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    MALEIC HYDRAZIDE        JMPR 1976

    IDENTITY

    Chemical name

         1,2-dihydro-3,6-pyridazinedione

    Synonyms

    MH,6-hydroxy-3(2H)-pyridazone

    Structural formula



    CHEMICAL STRUCTURE 1




    Other information on identity and properties

    Composition of the technical product

         The technical material contains 99% of maleic hydrazide;
    impurities are inorganic salts (e.g. Na2SO4 possibly with minor
    amounts of maleic or fumaric acid.

    Physical and chemical properties of maleic hydrazide

              physical form                 white crystalline powder
              molecular weight              112.1
              specific gravity at 25C      1.60
              melting point                 292C(min)
              odour                         faint
              volatility                    non volatile
              solubility (approximate)      g/100 g solvent at 25C
                 distilled water            0.6
                 alcohol                    0.1
                 acetone                    0.1
                 dimethyl formamide         2.4
                 xylene                     less than 0.1

         Ph of 0.5% aqueous solution at 25C: 4.

         Maleic hydrazide behaves as a weak monobasic acid. The
         alkanolamine and alkali metal salts are moderately soluble in
         water.

         Formulations used: liquid 30% and 40% a.i.; wettable powder 40%.


    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    Biochemical Aspects

         Maleic hydrazide does not appear to be extensively metabolized
    by mammals. In the rabbit, 43-62% of a single oral dose was
    excreted unchanged within 48 hrs. Isolation and characterization of
    the excreted maleic hydrazide following oral doses of 2 g showed
    the excreted product to be the benzylamine salt. No other
    metabolites were identified. (Barnes et al, 1957). Incubation of
    phenobarbital-induced rat liver microsomes with maleic hydrazide
    did not result in any degradation of the compound (Nelson and
    Kearney, 1975).

         Using maleic hydrazide - 14C labelled material, female rats
    were dosed with 0.27, 0.68, or 2.72 mg per rat (equivalent to 10,
    25 or 100 c/rat) by stomach tube. At the low dose level, 65.4% of
    the radioactivity was excreted in the urine in 12 hrs and 77.3%
    within 6 days.

         A further 12.4% of the administered radioactivity was detected
    in the faeces over the same period. Rats dosed with 2.5 c showed
    0.12-0.18% expired radioactivity in CO2 over the 72 hour period
    after administration. Tissue levels of radioactivity were
    statistically insignificant except in the carcass, where <0.001%
    of the administered radioactivity was detected. Using paper
    chromatography with two different solvent systems, urine from rats
    intubated with 100 c resulted in the identification of unchanged

    maleic hydrazide (92-94%) and a maleic hydrazide conjugate (6-8%).
    (Mays et al, 1968).

         Sixteen rats were given 4g/kg by stomach tube. Urine and
    faeces were collected for time intervals 0 to 2, 2 to 4, 4 to 8,
    and 8 to 16 days. Two rats/sex were sacrificed after 2, 4, 8, or 16
    days post-dosing. In male rats, residues in urine (30,400 mg/kg)
    were approximately double those in faeces (17,400 mg/kg) over the
    0-2 day period, whereas in females urine residues (1,330 mg/kg)
    were much less than in faeces (12,700 mg/kg). In both sexes,
    residue levels decreased rapidly, but were still detectable in 8-16
    day samples of both urine and faeces. Excretion in females was
    slightly slower than in males, however residues were undetectable,
    except for traces in the males sacrificed on day 8. (Food Research
    Laboratories Inc. 1955).

    TOXICOLOGICAL STUDIES

    Special Studies on reproduction

         Seven groups of approximately 10 male and 10 female rats fed
    0, 0.5, 1.0, 2.0 or 5.0 maleic hydrazide as the sodium salt, or 0
    or 0.1% maleic hydrazide as the diethanolamine salt were repeatedly
    bred using a cycle of 2 weeks pairing, 3 weeks gestation, 3 weeks
    lactation and one or two weeks rest prior to remating, for as long
    as possible, commencing at 12 weeks on test. The second litters
    (F1b) were used to produce the F2 generation which were mated
    twice. The F2b generation provided parents for the F3a and b
    offspring. Pooled data from the 8 matings of the Fo generation do
    not indicate any effects of the sodium salt of maleic hydrazide on
    fertility, litter size, gestation index, viability index, or
    lactation index. Pup weight at weaning was slightly reduced at the
    5.0% level. The diethanolamine salt at the 0.1% level resulted in
    reduced fertility, reduced litter size, reduced viability index,
    and reduced lactation index. The diethanolamine salt group was
    dropped from the study, no attempt being made to produce the F2
    generation. Mean data for all generations of rats receiving the
    sodium salt do not do not indicate any effects on reproduction,
    with respect to fertility, gestation index, viability index, or
    lactation index. At the 5.0% level, litter size was reduced in the
    F3 generation and weanling weight was reduced in all generations.
    (Food Research Laboratories, 1955).

    Special studies on mutagenicity

         Injection of 0.7% sodium chloride Ringer's solution containing
    0.4% maleic hydrazide abdominally in one to two-day old
    Drosophila melanogaster males did not result in an increase in
    mutation rate. On the other hand, D. melanogaster males fed on
    media containing 0.4% maleic hydrazide showed an increased
    incidence of lethal mutations in the first brood, although in
    subsequent broods, the effect was not apparent (Nasrat, 1965).

         In a mouse dominant lethal study, 500 mg maleic hydrazide/kg
    did not affect the calculated mutation index. (Epstein & Shafner,
    1968).

         Andersen et al (1972) tested maleic hydrazide and other
    chemicals on eight mutant strains of Salmonella typhimurium on
    T4 bacteriophage, and on bacteriophage AP72. In none of these ten
    systems was there any ~evidence of mutagenic activity. Maleic
    hydrazide was tested by McCann et al (1975, 1976) on several tester
    strains of Salmonella. Tests covered a wide dose range, both with
    and without liver microsome activation. There was no evidence of
    mutagenic activity in this extensive series of tests.

