PROPICONAZOLE
EXPLANATION
This chemical has not been previously evaluated by the WHO Expert
Group. It is a systemic fungicide with high activity against several
fungal pathogens which cause a wide range of problems such as powdery
wildrew, rusts and leaf spot disease. The compound can be used for
protective, curative and eradicative purposes.
EVALUATION FOR ACCEPTABLE INTAKE
BIOLOGICAL DATA
Biochemical aspects
Absorption, distribution and excretion
Male and female mice were fed a diet containing 5, 100 and
2500 ppm propiconazole for 21 days, followed by a single oral dose of
[14C]-phenyl propiconazole at a mean corresponding dose level
(0.8/1.0, 16.8/21.5 and 434/475 mg/kg bw for males/females).
Urinary excretion accounted for 45-81% of the administered dose
after 96 hours and tended to be higher by males than by females. In
the faeces 22-43% was excreted. At the lowest dose level (5 ppm
propiconazole) the residual radioactivity in blood, liver, kidneys,
lungs and in the remaining carcass was below 0.02 mg/kg propiconazole
equivalents and accordingly higher at the 100 and 2500 ppm dose level.
Residues in female mice were higher than in male mice, except in the
kidneys where the males showed higher or equal values. Independent of
the dose level and sex of the animals, the highest residues were found
in the liver, up to 2.3 and 3.0 mg/kg in males and females of the
highest dose level, respectively (Bissig, 1986).
Orally administered single doses (0.5 and 25 mg/kg bw) of
triazole labelled (3,5-14C)propiconazole to rats were rapidly
excreted within 24 hours (74-84%). After 6 days, 0.04-0.15%, 28-46%
and 53-67% had been recovered from expired air, faeces and urine
respectively. Only about 0.4% of the administered dose remained in the
tissues. Highest tissue residues were found in liver, blood and
kidneys. No unchanged propiconazole was excreted in the urine
(Hambock, 1979).
Within 3 days after treatment of male rats with a single oral
dose of about 32 mg/kg bw of triazole labelled (3,5-14C)
propiconazole or a phenyl-[U-14C] labelled propiconazole, more than
95% of the dose was excreted. Of this, 52% was found in the urine and
43-48% in the faeces. The excretion pattern for both compounds was
identical with no administered compound being found in the urine.
Approximately 20 metabolic fractions were identified in the urine
(Muecke, 1979).
Single doses of triazole-14C-propiconazole (1.0 and
10.0 mg/kg bw) applied dermally to rats were absorbed through the skin
following first order kinetics with half-lives averaging 24-31 hours
for low and high dosed rats, respectively. Equal amounts of the dose
were excreted within 72 hours in urine and faeces. The amount of
residual radioactivity on the skin averaged 20% of the applied dose
(Simoneaux, 1983).
Feed consumption, milk production or the general health of a
lactating goat were not affected after the daily oral administration
of 5 mg triazole-14C-propiconazole for 10 consecutive days (which
would correspond to 4.5 ppm in the feed) (Seim & Thomas, 1980). Of the
total dose, 89% was excreted within 24 hours after the last
administration (68% and 21% in urine and faeces, respectively). All
tissues contained less than 0.02 mg/kg propiconazole equivalents,
except liver (0.096 mg/kg) and kidney (0.029 mg/kg). The total
radioactivity secreted with the milk reached a plateau at day three of
0.013-0.016 mg/kg, representing 0.18% of the total dose (Fischer &
Cassidy, 1980).
Biotransformation
The metabolism of orally administered [14C]-phenyl
propiconazole was studied in mice pretreated with unlabeled
propiconazole followed by a single oral dose of [14C]-phenyl
propiconazole at a corresponding dose level.
The urinary metabolite pattern of propiconazole demonstrated a
marked sex dependency. In male mice, 60% of the radioactivity in
0-24 hour urine was represented by one metabolite, this metabolite
accounted for 30% in the 0-24 hour urine in female mice. This
metabolite was identified by spectroscopy as the glucuronic acid
conjugate of 1-(2,4-dichlorophenyl)-2-(1 H-1,2,4-triazol-1-yl)
ethanol. This demonstrates that the major metabolic pathway in mice
involves dioxolane ring cleavage (Bissig, 1986).
