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    CARTAP      JMPR 1976

    IDENTITY

    Chemical name

         1,3-di(carbamoylthio)-2-dimethylaminopropane

    Synonyms

         S,S'-[2-(Dimethylamino)trimethylene] bis(thiocarbamate)

         CaldranR  PadanR, PatapR, SanvexR, ThiobelR,
    Vegetox, NTD-2, TA-7, TI-1258.

    Structural formula

    FIGURE 1


    Other information on identity and properties

         Cartap is invariably used as the hydrochloride, to which the
    following information refers.

    Molecular weight:             273.8

    State:                        Colourless crystals

    Melting point:                179-181C(decomp.)

    Solubility(g/100 ml):         Soluble in water(13.2/10C,
                                  17.8/20C, 25.3/30C slightly soluble
                                  in methanol(2.08/5C), almost insoluble
                                  in acetone, benzene, chloroform,
                                  diethyl ether, ethyl acetate, and
                                  n-hexane.

    Purity of technical material: 97%. containing 3% of water and
                                  ammonium chloride as impurities.

    Hydroscopicity:               Slightly hygroscopic

    Volatility:                   Negligible

    Formulation:                  25% and 50% water-soluble powder, 2%
                                  dust, 4% and 10% granules and 2% fine
                                  granules are available. A bait
                                  formulation has recently been
                                  introduced.

         Cartap hydrochloride is an insecticide recently developed by
    Takeda Chemical Industries. It is a derivative of nereistoxin which
    is a naturally occurring insecticidal substance isolated from the
    marine segmented worms Lumbrinereis heteropoda and L.
    brevicirra.

         Nereistoxin was isolated by Nitta in 1934, the structure was
    elucidated by Okaichi and Hashimoto (1962) and synthesized in 1965
    by Hagiwara et al. A variety of nereistoxin derivatives were
    prepared and their insecticidal activities tested. Cartap
    hydrochloride is one of the most potent of the many compounds
    prepared.

         The chemistry and synthesis of nereistoxin and related
    compounds are dealt with by a number of authors including Hashimoto
    et al (1960); Okaichi and Hashimoto (1962); Hagiwara et al (1965);
    Konishi (1968a, 1968b); Hagiwara and Numata (1968); Konishi (1970a,
    1971); Sakai (1971); Nishi et al (1973).

    TOXICOLOGICAL STUDIES

    Special studies on reproduction

    Rat

         Groups of 10 male and 20 female rats were administered cartap
    hydrochloride in the diet at levels of 0, 100 and 1000 ppm for 9
    weeks prior to mating and subsequently for the remainder of the
    study which was a 2 litter, 2 generation reproduction study. One
    half of the F2b litters were delivered by caesarean section on day
    19 of gestation, the other half were delivered naturally and held
    to weaning. Parental animals showed reduced body weight gain and
    food consumption and an apparent impairment of fertility for the
    F1a generation at 1000 ppm. Gestation and live birth indices of
    the treated animals were comparable to those of the controls.
    Weanling survival index was lower in the F1b generation and pup
    weights in all generations at 7, 14 and 21 days after weaning were
    reduced at the upper dose level. There were no meaningful
    differences observed between groups with respect to number of
    implantation sites, resorptions or live and dead fetuses. No
    compound-related microscopic alterations were noted in selected
    tissues from weanling F2b progeny of the 1000 ppm group. However,

    a greater incidence of incomplete ossification was revealed on
    skeletal examination in this group, (Olson and Busey, 1972).

    Special studies on teratogenicity

    Mouse

         Three groups comprising 20, 12 and 14 pregnant mice received
    cartap hydrochloride by stomach tube at dose levels of 0, 50 and
    100 mg/kg body weight respectively from day 8 to day 13 of
    gestation. Twenty-one pregnant mice were employed as an untreated
    control group. Animals were killed on day 19 of gestation and
    fetuses removed by caesarean section. Weight gains were not
    affected. No significant variations were observed in the number of
    implantation sites, fetal mortality and mean body weight of fetuses
    between control and treated groups. No visceral abnormalities were
    observed. Skeletal examination revealed abnormalities (fusion of
    cervical vertebral arches and fusion of sternebrae) in 2/110
    fetuses (1.8%) at 50 mg/kg and 2/120 fetuses (1.7%) at 100 mg/kg.
    In respect to other skeletal variations, there were no significant
    differences between control and treated animals (Mizutani et al,
    1971).

    Rat

         Cartap hydrochloride was administered orally to three groups
    of 21, 12 and 17 pregnant rats at dose levels of 0, 50 and 100
    mg/kg body weight respectively from gestation day 9 to day 15.
    Twenty-three pregnant rats were used as an untreated control group.
    Animals were sacrificed on day 21 and fetuses were delivered by
    laparotomy. An increase in mortality and retarded weight gain were
    observed in the maternal animals at 100 mg/kg during the dosing
    period. There was no statistical difference between treated and
    control groups with respect to number of implantation sites, fetal
    mortality, sex ratio, external and visceral malformations. Skeletal
    examination revealed no major abnormalities except for an increase
    25/174 (14.4%) in bilateral twin thoracic vertebral centrae in the
    100 mg/kg group (Mizutani et al, 1971).

    Hamster

         Five groups comprising 9, 7, 8, 9 and 7 pregnant hamsters
    received cartap, hydrochloride orally at dose levels of 0, 2, 10,
    50 and 100 mg/kg body weight respectively from day 8 to day 13 of
    gestation. Fifteen pregnant hamsters were used as an untreated
    control group. Animals were killed on day 16 of gestation and
    fetuses removed by caesarean section. Treatment with 100 mg/kg
    resulted in the death of 2/7 animals and was associated with
    reduced weight gain. No compound-related effects were observed in
    the number of implantation sites, fetal mortality, fetal weights,
    external and visceral malformations. In hamsters receiving 100
    mg/kg, the frequency of skeletal anomalies increased slightly, 6/52
    (11.5%) showing abnormalities in the thoracic vertebrae and/or

    ribs. An increase in the incidence of fetuses with extra lumbar
    ribs was noted at dose levels of 50 and 100 mg/kg (Mizutani et al,
    1971).

    Special studies on pharmacological properties

         Cartap hydrochloride was shown to have neuromuscular blocking
    activity in vitro and in vivo in several animal species
    (rat, dog, cat). The effects were characterized as follows: 1)
    inhibition of acetylcholine induced contraction of the muscle, 2)
    antagonism by cholinesterase inhibitor, calcium ion,
    tetraethylammonium and posttetanic stimulation against the partial
    neuromuscular block caused by cartap hydrochloride, 3) complete
    antagonism by several sulphhydryl compounds (BAL, L-cysteine,
    cystine, D-penicillamine) against the neuromuscular block, 5)
    respiratory failure due to neuromuscular block, 6) stimulant effect
    on the superior cervical ganglion followed by postsynaptic
    depression (Nagawa et al, 1971).

    Special studies on antidotes

         Male mice pre-treated with an intraperitoneal injection of
    diazepam, phenobarbital, atropine sulphate, C-penicillamin cystine
    or other sulphhydryl compounds delayed the onset of symptoms from
    a toxic dose (500 mg/kg) of cartap hydrochloride. The intravenous
    administration of cystine (ED50 40 mg/kg) was shown to be effective
    in protecting rabbits from the toxic symptoms of an acute oral dose
    (50 mg/kg) of cartap hydrochloride. In dogs, a minimal effective
    dose of 12.5 mg/kg cystine was required in order to protect against
    intoxication from the dermal application of 200 mg/kg of cartap
    hydrochloride (Nagawa et al, 1970).

