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    CADUSAFOS

    First draft prepared by Dr. E. Bosshard
    Federal Office of Public Health
    Zurich, Switzerland

    S,S-di-sec-butyl O-ethyl phosphorodithioate

    EXPLANATION

         Cadusafos is an organophosphate insecticide, which was evaluated
    by the JMPR for the first time at this meeting.  It is effective for
    controlling attacks by nematodes and soil-borne insects on bananas,
    citrus, maize, potatoes and sugar cane.  It is formulated for soil
    application as granules, an emulsifiable concentrate and a
    microemulsion.

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    BIOLOGICAL DATA

    Biochemical aspects

    Absorption, distribution and excretion

         Adult rats (Sprague-Dawley, 5/sex) were dosed orally with single
    doses of 20 mg/kg bw 14C-labelled cadusafos.  Urine and faeces were
    collected for 7 days.  Animals were then sacrificed and carcass and
    tissues were analyzed for residual radioactivity.  About 75% of the
    applied radioactivity was excreted in urine and about 15% in faeces
    over the course of 7 days. Most radioactivity was eliminated within
    the first 24 hours after dosing.  Highest residues were measured in
    liver and in adipose tissue with a mean value of 0.7 ppm.  Another
    group of rats (5/sex) was monitored for 14CO2.  Expiration amounted
    to 13% of the applied radioactivity within three days. No sex
    difference in the elimination and distribution pattern was observed
    (Selim, 1984).

         Rats (Crl:CD(SD)BR, 10/sex/group) received one of four dosing
    regimens with 14C-labelled cadusafos.  Dosing regimens were a single
    oral low dose of 1 mg/kg bw, a single iv dose of 0.8 mg/kg bw,
    multiple oral low doses of 1 mg/kg bw nonlabelled material over 14
    days followed by an additional dose of labelled material and a control
    group. Urine and faeces were collected for 7 days and tissues were
    then analyzed for remaining radioactivity.  Animals for which 14CO2
    was monitored were sacrificed 3 days after dosing.  For all groups,
    more than 90% of the administered radioactivity was eliminated within
    48 hours after dosing.  Mean total urinary excretion was about 67%,
    78% and 71% after oral single, iv and oral multiple dosing,
    respectively. Corresponding  excretion values in faeces were 10%, 5%
    and  7%.  14CO2 expiration varied between 13% and 16% in the three
    dosing regimens. Residues in tissues were low.  Highest levels were
    measured in liver and in fat showing mean concentrations of up to
    about 0.07 ppm in liver and 0.03 ppm in fat after oral dosing.  In the
    iv study mean concentration in lung was highest with mean values of
    about 0.05 ppm, followed by a concentration of 0.03 ppm in liver and
    fat. No marked sex differences were observed (Puhl, 1987).

    Biotransformation

         Male and female rats (Sprague-Dawley, 5/sex/dose) were
    administered an oral dose of 14C-labelled cadusafos (at the butyl
    side chains) at rates of 1 and 21 mg/kg bw.  Another group received
    multiple oral doses of 1 mg/kg bw (labelled and non-labelled
    material).  Results from oral dosing were compared to those from iv
    dosing consisting of a single dose of about 0.8 mg/kg bw.  The
    excretion pattern found in previous experiments was confirmed.