The metabolism of propiconazole was also investigated in male
rats administered a single oral dose of 31.4 mg/kg triazole-
[3,5-14C-propiconazole]. Metabolites were isolated from
first day urine and faeces excretion representing 44.5% and 36.2% of
the applied dose, respectively. A wide array of biotransformations
occurred leading to numerous metabolites. The major site of enzymatic
attack oxidation of the propyl side chain leading via alcohols and
diols to carboxy acids and alpha-hydroxy carboxy acid or cleavage of
the dioxolane ring. The majority of the alcoholic and phenolic
metabolites are renally excreted as sulfuric acid and glucuronic acid
conjugates. In the rat the main metabolite is the alpha hydroxy
carboxylic acid of propiconazole (Muecke, 1981; 1983).
Comparative TLC studies on urines of propiconazole treated rats
and goats revealed that the goat is using similar metabolic pathways
for the elimination of propiconazole, except that sulfuric acid
conjugation was not evident. The major metabolite in goat urine is
less polar than the major metabolite in rat urine.
The metabolic patterns in milk and liver of the goat were very
similar and many of the individual metabolites are common to those
present in the urine. There is evidence that the alkyl chain between
the triazole and phenyl ring is cleaved and that most metabolites in
milk and liver are associated with the triazole ring. The major
metabolite (about 50%) in milk is 1,2,4-triazole (Madrid & Cassidy,
1981; 1983).
Effects on enzymes and other biochemical parameters
Doses of 0, 20, 80, 160 and 320 mg/kg bw propiconazole were
orally administered to groups of male rats and mice for 2 weeks prior
to a 24-hour food withdrawal and subsequent examination of their
livers for enzymatic activities and protein, DNA, RNA and phospholipid
contents.
At dose levels of 80 mg/kg and greater, microsomal protein,
phospholipid, cytochrome P-450 and the activities for ethoxycoumarin
deethylase, epoxide hydrolase, UDP-glucuronosyltransferase and
gamma-glutamyl transpeptidase were increased in rat livers. For the
mouse a comparable pattern was observed. Cytosolic protein and soluble
gluthathion S-transferase were increased from 160 mg/kg onwards.
Simultaneous proliferation of smooth-surfaced endoplasmic reticulum
was revealed by electron microscopic investigations
(Waechter et al., 1984).
Toxicological studies
Special studies on carcinogenicity (See also under "long term
studies").
The promoting action of propiconazole was studied in one day old
rats. A group of 45 rats/sex received an initiating dose of 15 mg of
N-nitrosodiethylamine (DENA), a known carcinogen, and other groups of
15 rats/sex were placed on a diet containing 2000 ppm propiconazole
(purity 89.7%) or 500 ppm phenobarbital. Similar groups of rats, which
received only the 0.9% saline solvent, were placed on the same diet.
At days 36, 50 and 78, the rats (5/group) were killed, liver sections
were prepared and examined for preneoplastic foci. These foci in liver
sections were identified by histochemical demonstration of GGT
(gamma-glutamyl transpeptidase).
Two thousand ppm propiconazole as well as 500 ppm phenobarbital
led to a significant increase of preneoplastic foci. The reaction was
more pronounced in males. Initiation with DENA resulted in a higher
incidence and a larger size of foci. It was concluded that
propiconazole acted as a promotor in rat liver comparable to
phenobarbital in this respect (Froelich et al., 1984).
Special studies on teratogenicity
Rats
Groups of 25 female albino rats received 0, 30, 100 and 300 mg
propiconazole (purity 91.0%)/kg bw by gavage from day 6-15 of
gestation. All animals were killed on day 21 of pregnancy. The dams
were observed for mortality, food consumption and body weight. The
number of implantations, early and late resorptions and corpora lutea
were recorded. The fetuses, delivered by caesarian section, were
counted and weighed, gross pathology and histopathology (skeletal and
visceral) were recorded.
At 300 mg/kg bw 3 dams died and growth and food consumption were
significantly reduced. No effects were found in the offspring except
for one fetus with hydro-cephalus at 100 mg/kg bw and an increased
total incidence of delayed ossification at the highest dose group. The
delayed ossification at the highest dose level suggests a slight
retardation of physiological growth and was considered to be related
to maternal toxicity (Fritz et al., 1979a).
Groups of 24 Charles River rats received 0, 30, 90, and
360/300 mg technical propiconazole (purity not specified)/kg bw by
gavage from day 6-15 of gestation. (Propiconazole was administered as
a suspension in 3% aqueous cornstarch containing 0.50% Tween 80.) The
high dose level was reduced to 300 mg/kg bw during the first 6 days of
treatment due to severe maternal toxicity. All animals were killed on
day 20 of pregnancy. The dams were observed for clinical signs,
mortality, body weight and food consumption. The number of corpora
lutea, implantations, early and late resorptions were recorded. The
fetuses, delivered by caesarian section, were counted and weighed,
external, visceral and skeletal findings were recorded.
