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    TRIADIMENOL

    EXPLANATION

         Triadimenol has not been reviewed previously by JMPR. It is a
    broad spectrum systemic fungicide consisting of a threo optical
    isomer (isomer A) and an esythro isomer (isomer B).  The ratio of
    isomers was intially 60:40 and is now 80:20 due to a change in the
    manufacturing process.

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    BIOLOGICAL DATA

    Biochemical aspects

    Absorption, distribution and excretion

    Rats

         A study of the absorption, distribution and excretion of 14C
    ring-labelled triadimenol (19.8 mCi/mM) was conducted in
    Sprague-Dawley albino rats (Puhl & Hurley, 1978).  Each of the two
    diastereoisomers of triadimenol were individually examined in the
    study of the pharmacokinetics.  Two male and two females were given
    a dose of 4 mg/kg bw by oral gavage.  The 4 animals were housed in
    glass metabolism cages and urine and feces were collected at 4, 8
    (or at 6 hours for one of the isomers), 12, 24 hours and then daily
    for 6 days.  Expired gases were also collected and analysed. 
    Animals were sacrificed by decapitation and blood was collected. 
    Liver, kidney, heart, brain, muscle, fat and skin were collected and
    analysed for radiolabel.

         A half-life for excretion based on this study is estimated to
    be approximately 24 hours for both males and females for isomer A
    with 55% of radiolabel found in the feces for males and about 36%
    for females.  For isomer  B, approximately 78% of the radiolabel was
    found in the feces for males and about 44% was found in the feces of
    females.  Thus, slightly more radioactivity was excreted in the
    feces by males with both isomers.  About one-half of the radiolabel
    was excreted in the urine by females with both of the isomers.  No
    radioactivity was found in the expired gas.  Absorption and
    distribution was rapid and excretion appeared to be first order. 
    Recovery ranged from 86.4 to 92.0%.  Residues were less than
    0.01 ppm, except in liver (0.01-0.06 ppm).

    Biotransformation

         In a study of metabolism and distribution, isomer A was
    administered by oral gavage to 10 males and 10 females at a dose
    level of 25 mg/kg bw.  Two animals of each sex were sacrificed 1, 2,
    4, 8 and 24 hours after dosing.  Urine and feces were collected from
    all animals at the time of sacrifice.  Animals were sacrificed by
    decapitation and blood, plasma and tissues (as noted above) were
    collected.  Radiolabel was counted and samples were extracted for
    identification of specific metabolites.

         Peak tissue levels were found after 4 hours in females and
    after 1 hour in males.  Levels fell rapidly after achieving peak
    levels.  The greatest amounts of radiolabel were found in the fat,
    liver, skin and kidney with somewhat higher levels present in

    females at all intervals.  The major metabolic pathway was found to
    be hydroxylation of the t-butyl moiety and subsequent oxidation to
    the carboxylic acid.  Oxidation of the hydroxyl of the parent
    compound also occurs to a minor extent.  The metabolic pathway for
    triadimenol is shown in Figure 1. The stereochemical orientation is
    retained throughout metabolism and much more of isomer II is
    excreted unchanged than isomer I.  This selectivity of metabolic
    enzymes for isomer I is more pronounced in males than females,
    probably due to the greater microsomal activity present in rats.

    FIGURE 1

         A dermal absorption study was conducted in Charles River Crl:CD
    rats using 14C ring-labelled triadimenol (15.78 mCi/mM) (Leeling
     et al. 1988).  Twenty-four animals per dose level were dosed with
    either .01, .1, 1 or 10 mg of test material on a 15 cm2 area of
    shaved skin (equivalent to .04 to 40 mg/kg bw).  Test material was
    covered by a gauze patch after application.  Four animals per dose
    level were bled and then sacrificed at 0.5, 1, 2, 4, 8 and 24 hours
    after dosing.  Urine and feces were collected from each animal. 
    Radioactivity was also determined in whole carcass, skin wash and
    excised skin.  Dermal absorption was rapid.  It was estimated that
    50% of test material was likely to be absorbed and that absorption
    was somewhat slower at higher concentrations (with half-lives for
    elimination ranging from 27 hours at the low dose to 86 hours at the
    high dose), suggesting a saturation of transport.

    Toxicological studies

    Acute toxicity

         See Table 1.

         In addition to the acute studies shown in the table above, skin
    and eye irritation studies (Thyssen & Kimmerle, 1976b) and skin
    sensitization studies (Flucke, 1981) were submitted for triadimenol. 
    All were considered to be "negative".  Although no skin irritation
    was observed in either man or the rabbit with 1, 2, 4-triazole, it
    was found to be "strongly irritating" to the eye of the rabbit
    (Thyssen & Kimmerle, 1976b).

    Short-term studies

    Rats

         Groups of 10 albino Wistar II strain rats were exposed by
    inhalation to triadimenol at concentrations averaging 0, 30.39
    (26.8-31.8), 68.03 (61.2-73.0) and 229.71 (201-255) mg/m3 for 6
    hours per day for 3 weeks (Kimmerle, 1976).  Measurements were
    gravimetric and concentrations reported are actual rather than
    nominal.  Control animals were exposed to only the
    ethanol/polyethylene glycol solvent.  No compound-related effect was
    observed on any parameter examined.  The NOAEL was 229.71 mg/m3.


