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    CHLORDIMEFORM     JMPR 1975

    Explanation

         This pesticide was evaluated for acceptable daily intake by the
    1971 Joint Meeting of the FAO Committee on Pesticides in Agriculture
    and the WHO Expert Committee on Pesticide Residues (FAO/WHO, 1972). A
    temporary ADI for man was estimated to be 0-0.01 mg/kg body weight. It
    was considered that a further long-term study in rats would be
    appropriate to obtain precise information on the incidence and nature
    of the histopathological changes in the liver and bile duct of rats
    exposed to levels above and below 100 ppm in the diet. In addition,
    the meeting requested further investigations of the nature of the
    hepatic lesions observed on the dog; metabolic studies in several
    animal species, including man; data on the nature and levels of
    residues in animal tissues after use in cattle sprays and dips; data
    on residues in milk after use in cattle sprays and dips; data on the
    residue levels in commercial butter and cheese. The present monograph
    addendum summarizes further relevant studies that have become
    available.

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    BIOCHEMICAL ASPECTS

    Effects on enzymes and other biochemical parameters

         Several studies have been reported to further define the
    mechanism of action following acute poisoning. Based on in vitro
    studies, Aziz and Knowles (1973) and Beeman and Matsumura (1973, 1974)
    suggested that inhibition of Monoamine oxidase through an accumulation
    of toxic biogenic amines could ultimately result in toxic signs
    following acute poisoning. However, Maitre and Gfeller (1975) and
    Robinson et al. (1975) demonstrated in acute studies that this
    mechanism does not play a significant role in the acute toxicity in
    rats. Groups of rats were administered chlordimeform by a single
    intraperitoneal injection or by four injections (each at a level of 10
    mg/kg) at 24 hour intervals. Monoamino oxidase activity in brain and
    liver using tyramine and serotonin as a substrate was not affected. No
    signs of acute intoxication were noted in the study.

         In one study following acute intoxication, there was an
    accumulation of serotonin and norepinephrine. Chlordimeform was found
    to antagonize the effects of reserpine (Beeman and Matsumura, 1973).
    Thus, while MAO inhibition may have a role in the toxic action of
    chlordimeform, there may be synergistic effect in combination with
    accumulated biogenic anines that may be more significant than the MAO
    inhibition.

         Chlordimeform has been shown to be ineffective in inhibiting
    Na/K-ATPase and cholinesterase (Dittrich, 1966; Beeman and Matsumura,
    1974) and has no effect on the acetycholine receptor of the isolated
    frog rectus abdominus muscle (Beeman and Matsumura, 1974). Uncoupling
    of oxidative phosphoxylation by chlordimeform and the desmethyl
    metabolite has been shown by Abo-Khatwa (1972, 1973). At high
    concentrations, RNA synthesis has been inhibited (Murakami and Fukami,
    1974).

    TOXICOLOGICAL STUDIES

    Special studies on pharmacological effects

         In vitro studies on the effect of chlordimeform on the isolated
    heart preparation of guinea pigs were performed in an effort to
    evaluate previously reported results indicating an effect on
    contractile force of rabbit heart. Isolated guinea pig atria and
    perfused heart preparations were treated with chlordimeform at doses
    varying from 0.1 to 100 g/ml. At 1 g and below contractile force was
    not affected, while at higher concentrations the heart rate and
    contractile force was decreased. The effects of noradrenalin in
    response to the effect of chlordimeform were examined. Under
    continuous perfusion with chlordimeform, noradrenalin caused the same
    qualitative changes and slight changes noted were believed to be due
    to the initial effects of chlordimeform. It was thus suggested that
    while chlordimeform has direct effects on heart rate and contractile
    force, the effect of noradrenalin was negligible (Meier, 1975).

    Long-term studies

         Rat

         Groups of rats (25 males and 25 female,/group) were fed
    chlordimeform in the diet at dose levels of 0, 50, 75, 100, 250 and
    500 ppm for one year. Growth and behaviour, as evidenced by food
    consumption and weight gain data, were recorded. Terminal organ
    weights and gross and microscopic examinations of tissues and organs
    were the only other parameters reported.

         The 500 ppm group was terminated at 37 weeks after 10 males and 8
    females had died. At the conclusion of the study there was
    considerable mortality noted in all groups. Food consumption was
    decreased at 500 ppm in both sexes and was slightly reduced at 100 ppm
    and above in males only. This reduced food consumption was not
    significantly reflected in the growth curves of males or females.
    Gross examination did not show any compound related abnormalities.
    Organ weights and organ/body weight or organ/brain weight ratios did
    not differ from control values.

         Histological examinations of liver and spleen were performed on
    all animals. There were no significant differences from control values
    with respect to fatty changes and inflammatory changes in the liver.
    Slight proliferation of the bile duct was more frequent in female rats
    treated with 500 ppm than in the rats of other treated groups or the
    control group. Results of examinations of the spleen for
    haemosiderosis suggested that while this condition was more pronounced
    in females there were no significant differences from control values
    (Zak et al., 1973).