The highest dose of 360/300 mg/kg bw and to a lesser extent also
90 mg/kg bw were maternally toxic as shown by clinical signs
(lethargy, ataxia and salivation and signs of rales, prostration,
hypothermia and bradypnea), decreased body weight gain and food
consumption. No effects were observed in the offspring except for what
the study authors described as a slight delay in the development of
the urinary system (dilated ureters) at the highest dose group and an
increased incidence of rudimentary ribs and non ossified sternebrae at
90 and 360/300 mg/kg bw. Cleft palate was observed in 3 fetuses from
3 litters, one (0.33%) at 90 mg/kg and two (0.7%) at 360/300 mg/kg bw,
respectively. These findings were not statistically significant, even
including one additional fetus at 90 mg/kg bw displaying cleft lip.
This indicates embryotoxicity at maternally toxic dose levels.
According to the authors, the low incidence of cleft palate may be a
consequence of maternal toxicity (Geknis et al., 1987).
In order to determine the reproducibility of the incidence of
cleft palate in the above study an additional study was conducted. A
total of 178 and 189 mated CD rats received 0 and 300 mg
propiconazole/kg bw, respectively, by gavage from day 6-15 of
gestation. All animals were killed on day 20 of gestation. The dams
were observed for clinical signs, mortality, food consumption and body
weight. The number of corpora lutea, implantations, live and dead
fetuses was recorded. The fetuses, delivered by caesarian section,
were sexed, numbered, weighed and examined for external abnormalities
and cleft palate.
Maternal toxicity was observed in dosed dams. Severe signs of
toxicity including ataxia, coma, respiratory difficulties, lethargy,
prostration, ptosis, salivation, palor, lacrimation as well as 4
deaths occurred. Bodyweight, bodyweight gain and food consumption were
decreased. Mean number of viable fetuses and mean fetal weight were
significantly reduced in the treated group.
Cleft palate was observed in 2/2064 (0.1%) fetuses from 2/158
litters in the compound treated group but not in the control group.
This figure is within the range of the frequency observed at
maternally toxic doses in a large number of experiments (0-1.4%)
(Mallows et al., 1987).
Rabbits
Groups of 20 pregnant female chinchilla rabbits were orally
administered daily doses of 0, 30, 90 and 180 mg propiconazole (purity
91.1%)/kg bw from day 6-18 of gestation. All animals were killed on
day 28 of pregnancy. The dams were observed daily, body weight and
food consumption were measured. The number of implantations, early and
late resorptions and corpora lutea were recorded. The fetuses were
counted and weight and external, skeletal and visceral anomalies were
recorded. There were no effects observed on the dams and offspring,
except for sedation in high dosed dams and a reduction in food intake
in dams (Fritz et al., 1979b).
Groups of 19 pregnant New Zealand White rabbits were orally
administered daily doses of 0, 100, 250 and 400 mg propiconazole
(purity not stated)/kg bw from day 7-19 of gestation. (Propiconazole
was administered as a suspension in 3% cornstarch with 0.5% Tween 80.)
All animals were killed on day 29 of pregnancy. The dams were observed
for clinical signs, mortality, body weight and food consumption. The
number of implantations, corpora lutea, early and late resorptions and
live and dead fetuses were recorded. The fetuses, delivered by
caesarean section, were sexed and weighted and examined for external,
visceral and skeletal anomalies. Dams of the high dose group had an
increased incidence of stool variations and abortions/early
deliveries. Decreased feed consumption and body weight gain were
observed at 250 and 400 mg/kg bw and a decreased body weight was
observed at 400 mg/kg. The incidence of resorptions was significantly
increased at 400 mg/kg bw. No effects were found in the offspring
except for a significantly increased incidence of fully formed
thirteenth ribs at 400 mg/kg bw (Giknis, 1986).
Special studies on eye irritation
Propiconazole (0.1 M) was instilled in the left eye of 6 New
Zealand white rabbits (3/6 eyes were rinsed). In unrinsed eyes
24 hours after treatment, corneal irritation (score 1-2) was observed
in 2/3 eyes ands slight conjunctival irritation (score 1) in 1/3 eyes.
Forty eight hours after treatment the corneal irritation was still
present in 1/3 animals. Full recovery was observed after 72 hours. The
substance is minimal irritating. Rinsing immediately after application
alleviated the irritation (Ullmann, 1978b).