    Analyses of excretion profiles showed that the majority of 14C
    activity was eliminated within the first 24 hours after dosing.  In
    the fraction of non-conjugated neutral metabolites the majority of the
    radioactivity excreted in urine was contributed by methyl-1-methyl-2-
    hydroxypropane sulfone.  Other metabolites detected were
    0-ethyl-S-(2-butyl) phosphorothioic acid, S,S-di-(2-butyl)
    phosphorodithioic acid, methyl-2-butyl-sulfone and sulfoxide. 
    0-ethyl-S-(2-butyl)phosphorothioic acid, methylsulfonic acid, hydroxy
    sulfone and  sec-butyl sulfonic acid were identified.  As major polar
    metabolites in the remaining fractions such compounds as
    4-hydroxy-2-butyl sulfonic acid, 3-hydroxy-2-butyl sulfonic acid,
     sec-butyl sulfonic acids, and S-(2-butyl) phosphorothioic acid were
    detected. In faeces the parent compound was found at rates of 6 to 64%
    in the different oral dosing regimens with highest values after
    administration of a single oral high dose.  In the intravenously dosed
    group parent compound was not detected in faeces. Major faecal
    metabolites were  sec-butyl sulfonic acid and monophosphorothioic
    acid-related acidic compounds.

         Cleavage of the thio-( sec-butyl) group is the initial step
    producing sec-butyl mercaptan and 0-ethyl-S-(2-butyl)phosphorothioic
    acid as major metabolites. Further cleavage and oxidation reactions
    may result in S-(2-butyl)phosphorothioic acid or 0-ethyl
    phosphorothioic acid, methyl  sec-butyl sulfide, sulfoxide, sulfone
    and finally hydroxysulfones.   Sec-butyl mercaptan can also be
    oxidized to butyl sulfonic acid, ethyl and methyl sulfonic acid.
    Formation of CO2 could be derived from either the  sec-butyl
    mercaptan moiety or the corresponding sulfonic acid.  CO2 may then
    be incorporated into urea or other endogenous substances (Wu, 1988).

    Toxicological studies

    Acute toxicity studies

         The predominant signs of toxicity were those typical for
    cholinesterase inhibition; tremors, loss of muscle control, decreased
    locomotion, diarrhoea, lacrimation and salivation.  These effects
    occurred irrespective of the species and application route.  The data
    are summarized in Table 1.

    FIGURE 1

    Table 1:  Acute toxicity of Cadusafos

                                                                            

    Species   Sex      Route     LD50            Reference
                                 (mg/kg bw)
                                                                        

    Mouse     M&F      oral      71              Rand (1983b)

    Rat       M&F      oral      39 (F)a         De Prospo (1986)

                                 132 (M)a
                                 42 (F)a         Freeman (1987b)
                                 80 (M)a
                                 30 (F)b         McCarty (1984c)
                                 48 (M)b

    Rabbit    M&F      dermal    11              Freeman (1987a)
                                 41 (F)b         Rand (1983a)
                                 24 (M)b

    Rat       M&F      inh       0.032 mg/lc     Dudek (1984)
                                                                        

    a  1% (w/v) in corn oil
    b  10% (w/v) in corn oil
    c  4-hour LC50
    
         Skin and eye irritation testing were performed in rabbits.  One
    hour after the application of 0.1 ml of Cadusafos (> LD50) into one
    eye moderate discharge, miosis and corneal depressions appeared. 
    Clinical signs including loss of muscle control were observed.  All
    animals died within two hours of dosing. In a repetition experiment
    only 0.01 ml of Cadusafos was applied. Slight irritation was observed
    only in the unwashed eyes (McCarty, 1984a).

         Primary skin irritation was tested with small doses of 0.015 ml
    on each  of two test sites for four hours. No skin reaction was
    observed, however clinical signs became manifest and most animals died
    within 24 hours after treatment (McCarty 1984b).

         No sensitizing potential was observed in guinea pigs after
    topical application at doses of 0.01 ml.

    Short-term studies

    Rats

         Groups of rats (Sprague-Dawley, 15/sex/group) received Cadusafos
    in their diet at concentrations of 0, 0.1, 0.5, 1.0, 5.0 and 800 ppm
    over at least 90 days.  An additional 10 animals were assigned to the
    control and 5 ppm groups to study reversibility of the effects or
    delayed toxicity over 28 days after termination of the main study.