    Special studies on dermal irritation

         Cartap hydrochloride was applied as a 5, 10 and 20% paste to
    the intact skin of two male rabbits daily for 5 days. No evidence
    of irritation was observed (Aramaki, 1972).

    Special studies on eye irritation

         Cartap hydrochloride was instilled into the right eye of 3
    rabbits as a 1.5 or 10% solution (0.2 ml) or 15 mg of the powder.
    No evidence of irritation to the bulbar or palpebral conjunctiva
    was observed when examined at 24 and 48 hours (Aramaki, 1972).

    Special studies on respiratory effects

         Groups of 5 male and 5 female rats were exposed continuously
    for 6 hours to the dust of a 50% water-soluble cartap hydrochloride
    powder at estimated concentrations of 0.086 and 0.54 mg/litre of
    air. Animals were observed for a period of 7 days following
    exposure. Severe eye and skin irritation, increased nasal and oral

    secretions, respiratory irritation and lethargy were observed at
    0.54 mg/litre. Exposure to 0.086 mg/litre caused slight dyspnoea,
    temporary eye irritation and polyuria. The signs of irritation of
    this group disappeared rapidly after termination of exposure.
    Post-mortem examination revealed no dose-related abnormalities in
    either test group (Berczy and Cobb, 1973)

         Four groups of 5 male and 5 female rats were exposed
    continuously for 6 hours/day, 5 days a week for 3 weeks to the dust
    of a 50% water-soluble cartap hydrochloride powder at estimated
    nominal concentrations of 0, 0.01, 0.1 and 1.0 mg/litre of air.
    Severe respiratory irritation, loss in body weight, injury to the
    eyes and skin were observed at the exposure level of 1.0 mg/litre.
    Certain clinical parameters (mean cell volume, neutrophil and
    lymphocyte cells, glucose, BUN, SGPT and SGOT) were found to be
    elevated in the high dose group. The changes in relative organ
    weights observed in this group were considered to be related to
    loss in body weight. Gross and histopathological examination
    revealed no abnormalities in the two lower dose groups. Extensive
    chronic respiratory effects in both sexes and acute ulceration in
    the urinary bladder in male rats were noted at the high dose level
    (Berczy et al, 1973).

    Acute toxicity
                                                                       
    Species       Sex      Route     LD50           Reference
                                     mg/kg b.w.
                                                                       
    Mouse         M        oral      225            Aramaki, 1972
                  M        oral      150            Toyoshima et al,
    1972
                  F        oral      154            ibid
                  M        s.c.      34.5           ibid
                  F        s.c.      35             ibid
                  M        i.v.      51             ibid
                  F        i.v.      52             ibid

    Rat           M        oral      380            Aramaki, 1972
                  F        oral      390            ibid
                  M        oral      345            Toyoshima et al,
    1972
                  F        oral      325            ibid
                  M        s.c.      40             ibid
                  F        s.c.      42             ibid
                  M        i.v.      44             ibid
                  F        i.v.      36             ibid
    Monkey                 oral      100-200**      Yokotani et al,.
    1968
    Rabbit        M&F      dermal    819*           Davies & Collins,
    1973
                                                                       
    * Padan water soluble powder (Cartap HCl 50%).
    ** exact estimate not possible owing to vomiting.

    Short-term studies

    Mouse (dermal)

         Cartap hydrochloride (0.2 ml of a 5 or 10% aqueous solution)
    was applied to the intact skin on the backs of 6 male mice. During
    the 7-day observation period no symptoms of intoxication developed and
    necropsy examination of subcutaneous tissues showed no adverse
    effects (Aramaki, 1972).

    Rabbit (dermal)

         Cartap hydrochloride was applied to intact or abraded skin of
    groups of 5 male and 5 female rabbits at dose levels of 0, 15, 60
    and 240 mg/kg body weight/day. Rabbits treated with 240 mg/kg died
    or were sacrificed after 1 week. Treatment of rabbits with 15 and
    60 mg/kg was continued 7 days a week, for 3 consecutive weeks.
    Pupillary dilatation and lack of hind limb coordination were
    observed in some animals of each group. Body weight gain and food
    consumption were reduced at 60 mg/kg especially during the 3rd
    week. PCV, hemoglobin concentration and RBC counts were also
    decreased in males (abraded) when compared to intact control
    animals at this dose level. Increased BUN and reduced plasm
    cholinesterase activity were observed at 240 mg/kg when compared to
    control values at week 3. Slight dermal irritation was noted during
    the 2nd and 3rd week in rabbits receiving 15 and 60 mg/kg.
    Ophthalmoscopy and macroscopic and microscopic pathology were
    comparable for all groups (Davies et al, 1974).

    Mouse (oral)

         Groups of 8 or 9 mice of each sex were fed cartap
    hydrochloride at dietary levels of 0, 100, 300 and 900 ppm for
    three months. Compound consumption was approximately 0, 15, 45 and
    135 mg/kg body weight/day. Body weight gain and food efficiency
    were slightly-reduced at the highest, dose level. No
    compound-related effects were observed in hematology (RBC, total
    WBC, hemoglobin and hematocrit) blood chemistry (plasma protein,
    SGOT, SGPT, alkaline phosphatase, BUN and cholesterol),urinalysis
    (pH, sugar & protein), organ weights or gross or histopathology
    (Tsubura et al, 1975).

    Rat (oral)

         Groups of 15 male and 15 female rats were fed 0, 10, 20 and 40
    mg/kg body weight/day of cartap hydrochloride in the diet for 13
    weeks. Body weight gain and food consumption in male rats was
    reduced at 40 mg/kg. Hematological values were within the normal
    range for the rat although the hemoglobin concentration was
    decreased and the erythrocyte count increased in male rats at the
    upper dose level. No compound-related effects were observed in food
    conversion ratio, urinalysis, ophthalmoscopy, plasma, erythrocyte

    and brain cholinesterase, relative organ weights or gross and
    microscopic pathological examination (Rivett et al, 1972).

    Hen (oral)

         Groups of 20 hens were fed cartap hydrochloride in the diet at
    levels of 0, 10, 30, 90 and 270 ppm for 4 weeks followed by a
    2-week post-treatment observation period. Body weight gain and food
    consumption were decreased and egg shell weight/egg weight ratio
    was lower at dietary levels of 90 and 270 ppm. Egg shell thickness
    increased in each group except 90 and 270 ppm groups. No effect on
    shell strength, egg yolk weight, egg yolk height or egg white
    height were observed (Shiomi et al, 1973).

    Long-term studies

    Mouse

         Groups of 40 male and 40 female mice were fed cartap
    hydrochloride in the diet at levels of 0, 10, 20 and 40 mg/kg body
    weight/day for a period of 80 weeks. No overt signs of toxicity
    were observed and survival rate was not affected. Body weight gains
    in the males during the first 52 weeks at 20 mg/kg and after 80
    weeks at 40 mg/kg were slightly reduced. This effect was associated
    with an impairment of food utilization. No compound-related effects
    were noted on hematology and urinalysis parameters. Erythrocyte
    cholinesterase activity was slightly reduced in the male and plasma
    cholinesterase activity was lower in the female at 40 mg/kg. Other
    blood chemistry parameters were within normal limits. No effect was
    observed on brain cholinesterase activity. Increases in heart
    weight (absolute and relative) in the female at 20 and 40 mg/kg and
    thyroid weight in the male at 40 mg/kg were noted. The changes
    noted on gross and histopathologic examination were common to both
    treated and control animals. There was no evidence to suggest an
    effect on the spontaneous tumour profile of this strain of mouse
    (Hunter et al, 1974).

