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    DODINE         JMPR 1974

    Chemical name

         dodecylguanidinium acetate

    Synonyms

         Dodine acetate, doguadine, laurylguanidine acetate, citrex,
         Melprex(R), Cyprex(R).

    Structural formula

                   NH
                    "  +
        n-C12H25-NH-C-NH3     CH3.COO-

    (Empirical formula C15H33N3O2)

    Other information on identity and properties

         Molecular weight:    287

         Physical state:      white crystals

         Melting point:       136C

         Solubility:          In alcohols of low molecular weight ranges
                              from 7% to 23% at room temperature; in water
                              0.063% by weight at 25C; soluble in acids;
                              insoluble in most other solvents.

         Stability:           At ordinary temperatures the compound is
                              stable as a solid or in solution and under
                              moderately acidic or alkaline conditions.
                              The free base will be released under extreme
                              alkaline conditions.

         Formulations:        Wettable powder 65%, water-miscible liquid
                              24% weight/volume.

         Information on the composition of the technical material was not
    available. There is a number of manufacturers.

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    BIOCHEMICAL ASPECTS

    Biotransformation

         No data are available on the metabolic degradation of dodine.
    Administration of dodine to the branches of apple trees resulted in no
    translocation of dodine from the foliage into the fruit of the tree.
    Preliminary experiments on the biodegradation of dodine suggested that
    natural products were the only materials observed (Curry, 1962). Owens
    (1969) suggested that the metabolism of dodine resulting in the
    formation of creatine was the result of beta-oxidation of the dodecyl
    group and subsequent methylation (from methionine or betaine).

    NHCNH2NHC12H25*CH3COOH -> NHCNH2NHCH2COOH ->NHCNH2N(CH3)CH2COOH

         dodine (acetate)           (CH3)            creatine

         The biotransformation of dodine in plants and soil is discussed
    further in the section "Fate of residues".

    TOXICOLOGICAL STUDIES

    Special studies on carcinogenicity

    Mouse

         Groups of mice (18 males and 18 females of each of two hybrid
    strains) were administered dodine from day 7 after birth, at 21
    mg/kg/day orally, for 21 days. Thereafter, for 18 months, the mice
    were fed 82 ppm in the diet, sacrificed and examined for tumors.
    Dodine did not cause a significant increase in tumors and this
    carcinogenic screening test was reported to be negative (Innes et al.,
    1969).

    Special studies on reproduction

    Mouse

         Groups of mice (CF1 strain, 8 males and 16 females per group)
    were fed dietary levels of 0, 400 and 800 mg/kg dodine for at least
    five weeks prior to mating in a standard three generation, two litter
    per generation, reproduction study. There were no effects on
    reproduction as evidenced by the fertility, gestation, and viability
    indices. The lactation index was significantly reduced at 800 ppm. No
    consistent abnormalities following gross and microscopic examination
    were observed. A no-effect level for this three generation
    reproduction study is 400 ppm (McNerney et al., 1967).

    Rat

         Two groups of rats removed from the two year feeding study were
    used in a two generation reproduction study. Groups of 9 males and 18
    females per group fed 0 and 800 ppm dodine for 105 days were mated.
    The F1 progeny when weaned were maintained on the same dietary level
    for 90-110 days and mated while the parents were removed to the
    original feeding study. The F1 parents were allowed to raise three
    litters (F2a, b, and c) which were examined and sacrificed after
    weaning. There were no effects on reproduction noted in either the
    control or 800 ppm group. There was a slight, nonsignificant,
    reduction in litter size in the F2a, b, and c litters.

         Some of the F1 generation animals were observed as long as one
    year, during which time they continued to receive 800 ppm dodine in
    the diet. Gross pathology and relative organ weights of these animals
    did not indicate adverse effects of the dodine feeding. A haematology
    and microscopic examination of some animals from all groups did not
    reveal differences when compared to controls. Parental growth was
    retarded at 800 ppm (Levinskas et al., 1961; O'Grady et al., 1958b).

    Acute toxicity

    TABLE 1  Acute toxicity of dodine to mammals

                                                                             

                                    (LD50)
    Species        Sex    Route     (mg/kg)        References
                                                                             

    Rat            M      oral      750-1540       (Levinskas et al., 1961)
                   F      oral      660            (Levinskas et al., 1961)

    Guinea Pig            oral      176            (Tovstenko, 1973)

    Mouse          M      oral      266-1720       (Tovstenko, 1970)

    Rabbit         M      dermal    2100-10 000    (Tovstenko, 1973)
                          oral      535            (Tovstenko, 1973)

    Dog                   oral      *              (West et al., 1958)
                                                                             

    * Dose of 2000 mg/kg induced emesis.