    Special studies on carcinogenicity

         Swiss mice (ICR/Ha) were injected sub-cutaneously with aqueous
    solutions, or tricaprylin suspensions of maleic hydrazide as free
    acid (0.4% hydrazine impurity), or with solvent alone in volumes of
    0.1, 0.1, 0.2 and 0.2 ml on post-natal days 1, 7, 14 and 21. Total
    doses were 3 mg for aqueous solution, and 55 mg for tricaprylin
    suspension. (A further group comprising 11 mice all died following
    10 mg maleic hydrazide injected on post-natal day 1). Preweaning
    mortality was 14% in controls, 5% in mice receiving 3 mg and 53% in
    mice receiving 55 mg. Post weaning mortality in males in all groups
    was high being 38, 57, and 52% at 0,3 & 55 mg respectively by 49
    weeks of age. Decreased weight gain (ca 5%) was noted in the high
    dose group. Hepatoma incidence in males at 49 Weeks was 8% in
    controls, 18% in the 3 mg group and 73% in the 55 mg group. No
    metastases were noted. (Epstein et al, 1967).

         Maleic hydrazide was administered by stomach tube in daily
    doses of 1000 mg/kg weight to 36 mice of each sex for 3 weeks,
    beginning when the animals were 7 days old. Then, 3000 ppm were
    mixed directly with the diet, which was fed for approximately 18
    months. No significant increase in the incidence of tumors was
    observed in comparison with untreated controls (Innes et al.,
    1969).

         Rats were injected subcutaneously with 1 ml of the
    diethanolamine salt (i.e. 5 mg) weekly for 14 months. Of 52 rats so
    treated in two experiments, 3 developed sarcomas. No sarcomas
    occurred in saline control rats. (Barnes et al, 1957).

         Groups of rats and mice were either injected with the
    monosodium salt, subcutaneously, once weekly at a dose level of 500
    mg,/kg or received 1% maleic hydrazide added to the diet for 100
    weeks. Maleic hydrazide did not affect growth or general health in
    either species, on either dose regime. One rat receiving maleic
    hydrazide by injection (out of a total of 29) developed a sarcoma.
    No sarcomas were observed in control rats. Total tumor incidence
    was increased in female test groups of both species, fed maleic
    hydrazide, the effect being more obvious in the mouse (Barnes et al
    1957).

         Groups of 25 male and 25 female rats were injected twice
    weekly for 65 weeks with arachis oil, water, solvents plus 2 mg
    maleic hydrazide or solvents plus 2 mg diethanolamine salt of
    maleic hydrazide. A further 39-week observation preceded autopsy.
    subcutaneous tumor incidence was increased (4) in the group
    receiving arachis oil plus maleic hydrazide when compared with the
    arachis oil control group (1). Incidences of tumors in all other
    groups were comparable. The increased subcutaneous tumor rate was
    attributed to impaired connective tissue repair mechanisms rather
    than chemical carcinogenesis induction. (Hunter et al, 1973).

         Three groups of 24 male rats were fed basal diet, basal diet
    plus 2% maleic hydrazide as the sodium salt, or basal diet plus
    0.06% p-dimethylaminoazobenzene for up to 26 weeks. No significant
    changes with regard to body weight, desoxyribose nucleic acid
    content per liver cell nucleus, average liver cell size, liver
    weight, number of cells/liver or DNA/liver were observed with
    maleic hydrazide, although the p-dimethylaminoazobenzene affected
    all these parameters. Pathological examination of animals fed
    maleic hydrazide did not reveal neoplasms, although these occurred
    in all rats fed the p-dimethylaminoazobene for more than 10 weeks.
    (Mannell & Grice, 1957).

    Special studies on mammalian cells in vitro

         The effect on mammalian cells was examined by studying the
    development of mitosis in fragments of mouse ear epidermis. In
    concentrations from 0.0001-0.001 M, maleic hydrazide had no effects
    on mitosis or cell division. Maleic hydrazide was also tested upon
    skin from the guinea pig's ear, grown in tissue culture. Up to a
    concentration of 0.01 M no gross or microscopical effects upon the
    explants were noted. The same concentration of maleic hydrazide was
    also without effect upon the respiration of skin cells, studied 2
    and 22 hr after adding the maleic hydrazide (Barnes et al., 1957).

         In vitro studies with mouse thymus cells in culture showed
    that maleic hydrazide in concentrations of 0.001 M or more
    inhibited growth. Mitotic inhibition occurred at and above 0.0001
    M. The ratio of dry mass to DNA content was increased, which was
    taken as an indication for inhibition of DNA, but not of protein
    synthesis (McCarthy and Epstein, 1968). Mitotic inhibition was also
    shown in cultures of human lymphocytes grown in the presence of
    0.001-0.01 M. Inhibition was more marked in 72 hr-old cultures than
    in fresh ones, probably because of the more active mitotic state in
    the former (Timson, 1968).

    Special studies on dermal irritation

         The diethanolamine salt of maleic hydrazide was applied as a
    20% aqueous solution to approximately 10 sq.cm. of abraded, and 10
    sq. cm. of intact skin on the backs of 6 rabbits. Repeated

    applications were made during a 6-hour period on five consecutive
    days on two occasions, separated by a ten-day rest period. No signs
    of irritation were noted during the study. (Food Research
    Laboratories, 1955).

    Special studies on dermal sensitization

         Ten guinea pigs were injected intradermally with one dose of
    0.5 ml, and 9 subsequent doses of 0.1 ml of a 0.1% aqueous solution
    of the diethanolamine salt of maleic hydrazide, dosing being on
    alternate days. Two weeks after the last dose, a challenge dose of
    0.5 ml was administered intradermally at a different site. No
    evidence of sensitization was observed. (Food Research
    Laboratories, 1955).

    Special studies on eye irritation

         Six rabbits received two drops of a 5% solution of the
    diethanolamine salt of maleic hydrazide in 5% saline in the right
    eye. No signs of irritation were observed in the 14 day
    post-treatment observation period. (Food Research Laboratories,
    1955).

