First draft prepared by Dr. E. Bosshard,
Federal Office of Public Health,
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
Short term studies
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).
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.
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.
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.