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    PENCONAZOLE

    First draft prepared by
    J.E.M. van Koten-Vermeulen and E.M. den Tonkelaar
    National Institute of Public Health and Environmental Protection
    Bilthoven, Netherlands

    EXPLANATION

         Penconazole is a systemic triazole fungicide with preventive
    and curative properties for the control of powdery mildew. It stops
    the development of fungi by interfering with the biosynthesis of
    sterols in cell membranes. It is used on fruit, especially apples
    and grapes, and vegetables. The compound was considered for the
    first time by the present Meeting.

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    BIOLOGICAL DATA

    Biochemical aspects

    Absorption, distribution, and excretion

    Mice

         Groups of Cr:CD(ICR)BR mice (20/sex/group) were fed diets
    containing 0, 10, 100, 300, 500, 1000 or 2400 ppm penconazole;
    purity 98.7%) for 13 weeks. At the end of the study the mice were
    given orally (10 mice/sex) or intravenously (10/mice/sex) a tracer
    dose of triazole-14C-penconazole. Urine was collected 24 and 48 h
    after dosing and faeces were collected at 48 h after dosing. Most of
    the 14Cin urine was excreted in the first 24 h after dosing both
    after oral and i.v. administration. Total recovery of 14C in urine
    amounted to 47-66% for males and 63-78% for females irrespective of
    the previously administered dose or the route of administration.
    After i.v. or oral adminis-tration, male mice excreted more 14C in
    the faeces than female mice, 19-31% and 9-17%, respectively (Hiles,
    1987b).

    Rats

         Groups of two Tif:RAIf (SPF) rats/sex were given a single oral
    dose of 0.5 or 25 mg/kg bw 14C-penconazole (triazole-labelled,
    purity >98%) in ethanol/PEG 200/water (2/3/5, v/v) by gavage. One
    rat/sex served as a control. Urine, faeces and expired CO2 were
    collected at 24 h intervals. The rats were sacrificed after 6 days
    and tissues were collected and analyzed for radioactivity. In both
    dose groups most of the radioactivity was eliminated in the urine
    (62-65% in males and 74-85% in females) and faeces (34-43% in males
    and 13-32% in females). Most of the excretion occurred within the
    first 24 h after administration. Especially at the high-dose level,
    females excreted a higher amount in the urine than the males. Minor
    amounts were detected in the expired air (ca 0.1%). At the 0.5 mg/kg
    bw dose level, most tissue residues were at or below the detection
    limit. Only in lungs (0.003-0.005 mg/kg), liver (0.003-0.004),
    kidney (0.002 mg/kg) and carcass (0.003 mg/kg) were detectable
    amounts of radioactivity found. The residues found at 25 mg/kg bw
    were about 20 times higher than those found at the 0.5 mg/kg bw dose
    level (Hamböck, 1980).

         Groups of Crl:CD(SD)BR rats (5/sex/group) were given a single
    dose of unlabelled penconazole (purity 98.7%) corresponding to 0,
    10, 100, 300, 500, 1000 or 2400 ppm in the diet, immediately
    followed by the administration by gavage of 0.1 mg 14C-triazole-
    labelled penconazole. Urine was collected 24 and 48 hours after
    dosing and faeces were collected 48 h after dosing. Rats were

    sacrificed 48 h after dosing. Most of the radioactivity was
    recovered in the first 24 h urine: 34-46% and 56-86% in males and
    females, respectively. After 48 h, the urinary excretion ranged from
    46-55% in males and from 69-90% in females. Recoveries in faeces
    ranged from 19-27% in males and from 9-13% in females. Average total
    recoveries were 80% and 93% for males and females, respectively. In
    female rats, total recoveries were higher at all dose levels but
    there was no apparent correlation between excretion of radioactivity
    and the pretreatment dose level (LeVan, 1987).

         Groups of Crl:CD(SD)BR rats (13/sex/group) were fed diets
    containing 0, 10, 100, 300, 500, 1000 or 2400 ppm non-labelled
    penconazole (purity 98.7%), for at least 13 weeks prior to a single
    oral or i.v. administration of 0.1 mg of 14C-penconazole (triazole
    ring-labelled) to 5 rats/sex/group; 3 rats/sex/group were available
    for replacement. Rats were sacrificed 48 h after receiving the
    radioactive dose. Urine was collected for 0-24 h and 24-48 h after
    radioactive dosing and faeces for 48 h. The samples were analyzed
    for radioactivity.