         Treatment-related effects occurred in animals at 800 ppm and
    consisted of decreased locomotion, tremors and emaciation, and splayed
    hindlegs. Thirteen of 15 female and 11/15 male animals at 800 ppm died
    or were sacrificed moribund prior to termination of the study.  No
    treatment-related increase in mortality was found in the other dose
    groups.  Marked reduction with respect to total body weight gain
    occurred in the animals dosed at 800 ppm, resulting in values of 50%
    of the control animals.  No dose-related decrease was observed in the
    other dose groups.  Animals at 800 ppm also showed reduced food
    consumption  particularly at the beginning of the study. 
    Haematological changes observed at 800 ppm included an increase in
    platelet count, a decrease of the haemoglobin level and haematocrit
    value and, particularly in male animals, a slight reduction in red
    blood cell count. Also various clinical chemistry values were changed
    at the highest dose level: depression of glucose (in males only),
    total protein and, particularly in females, an increase of the blood
    urea nitrogen level. Inhibition of the cholinesterase activity in
    plasma and erythrocytes was observed at 5 and 800 ppm.  At 5 ppm,
    maximal inhibition in plasma was about 24% in males,  almost 50% in
    females. Maximum erythrocyte inhibition was 22% in males and about 25% 
    in females at 5 ppm. Brain cholinesterase was only marginally
    inhibited (6%) at 5 ppm.  After the twenty-eight day recovery period
    no significant differences between animals treated with 5 ppm and
    control animals were found with respect to cholinesterase inhibition. 
    Severe cholinesterase inhibition occurred at 800 ppm.  In plasma,
    activity was below the detection limit and in erythrocytes in females
    inhibition amounted to 86% whereas males were somewhat less affected.
    Brain cholines-terase inhibition was about 85% in both  sexes. Changes
    in absolute and/or relative organ weights were seen at 800 ppm in
    different organs. No compound-related histologic alterations in
    tissues were seen.

         The no observed adverse effect level (NOAEL) in rats under the
    conditions of this study is 1.0 ppm in the diet (70 g/kg bw)
    considering the cholinesterase inhibition in erythrocytes and brain at
    higher dose levels as biologically significant (McCarty  et al.,
    1985).

    Dogs

         Groups of Beagle dogs (4/sex/dose) received cadusafos by capsule
    at dose levels of 0, 10, 30 and 90 g/kg bw over 91 days.  Treatment
    had no effect on clinical signs of toxicity, ophthalmoscopic findings,
    body weight, food consumption, parameters of clinical chemistry and
    haematology, gross or microscopic pathology.  Treatment-related
    effects consisted of a dose-related inhibition of cholinesterase
    activity in plasma at dose levels of 30 and 90 g/kg bw.  Inhibition
    resulted in values of about 60% and 40% of the pretest value at 30 and
    90 g/kg bw, respectively. Maximum inhibition at the 10 g/kg bw
    level resulted in an activity corresponding to about 80% of the
    pretest value.  No dose-related depression of acetylcholinesterase
    inhibition was observed in erythrocytes or brain.  A sex difference
    was not obvious. A decrease in absolute and relative testicular weight
    was observed at 30 and 90 g/kg bw.  The difference between these two
    dose groups was not dose-related and was not considered to be
    treatment-related.  No gross pathological or micropathological lesions
    attributable to the test compound were found (Seely  et al., 1985b).

         Groups of Beagle dogs (4/sex/dose) were dosed orally with
    cadusafos by capsule at dose levels of 0, 0.2, 1, 5 or 20 g/kg bw
    seven days a week over one year. Dose levels were selected based on
    results of a dose-range finding study and the 91-day study performed 
    previously in this laboratory (Seely  et al., 1985a,b). The treatment
    had no effect on survival, clinical signs, ophthalmoscopic findings,
    body weight food consumption, parameters of clinical chemistry and
    haematology, nor organ weights.  The only treatment-related effect
    observed in males was an inhibition of the plasma cholinesterase
    activity at 20 g/kg bw resulting in a 40% lower value compared to the
    pretest activity. In females treated with 5 or 20 g/kg bw
    cholinesterase activity inhibition in plasma was about 25%. No other
    compound-related differences in cholinesterase activities were
    observed.  Gross and microscopic examination revealed no
    compound-related lesions in any tissue (Shellenberger, 1986).

