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.