IMAZALIL
EXPLANATION
Imazalil was evaluated for acceptable daily intake by the Joint
Meeting in 1977, and reviewed in 1980, 1984, and 1985 (Annex 1,
FAO/WHO, 1978a, 1981a, 1985b, and 1986a). A toxicological monograph
was published in 1977 (Annex 1, FAO/WHO, 1978b) and monograph addenda
were published after each of the reviews (Annex 1, FAO/WHO, 1981b,
1985c, and 1986c). The 1985 Joint Meeting was aware of several
teratology studies that had not been submitted in full. Although 1 rat
teratology study had been evaluated earlier, the 1985 Meeting wanted
to review all the available teratology data, so it extended the
temporary ADI pending the submission of these data. This monograph
addendum summarizes these studies as well as other data on imazalil
analogues that were submitted to the 1986 Joint Meeting for
evaluation.
EVALUATION FOR ACCEPTABLE INTAKE
BIOLOGICAL DATA
Toxicological studies
Special studies on teratogenicity
Mice
Twenty-four female Cobs mice received orally 0, 2.5, 10, or 40 mg
imazalil sulfate/kg b.w./day from days 6 through 16 of pregnancy. All
animals were killed on day 19 of pregnancy. No effects were found on
mortality, body weight, food consumption, pregnancy rate, number of
live, dead, or resorbed fetuses, pup weight, or mean litter size.
During gross observations, talipes valgus (club foot) was observed in
all groups, the incidence not being significantly different in any
dose group when compared to the control group. No additional
abnormalities were seen after radiographic examinations and Lapras'
sectioning technique (Marsboom et al., 1985).
Rabbits
Groups of 20 female New Zealand white rabbits received imazalil
nitrate (purity 99.2%) in water by gavage at 0, 0.63, or 2.5 mg/kg
b.w./day on days 6 to 18 of pregnancy. All surviving animals were
killed on day 28 of pregnancy. Four females died during the test (3 in
the control group and 1 in the 0.63 mg/kg b.w./day group). Body-weight
gain of the dams was decreased in both dose groups, as well as average
litter size, the percentages of live fetuses, and 24-hour survival
rates. The percentages of resorbed fetuses increased with increasing
dose. Retrospective statistical analysis showed that the effects on
maternal body weight, litter size, and number of resorptions were not
statistically significant. A small number of anomalies in all groups
(hydrocephaly, fused ribs, and deformed legs) were considered to be
non-dose related. Individual data were not available to the Meeting.
In this study embryotoxic and maternally toxic effects were observed
in both dose groups. Therefore, this study was repeated at lower
dosages, as described in the next paragraph (Marsboom, 1974).
Groups of 15 female New Zealand white rabbits received imazalil
nitrate (purity 97.8%) in water by gavage at 0, 0.16, or 0.63 mg/kg
b.w./day from days 6 to 18 of pregnancy. The surviving animals were
killed on day 28 of pregnancy. Mortality (3 dams in the 0.16 mg/kg
b.w./day group died during the study), body weight, and pregnancy rate
were not significantly different among the groups. Mean litter size
was normal in all groups, and no statistically-significant differences
were seen with regard to the number of live, dead, or resorbed
fetuses, birth weight, or 24-hour survival rate. Fetal skeletal
examination and fetal sectioning revealed no compound-related
abnormalities (Marsboom & Dirkx, 1981).
Groups of 15 female New Zealand white rabbits received technical
grade imazalil nitrate (purity 97.8%) in water by gavage at 0, 1.25,
2.5, or 5 mg/kg b.w./day on days 6 - 18 of pregnancy. All animals were
killed on day 28 of pregnancy. The dams were examined for mortality
and body weight. The number of live, dead, and resorbed fetuses,
litter size, survival rate, and pup weight were recorded and all live
and dead fetuses were examined for gross pathology (fetal skeletal
examination and fetal sectioning).
One dam of the low-dose group and 1 of the high-dose group died
during the study. Decreased body weight was observed in dams of the
5 mg/kg b.w./day group. There were no differences with respect to the
number of live, dead, or resorbed fetuses, litter size, number of
implantations, or 24-hour survival rate. There was a slight decrease
in pup weight at 5 mg/kg b.w./day. In 1 fetus of the high-dose group a
split ninth thoracic vertebra on the right side, with each part having
1 rib, was observed. Individual animal data were not available to the
Meeting. The NOAEL for maternal toxic and embryotoxic effects was
2.5 mg/kg b.w./day (Marsboom & Dirkx, 1985).
Observations in humans
Results of some clinical and non-clinical studies on the
antifungal imidazoles miconazole, econazole, and ketonazole, which
belong to the same chemical family as imazalil, were provided to the
Joint Meeting. Clinical doses varied from 4 - 80 mg/kg b.w., and the
routes of administration were dermal, inhalation, oral, or i.v.