         A short-term toxicity study comparing cadusafos produced by the
    old and new manufacturing processes was performed in dogs.  Groups of
    Beagle dogs (4/sex/group) were treated with the two products by
    capsule at levels of 0, 1, 10 and 100 g/kg bw over 13 weeks.  No
    deaths nor clinical signs which were considered to be treatment
    related occurred. No differences were observed between the dose groups
    with respect to body weight, food consumption, organ weight or gross
    necropsy findings.  Plasma cholinesterase inhibition was about 20% at
    10 g/kg bw, about 60% at 100 g/kg bw.  No significant difference
    occurred between the old and the new material (Dalgard, 1988).  The no
    observable effect level was 1 g/kg bw/day.

    Long-term/carcinogenicity studies

    Mice

         Groups of mice (Swiss-Webster, 60/sex/group) received Cadusafos
    in the diet at concentrations of 0, 0.1, 0.5, 1.0, and 5.0 ppm over
    two years. Ten animals/sex/dose were sacrificed after one year of
    treatment for interim investigations.  Selection of dietary
    concentrations were based on the results of a range finding study
    conducted earlier in this laboratory (McCarty  et al., 1986).

         Feeding of Cadusafos did not influence the survival of the test
    animals, body weight, food consumption, parameters of hematology or
    organ weights. There were no clinical signs of toxicity other than
    decreased locomotor activity in treated animals.

         Marked inhibition of cholinesterase activity in plasma and
    erythrocytes at 5 ppm was observed (males 76%, females 68%). 
    Inhibition of cholinesterase activity in erythrocytes was about 26% in
    males and about 32% in females.  Brain cholinesterase activity was
    reduced by 13% only in males. Higher incidences of non-neoplastic
    effects included adrenal cortical atrophy in treated animals of both
    sexes, focal cortical cell hyperplasia in treated males and duodenal
    mucosal hyperplasia in females at 5 ppm.  In males necrotizing
    arteritis in kidney showed incidences of 6%, 8%, 10%, 22% and 24% in
    dose groups 0 to 5 ppm respectively. In male mice a slight increase in
    the incidence of lymphoreticular neoplasms  was found resulting in
    frequencies of 12%, 10%, 10%, 16% and 22% in groups 0, 0.1, 0.5, 1.0,
    and 5 ppm, respectively. In another carcinogenicity study with
    Swiss-Webster mice conducted in the same laboratory the control
    incidence was 14%. In NTP studies,  the total mean incidence was 16%
    with a standard deviation of 15.1. These tumours were not considered
    to have been treatment-related.

         A NOAEL of 0.5 ppm, corresponding to about 72 g/kg bw, was
    determined, based on renal necrotizing arteritis occurring in higher
    incidences at dose levels of 1 ppm and above in male mice (McCarty
     et al., 1987).

    Rats

         Cadusafos was administered continuously to groups of rats
    (Sprague-Dawley, 60/sex/dose) at dietary concentrations of 0, 0.1,
    0.5, 1.0 and  5.0 ppm over two years. Dose level selection was based
    on the results of a previous range-finding study (Rand, 1986) and a
    cholinesterase inhibition titration study (Geiger, 1986).  Ten
    animals/sex/group were used for interim histopathological examination
    after 12 months.

