PESTICIDE RESIDUES IN FOOD - 1980


    Sponsored jointly by FAO and WHO






    EVALUATIONS 1980





    Joint meeting of the
    FAO Panel of Experts on Pesticide Residues
    in Food and the Environment
    and the
    WHO Expert Group on Pesticide Residues
    Rome, 6-15 October 1980




    MALEIC HYDRAZIDE

    Explanation

    Maleic hydrazide was reviewed by the 1976 and 1977 Joint Meeting
    (FAO/WHO 1977, 1978).  The data were not adequate for the
    estimation of an acceptable daily intake for man and the following
    studies were required:
    1. The results of the carcinogenicity study with rats, which was
    currently in progress.
    2. Teratogenicity study with the sodium salt or the free acid.
    Part of these studies have been provided and are summarised in the
    following monograph addendum.


    DATA CONSIDERED FOR DERIVATION OF ACCEPTABLE DAILY INTAKE

    TOXICOLOGICAL STUDIES

    Special studies on carcinogenicity

    Rat

    Before the carcinogenicity study a breeding experiment was
    performed with groups of 50 female and 25 male rats, which were fed
    diets containing 0, 1.0 or 2.0% maleic hydrazide from 1 week before
    mating onwards.  After a one-week mating period the dams were
    separated from the males.  The dams were given the respective diets
    throughout pregnancy and lactating period.  The fertility index,
    viability, lactation index and the number of infertile rats were
    comparable between groups.

    The carcinogenicity study was conducted with one group of 65 males
    and 65 females (2% maleic hydrazide) and 2 groups of 55 animals of
    each sex (control and 1%).  The rats were kept on their respective
    diets for a period of 28 months after weaning.

    No clear differences between control and test groups were seen in
    respect to mortality, food consumption, haematology and organ
    weights. The body weight gain of the females of both treated groups
    was decreased especially during the first half of the experiment. 
    The males of the 2% group showed a tendency to a lower growth rate. 
    There was a significant increase in water consumption at the 2%
    level, measured during week 18 and 25.  In the 1% dietary level
    group a tendency to an increased water consumption was observed.

    Urinalysis revealed that 1 and 2% maleic hydrazide caused
    proteinuria and increased protein/oreatinin ratios in both males
    and females after 6 and 12 months.  However no histopathological
    lesions in the kidneys and other tissues were observed.  There was

    no treatment-related tumour incidence. The malaic hydrazide used 
    in the study contained less than 1.5 mg/kg hydrazine as impurity 
    (van der Heijden et al, 1979).

    Special studies on mutagenicity

    The cytotoxic effects of maleic hydrazide (MH), its potassium
    (K-MH) and diethanolamine (DEA-MH) salt and hydrazine
    dihydrocholoride (HDC) were tested in a Chinese hamster cell line. 
    The purity of the compounds tested is not given.  The LD50 values
    were, in µg/ml: 1100 (MH), 20,000 (K-MH) and 12,000 (DEA-MH).  HDC
    was more toxic with LD50 of 230 µg/ml.  The MH compounds showed
    weak but dose-related cytogenetic effects.  At the LD50 dose
    maximal frequencies of aberrant cells were 18% for MH and KMH
    compared with 4% for the controls.

    The cytogenetic effect of ethylmethanesulphonate was about equal to
    MH and its salts, whereas the positive control
    N-methyl-N'-nitrosoguanidine at 5 µg/ml induced 97% cells with
    aberrant chromosomes.

    The suspected carcinogenic and mutagenic compound HDC did not show
    an increased number of aberrant cells (Nishi et al, 1979).

    Six groups of either 2 or 4 male Swiss mice were injected
    intraperitoneally with DMSO, 100 or 200 mg/kg bw maleic hydrazide,
    and 40, 80 or 120 mg/kg bw hycanthone methane sulphonate.  The
    dosing was repeated after 24 hours after the second injection, the
    mice were killed and bone-marrow preparations made.

    Hycanthone showed a clear but not dose-related increase in the
    frequency of micronuclei, whereas maleic hydrazide did not show any
    mutagenic effect (Chaubey et al, 1977)


    EVALUATION

    COMMENTS

    The previous toxicological evaluation of maleic hydrazide in 1976
    (FAO/WHO 1977b) was not completed because studies on
    carcinogenicity were unfinished.  From the data now submitted it
    appears that maleic hydrazide containing less than 1.5 mg/kg
    hydrazine as impurity is not carcinogenic to rats.  Two new
    mutagenicity studies have been reviewed.  In a micronucleus test
    maleic hydrazide showed no mutagenic effect, whereas in a
    cytotoxicity test with Chinese hamster cells the number of
    chromosomal aberrations was slightly increased at a dose level
    similar to the LD50.  However, from this result it cannot be
    concluded that maleic hydrazide is a mutagen, which agrees with
    previous data on mutagenicity mentioned in the monograph of 1976,
    showing that maleic hydrazide is not mutagenic.

    No teratogenicity study was made available, but a reproduction
    study in 1976 showed no adverse effects.  In the present long-term
    carcinogenicity study with maleic hydrazide in rats, increased
    protein in the urine, and inhibition of growth in female animals
    were seen at doses of 10,000 and 20,000 mg/kg in the diet.  It was
    concluded that the study did not reveal a no-effect level.

    In the monograph of 1976 a no-effect level of 21% in the diet was
    found for the sodium salt of maleic hydrazide.  The data on the
    sodium salt are now adequate for toxicological evaluation. 
    However, owing to the lack of a teratogenicity study and the
    apparent difference in toxicity between the sodium salt and the
    free acid, only a temporary ADI with a high safety factor can be
    allocated.  It has to be stressed that this ADI is for maleic
    hydrazide of 99% purity, containing less than 15 mg/kg of free
    hydrazine.  No ADI was allocated for the diethanolamine salt.

    Level in the diet causing no toxicological effect (sodium salt)

    Rat: 20,000 mg/kg equivalent to 1,000 mg/kg bw/day.
    Dog: 20,000 mg/kg equivalent to 500 mg/kg bw/day.

    Estimate of temporary acceptable daily intake for man

    0-1 mg/kg bw/day (sodium or potassium salt)


    FURTHER WORK OR INFORMATION

    Required (by 1984)

    1. Teratogenicity study with the sodium or potassium salt.
    2. Short-term toxicological study with maleic hydrazide as free
    acid and as sodium or potassium salt to establish a no-effect level
    and to study the apparent difference in toxicity.
    3. Carcinogenicity study with the diethanolamine salt of maleic
    hydrazide before an ADI can be established for this salt.


    REFERENCES

    Chaubey, R.C., Kavi, B.R., Chauhan, P.S. and Sundaram, K. The
    effect of hycanthone and maleic hydrazide on the frequency of
    micronuclei in the bone-marrow erythrocytes of mice. Mut. Res. 51:
    187-191.

    Heijden, C.A. van der, Berkvens, J.M., Tonkelaar, E.M. den, Droes,
    R. Nesselrooy, J.H.J., Vries, Th. de and Esch, G.J. van. Maleic
    hydrazide: an oral carcinogenicity study in rats. (1979)
    Unpublished report nr. 7/79 Tox/Path of the National Institute of
    Public Health, The Netherlands.

    Nishi Y., Mori, M. and Inui, N. Chromosomal aberrations induced by
    maleic hydrazide and related compounds in chinese hamster cells in
    vitro. Mut. Res. 67: 245-257.

    

    See Also:
       Toxicological Abbreviations
       Maleic hydrazide (Pesticide residues in food: 1976 evaluations)
       Maleic hydrazide (Pesticide residues in food: 1977 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)