    Rat

         Groups of 45 male and 45 female rats were fed cartap
    hydrochloride in the diet at 0, 10, 20 and 40 mg/kg body weight/day
    for 104 weeks. A lower incidence in mortality in the treated males
    was recorded. Body weight gain and food consumption were depressed
    in both sexes, at 40 mg/kg in the male and at 20 mg/kg in the
    female throughout the study. No evidence of a compound-related
    effect was noted with respect to hematology, urinalysis, blood
    chemistry including plasma and erythrocyte cholinesterase, brain
    cholinesterase or ophthalmoscopy. There appeared to be a treatment-
    related decrease in the relative liver weights of the male. This
    effect was not dose-related. The increase in relative weights of
    certain other organs receiving 40 mg/kg would appear to reflect the
    body weight depression of this group. Gross and histopathological

    changes observed in the treated groups were comparable to those in
    the control group. There was no marked inter-group differences in
    tumor incidence (Hunter et al, 1975).

    OBSERVATIONS IN MAN

         Cartap hydrochloride has been manufactured in Japan since
    1966. Routine examinations of 98 workers employed in the
    manufacture were considered essentially normal. A more detailed
    medical examination which included urinalysis, blood chemistry,
    hematology including routine examination was conducted yearly on
    10 persons who were involved in the production of this chemical for
    more than 5 years. No adverse effects relating to cartap
    hydrochloride were observed in these workers (Hiraoka, 1975).

    COMMENTS

         Cartap hydrochloride is rapidly absorbed and metabolised.
    Metabolites are excreted primarily in the urine and are not stored
    to any great extent in the body.

         No adverse effects at dietary levels up to 100 ppm were
    observed in a two generation rat reproduction study. Teratogenic
    studies in the mouse, rat and hamster revealed no compound-related
    effect. However, these studies were considered inadequate because
    the animals were not exposed to cartap hydrochloride for the full
    period of organogenesis. Mutagenic studies were not preformed.

         Cartap hydrochloride was shown to be moderately toxic to
    mammals on acute exposure by several routes of administration. No
    evidence of irritation was observed when cartap hydrochloride was
    applied as a 20% paste to intact skin or was instilled as a 10%
    solution into the eye of rabbits. However, inhalation exposure of
    rats to relatively high concentrates of a 50% water-soluble dust
    caused severe eye, dermal and respiratory irritation.

         The reduced weight gain observed in the female rat at 20 and
    40 mg/kg bw which appeared to be related to a lower food
    consumption, was questioned. In various short and long term studies
    in the mouse and rat a very weak anticholinesterase activity was
    noted. In long term studies on the mouse and rat a compound-related
    increase in tumour incidence was not observed. Since data were
    submitted only on rodent species, concern was expressed as to the
    effect of this compound on a non-rodent species. A detailed medical
    examination of persons involved in the production of cartap
    hydrochloride for more than 5 years revealed no compound-related
    abnormalities.

         No-effect levels in the rat and mouse have been established
    and the data are sufficient to recommend a temporary acceptable
    daily intake.

    TOXICOLOGICAL EVALUATION

    Level causing no toxicological effects:

              Mouse               20 mg/kg bw/day

              Rat                 10 mg/kg bw/day

    ESTIMATE FOR TEMPORARY ACCEPTABLE DAILY INTAKE FOR
    MAN
                                  0 - 0.05 mg/kg bw

    RESIDUES IN FOOD AND THEIR EVALUATION

    USE PATTERN

         Cartap hydrochloride insecticides have been registered in
    Japan since 1967, and are widely used in Asia, Europe and South
    America.

         Cartap hydrochloride is used against a relatively broad
    spectrum of insects, e.g., Lepidoptera, Coleoptera, Diptera and
    Hemiptera. It is especially effective against Lepidopter such as
    the rice stem borer, diamond-back moth and common cabbage worm, and
    Coleoptera such as the Colorado potato beetle, Mexican bean beetle
    etc.

         Cartap is always applied as the hydrochloride, formulated into
    25% and 50% water-soluble powder, 2% dust, 4% and 10% granules and
    2% fine granules. A bait formulation has recently been introduced.
    Approximately 70% of the world production is applied to rice and
    30% to other crops, vegetables, potatoes, fruit, tea, etc.

         Products based on cartap hydrochloride are registered in a
    total of sixteen countries: Brazil, Bulgaria, Czechoslovakia, El
    Salvador, France, German Democratic Republic, Hong Kong, Hungary,
    Italy, Japan, Korea, Pakistan, Poland, Rumania, Spain, and Taiwan
    province of China and are officially recommended in Greece,
    Indonesia, Malaysia, Philippines, Thailand and Vietnam.

    Pre-harvest treatments

         Cartap hydrochloride is generally used at the rate of 0.5 -1.5
    kg a.i./ha. The officially registered and/or recommended uses of
    cartap hydrochloride are summarised in Table 1 which sets out
    application rates and pre-harvest intervals.

    Other uses

         Cartap hydrochloride is used for controlling the rice
    white-tip nematode by soaking rice seed in an aqueous solution of
    the insecticide.

    TABLE 1. Uses of cartap officially recommended in various countries
                                                                          

    Country and Crop           Dosage rate            Minimum
                               kg a.i./ha             pre-harvest
                               (as hydrochloride)     interval, days

                                                                          

    Brazil

    Cabbage, cotton,
    passion fruit,
    potato, sunflower,         0.5-0.75               14
    tomato, wheat

    Czechoslovakia

    Mustard                    0.5-0.6                7

    Potato                     0.5-0.6                14

    Hungary

    Potato, tomato             0.75-1.0               10

    Italy

    Potato                     0.25-0.5               14

    Japan (temporary)

    Cabbage                    0.5-0.75               7

    Chestnut                   1.5                    14

    Chinese cabbage            0.5-0.75               7

    Ginger                     0.5                    3

    Grape (vine)               1.5                    14

    Hop                        1.0                    14

    Japanese persimmon         1.5                    21

    Japanese radish            0.35-0.5               7

    Maize                      1.0                    7

    TABLE 1. (Cont'd.)

                                                                          
    Country and Crop           Dosage rate            Minimum
                               kg a.i./ha             pre-harvest
                               (as hydrochloride)     interval, days
                               
                                                                          

    Potato                     0.75                   7

    Rice                       0.5-0.75               21

    Sweet potato               0.5-0.75               7

    Tea                        1.0                    7

    Spain

    Potato                     0.35-0.65              15
                                                                          


    RESIDUES RESULTING FROM SUPERVISED TRIALS

         Residue data were obtained in Japan from supervised trials on
    a variety of vegetables, fruits, hops, forage and rice. A summary
    of these data is presented in Table 2 together with details of
    application rate and pre-harvest interval.

    Cabbage

         Two applications of cartap hydrochloride to cabbage seldom
    appear to produce detectable residues even when the last
    application is made seven days before harvest. When four
    applications were made throughout the growing season the residue
    found ranged up to 0.1 mg/kg in cabbage harvested fourteen days
    after the last treatment. Even eight treatments made at seven day
    intervals produced residues of only 0.13 mg/kg fourteen days after
    the last application.

         The half-life appears to be of the order of 10-14 days.

    Chestnut

         Detectable residues were not found in the nuts when chestnut
    trees were sprayed three times and the nuts were harvested 14 days
    after the last application.

    Chinese cabbage

         Chinese cabbage appears to retain cartap residues at higher
    levels and for longer periods than does cabbage. 4 sprays give rise
    to residues ranging up to 0.27 mg/kg when chinese cabbage was
    harvested 14 days after the last application. Residues up to 1.05
    mg/kg were found after a preharvest interval of 7 days. Fine
    granules appear to produce lower residues than sprays prepared from
    soluble powders.