    Special studies on respiratory effects

         Deeply anaesthetized rats (ethyl ether) were administered the
    diethanolamine salt of maleic hydrazide at various solution
    concentrations by instilling small droplets in alternate nostrils
    at the moment of inhalation. Doses of 50 to 400 mg diethanolamine
    salt were administered (i.e. 15-120 mg maleic hydrazide). At the
    400 mg dose level, 2/10 rats died after 10 days. Gross pathological
    examination showed haemorrhagic lungs, and in one case, a yellowish
    exudate and thoracic adhesions, laboured respiration (7/10) and at
    2 weeks, rats (5/7) were also observed at the 400 mg level. (Food
    Research Laboratories, 1955).

    Special studies on potentiation

         The acute toxicity of maleic hydrazide diethanolamine salt in
    combination with other pesticides was determined. Pretreatment with
    0.1 LD50 potentiated the toxicity of dieldrin and DDT in both
    sexes, but decreased the toxicity of diazinon. On the other hand
    pretreatment with DDT and dieldrin reduced the toxicity of maleic
    hydrazide diethanolamine salt by a factor of two. Diazinon
    pretreatment had a different effect, decrease of toxicity in
    females, increase in males (Luckens and Wattimena, 1968).

    Acute studies
                                                                   

    Species                  Route     LD50         References
                                       mg/kg b.w*             
                                                                            
    Diethanolamine salt                               Food Research
    Rat (fasted)             oral      1180           Labs. 1955

    Sodium salt
    Rat (fasted)             oral      5800           ibid

                                                                   
    * expressed in terms of maleic hydrazide moiety.


    Short term studies

    Rat

         Groups of 12 male and 12 female rats were fed 0, 0.5, 1.0, 2.0
    or 5.0% maleic hydrazide, as the sodium salt, for 12 weeks.
    Detailed data are not available. Mean body weight data indicate
    that in males, a slight reduction occurs in all groups on maleic
    hydrazide and a similar reduction occurs in females at 5.0% dietary
    levels. The reductions are stated to be statistically
    non-significant. Food utilization, hemoglobin, erythrocyte count,
    total and differential leucocyte counts, were comparable in all
    groups. Blood sugar was reduced at 5.0%, and non-protein nitrogen
    was increased at the same level. Methaemoglobin levels were (if
    present) below the limit of detection (0.2g/100 ml) and urinalysis
    for sugar, albumin, and microscopic inclusions was unremarkable.
    Gross pathology (on 2 males and 2 females at 12 weeks) was normal.
    No histological abnormalities were noted. (Food Research
    Laboratories, 1955).

         A group of 12 male and 12 female rats was fed 1.0% maleic
    hydrazide as the diethanolamine salt. Additional,  non-contemporary
    groups of 12 male and 12 female rats were fed 0.1% or 0% maleic
    hydrazide as the diethanolamine salt and a final group of 10 males
    and 10 females was fed 1.0% diethanolamine. All rats were on test
    for 12 weeks. Body weight was significantly reduced in all test
    groups. Mortality was increased markedly in groups receiving 1.0%
    diethanolamine, and 1.0% diethanolamine salt of maleic hydrazide.
    No further data are available for the group receiving 1.0%
    diethanolamine. Food efficiency is stated to be comparable in all
    groups except that receiving 1.0% diethanolamine salt of maleic,
    hydrazide which is markedly reduced. Haemoglobin and erythrocyte
    count are markedly reduced and an increased polymorph/lymphocyte
    ratio are noted in the group receiving 1.0% diethanolamine salt of
    maleic hydrazide. Mean data on the 0.1% diethanolamine maleic
    hydrazide indicate a tendency to reduced haemoglobin levels and

    erythrocyte counts, the statistical significance being
    non-assessible on the basis of available data. At the 1.0%
    diethanolamine maleic hydrazide level, death was preceded by loss
    of coordination and muscular control, accompanied by starvation.
    Pathological examination showed hyperaemic or haemorrhagic lungs,
    and evidence of anaemia. Brain histopathology showed brain oedema.
    No microscopic lesions were observed in liver, kidney or lung of
    four representative rats of the group. (Food Research Laboratories,
    1955).

    Dog

         Three dogs were given 1 g/kg of the sodium salt of maleic
    hydrazide five times weekly for five weeks by gavage. At 5 day
    intervals, haemoglobin, erythrocyte count and total and
    differential leucocyte counts were determined. Methaemoglobin,
    blood sugar and non-protein nitrogen were determined at sacrifice.
    Liver, kidney, spleen and bone marrow were examined
    histopathologically. No data are presented, but effects on the
    parameters listed above are stated to be negligible although
    transient eosinophilia, anemia, and leucocytosis were noted
    (Food Research Labs, 1955).

         Five groups of three mongrel dogs aged between four months and
    2 years were fed 0 (1 male, 2 female), 0.5 (2 male, 1 female), 1.0
    (1 male, 2 female), 2.0 (2 male, 1 female) % maleic hydrazide as
    the sodium salt, or 1.0 (2 male, 1 female)% maleic hydrazide as the
    diethanolamine salt in the diet for one year. Body weight and
    mortality were unaffected by the sodium salt. The diethanolamine
    salt caused loss of body weight, and 2/3 deaths by day 30 on test.
    This group was abandoned at day 37 on test. Food intake was
    unaffected in groups receiving the sodium salt. Haemoglobin,
    erythrocyte count, total and differential leucocyte counts were
    comparable in all groups. Blood sugar and non-protein nitrogen did
    not show any consistent effects. Gross pathology was comparable in
    all dogs. Histopathology on the bone marrow, liver kidney, spleen
    and gastrointestinal tract was considered to be within normal
    limits. Brains of dogs receiving the diethanolamine salt were
    moderately oedematous, and the spinal cord showed early neuronal
    degeneration and swelling of myelin sheath. (Food Research Labs.
    1955).