         Mortality, body weight, food consumption, parameters of clinical
    chemistry and haematology, urinalysis and organ weights were not
    affected by the treatment. Ophthalmoscopic examinations did not reveal
    dose-related alterations.  Cholines-terase activity was inhibited in
    plasma and erythrocytes at 5 ppm with maximum inhibition of 37% and
    23% respectively in males. Females were somewhat more affected showing
    maximum inhibition in plasma and erythrocytes of 52% and 31%,
    respectively.  Signs of toxicity consisting of decreased locomotion
    became apparent in females at 5 ppm. Inhibition of brain
    cholinesterase was not found.

         Tissues of all animals in the control group and the highest dose
    group were examined.  However, in the 0.1, 0.5 and 1.0 ppm dose
    groups, tissues of only some of the animals (about 60%) were examined
    histologically.  Based on the incomplete data submitted the incidences
    of neoplastic findings including astrocytoma in the brain, pituitary
    adenoma, adrenal pheochromocytoma, c-cell adenoma and carcinoma of the
    thyroid were higher in the 0.1, 0.5 and 1.0 ppm groups, particularly
    in males.  However, dose-response relationships were lacking and the
    increases were considered to be unrelated to treatment (Weiner
     et al., 1986).

         The level of 1 ppm (50 g/kg bw) is identified as the NOAEL based
    on significant inhibition of cholinesterase activity in erythrocytes
    and clinical signs of toxicity at higher dose levels.

    Reproduction study

         Cadusafos was administered continuously in the diet to groups of
    rats (Sprague-Dawley, 25/sex/group) over two consecutive generations. 
    Each generation consisted of two litters.  Dietary levels were 0, 0.1,
    0.5 and 5.0 ppm.  Breeding was initiated after 8 weeks of exposure for
    the animals of the parental generation (F0) and after 11 weeks of
    exposure for the following generation (F1).

        All adults and selected weanlings (10/sex/group) were subjected to
    a complete necropsy.  Microscopic examination of selected tissues was
    conducted for parental animals in the 0 and 5 ppm group and for all
    weanlings.  The treatment did not affect mortality. A slight reduction
    in total body weight gain (less than 10%) was observed in F0 males
    at 0.5 and 5 ppm without dose-relationship. In the F1 generation body
    weight gain was reduced about 10% in both sexes at 5 ppm.
    Cholinesterase premating activity in plasma and red blood cells was
    inhibited at rates of about 16% and 18%, respectively, in F0 males
    fed with 5 ppm.  In F0 females at 5 ppm inhibition of plasma
    cholinesterase relative to premating activity was 45%, in red blood
    cells 18%.  Similar values were found at termination.  F1 animals
    showed a similar inhibition pattern, resulting in cholinesterase
    inhibition in plasma (19% and 57%) and in erythrocytes (20% and 25%,
    in males and  females, respectively) fed with 5 ppm until termination

    of the study. There were no treatment-related effects on brain
    cholinesterase activities in  the F0 or F1 generation.  A higher
    incidence of stillbirths was observed in one litter of the F1
    generation at 0.5 and 5 ppm.  The same effect was not found in any
    other litter. The apparent dose-related increase probably is a
    reflection of the unusually low control incidence in that litter.
    There were no gross or microscopic alterations in any generation which
    were considered to be treatment-related. The NOAEL was 0.5 ppm
    (equivalent to 25 g/kg bw) based on decreased body weight gain
    (DeProspo  et al., 1987).

    Special studies on embryotoxicity and teratogenicity

    Rats

         Rats (Sprague-Dawley, 25 female/group) received oral doses of 0,
    2.0, 6.0  and 18 mg/kg bw by gavage on days 6 through 15 of gestation. 
    Caesarean section was performed on day 20 of gestation. At 18 mg/kg bw
    signs of toxicity between study days 7 and 20 were observed in all
    animals and included tremors, decreased locomotion, alopecia, oral
    discharge, lacrimation. The same signs were observed in a few animals
    at 6 mg/kg bw but to a lesser extent.  Reduced body weight gain and
    food consumption were also observed in the 18 mg/kg bw group.