Special studies on metabolites
Investigations of the toxicological properties of triazolyl
alanine, a plant metabolite of propiconazole and other triazole
fungicides, demonstrates that triazolyl alanine is virtually nontoxic
in acute, subchronic, mutagenicity and reproduction studies
(Bayer et al., 1986).
Special studies on mutagenicity
Propiconazole was negative in various mutagenicity assays. See
table 1. for a summary of the studies considered.
Special studies on reproduction
Rats
Groups of Tif: RAIf (SPF) albino rats (10 males and 20 females/group)
were fed diets containing 0, 400, 2000 and 5000 ppm propiconazole
(purity 91.9%) and subjected to a two generation reproduction study of
one liter each. F0 rats received the diet from days 28-32 post partum
until weaning of the F1 rats (160 days) and the selected F1 rats until
weaning of the F2 rats. F0 and selected F1 rats were sacrificed after
weaning of F1 and F2 rats, respectively. Not selected F1 rats and F2
rats were sacrificed after weaning (28-30 post partum).
Table 1. Special Studies on the Mutagenicity of propiconazole.
Type of test Test object Concentration Purity Results References
of propiconazole
In vitro
Ames test Salmonella 25 µg upto 83.9% negative Arni &
(with and without typhimurium 2025 µg/0.1 ml (1) Muller,
metabolic activation) TA 98, TA100 in DMSO 1979
TA 1535 and
Ames test Salmonella 20 µg upto 90.7% negative Deparade &
[with and without typhimurium 5120 µg/0.1 ml (1) Arni, 1983
metabolic TA98, TA100, in DMSO
activation (2)] TA 1535,
TA 1537 and
TA 1538
Yeast test Saccharomyces 10, 30, 90 and ? negative Arni &
(with and without cerevisiae D7 270/µg/ml in (1) Muller,
metabolic activation) DMSO; 90 and 1982
270/µg/ml
toxic
(1) positive control yielded positive results
(2) induction of liver enzyme activity with Aroclor 1254 and propiconazole
(3) test results available only in summary form
Table 1. cont.
Type of test Test object Concentration Purity Results References
of propiconazole
In vitro
Mouse lymphoma mouse L 5178Y7.81, 15.62, 90.7% negative Strasser &
forward mutation TK +/- cells 31.25, 62.5 (1) Muller,
assay (with and and 125.0 µg/ml 1982a
without metabolic in DMSO
activation)
Chromosomal human 11.25, 22.5, 89.7 negative Strasser &
aberration test lymphocytes 45.0, 90.0 and (1) Arni, 1984
(with and without 180 µg/ml in
metabolic activation) 1% DMSO
180 µg/ml toxic
DNA repair test rat 0.69, 3.44,17.2 90.7% negative Puri &
hepatocytes & 86 nl/ml in DMSO (1) (3) Muller,
1982b
DNA repair test human 0.077, 0.38, 1.92 90.7% negative Puri &
fibroblasts & 9.6 nl/ml (1) Muller,
in DMSO 1982a
Transformation mouse 1.16, 2.31, 4.63 90.7% negative Strasser &
assay fibroblasts 9.25 & 18.50 µg/ml (1) Muller,
(BALB/3T3) in DMSO 1982c
(1) positive control yielded positive results
(2) induction of liver enzyme activity with Aroclor 1254 and propiconazole
(3) test results available only in summary form
Table 1. cont.
Type of test Test object Concentration Purity Results References
of propiconazole
In vivo
Dominant lethal Tif:MAGf single oral dose 90% negative Hool &
test (SPF) mice of 165 or Muller,
495 mg/kg in 1979
2% CMC
Sister chromatid Chin. hamster single oral dose 90.7% negative Hool &
exchange assay bone marrow of 255, 510 or (1) Muller,
cells 1020 mg/kg in 1982c
arachid oil
Host mediated Salmonella 350, 700 and 90.7% negative Arni &
assay typhimurium 1400 mg/kg in (4) Muller,
TA98, TA100, 2% CMC 1983
TA1535
NMRI mice
Host mediated mouse L 5178Y496 mg/kg, 90.7% negative Strasser &
assay cells orally in Muller,
DBA mice 2% CMC 1982b
(1) positive control yielded positive results
(4) test was carried out with induced and not induced mice (with propiconazole)
Table 1. cont.
