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    DICHLORVOS

    First draft prepared by
    A. Moretto
    University of Padua, Padua, Italy

    EXPLANATION

            Dichlorvos was previously evaluated by the Joint Meeting in
    1965, 1966, 1967, 1970 and 1977 (Annex I, references 3, 6, 8, 14,
    28).  An ADI of 0-0.004 mg/kg bw was allocated in 1966 and was
    maintained at subsequent Meetings.  The compound was re-evaluated by
    the present Meeting on the basis of the CCPR periodic review
    programme.  Since 1977 many reviews on the toxicological aspects of
    dichlorvos have been published.  The most relevant are the IARC
    Monographs on the Evaluation of the Carcinogenic Risk of Chemicals
    to Humans (IARC, 1979, 1991) and the IPCS Environmental Health
    Criteria 79 on Dichlorvos (WHO, 1989).  This monograph summarizes
    new or not previously reviewed data as well as relevant data from
    previous monographs and monograph addenda on dichlorvos.

    BIOCHEMICAL ASPECTS

            Many studies have been performed on the biochemical aspects of
    dichlorvos and have been summarized by WHO (1989).  Summaries of the
    most relevant data are given here.

    Absorption, distribution and elimination

            Dichlorvos is readily absorbed via all routes of exposure.  In
    rats orally dosed with 32P-dichlorvos, 60-70% of administered
    radioactivity was recovered in the urine and about 10% in the faeces
    within 6 days after dosing.  Radioactivity in bones slowly increased
    with time because of the incorporation of 32P into the normal
    phosphate pool.  After the oral administration of
    methyl-14C-dichlorvos to rats and mice, the excretion of
    radioactivity was rapid.  The major routes of elimination after 4
    days were urine (approximately 60%) followed by expired air
    (approximately 16%).  Carcass contained about 5% of the administered
    radioactivity 4 days after dosing.  When vinyl-14C-dichlorvos was
    used, less radioactivity was recovered in urine (10-30%) while
    higher levels were recovered in liver, skin and carcass.  In
    carcass, levels of radioactivity were 14-34% after 1-4 days from
    dosing mice, rats and Syrian hamsters.  The higher levels found in
    carcass indicate that the vinyl moiety enters the 2-carbon metabolic
    pool.  Similar results were obtained using the inhalation and
    parenteral routes.  After a single i.p. dose (10 mg/kg bw), the
    dichlorvos concentration in brain peaked after 1 min. and than
    disappeared with a half-life of less than 1 min (Nordgren  et al.,
    1978).  Experiments with pregnant rabbits and pigs showed that
    dichlorvos readily crosses the placenta (WHO, 1989).

    Biotransformation

            A scheme of the metabolites of dichlorvos in mammals is given
    in Figure 1.  Two main pathways are responsible for the rapid
    degradation of dichlorvos.  Desmethyl-dichlorvos is produced by a
    glutathione-dependent enzymatic system while dimethylphosphate and
    dichloroacetaldehyde are the hydrolysis products of an A-esterase
    which is present mainly in plasma and liver (Reiner  et al., 1975). 
    This appears to be the dominant pathway.  The rate of hydrolysis of
    dichlorvos by rat plasma has been determined to be 12 mol/hour/ml
    at 37 C (Reiner  et al., 1980).  The metabolism of dichlorvos is
    rapid and similar in the various species, including humans. 
    Differences between species are related to the rate of metabolite
    formation rather than to the nature of the metabolites.  The
    metabolism of dichlorvos is so rapid that the half-life in blood
    could not be determined in experimental animals, and it appears to
    be shorter than 15 minutes.  No evidence of the accumulation of
    dichlorvos or potentially toxic metabolites has been found (WHO,
    1989).

    FIGURE 01

    Effects on enzymes and other biochemical parameters

             In vitro studies showed that rodent plasma ChE is more
    sensitive than erythrocyte and brain ChE to inhibition by
    dichlorvos.  Calculated I50s (concentrations which inhibit 50% of
    enzyme activity) at 37 C, pH 7.4-7.6, were 10-8 and 10-7 mol/l,
    respectively, for an incubation time of 20 minutes (Asperen &
    Dekhuijzen, 1958; Skrinjaric-Spoljar  et al., 1973; Lotti &
    Johnson, 1978).  The rate of phosphorylation of rat brain ChE was
    calculated to be 1.5 x 105 mol/l/min at 37 C, pH 7.4-7.6
    (Skrinjaric-Spoljar  et al., 1973).  Half-life of  in vitro
    reactivation (at 37 C, pH 7.4-7.6) was found to be about 100
    minutes; that of aging was found to be about 400 min.  This means
    that inhibited AChE almost completely reactivates within a few
    hours, leaving a small fraction (20% or less) irreversibly inhibited
    (i.e. aged) (Skrinjaric-Spoljar  et al., 1973).

    TOXICOLOGICAL STUDIES

    Acute toxicity studies

            The results of acute toxicity tests of dichlorvos administered
    by various routes to different animal species are summarized in
    Tables 1 and 2.  Typical cholinergic signs are observed.  WHO has
    classified dichlorvos as highly hazardous (WHO, 1992).

    Short-term toxicity studies

    Mice

            In a range-finding study, groups of 10 B6C3F1 mice/sex were
    administered by corn oil gavage 0, 5, 10, 20, 40, 80, or 160 mg
    dichlorvos/kg bw/day, 5 days per week for 13 weeks.  Animals were
    observed twice daily for clinical signs and body weight was recorded
    weekly.  Necropsy was performed on all animals.  Oesophagus and
    gastrointestinal tract of all animals dying after day 46 were
    examined histologically.  All vehicle controls and all animals in
    the highest dose group with survivors were examined histologically. 
    All mice at 160 mg/kg bw/day and 5 male mice at 80 mg/kg bw/day died
    before the end of the study.  Final mean body weights in all treated
    groups were comparable to controls.  No gross or microscopic
    pathologic effects were observed (Chan, 1989).

    Rats

            In a range-finding study, groups of 10 male and 10 female
    F344/N rats were administered by corn oil gavage 0, 2, 4, 8, 16, 32,
    or 64 mg dichlorvos/kg bw/day, 5 days per week for 13 weeks. 
    Animals were observed twice daily for clinical sign and body weights
    were recorded weekly.  Necropsy was performed on all animals. 
    Oesophagus and gastrointestinal tract of all animals dying after day
    46 were examined histologically.  All vehicle controls and all
    animals in the highest dose group with survivors were examined
    histologically.  All rats at 32 and 64 mg/kg bw/day and 1 male and 4
    females at 16 mg/kg bw/day died before the end of the study.  Final
    mean body weights of all dose groups were comparable to vehicle
    controls.  No gross or microscopic pathologic effects were observed
    (Chan, 1989).

    Table 1.  Acute toxicity of dichlorvos (WHO, 1989)
                                                        
    Species             Route             LD50 (mg/kg bw)
                                                        

    Mouse               oral                    68-275
                        i.p.                     28-41
                        i.v.                      8-10
                        s.c.                     13-33

    Rat                 oral                    30-110
                        dermal (24 h)           75-107
                        i.p.                        18
                        s.c.                        72

    Guinea-pig          s.c.                        28

    Hamster             i.p.                        30

    Rabbit              oral                     13-23
                        dermal                     205
    Cat                 oral                        28

    Dog                 oral                   100-316

    Chicken             oral                        15

    Swine               oral                       157

                                                        

    Table 2.  Acute inhalation toxicity of dichlorvos (WHO, 1989)
                                                             
    Species    Mode of exposure     Time of exposure      LC50
                                         (hours)        (g/l)
                                                             

    Mouse      whole body                  4                13
               head only                   4             > 218

    Rat        whole body                  4                15
               whole body                  1               140
               head only                   4               340
               head only                   1               455
               head only                   4             > 198

                                                             

    Dogs

            Groups of 3 male and 3 female beagle dogs received 0, 2.3, 6.9,
    12 or 23 mg dichlorvos/dog (93% in corn oil by gelatin capsule)
    daily, for 90 days.  The mean doses per group were equivalent to
    0.3, 1, 1.5 or 3 mg/kg bw/day.  No effects were observed on
    mortality, growth, haematology, liver and kidney function, organ
    weights, or at gross and histopathological examination.  In the two
    highest dose groups, the dogs showed excitement, increased activity
    and aggression.  Plasma and erythrocyte ChE activities, measured
    initially and at intervals of approximately 2 weeks, were normal in
    the lowest dose group (0.3 mg/kg bw/day) but inhibited in the other
    dose groups (up to about 60% in the highest dose group).  Inhibition
    was lower from day 70 onwards.  Brain ChE activity at termination
    was decreased (to 33%of control activity) only in the highest dose
    group.  The NOAEL in this study was 1.5 mg/kg bw/day based on
    reduction in brain ChE activity at termination.  However, taking
    into account the behavioural changes, a more conservative NOAEL can
    be considered to be 1 mg/kg bw/day (Hine, 1962).

    Pigs

            Young swine (35 days old) were fed a PVC-resin formulation of
    dichlorvos (10%) in dosages equivalent to 1, 4, or 16 mg
    dichlorvos/kg bw/day (divided over 2 daily doses) for 30 days.  No
    effects were found on body-weight gain, haematology, or clinical
    chemistry when compared with control animals fed a blank PVC
    formulation.  Plasma and erythrocyte ChE activities were
    significantly inhibited in the 4 mg/kg bw/day group (37 and 34% of
    controls, respectively) and in the 16 mg/kg bw/day group (33 and 21%
    of controls, respectively).  The NOAEL in this study was 1 mg/kg
    bw/day based on inhibition of erythrocyte ChE activity (Stanton  et
     al., 1979).

    Monkeys

            Rhesus monkeys (4/sex) were continuously exposed to dichlorvos
    vapour at an average actual concentration of 0.05 mg/m3 for 3
    months.  The control group consisted of 4 males and 1 female.  No
    adverse effects were observed in appearance, behaviour, or
    haematological and clinical chemical determinations.  Plasma ChE
    activity was slightly reduced (up to 28% inhibition), while
    erythrocyte ChE activity inhibition was 36%.  No changes in nerve
    maximum conduction velocities or muscular evoked action potentials
    were induced by exposure to dichlorvos (Coulston & Griffin, 1977).

    Long-term toxicity/carcinogenicity studies

    Mice

            Groups of 100 male and 100 female C57BI/6/Bln mice (5-6 weeks
    old) received by gavage 0.2 mg dichlorvos per mouse (97% in 0.2 ml
    water), freshly prepared, either twice or 3 times per week for 50
    weeks.  Control groups received by gavage either 0.2 ml water, 3
    times per week (about 50 males and 50 females), or no treatment (35
    males and 35 females).  Surviving animals were sacrificed after 110
    weeks.  This strain of mice is known for the spontaneous occurrence
    of mixed lymphomas (reticulocell sarcoma type B).

            From the age of 12 months onwards, some animals in all groups
    developed interstitial pneumonia.  The incidence of mixed lymphomas
    was decreased in both test groups (26-60% in control groups, 23-30%
    in treated groups).  An increased incidence of focal hyperplasia
    (transitional cell hyperplasia) of the urinary bladder was found in
    both dichlorvos groups (0-8% in control groups, 5-10% in treated
    groups).  The authors concluded that no neoplastic lesions were
    found which could be attributed to the treatment of the animals with
    dichlorvos (Horn  et al., 1987).