         The administered radioactivity was recovered primarily in the
    first 24 h urine sample after both oral and i.v. dosing, with
    considerably higher amounts in female rats than in male rats. Total
    recovery in urine ranged from 73-77% in female rats and from 49-53%
    in male rats after an i.v. dose, and from 74-79% in female rats and
    from 48-59% in male rats after an oral dose. In faeces, 22-29% was
    recovered in males and 12-17% in females after i.v. adminis-tration.
    After oral administration, 26-31% was recovered in male rats and 13-
    16% in females rats. There was no relationship between pre-treatment
    doses and excretion of radioactivity (Hiles, 1987a).

         Five Wistar rats/sex received a single oral dose of 0.5 or 50
    mg penconazole/kg bw (14C-phenyl-labelled; purity >99%). Urine
    and faeces were collected up to 96 h. Independent of the
    administered dose, male rats excreted equal amounts via the urine
    (46.9% and 41.1%) and faeces (43.5%-47.0%), female rats excreted
    69.0% and 72.2% via the urine and 21.1% and 18.1% in the faeces in
    the low- and high-dose, respectively. No radioactivity (<0.01%) was
    found in the expired air. In both sexes, detectable tissue residues
    at 0.5 mg/kg bw were found only in liver, kidney, femur and
    intestinal tract. In males at 50 mg/kg bw the highest residual
    activity was found in the intestinal tract (4.08 ppm penconazole
    equivalents) followed by liver, kidney, adrenals, skin, carcass,
    blood and plasma (0.15 to 1.46 ppm). In females at 50 mg/kg bw the
    residual activity was 2 to 9 times lower than in males (Van Dijk,
    1987).

         In a bile excretion study, 9 h after the oral administration of
    0.5 mg 14C-penconazole/kg bw to males and females, 48.7% and 28.8%
    of the administered dose was excreted via the bile, respectively.
    After 48 h, biliary, urinary and faecal excretion represented 54.6%,
    28.2% and 4.7% of the administered radioactivity for male rats and
    40.2%, 47.9% and 2.0% for female rats. Fourteen daily treatments
    with 0.5 mg penconazole/kg bw/day followed by a final treatment with
    14C-labelled penconazole had no influence on the rate and route of
    excretion (Van Dijk, 1987).

    Hens

         Groups of two laying hens received oral doses equivalent to 5
    ppm in the feed of 14C-triazole-labelled penconazole or 14C-
    phenyl ring-labelled penconazole for 16 consecutive days. Excreta
    and eggs were collected daily. Regardless of the radiolabel, nearly
    99% of the radioactivity was eliminated with the excreta. Total
    radioactivity in the tissues amounted to 0.008% and 0.025-0.08% for
    the triazole and phenyl labels, respectively. Individual tissue
    residues for both labels ranged from <0.003 ppm to 0.025 ppm. The
    radioactivity recovered in the eggs reached a plateau on day 10 with
    0.022 ppm (yolks) and 0.010 ppm (whites) for the triazol label, and
    on day 11 with 0.022 ppm (yolks) and 0.005 ppm (whites) for the
    phenyl label (Murphy & Capps, 1988a).

    Goats

         Two lactating goats were given an oral dose equivalent to 5 ppm
    in the feed of 14C-triazole-labelled penconazole or 14C-phenyl
    ring-labelled penconazole for 10 consecutive days. Daily samples of
    urine, faeces and milk as well as samples of blood, expired CO2,
    and volatiles were collected. The goats were sacrificed 24 h after
    the last dose. Excretion in the urine amounted to 92% and 77% for
    the triazole and phenyl label, respectively; 8% of the radioactivity
    was recovered in the faeces for both labels. About 0.2 and 0.1% of
    the administered dose was recovered as total tissue residue for the
    triazole- and phenyl-label, respectively. Individual 14C tissue
    levels were lower than 0.017 ppm penconazole equivalents except for
    kidney and liver with 14C levels of 0.061 and 0.103 ppm for the
    triazole-label, and 0.036 and 0.075 ppm for the phenyl-label,
    respectively. The radioactivity recovered in milk reached a plateau
    around day 4 with 0.013 ppm for the triazole-label and 0.009 for the
    phenyl-label. Total recovery for the phenyl-label was lower, but
    this was due to a technical error (Murphy & Capps, 1988b).