Type of test Test object Concentration Purity Results References
of propiconazole
In vivo
Nucleus anomaly Chin. hamster 251, 502 and 90% negative Hool et al.
test bone marrow 1004 mg/kg (1) 1979
cells orally in PEG
twice, 24 hr.
apart
Chromosomal Mouse 166 or 498 mg/kg 90.7% negative Hool &
aberration test spermatogonia orally in 0.5% Muller,
CMC once on days 1982a
0, 1, 2, 3 & 4
Chromosomal Mouse 166 or 498 mg/kg 90.7% negative Hool &
aberration test spermatocytes orally in 0.5% Muller,
CMC once on days 1982b
0, 2, 3, 5 & 9
(1) positive control yielded positive results
(4) test was carried out with induced and not induced mice (with propiconazole)
Observations were made on the general condition and behaviour.
Reproduction parameters such as delivery date, mating and fertility
indices, duration of gestation, implantation rate and general
condition during weaning, litter size, number and percent of live and
dead fetuses, litter and pupweight and abnormalities were recorded.
Autopsy and histopathological examinations were performed on a
selected number of F1 and F2 weanlings and F1 adults.
Bodyweight gain and food consumption was reduced in F0 males at
5000 ppm and in F0 females at 2000 and 5000 ppm. At 5000 ppm all the
pregnant females died shortly before or after birth of the F1
generation. For this reason, the study was discontinued for this
group. The implantation rate in F0 females was significantly reduced
in the 5000 ppm dose group. Body weight gain was reduced in pups of
both the dose groups 400 and 2000 ppm. The reproductive parameters
were not affected. A slight significant increase of the rel. liver
weight accompanied by slight hypertrophy of the centrilobular
hepatocytes was noted in the F1 adults of the 2000 ppm group
(Fritz et al., 1981).
Groups of 15 male and 30 female, 35 days old rats received 0,
100, 500 and 2500 ppm propiconazole (purity 89.7%) in the diet in a
two generation (two litters/ generation) study. Diets were maintained
during mating, gestation and lactation.
Maternal toxicity (significantly decreased, body weight gain and
food consumption) was observed at 2500 ppm and to a lesser extent at
500 ppm. F1 males showed a slightly decreased body weight gain at
2500 ppm. Reproductive observations and performance, expressed in
indices for mating, male and female fertility and gestation were not
affected.
F2a litter size and F2b pup survival (during lactation) were
significantly reduced at 2500 ppm. At day 0, F2b pup weight was
equally but significantly decreased in all dose levels. Pup weight (at
day 4-21) was significantly decreased in F1a, F1b, F2a and F2b pups at
2500 ppm and also in F2b pups at 500 ppm (at day 14-21). A significant
decrease in mean final body weight, brain weight (F1a only) and testes
with epididymus weight was observed in F1a and F2a male pups. F2b pups
exhibited significant reductions in final body weight and F2b female
pups showed a significantly decrease in absolute brain weight. In F0
and F1 females and F1a, F2a and F2b male pups relative brain weight
was significantly increased at 2500 ppm. Other organs (except ovaries)
were not weighed. Gross pathology showed no significant changes. At
2500 and 500 ppm, a statistically significant increase of cellular
swellings of hepatocytes was observed in the liver of both F0, F1b,
F1, F2b male and female rats. The incidence of clear-cell change in
the liver was also significantly increased in male F0 rats and male
and female F1 rats at 2500 and 500 ppm.
The NOAEL in this study is 100 ppm (Salamon et al., 1985).
Special studies on skin irritation
Treatment of the intact and abraded skin of 6 New Zealand white
rabbits with propiconazole produced erythema (score 1-2) and oedema
()score 1) in all animals after after 24, 48 and 72 hours. Full
recovery was observed after 7 days. The compound is slightly
irritating (Ullmann, 1978c).
Special studies on skin sensitization
Propiconazole has no sensitizing potential in the guinea-pig when
tested by Maurer's optimization test (Ullmann, 1979b).
Acute toxicity
The acute toxicity of propiconazole to several animal species is given
in table 2.
Table 2. Acute toxicity of propiconazole in animals
species sex route LD50 LC50 references
(mg/kg bw) (mg/l)
Mouse M&F oral 1490 -- Bathe, 1979a
Rat M&F oral 1517 -- Bathe, 1978
M&F oral 2233* -- Bathe, 1979d
M&F oral 1211** -- Bathe, 1979e
M&F dermal >4000 -- Bathe, 1979b
M&F i.p. 508 -- Bathe, 1979c
Rabbit M&F oral 1344 -- Ullmann, 1978a
M&F dermal >6000 -- Ullmann, 1979a
* Cis-isomer
** Trans-isomer
Short-term toxicity
Rats
Groups of RAIf (SPF) rats (10/sex/group) were orally administered
0, 50, 150 and 450 mg propiconazole (purity 91.6%) in 2% CMC/kg bw for
28 days. All animals were observed daily for mortality and signs of
toxicity while body weight and food consumption were recorded weekly.
