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    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 g upto           83.9%         negative      Arni &
    (with and without        typhimurium         2025 g/0.1 ml                     (1)           Muller,
    metabolic activation)    TA 98, TA100        in DMSO                                          1979
                             TA 1535 and

    Ames test                Salmonella          20 g upto           90.7%         negative      Deparade &
    [with and without        typhimurium         5120 g/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/g/ml in                       (1)           Muller,
    metabolic activation)                        DMSO; 90 and                                     1982
                                                 270/g/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 g/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 g/ml in
    metabolic activation)                        1% DMSO
                                                 180 g/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 g/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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    See Also:
       Toxicological Abbreviations