    Biotransformation

    Rats

         Twenty male Tif:RAIf (SPF) rats were given by gavage single
    oral dosages of 22.8 mg 14C-triazole-labelled penconazole (> 98%
    purity)/kg bw. Urine and faeces were collected 24 h and 48 h after
    dosing and analyzed for radioactivity. The pooled 0-48 h urine and
    faeces samples contained 62% and 33% of the dose, respectively.
    Numerous metabolites, mostly conjugated, were identified in urine
    and faeces (13 urinary metabolites were identified by mass and NMR
    spectroscopy). Only 0.8% of the administered dose was excreted with
    the faeces as unchanged penconazole. A major pathway of metabolism
    is the stepwise oxidation and shortening of the alkyl side chain
    (see Figure 1). Also free triazole (about 15%) was excreted in urine
    and faeces, demonstrating another major independent pathway, namely
    cleavage at the nitrogen-carbon bond between the triazole ring and
    the pentyl moiety. Also oxidation of the triazole ring moiety,
    producing the 3-(or 5-)-hydroxy derivative, is observed.
    Conjugation, in particular glucuronidation, of the hydroxylated
    metabolites was also found (Hamböck, 1982, 1984).

         Quantitative differences of the metabolite pattern of male and
    female urines were studied in groups of two male and female rats
    following a single oral dose of 0.5 mg/kg bw or 25 mg/kg bw
    triazole-labelled penconazole (Hamböck, 1980). Renal excretion was
    60-63% for the males and 73-85% for the females. Males excreted more
    via the faeces (35-37%) than females (14-31%). Although the pattern
    of metabolites found in the 0-24 h urine samples was qualitatively
    the same in males and females (irrespective of the dose), polar
    metabolites, consisting of conjugated hydroxy derivatives, were much
    more abundant in females, accounting for 45% of the administered
    dose as compared to 3% in males. Males tend to excrete more free
    triazole (7% of the dose) than females (1%). Carboxylic acid
    metabolites are also more abundant in males. (Hamböck, 1985).

         In a toxicokinetic study with 14C phenyl-labelled
    penconazole, similar metabolite patterns were found in urine, bile
    and extractable faeces of males and females given one oral dose of
    0.5 or 50 mg/kg bw. A total of 5 metabolites were in common to both
    sexes in urine, faeces and bile. Quantitatively more polar
    conjugated metabolites were found in the metabolite patterns of the
    females. Conjugated CGA 127841 was found in urine, faeces and bile.
    Unconjugated CGA 127841 was found in bile, liver and kidney and CGA
    189659 was found in faeces, liver and kidney (Van Dijk, 1987). These

    metabolites were not found by Hamböck, but they are essential
    intermediates in the metabolic pathway of penconazole (see Figure
    1).

    Hens

         Characterization of the radioactivity in the excreta of laying
    hens dosed with triazole or phenyl 14C-labelled penconazole for 16
    consecutive days revealed only 0.8% and 3.7% unchanged parent
    compound, respectively. After administration of both labels a
    carboxylic acid (metabolite 1) was the major metabolite accounting
    for 22% of the radioactive extractables. The metabolic pattern was
    comparable to female rats (no free triazole being detected) (Murphy
    & Capps, 1988a).

    Goats

         In goats fed a diet containing 5 ppm of 14C-labelled
    penconazole (triazole as well as phenyl ring) no parent compound was
    detected in the urine, while in faeces 17 and 21% parent compound
    were detected following administration of the phenyl- and triazole-
    label, respectively. The metabolic patterns in tissues, excreta and
    milk were the same for both labels, with the major metabolite
    identified as a carboxylic acid (metabolite 1). The metabolic
    pattern was comparable to female rats (no free triazole being
    detected) (Murphy & Capps, 1988b).

    Effects on drug metabolizing liver enzymes

         Groups of 6 male RAI albino rats or groups of 6 male Mag mice
    were orally administered 14 daily doses of 0, 10, 80, 160 or 320 mg
    penconazole/kg bw/day (purity 98,7%). The animals were fasted for 24
    h after the last administration and then killed. The livers were
    removed and biochemical determinations were performed in the
    homogenates, microsomal and cytosolic fractions. Part of the livers
    from mice and rats from the control and the high-dose group were
    fixed for electron microscopy.