Haematology, clinical chemistry and urinalysis were recorded at the
end of the test period on 5 rats/sex. All surviving animals were
killed and a complete gross and histopathological examination was
performed. Selected organs were weighed.
There were no effects on body weight. Food consumption was
decreased in high dosed females and these animals showed sedation,
dyspnoea and ruffled fur during the first week of treatment. One mid
and 2 high dose females died from causes which were not related to
treatment. Haematological changes were generally unremarkable.
Clinical chemistry determinations and urinalysis were within normal
biological variation, except for an increased blood glucose
concentration and a decreased chloride concentration in females at
450 mg/kg bw. A dose-related increase in absolute as well as relative
liver weight was observed in males at 150 and 450 mg/kg bw and in
females at all dose levels. Histopathology revealed minimal to
moderate hypertrophy of hepatocytes in all rats of the 450 mg/kg dose
group and in 4/10 males and 8/10 females of the 150 mg/kg dose. Recent
areas of necrosis were observed in the liver parenchyma in 3/10
females of the highest dose group (Basler et al., 1980).
Groups of Tif:RAIf SPF rats (20/sex/group) were orally
administered 0, 240, 1200 and 6000 ppm propiconazole (purity 90%) in
the diet for three months. All animals were observed daily for
mortality and clinical signs while body weight and food consumption
were observed weekly. Haematology, blood chemistry and urinalysis
examinations were recorded at weeks 4, 8 and 13 on all rats. At the
termination of the study all animals were killed, selected organ
weights and complete gross and histopathological examinations were
performed.
There were no effects on mortality and appearance. A trend to
reduced food consumption was noted in the 6000 ppm group during the
first three weeks. Body weights were significantly decreased in males
and females at 6000 ppm and in females at 1200 ppm. At the highest
dose level Hb, Ht and number of erythrocytes were lower than the
controls, in most cases significantly, after 4, 8 and 13 weeks.
Alkaline phosphatase activity in female rats at the high dose level
was increased and gamma-glutamyl transpeptidase activity was increased
in male and female rats. Urea and total protein were increased at
6000 ppm and a tendency for increased urea was present at 1200 ppm.
Relative brain, liver, testes and ovaries weight were significantly
increased in males and females at 6000 ppm. In high dosed females,
relative heart, kidney and adrenal weight were also increased. At
1200 ppm, relative brain, heart, liver, adrenal and ovaries weight
were significantly increased in females. In the spleen of all high
dosed females a slight increase of haemosiderosis was observed. No
adverse effects were observed at 2140 ppm (Sachsse et al., 1979a).
Groups of RAIf SPF rats (20/sex/group) were exposed by inhalation
to aerosols at 0, 21, 85 and 191 mg technical propiconazole (purity
91.9%)/m3 6 hours/day for 5 days/week for 90 days (head only). No
toxic symptoms or treatment related deaths occurred (2 male control
rats died and 1 female rat of the lowest dose group died). Food
intake, food conversion, opthalmoscopy, haematology and blood
chemistry values were within normal ranges. Mean female body weight
was decreased in all dose groups (significantly in the high and low
dose group)and in males at the 85 mg/m3 dose group. Liver weight was
increased in females at the high dose level. Neither gross nor
histopathological changes were observed in propiconazole exposed rats
(Sachsse et al., 1980a).
Rabbits
New Zealand white rabbits (10/sex/group) received dermal
applications of 0, 200, 1000 and 5000 mg propiconazole (purity
91.9%)/kg bw on the shaven skin of the back. The skin of half the
rabbits, at the exposure site, was abraded prior to, and once weekly
during the experiment. The rabbits were exposed 6 hours/day,
5 days/week for 3 weeks. High and mid dosed rabbits showed dyspnoea,
tremor, ataxia, sedation and ruffled fur starting from day 4. No
compound related effects were observed on mortality, food consumption,
food conversion, haematology and blood chemistry (except for increased
gamma-glutamyl transpeptidase in high dosed males and females). Body
weight was decreased in high dose females and relative liver weight
was significantly increased in males and females. Slight skin
irritation was observed in all treated rabbits. Local dermal changes
showing focal acanthosis and hyperkerntosis of the epidermis and
chronic inflammatory infiltration in the dermis were observed. The
changes were dose related and more pronounced in the highest dose
group. Focal necrosis and ulceration of the epidermis was noted in
4/20 rabbits of the highest dose group (Sachsse et al., 1979b).