         Signs of poisoning include depression, diarrhoea and death, but
    such signs may be delayed. Gross pathology revealed minor G.I. tract
    irritation.

         A 0.12% aqueous dispersion administered to the skin of rabbits
    resulted in no deaths or appreciable skin irritation at a dose of
    10 ml/kg. An aqueous paste contacting the skin for 24 hours produced
    severe erythema and edoema. After seven days, there was evidence of
    subcutaneous haemorrhage, enlarged mesenteric lymph nodes, hyperaemia
    and thickening of the pyloric area of the stomach.

         A 10 mg dose in the conjunctival sac of rabbits resulted in
    severe conjunctivitis. The onset of secondary infection complicated
    recovery and recovery was not complete after seven days. A volume of
    0.1 mg of the 0.12% dispersion caused transient reddening and swelling
    of the conjunctivae.

         Repeated administration to mice altered ADP and glycogen levels
    (Tovstenko, 1970). Acute administration to rats resulted in
    hypoglycaemia, increased ATP-ase activity in blood and decreased ATP
    in liver and myocardium, indicative of acute stress (Belonozhko et
    al., 1973).

         Dodine has been reported to be moderately accumulative in both
    guinea pigs and mice. Following daily administration of 1/20 LD50,
    the accumulation factor is 4.0 in Guinea pigs and 5.4 in mice. A
    threshold dose of 1.33 mg/kg and a no-effect dose of 0.67 mg/kg were
    reported in chronic tests. Doses of 1.33 mg/kg caused functional
    changes in the cerebral cortex and haemodynamic changes in the heart
    liver, kidney, brain, and lung in guinea pigs (Tovstenko, 1973).

    Short term studies

    Rat

         Groups of rats (19 males and 19 females = 0 ppm; 20 males and 18
    females = 3200 ppm) were fed dodine in the diet for 14 weeks. Growth
    was markedly reduced in all animals fed 3200 ppm. This was reflected
    in a significant reduction in food consumption. Behaviour was altered
    as noted by an increased irritability and increased spontaneous
    activity. A reduction of weight of several tissues and organs was not
    accompanied by pathological abnormalities as observed by microscopic
    examination (Levinskas et al., 1961).

    Dog

         Groups of dogs (2 males and 2 females per group) were fed dodine
    in a dry diet at levels of 0, 50, 200 and 800 ppm for one year. There
    was no effect on growth, behaviour, mortality, haematology, or on
    tissues and organs examined grossly at the conclusion of the study.
    Microscopic examination revealed changes in the thyroid glands of all
    animals at 800 ppm and in one female at 200 ppm. Thyroid changes
    consisted of an increase in vascularity, hyperaemia, and general
    evidence of thyroid gland stimulation. A shift was observed of the
    follicular epithelium from a squamous to a predominantly cuboidal
    variety. These signs were most evident in the animals receiving high

    doses and less evident in the single dog at 200 ppm. There was no
    evidence of hyperplasia although the thyroid gland, as noted by
    histological changes was definitely stimulated (O'Grady, 1958a;
    Levinskas et al., 1961).

    Long term studies

    Rat

         Groups of rats (40 males and 40 females per group) were fed
    dodine in the diet for two years at levels of 0, 50, 200 and 800 ppm.
    Food intake and growth were significantly depressed at 800 ppm. There
    was no apparent effect on survival, behaviour, haematological
    parameters, or gross pathology of any animals. Microscopic examination
    of tissues and organs of some animals from the control and 800 ppm
    groups at the conclusion of the study showed no differences between
    the two groups. An examination of the tumors produced in this study
    indicated no effect related to the incorporation of dodine in the
    diet. A. no-effect level in this study is 200 ppm (O'Grady, et al.,
    1959; Levinskas et al., 1961).

    OBSERVATIONS IN MAN

         Workers involved in the production of dodine in the United States
    from 1958-1964, during which time substantial quantities of this
    material were manufactured, have been monitored. It has been shown
    that the occupational exposure to dodine produces minor superficial
    effects. Acute dermatitis and acute eye irritation accompanied by
    conjunctival and corneal burn were readily reversible and are of no
    long lasting significance (Hartmann, 1964).