    Ginger

         Ginger appears to retain small quantities of cartap, (up to
    0.03 mg/kg after 14 days) although the level of residues does not
    appear to be significantly influenced by the number of treatments.

    Grapes

         The residue studies in grapes were designed to show the level
    of residues resulting from the application of 2, 4 and 6 sprays in
    grapes harvested 14, 21 and 30 days after the last application.
    There is some indication that the residue levels in the fruit might
    increase owing to systemic transfer for some time after application.
    Generally the results found 30 days after the last spray were just
    slightly lower than those found 21 days after the same treatment.

         The level of residues was higher in grapes treated 6 times than
    in those treated 4 times which in turn was distinctly higher than in
    grapes treated only twice.

    Hops

         There is a very noticeable decline in the level of cartap
    residues found in dried hops as the interval between last application
    and harvest increases from 7 through 14 to 21 days. The half-life of
    the residues appears to be of the order of 7 days but whether the
    drying process has an influence on this is not clear.

    Persimmon

         The data on cartap residues in persimmons gathered from 2 trials
    indicate only the quantity found 30 to 75 days after the last
    application. Whilst detectable residues still occur 75 days after the
    last application there is no great difference between the residue
    level in samples from trees treated 6 or 4 times.

    Japanese radish

         Systematic studies of both leaves and roots of Japanese radish
    (data on roots only are shown in Table 2) treated 2 and 4 times and
    harvested 3, 7 and 14 days after the last application showed,
    sometimes, a distinct increase in the residue concentration in the


    
    TABLE 2. Cartrap residues resulting from supervised trials - Japan

                                                                                                                                               

    Crop           Date     Formulation   Rate              No of         Residues (mg/kg) at interval (days) after last treatment
                                          kg/ha             treatments
                                          (hydrochloride)                 3      7             14          21        30        45        60-75
                                                                                                                                               

    Cabbage        10/69    SP            0.6               2                    <0,0.004      <0.004
                                                            4                    0.01          0.008
                   11/69    SP            0.75              2                    <0.004        <0.004
                                                            4                    0.09          0.08
                   7/72     SP            0.75              2                    0.02          0.06
                                                            4                    0.14          0.09
                   12/72    FG            1.0               2                                                                            <0.006
                                                            5                                                        0.07      0.05
                                                            8                                  0.13                  0.07
                   12/72    FG            1.0               2                                                                            <0.006
                                                            3                                                                            <0.006
                                                            5                                                                  <0.006    <0.006

    Chestnut       9/71     SP            60g/tree          3                                  <0.001      <0.001
                                                            3                                  <0.008      <0.008

    Chinese        11/74    SP            0.6               2                    0.03          0.02        0.02
    cabbage                                                 4                    0.03          0.03        0.03
                   12/74    SP            0.6               2                    0.7           0.07        0.06
                                                            4                    0.5           0.16        0.15
                   1/75     SP            0.6               2                    1.05          0.15        0.1
                                                            4                    0.4           0.27        0.2
                   9/72     FG            1.0               2                    0.03          0.01        <0.005
                                                            3                    0.05          0.02        <0.005
                                                            5                    0.12          0.03        <0.005

    TABLE 2. (Cont'd.)

                                                                                                                                               

    Crop           Date     Formulation   Rate              No of         Residues (mg/kg) at interval (days) after last treatment
                                          kg/ha             treatments
                                          (hydrochloride)                 3      7             14          21        30        45        60-75
                                                                                                                                               
    Ginger         10/72    SP            0.7               4             0.006                <0.005
                                                            6             0.01                 <0.005
                                                            9                    0.007                               <0.005
                   10/72    SP            1.0               3                    0.02          0.03
                                                            5                    0.02          0.02

                   11/73    SP            1.0               3                    0.02          0.02
                                                            5                    0.04          0.03

    Grape          7/73     SP            2.0               2                                  0.08                  0.12
                                                            4                                  0.54                  0.38
                                                            6                                  0.57                  0.97
                   9/73     SP            1.0               2                                  0.01        0.01      0.008
                                                            4                                  0.1         0.09      0.08
                                                            6                                  0.24        0.20      0.13
                   7/73     SP            2.0               2                                  0.08                  0.13
                                                            4                                  0.35                  0.40
                                                            6                                  0.75                  0.80
                   9/73     SP            2.0               2                                  0.05        0.04      0.03
                                                            4                                  0.13        0.10      0.07
                                                            6                                  0.24        0.28      0.20

    Hops           8/73     SP            2.0               3                                  0.56                  0.04
    (dry)                                                   4                                  0.50                  0.15
                                          3.0               3                                  2.2         0.32
                                                            4                    8.0           3.0
                   8/73     SP            2.0               3                                  0.30                  0.03
                                                            4                                  0.34                  0.14
                                          3.0               3                                  0.92        0.28
                                                            4                    4.9           2.7

    TABLE 2. (Cont'd.)

                                                                                                                                               

    Crop           Date     Formulation   Rate              No of         Residues (mg/kg) at interval (days) after last treatment
                                          kg/ha             treatments
                                          (hydrochloride)                 3      7             14          21        30        45        60-75
                                                                                                                                               

    Persimmon      11/70    SP            2.25              4                                                                            0.02
                                                            6                                                                            0.03
                   11/70    SP            7.5               4                                                        0.08      0.07
                                                            6                                                        0.19      0.05

    Potato         6/71     SP            1.5               3                    <0.008        <0.008
                                                            6                    <0.008        <0.008      <0.008

                   12/72    SP            1.0               2                                              <0.005              <0.005
                                                            5                                              <0.005              <0.005
                                                            8                                              <0.005              <0.005
                            FG            1.0               5                                              <0.001              <0.001
                                                            8                                              <0.001              <0.001

    Radish         10/73    SP            0.75              2             0.10   0.12          0.03
    (Japanese)                                              4             0.08   0.14          0.04
                   11/73    SP            0.5               2             0.52   0.12          0.15
                                                            4             0.57   0.22          0.22
                   11/73    SP            0.75              2             0.25   0.15          0.10
                                                            4             0.02   0.02          0.01

    Rice
    Grain          10/74    SP            0.5               8                                                        <0.01     <0.01     <0.01
                   8/74                   1.0               8                                                        <0.01     <0.01     <0.01
                                          0.5               8                                                        0.05      <0.01     0.02
    Straw          10/74    SP            1.0               8                                                        <0.01     0.02      <0.01
                   8/74
    Grain          10/74    SP            0.5               8                                                        <0.005    0.005     <0.005
                   8/74     SP            1.0               8                                                        <0.005    0.006     <0.005
    Straw          10/74    SP            0.5               8                                                        0.05      <0.01     0.02
                   8/74     SP            1.0               8                                                        0.02      <0.01     <0.01

    TABLE 2. (Cont'd.)

