IMAZALIL EXPLANATION 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. EVALUATION FOR ACCEPTABLE INTAKE BIOLOGICAL DATA Toxicological studies Special study on carcinogenicity Rat 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). COMMENTS 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 negative. 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. TOXICOLOGICAL EVALUATION LEVEL CAUSING NO TOXICOLOGICAL EFFECT Rat: 100 ppm in the diet, equal to 5 mg/kg b.w. Dog: 1.25 mg/kg b.w. ESTIMATE OF TEMPORARY ACCEPTABLE DAILY INTAKE FOR MAN 0 - 0.01 mg/kg b.w. FURTHER WORK OR INFORMATION REQUIRED (by 1986) Additional teratology studies known to be available but which have not been submitted to the JMPR. DESIRED Observations in man concerning the use of certain imazalil compounds, such as anti-fungal drugs. REFERENCE 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)