    COMMENTS

         Dodine acts as a cationic surfactant. Few data are available on
    the metabolic fate of dodine in animals or plants although suggestions
    have been made that the molecule degrades to natural products. The
    active ingredient has a moderate acute toxicity although irritation of
    the eye and skin was observed. No biochemical lesions have been
    identified in mammals and the signs of poisoning are typical of
    general debilitation of basic metabolism and nutrition. Results of
    reproduction studies in rats and mice were negative at a 400 ppm
    dietary level. In short and long term studies with rats and dogs, high
    dietary levels produced effects on growth in the rat and histological
    changes were noted in the thyroid of the dog. Dodine did not appear to
    have a carcinogenic effect in long term studies reported using rats
    and mice.

         Based on feeding studies, no-effect levels were observed with the
    rat, mouse, and dog. Although no specific reproduction problems were
    noted, the lack of teratogenesis and mutagenesis data was noted.
    Concern was expressed over the lack of metabolic data. A temporary ADI
    in man was allocated based on the no-effect level in the dog.

    TOXICOLOGICAL EVALUATION

    Level causing no toxicological effect

         Rat: 200 ppm in the diet equivalent to 10 mg/kg bw.

         Dog: 50 ppm in the diet equivalent to 1.25 mg/kg bw.

    ESTIMATE OF TEMPORARY ACCEPTABLE DAILY INTAKE FOR MAN

         0 - 0.01 mg/kg bw.

    RESIDUES IN FOOD AND THEIR EVALUATION

    USE PATTERN

         Dodine is a fungicide recommended for the control of a number of
    major fungal diseases of crops. It is used against apple and pear
    scab; cherry leaf spot; peach bacterial spot and leaf curl; pecan
    scab, liver spot, brown and downy leaf spot, leaf blotch and downy
    mildew; strawberry leaf scorch, spot and blight.

    Pre-harvest application

         The recommended dosage is 0.016-0.033% a.i. as wettable powder or
    0.03% a.i. as the liquid concentrate formulation at 5-10 day intervals
    or as needed to maintain efficient control. The coverage is 1.1-2.2
    kg/ha. The number of treatments varies from 3-10. Powell et al. (1958)
    showed that almost perfect control of scab infection on apples could
    be assured by the first three sprayings. The national use patterns and
    tolerances known to the Meeting are listed in Table 2.

    RESIDUES RESULTING FROM SUPERVISED TRIALS

         Residue data on apples, pears, sweet cherries, peaches,
    strawberries and grapes are summarised in Tables 3-9.

         Data provided by the American Cyanamid Co. (Petition 211) show
    that residues in apples were generally low at harvest (Table 3): 46 of
    59 samples analysed contained less than 0.5 mg/kg. The residue was
    above 1.5 mg/kg (between 1.5 and 5.0 mg/kg) in only one case; this was
    after the late application of high doses during a dry period. The
    disappearance of dodine is rapid initially, but slow below 0.5 mg/kg
    (Table 4). Residues decreased from 5-8 mg/kg to 0.6 mg/kg or less in
    about 30 days.

         The results in Table 4 show that residue levels and rates of
    disappearance are only slightly affected by apple variety and by
    differences in spraying programmes. Residue data obtained in 1957 and
    1958 were similar.



    
    TABLE 2  National use patterns, tolerances and preharvest intervals for dodine

                                                                                                                                               

                                                                                                                  Pre-harvest         Tolerance
    Country         Crop              Pest                  Rates a.i.       Treatment                            interval (days)     mg/kg
                                                                                                                                               

    Canada          Apple, pear       Scab                  0.02-0.04%       Regular protective treatments
                                                                               (including first cover) and
                                                                               cover sprays as needed

                    Peach             Leaf                  0.01-0.02%       2 treatments before bud
                                      curl                                   swelling

                                      Brown rot,            0.02%            3 treatments
                                      blossom blight

                    Cherry            Brown rot,            0.02%            3 treatments
                    (sour and         blossom blight,         "
                    sweet)            leaf spot               "              Repeated treatments at intervals
                                                                               of 7-10 days.