        TABLE 1.  RESULTS OF ACUTE TOXICITY TESTING OF TRIADIMENOL AND METABOLITES

                                                                                                                

      COMPOUND                                                      LD50
    ADMINISTERED             SEX       SPECIES   ROUTE           (mg/kg bw)       REFERENCE

                                                                                                                

    Form A                   M         Rat       oral                579          Flucke, 1979a

    Form B                   M         Rat       oral               5000          Flucke, 1979b

    Forms A/B 60:40          M         Rat       oral                819          Flucke, 1979c
                             M         Rat       oral                897          Flucke, 1979c

    Forms A/B 60:40          M         Rat       oral               1161          Thyssen & Kimmerle, 1976a
                             F         Rat       oral               1105          Thyssen & Kimmerle, 1976a
                             M         Rat       i.p.                367          Thyssen & Kimmerle, 1976a
                             F         Rat       i.p.                352          Thyssen & Kimmerle, 1976a
                             M&F                 dermal            >5000          Thyssen & Kimmerle, 1976a
                             M&F       Rat       inhalation         >305 mg/m3    Thyssen & Kimmerle, 1976a
                                                 (4 hrs)

    Forms A/B 80:20          M         Rat       oral                689          Mihail & Thyssen, 1980
                             M         Rat       oral                752          Mihail & Thyssen, 1980
                             M         Rat       oral               1098          Mihail & Thyssen, 1980
                             F         Rat       oral               1037          Mihail & Thyssen, 1980
                             M         Rat       i.p.                371          Mihail & Thyssen, 1980
                             F         Rat       i.p.                286          Mihail & Thyssen, 1980
                             M&F       Rat       dermal            >5000          Mihail & Thyssen, 1980
                             M&F       Rat       inhalation        >1557 mg/m3    Mihail & Thyssen, 1980
                                                 (1 hour)
                                                                                                                

    TABLE 1 (contd.)

                                                                                                                

      COMPOUND                                                      LD50
    ADMINISTERED             SEX       SPECIES   ROUTE           (mg/kg bw)       REFERENCE

                                                                                                                

    Rat, inhalation          M&F       Rat       inhalation         >954 mg/m3    Mihail & Thyssen, 1980

    Metabolite               M         Rat       oral              >1000          Heimann, 1985a

    KWG 1640 N               F         Rat       oral              >1000          Heimann, 1985a

    Metabolite               M         Rat       oral              >5000          Heimann, 1985b
    KWG 1342 N               F         Rat       oral              >1000          Heimann, 1985b

    Metabolite               M         Rat       oral              >5000          Heimann, 1985c
    KWG 1323 N               F         Rat       oral              >5000          Heimann, 1985c

    1,2,4-triazole           M         Rat       oral               1650          Thyssen & Kimmerle, 1976b
                             F         Rat       oral               1648          Thyssen & Kimmerle, 1976b
                             M         Rat       dermal             4200          Thyssen & Kimmerle, 1976b
                             F         Rat       dermal             3129          Thyssen & Kimmerle, 1976b
                                                                                                                
    

         Two subchronic rat studies of 90 days duration have been
    conducted.  In the first, fifteen SPF Wistar rats per sex/dose were
    fed diets containing either 150, 600 or 2400 ppm of triadimenol
    technical (98% purity, A:B = 60:40) for 90 days (Löser & Kaliner,
    1977).  Thirty male and 30 female animals were fed control diet. 
    The rats were 28 to 32 days old at the start of the study.

         One female rat in the mid-dose group died during the course of
    the study.  There was no compound-related effect on physical
    appearance or behaviour or food consumption.  Body weights of high
    dose males and females were slightly but significantly depressed
    during the course of the study.  Several changes in hematology
    parameters were significantly different at 2400 ppm: lower
    hematocrit percent volume in females at one month, lower MCH and MCV
    in males at 3 months, lower HCT in females at 3 months and a lower
    hematrocrit percent volume in females at 3 months.  Other hematology
    and clinical chemistry and urinalysis findings were considered by
    the authors to not be related to treatments.  Absolute liver weights
    of high dose males and females were elevated as were kidney and
    ovary weights in high dose females. No histopathological changes
    were considered to be related to test compound administration.  The
    NOAEL in this study was 600 ppm.

         In the second 90 day rat study, Crj:CD rats obtained from
    Charles River, Japan, were fed diets containing either 0, 120, 600
    or 3000 ppm triadimenol technical (94% purity, A:B = 80:20) for 90
    days  (Nishimura & Nobuo, 1983).  Twenty males and 20 females were
    used at each dose level.  Dose levels corresponded to 89.0, 39.6 and
    208.5 mg/kg bw/day for males and 9.4, 46.4 and 221.1 mg/kg bw/day
    based on food consumption measurements.

         Piloerection and depilitation were observed at the high dose
    level early in the study, no compound-related clinical observations
    were noted in other groups or after the first month in the high dose
    group.  Body weight and food consumption were decreased only at the
    high dose level.  Urinalysis findings were unremarkable. 
    Significant decreases in hematocrit, hemoglobin and platelet counts
    were noted in high dose males and females.  Significantly lower
    reticulocyte counts were noted in the mid and high dose groups of
    both sexes.  Because there were not corresponding histological
    changes in the spleen and bone marrow, these findings were judged
    not to be compound-related.  Several parameters suggestive of
    hepatotoxicity were affected at the highest dose level in this study
    - eosinophilic degeneration of hepatocytes, fatty changes and
    changes in triglycerides, free fatty acids, total cholesterol,
    phospholipid, total protein, A/G ratio and albumin.  The fatty
    changes were observed primarily in the central to midzonal region in
    male animals and in the peripheral region in female animals. 
    Increased absolute and relative liver weights were observed at both
    the mid and high dose levels in both sexes.  Several rats at both
    dose levels had livers diagnosed as hypertrophic or as having a

    "pronounced lobular pattern".  Other changes in histology and in
    other parameters were not considered to be compound-related.  The
    NOAEL was 120 ppm, equal to 8.0 for males and 9.4 for females for
    this study.

         In a comparison of the short-term toxicity of two ratios of
    isomers, 20 SPF Wistar albino rats/sex/dose were given by oral
    intubation either 0, 15, 45 or 100 mg/kg bw/day of 80:20 (A:B) or 45
    or 100 mg/kg bw/day of 60:40 (A:B) for 4 weeks (Mihail & Vogel,
    1981).  One half of each group was sacrificed at the end of 4 weeks
    and one half was observed for an additional 4-week recovery phase. 
    Liver enzymes (N- and O- demethylases and cytochrome P-450) were
    determined at sacrifice.

