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 µg/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)