                    Strawberry        Leaf blight           0.03-            Repeated treatments at weekly
                                      scorch and spot       0.035%           intervals

    Netherlands     Apple             Scab                  0.06%            1-2 before blossoming (in            28                   1 *
                                                            1.2 kg/ha        emergency cases also later)

                    Cherry            Blumeriella           0.04%            3 treatments until one
                                      jaapi/Rehm            0.8 kg/ha        month after blossoming               28

                    Pear              Scab                  0.06%            See apple                            28
                                                            1.2 kg/ha

    New Zealand     Pip fruit         Black spot            0.03-0.04%       No data                              14                   0

                    Roses             Black spot            0.04%            No data                              -                    -

    TABLE 2  (Cont'd.)

                                                                                                                                               

                                                                                                                  Pre-harvest         Tolerance
    Country         Crop              Pest                  Rates a.i.       Treatment                            interval (days)     mg/kg
                                                                                                                                               

    USA             Apple             No data               4.5 kg/ha        No data                              7                    5
                                                            1.8 kg/ha        No data                              5                    5

                    Black walnut      No data               7.3 kg/ha        No data                              -                    0.3

                    Cherry (sour      No data               3.7 kg/ha        Post-harvest or up to                0                    5
                    and sweet)                                               petal fall

                    Peach             No data               1.8 kg           No data                              15                   5
                                                            7.3 kg/ha        Dormant and/or delayed
                                                                             dormant application

                    Peers             No data               4.5 kg/ha        No data                              7                    5
                                                            1.8 kg/ha        No data                              5

                    Pecans            No data               5.2 kg/ha        Do not apply after shucks                                 0.3
                                                                             have started to open

                    Strawberries      No data               1.5 kg/ha        No data                              14                   5
                                                                                                                                               

    * Fruit and vegetables.

    TABLE 3  Residues of dodine in apples (various varieties) - supervised trials*

                                                                                                                           

          Application                Interval             Number of samples in range (mg/kg)
    Rate %            Number          (days)          n.d.+       <0.1        0.1-0.5       0.5-1       1-1.5       1.5-5
                                                                                                                           

    0.025             10             33                                       1
    0.05              9              77               1
    0.05              10             32-33                                    2
    0.05              11             56-69                        1           2
    0.05              13             32                           2           2
    0.05              15             ?                            1
    0.05-0.10         7-9            50-74                        2           3
    0.05-0.10         10             66-86                        1           1
    0.05-0.10         10-11          32-33                                                  1                       1#
    0.075             7              20                                       1
    0.075             7-9            71-111           2           2
    0.075             9              42                                                     1
    0.075             10-12          33-66                        2           2             3           1
    0.075-0.10        10             ?                                        3
    0.1               6-7            66-104                                   1             1
    0.1               9-12           55-72            1           3           1
    0.1               9.12           32-43                                    1             1           1
    0.2               3              117              1
    0.2               5              61                           1
    0.2               6              108              1
    0.2               6-7            27-36                                    1             1
    0.2               7-8            84-98                        2           1             1
    0.2               8-10           54-59                                    1             1
                                                                                                                           

                                     Totals           6           17          23            10          2           1#
                                                                                                                           

    *  American Cyanamide Co., Petition 211. Samples from 11 States in USA, 1957-1958.  Surface or macerate extraction.
    +  n.d. = not detectable.
    #  This residue following late application of high doses during a dry period in California. No dodine residues above
       5 mg/kg reported.

    TABLE 4  Dodine residues on McIntosh and Golden Delicious Apples in USA

                                                                                                                                               

                        Application                                 Dodine residue, mg/kg, after interval (days)
    Variety             rate a.i.%    Number    0         4         6-7       10-11     13-17     21-27     31-35     45-60     61-80     >80
                                                                                                                                               

    McIntosh            0.063         1                                                 2.62
    (American                         3                                                 6.7       1.8       0.81      0.42      0.27      0.15
    Cyanamid Co.                      3                                                 11.5
    Petition 211)                     4         17.1                          2.6
                                      5         10.8                          3.5                 1.22      0.95      0.42      0.40      0.21
                                      5         10.5                          1.77                1.01                          0.30
                                      7                                                 6.67
                                      8         16.05                         2.38
                                      9         10.21                         3.6
                                      10        7.2                           1.96
                                      11        10.1                          2.12
                                      12        6.05                                    2.07                1.04      0.66