    Observations in man

         Thirteen persons concerned with the packaging of chlordimeform
    developed gross haematuria with symptoms of bladder irritation in
    eight cases, asymptomatic microscopic haematuria in three cases and
    urinary symptoms in two cases. The most prevalent symptoms suggesting
    bladder and urethral inflammation included: urinary urgency, increased
    urine frequency, dysuria, nocturia, penile discharge and abdominal
    pain. There was also an incidence of sleepiness and a case of striking
    heat intolerance. Six patients reported a rash which typically
    involved the face and arms. No cyanosis, dyspnoea or photosensitivity
    was reported (Armstrong et al., 1975). Eleven cases of haematuria have
    been reported in workers exposed to 5-chloro-o-toluidine (Currie,
    1933).

    COMMENTS

         Chlordimeform was evaluated in 1971 and a no-effect level was
    estimated based on two year rat and dog studies. However, because of
    concern over observed effects on the liver and bile duct, a temporary
    ADI was estimated. In addition information was requested because of
    possible potentiating effects of chlordimeform and tyramine on the
    pharmacological effects on the heart and circulation and on the
    leucocyte count in rats.

         New studies on the mode of action of chlordimeform following
    acute poisoning suggest that the principal lesion is not MAO
    inhibition. The acute mode of action, however, remains undefined. A
    new one year study in rats did not show unusual liver or bile duct
    abnormalities. The study did not confirm the suggestion that
    chlordimeform enhanced the ageing process. While some of the concerns
    expressed by the previous meeting were alleviated, the present studies
    were not of sufficient duration to allow the Meeting to change the
    temporary ADI. In addition a preliminary report on haemorrhagic
    cystitis in occupationally exposed people was of concern to the
    Meeting.

    TOXICOLOGICAL EVALUATION

    Level causing no toxicological effect

         Rat: 100 ppm in the diet equivalent to 5 mg/kg body weight.

         Dog: 250 ppm in the diet equivalent to 6.25 mg/kg body weight.

    ESTIMATE OF TEMPORARY ACCEPTABLE DAILY INTAKE FOR MAN

         0 - 0.01 mg/kg body weight.

    RESIDUES IN FOOD AND THEIR EVALUATION

    USE PATTERN

         The uses of chlordimeform have been extended since 1971 and now
    include, in addition to those reported previously, use on rice to
    control stemborers in irrigated rice, on cotton to control
    lepidopterous larvae and on cabbage and tomatoes to control a wide
    range of lepidopterous larvae.

         Details of use patterns reported since 1971 are included in Table
    1.


    TABLE 1.  Registered use patterns for chlordimeform

                                                                         

                                                              Pre-harvest
    Country       Crop                  Rate                  interval
                                                                         

    Japan         Rice                  0.6-0.8 kg/ha         30

                  Rice                  0.1%                  30

                  Cabbage               0.05%                 -

                  Peppers               0.02-0.03%            -

                  Tea                   0.06%                 -

                  Japanese pear         0.06%                 7

                  Persimmons            0.06%                 7

    TABLE 1.  (Cont'd.)

                                                                         

                                                              Pre-harvest
    Country       Crop                  Rate                  interval
                                                                         

    USA           Apple                 0.05%                 14

                  Pear                  0.05%                 0

                  Peach, nectarine      0.05%                 21

                  Cole crops            0.05 kg/ha

                  Cherries              0.05%                 21

                  Walnuts               0.05%                 21

                  Plums, prunes         0.05%                 21

                  Alfalfa               0.8 kg/ha             For seed

    Mexico        Tomatoes              0.25-0.5 kg/ha        2 days
                                                                         


         See also FAO/WHO 1972 and list of national tolerances.

         The control of stemborers in irrigated rice is one of the most
    important uses of chlordimeform. The excellent results obtained are
    based on a threefold activity. The compound:

         (1)  kills eggs and young larvae;

         (2)  suppresses feeding by larvae; and

         (3)  interferes with moth flight resulting in irregular egg
              laying.

         Part of the active material is taken up by the rice plant from
    the irrigation water and translocated to the aerial plant parts. This
    results in an enhanced residual activity since not only the
    chlordimeform on the plant surface, but also that stored within the
    plant, is effective.

         Various formulations including emulsifiable concentrates, dusts,
    granules and water soluble granules are used depending upon the size
    of the plots and the method of irrigation.

         Considerable success has recently been obtained using
    chlordimeform in combination with other insecticides. When using such
    combinations the amount of active ingredient can be reduced
    considerably.

         In the case of cotton, chlordimeform has become one of the most
    important substitutes for DDT and other organochlorine insecticides,
    particularly when used in combination with such materials as
    parathion. Depending upon the spectrum of the pests, it is often
    combined with camphechlor and more recently with Baccilus
    thuringiensis, where a definite synergism has been demonstrated.

         The use of chlordimeform with its essentially ovicidal activity
    to control lepidopterous pests, necessitates a new approach to control
    techniques. The control of the pests at their egg stage prevents crop
    injury. On the other hand, treatments must start earlier than usual,
    that is as soon as egg laying has begun.

         For the control of lepidopterous insects on vegetables including
    tomatoes, it is likewise essential to treat at egg laying and to
    repeat treatments as further egg laying occurs. Combinations with
    Baccilus thuringiensis appear as important in vegetable culture as
    in cotton.