            Dichlorvos was not co-carcinogenic in C57BI/6/Bln mice when
    administered by gavage three times/week at 0.2 mg/animal to mice
    subcutaneously injected with 50 g N-nitrosodiethylamine per animal
    weekly for 50 weeks followed by an observation period of up to 110
    weeks (Horn  et al., 1990).

            Two groups of 50 male and 50 female B6C3F1 mice were fed
    1000 or 2000 ppm dichlorvos (purity > 94%) in corn oil in the diet
    for 2 weeks.  Due to severe signs of intoxication, doses were
    lowered to 300 and 600 ppm for the following 78 weeks.  Samples of
    the diets analyzed during the study showed that time-weighted
    average concentrations were 318 and 635 ppm.  Matched controls
    consisted of 10 mice of each sex; the pooled controls from
    simultaneous studies with other compounds consisted of 100 male and
    80 female mice.  All surviving mice were killed at 92-94 weeks. 
    Animals were observed twice daily for clinical signs.

            Alopecia and rough hair coats were noted in many treated
    animals, particularly in the male groups, beginning at week 20 and
    persisting throughout the study.  The average body weights of the
    high-dose mice of both sexes were slightly decreased compared with
    controls.  The low-dose female group showed 74% survival at 90 weeks
    compared to 84% and 90% in high-dose and control groups,
    respectively.  There was no significant increase in the incidence of
    tumours attributable to dichlorvos in either sex.

            Two squamous-cell carcinomas of the oesophagus (one in a
    low-dose male and one in a high-dose female), 1 papilloma of the
    oesophagus in a high-dose female and 3 cases of focal hyperplasia of
    the oesophageal epithelium in low-dose males were recorded in the
    treated mice.  The significance of the findings in the treated mice
    was considered uncertain because of insufficient information
    concerning the spontaneous incidence of these lesions and lack of
    statistical significance within the experiment.  Dichlorvos (up to
    635 ppm in the diet, equivalent to 95 mg/kg bw/day) was not
    demonstrated to be carcinogenic in this study (NCI, 1977;
    Weisburger, 1982).

            Studies in B6C3F1 mice given 0, 400 or 800 mg/litre
    dichlorvos in drinking-water for two years and in CFE rats exposed
    to 0, 0.05, 0.48, or 4.7 mg/m3 of dichlorvos 23 hours/day for 2
    years were summarized in WHO (1989).  There was no evidence of
    carcinogenic effects in these studies (Blair  et al., 1976;
    Konihishi  et al., 1981).

            Groups of 50 B6C3F1 mice were given dichlorvos (99% purity)
    by corn oil gavage at doses of 0, 10 or 20 (males) or 0, 20 or 40
    (females) mg/kg bw/day daily, 5 days per week, for 103 weeks.  The
    dose volume of the corn oil was 10 ml/kg bw/day.  Body weights were
    recorded once weekly for the first 12 weeks and then monthly. 
    Animals were observed twice per day for clinical signs.  Necropsy
    and histological examinations were performed on all moribund animals
    or at the end of the study.

            Body-weight gain and survival did not significantly differ
    between treated and control groups.  No compound-related clinical
    signs were observed.  Blood cholinesterase activity was not
    determined during the study.  However, a separate study showed
    inhibition of plasma ChE activity by 60-90% in all dose groups while
    erythrocyte ChE activity was normal (see "Special studies on
    Cholinesterase activity" for detailed description and comments).

            The incidences of forestomach squamous cell papillomas were
    1/50, 1/50 and 5/50 in control, low and high-dose males respectively
    and 5/49, 6/49 and 18/50 in control, low and high-dose females,
    respectively.  The positive trend was statistically significant in
    both sexes while by pairwise comparison only the incidence in high-
    dose females was significantly higher than in controls.  Two
    forestomach squamous cell carcinomas were seen in high-dose females
    and none in the other groups.  No increase in the incidence of
    forestomach hyperplasia was seen in the dosed mice compared with
    vehicle controls (10-20%).  In female mice the incidence of adenomas
    and adenomas or carcinomas (combined) of the pituitary gland (12/45,
    6/45 and 6/44 in control, low and high-dose groups, respectively)
    and the incidence of lymphomas (16/50, 11/50 and 9/50 in control,

    low and high-dose groups, respectively) showed a significant
    negative trend.  Based on the increased incidence of forestomach
    papillomas, the NOAEL was 10 mg/kg bw/day (Chan, 1989; Chan  et al.,
    1991).

    Rats

            Groups of 40 male and 40 female weanling CD rats were fed diets
    containing nominal concentrations of 0, 0.1, 1, 10, 100 or 500 ppm
    dichlorvos (93% purity) for 2 years.  Diets were prepared weekly. 
    Five males and 5 females from each group were killed after 6, 12 or
    18 months.  Analysis of diet samples showed a considerable loss of
    dichlorvos associated with a gradual increase in
    dichloroacetaldehyde (DCA) content (average concentrations ranging
    from 0.01 to 28.6 ppm.  The average actual concentrations of
    dichlorvos in each diet were 0.05, 0.5, 4.7, 47 or 230 ppm.  No
    cholinergic signs were observed.  No effects were seen on behaviour,
    mortality rate, weight gain, food consumption, terminal body and
    organ weights, haematology or urinalysis.  Plasma and erythrocyte
    ChE activities were measured 13 times during the study.  In the 100
    ppm group, plasma and erythrocyte ChE activities were reduced to
    60-90% and to 50-90% of control activities, respectively; in the 500
    ppm group, the activities were reduced to 20-70% and 20-60%,
    respectively.  Activities were higher toward the end of the study. 
    Brain ChE activity was decreased in the highest dose group by
    45-47%, 24-43%, 24-38% and 5-15% after 6, 12, 18 and 24 months,
    respectively.  Histological examination of major organs (liver,
    heart, lungs, kidneys, spleen, brain, gonads, pituitary, adrenals,
    and thyroids) revealed hepatocellular fatty vacuolization in all 500
    ppm rats, and in most females and several males at 100 ppm.  No
    effect was seen on serum total proteins or albumin: globulin ratio,
    or on hexobarbital sleeping time.  The tumour incidence was
    comparable with that of the control group.  The NOAEL, based on
    brain ChE inhibition, was 100 ppm (actual concentration 47 ppm,
    equivalent to 2.4 mg/kg bw/day) (Witherup  et al., 1967).

            Groups of 50 male and 50 female weanling CFE rats were exposed
    (whole body) to nominal air concentrations of 0, 0.05, 0.5 or 5 mg
    dichlorvos (97% purity)/m3 for 23 hours per day for two years.  The
    average actual dichlorvos concentrations were 0.05, 0.48, or 4.7
    mg/m3.  Body-weight gain was reduced in the two highest dose
    groups.  After two years of exposure, plasma and erythrocyte ChE
    activities were reduced by 20-30% at 0.5 mg/m3 and by > 60% in the
    highest dose group; brain ChE activity was reduced by 10%
    (statistically significant) at 0.5 mg/m3 and by 80% in the highest
    dose group.  No effects attributable to dichlorvos were seen on
    appearance, food consumption, haematological or blood chemistry
    values, organ weights, or gross or microscopic examinations of major

    organs.  Ultrastructural examinations of bronchi and alveoli of rats
    exposed to 0 or 5 mg/m3 showed no differences between the two
    groups.

            It was concluded that 2-year exposure to 0.05 mg/m3 dichlorvos
    did not cause observable adverse effects to CFE rats (Blair  et al.,
    1976).  It should be noted that in this study the rats were not only
    exposed by inhalation but also via their food, drinking-water, and
    by grooming.  This resulted in additional oral ingestion of
    dichlorvos (Stevenson & Blair, 1977).

            Osborne-Mendel rats (50/sex) were fed 1000 ppm dichlorvos
    (purity > 94%) in corn oil for 3 weeks.  Due to severe cholinergic
    signs, the dose was reduced to 300 ppm for the remaining 77 weeks. 
    Another group (50 males and 50 females) was fed 150 ppm dichlorvos
    for 80 weeks.  Samples of the diets analyzed during the study showed
    that time-weighted average concentrations were 330 and 150 ppm,
    respectively.  Matched controls consisted of 10 rats of each sex;
    the pooled controls from simultaneous studies of other compounds
    consisted of 60 rats of each sex.  Animals were observed twice daily
    for clinical signs.  All surviving rats were killed after 110-111
    weeks.

            The average body weights of the high-dose rats of both sexes
    were slightly decreased compared with controls.  There was no
    significant increase in the incidence and type of tumours
    attributable to dichlorvos in either sex.  Dichlorvos (up to 330 ppm
    in the diet, equivalent to about 30 mg/kg bw/day) was not
    demonstrated to be carcinogenic in this study (NCI, 1977;
    Weisburger, 1982).

            Groups of 70 and 100 rats per sex received 0.1 mg dichlorvos
    (97%)/rat in 0.2 ml water by gavage twice or 3 times per week,
    respectively, for 60 weeks.  Thereafter, the animals were observed
    for another 51 weeks.  A control group of 60 animals of each sex
    received 3 times per week 0.2 ml water.  From the age of 10 months
    onwards, the incidence of focal hyperplasia of urinary bladder and
    of renal pelvis increased in males but decreased in females from
    both test groups compared to controls.  No neoplastic lesions were
    found which could be attributed to treatment (Horn  et al., 1988).

            A study in Fischer 344 rats given drinking-water containing 0,
    140 or 280 mg/litre dichlorvos for 108 weeks was summarized by WHO
    (1989).  There was no evidence of carcinogenicity (Enomoto  et al.,
    1981).

            Groups of 50 male and 50 female F344/N rats were administered
    dichlorvos by corn oil gavage at 0, 4 or 8 mg/kg bw/day (99%
    purity), 5 days per week for 103 weeks.  Body weights were recorded

    once weekly for the first 12 weeks and then monthly.  Animals were
    observed twice daily for clinical signs.  Necropsy and histologic
    examinations were performed on all moribund animals or at the end of
    the study.

            Mild diarrhoea was observed in treated animals.  ChE activities
    were not determined during the study.  However, a separate study
    showed inhibition of plasma ChE activity by 50-80% in all dosed
    groups but no erythrocyte ChE inhibition (see "Special studies on
    cholinesterase activity" for detailed description and comments).  No
    significant differences in mean body weights or survival were
    observed between any groups of either sex.  Increased incidence of
    cytoplasmic vacuolisation of liver was observed in dosed males and
    of cortical cytoplasmic vacuolisation of adrenal glands in all dosed
    males and in low-dose females.  The incidence of pancreatic adenomas
    (cross and horizontal tissue sections were analyzed), in control,
    low and high-dose groups was 25/50, 30/50 and 33/50 in males and
    2/50, 3/50 and 6/50 in females, respectively.  The increased
    incidence in treated males was statistically significant.  The
    incidence of mononuclear cell leukaemia (11/50, 20/50, 21/50 in
    control, low and high-dose groups, respectively) was significantly
    increased in the treated male rats compared with controls.  The
    incidence of mammary gland adenomas or fibroadenomas in female rats
    was 11/50 in controls, 19/50 in the 4 mg/kg bw/day group and 17/50
    in the 8 mg/kg bw/day group.  The incidence in the low-dose group
    was only slightly higher than the historical control values.  Two
    mammary gland carcinomas were observed in control and low-dose
    groups.  The authors concluded that there was evidence that
    dichlorvos is carcinogenic to rats (Chan, 1989; Chan  et al., 
    1991).  The Meeting observed that the incidence of pancreatic
    adenomas in male control rats was unusually high and therefore the
    higher incidence found in treated animals was considered of
    questionable biological significance.  The increased incidence of
    mononuclear cell leukaemia, which is usually high and variable in
    this strain of rats, was also of questionable biological
    significance (Haseman  et al., 1985).