         All treated groups except those receiving 15 mg/kg bw/day
    exhibited slightly increased CNS activity after administration of
    test compound which lasted for approximately 2 hours after dosing. 
    The only other compound-related effects were on cytochrome P-450 and
    N- and O-demethylase.  Each of the induced enzymes returned to
    control levels by the end of the recovery period.  N-demethylase was
    induced to a slightly greater extent by the 80:20 mixture,
    cytochrome P-450 was slightly more induced by the 60:40 mixture. 
    There were no important toxicological differences between the
    mixtures.

         In a 4 week rat study, 20 male and 20 female Wistar II strain
    albino rats were dosed by gavage with either 0, 1.5, 5, 15 or
    45 mg/kg bw/day of technical material (98.5%) (Thyssen & Kaliner,
    1976).  One half of the animals in each group was kept under
    observation for an additional 28 days before sacrifice.

         No mortalities occurred and no compound-related behavioural
    effects were noted.  Body weights were similar in all groups.  No
    compound-related effects on clinical chemistry, hematology,
    urinalysis, organ weight, gross or histopathology were observed. 
    Absolute and relative thyroid weights (male and female combined)
    were significantly increased at 28 days but returned to normal at 56
    days.  The NOAEL was found to be 45 mg/kg bw/day (the highest dose
    tested) in this study.

    Rabbits

         Groups of 6 New Zealand rabbits were exposed dermally for 6
    hours to either 0, 50 or 250 mg/kg bw/day of test material (98%
    purity) (Heimann & Schilde, 1984).  Skin was clipped for all animals
    and abraded for 3 animals per sex/dose prior to treatment.  Material
    was applied dissolved in distilled water with cremophor as an
    emulsifier for 15 consecutive days.  There were no indications of
    topical or systemic effects which appeared to be compound-related. 
    The NOAEL was therefore 250 mg/kg bw/day.

    Dogs

         The first of three short-term toxicity studies in the dog was
    conducted utilizing 4 male and 4 female beagle dogs per dose level
    (Hoffmann & Kaliner, 1977).  Dogs were fed diet containing either 0,
    150, 600 or 2400 ppm of triadimenol technical (98.5% purity, A:B =
    60:40) for 13 weeks.  At the start of the study, the animals weighed
    between 6.9 and 9.5 kg and were between 24 and 30 weeks old.

         No mortalities were observed during the course of the study. 
    Occasional vomiting was observed after administration of the test
    compound, no other clinical observations appeared to be
    compound-related.  There were no effects on reflexes, body
    temperature, pulse or ophthalmology.  There were no marked
    differences between control animals and treated regarding water or
    food intake.  There was a slight depression of body weight gain in
    both male and female groups at the high dose level compared to
    control groups.  Differences in hematological parameters between
    groups did not appear to be compound-related.  Several enzymatic
    effects were as a consequence of test compound administration.  GPT
    levels were increased in a number of dogs in the mid and high dose
    groups at the 6 and 13 week measurements.  AP levels were generally
    higher than controls in all treated groups both at the intermediate
    and final measurements.  Plasma cholesterol levels were also higher
    in the mid and high dose groups both at the intermediate and final
    measurements.  Cytochrome P-450 and N-demethylase were elevated only
    in the high dose group.  Relative liver weights were increased in
    both males and females at the high dose level.  Absolute kidney
    weights were also elevated in males at the high dose.  No
    histological changes were observed that were attributable to
    treatment.  The NOAEL was 600 ppm (equivalent to 45 mg/kg bw/day).

         Purebred beagle dogs 32 to 36 weeks old and 7.5 to 12.5 kg in
    weight, were randomized and divided in groups of 4 dogs/sex/dose
    level and administered either 0, 150, 600 or 2400 ppm of triadimenol
    technical (95% purity, A:B = 60:40) via the diet for 104 weeks
    (Hoffmann & Vogel, 1984).

         One female was sacrificed in moribund condition (in the high
    dose group) during the course of the study but this was not
    attributed to treatment.  Clinical observations, tests of reflexes,
    ophthalmoscopic observations, body weights and food intake were not
    affected by treatment.  However, body weights of all treated groups
    were consistently lower than the control groups.  This was
    attributed to the unusually great body weight gain in both male and
    female control groups.  Hematological parameters that were examined
    differed randomly and no effect of test compound was evident. 
    Elevated AP activity was noted in 4 high dose animals over the
    course of the study.  Slightly increased N-demethylase and
    cytochrome P-450 were noted in the high dose group.  Urinalysis
    findings were similar in all groups. Organ weights were not affected

    by treatment.  No gross or histological findings were attributed to
    treatment.  A NOAEL cannot be established in this study due to an
    apparent decrease in body weight gain in all treated groups.

         A third feeding study in the dog was conducted using 6
    animals/sex/dose (Hoffmann, 1984).  The study was of 6 months'
    duration and used dose levels of 90, 10, 30 and 100 ppm (purity
    98.0%, A:B = 80:20).  Parameters examined were identical to those in
    the study discussed above with the exception of histology, for which
    no examination took place.  No effects were attributed to test
    compound at the highest dose tested (equivalent to 7.5 mg/kg bw).