    Post-harvest treatment

         No recommendations have yet been made for any post-harvest use of
    chlordimeform.

    Non-crop uses

         Chlordimeform has no significant usage in non-crop situations
    other than on ornamentals.

    RESIDUES RESULTING FROM SUPERVISED TRIALS

         Several of the maximum residue limits for chlordimeform proposed
    by the 1971 Joint Meeting were considered by member countries of the
    Codex Committee on Pesticide Residues to be rather high in the light
    of the data available from the 1971 Monograph (FAO/WHO 1972).
    Additional supporting data for the tolerances previously recommended
    are presented in Table 2 of this monograph.

    Residues in apples

         Extensive new data were available from supervised residue trials
    carried out in several countries. These are summarized in Table 2.
    Attention is drawn to the relative stability of residues and the fact
    that there is no significant decline in residue levels over the period
    2-30 days after application.

         These new data support the temporary tolerance recommended in
    1971.

    Residues in grapes

         Further data from residue trials indicate that the residue level
    on grapes declines hardly at all during the interval 1-30 days after
    application.

         Because of the wide range of grape varieties and the varying
    conditions under which they are grown, the Meeting considered that the
    maximum residue limit previously recommended should not be lowered.

    Residues in citrus

         Likewise, in the case of citrus many new data available to the
    Meeting indicate the comparative stability of the residue and the
    range of residue levels that can occur in different citrus varieties.
    The Meeting considered that the maximum residue limits previously
    recommended were necessary to cover good agricultural practices in
    many countries.

    Residues in peaches

         Results from a number of supervised residue trials are summarized
    in Table 2 and indicate that, while the residue levels appear to
    decline during the 30 days after application, the rate of decline
    during the first 21 days is relatively slow. The initial uptake by
    peaches appears to be somewhat higher than by other crops, possibly
    due to the skin texture, so that an interval of 21 days was required
    before the residue levels declined to the maximum residue level
    recommended.

    Residue in pears

         Data from extensive supervised residue trials carried out on
    pears in the USA have been summarized in Table 2. These indicate that
    approximately 10 mg/kg of chlordimeform is to be found on fruit
    treated at the recommended rate with either the base or hydrochloride
    formulation. The residue level at 14-18 days post-application is at or
    above 5 mg/kg. Even after 35-40 days residue levels of 4 mg/kg or
    above are not uncommon. In the light of these new data, the Committee
    agreed to revise the recommended maximum residue limit.

    Residues in tomatoes

         Since 1971 there has been considerable interest in the use of
    chlordimeform for the control of lepidopterous pests of tomatoes
    largely as a replacement for DDT and other organochlorine
    insecticides. Results from many supervised residue trials in Mexico,
    USA and Switzerland were submitted to the Meeting and are summarized
    in Table 2.


    
    TABLE 2. Residues of chlordimeform resulting from supervised trials
                                                                                                                                               

                                                                                                    Residue, mg/kg, after interval (days)
                                                                                                                                              
                                                   Concentration,   No. of
    Commodity                Origin         Year         %          sprays   Formulation    0-1     2-4     5-9     10-19    20-30        31-60
                                                                                                                                               

    Apples                   USA            1969        0.06        3            EC                         1.5     1.0      0.8
                             USA            1969        0.06        2            EC         3.3             2.2              1.2          0.4
                             USA            1969        0.06        2            EC         8.8             3.4     2.8      2.4          1.4
                             USA            1969        0.12        3            EC         5.1             1.5     1.4      1.0
                             Australia      1965        0.05        1            EC         0.7     1.0     0.5     0.4      0.5
                             Germany        1969        0.07        1            SP         1.4             1.5     1.3      1.0
                             Italy          1965        0.05        1            EC         1.1     0.8             0.4                   0.5

    Grapes                   USA            1969        0.12        2            SP         3.5             3.2     2.6      2.5          2.2
                             Italy          1965        0.05        1            EC         1.8     2.0     2.1     2.2      2.9          2.3

    Lemons                   Italy          1967        0.05        2            EC                                 2.0                   0.1

    Mandarins                Japan          1966        0.05        1            EC                                          0.4

    Oranges whole            Italy          1968        0.034       1            SP         0.7     0.6     0.4     0.7      0.3          0.3
            pulp             Italy          1968        0.034       1            SP         0.08    0.1     0.1     0.2      0.05         0.06

    Peaches                  USA            1968        0.04        1            SP         6.7                     2.6      1.5          0.6
                             USA            1967        0.06        1            EC         10.4            8.6     5.6                   0.7
                             USA            1973        0.06        1            SP         13.5            8.4     3.9      3.1
                             Australia      1970        0.07        1            SP         0.9     1.2     0.4     1.67     0.62         0.53

    Pears                    USA            1969        0.12        2            SP         17.3            11.3    8.0      6.2
                             USA            1969        0.12        2            EC         8.3             5.3     4.7      3.4
                             Italy          1965        0.05        1            EC         1.1     1.2     1.0     1.0      0.9          0.5
                             USA            1973        0.06        3            SP         7.7             5.7     4.3      4.0          3.1
                             USA            1973        0.06        3            EC         7.9             5.0     4.3      3.3          3.2
                             USA            1973        0.06        3            SP         6.5             6.3     4.7      3.6          2.7