         No treatment-related effects were observed regarding the number
    of corpora lutea, implantations, resorptions or litter size. A
    decrease in fetal body weights was found among fetuses from the 18
    mg/kg bw group.  Gross external changes were  observed as single
    findings in pups of the 18 mg/kg bw including an umbilical hernia and
    a microphthalmia.  Single findings also occurred in fetuses from the
    6 mg/kg bw group (one anophthalmia, one atresia of genital papillae,
    one acaudate). At 18 mg/kg bw skeletal changes included fused ribs and
    vertebrae, absence of metatarsals and sternebrae and partial
    ossification. Various other findings were observed sporadically in the
    other dose groups.  The NOAEL in this study was 2 mg/kg bw for
    maternal toxicity and 6 mg/kg bw for fetotoxicity (Freeman, 1985).

    Rabbits

         Groups of rabbits (New Zealand White, 20 female/group) received
    Cadusafos orally by gavage at dosages of 0, 0.1, 0.3, or 0.9 mg/kg bw
    on day 7 through 19 of gestation. Caesarean section was performed on
    day 29 of gestation. Treatment related clinical signs were observed in
    animals at 0.9 mg/kg bw including hypersensitivity, rales, diarrhoea,
    dyspnoea, ataxia, loss of muscle control, prostration. In a few
    animals at 0.3 mg/kg bw similar clinical signs occurred.  One animal
    at 0.3 mg/kg bw and two animals at 0.9 mg/kg bw died.  One control
    animal died from undetermined causes and another animal in this group
    was sacrificed due to an early delivery.  Two rabbits at 0.9 mg/kg bw
    aborted.  Early delivery occurred in a control animal and in one
    animal at 0.9 mg/kg bw.

         Treatment did not influence implantation, litter size or fetal
    weights.  Malformations observed in pups consisting of fused or
    serrated sternebrae, manubrium and xiphoid bone showed incidental
    distribution over the dose groups.  The incidences of delayed skeletal
    ossification did not indicate a treatment relationship.

         Cadusafos caused maternal toxicity at levels of 0.3 mg/kg bw and
    above, most probably explaining the slight increase in the incidence
    of resorptions in the dose groups. The study gave no indication of a
    teratogenic effect of cadusafos.  The NOAEL in this study was shown to
    be 0.1 mg/kg bw (Freeman  et al., 1985).

    Special studies on genotoxicity

         Results of genotoxicity testing are summarized in Table 2. 
    Cadusafos showed no genotoxic activity in five tests screening for
    gene mutations nor one test screening for chromosome aberrations.  An
    increase in transformation frequency in the presence of exogenous
    metabolic activation, however, was found in a transformation test with
    BALB/3T3 mouse embryo cells. Positive results were limited to this
    single test system, and there were no other supportive indications for
    genotoxic activity.

    Special study on acute delayed neurotoxicity

         Four groups of ten hens were treated with a single oral dose of
    8 mg/kg bw, a dose corresponding to the approximate oral LD50.
    Atropine was administered to all test birds by intramuscular injection
    of 10 mg/kg bw immediately prior to dosing. Retreatment with cadusafos
    and atropine was performed after a 21-day observation period.  An
    additional group was treated with a single oral dose of 500 mg/kg bw.
    tri-o-cresylphosphate (TOCP) as positive control, another group only
    with corn oil as negative control group.  Mortalities (16/40) and
    clinical signs of toxicity including unsteadiness, leg stiffness and
    weakness were observed in animals treated with Cadusafos.  Surviving
    birds had recovered by days 4-6 after dosing. Similar observations
    were recorded after re-dosing. No clinical signs of neurotoxicity,
    assessed by the appearance of ataxia, were recorded in the control or
    surviving test birds. All positive control birds dosed with TOCP
    developed ataxia within the 21-day observation period (Roberts
     et al., 1984).

         As recorded in a summary report, treatment did not cause
    alterations in nerve tissue in 9/10 birds.  The effects observed in
    the remaining bird are probably not treatment-related (FMC, 1990a).