                                                                                                                                               

    Crop           Date     Formulation   Rate              No of         Residues (mg/kg) at interval (days) after last treatment
                                          kg/ha             treatments
                                          (hydrochloride)                 3      7             14          21        30        45        60-75
                                                                                                                                               

    Rice

    Grain          10/74    SP            1.6               8                                                        <0.01     <0.01     <0.01
                   8/74     SP            2.0               8                                                        <0.01     <0.01     <0.01
    Straw          10/74    SP            1.6               8                                                        0.02      <0.01     <0.01
                   8/74     SP            2.0               8                                                        <0.01     <0.01     <0.01

    Grain          10/74    FG            0.8               8                                                        <0.005    <0.005    <0.005
                   8/74     FG            1.0               8                                                        <0.005    <0.005    <0.005
    Straw          10/74    FG            0.8               8                                                        0.05      <0.01     0.03
                   8/74     FG            1.0               8                                                        <0.01     <0.01     <0.01

    Tea (dry)      7/73     SP            1.0               1             1.0    1.2           0.6
                   7/73     SP            1.0               2             1.4    1.8           0.6
                   7/73     SP            1.0               1             0.7    0.8           0.7

    Sweet corn     9/71     FG            0.6               1             <0.008 <0.008        <0.005                <0.005

    Forage

    Orchard grass  9/71     SP            0.5               1             0.03   0.01
                                                            2             0.06   0.04

    Red clover     8/71     SP            0.5               1             0.01   0.03
                                                            2             0.11   0.01

    White clover   9/71     SP            0.5               1             0.22   0.05
                                                            2             0.52   0.45
                                                                                                                                               
    

    leaves during the first 7 days. This trend was not noticeable in the
    roots. In radish root the half-life appears to be of the order of 10
    days.

    Potatoes

         A number of trials confirm that detectable cartap residues do not
    occur in the tubers of potatoes even when the crop is treated 8 times
    during the season and the tubers are harvested 7, 14 or 21 days after
    the last application.

    Rice

         Numerous trials have demonstrated that rice grain harvested 30 or
    more days after 8 applications of cartap hydrochloride sprays almost
    invariably contains no residues above the limit of determination. A
    few of the many samples of rice straw from these trials were found to
    contain residues at or just above the limit of determination.

    Tea

         Green tea produced from leaves harvested 7, 14 and 21 days after
    the application of cartap hydrochloride contained residues ranging up
    to almost 2 mg/kg. In 2 of the 3 trials the concentration of residues
    increased slightly between the 7th and 14th day following treatment
    but declined by the 21st day.

    FATE OF RESIDUES

    General comments

         Cartap hydrochloride is stable to acid, but is hydrolysed in
    neutral or alkaline solutions to give dihydronereistoxin (NTXH) which
    is quite easily oxidised to nereistoxin (NTX) by air. NTXH and NTX may
    be biologically convertible to one another, an shown in the following
    reaction:

    CHEMICAL STRUCTURE 1

         Sakai (1970) in discussing nereistoxin and its relatives
    indicates that the contact toxicity to Azuki bean weevil, rice stem
    borer and mouse, and the activity in blocking the synaptic response of
    the 6th abdominal ganglion of the American cockroach are remarkably
    similar for cartap hydrochloride and nereistoxin. It seems possible
    that the activity of cartap hydrochloride is due to its conversion to
    nereistoxin in plants and animals.

    In animals

         The absorption, distribution and excretion of cartap
    hydrochloride in rats and mice is described above ("Bio-chemical
    aspects") and further studies are in progress. Chromatographic studies
    have revealed that there are about nine main metabolites in the urine
    from animals receiving cartap, hydrochloride orally. There appears to
    be no significant difference in the pattern between rats and mice.
    Unchanged cartap hydrochloride could not be detected. One of the
    identified metabolites was the mono-sulphoxide of
    1,3-di(methylthio)-2-dimethylaminopropane and it comprised 18% and 8%
    of the urinary metabolites in the rat and mouse respectively
    (Shirakawa et al, 1971).

    In plants

         Tomizawa and Endo (1972) studied the uptake of 35S-labelled
    cartap hydrochloride in rice plants. The basic fraction which was
    assumed to retain biological activity reached a maximum concentration
    in the leaf sheath and leaf blade on the 7th day after application and
    thereafter declined rapidly until the 15th day. A small but consistent
    amount of radio-activity remained in both leaf sheath and leaf blade
    for 30 days. Radio-activity in the ear remained consistently low
    throughout the test period.

         Among the metabolites, nereistoxin and sulphuric acid were
    identified. The metabolic degradation of cartap hydrochloride in
    plants was judged to proceed in the following sequence (Tomizawa and
    Endo, 1972; Tomizawa et al., 1974).

    CHEMICAL STRUCTURE 2

         Dust, fine granule and granule formulations of cartap
    hydrochloride were applied to rice plants in a paddy field, and the
    cartap residue in the plants was determined by analysing the leaf
    blades and leaf sheathes separately. Further measurements were also
    made on water and soil from the treated plots. The concentration of
    cartap in the rice plants immediately after application was found to
    be of the order of 1 to 2 mg/kg for dust and fine granule treatments
    but only 0.1 mg/kg in the case of granules. 3 days later the
    concentration on the whole plants had fallen to approximately 0.05
    mg/kg except on those treated with dust which were found to contain
    0.2 mg/kg. After 5 days the concentration had fallen slightly in the
    case of plants treated with dust and fine granules but plants treated
    with granules were found to have a noticeable increase in cartap
    residues, apparently owing to uptake from the water into which the
    granules had fallen. This trend continued until the 7th day after
    which residues began to decline slowly. The leaf blade was found to
    have significantly higher residues than the leaf sheath (Koyama et al,
    1975). It is difficult to tell how much of the residue determined in
    these trials was a surface deposit on the outside of the leaves and
    how much was taken into the plant.

         Koyama et al (1975), quote work by Sakai which indicates that
    when relatively high concentrations of cartap hydrochloride are
    applied to rice plants in nursery boxes, the plants are capable of
    taking up concentrations of the order of 20 mg/kg which, even after 42
    days, remain at about 0.5 mg/kg. Due allowance must be made for the
    extensive dilution which would occur owing to the growth of the plant
    over this period.

         Tomizawa et al (1974), using 35S-labelled cartap hydrochloride
    showed that the rate and degree of absorption of cartap hydrochloride
    by rice plants was much greater when the insecticide was applied in
    the paddy water than when it was applied to the plants in the form of
    a spray, and an effective concentration remained in the rice plant for
    a longer period. By using ion-exchange chromatography it was possible
    to show that the conversion of cartap hydrochloride to nereistoxin
    occurred rapidly after application.

    In soil

         Tomizawa and Endo (1972) studied the movement of cartap
    hydrochloride in soil under laboratory conditions. They took alluvial
    clay from a paddy field and from an unirrigated field, volcanic ash
    and sandy loam and applied radio-active cartap hydrochloride at a
    dosage of 1 mg/50 g of soil. The authors do not mention the
    temperature at which the treated soil was held but indicate that the
    soil from the paddy field had the water content adjusted to 150% of
    field capacity while for the other three soils the water content was
    adjusted to 75% of field capacity. Samples of soil were removed at 6
    intervals over the next 30 days and were extracted in order to
    determine the cartap content. The concentration was measured in the
    basic fraction extracted with aqueous ammonia. It was found that the
    concentration in the soil one day after treatment was of the order of

    1 to 2 mg/kg in all four samples. The concentration in the soil from
    the paddy field remained virtually constant for 10 days and by the
    30th day had declined to one-sixth. The volcanic ash yielded only one
    thirtieth and the other two soils about one tenth of the original
    concentration by the 30th day.

         It is not clear whether the difference in concentration found
    after 30 days is due to a difference in the speed of decomposition of
    cartap hydrochloride or whether it results from the higher capacity of
    volcanic ash to absorb cartap hydrochloride and its decomposition
    products. There is a strong indication that cartap hydrochloride acts
    as a chelating agent in soil (Takei, 1976). This may explain the low
    recoveries reported by Tomizawa and Endo (1972).

         Koyama et al (1975) demonstrated that when various cartap
    hydrochloride formulations were applied to rice plants growing in
    paddy fields there was a distinct transfer of cartap in the case of
    granules. There appeared to be an increase in the concentration in the
    soil of plots treated with granules over the first 14 days. In the
    case of other formulations detectable residues were found in the soil
    of all plots at the end of 14 days but at the time of harvest, 41
    months after initial treatment, the concentration was below the limit
    of determination.