    TABLE 2. (continued)
                                                                                                                                               

                                                                                                    Residue, mg/kg, after interval (days)
                                                                                                                                              
                                                   Concentration,   No. of
    Commodity                Origin         Year          %         sprays   Formulation    0-1     2-4     5-9     10-19    20-30        31-60
                                                                                                                                               

    Pears (cont'd)           USA            1973        0.06        3            EC         7.3             6.1     5.0      4.6          3.7
                             USA            1973        0.06        3            SP         10.4            9.7     6.1      4.7          4.3
                             USA            1973        0.06        3            EC         9.3             7.6     4.9      4.3          4.0

    Tomatoes                 Mexico         1970         1.0        1            SP                 0.19
                             Mexico         1973         1.0        8            SP         0.13    <0.05   <0.05
                             Mexico         1973         0.2        10           SP         0.11    0.6     0.1     <0.05
                             USA            1970        0.06        7            EC         0.3     0.36    0.45    0.29     0.1
                             USA            1971        0.06        6            EC         0.45    0.5     0.18    0.12
                             USA            1970        0.12        7            EC         0.67    0.9     0.6     0.46     0.75
                             Switzerland    1972        0.05        3            EC         0.37            0.33    0.37     0.26         0.31
                             USA            1973        0.12        5            SP         0.5     0.4     0.31    0.28     0.3

    Hops (green)             Germany        1970        0.05        3            EC                                 12.5

    Strawberries             Australia      1971        0.04        1            SP         2.17    1.41    1.07    0.75
                             Australia      1971        0.08        1            SP         3.5     2.53    2.19    1.32
                             New Zealand    1968        0.07        1            SP                         0.8
                                                                                                                                               
    

         It is interesting to note that notwithstanding repeated
    applications of both the hydrochloride and base formulation, the
    uptake of chlordimeform by tomatoes is considerably below that of
    pears, peaches or apples. The level of residues found in fruit treated
    three weeks before harvest is substantially the same as on the day of
    application.

    FATE OF RESIDUES

    General comments

         Extensive information on the nature and fate of chlordimeform
    residues was considered at the 1971 Meeting and a review of this
    information is contained in the monographs (FAO/WHO 1972). Since then
    only limited information has been received on the general fate of
    chlordimeform residues.

    In plants

         An abstract of the thesis by Witkonton, 1974, indicates that
    radio tracer studies of apples treated with chlordimeform revealed a
    rapid disappearance of the chemical from the surface of the treated
    fruit. Less than 1% of the applied chemical remained on the surface at
    harvest 60 days after application. However, 25% of the applied
    chemical was recovered in apple peel and pulp. This mainly comprised
    the parent compound and N-formyl-4-chloro-o-toluidine.

         Studies on tomatoes grown in Mexico revealed that little of the
    chlordimeform residue was removed by simple washing. Field treated
    tomatoes picked two days after application were found to contain 0.19
    mg/kg of chlordimeform (range 0.17 to 0.20). Following a simple
    washing process, these same tomatoes contained 0.12 mg/kg
    chlordimeform (range 0.07 to 0.17).

    In cooking and processing

         In solution, chlordimeform. is susceptible to hydrolysis but not
    to oxidative processes, provided that enzyme systems from living
    organisms are not present. The rate of hydrolysis depends on the Ph
    value of the medium. Chlordimeform is stable under strongly acid
    conditions (in the region of Ph 2). Considerable instability occurs in
    neutral medium with a half-life of 42 hours at 30C in a buffer of pH
    7 containing 5% of methanol (Kosmann et al., 1971).

         Hydrolysis of chlordimeform in neutral medium yields
    N-formyl-4-chloro-o-toluidine. Further hydrolysis to
    4-chloro-o-toluidine is very slow under these conditions. It is,
    however, much more rapid in extremely acid or alkaline solutions.

         Chlordimeform residues in crops decrease during cooking processes
    through hydrolysis of the parent compound, but volatilization in steam
    is not an important contributing factor. It has been demonstrated that
    the rate of disappearance of chlordimeform is a function of pH since
    the loss is much more rapid in weakly acid or neutral material such as
    cauliflower than in strongly acid fruit like apples. This finding is
    in agreement with the known chemical properties of the compound.

         Cooking processes do not reduce substantially the total residue
    which can be estimated by the method which determines the total
    4-chloro-o-toluidine moiety. In the light of these results, which
    were derived from detailed studies with different crops (apples,
    grapes, tomatoes, cauliflowers, beans, sugar beet foliage) (Kossmann,
    1971), it can be concluded that cooking procedures reduce the
    proportion of parent compound while at the same time increasing the
    proportion of the hydrolysis product N-formyl-4-chloro-o-toluidine.
    This change is not large except in the case of neutral or alkaline
    conditions and in any event is not likely to be detected when making
    analyses by the accepted method. Results of studies using analytical
    methods specific for the parent compound are set out in Tables 3-5.

         Further studies on the fate of chlordimeform residues in cooking
    and processing have been reported. These include studies on the
    following commodities.