         Relative liver weight was increased at doses > 80 mg/kg
    bw/day in both rats and mice. At the highest dose, total liver DNA
    content was increased to 120% in rats and to 125% in mice.
    Microsomal protein, phospholopid contents and enzyme activities were
    significantly increased in both mice and rats at 80 mg/kg bw/day and
    above. Cytochrome P-450, ethoxycoumarin O-deethylase and epoxide
    hydrolase were also significantly increased in rats at 10 mg/kg
    bw/day. Electron microscopy revealed proliferation of smooth
    endoplasmic reticulum membranes in both species (Waechter  et al.,
    1985)

    FIGURE 1

         Metabolites 9, 10, 11 and 12 were mainly found as glucuronides
    or other conjugates.

    Toxicological studies

    Acute toxicity studies
    
    Table 1.  Acute toxicity of penconazole
                                                                                         
    Species           Sex   Route   LD50      LC50     Purity  Reference
                                    mg/kg bw  mg/m3
                                                                                         

    Mouse             M&F   oral    2444               88.4    Sarasin (1980)
    Rat               M&F   oral    2125               88.4    Bathe & Gfeller (1980a)
                      M&F   dermal  >3000              88.4    Bathe & Gfeller (1980b)
                      M&F   inhal             >4046    96.1    Hartmann & Gfeller (1987)
    Chinese hamster   M&F   oral    >5000              88.4    Bathe & Gfeller (1980c)
    Rabbit            M&F   oral    971                88.4    Kobel (1981)
                                                                                         
    
         Penconazole shows low acute oral toxicity to mice, rats and
    hamsters, but is slightly more toxic to rabbits.

    Short-term toxicity studies

    Mice

         Groups of Cr:CD(ICR)BR mice (15/sex/group) were fed diets
    containing 0, 10, 100, 300, 500, 1000 or 2400 ppm penconazole
    (purity 98.7%) equivalent to 0, 1.5, 15, 45, 75, 150 or 360 mg/kg
    bw/day for 13 weeks. Histopathology was only reported for the liver.
    No treatment-related effects were observed on clinical signs,
    mortality, ophthalmoscopy, food consumption, food efficiency,
    haematology or urinalysis. Body-weight was lower at 2400 ppm.
    Cholesterol levels were decreased at 1000 and 2400 ppm, ALAT
    increased in high-dose males and total protein and albumin were
    decreased in females at 2400 ppm. Relative liver weight was
    significantly increased at 500, 1000 and 2400 ppm. An increased
    incidence of centrilobular hypertrophy of the liver was observed in
    males at doses > 500 ppm and in females at the highest dose.
    Hepatic degeneration and vacuolisation was also observed in high-
    dose males. Coagulative necrosis in the liver was observed in males
    at 1000 and 2400 ppm. The NOAEL in this study was 300 ppm in the
    diet, equivalent to 45 mg/kg bw/day (Hiles 1987b).

    Rats

         Groups of Tif:RAIf(SPF) rats (10/sex/group) were orally
    administered 0, 20, 100 or 500 mg penconazole (purity 91.7%)/kg
    bw/day for 28 days. Since no marked symptoms of toxicity showed up
    during the first week of treatment the doses were increased to 100,
    500 or 1000 mg/kg bw/day on day 8 of treatment. After increasing the
    doses, 3 male and 3 female high-dose rats showed marked apathia and
    lateral body position at day 10 but the animals recovered on day 11.
    No effects were observed on mortality, ophthalmic or hearing
    examinations. In the mid- and high-dose groups male mean body weight
    was decreased, food consumption and food conversion were decreased
    in males and females, haemoglobin and haematocrit values were
    decreased in females and ALP and ALAT as well as cholesterol and
    total proteins were increased in males and females and total
    globulin was increased and A/G ratio was decreased in females.
    Phosphate and glucose were increased in high-dose females. Albumin
    increased in high-dose males and females. Urine volume was increased
    in males at the highest dose and in females at the mid- and high-
    dose. Relative liver, kidney and adrenal weight was increased in
    mid- and high-dose males and females. Relative brain, spleen and
    thyroid weight were increased in high-dose females. Enlarged livers
    with slight hypertrophy of the hepatocytes were observed in 8/10 and
    3/10 males and females at the mid-dose and in all animals at the
    highest dose. The lowest dose (20-100 mg/kg bw/day) was considered
    as the NOAEL (Basler  et al., 1984).

