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    PESTICIDE RESIDUES IN FOOD - 1984


    Sponsored jointly by FAO and WHO






    EVALUATIONS 1984




    The monographs



    Data and recommendations of the 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, 24 September - 3 October 1984

    Food and Agriculture Organization of the United Nations
    Rome 1985

    IMAZALIL

    Explanation

         Imazalil was reviewed by the JMPR in 1977 and 1980 (FAO/WHO,
    1978, 1981) and a temporary ADI was estimated to be 0-0.01 mg/kg bw.
    The meeting determined that an adequately performed long-term feeding
    study in rats was necessary to define fully a no-effect level. In
    addition, short-term tests to evaluate the mutagenic potential were
    also required by 1984. Certain of these studies have been provided to
    the meeting and are reviewed below in this monograph addendum.

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    TOXICOLOGICAL STUDIES

    Long-term Studies

    Rat

         Four groups of SPF Wistar rats (20 males and 20 females/group)
    were administered imazalil (base, technical grade) in the diet at
    dosage levels of 0, 25, 100 or 400 ppm for 18 months. Animals were 4
    to 5 weeks old at the start of the test and were housed five to a
    cage, separated by sex and dose. Animals were observed daily for
    cageside clinical symptoms, weekly for body weight determinations and
    food consumption (per cage) measurements. Haematological parameters
    (tail vein) were evaluated ten days prior to necropsy in ten males and
    ten females per dose group. Urinalysis was performed on fasted animals
    (ten males and ten females per dose group) on test day 541, and
    clinical chemistry determinations were taken at autopsy from the aorta
    on ten animals/sex/groups. Liver and kidneys were examined in all
    animals.

         There were no compound-related effects on mortality, with only
    5-10 percent mortality reported in all groups. Clinical cageside
    observations were unremarkable except for generalized sniffing,
    stained fur, partly closed eyes and encrustation around the nose
    observed among all groups. There were no effects on food consumption,
    urinalysis, clinical chemistry or haematological parameters which were
    associated with dietary ingestion of imazalil. Female rats in the
    high-dose group had significantly depressed (p<0.05) body weight gain
    throughout the last six months of the study.

         There were no observed compound-related effects on absolute or
    relative organ weight changes in male rats. Females, however, were
    somewhat more sensitive with increased absolute and relative adrenal
    weights in all treated groups, increased relative kidney weights in
    mid-and high-dose groups, and increased relative brain and heart
    weights in the high-dose group only. Apparent organ weight changes
    were attributed to low control values (in comparison to historical
    controls) and body weight changes due to fasting prior to necropsy and
    were not related to compound ingestion. Histopathological examination

    did not demonstrate any compound-related effects except for a
    pronounced lobular pattern in livers of high-dose males. There were
    also intracytoplasmic inclusion bodies noted in high-dose males only.
    Oil Red O and PAS staining techniques demonstrated the absence of
    glycogen or fat in these inclusion bodies.

         Although there were no apparent oncogenic responses from the
    ingestion of imazalil, the number of animals examined and the duration
    of the study are inadequate to confirm the absence of such effects.
    (Til, et al., 1984).

    Special Studies on Mutagenicity

         Imazalil was negative in a series of mutagenicity studies
    conducted. See Table 1 for a summary of the studies considered.

    Comments

         Previous meetings have recognized the need for an adequate 
    long-term study in rats. An 18-month dietary study in rats was
    submitted to the 1984 JMPR, but was not included in the evaluation
    because of the few animals examined histologically and the 
    less-than-lifetime duration of the study. Therefore, the oncogenic
    potential in rats could not be evaluated. The requirement for an
    adequate long-term study in rats has not been fulfilled. The meeting
    was informed that a full two-year study is in progress and will be
    made available. Accordingly, the meeting reaffirmed the temporary ADI
    on the basis of studies in rats and dogs. Short-term mutagenicity
    tests reviewed were negative.

    Level Causing no Toxicological Effect

         Rat: 50 ppm in the diet, equivalent to 3.4 mg/kg bw.

         Dog: 1.25 mg/kg bw/day.

    Estimate of Temporary Acceptable Daily Intake for Humans

         0 - 0.01 mg/kg bw.

    FURTHER WORK OR INFORMATION

    Required (by 1986)

         An adequate life-span study in rats to define fully a no-effect
         level.


        TABLE 1.  Special Studies on Mutagenicity

                                                                                                                            

    Test System         Test Object         Concentration of         Purity              Results              Reference
                                            Imazalil Used
                                                                                                                            

    Ames Test           S. typhimurium      0.5, 5, 10, 20           Base, technical     Negative             Steelman &
    (both with          TA 98               and 30 g/plate          grade 98.1%                              Schreiner,
    and without         TA 100                                                                                1977
    metabolic           TA 1535
    activation)         TA 1537
                        TA 1538

    Micronucleus        Rat, bone           10, 40 and 160           Base, technical     Negative             Ph. Vanparys
    test                marrow              mg/kg i.p.               grade 98.1%         for an               & Marsboom,
                                                                                         increase             1979
                                                                                         in polychromatic
                                                                                         erythrocytes

    Sex-linked          Drosophila          250 and 1 000 ppm        Base, technical     Imazalil             Ph. Vanparys
    Recessive           melanogaster        for 3 days.              grade 98.1%         was                  & Marsboom,
    Lethal Test                             Positive control                             negative             1982
                                            (procarbazine)                               Procarbazine
                                            1 280 ppm.                                   gave expected
                                                                                         increase in
                                                                                         recessive
                                                                                         lethals
                                                                                                                            
    
    REFERENCES

    Steelman, J.A. and Schreiner, C.A. In vitro mutagenicity screening of
    1977      Imazalil, McN-JR-23979, by microsomal activation bacterial
              assays. Toxicological Research Report No. 515 (770914),
              McNeil Laboratories, Inc. Submitted by Janssen Pharmaceutica
              to WHO.

    Ph. Vanparys and R. Marsboom. Micronucleus test in Rats - Imazalil
    1979      R23.979; Submitted by Janssen Pharmaceutica to WHO.
              (Unpublished)

    Ph. Vanparys and R. Marsboom. Sex-linked lethal test in Drosophila
    1982      melanogaster, Imazalil R23.979. Submitted by Janssen
              Pharmaceutica to WHO. (Unpublished)

    Til, H.P. et al. Eighteen-month oral toxicity study with Imazalil
    1984      base - R23.979 in rats. (Unpublished)


    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: 1985 evaluations Part II Toxicology)
       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)