            Dichlorvos at 8 or 16 mg/kg bw/day was administered by gavage
    to groups of 8-12 male F344 rats, either with or without leukaemia
    transplant, for 5 days a week.  Other groups of rats were either not
    treated or given the leukaemia transplant only.  At 70-days
    post-transplant, the animals were killed.  The rats dosed with
    dichlorvos developed the disease earlier and the rate of tumour
    progression was increased.  Three out of 16 transplant recipients
    dosed with 16 mg/kg bw/day died of leukaemia during the last week of
    dosing.  The severity of the mononuclear cell leukemia in the
    transplant recipients, as measured by histopathological examination
    of spleen and liver, was correlated with the changes in tumour
    growth rates.  However, no dose-response was found for spleen weight
    and WBC count (Dieter  et al., 1989).

    Dogs

            Groups of beagle dogs (3/sex) were fed diets containing nominal
    concentrations of 0, 0.1, 1, 10, 100 or 500 ppm dichlorvos (93%
    purity) for 2 years.  The average actual concentrations were 0,
    0.09, 0.32, 3.2, 32 or 260 ppm dichlorvos; the average
    dichloroacetaldehyde concentrations at the three highest dosages
    were 0.6, 6.4 and 20 ppm.  Since diet analysis was performed weekly
    on a mixture of diet samples taken the previous 7 days, it is
    likely, given the high volatility of dichlorvos, that at the end of
    the week the actual concentration was much lower than 30% of the
    nominal concentration.

            No effects were seen on general appearance, survival, weight
    gain, food consumption, haematology or urinalysis.  Erythrocyte ChE
    activity was reduced up to 50% of controls in the 10 ppm group with
    recovery to control values at the end of the feeding period.  At the
    highest dose level, inhibition was more than 90% but complete
    recovery was observed at 24 months.  A similar pattern was observed
    for plasma ChE activity.  Brain ChE activity, measured at the end of
    the study was similar to that of the controls in all treated groups. 
    Relative liver weights were slightly increased in males at 100 ppm
    and in both sexes at 500 ppm.  Histological examination of major
    organs revealed slight dose-related cytoplasmic vacuolization and
    enlargement of hepatocytes in animals at the two highest levels.  No
    differences were seen in serum alkaline phosphatase, transaminase
    activities, total serum proteins or albumin:globulin ratios (Jolley
     et al., 1967).

    Reproduction studies

            See also under special studies on testes.

    Mice

            Male and female Crl:CD3-1 mice were exposed to dichlorvos
    concentrations of 0, 1.9, 3.0 or 4.6 mg/m3, generated from
    dichlorvos-impregnated PVC strips in their cages. Exposure began
    4 days prior to formation of breeding groups (3 females and 1 male)
    and continued throughout pregnancy.  Signs of intoxication were not
    observed.  Plasma ChE activity was significantly inhibited (by 90%,
    93% and 95% in the 1.9, 3.0 and 4.6 mg/m3 groups, respectively)
    when measured on day 4 after beginning of treatment.  Gestation
    length, number of litters, litter frequency and mean litter size
    were comparable to controls.  No grossly detectable congenital
    anomalies were detected in any of the offspring (Casebolt  et al.,
    1990).

    Rats

            A 3-generation, 2-litter/generation reproduction study in rats
    summarized by WHO (1989) was negative at doses up to 235 ppm in the
    diet, equivalent to 12 mg/kg bw/day (Witherup  et al., 1965).

    Domestic animals

            Several studies have been carried out with pregnant sows but no
    adverse effects on piglets were observed with doses which inhibited
    plasma and erythrocyte ChE activity in the sows (WHO, 1989).

    Special studies on delayed neurotoxicity

            Several studies have shown that a single dose of dichlorvos
    does not produce delayed neurotoxicity in pre-medicated hens,
    whether it is administered orally or subcutaneously (WHO, 1989). 
    However, Caroldi & Lotti (1981) reported mild signs of ataxia in
    pre-medicated hens 2 weeks after a single massive subcutaneous dose
    (100 mg/kg bw) and severe (> 80%) inhibition of  NTE in peripheral
    nerve, spinal cord and brain.  Johnson (1978) did not observe ataxia
    in pre-medicated hens given the same dose in the same way.  However,
    in this experiment spinal cord NTE inhibition was below the
    threshold.  When the dose was repeated 1-3 days after the first
    dose, spinal cord NTE inhibition increased and the hens became
    ataxic.

            In a 90-day study, white leghorn hens were given dichlorvos
    (99.9% purity) either dermally or orally.  For oral administration,
    a 10-20% solution of dichlorvos in corn oil in gelatin capsules was
    used whereas, dermally, 1-20% emulsifiable concentrates in technical
    grade xylene (containing 2% Triton X-100) were used.  Dichlorvos at
    doses greater than 1 mg/kg bw/day (dermal) or 6 mg/kg bw/day (oral)
    led to cholinergic symptoms and death after 2-3 days.  None of the
    animals developed organophosphate-induced delayed neuropathy
    (Francis  et al., 1985).

            In summary, it is possible to produce clinical neuropathy in
    hens, but the doses required are far in excess of the LD50.  This
    is consistent with the low  in vitro ratio of AChE I50/NTE I50 for
    dichlorvos (Lotti & Johnson, 1978).

    Special studies on embryotoxicity and teratogenicity

            Several embryotoxicity/teratogenicity studies have been
    performed with dichlorvos in mice, rats and rabbits.  These studies
    are summarized in WHO (1989).  Dichlorvos given orally, by
    inhalation or intraperitoneally, was not teratogenic at doses which
    were toxic to the pregnant animals.  However, in a study in rats
    where a single i.p. dose of 15 mg/kg bw was given on day 11 of

    gestation, 3/41 fetuses in the treated group had omphaloceles (0/50
    in controls) (Kimbrough & Gaines, 1968).  This finding has not been
    confirmed in other studies.

    Special studies on cholinesterase activity

            This section summarizes studies in which the effect of
    dichlorvos on ChE activity was the only parameter investigated.

            Studies on the inhibition of ChE activity resulting from a
    single oral or parenteral dose of dichlorvos in relation to the time
    elapsed after dosing are summarized in Table 3.  In general, the
    maximum inhibition occurred within one hour followed by rapid
    recovery.

    Mice/Rats

            Groups of 8-week old B6C3F1 mice and F344/N rats (10/sex)
    were administered dichlorvos (99%) by corn oil gavage at daily doses
    of 0, 5, 10, 20, or 40 mg/kg bw (mice) and 0, 2, 4, 8, or 16 mg/kg
    bw (rats), five days per week for one week.  Plasma and erythrocyte
    ChE activities were measured on days 10 or 11, 25 or 26 and 32 or
    33; blood was obtained about 3 hours after treatment.

            Plasma ChE activity was significantly inhibited in all dose
    groups of mice (50 and 90% inhibition in low and high-dose groups,
    respectively) and rats (25 and 80% inhibition in low and high-dose
    groups, respectively).  At all time-points, erythrocyte ChE activity
    in dosed and vehicle-control mice and rats was similar.  However,
    the timing for determination of the enzyme activities might have
    underestimated the inhibition (Chan, 1989).

    Rats

            Reiner & Plestina (1979) compared  in vivo reappearance of ChE
    activity in rats after treatment with either dichlorvos (2.5 mg/kg
    bw i.v.) or metrifonate (300 mg/kg bw i.v.).  Half-lives of recovery
    of brain and plasma ChE (acetylcholine was the substrate) were found
    to be 2 and 2.5 hours, respectively, both in dichlorvos-treated and
    in metrifonate-treated rats.  This was consistent with  in vitro
    data (Skrinjaric-Spoljar  et al., 1973).

            In a study on the influence of temperature on ChE activity,
    rats were injected i.p. with a single dose of 6.3 mg/kg dichlorvos
    and kept at either 28 C or 5 C.  The maximum inhibition of whole
    blood ChE activity (40% and 50% in the two groups, respectively)
    occurred after 0.5 hour.  The animals kept at 5 C showed slightly
    less inhibition of whole blood ChE activity than those at room
    temperature (Chattopadhyay  et al., 1982).


        Table 3.  Time-related inhibition of ChE activity in animals after administration of a single dose of dichlorvos
                                                                                                                     
    Species             Route     Dose           Time              Mean % inhibition          Reference
                                  (mg/kg bw)                              
                                                              plasma      erythr.   brain     
                                                              ChE         AChE      AChE      
                                                                                                                     

    Mouse, male         i.p.      10             15 min                             70        Nordgren et al., (1978)
    (n = 6-8)                                    60 min                             50        
                                                 2 hours                            20        

    Mouse, male         i.p.      15             2 hours                            20        Cohen & Ehrich, 1976
    Mouse, male         i.p.      30             15 min                             63        Cohen & Ehrich, 1976
    (n = 4)                                      1 hour                             50        
                                                 5 hours                            35        
                                                 18 hours                           10        

    Rat, male           oral      1.6            2 hours                            0         Pacheka et al., 1975
    (n = 6)                       10             2 hours                            15        
                                  40             1 hour                             60*       

    Rat, male           oral      40             1 hour                             70        Teichert et al., 1976
    (n = 1)

    Rat, male           oral      40             5 min                              45        Pacheka et al., 1975
    (n = 6)                                      15 min                             80        
                                                 1 hour                             85        
                                                 2 hours                            70        
                                                 8 hours                            35        
                                                 24 hours                           25        
                                                 48 hours                           6         

    Rat, male           oral      50             15 min       68          80        97.91**   Modak et al., 1975
    (n = 6)                                      3 hours      73          37        68-70**   
                                                 24 hours     39          24        31-38**   
                                                                                                                     

    Table 3 (contd)
                                                                                                                     
    Species             Route     Dose           Time              Mean % inhibition          Reference
                                  (mg/kg bw)                              
                                                              plasma      erythr.   brain     
                                                              ChE         AChE      AChE      
                                                                                                                     

    Rat, male           i.v.      2.5            30 min       60                    85        Reiner & Plestina, 1979
    (n = 5-12)                                   90 min       40                    65        
                                                 3 hours      7                     44        
                                                 12 hours     0                     17        
                                                 48 hours     -                     10        

    Dog, greyhounds     oral      11             1 hour       90          93                  Snow & Watson, 1973
    1 male                                       2 hours      80          70                  
    1 female                                     24 hours     15          35                  
                                                 72 hours     8           25                  

    Dog, 2 male         oral      22             fatal        90          95        66***     Snow & Watson, 1973
    greyhounds,
    1 female
    crossbred

    Dog, greyhounds     oral      22             1 hour       88          83                  Snow & Watson, 1973
    and crossbred                                3 hours      76          66                  
    (n = 7-9)                                    6 hours      60          50                  
                                                 24 hours     30          30                  
                                                 48 hours     13          30                  
                                                 72 hours     5           35                  

    Dog, beagle         oral      50             2 hours      68          37                  Ward & Glicksberg, 1971
    sex not specified                            24 hours     37          26                  
    (n = 15)                                     5 days       8           22                  
                                                 14 days      5           20                  
                                                 21 days      0           8                   

                                                                                                                     

    Table 3 (contd)

    *    Daily dosing for 14 days caused 60% AChE inhibition when measured 24 hours after the last dose.
    **   Determinations were performed in striatum, hippocampus, medulla and cortex. No significant difference 
         was found between these brain areas.
    ***  Measured 20-155 min. after treatment.
    