    Tea

         The total residues of chlordimeform in three different tea leaf
    samples were determined to be 30.4, 12.3 and 3.7 ppm respectively. Tea
    prepared from these samples (1 g per 100 ml of boiling water)
    contained total residues of 0.18, 0.07 and 0.02 ppm. These results
    indicate that more than 50% of the total residues present in the dried
    tea are extractable under the conditions of infusion and will thus
    move into the beverage (CIBA-GEIGY, 1972a).

    Apple juice

         Apple juice was prepared using a pneumatically operated press to
    yield 80% juice and 20% wet pomace. Whole apples containing 5 mg/kg
    total chlordimeform residue yielded juice containing 2 mg/kg
    (CIBA-GEIGY, 1972b). The wet pomace on the other hand contained 9.2
    mg/kg chlordimeform. Upon drying, the dry pomace yielded 35.7 mg/kg.

         The level of residues in the juice is only half what would be
    expected had the residue been distributed homogeneously between the
    pulp and the juice. Earlier studies (Schering, 1967a,b) had shown that
    apples containing 1.9% total chlordimeform only contain 0.2 ppm in the
    flesh but 9.2 ppm in the skin and outer layer, which represents 20% of
    the total weight of the apple.

    Grape juice and wine

         Grape berries containing 1.4 mg/kg of total chlordimeform when
    pressed, yielded juice containing 0.9 mg/kg (CIBA-GEIGY, 1972c). This
    is in agreement with earlier studies (Schering, 1967a,b) which showed
    that depending upon the interval between spraying and harvest, the
    grape skins contained from 60 to 76% of the residues found in the
    whole grapes. The skins, on the other hand, only represented 17% of
    the total weight of fruit pressed.


    TABLE 3. Effect of cooking on chlordimeform residuesa in crops

                                                                             

                              Residue found                     Residue found
                              before cooking         Cooking    after cooking
    Crop                                             period                 
    (variety)        Code     mg/kg     %      pH    min.       mg/kg    %
                                                                             

    Apples           73/70    0.76      100    2.5   15         0.61     80
    (Ontario)        74/70    0.73      100    2.5   15         0.57     78
                     73/70    0.76      100    2.5   60         0.55     72
                     74/70    0.73      100    2.5   60         0.46     63

    Grapes           89/70    2.35      100    2.5   15         2.30     98
    (Riesling)                2.35      100    2.5   60         2.05     87

    Grapes           94/70    1.95      100    2.5   15         2.20     113
    (Muller-Thurgau)          1.95      100    2.5   60         1.48     76


    Sugar beet       119/70   4.10      100    6     15         0.70     17
    foliage          120/70   7.95      100    6     15         1.05     13
                     119/70   4.10      100    6     60         0.24     6
                     120/70   7.95      100    6     60         0.17     2
                                                                             

    a Residues were determined by means of a method specific for chlordimeform
        parent compound.

    TABLE 4.  Effect of cooking on chlordimeform contenta of samples
              spiked with chlordimeform

                                                               

                                                 Chlordimeform
                                       Cooking   recovered
                Chlordimeform          period                
    Crop          added mg/kg    pH    min.      mg/kg     %
                                                               

    Apples           2.0         2.5   15        1.60      80
    (deep freeze)    2.0         2.5   60        1.85      92

    Tomatoes         2.0         3     15        2.00      100
    (fresh)          2.0         3     60        1.75      88

    Green beans      2.0         5     15        0.76      38
    (fresh)          2.0         5     60        0.23      11

    Cauliflower      2.0         6     15        0.45      22
    (fresh)          2.0         6     60        <0.02     <1
                                                               

    a Chlordimeform content determined by means of a method specific
        for chlordimeform parent compound.


    TABLE 5.  Effect of cooking on total chlordimeform, contentb
              of samples spiked with chlordimeform

                                                               

                                                 Chlordimeform
                                       Cooking   recoveredc
                Chlordimeform          period                
    Crop          added mg/kg    pH    min.      mg/kg     %
                                                               

    Tomatoes         2.0         3     60        1.94      97
    (fresh)

    Green beans      2.0         5     15        1.68      84
    (fresh)          2.0         5     60        1.80      90

    Cauliflower      2.0         6     15        2.06      103
    (fresh)          2.0         6     60        1.78      89
                                                               

    b Total chlordimeform content determined by a procedure that
        accounts for the active ingredient and its hydrolysis products
        N-formyl-4-chloro-o-toluidine and 4-chloro-o-toluidine.
    c Average of three determinations.

         Fermentation of the grape juice over a period of 72 days yielded
    a wine still containing about 1 mg/kg of chlordimeform, (CIBA-GEIGY,
    1972d). This result indicates that the fermentation process for wine
    production does not significantly lower the total chlordimeform
    residues found in the raw grape juice.

    Beer

         Green hop cones containing 12.5 mg/kg chlordimeform were used to
    prepare beer. Residues in the beer prepared from the treated cones
    were found to be below the limit of detection as calculated
    statistically from the control and analytical values (CIBA-GEIGY,
    1971). The limit of determination was 0.03 mg/kg.