    Long-term/carcinogenicity studies

    Mice

         Strain CF1/W 74 mice were administered triadimenol (A:B = 80%
    premix) for 24 months in a combined oncogenicity/long-term toxicity
    study (Bomhard & Löser, 1982).  A total of 50 mice/sex/dose level
    were fed diet containing either 0, 125, 500 or 2000 ppm of technical
    triadimenol (95% purity) starting at 5 to 6 weeks of age.  Animals
    were examined daily, and were weighed weekly for the first 15 weeks
    and every 3 weeks thereafter.  Food consumption and concentration of
    test compound was measured regularly.  Clinical chemistry
    measurements and hematological measurements were conducted at 0, 12
    and 24 months.  Gross pathological examination was conducted on all
    animals dying or sacrificed.  Heart, lungs, liver, spleen, kidney
    and testicles were weighed.  In addition to the weighed organs,
    brain, pituitary, thyroid, adrenals, stomach, pancreas, urinary
    bladder, ovaries and uterus, femur with skeletal muscle and nerve
    were fixed, stained and examined histopathologically for all
    animals.

         Actual doses, based on food consumption measurements, were 30,
    140 and 620 mg/kg bw/day for male mice and 50, 200 and 810 mg/kg
    bw/day for female mice.  Transient depressions of body weight gain
    were observed in the low dose group.  Consistent depression of body
    weight gain was observed in males and females of both the mid and
    high dose groups with the extent of depression somewhat greater in
    male than in female mice.  No group showed any apparent signs of
    toxicity.  Mortality was similar in all groups and ranged from 20 to
    32% at 18 months and 62 to 78% at 24 months.  Hematological
    parameters did not appear to be affected by treatment. 
    Significantly elevated GOT was observed in male mice at the high
    dose level and in female groups receiving test compound at 12
    months.  GPT was elevated and cholesterol depressed for the high
    dose levels of both sexes at 12 months.  SAP was elevated for mid-
    and high dose male animals and total protein was depressed at the
    interim measurement. At 24 months, GPT was slightly elevated in the
    low dose and significantly elevated in the mid- and high dose levels
    of both sexes. GOT was elevated in all treated groups, significantly

    in low and high dose males and in mid- and high dose females.  Other
    clinical chemistry changes were not considered to be toxicologically
    significant.

         Organ weights were similar between groups with the exception of
    liver weights, which were elevated in both sexes at the high dose
    level.  Females at the high dose level had a slightly increased
    incidence of hyperplastic nodules (7 compared to 2 in the control
    group) and there were more hyperplasias of the liver in high dose
    males (5) than in the control group (2).  No increase was observed
    in total tumour incidence or the number of tumour-bearing animals. 
    A significantly higher incidence of liver adenomas was observed in
    high dose females (6 adenomas compared to 0 adenomas and 1
    adenocarcinoma in the control group).  No liver tumours were noted
    in the low dose and 4 adenomas and 1 adenocarcinoma were observed in
    the mid dose group.  This corresponds to an incidence of 2.3, 0,
    10.4 and 12.3% for the 0, 125, 500 and 2000 ppm groups,
    respectively.  A higher incidence of thyroid cysts was noted in the
    high dose males dying during the course of the study (5) than in
    controls or in any other treated group (2 per group).  Two
    nonepithelial carcinosarcomas (a relatively rare tumour) were
    observed in high dose males.  The incidence of other neoplastic and
    non-neoplastic findings were similar in all groups.  Aspartate
    aminotransferase (GOT) was elevated in all treated groups and the
    increased incidence of liver tumours in mid and high dose females,
    both of which appear to be compound-related.  A NOAEL could not be
    established for this study.

    Rats

         SPF rats of the strain BOR:WISW were administered test compound
    (94.9% purity, A:B = 60:40) in the diet for 24 months at dose levels
    of either 0, 125, 500 or 2000 ppm (Krötlinger  et al. 1982).  Each
    dose level consisted of 60 males and 60 females.  All animals were
    observed daily.  Body weights were recorded weekly until week 26;
    afterwards, they were recorded every two weeks.  Food consumption
    was measured weekly.  Urinalysis, hematology and clinical chemistry
    measurements were conducted on 10 males and 10 females per dose
    level at 3, 6, 12 and 24 months.  All animals were examined grossly. 
    Thyroid, heart, lungs, liver, spleen, kidneys, adrenals, testes and
    ovaries were weighed.  In addition to the above tissues, the
    following were examined microscopically for all animals: aorta,
    eyes, intestine, femur, muscle, nerve, brain, urinary bladder,
    pituitary, lymph nodes, stomach, spleen, epididymides, adrenals,
    seminal vesicles, sternum, trachea and uterus.  All grossly
    remarkable tissues were examined histologically.

         Survival during the course of the study was good with only 13%
    to 30% mortality by the end of 24 months.  Body weights of both
    males and females at the high dose level were depressed during most
    of the study compared to the respective control groups.  Test

    compound intake, taking into account food consumption, averaged 7,
    25 and 105 mg/kg bw/day for males and 9, 35 and 144 mg/kg bw/day for
    females.  Although RBC counts were low for the high dose females and
    males compared to the controls, the study authors noted that these
    were within the physiologically normal range. Other hematological
    parameters were similar in treated and control animals.  GOT and GPT
    were generally elevated in both males and females in the mid and
    high dose levels during the course of the study.  A slight elevation
    in these parameters was observed in the low dose level animals
    throughout the study which did not achieve statistical significance. 
    SAP was elevated only at the 12 month measurement in high dose
    females.  Other clinical chemistry parameters were not considered to
    be affected by treatment.  Both absolute and relative liver weights
    were elevated in high dose females.  Although both relative and
    absolute ovarian weight was decreased in high dose females, these
    and other organ weight changes (except for liver) were considered
    random or the consequence of lower body weights in the high dose
    group.

         No gross pathological observations were noted that appeared to
    be attributable to test compound.  The most common tumour types were
    pituitary and thyroid adenomas, adrenal pheochromocytomas, Leydig
    cell tumours and uterine adenocarcinomas.  No tumour type appeared
    to be compound-related.  The total number of tumours and the total
    number of malignant tumours was similar in each group.  No
    non-neoplastic histopathological findings could be attributed to
    treatment.  The NOAEL was 125 ppm, equal to 7 mg/kg bw in males and
    9 mg/kg bw in females.