         Groups of Tif:RAIf(SPF) rats (20/sex/group) were fed diets
    containing 0, 30, 300 or 3000 ppm (equal to 2.1, 19.4 or 202.3 mg
    penconazole/kg bw/day for males and 2.1, 20.7 or 208.6 mg
    penconazole/kg bw/day for females, respectively) (purity 91.7%) for
    3 months. No effects were observed on clinical signs, mortality,
    food and water consumption, food conversion, hearing tests or eye
    examinations. Body weight was decreased in males and females at the
    highest dose. An increase in total plasma protein and albumin was
    observed in male rats at all doses and a trend to an increase in
    total plasma proteins was seen in females at 3000 ppm. GGT was
    slightly increased in females at 300 and 3000 (significantly) ppm.
    Cholesterol levels were increased in both sexes at 3000 and also in
    females at 300 ppm. A significant dose-related increase in relative
    liver weight was observed at all dose levels. Relative testes
    weights were increased in males at 3000 ppm and brain, kidney and
    thymus weight were increased in high dose females. At histopathology
    minimal hypertrophy of the hepatocytes was seen in 20/20 male rats
    and 9/20 female rats at 3000 ppm. In this study no NOAEL was
    identified, although the liver weight increase at 30 ppm was
    marginal (Basler  et al., 1982).

         In another 3 month feeding study groups of Tif:RAIf(SPF) rats
    (20/sex/group) were fed diets containing 0, 10, 30 or 100 ppm
    penconazole (purity 91.7%) (equal to 0.8, 2.1 or 7.1 mg

    penconazole/kg bw/day for males and 0.8, 2.1 or 7.3 mg
    penconazole/kg bw/day for females, respectively). No effects were
    observed on clinical signs, mortality, body-weight, food and water
    consumption, food conversion, eye examinations, hearing tests, organ
    weight or histopathology. Total proteins were increased in male and
    female rats at 30 and 100 ppm. Total globulin was increased in high
    dose females. GGT was slightly increased in females at both 30 and
    100 ppm. Liver weight was increased at 10 and 30 ppm in male rats
    only, but not at 100 ppm. No liver histopathological effects were
    observed. The NOAEL in this study was 10 ppm penconazole, equal to
    0.8 mg/kg bw/day (Basler  et al., 1983).

         In an additional study groups of albino [Crl:CD(SD)BR] rats
    (15/sex/group) were fed diets containing 0, 10, 100, 300, 500, 1000
    or 2400 ppm penconazole (purity 98,7%) equivalent to 0.5, 5, 15, 25,
    50 or 120 mg penconazole/kg bw/day for 90 days. In this study only
    the liver as target organ was studied histopathologically.
    Observations included clinical signs mortality, body-weight, food
    consumption, food efficiency, ophthalmoscopy, haematology, clinical
    chemistry (including GGT), urinalysis, organ weights, macroscopy and
    histopathology. Female body weight gain was lower at 500, 1000 and
    2400 ppm and food consumption was decreased at the highest dose.
    Urea nitrogen was increased in males at all dose levels, but not
    clearly dose-related. Relative liver weight was significantly
    increased in rats at 500 (females only), 1000 and 2400 ppm. Relative
    kidney weight was increased in rats at 2400 ppm. At histopathology
    the incidence of vacuolization, degeneration and centrilobular
    hyperthrophy of hepatocytes was increased at 500 ppm and above. The
    NOAEL in this study was 300 ppm, equivalent to 15 mg/kg bw/day
    (Hiles, 1987c).

    Rabbits

         Groups of New Zeeland white rabbits (5/sex/group) were given
    1000, 1500 or 2000 mg penconazole/kg bw/day (purity 91.7%) by dermal
    application once/day for 5 days/week for 21 days. Two satellite
    groups received 0 or 2000 mg penconazole/kg bw/day for 21 days
    followed by a recovery period of 14 days. Transient signs of
    dyspnea, curved body position and ruffled fur were observed at all
    dose levels including control rabbits, but symptoms disappeared
    during the recovery period. No dose-related effects were observed on
    mortality, body-weight, food consumption and food conversion,
    haematology, clinical chemistry, macroscopy and histopathology. The
    NOAEL in this study was > 2000 mg/kg bw/day (Seifert  et al.,
    1983).