Occasional side effects of treatment of miconazole to patients
were chills, dizziness, itching, skin rash, and diarrhoea. At high
dose levels loss of appetite, nausea, and vomiting were seen. After
prolonged treatment with miconazole in severely debilitated subjects
and after oral treatment of 3 g/day for 9 weeks to normal volunteers,
no adverse effects on renal, hepatic, or bone marrow functions were
observed. Metabolism studies showed that the metabolic breakdown of
miconazole was comparable in humans and rats (Brugmans et al., 1972;
Symoens, 1977).
Five days after oral administration of 500 mg (3H)-econazole to
2 human subjects, the excretion of radioactivity was prolonged and
incomplete (40% and 27% of the dose were found in the urine and
faeces, respectively). Peak values in plasma of unchanged econazole
and total radioactivity were reached 1.5 to 3 hours after adminis-
tration, but the half-life of unchanged econazole (< 24 hours) in
plasma was much shorter than that of the econazole metabolites. The
main route of biotransformation of econazole in man involved multiple
oxidation of the imidazole ring carbons followed by O-dealkylation and
conjugation of the resulting alcohols, probably with glucuronic acid
(Midgley et al., 1981).
Kinetic studies with ketoconazole in man have shown that the drug
is rapidly absorbed and widely distributed after oral administration.
It is extensively metabolised by the liver to a series of inactive
products, and is excreted mainly in the faeces. Plasma levels of
ketonazole in man remained stable during chronic administration
(Gascoigne et al., 1981).
COMMENTS
Additional teratogenicity studies in rabbits showed that in the
first study there were maternally toxic and embryotoxic effects at
both dose levels of 0.63 and 2.5 mg/kg b.w./day. However, these
results could not be confirmed in 2 later studies. In the last one
only minimal maternally toxic and embryotoxic effects occurred at
5 mg/kg b.w./day and a NOAEL of 2.5 mg/kg b.w./day could be
established. In an additional teratogenicity study in mice, no effects
were observed at dosages up to 40 mg/kg b.w./day There were no
indications of a teratogenic effect in any of the studies.
Data on structurally-similar human antimycotic drugs indicated
the improbability of adverse effects in man.
TOXICOLOGICAL EVALUATION
LEVEL CAUSING NO TOXICOLOGICAL EFFECT
Rat: 100 ppm in the diet, equal to 5 mg/kg b.w./day
Dog: 1.25 mg/kg b.w./day
ESTIMATE OF ACCEPTABLE DAILY INTAKE FOR MAN
0 - 0.01 mg/kg b.w.
STUDIES WHICH WILL PROVIDE INFORMATION VALUABLE FOR THE CONTINUED
EVALUATION OF THE COMPOUND
Observations in man.
REFERENCES
Brugmans, J., Van Cutsem, J., Heykants, J., Schuermans, V., &
1972 Thienpont, D. Systemic antifungal potential, safety,
biotransport and transformation of miconazole nitrate.
Europ. J. Clin. Pharmacol. 5, 93 - 99.
Gascoigne, E.W., Barton, G.J., Michaels, M., Meuldermans, W., &
1981 Heykants, J. The kinetics of ketoconazole in animals and
man. Clin. Res. Rev. 1, 177 - 187.
Marsboom, R. Potential of oral R 18531 for embryotoxicity and
1974 teratogenic effects in rabbits. Unpublished report No. 535
from Janssen Research Laboratories. Submitted to WHO by
Janssen Pharmaceutica N.V., Beerse, Belgium.
Marsboom, R. & Dirkx, P. Imazalil: R 18531. Oral embryotoxicity and
1981 teratogenicity study in New Zealand white rabbits
(Segment II). Unpublished experiment No. 10816 from Janssen
Research Laboratories. Submitted to WHO by Janssen
Pharmaceutica N.V., Beerse, Belgium.
Marsboom, R. & Dirkx, P. Imazalil: R 18531. Oral embryotoxicity and
1985 teratogenicity study in New Zealand white rabbits
(Segment II). Unpublished report No. 1482 from Janssen
Research Laboratories. Submitted to WHO by Janssen
Pharmaceutica N.V., Beerse, Belgium.
Marsboom, R., Gillardin, J.M., & Sanz, G. R 27180 Imazalil.
1985 Embryotoxicity and teratogenicity study in Cobs mice.
Unpublished experiment No. 85-02 from Janssen Research
Laboratories, submitted to WHO by Janssen Pharmaceutica
N.V., Beerse, Belgium.
Midgley, I., Biggs, S.R., Hawkins, D.R., Chasseaud, L.F., Darragh, A.,
1981 Brodie, R.R., & Walmsley, L.M. The metabolic fate of
(3H)econazole in man. Xenobiotica, 11, 595 - 608.
Symoens, J. Clinical and experimental evidence on miconazole for the
1977 treatment of systemic mycoses: A review. Proc. Roy. Soc.
Med. 70, (Suppl. 1), 4 - 8.
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: 1985 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)