Imazalil was reviewed by the Joint Meetings in 1977, 1980, and
    1984 (Annex 1, FAO/WHO, 1978a, 1981a, and 1985b). A toxicological
    monograph was prepared by the Joint Meeting in 1977 (Annex 1, FAO/WHO,
    1978b) and monograph addenda were prepared in 1980 and 1984 (Annex 1,
    FAO/WHO, 1981b and 1985c). A temporary ADI of 0-0.01 mg/kg b.w. was
    estimated in 1977, which was retained by the Joint Meetings in 1980
    and 1984. The previous Joint Meetings determined that an adequately-
    performed long-term feeding/oncogenicity study in rats was necessary
    to accurately define a no-effect level and to assess the oncogenic
    potential of imazalil. These studies were provided to the present
    Meeting and are reviewed in this monograph addendum.



    Toxicological studies

    Special study on carcinogenicity


         Four groups of SPF Wistar rats (50 male and 50 female rats/group)
    were administered imazalil (base, technical grade 98.1% purity) in the
    diet at dosage levels of 0, 25, 100, or 400 ppm for 30 months. Animals
    were 4-5 weeks old at the start of the study and were housed
    5/sex/cage. Animals were observed daily for general condition and
    behaviour, examined periodically for visible/palpable tumours or signs
    of illness, and weekly for body weight and food consumption (per cage
    measurements). Ophthalmoscopic examinations were performed on control
    and high-dose animals initially and at weeks 52 and 104. Plasma
    albumin measurements were determined in 10 male and 10 female rats in
    each of the control and high-dose groups from blood collected, after
    overnight fasting, from the aorta.

         Macroscopic examinations were performed on all animals. Organ
    weights were determined on all surviving animals and included
    adrenals, brain, heart, kidneys, liver, lungs, ovaries, pancreas,
    pituitary, spleen, testes, thymus, and thyroid. Histopathological
    examinations were performed on all control and high-dose animals for
    the presence of hyperplastic, pre-neoplastic and neoplastic changes.
    The same evaluations were conducted on all low- and mid-dose animals,
    but included only the liver, spleen, pituitary, thyroid, adrenals,
    brain and testes. Similarly, microscopic examinations for non-
    neoplastic changes in the liver and kidney were performed in control
    and high-dose animals only.

         General cageside observations were unremarkable and there were no
    compound-related effects on mortality, with 50% mortality occurring
    approximately 812 days into the study for both sexes. Body weight of
    high-dose males was reduced for the first 13 weeks and remained lower
    than controls throughout the study, but did not adversely affect their
    lifespan. There were no effects on body weight in females. Mean weekly
    food consumption and plasma albumin were unaffected by treatment.
    Absolute and relative organ weights were variable in males among all
    groups with only decreased absolute brain weight in 100- and 400-ppm
    males being significant. There were no significant differences between
    controls and treated females regarding organ-weight changes.
    Ophthalmoscopic examinations were unremarkable between treated and
    control groups, except for a marginally-increased incidence of
    cataracts among high-dose males (i.e., 37 control, 43 high dose).
    Macroscopic examinations were limited and unremarkable. There were
    also no compound-related effects detected upon microscopic
    examination. Although imazalil was not oncogenic in this study, there
    were several tumours reported among all groups, including control,
    which are indicative of geriatric changes (e.g. benign pituitary
    tumours, fibroadenomas of the mammary gland, benign fibromatous polyp
    in the uterus, as well as pheochromocytoma of the adrenal, the latter
    predominantly in males). Imazalil was not oncogenic at dose levels up
    to and including 400 ppm in the diet (equal to 15 and 19.7 mg/kg b.w.
    for males and females, respectively) (Til et al., 1985).


         Previous Meetings have recognized the need for an adequate long-
    term evaluation in rats. The data submitted were considered sufficient
    to determine a NOEL of 100 ppm for non-oncogenic effects. There was no
    evidence of oncogenic potential at dietary levels up to and including
    400 ppm. As reviewed in 1984, short-term mutagenicity tests were

         Although 1 teratology study was evaluated in 1977, the Meeting
    was aware of several other teratology studies which have not been
    presented in full to the JMPR. Considering its desire to review these
    data, the Meeting recommended continuation of the temporary ADI at the
    same level.



         Rat: 100 ppm in the diet, equal to 5 mg/kg b.w.

         Dog: 1.25 mg/kg b.w.


         0 - 0.01 mg/kg b.w.


         Additional teratology studies known to be available but which
    have not been submitted to the JMPR.


         Observations in man concerning the use of certain imazalil
    compounds, such as anti-fungal drugs.


    Til, H.P., Lina, B.A.R., Falke, H.E., van Nesselrooij, J.H.J., Beems,
    (1985)    R.B., & de Groot, A.P. Lifespan oral carcinogenicity study
              with imazalil base-R 23979 in rats. Unpublished report No. V
              85.153/220555 from Civo Institutes TNO. Submitted to WHO by
              Janssen Pharmaceutica.

    See Also:
       Toxicological Abbreviations
       Imazalil (ICSC)
       Imazalil (Pesticide residues in food: 1977 evaluations)
       Imazalil (Pesticide residues in food: 1980 evaluations)
       Imazalil (Pesticide residues in food: 1984 evaluations)
       Imazalil (Pesticide residues in food: 1984 evaluations)
       Imazalil (Pesticide residues in food: 1986 evaluations Part II Toxicology)
       Imazalil (Pesticide residues in food: 1991 evaluations Part II Toxicology)
       Imazalil (JMPR Evaluations 2000 Part II Toxicological)
       Imazalil (JMPR Evaluations 2001 Part II Toxicological)
       Imazalil (JMPR Evaluations 2005 Part II Toxicological)