    Reproduction studies

    Rats

         A two-generation reproduction study was conducted in strain
    BOR: WISW SPF rats (Löser & Eiben, 1984). Ten males and 20 females
    were fed test compound (97.5% purity, A:B = 80:20) for 100 days
    prior to the first mating at dose levels of 0, 20, 100 and 500 ppm. 
    Animals were weighed at weekly intervals before and after mating. 
    F0 animals were weighed at 3-day intervals during mating.  F1b
    females were weighed 1, 6, 15 and 20 days after insemination. 
    Animals were caged together for 5 days during mating and vaginal
    smears were taken daily.  The F1b litter was used to produce the
    second generation.  The F1a, F2a and F2b pups were lactated for 4
    weeks after birth and sacrificed.  Fertility, gestation, viability,
    lactation and insemination indexes were calculated.  Animals dying
    during the course of the study and F2b pups and F1b parents were
    grossly examined after sacrifice.  The F1b parents had the
    following organs weighed:  liver, kidney, testicle and ovary. 
    Histopathological examination was conducted on tissues from the high
    dose and control groups of F1b parents and 10 F2b male and 10 F2b
    females.

         Behaviour and mortality were not affected by treatment.  Mean
    group body weights were similar at all dose levels in the F0
    generation but were depressed in the high dose level parental
    animals of the F1b group and in F2a pups. Food consumption was also
    slightly less for this group.  There were no significant differences
    between groups with regard to food intake.  The fertility index,
    mean litter size, lactation index, viability and insemination
    indexes were not affected by treatment.  The mean birth weight was
    significantly decreased in the high dose pups F1b generation but no
    effect on birth weight was observed in the first litter or in either
    litter of the second generation.  No apparent compound-related
    toxicity was observed in any autopsied animals.  There were no
    histopathological changes which appeared to be related to treatment. 
    No toxicologically significant organ weight changes were found.  The
    No Observed Effect Level was 125 ppm (equal to 5 mg/kg bw/day).

    Special studies on central nervous system effects

    Mice

         A study to investigate the central nervous system effects of
    triadimenol was undertaken (Polacek, 1983).  Test compound (98%
    purity) was administered by a single gavage dose at levels of 0, 3
    or 3.75, 15.0 and 60.0 mg/kg bw (except as noted below). 
    Hexobarbital sodium was administered to 10 mice per dose level 60
    minutes after test compound.  Mean time to anesthesia was
    calculated.  Examination of spontaneous motility was assessed by
    administering test compound by gavage to 6 mice per dose level
    (including dose levels of 1.0 and 4.0 mg/kg bw in addition to those
    noted above) and recording motility every 5 minutes for 25 minutes. 
    Behaviour was assessed in mice by administering test compound
    (including a dose level of 1.0 mg/kg bw) to 3 mice per dose to mice
    which had been given glucose solution rather than food pellets the
    previous night.  Behavioural characteristics were assessed 30, 60
    and 180 minutes after dosing.  An "open field" test was conducted by
    treating 10 mice with 2.5 mg amphetamine/kg bw 15 minutes after they
    had received the test substance.  Movement was quantitated after 30,
    60 and 120 minutes.  Finally, 5 mice were treated with reserpine
    (5 mg/kg bw i.p.) and administered test compound 3 hours later. 
    Spontaneous activity and ptosis were assessed.

         Triadimenol was found to potentiate hexabarbital anesthesia in
    mice at all dose levels.  Increased spontaneous motility was
    observed with test compound alone at all dose levels except
    1.9 mg/kg bw.  Results were comparable between test compound and
    caffeine with respect to increased motility at a given dose level. 
    Dose levels of 3.0 mg/kg bw was found to increase irritability and
    12 mg/kg increased alertness, spontaneous activity and escape
    response.  The "open field-2 test found increased motor activity at
    dose levels of 15 mg/kg bw and greater.  The NOAEL was 3.75 mg/kg bw

    for this test.  Antagonism of reserpine was observed at doses of
    12 mg/kg bw and greater.

    Rats

         As part of the study discussed above (Polacek, 1983), a "novel
    box" behavioural test was conducted by dosing 10 rats with test
    substance (at dose levels of 0, 3, 12 and 48 mg/kg bw) and observing
    behaviour from 15 to 50 minutes.  A dose of 48 mg/kg bw/day induced
    CNS stimulation in the rat in the "novel box" test.  The NOAEL was
    12 mg/kg bw.

    Special studies on metabolites

         Short-term and teratology studies of the triadimenol metabolite
    1,2,4-triazole are available (in addition to acute studies, see
    above).

         In the short-term study, 15 male and 15 female Wistar strain
    rats received either 0, 100, 500 or 2500 ppm of 1,2,4-triazole in
    the diet for 90 days (Bomhard  et al. 1979).  Lower body weights
    and convulsions were observed in both sexes dosed at 2500 ppm. 
    Decreased hemoglobin, hematocrit, MCV and MCH were observed in males
    dosed at 2500 ppm at the study termination.  Several high dose males
    exhibited centro-lobular fat infiltration of the liver parenchyma
    cells.  The NOAEL was determined to be 500 ppm.

         In the first teratology study, three groups of 25 Wistar rats
    each received either 0, 100 or 200 mg/kg bw/day of 1,2,4-triazole by
    oral gavage on days 6-15 of pregnancy (Renhof, 1988a).  Body weight,
    food consumption and behavioural signs were recorded for dams during
    pregnancy.  Fetuses were delivered on day 20 of gestation and were
    examined for visceral, skeletal and external abnormalities.