        Table 2:  Results of genotoxicity assays on Cadusafos
                                                                                                                       

    Test System          Test Object            Concentration                Results        Reference
                                                                                                                       

    Ames test            Salmonella             3.4-340 g/plate             Negative       Haworth et al. (1984)
                         typhimurium            (without activation)
                         (5 strains)            12-1200 g/plate
                                                (with activation)

    Ames test            Salmonella             8-900 g/plate               Negative       Lawlor (1985)
                         typhimurium            (with and without
                                                metabolic activation)

    CHO/HGPRT            Chinese hamster        2.5-75 g/ml                 Negative       Stankowski et al. (1985)
                         ovary cells            (without activation)
                                                5-125 g/ml
                                                (with activation)

    CHO/HGPRT            Chinese hamster        80-110 nl/ml                 Negative       Thilagar et al. (1984c)
                         ovary cell             (without activation)
                                                110-140 nl/ml
                                                (with activation)

    Chromosome           Chinese hamster        6.25-75 nl/ml                Negative       Thilagar et al. (1984a) 
    aberration test      ovary cells            (with and without
                                                metabolic activation)

    Unscheduled          Primary rat            10-45 nl/ml                  Negative       Thilagar et al. (1984b)
    DNA synthesis        hepatocytes

    Transformation       BALB/3T3 mouse         0.01-0.07 l/ml              Positive       Putman et al. (1984)
    assay                embryo cells           (without activation)         (activated
                                                0.06.0.09 l/ml              only)
                                                (with activation)
                                                                                                                       
    

    Special studies on antidotal effects

         Four groups of rats (Sprague-Dawley, 10/sex/group) were dosed
    orally in a 5% (w/v) solution in corn oil at dosage levels of 66 mg/kg
    bw (males) and 38 mg/kg bw (females).  Following treatment with
    cadusafos, one group received no antidotal treatment, one group
    received 100 mg/kg bw. atropine, one group 100 mg/kg bw, 2-PAM
    (2-pralidoxime) and one group 100 mg/kg bw atropine + 100 mg/kg bw
    2-PAM.  Observations for toxicity were conducted over 14 days after
    treatment.  Antidotes were administered immediately after the onset of
    clinical signs (Atropine sc injection, 2-PAM im injection).  Generally
    clinical signs including decreased locomotion, diarrhoea, lacrimation,
    mydriasis appeared earlier in females. Atropine treatment alone or in
    conjunction with 2-PAM was effective in amelioration of toxicity
    induced by oral administration of Cadusafos with respect to mortality,
    incidence, duration and severity of clinical signs.  2-PAM therefore
    seems not to be effective (Kedderis, 1988a).

         A similar study with dose levels of Cadusafos of 66 and 115 mg/kg
    bw (males) and 38 or 100 mg/kg bw (females) and the same antidotal
    treatment gave generally the same results concerning antidotal effects
    (Kedderis, 1988b).

    Studies on Cadusafos after the manufacturing change

         Short-term and long-term studies presented earlier in this paper
    (except for the short-term study in the dog) did not contain the
    impurity arising at a rate of 1-3% as a result of manufacturing
    change.   An additional long-term non-rodent study, an acute oral
    study as well as a mutagenicity study with Cadusafos containing the
    new impurity have been conducted.  Oral LD50 values for rats for the
    product after the manufacturing change are reported to be 131 mg/kg bw
    for males (vs 47.5 mg/kg bw before the change) and 30 mg/kg bw (vs 39
    mg/kg bw) for females.  No mutagenic activity was observed when tested
    with and without activation in the Ames-test.

         The available data do not give evidence of any differences in
    toxicity of the new product compared to the old product.