Dogs
Beagle dogs (4/sex/group) were administered diet containing
0, 50, 250 and 1250 ppm propiconazole (purity 93%) for three months.
No compound-related effects were observed with respect to mortality,
clinical signs, food consumption, opthalmoscopy, haematology,
urinalysis and blood chemistry (except for an increased activity of
alkaline phosphatase in males and females at 1250 ppm). In females of
the highest dose group, a tendency for a lower body weight gain was
observed. Liver weight was slightly increased in both males and
females at 1250 ppm. In 3/6 dogs of the highest dose group a slightly
increased amount of lymphoid follicules in the mucous membrane of the
stomach was observed. The NOAEL is 250 ppm, equivalent to 7 mg/kg/day
(Sachsse et al., 1980b).
Beagle dogs (5-7/sex/group) were orally administered 0, 5, 50 and
250 ppm propiconazole (purity 90.2%) in the diet for one year.
2 dogs/sex in the control and high dose group were maintained
untreated for a 28 day recovery period. No compound related effects
were reported in any of the tested parameters measured: clinical
signs, mortality body weight, food consumption, haematology, clinical
chemistry, urinalysis, opthalmoscopy, gross and histopathology. Organ
weights were not different than those of control animals except for
significantly increased relative adrenal weight in females of the 50
and 150 ppm dose group (not dose related) and a decreased relative
pituitary weight in males of the highest dose group.
The NOAEL was 250 ppm in the diet, equivalent to 7 mg/kg/bw
(Johnson et al., 1985).
Long term studies
Mice
Groups of 52 male and 52 female mice (CD) were fed diets
containing 0, 100, 500 and 2500 ppm propiconazole (purity 91.9%) for
104 weeks. Satellite groups of 12 male and 12 female mice were fed
diets containing propiconazole at the same dietary levels and
sacrificed after 53 weeks of treatment. Observations included clinical
signs, mortality, body weight, food consumption, food efficiency,
water consumption, haematology, clinical chemistry and urinalysis.
Surviving mice were sacrified after 104 weeks. Organs were weighed and
comprehensive histopathological examinations were made.
During the first 26 weeks mortality was significantly increased
in males at 2500 ppm. At 2500 ppm, growth rate was reduced
significantly throughout the study in male and female mice. In male
mice of the same dose group, food consumption was increased during the
study and during the first 5 months in females. Ht and Hb were
decreased at 2500 ppm in males and females (males only at week 52).
ASAT, ALAT and alkaline phosphatase activity was significantly
increased in males (week 52 and 104) and to a lesser extent in females
(week 52) receiving 2500 ppm. Lower cholesterol levels (statistically
significant in males) were observed at week 52 in mice receiving
2500 ppm and in females of the same dose group at termination of the
study. Liver weight was significantly increased in male and female
mice receiving 2500 ppm and in males (only significantly after
53 weeks) receiving 500 ppm. The gross examination revealed a higher
incidence of liver masses and/or enlarged livers in males and females
receiving 2500 ppm propiconazole. Histological examination showed an
increase in the incidence of benign and malignant liver cell tumors in
males at 2500 ppm (see table 3.). In the male animals a trend was
present for a shorter latency period for the liver tumours, since at
the interim kill (week 53) the incidence of benign liver tumours was
0/11, 0/11, 1/11 and 2/9 for control, 100, 500 and 2500 ppm test
groups, respectively. For malignant tumours, the incidences were 1/11,
0/11, 2/11 and 3/9 respectively. The liver tumour incidence in females
at 2500 ppm appeared marginally increased: 5/52, 1/52, 2/52 and 8/52
for control, 100, 500 and 2500 ppm, test groups, respectively).
The NOAEL for non neoplastic effects was 1000 ppm in the diet,
equivalent to 10.04 mg/kg bw in males and 55.60 mg/kg bw in females
(Hunter et al., 1982b). The NOEL for neoplasia was 500 ppm.
