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)