    COMMENTS

         Following oral administration to rats cadusafos was absorbed and
    eliminated mainly via the urine (50-70%), but also via expired air
    (10-15%) and faeces (5-10%).  Extensive metabolism proceeds by
    hydrolysis and oxidation.

         Cadusafos has a marked acute oral toxicity with typical signs of
    cholinesterase inhibition in the rats and mice tested.

         In a 90-day study in rats at dietary concentrations of 0.1, 0.5,
    1, 5 or 800 ppm, a NOAEL of 1 ppm (equal to 0.07 mg/kg bw/day) was
    determined, with 5 ppm causing inhibition in plasma and erythrocyte
    cholinesterase.

         In short-term studies in dogs cadusafos was administered by
    capsule at dose levels 0, 0.01, 0.03, 0.09 or 0.1 mg/kg bw/day for 91
    days or 0.0002, 0.001, 0.005 or 0.02 mg/kg bw/day for 1 year.  No
    adverse toxicological effects were observed.  The NOAEL for dogs,
    based on these studies, was 0.1 mg/kg bw/day.

         In a 2-year long-term/carcinogenicity study in mice using dietary
    concentrations of cadusafos of 0, 0.1, 0.5, 1 or 5 ppm, a NOAEL of 0.5
    ppm, equal to 0.089 mg/kg bw/day, was determined, based on the
    occurrence of renal necrotizing arteritis at 1 ppm.  There was no
    evidence of carcinogenicity.

         In a 2-year long-term/carcinogenicity study in rats at dietary
    concentrations of 0, 0.1, 0.5, 1 or 5 ppm, a NOAEL of 1 ppm, equal to
    0.05 and 0.06 mg/kg bw/day for males and females, respectively, was
    established.  At 5 ppm, erythrocyte acetylcholinesterase was inhibited
    without a corresponding inhibition of brain acetylcholinesterase. 
    However, clinical signs of toxicity were observed in females at 5 ppm. 
    There was no evidence of carcinogenicity.

         In a multi-generation study in rats at dietary concentrations of
    0, 0.1, 0.5 or 5 ppm, a NOAEL of 0.5 ppm, equal to 0.03 mg/kg bw/day,
    was determined.  At 5 ppm, reduction in body-weight gain and
    inhibition of cholinesterase in plasma and erythrocytes were noted in
    the F1 generation.  There were no adverse effects on reproduction.

         An oral teratogenicity study in rats at dose levels of 0, 2, 6 or
    18 mg/kg bw/day indicated dose-related maternal toxicity including
    clinical signs such as tremors, and red oral discharge at 6 and 18
    mg/kg bw/day. Embryo/fetotoxicity  at 18 mg/kg bw/day was indicated by
    a decrease in fetal body-weight gain.  There were no teratogenic
    effects.  The NOAEL was 2 mg/kg bw/day.  A teratogenicity study in
    rabbits at dose levels of 0, 0.1, 0.3 or 0.9 mg/kg bw/day showed
    maternal toxicity and embryotoxic effects at dose levels of 0.3 and
    0.9 mg/kg bw/day respectively.

         After reviewing the  in vitro genotoxicity data it was concluded
    that, on the basis of the limited data available, there was no
    evidence of genotoxicity.  A positive response was limited to a cell
    transformation assay with BALB/3T3 mouse embryo cells after
    activation.

         The ADI was based upon the results of the reproduction study in
    rats, using a 100-fold safety factor.

    TOXICOLOGICAL EVALUATION

    Level causing no toxicological effect

         Mouse:    0.5 ppm, equal to 0.089 mg/kg bw/day
         Rat:      1 ppm, equivalent to 0.05 mg/kg bw/day
                   (2-year study)
                   0.5 ppm, equal to 0.03 mg/kg bw/day
                   (reproduction study)
         Dog:      0.1 mg/kg bw/day

    Estimate of acceptable daily intake for humans

         0-0.0003 mg/kg bw

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

         Observations in humans.

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    See Also:
       Toxicological Abbreviations