    Golden delicious    0.06          1         7.5       2.3       1.7                 1.2       0.9       0.6
    (Frear et al.,      0.04          1         4.2       2.0       1.5                 0.9       0.6       0.4
    1960)               0.02          1         3.6       1.2       0.7                 0.3       0.2       0.2

    Golden delicious    0.02          10        3.6       1.2       0.7                 0.6       0.2       0.2
    (American           0.04          10        1.5       0.8       0.65                0.5       0.3       0.2
    Cyanamid Co.        0.06          10        7.9       2.1       1.9                 1.2       0.8       0.6
    Petition 211
    1957 trial)

    Golden delicious    0.04          10        4.2       1.6       1.7                 0.9       0.7       0.4
    (American           0.08          10        2.05      1.65      1.2                 0.95      0.55      0.3
    Cyanamid Co.        0.12          10        3.2       1.65      1.45                1.35      1.15      0.65
    Petition 211
    1958 trial) +
                                                                                                                                               

    *  Residues determined in surface extraction.
    +  Residues determined in extract of macerated fruit.

    TABLE 5  Dodine residues on pears1
                                                                                                                                               

                        Application                    Dodine residue      mg/kg after interval (days)
    Variety             Rate a.i.%          Number      0       1         3         7         14        44        86        118       166
                                                                                                                                               

    Comice              0.08                1         3.97      2.17      2.29      1.41      1.61

                        0.08                6                                                                     0.33

                        0.16                1                                                                                         0.0

    Bartlett            0.08                5                                                                               0.43-
                                                                                                                            0.47

    Bosc                0.09                6                                                           1.04
                                                                                                                                               

    1  American Cyanamide Co., Petition 211.

    TABLE 6  Dodine residues on sweet cherries1
                                                                                                                                               

                        Application                               Dodine residue  mg/kg, after interval (days)
    Variety             Rate a.i.%        Number        1         3           7           12                 23-29
                                                                                                                                               

    Schmidt             0.02              4                                                                  0.4-0.78

    Emperor             0.02              4                                                                  0.27-0.35
      Francis
                        0.02              5                                               0.59-0.63

                        0.04              5                                               1.06-1.18

    Royal Ann           0.04              1           0.7         0.5         0.2

                        0.08              1           2.3         1.2         0.2
                                                                                                                                               

    1  American Cyanamide Co., Petition 391.

    TABLE 7  Dodine residues on peaches1

                                                                                                                                       

                   Region                                             Dodine residue  mg/kg, after interval (days)
    Variety        & date         Treatment           Number         0         3            6           10-12        12-18       22
                                                                                                                                       

    Sunhigh        New Jersey     dodine 0.02%        6                                                              0.5
                   1961
                                  dodine, 0.02%+      6                                                              0.73
                                  sulphur 0.35%

                                  dodine 0.04%        6                                                              0.75

                                  dodine 0.04%+       6                                                              1.5
                                  sulphur 0.36%

                                  dodine 0.08%        6                                                              0.27

                                  dodine 0.08%+       6                                                              4.85
                                  captan 0.72%

                   New Jersey     dodine 0.04%        7                        0.58-0.69
                   1962           dodine 0.08%        7                        1.18-1.52

    Elberta        Alabama        dodine 0.04%        3                                                 0.19
                   1963
                                  dodine 0.08%        3                                                 0.27         0.21        0.1

    Hale           Michigan       dodine 0.04%        1              0.56                   0.49
                   1963

    No data        New Jersey     dodine 0.04%+                                                         3.2
                   1963           captan 0.12%
                                                                                                                                       

    1  American Cyanamid Co., Petition 416.

    TABLE 8  Dodine residues on strawberries

                                                                                                                                               
                            Application
                        Rate, a.i.,                             Dodine residue, mg/kg, after interval (days)
    Variety             % or kg/ha     Number         0-1       2         4         6         7-8       11-12     15        21        24
                                                                                                                                               

    Jerseybelle         0.12%          4              6.1       8.0       5.3                 4.3

    No data             0.12%          2                                                                                              5.2
                        0.12%          3              10.9                12                  7.8

    No data             0.84 kg/ha     5              12.8                14.4
                                       4                                  4.9

    Pocahontas          0.56 kg/ha     5              0.5                 0.3

                        1.12 kg/ha     5              2.3                 0.9

                        0.84 kg/ha     1                                                                0.52

                        1.68 kg/ha     1                                                                0.57