            When pregnant rats were given oral doses of 1.1 or 5.6 mg
    dichlorvos/kg bw/day during days 14-21 of gestation, plasma ChE
    activity of the high-dose mothers was inhibited (30-50%) but not
    that of the young.  Brain ChE activity did not show any significant
    inhibition (Zalewska  et al., 1977).

    Rabbits

            Dichlorvos, when infused into the ear vein of adult male
    rabbits, produced dose- and time-related inhibition of whole blood
    ChE activity during infusion.  Spontaneous but incomplete recovery
    to 60-80% of the normal activity occurred within 60-90 minutes after
    infusion.  Almost complete recovery was obtained by injecting oximes
    up to 2.5 hours later (Shellenberger  et al., 1965; Gough &
    Shellenberger, 1977-1978; Shellenberger, 1980).

            The progeny of rabbits, treated orally with 6 mg/kg bw/day for
    the last 10 days of gestation, showed inhibition of brain ChE
    activity at one day (30%) and 8 days of life (15%).  Plasma ChE
    activity was higher throughout days 1-16 of life (Maslinska &
    Zalewska, 1978).

    Guinea-pigs

            Groups of 5 male and 5 female guinea-pigs were given daily
    applications of 0, 25, 50 or 100 mg/kg bw/day dichlorvos (94%
    purity) on the shorn skin for 8 days.  All animals survived.  A
    dose-dependent inhibition of both plasma and erythrocyte ChE
    activities occurred in all test groups.  Recovery of plasma ChE
    activities was complete within one week of the last exposure, and
    that of erythrocyte ChE was complete within one week in the females
    and 2 weeks in the males (Brown & Roberts, 1966).

    Hens

            Chickens dosed once orally with 1,3, or 6 mg/kg bw showed a
    rapid inhibition of plasma ChE activity followed by recovery with an
    half-life being estimated at three days (Rauws & van Logten, 1973).

            White Leghorn pullets and hens were fed a diet containing 30
    ppm dichlorvos for 35 days followed by a 21-day recovery period. 
    Plasma ChE activity was inhibited by 70% after four weeks of
    treatment but returned to normal during the recovery period (Pym  et
     al., 1984).

    Monkeys

            Thirty-two Rhesus monkeys were given a pelleted PVC-resin
    formulation containing 20% dichlorvos at dosages ranging from 1 to
    16 mg dichlorvos/kg bw once daily or 1.6 and 4 mg dichlorvos/kg bw

    twice daily for 10 to 21 consecutive days.  None of the monkeys
    showed overt signs of intoxication, although they ate less food and
    had soft faeces.  Plasma and erythrocyte ChE activities were reduced
    by approximately 80% in all animals (irrespective of the dose) and
    remained inhibited throughout the study.  Plasma ChE activities
    returned to normal values within approximately 3 weeks and the
    erythrocyte ChE activities within 50 to 60 days following cessation
    of exposure (Hass  et al., 1972).

    Special studies on genotoxicity

    Methylating reactivity

            In vitro studies

            In a quantitative colour test in which methylation of
    4-(p-nitro-benzyl) pyridine was measured to predict DNA alkylating
    potential, dichlorvos gave a positive response, the reaction being
    about 1/3 that of the known alkylating compound
    methylmethanesulfonate (MMS) (Bedford & Robinson, 1972).

            Alkylation by dichlorvos of calf thymus DNA, resulting in the
    formation of N-7-methylguanine, was reported by Lofroth (1970).

            Methylation by dichlorvos of isolated salmon sperm DNA and of
    DNA from intact  E.coli and from human HeLa cells broadly resembled
    that by MMS (Lawley  et al., 1974).  In this study a very high
    dichlorvos concentration (14 mmol/l) was used with isolated DNA
    (12.5 mmol/l DNA-P).  Dichlorvos concentrations with  E. coli and
    HeLa cells were 1-3 mmol/l.  The rate of methylation of guanine-N-7
    from salmon sperm DNA or from intact HeLa cell DNA by dichlorvos was
    2-3 x 10-4 mol/l/min (calculated assuming guanine as 23-25% of DNA
    with an average molecular weight of DNA base pair of 649, Lawley  et
     al., 1974).  This is about 15 times lower than the rate of
    methylation by MMS.  This rate is to be compared with the rate of
    reaction with AChE (phosphorylation) (1.5 x 105 mol/l/min at 37 C)
    (Skrinjaric-Spoljar  et al., 1973).  Therefore, the relative rate
    of phosphorylation is about 9 orders of magnitude higher than that
    of alkylation.

            Labelled 7-methylguanine was present in both DNA and RNA
    isolated from  E. coli exposed to [Me-3H]-dichlorvos (1.1 mmol/l
    for 4 hours).  The methylating capability of dichlorvos was less, by
    a factor of 10-100, than that of strongly genotoxic methylating
    compounds (Wennerberg & Lofroth, 1974).

            Incubation of bacteriophage R17 with 0-100 mmol
    dichlorvos/litre for 90 hours did not result in methylation of the
    phosphate groups of the RNA to any significant extent (Shooter,
    1975).

            In vivo studies

            Mice were given i.p. injections of methyl-14C-dichlorvos (1.9
    mol/kg bw, approximately 420 g/kg bw).  The degree of alkylation
    of guanine-N-7 in DNA isolated from soft tissues amounted to 8 x
    10-13 mol methyl per gram of DNA (about 5 x 10-10 mol/mol guanine)
    (Segerback, 1981; Segerback & Ehrenberg, 1981).  From acute toxicity
    data in mouse (see Table 1) it can be extrapolated that this dose
    would cause 1 mol/mol phosphorylation of erythrocyte ChE.

            DNA and RNA from the total soft tissues of male rats exposed to
    atmospheres containing 0.064 mg/m3 (about 0.1% of the LC50) of
    methyl-14C-dichlorvos for 12 hours did not show methylation of the
    N-7 atom of guanine moieties.  The exposure period constituted a
    significant fraction of the half-life of the 7-methylguanine
    moieties in DNA (Wooder  et al., 1977; Wooder & Wright, 1981).

            Excretion of labelled 7-methylguanine in the urine by NMRI mice
    and rats injected i.p. with [Me-14C]-dichlorvos, or exposed by
    inhalation for 2 hours (mice only) was reported by Wennerberg &
    Lofroth (1974) and Lofroth & Wennerberg (1974).  In rat urine,
    labelled 3-methyladenine and 1-methyl-nicotinamide were also present
    (Lofroth & Wennerberg, 1974).  According to the authors, these
    results demonstrate that dichlorvos spontaneously methylates guanine
    and adenine moieties in nucleic acids.  However, administration of
    radiolabelled adenine and guanine to otherwise untreated rats gave
    rise to the excretion of radiolabelled methylated purines in the
    urine.  Therefore, the detection of radiolabelled purines,  per se,
    in the urine of animals exposed to methyl-labelled methylating
    agents does not constitute evidence for the spontaneous methylation
    of the purine moieties of nucleosides or nucleic acids by
    methylating agents (Wooder  et al., 1978; Wooder & Wright, 1981). 
    Moreover, a natural biosynthetic pathway has been demonstrated
    whereby the methyl carbon atoms of dichlorvos can be incorporated
    into the heterocyclic rings and the methyl groups of urinary
    7-methylguanine after entering the 1-C pools,  in vivo (Wright  et
     al., 1979; Wooder & Wright, 1981).

    Genotoxicity

            In vitro studies

            Several studies using bacteria and fungi as test organisms have
    been carried out (Table 4).  In most of the studies, only one, often
    high, dichlorvos concentration was tested, sometimes resulting in
    low survival of the test organism.  The alkylating properties of
    dichlorvos (see above) are most probably the cause of the mutagenic
    action.  This is suggested, for instance by data in  E. coli 
    strains deficient at four repair loci (Bridges  et al., 1973).

             In vitro studies using mammalian cells are summarized in
    Table 5.  Dichlorvos caused cell transformation, mutations, DNA
    strand breaks, sister chromatid exchanges and chromosomal
    aberrations in cultured animal cells.  In cultured human cells,
    dichlorvos induced unscheduled DNA synthesis but did not induce
    sister chromatid exchanges or chromosomal aberrations.  Negative
    results from chromosomal aberration tests in cultured human
    lymphocytes were also cited by Fahrig (1974) and Wild (1975).

            Dichlorvos (0.3 g/ml) caused a synergised an increase in
    sister chromatid exchanges in Chinese hamster ovary cells when
    tested in combination with synthetic pyrethroids or propoxur which,
    as such, were negative; however, in the combination phenothrin +
    dichlorvos (0.3 g/ml) the induction of SCE by phenothrin was
    negative (Wang  et al., 1988).

            In vivo studies

             In vivo studies are summarized in Table 6.

            In  Drosophila melanogaster, chromosomal aberrations but not
    sex-linked recessive lethal mutations were induced.  Negative
    results were obtained in host-mediated, dominant lethal, sister
    chromatid exchange and micronucleus assays (except on skin after
    local application at cytotoxic doses).  Dichlorvos did not induce
     in vivo chromosomal aberrations in bone-marrow cells,
    spermatocytes or spermatogonia, DNA strand breaks or unscheduled DNA
    synthesis.

    Special studies on liver microsomal enzymes

            A decrease in liver microsomal cytochrome P-450 occurred in
    rats after three daily i.p. injections with 6 mg dichlorvos/kg bw
    (Purshottam & Kaveeshwar, 1982) but no effect on liver microsomal
    UDP-Glucuronyl transferase was found in mice 4 hours after a single
    i.p. injection of 25 mg/kg bw (Yoshida  et al., 1976).

            Pre-treatment of rats with three daily i.p. injections of
    sodium phenobarbital did not significantly change mortality and
    plasma ChE inhibition caused by an i.p. injection of dichlorvos (20
    mg/kg bw) (Purshottam & Kaveeshwar, 1979).

            Short- and long-term studies with mice, rats or dogs dosed
    orally or intraperitoneally with dichlorvos did not show any effect
    on microsomal drug metabolizing enzymes (Witherup  et al., 1967;
    Uchiyama  et al., 1975; Farber  et al., 1975).