    In water

         In the experiments with soil and rice plants described above,
    Koyama et al (1975) also studied the concentration of cartap
    hydrochloride in the water of paddy fields treated with various cartap
    hydrochloride formulations. It was found that immediately after
    application the concentration of cartap hydrochloride in the water of
    paddy fields ranged between 1 and 2 mg/l but by the third day after
    treatment it had generally fallen below the limit of determination,
    except in the plots treated with granules where it was marginally
    above this limit. The apparent difference in the stability of cartap
    hydrochloride in water and soil of the same paddy fields seems
    attributable to the fact that cartap hydrochloride dissolved in water
    is easily degraded by direct sunlight while the residue held in soils
    is relatively stable. Cartap hydrochloride is stable in aqueous
    solution at pH3-4. In the water of paddy fields which would have a pH
    ranging from 5 to 7, it may be decomposed gradually to nereistoxin as
    described at the beginning of this section.

         Tomizawa and Endo (1972) applied radio-active cartap
    hydrochloride to the surface of water in which rice seedlings were
    transplanted, at a rate corresponding to 1.5 kg/ha. The radio-activity
    of samples of water was measured after various intervals. Although the
    concentration in the water sampled immediately after application
    indicated the presence of approximately 10 mg of cartap hydrochloride
    per litre of water, within the first 24 hours the concentration had
    fallen by more than 90% with a further slow decline over the
    succeeding days. The loss of the compound from the aqueous phase may
    probably be attributable to rapid absorption onto soil particles.

    METHODS OF RESIDUE ANALYSIS

         Several colorimetric, iodometric, oscillopolarographic and
    gaschromatographic methods have been developed for the determination
    of cartap. The oscillopolarographic and gaschromatographic methods are
    suitable for residue analysis. Both are based on the measurement of
    4.N,N-dimethylamino-1,2-dithiolane (nereistoxin, NTXH) which is
    quantitatively derived from cartap. Cartap hydrochloride and its
    metabolite dihydronereistoxin (NTXH) and nereistoxin are extracted
    from samples with diluted hydrochloric acid and the unchanged cartap
    hydrochloride is hydrolysed and oxidized in basic solution to NTX.
    Total NTX is extracted from the reaction mixture with ethyl ether and
    is used for analysis.

         Recoveries by both the oscillopolarographic and the
    gaschromatographic methods were generally between 75 and 95% (Nishi et
    al, 1973). Soil, rice, tea and straw present difficulties in analysis
    whereas substrates such as cabbage are easily extracted with good
    recovery. Apparently there is a high degree of disulphide binding with
    some commodities, because the addition of cystine results in a release
    of residues and significantly better recovery (Takei, 1976).

         In the oscillopolarographic method, liquid/liquid partition is
    required during the clean-up in order to minimise the carry-over of
    possible interfering compounds. A single sweep oscillopolarograph
    (Randles-Sevcik type) is used. The polarogram of NTX appears at -0.78
    0.05 V vs. Hg pool, and the concentration is quantitatively
    determined by the peak height. The limit of determination of this
    method is 0.004 mg/kg. Some reducible pesticides, such as
    organophosphorus pesticides containing a nitro group, did not
    interfere with the determination (Nishi et al, 1973).

         Residues of cartap can be determined easily by gaschromatography
    with a high sensitivity and specificity. A flame photometric detector
    (FPD) equipped with a sulphur mode filter and a glass column
    containing 3% OV-1 on chromosorb W or 5% PEG 20 on Gaschrom Q at a
    temperature of 130-165C are used. The limit of determination by this
    method is 0.005 mg/kg. Investigation by Nishi et al, (1973) of the
    gas-chromatographic method indicates that it should be applicable to
    all types of residue analysis. Since the treatment is simple and less
    rigorous clean-up is required, the gas-chromatographic method is
    superior to the polarographic method. It appears suitable for
    regulatory analysis.

         Most of the residue data from supervised trials have been
    obtained by the gas-chromatographic method, and in the course of this
    work almost 100 samples of 12 different commodities have been analyzed
    independently by analysis from two of three separate laboratories. In
    some cases the results presented by the two analysts differ by
    relatively large factors. The percentage difference between the means
    obtained by the two analysts does not give a true picture of the
    variability. In Table 3 the significance of the difference between

    laboratory means has been assessed in relation to the variation
    between replicates (a) of pooled over values of <0.050 mg/kg, where
    within-pair variability tends to be lowest and (b) pooled over values
    between 0.050 and 0.500 mg/kg where this variability is greater. Where
    levels above 0.5 mg/kg are found the differences within and between
    pairs of duplicates are inconsistent and there are insufficient data
    to make a valid comparison of laboratory means.

    TABLE 3. Mean differences between samples analysed by 2 laboratories
                                                                        

                      Laboratory 1   Lab. 2     Mean          Significance
                      Mean           Mean       difference
                                                                        
    Chinese cabbage   0.0275         0.1195     0.092         P<.001
                      0.0335         0.1085     0.075         P<.001
                      0.0315         0.1625     0.131         P<.001
                      0.7060         0.9750     0.269         -
                      0.0700         0.1445     0.0745        P<.001

    Ginger            0.0245         0.0220     0.0025        NS
                      0.0205         0.0330     0.0125        P<.001
                      0.0380         0.0220     0.016         P<.001

    Grape             0.0765         0.0800     0.0035        NS
                      0.5345         0.3500     0.1845        P<.001
                      0.5645         0.7400     0.1755        P<.001
                      0.1245         0.1800     0.0555        P<.001

    Hops              0.9150         2.0900     1.175         -
                      0.2700         0.3200     0.05          P<.001
                      4.8200         7.7150     2.895         -
                      0.2700         0.4950     0.225         P<.001

    Japanese          0.0610         0.0935     0.0325        P<.01
    radish            0.0520         0.1150     0.063         P<.001
    leaf              0.0580         0.1270     0.069         P<.001
    root              0.0290         0.0245     0.0045        NS
                      0.0115         0.0085     0.003         NS
                      0.0135         0.0160     0.0025        NS

    Potato            0.0010         0.0050     0.004         NS
                      0.0070         0.0050     0.002         NS

    Rice grain        0.0050         0.0100     0.005         NS
                      0.0060         0.0100     0.004         NS

    Rice straw        0.0100         0.0200     0.01          P<.01
                      0.0450         0.0450     0.00          NS

    Orchard grass     0.0260         0.0200     0.006         NS
                      0.0590         0.1500     0.091         P<.001

    TABLE 3. (Cont'd.)

                                                                        

                      Laboratory 1   Lab. 2     Mean          Significance
                      Mean           Mean       difference
                                                                        

    Red clover        0.0095         0.1050     0.0955        P<.001
                      0.0255         0.1800     0.1545        P<.001
                      0.1080         0.0200     0.088         P<.001
    White clover      0.2150         0.0800     0.135         P<.001
                      0.4430         0.0450     0.398         P<.001
                                                                        

    Least difference in means necessary for significance:

                                        P <0.05   P <0.01    P <0.00
         Single estimates    <0.050 =   0.0059    0.0080     0.0106
         "      "            >0.050 =   0.0231    0.0311     0.0413

    - = insufficient high values to assess significance.
    NS = not significant

         The results show that in most cases very highly significant
    differences (P<0.001) occur between laboratories analysing samples of
    the same commodity, while in some cases, notably commodities having
    residues below 0.05 mg/kg, the differences are not significant. The
    low residues occur mainly in root crops and grains, which would be
    expected to be less subject than leafy plants to sampling variations
    and therefore to give more consistent analytical results.