                        1.68 kg/ha     no data        41.5                10.1                3.8       3.8

                        3.2 kg/ha      no data                            23-33.4             13.2      13.2

    Robinson            1.45 kg/ha     4                                            4.4       4.6       3.0

                        2.9 kg/ha      4                                            6.2       7.1       6.2

    Paymaster           1.45 kg/ha     4                                                                3.5       2.3

                        2.9            4                                                                6.9       4.7

    Armore              1.1 kg/ha      4                                            1.2                 1.1       0.95      0.7

                        4.4 kg/ha      4                                                                1.6       1.0       0.9

    Robinson            5.8 kg/ha      1                        24.4                23.2
                                                                                                                                               
    

    TABLE 9  Dodine residues in Raboso grapes1

                                                                             

      Application
    Rate, a.i.,                 Dodine residues, mg/kg, after interval (days)
    kg/ha       Number          6                10             20
                                                                             

    30          1               0.42             1.22           0.91

    30          2               1.96             1.72           1.79

    30          3               1.58             3.81           2.81
                                                                             

    1 The trial was in Bologna, Italy, 1973.


         The behaviour of residues on pears is similar to that on apples
    (Table 5).

         In peaches residues were low if dodine was applied alone, but
    were higher when captan or sulphur were incorporated in the spray
    (Table 7).

         In strawberries the residue level was relatively high (up to
    about 40 mg/kg usually in the range 5-20 mg/kg) but usually decreased
    below 5 mg/kg within about two weeks.

         Residues in grapes (Table 9) increased with the number of
    applications. There was no consistent relation between the residue
    level and the interval after the last application, possibly owing
    partly to the high application rate.

    FATE OF RESIDUES

    In apples and apple trees

         Curry (1962) examined the translocation and metabolism of dodine
    in apple trees. He painted the lower surfaces of leaves with
    14C-dodine (7 applications at 10-14 day intervals), and found that
    only 5% of the activity on the bottom surfaces could be detected on
    the top surfaces of the same leaves one month after the last
    application. 8 of 16 apples from the treated branches were analysed
    and found to contain radioactivity equivalent to 0.006-0.21 mg/kg of
    total residue calculated as dodine. This represented less than 0.2% of
    the total dodine applied during the season. The total residue in the
    apples decreased in the order flesh > skin > seeds, based on dried
    material.

         Since an analytical method sensitive only to dodine showed that
    the entire residue of the parent compound was on the surface, the
    radioactivity in the flesh was presumably due to metabolites. Curry
    discusses evidence that the metabolites may become bound to proteins
    and peptides as simple amino-acid and guanidine moieties. Curry's
    results are at variance with those of Hamilton (1958) who reported
    evidence of local translocation in apple trees. This may have been the
    result of contact between treated and untreated surfaces and transfer
    by rain washing.

    In soil

         Dodine was found (Gatterdam, 1973) to be practically immobile in
    soil, with a mobility as low as that of paraquat. Goldberg (1969)
    demonstrated that two naturally occurring soil organisms
    (Flavobacterium sp. and Achromobacter sp.) utilize dodine as a
    source of carbon. He estimated the probable rate of degradation of
    dodine in soil under natural conditions to be of the order of 5% in 60
    days. It has been reported that dodine temporarily inhibited soil
    microfloral activity but did not affect the structure or stability of
    the soil (Rotini, 1972).

    Residues in food moving in commerce

         Only New Zealand provided information on apples known to have
    been treated with dodine. 9 samples were analysed in 1969 and the
    residue levels were between 0.1 and 1.5 mg/kg, while in 1971 5 samples
    were analysed and a maximum of 0.1 mg/kg was found.

    METHODS OF RESIDUE ANALYSIS

         A colorimetric method for dodine was developed by Steller et al.
    (1960). The residue is extracted from the surface of the fruit with
    methanol or from the whole fruit by macerating with
    methanol-chloroform (2:1) and the dodecylguanidine is complexed with
    bromocresol purple in a buffered aqueous alcohol solution. The complex
    is extracted with chloroform and hydrolysed with aqueous alkali to the
    sodium salt of the indicator. The aqueous solution of the sodium salt
    is separated from the chloroform and its absorbance at 590 nm is
    measured. Results obtained by the two extraction procedures were
    similar (see Table 10 below).