        Table 4.  Mutagenicity tests on microorganisms in vitro
                                                                                                                                              
    Test system                   Test object                   Concentration          Purity           Results 1   Reference
                                                                                                                                              

    Mitotic                       A. nidulans strain p          ?                      ?                +           Morpurgo et al., 1979
    non-disjunction 
    and crossing over

    Recombinant assay             B. subtilis  H17 Rc+          2 mg/plate             ?                -           Shirasu et al., 1976
                                               M45 Rec-             "                                   +              "     "

    Forward mutation              A. nidulans strain 35         14 mg/disc             ?                +           Bignami et al., 1977

                                  E. coli  B                    5-25 mmol/l            95%              +2          Wild, 1973
                                           Gal RS               ?                      ?                +           Fahrig, 1974
                                           K12(5-MT)            0.3-3.2 mmol/l         ?                +           Mohn, 1973

                                  S. coelicolor A 3(2) his A1   5.6 mg/disc            99.9%            +           Carere et al., 1978a, 1978b

    Reverse mutation              E. coli B/r WP2               5 mg/plate             > 97%            +3          Moriya et al., 1978

                                  S. typhimurium TA 1535        5 mg/plate             > 97%            +4             "     "

                                  E. coli WP2 hcr               up to 5 mg/plate       ?                +3          Moriya et al., 1983

                                  S. typhimurium  TA 98         up to 5 mg/plate       ?                -              "     "
                                                  TA 100           "     "             ?                +              "     "
                                                  TA 1535          "     "             ?                ?              "     "
                                                  TA 1537          "     "             ?                -              "     "
                                  TA 1538                          "     "             ?                -              "     "

                                                                                                                                              

    Table 4 (contd)
                                                                                                                                              
    Test system                   Test object                   Concentration          Purity           Results 1   Reference
                                                                                                                                              

    Reverse mutation (cont'd)     E. coli  B/r Wp2( ); SR714    0.04-2.3 mmol/l        99%              +3          Houk & DeMarini, 1987
                                           CM 561               0.2%                   "                +5          Bridges et al., 1973
                                           CM 571; CM 611       "                      "                -6             "     "
                                           WP2                  "                      "                +5             "     "
                                           WP2 uvr A            "                      "                +5             "     "
                                           WP2                  micro drop of          ?                -7          Dean, 1972a
                                                                analytical grade, 
                                                                technical grade 
                                                                or 10% acqueous 
                                                                solution/plate

                                           K12HfrH              0.1%                   97.5%            +           Voogd et al., 1972

                                  C. freundii 425               0.05% or 0.1%          "                +8             "     "

                                  E. aerogenes                  0.1%                   "                +              "     "

                                  K. pneumoniae                 0.05% oe 0.1%          "                +              "     "

                                  S. typhimurium 64-320         "                      "                +              "     "

                                  S. marcescens  Hy/alpha 13    1.25-5 mg/disc         ?                +           Dean, 1972a
                                                 Hy/alpha 21

                                  E. coli  WP2   WP2            5 g/ml                ?                +9          Green et al., 1976
                                                 hcr+/hcr-      20-25 l/disk          50% commercial   +10         Nagy et al, 1975
                                                 WP2            5 mg/plate             formulation                     "     "
                                                 hcr+/hcr-                             ?

                                                                                                                                              

    Table 4 (contd)
                                                                                                                                              
    Test system                   Test object                   Concentration          Purity           Results 1   Reference
                                                                                                                                              

    Reverse mutation              S. typhimurium  TA 1535       5 mg/plate             ?                +           Shirasu et al., 1976
    (cont'd)                                      TA 1536       "                      ?                +              "     "
                                                  TA 1537       "                      ?                -              "     "
                                                  TA 1538       "                      ?                -              "     "

                                  E. coli  WP2                  5 l/plate11           ?                +           Hanna & Dyer, 1975
                                           WP2 uvr A            "                      ?                +              "     "
                                           WP 67                "                      ?                +              "     "
                                           CM 561               "                      ?                -              "     "
                                           CM 571               "                      ?                -              "     "
                                           CM 611               "                      ?                -              "     "

                                  S. typhimurium  TA 1530       
                                                  TA 1535       5 l/plate             ?                +           Hanna & Dyer, 1975
                                                  his C117      "                      ?                +              "     "
                                                  his G46       "                      ?                -              "     "
                                                                "                      ?                -              "     "

                                  P. aeroginusa PAO 38          0.08 mol/l             ?                +           Dyer & Hanna, 1973

                                  S. typhimurium his C117       0.03 mol/l             ?                +              "     "

                                  S. typhimurium  TA 98         ?                      ?                -3          Braun et al., 1982
                                                  TA 100        ?                      ?                +3             "     "
                                                  TA 1535       ?                      ?                -3             "     "
                                                  TA 1536       ?                      ?                -3             "     "
                                                  TA 1537       ?                      ?                -3             "     "
                                                  TA 1538       ?                      ?                -3             "     "
                                                  TA 98         0.1-6.6 mg/plate12     99%              -3          Chan, 1989: 
                                                                                                                    Zeiger et al., 1988 

                                                                                                                                              

    Table 4 (contd)
                                                                                                                                              
    Test system                   Test object                   Concentration          Purity           Results 1   Reference
                                                                                                                                              

                                                  TA 100           "     "             "                +3          Carere et al., 1978a,b
                                                  TA 1535       2.8 mg/plate           99.9%            -3             "     "
                                                  TA 1536          "     "             "                -3          
                                                  TA 1537          "     "             "

                                  S. typhimurium  TA 1538       2.8 mg/plate           99.9%            -3          Carere et al., 1978a,b
                                                  TA 1535       1.5 mg/ml              99.9%            +           

                                  Schizosaccharmoyces pombe     1.5-14 mmol/plate13    > 99%            +3          Gilot-Delhalle et al., 
                                  ade 6                                                                             1983

    Gene conversion               S. cerevisiae  D4             2-8 mg/ml              > 97%            +14,15      Dean  et al., 1972
                                                 D4             6-40 mmol/l            ?                +2          Fahrig, 1973, 1974
                                                 632/4          ?                      ?                -           Guerzoni et al., 1976 
                                                                                                        +16         Griffin & Hill, 1978
    DNA strand breaks             E. coli K-12CR34Co1E1         1 mg/ml                ?

    Growth inhibition             E. coli W3110 pol A+/pol A-   6.4 mmol/l             ?                +           Rosenkranz, 1973

                                  P. mirabilis PG 273; PG 713   ?                      ?                +15         Braun et al., 1982

                                                                                                                                              

    1    Without metabolic activation except where noted.
    2    Positive controls (methyl methanesulfonate 1-4 mmol/l) yielded expected positive results.
    3    Both with and without metabolic activation.
    4    Only without metabolic activation.
    5    Methyl methane sulfonate (0.04%) yielded positive responses.
    6    Methyl methane sulfoante (0.04%) yielded negative responses.
    7    Methyl methane sulfonate, N-methyl-N'-nitro-N-nitroso guanidine yielded positive response.
    8    At 0.1%
    9    Positive controls (methyl methanesulfonate 0.5-2.0 g/ml) yielded expected positive results.

    Table 4 (contd)

    10   Positive controls (N-methyl-N'-nitro-nitroso guanidine, N-nitroso-N-methylurethane and acridium chloride)
         yielded positive responses.
    11   Toxic dose.
    12   Toxic effect at 3.3 mg/plate.
    13   The LD50 was 5.5 mmol/l.
    14   Positive controls (ethyl methane sulfonate) yielded positive responses.
    15   From 4 mg/ml.
    16   Methyl methane sulfonate (2-10 mmol/l), N-methyl-N'-nitro-N-nitroso guanidine (3.4-6.8 mmol/l) yielded positive responses.

    Table 5.  Mutagenicity tests in mammalian cells  in vitro
                                                                                                                                              
    Test system                       Test object                             Concentration         Purity    Results   Reference
                                                                                                                                              

    Viral transformation              Syrian hamster embryo                   0.05-0.45 mmol/l         ?        +1      Hatch et al., 1986
                                      cells/adenovirus SA7                    cytotoxic

    Gene mutation                     Chinese hamster V79 cells               up to 1 mmol/l           ?         -      Wild, 1975
                                      (azaguanine resistance)                 1.25-5 mmol/l            ?        +2      Aquilina et al., 1984

                                      Mouse lymphoma L5178Y cells             6.25-50 nl/m3            ?       +4,5     Chan, 1989
                                      (trifluorothymidine resistance)         12.5-200 nl/m6                   +5,7     Chan, 1989

    DNA strand breaks                 Chinese hamster V79 cells               0.2%                     ?        +8      Green et al., 1974

    Sister chromatid exchange         Primary rat tracheal epithelial cells   5-160 g/ml9           93.9%    +10,11    Lin et al., 1988

                                      Chinese hamster ovary cells             0.03 and 0.1 mmol/l     98         +      Nishio & Uyeki, 1981
                                                                              0.1-0.5 mmol/l         > 98%       +      Tezuka et al., 1980
                                                                              0.3-1000 g/ml           ?        +12     Wang et al., 1988
                                                                              1-50 g/ml               ?        +13     Chan, 1989

                                      Human lymphocytes                       2.5-10 g/ml            99%        -      Nicholas et al., 1978

                                      Human fetal lung fibroblasts                                    99%        -      Nicholas et al., 1978

    Chromosomal aberrations           Rat tracheal epithelial cells           5-160 g/ml9           93.9%    +11,14    Lin et al., 1988

                                      Chinese hamster lung fibroblasts        ?                        ?         +      Ishidate et al., 1981

                                      Chinese hamster V79 cells               0.1-0.5 mmol/l         > 98%      +15     Tezuka et al., 1980

                                      Chinese hamster ovary cells             16-160 g/ml             ?        +16     Chan, 1989

                                      Human lymphocytes                       1-40 g/ml             > 99%      -17     Dean, 1972b 

                                                                                                                                              

    Table 5 (contd)
                                                                                                                                              
    Test system                       Test object                             Concentration         Purity    Results   Reference
                                                                                                                                              

    Unscheduled DNA synthesis         Human lymphocytes                       5-500 g/ml            99.8%       +      Perocco & Fini, 1980

                                      EUE human cells                         6.5-650 mmol/l           ?        +18     Aquilina et al., 1984

    DNA (sedimentation coefficient)   Calf thymus DNA                         0.1%                     ?         +      Rosenkranz & 
                                                                                                                        Rozenkranz, 1972

    DNA (thermolabile regions)        Calf thymus DNA                         45 mmol/l               99%        -      Olinski et al., 1980

    DNA (resistance to micrococcal)   Chinese hamster ovary cells             10 mmol/l                ?         +      Nishio & Uyeki, 1980

                                                                                                                                              

    1    Positive controls (benzo(a)pyrene 0.001-0.002 mmol/l) yielded expected positive responses.
    2    Positive controls (ethyl methan sulfonate 20 mmol/l) yielded expected positive responses.
    3    Growth inhibition from 12.5 nl/ml.
    4    From 12.5 nl/ml.
    5    Positive controls (methyl methanesulfonate 5 nl/ml) yielded expected positive responses.
    6    Growth inhibition from 100 nl/ml.
    7    From 100 nl/ml.
    8    Negative at lower concentrations.
    9    50% mortality was observed at 80 g/ml.
    10   From 10 g/ml.
    11   Positive controls (N-methyl-N'-nitro-N-nitroso guanidine 0.25-1 g/ml, 50% mortality at 0.5 g/ml)
         yielded expected positive responses.
    12   From 40 g/ml.
    13   From 10 g/ml. When incubated with S9, positive response at 50 g/ml.
    14   From 80 g/ml.
    15   At 0.5 mmol/l.
    16   At 160 g/ml.
    17   Cytotoxicity was observed at 5-40 g/ml.
    18   Positive controls (N-methyl-N'-nitro-N-nitroso guanidine) yielded expected positive responses.
    19   Possible index of DNA alkylation.
    20   Possibly indicating structural rearrangement of chromatin.