    Long-term studies

    Rat

         Five groups of approximately 10 male and 10 female rats were
    fed 0, 0.5, 1.0, 2.0, or 5.0% maleic hydrazide as the sodium salt,
    for 2 years. A further two noncontemporary groups were fed 0 or
    0.1% maleic hydrazide as the diethanolamine salt, also for 2 years.
    After 12 weeks on test, rats were bred one to one, within groups,
    following a 2 week mating, 3 week gestation, 3 week lactation, 1
    week rest cycle throughout the study. (The report states 1 week

    rest, or 2 week rest after lactation, in different sections). Body
    weight of males in all test groups was slightly reduced up to 1
    year, but exceeded controls at 2 years. In females, body weight was
    reduced at 5.0% Na salt at 12 weeks only. Mortality was generally
    comparable between groups, except for the 0.1% diethanolamine salt
    group, where life span was reduced, mortality being increased
    between 52 and 96 weeks on test. Haemoglobin and erythrocyte counts
    were reduced in the group receiving 0.1% diethanolamine salt, at
    all reported time intervals (52,78 and 104 wks). In all other
    groups, values were comparable. Total and differential leucocyte
    counts were comparable in all groups. Blood glucose and non protein
    nitrogen were comparable in all groups receiving the sodium salt at
    12 and 24 months. Non protein nitrogen was slightly elevated in the
    only measurement taken (24 months) on the sole male and sole female
    survivor of the 0.1% diethanolamine salt group. Methaemoglobin was
    not detected in any group. Urinalysis was stated to be normal in
    all groups. No consistent changes occurred in liver, kidney or
    spleen organ/body weight ratios. Tumor incidence was comparable in
    all groups. Pathological changes are stated to be attributable to
    infections, parasites, or age. (Food Research Laboratories, 1955).

    COMMENTS

         Maleic hydrazide was evaluated by the IARC in 1974 and it was
    concluded that "no carcinogenic effect was observed in adult mice
    and rats following oral or subcutaneous administration of maleic
    hydrazide. The significance of hepatomas obtained in new born mice
    cannot be assessed because of the contamination of maleic anhydride
    with hydrazine". A mammalian dominant lethal study was negative.

         Reproduction studies indicate an absence of adverse effects of
    the sodium salt of maleic hydrazide at 2% of the diet. At 5%, post
    natal weight gain in pups is reduced. The diethanolamine salt of
    maleic hydrazide, even at 0.1% in the diet, reduces fertility,
    litter size, viability index and lactation index. Short term
    studies indicate that effects on body weight, and mortality are due
    to the diethanolamine moiety. It seems probable that the effects on
    reproduction can also be attributed to the same cause although
    there are no data available to support this hypothesis. Teratogenic
    studies have not been conducted.

         A no-effect level was not demonstrated for the diethanolamine
    salt in respect to reproduction, short term or long term feeding
    studies. Concern was expressed as to the possible use of the
    diethanolamine salt of maleic hydrazide without complete
    toxicological data being available on the diethanolamine salt. Data
    are available on the sodium salt with regard to reproduction in
    rat, short term studies in rat and dog and long term studies on
    small numbers of rats. The no-effect level in these studies would
    appear to be 2% in the diet.

         No information was available on the occurrence of hydrazine as
    a residue in crops or on the potential for its formation under use
    conditions. It was noted that maleic hydrazide and its
    -D-glucoside were the principal residues found on plants. Data on
    the metabolic fate of the -D-glucoside in mammals are not
    available. Since the carcinogenicity potential cannot be assessed
    adequately and the long term rat feeding study is on small numbers
    of animals, no toxicological evaluation has been attempted for the
    sodium salt of maleic hydrazide. Data are totally inadequate for
    toxicological evaluation of the diethanolamine salt.

    TOXICOLOGICAL EVALUATION

    No acceptable daily intake was allocated.

    RESIDUES IN FOOD AND THEIR EVALUATION

    USE PATTERN

         Maleic hydrazide is used as a sprout inhibitor on potatoes at
    2-3 kg/ha with a pre-harvest interval (PHI) of 4-6 weeks and on
    onions at 2-2.5 kg,/ha with a PHI of 2-4 weeks.

         The compound is also used on potatoes, about 10 days before
    planting, on young non-bearing Citrus trees, to induce dormancy and
    on tobacco for sucker control when in full flower (3 kg a.i./ha).

         It is further used on a limited scale as a growth inhibitor on
    grass on road verges.

    RESIDUES RESULTING FROM SUPERVISED TRIALS

         Extensive residue data are available from supervised trials on
    onions and potatoes and are summarized in Table 1. Some
    supplementary results, together with the limited data available for
    apples, carrots and tobacco, are discussed below.

    Apples. Pre-harvest spraying of apples with 1000 and 2500 mg/kg
    a.i. resulted in residues in the total apple of 1.5 and 3.4 mg/kg
    respectively. A considerable part of the residue remained in the
    peel: residue levels found in the peel were 4.1 and 10.0 mg/kg
    respectively (Hoffman and Carson 1962).

    Carrots. Samples taken from plots sprayed at different times
    before harvest showed residues of 5.1 mg/kg after a spray
    application shortly before harvest and much lower residues, 0.36
    mg/kg, when sprayed three weeks earlier (Hoffman and Carson 1962).

    Onions. In supervised trials in Poland carried out by Drygus et
    al (1968), onions were treated 21 weeks before harvest with maleic
    hydrazide at dosages of 12-2.3 kg/ha. The residues after storage
    periods of 7-32 weeks ranged from 2.5 to 23 mg/kg. (Table 1.) The

    highest residues were found after a storage period of 28 weeks
    (i.e. 30 weeks after application) and at the highest application
    rate.

    Potatoes. Foliar application about 5 weeks before harvest with
    sprays containing 0.1, 0.25, 0.5 and 0.75% a.i. resulted in residue
    levels in the tuber of 3.1, 15.6, 37.9 and 92.6 mg/kg respectively.
    The level in the peelings tended to be higher than in the remainder
    of the potato. (Hoffman and Carson 1962). Of 144 samples taken in
    the USA from plots treated with maleic hydrazide at 3 kg a.i.
    mainly in the period 1950-1960 8% of the samples showed residues
    exceeding 30 mg/kg and about 5% contained residues exceeding 40
    mg/kg (Uniroyal 1976). Drygas et al (1968) treated potatoes about
    8 weeks before normal harvest with maleic, hydrazide at dosage
    rates of 1.4 - 2.7 kg/ha. After storage periods of 3 - 24 weeks
    residues ranged between 4 and 30 mg/kg (Table 1). The highest
    values were found at the highest application rate and after a
    storage period of 24 weeks.

    Tobacco. After applying maleic hydrazide on tobacco at a rate of
    2.25 kg a.i./ha the tobacco leaves contained 37 mg/kg (fresh
    weight), whereas the green sucker leaves contained 482 mg/kg.
    (Hoffman et al., 1962).