         The weight gain of dams dosed at 200 mg/kg bw was significantly
    inhibited during and after dosing.  At the 100 mg/kg bw dose level,
    the incidence of fetuses with what were described as "slight bone
    deviations" was increased, mean fetal weights were decreased and the
    number of runts per litter was increased.  An increase was found in
    the number of pups with undescended testicles (11 pups from 7
    litters compared to 2 pups from 2 litters in the control group).  At
    200 mg/kg bw, increases of resorptions and malformations were noted. 
    Malformations that appeared to be related to test compound included
    hydronephrosis, cleft palate long bone dysplasia.  Six fetuses were
    noted to have undescended testicle in this group.  A NOAEL was not
    established in this study for embryo/ fetotoxicity.  The NOAEL for
    maternal toxicity was 100 mg/kg.

         In a summary report for the second teratology study, it was
    indicated that 25 Wistar rats per group received either 0, 10, 30 or
    100 mg/kg bw/day by oral gavage on days 6 through 15 of gestation

    (Renhof, 1988b).  Parameters that were examined were identical to
    the previous study.

         Weight gain in the 100 mg/kg bw/day dams was less than other
    groups.  There was a decrease in fetal weight in this group and a
    higher incidence of runts. There appeared to be no increase in
    malformations or anomalies in any groups.  The NOEL for maternal and
    developmental toxicity was 30 mg/kg.

    Special studies on mutagenicity

         A variety of mutagenicity assays have been conducted with
    triadimenol using both  in vivo and  in vitro systems.  With the
    exception of a Sister Chromatid Exchange assay which could not be
    replicated, all assays were negative.

    Special studies on teratology

    Rat

         In a summary report, no embryotoxicity or teratogenicity were
    noted at dose levels of 10 or 30 mg/kg bw (A:B = 80:20, 95.2%
    purity) administered by gavage to 25 strain BAY:FB 30 rats. 
    Maternal toxicity was reported at the highest dose level in the form
    of decreased body weight gain (Renhof, 1984).

         A range-finding study was conducted using Wistar/HAN rats
    (Becker  et al. 1986a).  Five rats were dosed at either 0, 10, 50
    or 150 g/kg bw/day on days 6 through 15 of gestation.  Animals were
    sacrificed on day 21.  No maternal mortalities or signs and symptoms
    of toxicity were reported.  Body weight gain was clearly decreased
    at the high dose level during and after treatment.  Body weight gain
    in other treated groups was similar to, or slightly greater than, in
    control animals.  A high rate of post-implantation loss (41.5%) was
    observed at the high dose level.  No external malformations were
    observed in any group and fetal body weights were decreased only in
    the high dose level compared to controls.

         In the primary study, groups of Wistar/HAN rats were
    administered technical triadimenol by gavage on days 6 through 15
    post-coitum at dose levels of 0, 30, 60 and 120 mg/kg bw/day (Becker
     et al. 1987a). Test material (purity 97.0%, A:B = 80:20) was
    administered in distilled water with 0.5 cremophor EL as an
    emulsifier.  A total of 24, 25, 23 and 23 dams were utilized for the
    0, 30, 60 and 120 mg/kg groups.  Rats had been naturally mated until
    a positive vaginal smear or a post-copulation plug was observed and
    that day was designated as day 0 post-coitum.  Body weights were
    recorded daily, food consumption on days 6, 11, 16 and 21, and
    clinical observations at least twice daily.  All animals were
    sacrificed by CO2 asphyxiation on day 21 and the fetuses delivered


        TABLE 2.  MUTAGENICITY STUDIES ON TRIADIMENOL

                                                                                                                               
                                                          CONCENTRATION
    TEST SYSTEM             TEST OBJECT                   OF TRIADIMENOL        PURITY    RESULTS      REFERENCE
                                                                                                                               

    Lymphoma forward        Mouse L5178Y cells            3.91-150 ug/ml        97.5%     Negative     Cifone, 1982
    mutation assay (*)

    Gene mutation (*)       E. coli pol. A+, pol. A-      62.5-1000 ug/plate    97.5%     Negative     Herbold, 1981

    Ames (*)                S. typhimurium TA98,          4-2500 ug/plate       93.7%     Negative     Herbold, 1979b
                            TA100, TA1535, TA1537

    Dominant lethal         Mice                          500 mg/kg             93.7%     Negative     Herbold, 1978a

    Micronucleus            Mice (NMRI bone marrow        2 x 350 mg/kg         93.7%     Negativeq    Herbold, 1978b
                            cells)                        2 x 175 mg/kg

    Micronucleus            Mice (NMRI bone marrow        2 x 500 mg/kg         96.5%     Negative     Herbold, 1979a
                            cells)                        2 x 350 mg/kg

    Unscheduled DNA         Rat hepatocytes               .25-50 ug/ml          97.5%     Negative     Myhr, 1982
    synthesis

    Sister chromatid        Chinese hamster ovary         38-225 ug/ml          93        Negative     Putman, 1987
    exchange                cells

    Sister chromatid        Chinese hamster ovary         300 ug/ml             93        Equiv/Neg.   Putman, 1982
    exchange                cells

    Rec-assay               Bacillus subtilis             .05-10 mg/disk                  Negative     Tanahashi & Miriya
                            NIG 45, 17                                                                 1982
                                                                                                                               

    (*)  With and without metabolic activation.
    

    by cesarian section.  Gross pathological examination was conducted
    on all dams, the uterine examined and corpora lutea and resorptions
    were counted.  All fetuses were weighed, sexed, and examined
    grossly.  One half of the fetuses were examined viscerally and the
    remaining fetuses were cleared, stained and examined for skeletal
    abnormalities.