    Table 6.  Mutagenicity tests  in vivo
                                                                                                                                              
    Test system            Test object                   Concentration                 Purity       Results*  Reference
                                                                                                                                              

    Crossing over/         Drosophila melanogaster       0.035%1                       ?            -         Jayasuriya & Ratnayaka, 1973
    recombination          ++++/dp b cn bw

    Sex-linked             Drosophila melanogaster       0.035%1                       ?            -         Jayasuriya & Ratnayaka, 1973
    recessive lethal                                                                                          Sobels & Todd, 1979
    mutation

                           Oregan K                      0.01-0.1 ppm in food          ?            -2        Kramers & Knapp, 1978
                                                         commercial formulation

    Chromosomal            Drosophila melanogaster       1 ppm in food                 ?            +         Gupta & Singh, 1974
    aberration

    Autosomal recessive    Drosophila melanogaster       0.1-0.75 ppm in food for      ?            +         Hanna & Dyer, 1975
    levels                                               18 months

    Host-mediated assay    Salmonella typhimurium        25 mg/kg bw s.c.              ?            -         Buselmayer et al., 1972
                           G46 His- in mice (NMRI)

                           Salmonella typhimurium        8-10 mg/kg bw p.o.            97.5%        -3        Voogd et al., 1972
                           (64-320) in mice (Swiss) 

                           Serratia marcescens           25 mg/kg bw s.c.              ?            -         Buselmayer et al., 1972
                           (a 21 Leu-) in mice (NMRI)

                           Sacchoromyces cerevisiae      50 or 100 mg/kg bw p.o.       > 97%        -3        Dean et al., 1972
                           (D4) in mice (CF1)

                                                                                                                                              

    Table 6 (contd)
                                                                                                                                              
    Test system            Test object                   Concentration                 Purity       Results*  Reference
                                                                                                                                              

    Dominant lethal        Female mice (CF1)             0, 25 or 50 mg/kg bw p.o.     > 97%        -4        Dean & Blair, 1976

                                                         0, 2 or 8 mg/m3 inhalation,   > 97%        -         Dean & Blair, 1976
                                                         from weaning to 11 weeks 
                                                         of age 

                           Male mice (ICR/Ha Swiss)      0, 5 or 10 mg/kg bw/day       ?            -         Epstein et al., 1972
                                                         p.o. for 5 days 
                                                         (8 weeks of mating)

                                                         Single i.p. injection of      ?            -         Epstein et al., 1972
                                                         13 or 16.5 mg/kg bw 
                                                         (8 weeks of mating)

                           Male mice (Q)                 2 ppm in drinking water,      99%          -         Degraeve et al., 1984a
                                                         5 days/week for 7 week

                                                         10 mg/kg bw i.p.              99%          -5        Moutschen-Dahmen et al., 1981

                           Male mice (CF1)               30 or 55 mg/m3 inhalation     > 97%        -         Dean & Thorpe, 1972b
                                                         for 16 h 

                                                         2.1 or 5.8 mg/m3 inhalation   > 97%        -6        Dean & Thorpe, 1972b
                                                         for 23 hours/day for 4 weeks

    Sister chromatid       Male mice (B6C3F1)            5-35 mg/kg bw i.p.            99%          -7        Kligerman et al., 1985
    exchange               peripheral lymphocytes

                           Male mice (B6C3F1)            6-40 mg/kg bw i.p.            ?            -8        Chan, 1989
                           bone marrow cells

                                                                                                                                              

    Table 6 (contd)
                                                                                                                                              
    Test system            Test object                   Concentration                 Purity       Results*  Reference
                                                                                                                                              

    Micronucleus test      Mice (Swiss Webster)          0.0075-0.015 mg/kg bw/day     ?            -9        Paik & Lee, 1977
                                                         i.p. for 2 or 4 days

    Micronucleus test      Mice (HRA/Skh, hairless)      skin painting with            tech.grade   +10       Tungul et al., 1991
    (in vitro/in vivo)     skin keratinocytes            0-228 g 
                                                         (in 100 l acetone)

    Chromosomal            Chinese hamster, both         10-15 mg/kg bw p.o.           > 97%        -11       Dean & Thorpe 1972a
    aberrations            sexes bone-marrow cells

                           Male mice (Q)                 2 ppm in drinking-water,      99%          -         Moutschen-Dahmen et al., 1981; 
                           bone-marrow cells             5 days/week for 7 weeks                              Degraeve et al., 1984b

                                                         10 mg/kg bw i.p.              99%          -         Degraeve et al., 1984b
                                                                                                              Degraeve et al., 1984b

                           Male mice (B6C3F1) bone       6-40 mg/kg bw i.p.            ?            -12       Chan, 1989
                           marrow cells

                           Female Syrian golden          0, 3, 6, 15 or 30 mg/kg       50%          +13       Dzwonkowska & Hbner, 1986
                           hamster                                                     commercial 
                                                                                       formulation
                           bone-marrow cells             bw i.p.

                           Mice (CF1), both sexes        64-72 mg/m3 inhalation        > 97%        -11       Dean & Thorpe, 1972a
                           bone-marrow cells             for 16h 

                           5 mg/m3 inhalation            > 97%                         > 97%        -11       Dean & Thorpe, 1972a
                           23 hours/day for 21 days

                           Male Chinese hamsters         28-36 mg/m3 inhalation        > 97%        -11       Dean & Thorpe, 1972a
                           bone-marrow cells             for 16h. 

                                                                                                                                              

    Table 6 (contd)
                                                                                                                                              
    Test system            Test object                   Concentration                 Purity       Results*  Reference
                                                                                                                                              

    Chromosomal            Mice (Q) spermatocytes        2 ppm in drinking-water       99%          -         Moutschen-Dahmen et al., 1981;
    aberrations                                          5 days/week for 7 weeks                              Degraeve et al., 1984a
    (cont'd)

                           Chinese hamsters              15 mg/kg bw p.o.              > 97%        -11       Dean & Thorpe, 1972a
                           spermatocytes

                           Mice (Q) spermatocytes        10 mg/kg bw i.p.              99%          -         Moutschen-Dahmen et al., 1981;
                                                                                                              Degraeve et al., 1984a

                           Mice (CF1) spermatocytes      64-72 mg/m3 inhalation        > 97%        -11       Dean & Thorpe, 1972a
                                                         for 16h 

                                                         5 mg/m3 inhalation            > 97%        -11       Dean & Thorpe, 1972a
                                                         23h/day for 21 days

                           Chinese hamster               28-36 mg/m3 inhalation        > 97%        -11       Dean & Thorpe, 1972a
                           spermatocytes                 for 16 h

                           Mice (CF1) spermatogonia      2 ppm in drinking-water,      99%          -         Moutschen-Dahmen et al., 1981;
                                                         5 days/week for 7 weeks                              Degraeve et al., 1984b

                                                         10 mg/kg bw i.p.              99%          -         Moutschen-Dahmen et al., 1981;
                                                                                                              Degraeve et al., 1984b

    DNA strand breaks      Rats (Wistar), both           10 mg/kg bw i.p.              99.8%        -14       Wooder & Creedy, 1979
                           sexes rat liver cell DNA

                                                                                                                                              

    Table 6 (contd)
                                                                                                                                              
    Test system            Test object                   Concentration                 Purity       Results*  Reference
                                                                                                                                              

    Unscheduled DNA        Male rats (F344)              0, 2, 10 or 35 mg/kg          ?            -         Mirsalis et al., 1989
    synthesis              hepatocytes                   bw p.o.

                           Mice (B6C3F1) (both sexes)    0, 10, 20, 40 or              > 98%        -15       Bedford, 1991
                           forestomachrats               100 mg/kg bw p.o.

                                                                                                                                              

    1    Approximate LD50
    2    Positive controls (2.5 mmol/l ethyl methanesulfonate) yielded expected positive responses.
    3    Positive controls (400 mg/kg bw p.o. ethyl methanesulfonate) yielded expected positive responses.
    4    Positive controls (100 mg/kg bw p.o. methyl methanesulfonate) yielded expected positive responses.
    5    Positive controls in 2nd and 5th week of mating.
    6    Positive controls (2000 mg/kg bw p.o. methyl methanesulfonate) yielded expected positive responses.
    7    Positive controls (2-acetylaminofluorene, ethyl methane sulfonate and N-nitroso morpholine) yielded positive results. 
         All animals treated with 35 mg/kg bw i.p. died.
    8    Positive controls (ethyl methane sulfonate 100 mg/kg bw p.o.) yielded expected positive responses.
    9    Positive controls (cyclophosamide 30-240 mg/kg bw i.p.) yielded expected positive responses.
    10   Recovery of plated cells  in vitro after a single topical application of dichlorvos was about 50% of controls.
    11   Positive controls (endoxan 100-200 mg/kg bw i.p.) yielded expected positive responses.
    12   Positive controls (ethyl methane sulfonate 300-375 mg/kg bw p.o.) yielded expected positive responses.
    13   LD50 = 30 mg/kg bw i.p.  No dose related response.  Positive controls (cyclophosphamide 40 s. mg/kg bw i.p.) 
         yielded expected positive responses.
    14   Positive controls (methyl methane sulfonate 30-60 mg/kg bw i.p.) yielded expected positive responses.
    15   Positive controls (N-methyl-N'-nitro-N-nitroso guanidine 200 mg/kg bw p.o.) yielded weakly positive results.  
         Dichlorvos treatment induced a hyperplastic response similar to that induced by the non-genotoxic carcinogen butylated
         hydroxyamisole (300 mg/kg bw p.o.).
    

    Special studies on metabolites

    Acute and short-term toxicity studies

         The intraperitoneal toxicity of metabolites of dichlorvos in
    female mice is considerably less than that of dichlorvos.  The LD50
    (mg/kg bw) was 250 for dichloroacetic acid, 440 for
    dichloroacetaldehyde and 890 for dichloroethanol.  For other
    metabolites it was > 1000 mg/kg bw.  A short-term inhalation study
    with dichloroacetaldehyde in rats did not show adverse effects at
    concentrations up to 2 mg/m3 for 30 days (WHO, 1989).

    Methylating reactivity

         In a quantitative colour test in which methylation of
    4-(p-nitrobenzyl) pyridine was measured to predict DNA alkylating
    potential, desmethyl-dichlorvos, dimethyl phosphate,
    dichloroethanol, dichloroacetaldehyde and dichloroacetic acid gave
    no reaction (Bedford & Robinson, 1972).

    Mutagenicity

         In a rec-type repair test with  Proteus mirabilis strains
    PG713 and PG273, desmethyldichlorvos (10 or 40 mol/plate) did not
    induce base-pair substitutions or other DNA damage (Braun  et al.,
    1982).

         Dichloroacetaldehyde (DCA) appeared to be mutagenic in the
     Salmonella test using  S. typhimurium TA 100 and TA 1535.  The
    mutagenicity decreased in the presence of a microsomal activation
    system (Lofroth, 1978; Bignami  et al., 1980).  It was also
    positive when tested in concentrations of 10-40 g/plate in a
    forward and a back mutation system in  S. coelicolor and two
    forward mutation systems in  A. nidulans (Bignami  et al., 1980). 
    DCA (0.01%) was not mutagenic to  K. pneumoniae in a fluctuation
    test (Voogd  et al., 1972).  DCA did not induce unscheduled DNA
    synthesis in the human epithelial-like cell EUE as well as
    ouabain-resistant mutations in cultured V-79 Chinese hamster cells
    (Aquilina  et al., 1984).  In a dominant lethal assay with DCA
    administered as a single i.p. injection of 176 mg/kg bw to two
    strains of male mice (AB Jena-Halle and DBA), positive effects were
    reported (Fischer  et al., 1977).  It should be noted, however,
    that the dose used would never be reached after dichlorvos treatment
    (i.p. LD50 = 28-41 mg/kg bw).  Ramel (1981) reported negative
    results in a dominant lethal study with another strain of mice.

         No evidence for mutagenicity of dichloroethanol was obtained in
     S. typhimurium TA 100 and TA 1535 (Lofroth, 1978; Bignami  et al.,
    1980).  In  S. coelicolor (test doses 60-80 g/plate) and  A.
     nidulans (test doses 10-50 g/plate), dichloroethanol was a weak

    mutagen (Bignami  et al., 1980).  Dichloroethanol (1 M and 0.1%)
    was mutagenic to  K. pneumoniae in a fluctuation test (Voogd  et
     al., 1972).