    Dogs

         Groups of beagle dogs (10/sex/group) were fed diets containing
    0, 100, 500, or 5000/2500 ppm penconazole (purity 91.7%), equal to
    3.0, 16.9 or 133 mg penconazole/kg bw/day for males and 3.3, 16.7 or

    139 mg penconazole/kg bw/day for females, respectively, for 12
    months. Due to poor feed intake the highest dose was lowered to 2500
    ppm in week 20. An interim kill on 4 dogs/sex/group was carried out
    at week 14 and 2 dogs/sex/group were kept for a 4-week recovery
    period. Observations included clinical signs, mortality, body-
    weight, food consumption, food conversion, ophthalmoscopy, auditory
    perception, haematology, blood chemistry, urinalysis, macroscopy,
    organ weights and histopathology.

         An increased incidence of vomiting was observed in high-dose
    dogs during the first three months of treatment; thereafter
    occasionally vomiting was observed only in females. The high-dose
    dogs lost body-weight and had a reduced food consumption during the
    first months. After lowering the dosage food consumption and male
    bodyweights were comparable to the controls but the mean weight of
    the females remained lower than the control value. ASAT, ALP, OCT,
    GGT and ALAT activities were increased in dogs at the highest dose
    during the whole administration period. Total globulin concentration
    was increased in males at the highest dose during weeks 13, 26 and
    53, consequently the total protein was slightly increased and the
    A/G ratio was decreased. Terminal body-weight of high-dose male and
    female dogs were decreased after 3 months. At this time relative
    liver weights were increased at 500 and 5000 ppm. Relative kidney
    weight was increased at the highest dose in both males and females.
    Relative brain and adrenal weight were increased and relative heart
    weight was decreased in high-dose females. All males at 5000 ppm
    showed a reduction in testes weights and atrophy of the seminiferous
    epithelium. At macroscopy emaciation was observed in dogs at the
    highest dose after 3 months. At histopathology after 3 months,
    minimal lesions characterized by monocellular hepatocyte necrosis
    associated with inflammatory cell infiltration were noticed in
    nearly all interim sacrificed dogs at the highest dose and in one
    male dog at 500 ppm. After 12 months, testes weights were reduced in
    males at 2500 ppm and liver weight was increased in females at 500
    and 2500 ppm. At histopathology, bilateral tubular atrophy and
    reduced spermatogenesis in the testes was observed in the high-dose
    males and an increased incidence of inflammation with fibrosis in
    the peripheral lobular region of the liver occurred in the mid- and
    high-dose animals. The only abnormalities found after the recovery
    period were decreased relative testes weights and tubular atrophy at
    2500 ppm. The NOAEL in this study was 100 ppm, equal to 3.0 mg/kg
    bw/day for males and 3.3 mg/kg bw/day for females (Gfeller  et al.,
    1984).

    Long-term toxicity/carcinogenicity studies

    Mice

         Groups of Tif:MAGf(SPF) mice (80/sex/group) were fed diets
    containing 0, 5, 75, 150 or 300 ppm penconazole (purity 91.7%),
    equal to 0.75, 9.8, 19.3 or 40.8 mg/kg bw/day for males and 0.67,

    8.8, 17.2 or 35.7 mg/kg bw/day for females, for 24 months. An
    interim kill was carried out on 10 mice/sex/group at 52 weeks. No
    effects were observed on mortality, clinical signs, body-weight,
    food and water consumption, food conversion, ophthalmic and hearing
    inspections, haematology, blood chemistry, urinalysis, macroscopy or
    histopathology. Relative liver weight was increased in high-dose
    males and females at the interim kill. At the end of the study
    adrenal weight (not dose-related) and prostate weight were increased
    in males at 75, 150 and 300 ppm. There was no treatment-related
    increase in tumour incidence (Basler  et al., 1985b). Since
    weighing of prostate glands is not very reliable and the increased
    weight was not found at 53 weeks, the Meeting concluded that this
    effect was probably biologically insignificant. The NOAEL was
    therefore 150 ppm, equal to 19.3 mg/kg bw/day for males and 17.2
    mg/kg bw/day for females based on the increased liver weight.