         No maternal deaths occurred during the course of the study. 
    The only clinical observation was a bloody vagina in one female of
    the high dose group.  No abnormal findings were noted in dams upon
    necropsy.  Mean body weights of treated groups were somewhat less
    than the control groups at all times, including prior to dosing. 
    Body weights were significantly less at dose levels of 60 and
    120 mg/kg than controls from day 7 (at 120 mg/kg) or day 8 (at
    60 mg/kg) until day 18.  Food consumption was significantly reduced
    in all groups receiving test compound from day 6 to day 11.  Reduced
    food consumption continued to be evident in groups 3 and 4 until
    study termination.  Numbers of live fetuses, fetal weights, sex
    ratios were similar at all dose levels.  The number of embryonic
    resorptions was increased at the high dose level (11.1% of total
    implants compared to 5.9, 5.3 and 6.6% in the 0, 30 and 60 mg/kg
    dose levels).

         A variety of skeletal abnormalities were observed with an
    elevated, but not dose-related, incidence in each treated group
    compared to controls.  A total of 5 fetuses (3.4%) from 4 litters
    were affected in the control, 10 fetuses (6.6%) from 8 litters in
    the low dose group, 16 fetuses (11.5%) from 12 litters in the
    mid-dose group and 9 fetuses (6.7%) from 7 litters in the high dose. 
    Findings consisted primarily of abnormal ossification and
    dumb-bell-shaped vertebrae.  One case of hydrocephalus was observed
    in both the control and low dose groups. One fetus evidenced
    kyphosis and one multiple defects in the low dose group.  No
    malformations were observed in the mid or high dose groups.  The
    rate of skeletal malformations and/or anomalies was 0.99% in the
    historical control population of 8492 (time period not specified). 
    The NOAEL for maternal toxicity was 30 mg/kg bw based on reduced
    food consumption and body weight gain at 60 and 120 mg/kg bw and
    that the test compound did not reveal a teratogenic or embryotoxic
    potential up to and including the highest dose tested.

         In another rat teratology study, Long Evans FB 30 rats were
    administered either 0, 10, 30 or 100 mg/kg bw (purity 93.7%, A:B =
    60:40) by gavage on days 6 through 15 of gestation (Machemer, 1977). 
    Animals were naturally mated and the day that a positive vaginal
    smear was found was considered to be day 0 of gestation.  Twenty
    animals at each dose level delivered litters for evaluation. 
    Animals were weighed during the treatment period and at the end of
    gestation. Dams were examined at unspecified intervals.  On day 20,
    dams were sacrificed, the uterus examined and the fetuses and
    litters were weighed.  One-third of the fetuses at each dose level

    were viscerally sectioned using the method of Wilson, two-thirds of
    the fetuses were examined for skeletal abnormalities.  All fetuses
    were examined externally for malformations.

         No compound-related effects on the appearance of the dams were
    reported.  No mortalities occurred.  Weight gain was reported to be
    significantly depressed during the treatment period although
    individual data was not presented.  A significant decrease in the
    number of implantations was noted in the low dose group when
    compared to controls, no effect was observed at other dose levels. 
    Four malformations in 3 litters were noted in the control group, 5
    malformations in 2 litters in the low dose and 13 malformations in 3
    litters was noted in the mid dose group.  No malformations were
    reported in the high dose group.  Although data were not reported
    for individual fetuses and neither group nor individual specific
    variations were identified, the NOAEL for embryo/fetal toxicity
    appeared to be 100 mg/kg bw and the NOAEL for maternal toxicity was
    30 mg/kg bw based on decreased weight gain throughout gestation.

    Rabbits

         A range-finding study was conducted in Chinchilla hybrid
    rabbits (Becker  et al. 1986a).  Dams were administered either 0,
    50, 150 or 300 mg/kg bw of technical triadimenol (purity 97.0%, A:B
    = 80:20) on days 6 through 18 post-coitum (3 per dose level for all
    groups although only one rabbit at the high dose level delivered
    live fetuses).  One dam died at high dose level.  Salivation,
    dyspnea and abnormal posture were observed in dams at the high dose
    level.  Slight decreases in body weight gain and food consumption
    were noted in the low and mid dose levels (although not
    dose-related).  Weight loss was noted at the high dose level.  Total
    post-implantation loss was noted in one of the two surviving dams at
    the high dose.  One malformed dead fetus was found upon external
    examination of the uterine contents from a dam at the 150 mg/kg bw
    dose level.  Visceral and skeletal examinations were not conducted.

         In the primary rabbit teratology study, groups of Chinchilla
    hybrid rabbits were administered by daily gavage either 0, 8, 40 of
    200 mg/kg bw triadimenol technical (97% purity, A:B = 80:20) in
    water with 0.5% cremophor as an emulsifier on days 6 through 18
    post-coitum (Becker  et al. 1986b).  Rabbits had been naturally
    mated and the day mating was observed was recorded as day 0
    post-coitum.  A total of 16 pregnant rabbits served as the control
    population and 15 rabbits in each of the remaining groups.  All
    animals were weighed daily, food consumption was measured on days 6,
    11, 15, 19, 24 and 28.  Clinical observations were recorded at least
    twice daily.  On day 28 of gestation, all rabbits were sacrificed
    and fetuses delivered by Cesarean section.  All fetuses were
    examined externally, viscerally and cleared, stained and examined
    for skeletal anomalies.  Dams were subject to gross pathologic

    examination, the uteri weighed and numbers of corpora lutea and
    resorptions were recorded.

         Maternal toxicity was observed at 200 mg/kg bw in the form of
    CNS stimulation one-half hour to 6 hours after dosing, local areas
    of hair loss, decreased food consumption and body weight gain. 
    There were no mortalities in any group. A marginal decrease in body
    weight gain was observed at 40 mg/kg day.  No other effects
    attributed to test compound were noted at this dose level or at
    8 mg/kg bw.