    Special studies on skin sensitization

         In the guinea-pig maximization test by Magnusson & Kligman,
    using intradermal and topical induction concentrations of 5% and 25%
    in water respectively, a 0.5% challenge concentration caused
    sensitization in 30-40% of the animals but a 0.05% challenge
    concentration caused no sensitization (Matsushita  et al., 1985).

    Special studies on testes

    Mice

         Groups of 14 male NMRI/Han mice received either a single oral
    dose of 40 mg/kg bw dichlorvos in olive oil or 18 daily oral doses
    of 0 or 10 mg/kg bw dichlorvos in olive oil.

         On days 9,18, 27, 36, 54 and 63, two animals from each group
    were killed and their testes examined histologically.  A significant
    increase in the number of damaged seminiferous tubules
    (desquamation, decreases in cell population, "holes") was observed
    in both dichlorvos groups.  The supporting Sertoli cells were also
    damaged, which may have resulted in the above effects.  In addition,
    there was an increase in the number and hypertrophy of Leydig cells. 
    No explanation was given for these effects (Krause & Homola, 1972,
    1974).

         An increased incidence, just above background, of sperm
    abnormalities, was observed in a screening study on hybrid mice
    given five daily i.p. injections of 10 mg/kg bw dichlorvos
    (approximately half the LD50).  At lower doses, 1 mg/kg bw, the
    number of sperm abnormalities was either similar to or lower than
    those in the controls (Wyrobek & Bruce, 1975).

    Rats

         Groups of 16 male juvenile Wistar rats received either 20 mg/kg
    bw dichlorvos in olive oil on days 4 and 5, 10 mg/kg bw dichlorvos
    in olive oil daily from days 4 to 23, or 0.1 ml olive oil daily from
    days 4 to 23.  On days 6, 12, 18, 26, 34, and 50 of life, two rats
    from each group were sacrificed.  Histological examination of the
    testes showed slight reduction in the number of spermatogenic cells
    and Leydig cells.  All changes were reversed by the 50th day of
    life.  It was assumed that a reduction in testosterone synthesis
    resulted in damage to the spermatogenic cells (Krause  et al.,
    1976).

         In a subsequent experiment measurement of testosterone
    concentrations in the testes, and luteinizing hormone (LH) and
    follicle stimulating hormone (FSH) concentrations in serum showed no
    differences between treated animals and olive-oil treated controls
    (Krause, 1977).  However, in this study the use of a different
    dosing regimen (10 mg/kg bw by gavage every other day for 2 weeks)
    prevented a strict comparison with the earlier study by Krause  et
     al. (1976).

         Fifty-five male Wistar rats (aged 5 months) were orally
    administered dichlorvos at levels of 5 or 10 mg/kg bw every other
    day for 8 weeks.  Eleven rats were killed every 4 weeks.  No change
    was seen in body-weight gain or testes weight.  The score values of
    the seminal cellular system decreased after 4-8 weeks of treatment,
    but were restored 8 weeks after the end of treatment (Fujita  et
     al., 1977).

    Miscellaneous studies

         Effects of inhaled ChE inhibitors, including dichlorvos
    (dissolved in acetone), on bronchial tonus were studied in young
    adult rats exposed head-only.  Bronchoconstriction did not occur at
    toxicologically significant doses.  An increase in response to
    acetylcholine provocation test was observed (Pauluhn  et al., 
    1987).

         The effect of diet on the toxicity of dichlorvos was
    investigated using young male rats kept for 30 days on the following
    diets: high protein (HPD), low protein (LPD), high fat (HFD), and
    standard (SD).  Growth rates were normal except for a slightly
    decreased body-weight gain in the HFD group.  A single i.p.
    injection of 50 mg/kg bw dichlorvos led to slightly higher mortality
    in LPD rats and slightly lower mortality in HPD rats, compared with
    SD rats (Purshottam & Kaveeshwar, 1979).

         In a further study, growing male rats were kept on an HFD or
    HPD for 30 days.  At the end of this period, a single i.p. dose of
    dichlorvos (20 or 30 mg/kg bw) was administered.  No difference in
    plasma and erythrocyte ChE inhibition was found.  In the case of the
    HPD, the spontaneous recovery of plasma and erythrocyte ChE activity
    was slightly reduced (Purshottam & Srivastava, 1984).

    Observations in humans

         In vitro studies

         The sensitivity to inhibition by dichlorvos of erythrocyte and
    brain ChE was higher than that of plasma ChE, the I50s being about
    10-8 and 10-7 mol/l, respectively (Skrinjaric-Spoljar  et al.,
    1973; Carter & Maddux, 1974; Lotti & Johnson, 1978; Boyer, 1978;

    Casale  et al., 1989).  The rate of phosphorylation of human
    erythrocyte ChE was similar to that of rat brain ChE (1.2 x 105 and
    1.5 x 105 mol/l/min at 37 C, pH 7.4-7,6, respectively).

         The rate of dichlorvos hydrolysis by human plasma at 37 C was
    found to be 7-11 mol/hour/ml (Reiner  et al., 1980; Traverso  et
     al., 1989).

    Studies on volunteers

         Six healthy male volunteers were given single oral doses of 7.5
    mg/kg bw of metrifonate. Concentrations of metrifonate (trichlorfon)
    and dichlorvos, which is a metrifonate rearrangement product, were
    determined in whole blood at different times for up to 24 hours. 
    The half-life of metrifonate was about 2 hours.  The concentrations
    of dichlorvos closely followed those of metrifonate with a constant
    ratio of 0.01-0.02.  However, a half-life for dichlorvos of 2 hours
    cannot be accepted because dichlorvos is continuously formed from
    metrifonate (Abdi & Villen, 1991).

         Groups of five young men received total daily doses of 1, 1.5,
    2 or 2.5 mg dichlorvos in corn oil per person, divided in two
    gelatin capsules administered at 08.00 h and at 15.00 h for 28 days. 
    A further group of ten men received 1.5 mg/day for 60 days.  Control
    groups of two men per dose level received gelatin capsules with corn
    oil.  Plasma and erythrocyte ChE activities were determined twice
    weekly before, during and after dosing.  Once each week a medical
    interview, complete blood count, and urinalysis were done on each
    subject.  Before dosing and after the last dose SGOT, ALP, PT,
    thymol turbidity, and total bilirubin were determined.

         The 2.5 mg/day dose produced a decrease in plasma ChE activity
    from the second week of treatment; dosing was discontinued after 20
    days when plasma values showed a 30% decrease.  The plasma ChE
    activity returned to control values 15 days after dosing was ended. 
    The 2 mg/day dose produced also a reduction in plasma ChE activity
    from the second week of treatment which reached a maximum inhibition
    of 29% the second day after the last dose.  The group receiving 1.5
    mg/day for 28 days showed no change in plasma ChE activity while in
    the group dosed for 60 days this activity was inhibited by 27%
    compared to the control values.  None of the groups showed an effect
    on erythrocyte ChE activity, haematology, clinical chemistry or
    urinalysis.  The NOAEL in this study was the highest dose tested of
    2.5 mg/day/man (approximately 0.03 mg/kg bw/day) based on the
    absence of inhibition of erythrocyte ChE activity (Rider, 1967;
    Rider  et al., 1967, 1968).

         Two groups of six men (21-45 years of age, 64-106 kg bw)
    received 0.9 mg dichlorvos three times a day for 21 days, either in
    a pre-meal capsule filled with cottonseed oil or in a gelatin salad

    consumed during the course of the meal.  Control subjects were dosed
    with either cotton seed oil capsules or plain gelatin.  No
    cholinergic signs or symptoms were observed.  Plasma ChE activity
    was inhibited by 30-40%, the inhibition being higher when dichlorvos
    in cotton seed oil was ingested before the meal.  The half-life for
    the regeneration of plasma ChE activity was 13.7 days.  Erythrocyte
    ChE activity was not reduced.  The NOAEL in this study was 0.04
    mg/kg bw/day, based on absence of erythrocyte cholinesterase
    inhibition (Boyer  et al., 1977).

         A number of studies have been done with a slow-release PVC
    formulation of dichlorvos intended for use as an anthelminticum. 
    Single oral doses of above 4 mg dichlorvos/kg bw resulted in
    inhibition of erythrocyte ChE activity 24 hours after application,
    the maximum being 46% at 32 mg/kg bw.  Plasma ChE activity was
    affected at single doses of 1 mg/kg bw (50% inhibition) and above. 
    However, no dichlorvos-related symptoms were observed.  Repeated
    oral dosing for 7 days produced clinical symptoms with doses of 8
    mg/kg bw/day and above.  Plasma ChE activity was inhibited by about
    80% at all dose levels (1-16 mg/kg bw/day).  Erythrocyte ChE
    activity showed a dose-related decrease from 5-30% at 1 mg/kg bw/day
    up to 50-80% inhibition at the highest dose.  Blood count, urine,
    liver function, PT and BUN were normal in all studies (Hine &
    Slomka, 1968, 1970; Pena-Chavarria  et al., 1969; Slomka & Hine,
    1981).

         In children (aged 7-18 years) orally treated with metrifonate
    (7.5, 10.0 or 12.5 mg/kg bw), the half-lives of recovery of
    inhibited erythrocyte AChE and plasma ChE were 15 and 6.7 days,
    respectively (Reiner & Plestina, 1979).  It is known that the
    anticholinesterase activity of metrifonate is due to its
    decomposition to dichlorvos (Reiner  et al., 1975).  Similar
    half-lives for plasma ChE have been described by Boyer  et al.,
    (1977) after repeated oral dosing with dichlorvos and by Bisby &
    Simpson (1975) after cutaneous exposure of a sprayman to dichlorvos. 
    This longer half-life contrasts with faster  in vitro half-lives,
    which are similar to those of the rodent (Skrinjaric-Spoljar  et
     al., 1973).

         Several inhalation studies have been carried out and are
    summarized by WHO (1989).  These studies confirmed that plasma ChE
    is more sensitive to inhibition by dichlorvos than RBC ChE.  The
    latter was found inhibited when the dichlorvos dose (concentration x
    time) was higher than about 1500 mg/m3/min (WHO, 1989).

         Thirteen men (31-53 years of age) were exposed to dichlorvos
    strips (20% dichlorvos; 1 strip per 30 m3) for 3 months.  No
    biologically or statistically significant changes were observed in
    their electromyography results nor in their whole blood ChE activity
    (Ottevanger, 1975).

    Poisoning incidents

         Fournier  et al. (1978) reported that dichlorvos was detected
    in blood in three cases of human intoxication within 24 hours after
    poisoning (exact timing not reported).

         A woman who intentionally ingested an estimated 100 mg
    dichlorvos/kg bw survived following intensive care for 14 days
    (Watanabe  et al., 1974).  A suicide with a dichlorvos dose of
    about 400 mg/kg bw succeeded in spite of treatment (Shinoda  et al.,
    1972).  A female patient, aged 35 years, who had accidentally
    ingested 60 g fluid Divipan (dichlorvos concentration not reported),
    was comatose for a week and recovered slowly.  Clinical and
    electrophysiological examinations showed a pure motor form of
    neuropathy, according to the authors (Vasilescu & Florescu, 1980). 
    Three cases of poisoning with dichlorvos taken orally in unspecified
    but high quantities have been reported from India.  The patients
    first showed severe cholinergic signs for a few days.  After
    recovery, delayed neurotoxicity developed.  Nerve conduction studies
    showed a severe axonal degeneration (Wadia  et al., 1985, 1987). 
    Thirteen cases of dichlorvos ingestion, either accidental or
    deliberate, were reported from a hospital in Beijing, China.  The
    patients included 10 women and three men, aged 11-38 years.  Twelve
    of the 13 patients ingested 25-50 ml of dichlorvos (80% purity). 
    Ten cases were associated with acute pulmonary oedema.  Two patients
    died because OP poisoning was not diagnosed in time.  The others
    recovered completely 2-5 days after treatment (Li  et al., 1989).