    TABLE 10  Dodine residues in fruit determined by surface and
              macerate extraction procedures.
                                                                            
                                       Dodine residue*, mg/kg, at interval
                                            (days) after treatment
                                       3         14        35        56
                                                                            
    Surface extraction                 1.3       0.7       0.3       1.0
    Macerate extraction                0.9       0.5       0.3       0.9
                                                                            
    * Corrected for crop blank.

    APPRAISAL

         The fungicide dodine has been used for controlling apple scab
    since 1955. It is effective against various crop diseases such as
    apple scab, cherry leaf spot, peach leaf curl, pear scab and
    strawberry leaf scorch.

         The main uses are from pre-bloom to first cover at a rate of
    1.1-2.2 kg/ha at 5-7 day intervals and, if necessary, up to ten
    further applications at 1.1 kg/ha.

         Dodine is marketed as a wettable powder (65% a.i.) and as a
    water-miscible liquid concentrate (24% a.i.).

         Residues of the parent compound are determined by a colorimetric
    method which is suitable for surface deposits or for macerates.
    Analysis shows that virtually all the residue is on the surface of the
    fruit. The colorimetric method is suitable for regulatory purposes.
    Limited information is available on the fate of residues in apples.
    Experiments with radio-labelled material showed that the degradation
    products of dodine were translocated only very slightly and appeared
    to be simple amino acids and guanidine type moieties bound to proteins
    and peptides. No data have been provided on the metabolism in mammals.

         Residue data from supervised trials were obtained from various
    regions of the United States and, for grapes, from Italy.

         Residues in apples were generally low at harvest (<0.5 mg/kg),
    but higher residues can occur under dry conditions. Disappearance of
    dodine is rapid initially but slow below 0.5 mg/kg. Residues decreased
    from 5-8 mg/kg to 0.6 mg/kg or less in approximately 30 days.

         The residue level and the rate of disappearance appear to be
    slightly affected by apple variety or variation in use pattern.
    Residue data were similar in 1957 and 1958.

         The behaviour of residues in pears is similar to that in apples.

         Residues in sweet cherries were relatively low in all experiments
    immediately after treatment, and degradation was rapid.

         In peaches the residues were low if dodine was applied alone, but
    higher after simultaneous application with captan or sulphur.

         Residues in grapes vary widely. They seem to be directly related
    to the number of applications rather than to the interval after
    application. No data were available on the fate of residues during the
    processing of wine.

    RECOMMENDATIONS

         In the light of the information provided the following temporary
    tolerances, for the parent compound only, are recommended.

    TEMPORARY TOLERANCES

                                             Pre-harvest intervals on
                             Tolerances      which recommendations
                                mg/kg             are based

    Apples, pears                2                   21

    Grapes, peaches,
    strawberries                 5                   14

    Cherries                     2                    7


    FURTHER WORK OR INFORMATION

    REQUIRED (by 1976)

    1.   Metabolic studies of dodine in animals and plants.

    DESIRABLE

    1.   Teratogenicity studies in appropriate animal species.

    2.   Fate of residues in apple and grape pomace when fed to dairy
         cows.

    3.   Supervised trials on various crops in countries other than the
         USA.

    4.   Further details on residues arising in supervised trials on
         peaches and grapes, and during wine processing.

    REFERENCES

    American Cyanamid Co. Apple, pear and sour cherry residue data.
    Petition 211. (Unpublished).

    American Cyanamid Co. Strawberry residue data. Petition 324.
    (Unpublished).

    Anonymous. (1974) Information on dodine from the Netherlands.

    Anonymous. (1974) Information on dodine from New Zealand.

    Belonozhko, G., Tovstenko, A. and Shevchenko, N. (1973) Mechanism of
    action of dodecylguanidine acetate (dodine). Farmakol. Toksikol.,
    Kiev, 8:134-137. (Abstract only).

    Chu, J.P., Kirsch, E.J. and Born, G.S. (1971) Thin layer
    chromatography of n-dodecylguanidines. Bull. Environ. Contam.
    Toxicol., 6(4):343-344.

    Curry, A.N. (1962) Translocation and metabolism of dodecylguanidine 
    acetate (dodine) fungicide in apple trees using C14 radiotagged
    dodine. J. agr. Food Chem., 10:13-17.

    Frear, D.E.H., Smith, E.C. and Bowery T.G. (1960) Dodecylguanidine 
    acetate (dodine) residues on apples. J. agr. Food Chem., 8(6):465-466.