         Post-implantation loss was elevated at 200 mg/kg bw with the
    percentage of resorptions increasing from 3.8% per dam in the
    control population to 12.8% in the 200 mg/kg bw group.  Slight
    reductions were observed in group mean body weight and litter mean
    body weight in the high dose group.  No malformations or anomalies
    were observed in the control fetuses.  A total of 3 fetuses from 3
    litters, 2 fetuses from the same litter and 7 fetuses from 7 litters
    were diagnosed with a variety of developmental abnormalities,
    consisting primarily of ossification defects in the sternebrae and
    vertebrae.   The NOAEL for maternal toxicity was 8 mg/kg bw/day
    based on slightly decreased weight gain.  A teratogenic potential
    was not observed at dose levels as high as 200 mg/kg bw/day.  The
    NOAEL for fetotoxicity was 40 mg/kg bw based on increased
    resorptions.

         A teratology study had been previously conducted using New
    Zealand rabbits (Korte & Osterburg, 1980).  Groups of animals were
    naturally mated and after a positive vaginal smear (considered as
    gestation day 0), animals received HCG.  On days 6 through 18 after
    mating, 0, 10, 30 or 100 mg/kg bw (purity 97%, A:B = 80:20) was
    administered by oral gavage in a water vehicle with cremophor EL as
    an emulsifier.  Although between 18 and 21 rabbits were inseminated
    in each group, only 13, 10, 10 and 11 rabbits delivered live
    offspring in the 0, 10, 30 and 100 mg/kg dose groups (2 animals in
    the low dose and one each at the mid and high dose had complete
    mortality of the litter).  Two high dose animals died during the
    course of the study with postmortem evidence of pneumonia.  Body
    weights were measured on days 0, 6, 18 and 28.  After sacrifice,
    gross autopsy was performed on each maternal animal.  The number of
    corpora lutea, implantations, live and dead fetuses were recorded. 
    All fetuses were examined for external, visceral and skeletal
    abnormalities.

         Body weight was slightly (but significantly) decreased in
    females at the high dose level during the period of days 6-18.  No
    other indications of toxicity were observed in the dams.  No
    malformations of any type were observed in any of the fetuses.  A
    high incidence (ranging from 83 to 90%) of minor skeletal variations
    were observed in each group.  There was no apparent compound effect
    on the incidence or pattern of these variations.  The NOAEL for

    maternal toxicity is 30 mg/kg bw in this study.  The NOAEL for
    fetotoxicity/ teratogenicity is 100 mg/kg bw.

    Observations in humans

         A statement was submitted which noted that "no adverse effects
    on production workers engaged in the manufacture of the
    (triadimenol) have been observed by us" (Kollert, 1981).  Another
    statement noted "no cases of health impairment were observed by us
    with the periodically medically supervised employees (males and
    females) which are involved in the formulation of BAYTAN applying
    the usual safety measures" (Miksche, 1981).

    COMMENTS

         The two optical isomers of this chemical are both rapidly
    absorbed and excreted, with slightly more of each isomer excreted in
    urine by males than females.  Hydroxylation of the tert-butyl
    moiety and subsequent oxidation to carboxylic acid is the primary
    route of metabolism.  Although one of the two specific isomers is
    about 10 times more acutely toxic than the other, no differences in
    short-term toxicity were found in tests of the 80:20 and 60:40
    mixtures of isomers in rats.

         Triadimenol has a low acute toxicity in the species examined.

         Several short-term studies have been conducted in rats.  At
    higher doses increased liver weights and liver hypertrophy were
    observed.  The NOAEL was 120 ppm, equal to 8 mg/kg bw/day.

         Three short-term dog studies have been conducted.  The NOAEL
    was 100 ppm in the diet (equal to 7.5 mg/kg bw/day) based on
    hepatotoxicity at the higher dose levels.

         A long-term toxicity study was conducted in mice. An increased
    incidence of hyperplastic nodules in the liver was observed in
    females at 2000 ppm (equivalent to 300 mg/kg bw/day).  There was an
    increased incidence of liver tumours in females at the 500 and
    2000 ppm levels (equivalent to 75 and 300 mg/kg bw/day). A NOAEL
    could not be established for this study since aspartate
    amino-transferase was elevated in all treated groups in a
    dose-dependent manner.

         No increases in any tumour type were observed in a long-term
    feeding study in rats.  Hepatotoxicity was observed at 500 ppm and
    above.  The NOAEL was 125 ppm (equal to 7 mg/kg bw/day).

         In a 2-generation, 2 litters per generation reproduction study
    in rats, the NOAEL was 125 ppm in the diet, equal to 5 mg/kg bw/day. 
    Decreased parental pup body weights were observed at a dose level of
    500 ppm.  Teratology studies were conducted in rats and rabbits.  An
    increased rate of resorption was found at the high dose in the rat
    study (120 mg/kg bw/day) and rabbit study (200 mg/kg bw/day).  The
    NOAELs for embry-fetotoxicity were 60 mg/kg bw/day in the rat and
    40 mg/kg bw/day in the rabbit.

         After reviewing all available  in vitro and  in vivo
    short-term tests, the meeting concluded that there was no evidence
    of genotoxicity.

    TOXICOLOGICAL EVALUATION

    Level causing no toxicological effect

         Rat:      125 ppm in the diet, equal to 5 mg/kg bw/day (based
                   on reproductive effects)
         Dog:      100 ppm in the diet, equal to 7.5 mg/kg bw/day.

    Estimate of acceptable daily intake for humans

         0-0.05 mg/kg bw.

    Studies which will provide information in the continued evaluation
    of the compound

         Observations in humans.

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    Thyssen, J. & Kimmerle, G. (1976a)  KWG 0519 - Acute toxicity
    studies.  Institute of Toxicology, Bayer, AG, Wuppertal-Elberfeld,
    FRG.  Report No. 6090.

    Thyssen, J. & Kimmerle, G. (1976b)  1,2,4-triazole.  Institute of
    Toxicology, Bayer, AG, Wuppertal-Elberfeld, FRG.  Report No. 5926.


    See Also:
       Toxicological Abbreviations