    FATE OF RESIDUES

    In soil

    Mobility. Helweg-Andersen (1971) showed that maleic hydrazide and
    its degradation products are only moderately mobile in typical soils.
    After application of 5 and 10.1 kg/ha all the maleic hydrazide was
    found in the top 10 cm of the soil from 0 to 129 days (the latest
    interval checked) under danish field conditions.

         Uniroyal (1973-75), in an outdoor test on sandy loam 14C-MH
    found only 2.5 - 3.1% of the applied 14C below a depth of 15 cm after
    4 - 6 months.

         The diethanolamine salt of maleic hydrazide is rather mobile in
    the soil. An aqueous solution of the salt put on top of a soil column
    of 1 m was distributed through the whole column within 24 hours. The
    initial amount of water was chosen in such way that no water flowed
    from the column. Subsequent additional watering removed a considerable
    amount of maleic hydrazide from the column (Levi and Crafts 1952).

    Persistence. Uniroyal (1973-1975) monitored soil from plots treated
    with maleic hydrazide under field conditions. A plot treated for four
    consecutive years with 3.4 kg a.i./ha and sampled 10 months after the
    last application showed no detectable residues. At another site, soil
    treated at the same rate and sampled 4 months after treatment again
    contained no detectable residues (lower limit of detection 0.5 mg/kg).
    Since the analytical technique used in this case involved caustic



        TABLE 1. Residues of maleic hydrazide resulting from supervised trials
                                                                                                                                           

                                      Application                      Residues, mean and range mg/kg*, at intervals after
                                                                       application (pre-harvest- + storage period)
    Crop      Country        Year
                                      no   kg/a.i./ha   formulation    2        2       2.5      2 3/4    3        4-4.5    7         Ref.
                                                                       months   months   months   months   months   months   months
                                                                                                                                           

    onions    U.S.A.         1951     1    1            wp 40%                           1.7                                           1
                                                                                         1.5
                             1951     1    2            wp 40%         7.3      9.8      4.2               7        2.8                1
                                                                       12.5     11.5                       (2.7
                                                                                                           11.7)    5.7
                                                                                                                    3.9
                                      1    2.4                                                                      2.7                1
                             1952     1    2.0          wp 40%                                                      2.5                1

                             1952     1    2.5          wp 40%                                                               10.0      1

                             1952     1    3.2          wp 40%                           3.0      2.2                                  1
                                                                                         2.3

              Netherlands    1955     1    2.5          liquid                           2                                             2

                                                        40%                              (1.2
                                                                                         4)
                                      1    2.5          liquid                           8.1                                           2
                                                        40%                              (n.d.
                                                                                         12.1)
                                                                                         1.5
                                                                                         (n.d.-                                        2
                                                                                         1.5
                                                                       2
                                                                       days

                             1964     1    1.8          liquid         7.4                                                             3
                                                        30%            (6.6
                                                                       9.0)

    TABLE 1. (Cont'd.)

                                                                                                                                           

                                      Application                      Residues, mean and range mg/kg*, at intervals after
                                                                       application (pre-harvest- + storage period)
    Crop      Country        Year
                                      no   kg/a.i./ha   formulation                                                                    Ref.
                                                                                                                                           

    Onions    Netherlands             1    2.5          liquid         13.0     9        14       35       44
                                                        30%            (10.8-   days     days     days     days                        3
                                                                       14.2)

              U.S.A.         1951-    1    2.3                                  2.7-     2.3-     3.1      2.5                         4
                             2                                                  11.7     14.5

                                                                                9        16       23       30       34
                                                                                weeks    weeks    weeks    weeks    weeks

              Poland         1968     1    1.2          EC                      2.5      6        3        8        4                  5
                                      1    1.7          EC                      3        4        5        13       13                 5
                                      1    2.25         EC                      6        8        6        14,23    13                 5


    Potatoes  U.S.A.         1951     1    1.5          wp 40%                  1.7      3.3,              3.4                         1
                                                                                         4.2               2.0

                             1951     1    1.8          wp 40%                  2.9                                                    1
                                                                                (1.1-4.
                                                                                5)

    Potatoes  U.S.A.         1951     1    2            wp 40%                  10.8     3.0,                                          1
                                                                                9.8      4.8

                             1951     1    3            wp 40%                           2.7                                           1
                                                                                         8.7

    TABLE 1. (Cont'd.)

                                                                                                                                           

                                      Application                      Residues, mean and range mg/kg*, at intervals after
                                                                       application (pre-harvest- + storage period)
    Crop      Country        Year
                                      no   kg/a.i./ha   formulation    1.5-2    3 - 4    4 - 5    6 - 7    7 - 8    9 -12              Ref.
                                                                       months   months   months   months   months   months
                                                                                                                                           

                             1951     1    3            wp 40%         9.8      1.0      2.9      4.7      8.8      6.0                1
                                                                       3.0      8.6      8.9               8.9      4.7
                                                                       3.6               9.1               9.4
                                                                       4.7               2.9
                                                                       6.0               3.0
                                                                                         11.9
                                                                                         7.4
                                                                                         5.8
                                                                                         1.0

                             1955     1    2.8          wp 40%                           11.3              16.1     10.2               1
                                                                                         14.7              10.8     10.4
                                                                                         4.7               11.1     21.9
                                                                                         3.7                        24.2
                                                                                                                                           

                                      Application                      Residues, mean and range mg/kg*, at intervals after
                                                                       application (pre-harvest- + storage period)
    Crop      Country        Year
                                      no   kg/a.i./ha   formulation    14-18    29-30     35      40-45                                Ref.
                                                                       days     days     days     days
                                                                                                                                           

    Potatoes  U.S.A.         1969     1    2                                    7.3      6.5      20                                   1
                                                                                (4-10)   (6-7)    1

    TABLE 1. (Cont'd.)
                                                                                                                                           
                                      Application                      Residues, mean and range mg/kg*, at intervals after
                                                                       application (pre-harvest- + storage period)
    Crop      Country        Year
                                      no   kg/a.i./ha   formulation    14-18    29-30     35      40-45                                Ref.
                                                                       days     days     days     days
                                                                                                                                           