         It is rarely possible to make such a comparison as this, since
    investigators rarely submit samples to two different laboratories for
    check analysis. The opportunity to see practical evidence of the
    difficulties confronting residue analysts seeking to determine small
    quantities of complex substances in a variety of raw agricultural
    commodities is valuable. Such data are needed to provide an adequate
    basis for the establishment of maximum residue limits appropriate to
    the problems facing residue analysts and food control officials.

    NATIONAL TOLERANCES REPORTED TO THE MEETING

    Brazil
         Cotton, sunflower             0.03 mg/kg

         Potato, passion fruit         0.01 mg/kg

         Cabbage, tomato, wheat        0.01 mg/kg

    Hungary
          Potato, tomato               0.1 mg/kg

    APPRAISAL

         The insecticide cartap, invariably used as the hydrochloride, is
    a derivative of nereistoxin, a naturally occurring insecticidal
    substance isolated from the marine segmented worms, Lumbrineris spp.
    Extensive information is available on the chemistry and synthesis of
    nereistoxin and its derivatives, of which cartap hydrochloride is one
    of the most potent.

         Cartap hydrochloride insecticides have been registered in Japan
    since 1967, and are widely used in Asia, Europe and South America.
    Cartap hydrochloride is used against a relatively broad spectrum of
    insects but particularly against the rice stem borer, Lepidopterous
    pests of vegetables and Colorado potato beetle. Commercial
    formulations include water soluble powders, dusts and granules.
    Approximately 70% of the world production is applied to rice. Cartap
    hydrochloride is generally used at the rate of 0.5 - 1.5 kg/ha with a
    pre-harvest interval of 7 to 21 days.

         Extensive data obtained from supervised trials in Japan on a
    variety of vegetables, fruit, hops, forage and rice were available to
    the Meeting. The compound shows some systemic action and some of the
    data indicate an increase in the residue concentration in fruits and
    vegetables during the first 7 days. Although the residues resulting
    from approved applications are generally well below 1 mg/kg soon after
    application, detectable residues remain for up to 45 days.

         It appears that the insecticidal activity of cartap hydrochloride
    is due to its conversion to nereistoxin in plants and animals. The
    metabolism of cartap hydrochloride in mammals has been studied in rats
    and mice where it is apparently rapidly converted to nereistoxin which
    in turn is further metabolised. No information is available on the
    fate in livestock.

         Metabolism studies in plants indicate quantitative conversion to
    nereistoxin which in turn is oxidised, through the mono-oxide,
    eventually to sulphuric acid.

         Cartap hydrochloride and nereistoxin are readily degraded in
    water by direct sunlight but residues held in soils appear relatively
    stable except in highly active soils such as volcanic ash.

         Several methods have been developed for the determination of
    cartap residues and a gas-chromatographic method appears suitable for
    regulatory analysis. The method is based on the conversion of the
    parent compound and metabolites to nereistoxin which can be measured
    by means of a flame photometric detector equipped with a sulphur mode
    filter. The limit of determination is 0.005 mg/kg.

         The meeting welcomed the fact that most of the extensive residue
    data generated from these supervised trials had been obtained by
    independent analysis in two separate laboratories. Although there is
    excellent agreement in the results presented for some samples by the

    two laboratories there are many instances where the difference between
    the means obtained by the two analysts is very highly significant.
    This is not altogether remarkable in view of sampling difficulties and
    the low levels of the residues analysed. The meeting welcomed this
    practical expression of the difficulties confronting residue analysts
    seeking to determine small quantities of complex substances in a
    variety of raw agricultural commodities.

         A number of countries have established maximum residue limits.

    RECOMMENDATIONS

         The following maximum residue limits are for cartap, expressed as
    the free base. (The usual methods of residue analysis convert cartap
    to its metabolite nereistoxin, and will therefore record cartap,
    nereistoxin and dihydronereistoxin as cartap.)

                                            Pre-harvest Interval
                                  Limit     on which Recommendations
    Commodity                     (mg/kg)   are based

    Hops (dried)                  5             14

    Chinese cabbage               2             7

    Tea (green, dried)            2             7

    Grapes                        1             14

    Persimmons                    1             21

    Radishes                      1             7

    Cabbage                       0.02          7

    Chestnut (seed including      0.01          14
    pericarp)

    Ginger                        0.01          3

    Potatoes                      0.01          7

    Rice (hulled)                 0.01          21

    Sweet corn                    0.01          7

    FURTHER WORK OR INFORMATION

    Required (by 1978)

    1.   Submission of the details of the studies on metabolism and the
         identification of metabolites.

    2.   Teratogenic studies covering full period of organogenesis.

    3.   A feeding study in a non-rodent species.

    4.   Information on the fate of residues in foods of animal origin
         when treated fodder or plant parts are fed to livestock including
         poultry.

    5.   Effect of cooking on the level and fate of cartap residues.

    6.   Information on the fate of residues in manufactured tea.

    Desirable

    1.   A paired feeding study in the rat.

    REFERENCES

    Aramaki, Y. Acute oral, dermal and eye toxicity and irritation
    1972                studies on cartap hydrochloride and its
                        formulation, padan water soluble powder. Submitted
                        by Takeda Chemical Industries, Ltd. (Unpublished).

    Berczy, Z.S., and Cobb, L. M., Acute inhalation toxicity to the
    1973                rat of Padan 50 SP. Report from Huntingdon
                        Research Centre, submitted by Takeda Chemical
                        Industries, Ltd. (Unpublished).

    Berczy, Z.S., Cobb, L.M., Street, A.E. and Cherry, C.P. Subacute
    1973                inhalation toxicity to the rat of Padan 50 SP.
                        Report from Huntingdon Research Centre, submitted
                        by Takeda Chemical Industries, Ltd. (Unpublished).

    Davies, R.E. and Collins, C.J. Acute percutaneous toxicity to
    1973                rabbits of TA-7(50 s.p.). Report from Huntingdon
                        Research Centre, submitted by Takeda Chemical
                        Industries, Ltd. (Unpublished).

    Davies, R.E., Elliott, P.H., Street, A.E., Heywood, R. and Cherry,
    1974                C.P. The effect of repeated applications of TA-7
                        to the skin of rabbits for three weeks. Report
                        from Huntingdon Research Centre, submitted by
                        Takeda Chemical Industries, Ltd. (Unpublished).

    Hagiwara, H., Numata, M., Konishi, K. and Oka, Y. Synthesis of
    1965                nereistoxin and related compounds. I. Chem. Pharm.
                        Bull., 13, 253-260.

    Hagiwara, H. and Numata, M. Synthesis of nereistoxin and related
    1968                compounds. II. Chem. Pharm. Bull., 16, 311-317.

    Hashimoto, Y. and Okaichi, T. Some chemical properties of
    1960                nereistoxin. Ann. N.Y. Acad. Sco., 90, 667-673.

    Hiraoka, T. The survey of the health condition in workers engaged
    1975                in manufacturing cartap hydrochloride. Report from
                        Hikari Plant Hospital, submitted by Takeda
                        Chemical Industries, Ltd. (Unpublished).

    Hunter, B., Graham, C., Street, A.E. and Gallagher, P.J. Long
    1974                term feeding of TA-7 in mice. Report from
                        Huntingdon Research Centre, submitted by Takeda
                        Chemical Industries, Ltd., (Unpublished).

    Hunter, B., Benson, H.G., Street, A.E., Heywood, R. and Prentice,
    1975                D.E. TA-7, Toxicity following dietary
                        administration to rats for two years. Report from
                        Huntingdon Research Centre, submitted by Takeda
                        Chemical Industries, Ltd., (Unpublished).