    Milk and butter

         Extensive studies carried out in Australia and reported by Bull
    (1971a,b) indicate that when chlordimeform is used on cows as a dip or
    spray for the control of cattle ticks, the maximum concentration of
    chlordimeform occurs in the milk of the first milking after treatment.
    The maximum concentration found in a number of trials was 0.04 mg/kg
    (just above the limit of determination). Butter prepared from this
    milk, which contained 3.8 to 4.0% butterfat, was found to contain 0.26
    to 0.34 mg/kg chlordimeform.

         Butter prepared from milk collected 12 hours later contained only
    0.08 mg/kg chlordimeform. Thereafter the residue level declined
    rapidly, being below the limit of determination in butter on the
    fourth day after treatment. These studies indicate that only about one
    third of the total chlordimeform excreted in the milk is located in
    the butterfat and finds its way into butter.

         Further studies using chlordimeform at 0.05% concentration (four
    times the label recommendation), showed that residues in whole milk
    collected six hours after treatment contained up to 0.3 mg/kg
    chlordimeform. Butter prepared from this milk contained up to 1.75
    mg/kg. Residues in milk did not decline below the limit of
    determination for 72 hours following such treatment but, even at this
    stage, the butter was found to contain 0.1 mg/kg chlordimeform. These
    studies further indicate that chlordimeform is only partly partitioned
    into the lipid portion of milk.

    RESIDUES IN FOOD IN COMMERCE OR AT CONSUMPTION

         Only one piece of information was submitted to show results of
    monitoring for chlordimeform residues in food moving in commerce. The
    Australian Department of Agriculture reported that during the
    continuous survey of raw agricultural commodities for a wide range of
    residues, 152 samples of beef fat collected at abbatoirs within the
    cattle tick zone were analysed for chlordimeform residues. None of the
    samples were found to contain residues at or above the limit of
    determination (0.05 ppm).

    METHODS OF RESIDUE ANALYSIS

         No significant developments appear to have been made since the
    available data were reviewed in 1971. Voss et al. (1973) have
    published a detailed review of the available methods and have
    confirmed the techniques suitable for research and regulatory purposes
    including automated modifications. The methods most suitable for
    regulatory residue analysis appear to be those involving the
    determination of chlordimeform and metabolites hydrolyzable to
    4-chloro-o-toluidine using gas chromatography following iodination
    of the diazotised aromatic amine (Baunok and Geissbuhler, 1968;
    Geissbuhler et al., 1971).

         At the present time there are a number of other formamidine
    compounds being developed as insecticides and acaricides for the
    treatment of cattle. Same of these also contain the
    4-chloro-o-toluidine moiety and would be determined quantitatively
    by the same procedure. A means of distinguishing such residues will be
    required if and when both classes of compounds are available
    concurrently.

    NATIONAL TOLERANCES REPORTED TO THE MEETING

         The following are examples of national tolerances and withholding
    periods that have been established.
                                                                                               
                                                                              Withholding
                                                                              period (days)
                                                                 Tolerance    (pre-harvest
    Country        Crop                                          mg/kg        interval)
                                                                                           

    Argentine      Apples, pears                                 -            28

    Australia      Apples, grapes                                3            7
                   Citrus, cole crops                            2            7
                   Cotton seed                                   2            2
                   Pears, stone fruit                            5            7
                   Strawberries                                  3            2
                   Tomatoes                                      1            1
                   Fat of meat and edible offal of cattle        1            3
                   Milk and milk products (fat basis)            0.5          -
                   Edible vegetable oil                          0.05         -

    Canada         Apples                                        3            14
                   Broccoli                                      2            7
                   Brussels sprouts                              3            14
                   Cabbage                                       0.5          7
                   Cauliflower                                   3            7
                   Peaches                                       4            28
                   Pears                                         5            28
                   Plums and prunes                              4            21
                   Turnip roots (Brassica)                       <0.05        7

    (Continued)
                                                                                           
                                                                              Withholding
                                                                              period (days)
                                                                 Tolerance    (pre-harvest
    Country        Crop                                          mg/kg        interval)
                                                                                           
    Federal        Fruits                                        3            14
    Republic       Vegetables                                    2            14
    of Germany     Sugar beets                                   0.2          42

    France         Not specified                                 -            15
    Italy          Not specified                                 1            -

    Japan          Citrus                                        2            30
                   Fruits                                        2            7
                   Grapes                                        -            45
                   Rice                                          0.1          30
                   Strawberries                                  -            7
                   Tea                                           0.6          -
                   Vegetables                                    0.6          -

    New Zealand    Fruits                                        -            14
    Peru           Cotton (seed)                                 -            15

    South Africa   Apples, pears                                 1            -
                   Citrus                                        -            14

    Spain          Fruits, cotton                                -            21
    Switzerland    Pome fruits, grapes                           1            42

    USA            Apples                                        3            14
                   Pears                                         12           0
                   Dried apple pomace                            25           -
                   Cherries                                      5            21
                   Peaches                                       5            21
                   Nectarines                                    5            21
                   Plums                                         4            21
                   Dried prunes                                  15           21
                   Walnuts                                       0.1          21
                   Broccoli                                      2            14
                   Brussels sprouts                              2            14
                   Cabbage                                       2            14
                   Cauliflower                                   2            14
                   Tomatoes                                      1            -
                   Cotton seeds                                  5            21
                   Cotton seed hulls                             10           -
                   Meat, fat, meat byproducts                    0.25         -
                   Eggs, milk                                    0.25         -

    Venezuela      Fruits, citrus                                2            -
    
    APPRAISAL

         The 1971 Joint Meeting, having reviewed the available information
    on chlordimeform, specified that further work or information was
    required on the nature and level of residues in animal tissues,
    residues in milk, residues in butter and cheese, further data on
    disappearance of residues during storage, processing and cooking, and
    data on residue levels in commodities moving in commerce.