    Potatoes  U.S.A.                                                            13
                                                                                (11-15)

                             1969     1    3                           9        14       9        6                                    1
                                                                       (9-24)   (7-11)

                                                                                12.5              1
                                                                                (8-15)            (0-2)
    Whole
    potato    U.S.A.         1951     1    1.6. - 3                    10-0-    5.5-     3.0-     10.2                                 4
                                                                       16.1     24.2     8.6
                                                                       32.5     16.3-             27.0
                                                                       48.9     41.0              32.9                                 4

                                                                       11       18       23       32
                                                                       weeks    weeks    weeks    weeks

    Potatoes  Poland         1968     1    1.4          EC             8        6        11       9                                    5
                                      1    2.0          EC             5        4        14       15                                   5
                                      1    2.7          EC             6        4        10       8,30                                 5
                                                                                                                                           

    *    With the exception of the data from Poland (Ref. 5), each entry in the Table refers to a separate trial.

    References

    1.   Uniroyal 1973-1975
    2.   R.I.V. 1955
    3.   R.I.V. 1964
    4.   Naugatuck Chem. Comp. 1956.
    5.   Drygas et al. 1968.
    

    treatment of the soil, it would measure both free and bound maleic
    hydrazide owing to hydrolysis of the latter.

         Data on the residue extractable with organic solvents show that
    half of the applied material is lost in periods varying from less than
    one to about six weeks in different soil types. Usually over 90% has
    disappeared in about 2-10 weeks. When soil was analysed for
    extractable residues more than 3 months after application only traces
    of maleic hydrazide were detected, if any. The bound residues in the
    soil are degraded less rapidly. Half of the applied maleic hydrazide
    is lost over periods varying from one to 14 weeks. Helweg (1975b)
    studied the effect of absorbtion on the rate of maleic hydrazide
    degradation using activated carbon as a model absorbent. While
    absorption caused an initial delay in 14C evolution from 3, 6 14C-MH,
    after 4 months almost equal amounts of 14CO2 were evolved from
    control soils and those containing activated carbon. In standard soil
    types 1 and 2 as recommended for leaching experiments in the Federal
    Republic of Germany (Characteristics: organic carbon 2.58 and 1.0%
    hydrazide particles <20  10.1 and 19.1% respectively) the initial
    residues of 30.5 and 36.1 mg/kg decreased in 8 weeks to 0.76 mg/kg
    (2.5%) and 0.44 mg/kg (1.2%) (BASF 1975). In sterile soil the residue
    hardly decreased in 6 weeks; in non-sterile soil of the same type an
    initial residue of 100 mg/kg decreased in 3 weeks to 5 mg/kg, mainly
    as a result of microbial degradation.

    Biodegradation. Helweg (1975a , 1975b) found CO2 to be the main
    degradation product of maleic hydrazide. From a sandy loam soil
    containing 20 mg/kg, kept under laboratory conditions, about 50% of
    the 14C was liberated as CO2 within two weeks.

         Uniroyal (1973-1975) treated two soil types with 3,6-14C at a
    rate of 55 mg/kg (an excessive dosage compared with normal practice).
    The 14C release reached 34% of the 14C applied in Connecticut sandy
    loam and 57% in Mississippi silt loam after two weeks. 

         Kaufman and Kalayanova 1975 studied the degradation of MH-14C in
    two soils under laboratory conditions, with the results shown in Table
    2.

    TABLE 2. Laboratory aerobic metabolism of maleic hydrazide.
              Cumulative 14CO2 evolved in 23 days
                                                                   
                                      % of applied 14C evolved
    Soil                rate          MH-3,6-14C         MH-4,5-14C
                        kg/ha
                                                                   
    Sandy loam          0.56          67.8               43.5
                        5.6           57.0               40.5

    Silty clay          0.56          47.8               17.7
                        5.6           48.0               18.3
                                                                   


         Methanol extraction of the MH-14C treated soil after 29 days
    removed only 1-3% of the applied 14C. In addition to maleic
    hydrazide, maleimide was identified as a degradation product, showing
    the likelihood of an early cleavage of the N-N bond in the degradation
    process. No hydrazine formation could be detected in the extracts from
    these soils, nor was hydrazine evolved when
    p-dimethylaminobenzaldehyde-sulphuric acid solutions were substituted
    for CO2 trapping solutions in the Warburg flask. Some of the 14C not
    extracted from the soil by methanol could be removed by aqueous
    alkali. The humin, and to a lesser extent the humic- and fulvic acid
    fractions contained 14C. The authors suggest that the radioactivity
    in these fractions could be present as sorbed unchanged maleic
    hydrazide, and/or as degradation products incorporated into the
    natural organic matter of the soil. There is some evidence that both
    sorption and chemical reaction occur. Uniroyal (1973-1975) found that
    aqueous base can release unchanged MH-14C from soil-bound residues
    not extracted by milder procedures. Helweg, (1975a) found some
    evidence for the incorporation of14C into an amino acid fraction of
    the soil. Since the microbial degradation of maleic hydrazide produces
    CO2 it is very likely that CO2 originating from the degradation of
    maleic hydrazide will be incorporated into natural products. It is
    evident that CO2 in the major metabolite in maleic hydrazide
    degradation, and small amounts of maleimide and natural products have
    been detected as intermediate steps in the metabolic pathway. However
    the small amounts of 14C products extracted from soil make it
    difficult to propose an overall metabolic pathway. On the basis of
    some similarity with experiments in which they used Fenton's reagent
    as a model of a free radical generating oxidation system, Kaufman and
    Kalayanova (1975) tentatively suggest the degradation pathway of
    maleic hydrazide in soil shown in Figure 1.

         Stoessl 1964 has reported similar products (fumaric, maleic,
    succinic, formic and nitric acids) from the photo oxidation of maleic
    hydrazide in dilute aqueous solutions in the presence of oxygen. Other
    authors e.g. Andreae (1955), Winder and Denneny (1959) and
    Povolotskaya (1961) confirm the photo-oxidation reactions of maleic
    hydrazide.