    Kato, M., Sato, Y. and Sakai, M. Foliage spray treatment of cartap
    1967                hydrochloride mixed with DCPA for simultaneous
                        control of rice stem borer and barnyardgrass.
                        Japan J. appl. Ent. Zool., 32, 678-679.

    Konishi, K. New insecticidally active derivatives of nereistoxin.
    1968a               Agr. Biol. Chem., 32, 678-679.

    Konishi, K. Studies on organic insecticides. Part X. Synthesis
    1968b               of nereistoxin and related compounds. III. Agr.
                        Biol. Chem., 1199-1204.

    Konishi, K. Studies on organic insecticides. Part XI. Synthesis
    1970a               of nereistoxin and related compounds. IV. Agr.
                        Biol. Chem., 34, 926-934.

    Konishi, K. Studies on organic insecticides. Part XII. Synthesis
    1970b               of nereistoxin and related compounds. VI. Agr.
                        Biol. Chem., 34, 935-940.

    Konishi, K. Studies on organic insecticides. Part XIII. Synthesis
    1970c               of nereistoxin and related compounds. VI. Agr.
                        Biol. Chem., 34, 1549-1560.

    Konishi, K. Nereistoxin and its relatives. Proc. 2nd IUPAC
    1971                International Congress of Pesticide Chemistry, 1,
                        179-189.

    Kono, Y., Nagaarashi, C. and Sakai, M. Effects of cartap,
    1975                chlorodimeform and diazinon on the probing
                        frequency of the green rice leafhopper (Hemiptera
                        deltocephalidae). Appl. Ent. Zool., 10, 58-60.

    Koyama, S., Emura, K. and Kojima, A. Residue fate of cartap
    1975                hydrochloride applied in paddy field and its
                        effect against the rice leaf beetle and the rice
                        stem borer of the first generation. Proc. Assoc.
                        Plant Prot. Hokuriku (Japan), No. 22, 72-76.
                        Translated in English.

    Mizutani, M., Ihara, T., Kanamori, H., Takatani, O., Matsukawa,
    1971                J., Amano, T. and Kaziwara, K. Teratogenesis
                        studies with cartap hydrochloride in the mouse,
                        rat and hamster. J. Takeda Res. Lab., 30, 776-785.

    Nagawa, Y., Saji, Y., Chiba, S. and Yui, T. Neuromuscular blocking
    1971                actions of nereistoxin and its derivatives and
                        antagonism by sulfhydryl compounds. Japan J.
                        Pharmacol., 21, 185-197.

    Nagawa, Y., Saji, Y. and Kuriki, H. Antidotal effects of sulfhydryl
    1970                compounds against intoxication with
                        1,3-bis(carbamoylthio)-2-N,N-dimethylaminopropane
                        hydrochloride(NTD-2) in experimental animals. J.
                        Takeda Res. Lab., 29, 624-629.

    Nishi, K., Owaki, R. and Tan, N. Method for determination of
    1968                1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)
                        propane hydrochloride. II. Polarography. Ann.
                        Rept. Takeda Res. Lab., 27, 47-53.

    Nishi, K., Konishi, K. and Tan, N. PadanR. in Analytical Methods
    1973                for Pesticides and Plant Growth Regulators, G.
                        Zweig. Ed. - Academic Press N.Y., 7, 371-384.

    Nitta, S. Yakugaku Zasshi, 54, 648. ber Nereistoxin, einen
    1934                giftigen Bestandteil von Lumbriconereis
                        heteropoda Marenz (Eunicidae)

    Okaichi, T. and Hashimoto, Y. The structure of nereistoxin.
    1962                Agr. Biol. Chem., 26, 224-227.

    Olson, W.A. and Busey, W.M. Two-generation reproduction study
    1972                - rats, cartap. Report from Hazleton Laboratories,
                        Inc., submitted by Takeda Chemical Industries,
                        Ltd. (Unpublished).

    Rivett, K.F., Batham, P., Heywood, R., Street, A.E. and Newman, A.J.
    1972                TA-7, oral toxicity to rats dietary administration
                        for 13 weeks. Report from Huntingdon Research
                        Centre, submitted by Takeda Chemical Industries,
                        Ltd. (Unpublished).

    Sakai, M. Studies on the insecticidal action of nereistoxin.
    1964                4-N,N-dimethylamino-1,2-dithiolane. I.
                        Insecticidal properties. Japan J. appl. Ent.
                        Zool., 8, 324-333.

    Sakai, M., Sato, Y. and Kato, M. Insecticidal activity of
    1967                1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)
                        propane hydrochloride, cartap; with special
                        references to the effectiveness for controlling
                        the rice stem borer. Japan J. appl. Ent. Zool.,
                        11, 125-134.

    Sakai, M. Nereistoxin and its derivatives; their ganglionic
    1970                blocking and insecticidal activity. Biochemical
                        toxicology of insecticides, 13-20. (Academic Press
                        Inc.)

    Sakai, M. The chemistry and action of cartap. Japan Pestic.
    1971                Inform., (6) 15-19.

    Sakai, M. and Sato, Y. Metabolic conversion of the nereistoxin
    1971                related compounds into nereistoxin as a factor of
                        their insecticidal action. Insecticides Proc. 2nd
                        Intern. IUPAC Congr. Pesticide Chemistry, 1,
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    Shiomi, Y., Sasa, Y. and Takeda, K. Effects of feeding cartap
    1973                hydrochloride on laying performance and egg
                        quality in hens. Submitted by Takeda Chemical
                        Industries, Ltd. (Unpublished).

    Shirakawa, Y., Fujita, T., Maki, K. and Suzauki, Z. Metabolic
    1971                fate of
                        1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)
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    Takei, N. Personal communication to FAO Panel of Experts 1976
                        on Pesticide Residues.

    Tan, N., Nishi, K., Owaki, R. and Asahi, Y. Simultaneous analysis
    1967                of 2-N,N-dimethylaminopropane-1,3-dithiocyanate
                        and 4,4-dimethylaminodithiolane by polargraphic
                        method. Noyaku Seisan Gizyutu (Japan), No. 16,
                        20-22.

    Tomizawa, C. and Endo, T. Movement of cartap hydrochloride in soil,
    1972                paddy water and rice plant. Report from National
                        Institute of Agricultural Sciences (Japan),
                        submitted by Takeda Chemical Industries, Ltd.
                        (Unpublished).

    Tomizawa, C., Endo, T. and Naka, H. Fate and significance of
    1974                labelled insecticide residues in rice. Isotope
                        Tracer Studies of Chemical Residues in Food and
                        the Agricultural Environment, 59-64. International
                        Atomic Energy Agency (Vienna).

    Toyoshima, S., Sato, R. and Satoh, H. Acute toxicity of cartap
    1972                hydrochloride in rats and mice. Report from Nippon
                        Experimental Medical Research Institute, submitted
                        by Takeda Chemical Industries, Ltd. (Unpublished).

    Tsubura, Y., Shimomura, T., Watanabe, T., Tsuji, H., Takahashi,
    1976                A. and Fukuyama, T. Toxicity test of
                        1,3-bis(carbamoylthio)-2-(N,N-dimethylamino)
                        propane hydrochloride (cartap) on mice by oral
                        administration for three months. J. Nara Medical
                        Association (Japan), 26, 368-378.

    Yokotani, H. Approximate estimation of acute oral toxicity of
    1968                cartap hydrochloride in monkeys. Submitted by
                        Takeda Chemical Industries, Ltd. (Unpublished).
    


    See Also:
       Toxicological Abbreviations
       Cartap (Pesticide residues in food: 1978 evaluations)