         The Meeting received considerable information on all these
    questions with the exception of residues in commodities moving in
    commerce. There was additional information on new uses, including
    application to irrigated rice. Residue studies to indicate the
    incidence and level of residues resulting from the use of
    chlordimeform on rice were not available.

         Additional information was received on supervised residue trials
    carried out in several countries on apples, grapes, citrus, peaches,
    pears, tomatoes and strawberries. These data indicate that in the case
    of apples, grapes, citrus and peaches, the information reviewed
    confirmed the recommendations made in 1971 and the Meeting agreed that
    the maximum residue limits then recommended could not be lowered. Data
    from extensive supervised residue trials carried out on pears in the
    USA indicate that approximately 10 ppm of chlordimeform is to be found
    on fruit treated at the recommended rate with either the base or
    hydrochloride formulation. The residue level at 14 to 18 days
    post-application is at or above 5 mg/kg. Even at 35 to 40 days after
    application, residue levels of 4 mg/kg are not uncommon. In the light
    of these new data, the Meeting agreed to revise the recommended
    maximum residue limit.

         The need to use chlordimeform for the control of lepidopterous
    pests of tomatoes has resulted in the generation of extensive residue
    data on the basis of which the Meeting has proposed a maximum residue
    limit.

         Only limited new information has been received on the general
    fate of chlordimeform residues but in view of the extensive
    information reviewed in 1971, this is not surprising. It is, however,
    clear that little of the residue will be removed by a simple washing
    process but the bulk will be removed with the peel of such commodities
    as apples, citrus, peaches and grapes.

         Further studies on the fate of chlordimeform residues during
    cooking and processing have shown that the cooking of acid fruits and
    vegetables does not substantially reduce the residue of the active
    ingredient. Any metabolites, including the terminal
    4-chloro-o-toluidine, are not particularly volatile in steam and are 
    thus not lost during cooking.

         In the preparation of fruit juices the bulk of the residues
    remain in the pomace. Any residues which occur in the juice are
    resistant to further processing, including the fermentation of wine.

         In the case of residues in milk arising from the application of
    chlordimeform to dairy cows for tick control, the residue levels
    decline rapidly and are only of significance in butter made from such
    milk from the first and second milkings following treatment. It has
    been shown that only a portion of the chlordimeform residue is
    partitioned into the lipid fraction of the milk. It is not yet clear
    whether the residues in milk contain any of the parent compound or
    whether they represent metabolites and terminal residues.

    RECOMMENDATIONS

         The following amended (pears) and new temporary maximum residue
    limits are recommended:

                                                                  

                                            Temporary maximum
              Commodity                     residue limit, mg/kg
                                                                  

              Pears                                10

              Tomatoes                             1

              Rice (hulled)                        0.1
                                                                  

    FURTHER WORK OR INFORMATION

    Required before 30 June 1978

    1.   Long-term study to consider the occurrence of changes in liver
    and bile duct of rats.

    2.   Further metabolic studies in several animal species including
    observations in man.

    3.   Further studies to elucidate the mode of action.

    4.   Continued observations on the possible occurrence of haemorrhagic
    cystitis in people exposed to chlordimeform.

    5.   Information to justify the short pre-harvest interval on pears in
    the USA.

    REFERENCES

    Abo-Khatwa, N. and Hollingworth, R. M. (1972) Chlordimeform: the
    relation of mitochondrial uncoupling to toxicity in the German
    cockroach. Life Sciences II, 11:1181-90

    Abo-Khatwa, N. and Hollingworth, R. M. (1973) Chlordimeform,
    uncoupling activity against rat liver mitochondria, in vitro.
    Pesticide Biochemistry and Physiology, 3:358-69

    Armstrong, J., Graves, O., Lovejoy, G., Swiggart, R. and Kimbrough, R.
    (1975) Insecticide induced acute haemorrhagic cystitis. Morbidity,
    Mortality Weekly Report, US, CDC, Atlanta, Georgia. Vol. 24, No. 44,
    p.374

    Aziz, S. A. and Knowles, C. O. (1973) Inhibition of monoamine oxidase
    by the pesticide chlordimeform and related compounds. Nature, 242:
    417-18

    Baunok, I. and Geissbuhler, H. (1968) Specific determination of urea
    herbicide residues by EC gas chromatography after hydrolysis and
    iodine derivative formation. Bull. Env. Contam & Toxicol, 3(1)7

    Beeman, R. W. and Matsumura, F. (1973) Chlordimeform: a pesticide
    acting upon amine regulatory mechanisms. Nature, 242:273-74