         Frear (1975) showed that bound residues of 14C-MH in tobacco
    root were degraded to 14CO2 and released. About 18% of the 14C-MH
    and 3,6-14MH and 0.5% of the 4,5-14C was released as 14CO2 from
    tobacco root tissue during 43 days incubation in soil owing to
    microbial activity.

         In subsequent work it was shown that the bound residue remaining
    in tobacco roots after methanol extraction, was partially released by
    treatment with aqueous ammonia at 80C for four days. The 14C
    extracted in this way was shown to be unchanged maleic hydrazide.
    Noodn (1970) found that the bound maleic hydrazide residue in other
    plants consists mainly of unchanged maleic hydrazide.

    In plants

    Uptake from the soil. In Canada, sandy loam soil was treated with
    0.2, 0.5, 1.0 and 5.0 mg/kg maleic hydrazide. Tobacco seedlings were
    planted in pots containing the treated soil and grown under glass.
    After 8 weeks 10% of the original amount added to the soil remained.
    No maleic hydrazide could be detected in the green leaves of the
    tobacco plant except in the plants grown on soil treated with the
    highest dosage of 5 mg/k The average residue in the leaves of these
    was 0.9 mg/kg (Hoffman et al, 1962).

         Haeberer et al (1974) showed that even when tobacco was planted
    in soil immediately after the application of maleic hydrazide at an
    exaggerated rate, no residues were found in the tobacco at harvest.
    From these experiments it may be concluded that maleic hydrazide will
    not be transferred to next years crop.

    Fate in the plant. Frear and Swanson (1975) studied the uptake and
    fate of 14C-MH in two flue-cured and two Burley tobacco varieties
    grown under glasshouse conditions. It was shown that the
    foliar-absorbed maleic hydrazide moves rapidly, both acropetally and
    basipetally to actively growing tissues in the tobacco plant including
    the roots. Most of the foliar-absorbed maleic hydrazide is transported
    to the roots and excreted into the external medium, but a significant
    proportion remains in the roots and other tissues as a
    methanol-insoluble residue, which was shown to consist largely of
    unchanged metabolite of maleic hydrazide. In tobacco the methanol-
    soluble metabolite of maleic hydrazide is the -D-glucoside of the
    phenolic tautomer, 6 hydroxy-3-(2H)-pyridazone.

         Towers et al (1958) also found this -D-glucoside in tobacco
    leaves. They reported that 15% of maleic hydrazide in tobacco leaves.
    They reported that 15% of maleic hydrazide was transformed into ito
    its -D-glucoside when applied to leaf segments. This metabolite was
    also seen in apple and willow.

         Callaghan (1961) reported the incorporation of maleic hydrazide
    into heterochromatin of root-tip colls of Allium cernuum, Vicia
    faba and Tradescantia palludosa.

         Biswas et al (1967) isolated two unknown transformation products
    from tea plants grown in nutrient solution containing 14C-MH. They
    speculate on various modes of ring opening, but did not provide
    experimental evidence of it.

         Noodn (1970) concluded from studies on the uptake of 14C-MH by
    roots that maleic hydrazide is bound to cell wall fragments as a
    stable complex which is insoluble in 80% ethanol. The bound maleic
    hydrazide could be released by heating the tissue with aminoethanol.
    Chromatography of the 14C-material released in this way showed that
    there was no indication of degradation and the maleic hydrazide was
    bound to the cell-walls in an unchanged form.

    FIGURE 1

         From the above studies on tobacco and other plants it may be
    concluded that the principal residues are unchanged maleic hydrazide
    (free or bound) and its, -D-glucoside. Cleavage of the N-N bond and
    opening of the ring structure does not appear to be a significant
    metabolic pathway in tobacco or in other crops studied.

    Effect of maleic hydrazide on biochemical processes in the plant.
    Patterson et al (1952) showed that a foliar spray of 2500 mg/l, about
    6 weeks before harvest caused a decrease in reducing and non-reducing
    sugars in tubers stored seven months at 7 C. Similar though less
    striking decreases were evident when tubers were stored at 13C.

         In other experiments (Gooding and Hubbard, 1956) no effect on the
    accumulation of reducing sugars or sucrose was found when potatoes
    were stored under cool conditions (0.5 - 4C) following a pre-harvest
    foliar application.

    In storage, processing and cooking

    Household cooking. Maleic hydrazide is fairly stable during
    household cooking. After cooking onions for half an hour, 80% of the
    original residue could still be detected. Of this about 25% remained
    in the onion and about 75% was found, in the cooking water. (R.I.V.
    Netherlands, 1964).

    Carry-over in cigarettes and cigarette-smoke. Cigarettes made from
    tobacco treated with 2.25 kg a.i./ha contained 10-30 mg/kg maleic
    hydrazide. When cigarettes containing 30 mg/kg maleic hydrazide were
    smoked in an automatic smoking machine 93% of the original residue was
    decomposed or transferred to the side stream. In smoke from cigarettes
    containing 10 mg/kg maleic hydrazide and smoked in a similar way, no
    maleic hydrazide could be detected in the mainstream smoke. In a third
    experiment in which 14C-MH was infused into cigarettes at a rate of
    105 mg/kg, 25% of the radioactivity was found in the mainstream
    (unpublished experiments of Stone (1957) referred to by Guthrie and
    Bowery, 1967).

    Residues in food moving in commerce

         No information was available to the Meeting.

    METHODS OF RESIDUE ANALYSIS

         A spectrophotometric method for the determination of maleic
    hydrazide residues in plant tissues was originally developed by Wood
    (1953) and improved by Lane et al (1958). The sample is boiled in
    caustic solution to drive off interfering volatile bases. Distillation
    with zinc in a stream of nitrogen then expels hydrazine, which is
    reacted in acid solution with p-dimethylamino-benzaldehyde. The yellow
    reaction product is measured spectro photometrically. Although the
    method is not very sensitive (limit of determination 0.5 -1 mg/kg), it
    may be adaptable to regulatory purposes.

         Hoffman (1961) and Hoffman et al (1962) describe further
    modifications of the Wood method for the spectrophotometric
    determination of maleic hydrazide residues.