    Occupational Exposure

         A number of fatal and non-fatal dichlorvos poisoning cases have
    been described and summarized by WHO (1989).  Two workers who failed
    to promptly wash off the concentrated formulation of dichlorvos,
    which splashed on to their skin, died subsequently.  However, in
    those cases where the spilled solution was washed off immediately,
    the victims showed symptoms of intoxication but recovered after
    treatment.  Occupational exposure of spraymen entails both dermal
    and respiratory absorption of dichlorvos.  When appropriate
    protective equipment was not used, inhibition of plasma ChE and less
    frequently of RBC ChE was found.  Sometimes mild, short lasting,
    cholinergic symptoms and signs have been reported (WHO, 1989).

         Each of 13 pest-control operators carried out urban
    pest-control work for one day in 4 houses using 230-330 g dichlorvos
    as aerosol and 40-50 g dichlorvos as emulsion spray.  At the end of
    the day's work, an operator had an average dichlorvos residue of 0.8
    mg/m2 on the back, 0.4 mg/m2 on the chest, and 11 mg/m2 on the
    respirator filter.  Urinary dimethylphosphate excretion in 3
    applicators ranged from 0.32 to 1.39 micrograms on the day of
    treatment, but approached the level of detection by the following

    morning.  Blood and urine analyses revealed no changes in various
    clinical parameters, including serum cholinesterase levels (Das  et
     al., 1983).

    COMMENTS

         Dichlorvos is rapidly absorbed by all routes of exposure and
    rapidly degraded.  The metabolic pathways of dichlorvos are similar
    in mammalian species, including humans.  Metabolites are rapidly
    excreted or incorporated into natural enzymatic pathways.

         Dichlorvos has a marked acute oral toxicity with typical
    cholinergic signs and has been classified by WHO as highly
    hazardous.

         Rat erythrocyte and brain cholinesterase inhibited by
    dichlorvos spontaneously reactivates with a half-life of about two
    hours both  in vitro and  in vivo.

         Several carcinogenicity studies in mice and rats using routes
    other than gavage were negative, even when doses causing signs of
    toxicity were used.  It should be noted that two squamous-cell
    carcinomas of the oesophagus have been observed in treated mice in
    one study.

         In a carcinogenicity study in mice dichlorvos administered by
    corn oil gavage (0, 10 or 20 mg/kg bw/day to males, and 0, 20 or 40
    mg/kg bw/day to females), caused forestomach papillomas
    (statistically-significant positive trend with increased incidence
    in the high-dose female group).  Elements of the mechanism by which
    these papillomas might arise have not been established, but the
    induction of hyperplasia in the forestomach was demonstrated. 
    Additionally, genotoxic effects might occur at high local
    concentrations of dichlorvos (see below) as can be obtained in
    gavage dosing but not in dietary exposure.  Based on the increased
    incidence of forestomach papillomas, the NOAEL was 10 mg/kg bw/day.

         In a two-year feeding study in rats (0, 0.1, 1, 10, 100 or 500
    ppm), no neoplastic lesions were attributed to treatment.  The
    NOAEL, based on brain cholinesterase inhibition, was 100 ppm (actual
    concentration 47 ppm, equivalent to 2.4 mg/kg bw/day).

         In a carcinogenicity study in Fischer 344 rats, dichlorvos
    administered by corn oil gavage (0, 4 or 8 mg/kg bw/day) caused an
    increased incidence of pancreatic adenomas (statistically
    significant in males only), mononuclear cell leukemias
    (statistically significant in males only, no dose response) and
    mammary gland adenomas or fibroadenomas (females only, no dose
    response, statistically-significant in the low-dose group only). 
    The Meeting observed that the incidence of pancreatic acinar
    adenomas in male control rats was unusually high and therefore the
    higher incidence found in treated animals was considered of
    questionable biological significance.  The increased incidence of
    mononuclear cell leukaemia which is usually high and variable in

    this strain of rats, was also of questionable biological
    significance.  The doses used significantly inhibited plasma, but
    not erythrocyte, cholinesterase activity when measured three hours
    after treatment.  However, given the rapid recovery of erythrocyte
    cholinesterase activity after inhibition by dichlorvos, the timing
    might have underestimated the inhibition.

         Dichlorvos has been adequately tested in a series of  in vitro
    and  in vivo genotoxicity assays.  These data indicate that
    dichlorvos is genotoxic in bacteria and cultured mammalian cells,
    but that it is not clastogenic  in vivo except under conditions
    where an unusually high tissue dose can be attained.  Dichloro-
    acetaldehyde, a major metabolite of dichlorvos, is a weak bacterial
    mutagen.  Positive results have been reported in mice given a dose
    of dichloroacetaldehyde far greater than that which could derive
    from sublethal doses of dichlorvos.  Dichlorvos has been shown to
    methylate DNA  in vitro at a rate that is 8-9 orders of magnitude
    lower than the rate of phosphorylation.  Therefore, DNA alkylation
    is not likely to occur at doses of dichlorvos which are not
    inhibitory to erythrocyte/brain cholinesterase.

         A three-generation reproduction study in rats was negative at
    doses up to 235 ppm in the diet, equivalent to 12 mg/kg bw/day.  A
    one-litter, one-generation study in mice in which dichlorvos was
    administered by inhalation at doses which caused > 90% plasma
    cholinesterase inhibition, but no signs of toxicity, was negative. 
    Dichlorvos caused reversible damage of seminiferous tubules, Leydig
    and Sertoli cells at oral doses of 10 mg/kg bw daily for 18 days in
    mice and at 5 mg/kg bw and above every other day for 8 weeks in
    rats.

         Dichlorvos appeared not to be teratogenic in mice, rats and
    rabbits at doses which caused maternal toxicity.

         Dichlorvos caused delayed polyneuropathy in hens at doses much
    higher than the unprotected LD50.  Cases of delayed polyneuropathy
    also have been reported in humans after severe intoxications.

         In humans, the rate of dichlorvos hydrolysis by plasma is
    similar to that in rats.  The rate of recovery of inhibited
    erythrocyte and plasma cholinesterase activity in humans given
    dichlorvos is much slower than in rats.  Half-lives of recovery are
    about 15 days in humans and about two hours in rats.  A daily dose
    of 1 mg/kg bw to male human volunteers for seven days caused 5-30%
    inhibition of erythrocyte cholinesterase.  The NOAEL in humans,
    based on absence of erythrocyte cholinesterase inhibition in 12
    volunteer males for 21 days was 0.04 mg/kg bw/day.

         In 1986, the Joint Meeting discussed the significance of
    carcinogenicity studies for organophosphorus pesticides and the

    requirements for further studies (Section 3.1 of Annex 1, reference
    47).  At that time none of the organophosphorus pesticides had
    caused a carcinogenic response in experimental animals.  That Joint
    Meeting recommended that, depending upon future evaluation on a case
    by case basis, further consideration should be given to the need for
    carcinogenicity studies for organophosphates.

         In assessing the potential hazard to humans of residues of
    dichlorvos, the following considerations were taken into account in
    view of the weakly positive results in the gavage carcinogenicity
    study in mice.

         Organophosphorus esters used as insecticides react with
    biological molecules by means of phosphorylation of serine
    hydrolases and of alkylation of macromolecules.  Phosphorylation of
    acetylcholinesterase and alkylation of DNA are considered to account
    for the acute cholinergic toxicity and initiation of the
    carcinogenic process, respectively.  These biochemical reactions
    occur at different rates.  When the rate of phosphorylation is
    substantially higher than the rate of alkylation,  in vivo
    genotoxic effects are unlikely to occur because effective doses
    cannot be achieved due to acute toxicity.  Dichlorvos meets these
    criteria, the rate of phosphorylation of acetylcholinesterase being
    much faster (eight orders of magnitude) than that of alkylation of
    several macromolecules, including DNA.  Hence positive mutagenicity
    tests were seen only  in vitro and, as indicated in the 1986 Joint
    Meeting report, carcinogenicity studies are unlikely to give more
    information.  The weak carcinogenic response of dichlorvos obtained
    in mice in a corn oil gavage study should be interpreted as a local
    effect of dichlorvos.

         Information on comparative cholinergic toxicity might be of
    critical relevance for the extrapolation of toxic effects (other
    than acute effects) of organophosphates in experimental animals to
    humans.  The characteristics of the interactions of a given compound
    with acetylcholinesterase (rates of phosphorylation, spontaneous
    reactivation and ageing) from different species can be compared  in
     vitro.  Also, the  in vivo rate of reappearance of blood
    acetylcholinesterase activity can be measured.  In some cases,
    metabolic degradation of organophosphates can be assessed
    comparatively by measuring the level of serum A esterase, which
    hydrolyses a given compound.  All these data enable an improved
    assessment of cholinergic toxicity of organophosphates in different
    species.  This knowledge may be of special significance in the case
    of dimethyl phosphates since the rates of  in vivo reactivation
    vary substantially across species.  Therefore, chronic dosing is
    more critical for extrapolation from animal data to humans.  In a
    repeated dose regime, the longer the half-life of reactivation the
    more rapid and/or more toxic will be the resulting effect (i.e. in a
    chronic dosing regime, humans will survive much lower doses of
    dichlorvos causing, when given alone, peak erythrocyte/brain

    cholinesterase inhibition than those which can be reached in
    rodents).  Therefore, comparison between the  in vivo rates of
    recovery of enzyme activity will enable an assessment of the
    repeated doses of compounds and the resulting cholinesterase
    inhibition, which would represent the limiting factors for other
    toxicities (including mutagenicity and carcinogenicity).

         In the case of dichlorvos, the Meeting considered the
    extrapolation of carcinogenicity data derived in rodents and its
    applicability to human safety, and concluded that the compound would
    not result in chronic human health hazards at doses below those
    which result in acetylcholinesterase inhibition.

         The Meeting maintained the ADI, which is based on studies in
    humans with a NOAEL of 0.04 mg/kg bw/day, using a 10-fold safety
    factor.

    TOXICOLOGICAL EVALUATION

    Level causing no toxicological effect

         Mouse:    10 mg/kg bw/day (two-year study)

         Rat:      47 ppm in the diet, equivalent to 2.4 mg/kg bw/day
                   (two-year study)

         Human:    0.04 mg/kg bw/day (21-day study)

    Estimate of acceptable daily intake for humans

                   0-0.004 mg/kg bw

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

         Further observations in humans.

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    See Also:
       Toxicological Abbreviations
       Dichlorvos (EHC 79, 1988)
       Dichlorvos (HSG 18, 1988)
       Dichlorvos (ICSC)
       Dichlorvos (FAO Meeting Report PL/1965/10/1)
       Dichlorvos (FAO/PL:CP/15)
       Dichlorvos (FAO/PL:1967/M/11/1)
       Dichlorvos (FAO/PL:1969/M/17/1)
       Dichlorvos (AGP:1970/M/12/1)
       Dichlorvos (WHO Pesticide Residues Series 4)
       Dichlorvos (Pesticide residues in food: 1977 evaluations)
       Dichlorvos (IARC Summary & Evaluation, Volume 53, 1991)