    Beeman, R. W. and Matsumura, F. (1974) Studies on the action of
    chlordimeform in cockroaches. Pesticide Biochemistry and Physiology,
    4: 325-26

    Bull, M. S. (1971b) Determination of chlordimeform residues in milk
    and butter following treatment of cows with chlordimeform at label
    recommended strength for plunge dipping and spraying. Ciba-Geigy
    (Australia) Technical Report 71/10/354

    Bull, M. S. (1971a) Determination of chlordimeform residues in milk
    and butter following treatment of dairy cows with 0.05% chlordimeform.
    Ciba-Geigy (Australia) Technical Report 71/8/348

    CIBA-GEIGY (1971) Galecron residues - German hops and beer 1970.
    Report by G. Voss RVA 42/71 (June 15, 1971)

    CIBA-GEIGY (1972a) Galecron residues in Japanese tea. Report by W.
    Blass, RVA 5/72 (January 11, 1972)

    CIBA-GEIGY (1972b) Chlordimeform residues in McIntosh apples, cider
    and wet and dry pomace. Research Report CF 10824

    CIBA-GEIGY (1972c) Galecron residues in Swiss grapes. Report by W.
    Blass, RVA 11/72 (January 17, 1972)

    CIBA-GEIGY (1972d) Galecron residues in Swiss wine 1971. Report by W.
    Blass, RVA 16/72 (February 4, 1972)

    Currie, A. N. (1933) Chemical haematuria from handling
    5-chloro-o-toluidine. J. Ind. Hyg., 15:

    Dittrich, V. (1966) N-(2 methyl-4-chlorphenyl)-N',N'-dimethyl
    Formamidine (C8514/Schering 36268) Evaluated as an acaricide. J. Econ.
    Entomol., 59:889-93

    Geissbuhler, H., Kossman, K., Baunok, I. and Boyd, V. F. (1971)
    Determination of total residues of chlordimeform in plant and soil
    material. J. Agr. Food Chem., 19:365

    Kossman, K. (1971) Effect of cooking on chlordimeform residues in
    apples, grapes, tomatoes, cauliflower, beans and sugar been foliage.
    Schering AG report PC 29/64 (September 28, 1971)

    Kossman, K., Geissbuhler, H. and Boyd, V. F. (1971) Specific
    determination of chlordimeform and some potential metabolites in plant
    materials by thin-layer and flame ionisation gas chromatography. J.
    Agr. Food Chem., 19:360

    Maitre, L. and Gfeller, W. (1975) Influence of Compound 8514
    (chlordimeform) on the brain and liver monamino oxidase of rats.
    Unpublished report from Ciba-Geigy Pharmaceutical Division submitted
    to the World Health Organization by Ciba-Geigy Ltd., Basel,
    Switzerland

    Meier, M. (1975) Investigation of the effect of chlordimeform in
    isolated heart preparations of the guinea pig. Unpublished report from
    the Ciba-Geigy Pharmaceutical Division submitted to the World Health
    Organization by Ciba-Geigy Ltd., Basel, Switzerland

    Robinson, C. P., Smith, P. W., Zelenski, J. D. and Endecott, B. R.
    (1975) Lack of an effect of interference with amine mechanisms on the
    lethality of chlordimeform in the rat. Tox. Appl. Pharmacol.,
    33:380-83

    Schering AG (1967b) Ruckstandsuntersuchungen chlorphemidin (Schering
    36268) IV Mitteilung 1968 -Lokalisation eines chlorphenamidin -
    Ruckstandes auf Apfelen de Sorte Cox Orange. Report of Schering AG, Dr
    Ko/So, 17.10.67

    Schering AG (1967a) Ruckstandsuntersuchungen chlorphenamidine III
    Mitteilung 1967. Erntegut: Weintrauben. Report of Schering AG, Dr
    Ko/So, 13.10.67

    Witkonton, S. (1974) Fate of the pesticide in fruit and soil and
    toxicological properties of some of its conversion products. Diss.
    Abstr. Int., 38(8) 3831 B (Thesis, Pennsylvania State University)

    Voss, G., Kossmann, K. and Geissbuhler, H. (1973) Chlordimeform in
    analytical methods for pesticides and plant growth regulators. Edited
    by G. Zweig, Academic Press, New York, p.211-230

    Zak, F., Sachsse, K., Bathe, R. and Hess, R. (1973) One-year feeding
    study on the rat with Technical C-8514. Unpublished report from the
    Toxicology/Pathology Division, Ciba-Geigy, submitted to the World
    Health Organization by Ciba-Geigy Ltd., Basel, Switzerland
    


    See Also:
       Toxicological Abbreviations
       Chlordimeform (EHC 199, 1998)
       Chlordimeform (ICSC)
       Chlordimeform (WHO Pesticide Residues Series 1)
       Chlordimeform (Pesticide residues in food: 1978 evaluations)
       Chlordimeform (Pesticide residues in food: 1979 evaluations)
       Chlordimeform (Pesticide residues in food: 1980 evaluations)
       Chlordimeform (Pesticide residues in food: 1985 evaluations Part II Toxicology)
       Chlordimeform (Pesticide residues in food: 1987 evaluations Part II Toxicology)
       Chlordimeform (IARC Summary & Evaluation, Volume 30, 1983)