    Gatterdam, P.E. Mobility of Melprex(R) fungicide in soils by the
    thin-layer technique. American Cyanamid Co., Report IC-1.
    (Unpublished).

    Goldberg, M.C. and Wershaw, R.L. Biodegradation of dodecylguanidine
    acetate (dodine). Geological Survey Prof. Paper 650 D - D 235 - D 239.

    Hamilton, J.M., Szkolnik, M. (1958) Movement of dodecyl guanidine
    derivatives through the leaf in the control of apple scab and
    cedar-apple rust fungi. Phytopathology, 48:262. (Abstract only).

    Hartmann, E. (1964) Health experience in the manufacture of cyprex
    dodine. Report from the Am. Cyanamid Co. (Unpublished).

    Huntingdon Research Centre. (1974) Dodine residues in grapes.
    Technical Report No. 364. (Unpublished).

    Innes, J.R.M., Ulland, B.M., Valerio, M.G., Petrucelli, L., Fishbein,
    I., Hart, E.R., Pallotta, A.J., Bates, R.R., Falk, H.L., Cart, J.J.,
    Klein, M., Mitchell, L. and Peters, J. (1969) Bioassay of pesticides
    and industrial chemicals for tumorigenicity in mice: A preliminary
    note. J. natn. Cancer Inst., 42:1101-1114.

    Levinskas  G.J., Vidone, L.B., O'Grady, J.J. and Shaffer, C.B. (1961)
    Acute and chronic toxicity of dodine. Toxic. appl. Pharmac.,
    3:127-142.

    McNerney, J., Ribelin, W., Levinskas, F. and Shaffer, C.B. (1967)
    Report on Cyprex fruit fungicide: successive generation studies with
    mice. Report from American Cyanamid Co. (Unpublished).

    O'Grady, J., Winter, G. and Shaffer, C.B. (1958a) Report on
    dodecylguanidine acetate (DDGA): one year feeding to dogs. Report from
    American Cyanamid Co. (Unpublished).

    O'Grady, J., Vidone, L., Winter, G., Levinskas, G and Shaffer, C.B.
    (1958b) Report on dodecylguanidine acetate (DDGA): repeated feeding to
    rats, successive generation studies. Report from American Cyanamid Co.
    (Unpublished).

    O'Grady, J., Vidone, L., Winter, G., Levinskas, G. and Shaffer, C.B.
    (1959) Report on dodecylguanidine acetate: two year feeding to rats.
    Report from American Cyanamid Co. (Unpublished).

    Owens, R. (1969) Metabolism of fungicides and related compounds. Ann.
    N.Y. Acad. Sci., 160:114-132.

    Pasarela, N.R. (1964) Total dodine residues in fruits. J. Ass. off. 
    analyt. Chem., 47:300-303.

    Powell, D., Khetry, A., Sasaki, P.J. and Brussell, G.E. (1958) The
    fungicidal efficacy of Cyprex against apple scab. Pl. Dis. Rept.,
    42(4):493-498.

    Sisto, A.M. (1972) Behaviour of Melprex in Soil. Personal
    communication, Cyanamid Italia.

    Steller, W.A., Klotsas K., Kuchar, E.J. and Norris, M.V. (1960)
    Colorimetric estimation of dodecylguanidine acetate residues. J. agr.
    Food Chem., 8:460-464.

    Tovstenko, A. (1970) Toxicological and hygienic evaluation of
    Melprex(R) (Karpen). Gig. Primen. Toksikol. Pestits Klinica Otravl.,
    8:372-375. (Abstract only).

    Tovstenko, A. (1973) Hygienic evaluation of residual amounts of the 
    fungicide carpene (dodecylguanidine acetate) in apples. Vop. Pitan.
    5:72-74. (Abstract only).

    West, B., O'Grady, J., Vidone, G., Levinskas, G. and Shaffer, C.B.
    (1958) Report on dodecylguanidine acetate (DDGA): acute and subacute
    toxicity (CL 7521). Report from American Cyanamid Co. (Unpublished).
    


    See Also:
       Toxicological Abbreviations
       Dodine (Pesticide residues in food: 1976 evaluations)
       Dodine (Pesticide residues in food: 1977 evaluations)
       Dodine (JMPR Evaluations 2000 Part II Toxicological)