    Rats

         Groups of Tif:RAIf(SPF) rats (80/sex/group) were fed diets
    containing 0, 5, 75, 150 or 300 ppm penconazole (purity 91.7%) for
    24 months. An interim kill was carried out on 10 rats/sex/group at
    12 months. Twenty rats/sex/group were maintained for laboratory
    investigations and sacrificed after 24 months. The remaining 50
    rats/sex/group were sacrificed after 116/117 weeks. No effects were
    observed on mortality, clinical signs, body-weight, food and water
    consumption, food conversion, ophthalmic and hearing inspections,
    haematology, blood chemistry, urinalysis, macroscopy or
    histopathology. At the interim kill, liver weight was increased in
    females at 150 and 300 ppm and pituitary weight was decreased in
    high-dose males. A tendency to increased liver weight was still
    observed in females at the highest dose at 104 weeks. Tumour
    incidence was not enhanced. The NOAEL in this study was 75 ppm,
    equal to 3.8 and 4.0 mg/kg bw/day for males and females,
    respectively (Basler  et al., 1985b).

    Reproduction studies

    Rats

         Penconazole (purity 91.7%) was administered in the diet to
    groups of 20 Tif:RAIf(SPF) rats/sex at concentrations of 0, 80, 400
    or 2000 ppm (continuously over a period of 110 days to the parental
    generations (F0 and F1), including a 12-day mating period for
    each generation at the age of 3 months. These dose levels were equal
    to 5.5-6.5, 28.5-31 or 146-166 mg/kg bw/day for males and 7.5-8.5,
    40-42.5 or 202-227 mg/kg bw/day for females during the whole period.
    Parental rats were killed after weaning of the F1 and F2
    generation, respectively. Observations included clinical signs,
    body-weight, food consumption, fertility index, implantation rate,
    litter size, live and dead fetuses, sex ratio, organ weight,
    macroscopy and histopathology.

         A slightly depressed body-weight gain and food consumption was
    seen at the highest dose in F0 females. Parturation was delayed
    and the average duration of pregnancy was 21.1, 21.2, 21.3 and 21.6
    days for the 0, 80, 400 and 2000 ppm group. Four dams died, two (1
    at 400 and 1 at 2000 ppm) at or a short time after parturation, one
    (at 2000 ppm) after 4 days and one (at 2000 ppm) after 11 days.
    Testes weights of F0 males were slightly increased at 2000 ppm
    (liver weight was not determined).

         Body-weight gain of F1 pups was slightly reduced at 2000 ppm.
    The activity index (ELP, exploratory locomotion pattern) was
    slightly but not significantly depressed at 400 and 2000 ppm; there
    was however no effect on general development and behaviour. At 2000
    ppm, relative liver weight was increased in male and female F1
    pups and brain and ovary weight was increased in F1 female pups.
    Body-weight gain and food consumption of F1 parents was slightly
    reduced at 2000 ppm. One dam died at 400 ppm and 2 at 2000 ppm at or
    some days after parturation. The average pregnancy duration was
    increased at the highest dose (21.3, 21.4, 21.2 and 21.8 days at 0,
    80, 400 and 2000 ppm, respectively). At 2000 ppm, relative liver
    weight and relative ovary weight were increased in F1 parents,
    while relative brain and testes weight were increased in F1 males.
    A decreased implantation rate was observed at 2000 ppm.

         The ELP was slightly but not significantly decreased in high-
    dose F2 pups without any effect on general development and
    behaviour. Relative liver weight was increased in high-dose F2
    pups.

         Histopathological examination of the livers of F1 adults
    revealed slight hypertrophy of the hepatocytes mainly in the
    centrilobular region in 17/20 males and in 16/16 females at 2000 ppm
    and in 5/19 males and 14/16 females at 400 ppm. Additionally, small
    recent necrosis in the liver was observed in 2/16 high-dose females.
    No histopathological changes were seen in weanling rats from both
    F1 and F2 generations. The NOAEL in this study was 80 ppm, equal
    to 5.5-6.5 mg/kg bw/day and 7.5-8.5 mg/kg bw/day for males and
    females, respectively (Fritz  et al., 1983a; Fritz  et al.,
    1983b).