         Haeberer et al (1974) and Haeberer and Chortyk (1974) developed a
    rapid quantitative GLC method for non-bound maleic hydrazide residues.
    The plant material is extracted with dimethylformamide or directly
    with N,O-bis (trimethylsilyl) acetamide. The bis-(trimethysilyl)
    derivative is formed by heating for 30 min. at 100C and measured by
    flame ionization gas chromatography. Interfering plant substances are
    removed by TLC on alumina with ethyl acetate as developing solvent.
    The recovery of maleic hydrazide added to tobacco powder at the rate
    of 0.5-10 mg/kg was 94-108%.

    NATIONAL TOLERANCES

         The national tolerances listed in Table 3 were reported to the
    Meeting.

    TABLE 3. National tolerances for maleic hydrazide reported to
              the Meeting
                                                                  
    Country             Commodity                     Tolerance
                                                      mg/kg
                                                                  
    Argentine           potatoes                      50

                        lettuce                       0.1

    Canada              potatoes                      50

                        beets, carrots, swedes
                          (rutabagas)                 30
                        onions                        15

    Netherlands         onions                        15

                        other vegetables, fruits,
                        other agricultural
                          commodities                 0*

    U.S.A.              potato chips                  160**

                        potatoes                      50

                        onions (dry bulb)             15
                                                                  

    * The limit of determination = 1 mg/kg

    ** By weight in finished product.

    APPRAISAL

         Maleic hydrazide is used in various countries on an extensive
    scale as an inhibitor of sprouting in onions. It is also used in a few
    countries on potatoes for a similar purpose and on tobacco for
    checking sucker growth. On both onions and potatoes the material is
    applied as a pre-harvest spray, when biological processes in the
    aerial parts of the crops are still very active. Maleic, hydrazide
    penetrates extensively into the plant and is transported in the phloem
    to actively growing tissues including the bulbs and tubers. Residues
    persist in these parts sufficiently to induce dormancy and hamper
    sprouting for fairly long periods.

         Extensive information from various countries on residues from
    supervised trials on onions and from two countries on residues in
    potatoes was provided. Limited data were available on residues in
    apples, carrots and tobacco, including data on residues in cigarettes
    and cigarette smoke.

         Considerable information was available on the metabolic pathways
    of maleic hydrazide in soil and plants. There is some evidence that
    the biodegradation of maleic hydrazide in the soil caused by bacteria
    and other micro-organisms leads via maleimide and maleimic acid to
    naturally occurring acids such as maleic and fumario, which may be
    converted to lactic and succinic acids and finally to CO2. From
    studies on tobacco and other plants it appears that the principal
    residues in plants consist of unchanged maleic hydrazide, either free
    or strongly bound to cell-wall fragments, and the B-D-glucoside of the
    phenolic tautomer -hydrozy-3-(2H)-pyridazone. Cleavage of the N-N
    bond and opening of the ring does not appear to be a significant
    metabolic pathway in the crops studied.

         Maleic hydrazide residues are fairly stable during cooking. After
    normal household cooking of onions about 20% of the residue remained
    in the onion and 60% was found in the cooking water.

         It was shown that during the manufacture of potato chips, drying
    and frying does not lead to any appreciable lose of maleic hydrazide.
    Owing to the loss of water during the manufacturing process the
    concentration of maleic hydrazide residues in the manufactured product
    is higher than in the fresh potatoes.

         When cigarettes made from field-treated tobacco and containing 30
    and 10 mg/kg maleic hydrazide were smoked in a smoking machine, 93% of
    the original residue was decomposed or transferred to the side stream
    of the 30 mg/kg level and no maleic hydrazide could be detected in the
    mainstream smoke at the 10 mg/kg level.

         A fairly specific spectrophotometric method of analysis is
    available. Although the method is not very sensitive (limit of
    determination 0.5 - 1 mg/kg) it may be suitable for adaptation to
    regulatory purposes.

         Recently a rapid quantitative GLC method has been developed to
    determine the bis(trimethylsilyl) derivative by flame ionisation gas
    chromatography. It is uncertain whether the method can be adapted to
    include not only the free maleic hydrazide residue but also bound
    unchanged maleic hydrazide and its -D-glucoside and whether it can be
    used for crops other than tobacco.

    EVALUATION

         As no ADI was allocated, maximum residue limits could not be
    recommended. Data were sufficient to record guideline levels for
    onions and potatoes.

         The following guideline levels are recommended. They refer to the
    sum of free and bound unchanged maleic hydrazide and its
    -D-glucoside.

    Commodity                             mg/kg

    Potatoes                                50

    Onions                                  15

    FURTHER WORK OR INFORMATION

    Required (before an acceptable daily intake can be allocated and
    maximum residue limits can be recommended).

    1.   The results of the carcinogenicity study with rats which is
         currently in progress.

    2.   Teratogenicity study with the sodium salt or the free acid.

    3.   Further studies clarifying the situation relating to the possible
         presence of hydrazine in or on crops.

    4.   Residue data on other crops for which usage recommendations are
         made including tobacco, carrots and swedes and similar crops.

    5.   Data on the fate of maleic hydrazide and its metabolites in
         livestock animals and residues in products of animal origin after
         feeding commodities containing maleic hydrazide residues, e.g.
         potatoes.

    6.   Data on the effect of cooking on residues in potatoes and the
         effect on residues of different methods of industrial processing
         in the manufacture of various potato products, e.g. potato chips,
         dried potatoes and potato starch. Data on residues in the wastes
         from these products intended for feeding purposes.

    7.   Further development of the gas-chromatographic method to make it
         suitable for regulatory purposes.

    8.   More information on the carry-over of maleic hydrazide from raw
         into cured tobacco and into cigarette smoke.

    Desirable

    1.   Studies on the metabolism of the beta-D-glucoside of maleic
         hydrazide.

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    See Also:
       Toxicological Abbreviations
       Maleic hydrazide (Pesticide residues in food: 1977 evaluations)
       Maleic hydrazide (Pesticide residues in food: 1980 evaluations)
       Maleic hydrazide (Pesticide residues in food: 1984 evaluations)
       Maleic hydrazide (Pesticide residues in food: 1984 evaluations)
       Maleic hydrazide (Pesticide residues in food: 1996 evaluations Part II Toxicological)
       Maleic Hydrazide (IARC Summary & Evaluation, Volume 4, 1974)