IMAZALIL

    First draft prepared by Dr. E. Bosshard,
    Federal Office of Public Health,
    Zurich, Switzerland

    EXPLANATION

         Imazalil is an imidazol plant fungicide that was first evaluated
    by the JMPR in 1977 (Annex I, 28).  At that time a temporary
    acceptable daily intake of 0-0.01 mg/kg bw was estimated. The compound
    was re-evaluated in 1980, 1984, 1985 and 1986 (Annex I, 34, 42, 44 and
    47).  An acceptable daily intake for man of 0-0.01 mg/kg bw was
    estimated by the JMPR in 1986.

         An additional short-term study in dogs and human data have been
    submitted and are summarized in the following monograph addendum.

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    BIOLOGICAL DATA

    Toxicological studies

    Short term studies

    Dog

         Groups of Beagle dogs (4/sex/group) received imazalil orally in
    capsules at dose levels of 0, 1.25, 2.5 and 20 mg/kg bw/day over 12
    months.  The treatment had no effect on mortality, ophthalmoscopic
    findings, parameters of electro-cardiographic analysis nor urinalysis. 
    At 20 mg/kg bw clinical signs became apparent consisting of increased
    salivation, vomiting and soft faeces.  Body weight gain was depressed
    to about 54% of the control value and food consumption was also
    reduced in the highest dose group.  A slight increase in white blood
    cell count and segmented neutrophils was found which was within the
    normal range of the historical control data.  Alkaline phosphatase was
    increased at 20 mg/kg bw/day.  An increase in absolute and relative
    liver weight was observed at 20 mg/kg bw/ day.  No gross pathological
    or histopathological tissue alterations were seen.  The NOAEL is 2.5
    mg/kg bw (Verstraeten  et al., 1989).

    Observations in man

         Imazalil was used at oral therapeutic doses of up to 1200 mg over
    6 months for the treatment of chronic fungal infection due to
     Alternaria alternata in a single patient (female).  The drug was
    tolerated without evident toxicity based on haematology and clinical
    observations with the exception of the induction of nausea at
    high-dose levels.  Measurements of blood levels found rapid clearance
    and no bioaccumulation even after repeated administration of high-dose
    levels (Stiller  et al., 1986).

    COMMENTS

         In a 12-month study in dogs at dose levels of 0, 1.25, 2.5 or 20
    mg/kg bw/day administered by capsule, a NOAEL of 2.5 mg/kg bw was
    determined.  This was based on clinical signs, decreased body-weight
    gain, and increased liver weight at higher doses.

         Imazalil was used in the therapy of alternariosis in a female
    patient unresponsive to conventional therapy.  Oral administration was
    initiated at a dose of 50 mg daily and gradually increased to 1200 mg
    daily.  For six months the drug was tolerated without evident
    toxicity.  Measurements of serum concentrations over time found a
    short half-life with no accumulation or effects on clearance after
    repeated administration.  These findings are similar to those observed
    in rodents after the administration of imazalil.

         An ADI was allocated on the basis of the NOAEL established for
    the newly evaluated study in dogs utilizing a 100-fold factor.

    TOXICOLOGICAL EVALUATION

    Level causing no toxicological effect

         Rat:      100 ppm, equal to 5 mg/kg bw/day
         Dog:      2.5 mg/kg bw/day

    Estimate of acceptable daily intake for humans

         0-0.03 mg/kg bw

    Studies which will provide information valuable in the
    continued evaluation of the compound

         Further observations in humans.

    REFERENCES

    Stiller, R.L., Stevens, D.A. (1986)  Studies with a plant fungicide,
    imazalil, with vapor-phase activity, in the therapy of human
    alternariosis,  Mycopathologia, 93 S: 169-172.

    Verstraeten, A.  et al. (1989)  Imazalil base: R 23979 Chronic
    Toxicity Study in Beagle Dogs.  Repeated dosage for 12 months. Exp. No
    1899.  Unpublished report prepared by the Department of Toxicology,
    Janssen Research Foundation, Belgium.

    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: 1985 evaluations Part II Toxicology)
       Imazalil (Pesticide residues in food: 1986 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)