Table 3. Incidence of liver cell tumors in male mice
Occurrence Control 100 ppm 500 ppm 2500 ppm
Animals with 16/51 11/51 12/50 31/52
preneoplastic foci
Animals with liver 12/51 7/51 8/50 21/52
adenomas only
Animals with liver 15/51 7/51 14/50 23/52
carcinomas*
* including animals with both liver adenomas and carcinomas
Rats
Groups of 80 male and 80 female CD Sprague-Dawley rats (of which
50 animals/sex/group were for tumorigenic evaluation and 10
animals/sex/dose for interim kills, 10 animals/sex/dose for
haematology and 10 animals/sex/dose for blood chemistry and
urinalysis) were fed diets containing 0, 100, 500 and 2500 ppm
propiconazole (purity 91.9%) for 107-109 weeks. Observations included
clinical signs, mortality, body weight, food and water consumption,
haematology and urinalysis (10 animals/sex/group), clinical chemistry
(10 animals/sex/group) opthalmoscopy and hearing tests, absolute and
relative organ weight (interim kill and all surviving animals at the
end), gross and histopathology.
At 2500 ppm, propiconazole growth, food consumption and food
efficiency was reduced. The survival of the rats in this dose group
was better (significantly with females), possibly caused by the
decreased food consumption. At 500 ppm, growth and food efficiency was
decreased in females during the first 26 weeks. At 2500 ppm, numerous
changes in haematology (Hb, Ht, MCV and MCH decreased) were observed.
At 2500 ppm, the concentrations of urea and cholesterol, were
increased and of glucose decreased (to a greater extent in females)
and the A/G ratio decreased. At 500 ppm, only in a few cases were
changes observed in haematology and blood chemistry which were
compound related. At interim kill as well as at the termination of the
study, an increased liver weight was observed in males and females at
2500 ppm associated with an increased incidence of foci of enlarged
liver cells in females. At 52 weeks, heart and ovaries weight was
increased in females at 2500 ppm.
No enhanced tumour incidence was observed in treated animals. The
NOAEL was 100 ppm (equal to 3.60 mg/kg males - 4.57 mg/kg females)
(Hunter et al., 1982a).
COMMENTS
After oral administration to mice and rats the compound was
rapidly excreted via the urine and faeces. Excretion was generally
higher in the urine. No unchanged propiconazole was excreted in the
urine. The compound is metabolized by oxidation of the propyl side
chain, cleavage of the dioxolane ring and oxidation of the triazole
and phenyl rings. The alcoholic and phenolic derivatives are excreted
as sulphuric and glucuronic acid conjugates. The compound apparently
induces drug metabolizing enzymes in the liver of rats and mice.
Propiconazole presented low acute toxicity in mice, rats and
hamsters. It did not show any effects on reproductive performance.
Maternal effects decreased pup growth, swelling of liver hepatocytes
and an increased incidence of clear-cell changes in the liver were
seen at 500 ppm and above in a two-generation reproduction study in
rats. In three rat and two rabbit teratogenicity studies, embryonic
effects were found at maternally toxic dose levels, but no teratogenic
effects were observed.
Subchronic administration of propiconazole to rats, rabbits and
dogs revealed body weight reduction and liver changes indicative of
increased metabolic activities with necrosis at relatively high doses
as the main toxicological effects.
Propiconazole was not mutagenic in a battery of mutagenicity
tests.
In long-term studies the same effects were found as in short-term
studies. In the mouse study the highest dose (2500 ppm) was associated
with a significant increase in preneoplastic and neoplastic liver
changes in males only. In the two year feeding study with rats no
indication of carcinogenicity was found. However, propiconazole has
enzyme-inducing properties In a separate study in rats, the effect of
propiconazole on proliferative liver changes, initiated by
N-nitrosodiethylamine, was very similar to that of phenobarbital.
An ADI was allocated for propiconazole, on the basis of the
toxicological data in rat and dog.
The committee noted that application of propiconazole resulted in
residues of triazolylalanine as well as propiconazole. The available
data on propiconazole cannot be used to assess the toxicity of
triazolylalanine since this does not appear to be a metabolite in
animal species other than ruminants. While an ADI has been allocated
for propiconazole, attention is drawn to the need for an evaluation of
triazolylalanine to assess the toxicological significance of this
metabolite.
TOXICOLOGICAL EVALUATION
LEVEL CAUSING NO TOXICOLOGICAL EFFECT
Rat: 100 ppm in the diet, equal to 4 mg/kg bw/day
Dog: 250 ppm in the diet, equivalent to 7 mg/kg bw/day
ESTIMATE OF ACCEPTABLE DAILY INTAKE FOR MAN
0-0.04 mg/kg bw.
STUDIES WHICH WILL PROVIDE INFORMATION VALUABLE IN THE CONTINUED
EVALUATION OF THE COMPOUND
Observations in man.
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