation:
         4-nitroquinoline-N-oxide, 0.05 mM gave expected positive
         response. Positive control with metabolic activation:
         Dimethylnitrosoamine, 50 mM gave expected positive response.

    (12) Positive control: cyclophosphamide, 64 mg/kg x 2 gave expected
         positive response.

    (13) Positive control: cyclophosphamide, 128 mg/kg x 2 gave expected
         positive response.

    (14) Positive control: trimethylphosphate, 1 g/kg x 2 gave expected
         positive response.

    (15) Positive control: ethyl methane sulfonate, 62.5-250 mg/kg x 2
         gave  expected positive response.  Monochrotophos caused a
         dose-related  increase of the frequency of aberrant cells, but
         the increase was significant only for the highest dose.

    (16) Positive control: triethylenemelamine, 0.2 mg/kg i.p. gave
         expected positive response.

    COMMENTS

         In a 13-week study in rats at dietary concentrations of 0, 0.1,
    0.25, 0.5, 2, or 8 ppm, the NOAEL was 0.5 ppm, equivalent to 0.025
    mg/kg bw/day, based on brain acetylcholinesterase inhibition at 2 ppm.

         In a 2-year study in mice at dietary concentrations of 0, 1, 2,
    5 or 10 ppm a NOAEL could not be established because brain
    acetylcholinesterase inhibition was detected at the lowest dietary
    concentration (approximately 20% inhibition).  There was no evidence
    of a treatment-related carcinogenic effect.

         In a 2-year study in rats at dietary concentrations of 0, 0.01,
    0.03, 0.1, 1.0 or 10 ppm the NOAEL was 0.1 ppm, equivalent to 0.005
    mg/kg bw/day, based on brain acetylcholinesterase inhibition at the
    next higher dose.  Again, there was no evidence of carcinogenicity.

         Monocrotophos did not cause delayed neuropathy in hens.

         In a multigeneration reproduction study in rats at dietary
    concentrations of 0, 0.1, 1, 3, or 10 ppm, the NOAEL was 1 ppm,
    equivalent to 0.05 mg/kg bw/day, based on toxicity in pups seen in the
    F2 generation at 3 ppm.

         In a teratology study in rats at doses of 0, 0.3, 1 or 2 mg/kg
    bw/day, the NOAEL was 0.3 mg/kg bw/day for both maternal toxicity and
    teratogenicity.  There was a slightly increased incidence of malformed
    and/or misshapen brain at all dose levels (0.3 mg/kg bw/day included). 
    A dose-effect relationship for this uncommon malformation was lacking
    and historical control data were not available.

         Substantial variations in the purity of the test material used in
    the genetic toxicology studies hampered thorough evaluation for
    genotoxicity.  When purity was at the level of technical grade
    monocrotophos (78%) there were significant responses in tests for
    mutagenicity in bacteria and sister chromatid exchange in Chinese
    hamster ovary cells;  in vivo studies for clastogenic activity were
    negative.

         The Meeting concluded that the significance of the brain
    malformations observed in the teratology study in rats warranted
    clarification, as did the genotoxic potential of monocrotophos. 
    Accordingly, the Meeting recommended that monocrotophos be reviewed
    in 1994.

         An ADI was allocated on the basis of the 2-year study in rats
    using a 100-fold safety factor.

    TOXICOLOGICAL EVALUATION

    Level causing no toxicological effect

         Mouse:    < 1 ppm in the diet, equivalent to < 0.15 mg/kg
                   bw/day
         Rat:      0.1 ppm in the diet, equivalent to 0.005 mg/kg bw/day

    Estimate of acceptable daily intake for humans

         0-0.00005 mg/kg bw

    Studies which will provide information valuable in the
    continued evaluation of the compound

    1.   Genotoxicity studies, known to exist, with commercial and
         purified monocrotophos.

    2.   Historical control data on the incidence of brain malformations
         in rats at the relevant laboratory.

    REFERENCES

    Adhikari, N., Grover, I.S. (1988)  Genotoxic effects of some systemic
    pesticides:   in vivo chromosomal aberrations in bone marrow  cells
    in rats.   Environmental and Molecular Mutagenesis, 12: 235-242.

    Becci, P.J., Parent, R.A. (1981)   Neurotoxicity evaluation of Azodrin
    insecticide:  subchronic oral administration in hens. Unpublished
    Report 6535-II by Food and Drug Research Laboratories, Inc. Waverly,
    NY, USA. Submitted to WHO by CIBA-GEIGY Ltd, Basle, Switzerland.

    Borders, C.K., Salamon, C.M., Mayhew, D.A. (1983)  Technical Azodrin
    (SD 9129) teratology study in SD CD rats.  Unpublished Report 450-1248
    by Toxi-Genics Inc. USA. Submitted to WHO by CIBA-GEIGY Ltd, Basle,
    Switzerland.

    Dix, K.M. & Thorpe, E. (1981)  A reproduction study in rats fed
    Azodrin.  Unpublished Report 1752 by Sittingbourne Research Centre,
    England.  Submitted to WHO by CIBA-GEIGY Ltd, Basle, Switzerland.

    Hend, R.W  & Brown, V.K.H. (1981)  A reversibility study of
    cholinesterase activity in rats fed Azodrin for 8 weeks. Unpublished
    Report 1720 by Sittingbourne Research Centre, Shell Toxicology
    Laboratory (Tunstall), Sittingbourne, England. Submitted to WHO by
    CIBA-GEIGY Ltd, Basle, Switzerland.

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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: 1993 evaluations Part II Toxicology)
       Monocrotophos (Pesticide residues in food: 1995 evaluations Part II Toxicological & Environmental)