         Groups of 30 Charles River COBS CD rats/sex were fed diets
    containing 0, 25, 250 or 2500 ppm penconazole (purity not given).
    After 63 days of treatment the rats were mated to start a two-
    generation (1 litter/generation) study. The F1 parents (randomly
    selected) were mated after 84 days of treatment. Only weights of
    ovaries and testes were determined. At 2500 ppm body-weight and food
    consumption were decreased in F0 females and body-weight was
    decreased in F1 parents. Mating indices were slightly reduced in
    the F0 and F1 generations at 2500 ppm, but fertility indices
    were not affected. Reduced pup weight and an increase in the number
    of stillborn pups or pups that died during the first days of

    lactation was observed at the highest dose. Relative ovary weight
    was significantly increased in females of the F0 and the F1
    generation at 2500 ppm. The NOAEL in this study is 250 ppm,
    equivalent to 12.5 mg/kg bw/day (Schardein, 1987)

    Special studies on embryotoxicity and/or teratogenicity

    Rats

         Groups of 25 pregnant Tif:RAIf(SPF) female rats were
    administered orally by intubation 0, 30, 100 or 300 mg penconazole
    (purity 88.4%)/kg bw/day suspended in CMC from days 6 to 15 of
    gestation. The dams were observed for clinical signs, body-weight
    and food consumption and were killed at day 21 of gestation. The
    number of total implantations, resorptions, live and dead fetuses
    were recorded and the uterus was weighed. Fetuses were weighed,
    sexed and examined for external, visceral and skeletal
    malformations. Two dams at 300 mg/kg bw/day died shortly before
    autopsy. Maternal bodyweight gain in the highest dose group was
    slightly reduced. Food consumption was reduced in all experimental
    groups. An increase in the numbers of unossified phalangeal nuclei
    of the hind limb was observed at 100 and 300 mg/kg bw/day (not dose-
    related). At the highest dose, acaudia (taillessness) was observed
    in 1/182 fetuses, and the overall incidence of skeletal anomalies
    including irregularly shaped sternebrae was increased at the highest
    dose. The NOAEL for maternal and embryofetal toxicity was 30 mg/kg
    bw/day.

         In a supplementary study, 0 or 300 mg penconazole/kg bw/day was
    administered by gavage to groups of 15 pregnant rats from days 6-15
    of gestation and another group of 15 rats received 450 mg
    penconazole/kg bw/day from days 10-14 of gestation. Body-weight gain
    and food consumption were decreased at both dose levels. Four and 2
    females died shortly before autopsy at 300 and 450 mg/kg bw/day,
    respectively. The average weight of live fetuses was decreased at
    300 and 450 mg/kg bw/day. The incidence of unossified phalangeal
    nuclei of the forelimb was increased at 450 mg/kg bw/day and the
    incidence of unossified phalangeal nuclei of the hind limbs and
    calcaneus were increased at both 300 and 450 mg/kg bw/day. No
    irregular ossification of sternebrae was observed at 300 mg/kg
    bw/day. At 450 mg/kg bw/day an irregularly ossified sixth sternebrae
    was recorded in one foetus (Fritz & Giese, 1981). The increased
    incidence of these variants may indicate delayed fetal development,
    but in the absence of any associated malformations should not be
    considered as indicative of teratogenicity.

         Groups of 25 pregnant Charles River rats were administered by
    gavage 0, 5, 100, or 500 mg penconazole (purity 98.7%)/kg bw/day in
    corn oil from days 6-15 of gestation. The females were observed for
    clinical signs, body-weight and food consumption and sacrificed on
    day 20 of gestation. The number of implantation sites, resorption

    sites, corpora lutea were recorded. Fetuses were weighed, sexed and
    examined for external, internal and visceral anomalies. Two high-
    dose dams and 1 dam at 5 mg/kg bw/day died during the study. High-
    dose dams exhibited damp fur, crusty eye, crusty muzzle, crusty
    nose, and yellow/brown stained fur as well as staggered gait,
    emaciated loose stools, weakness and/or lethargy (5/25) and clear
    salivation (4/25). Body-weight and body-weight gain were
    significantly decreased at the highest dose. Food consumption was
    decreased from days 6-13 at 100 and 500 mg/kg bw/day. At the highest
    dose, the number of early and late resorption sites was increased
    and the number of viable fetuses as well as the fetal weight were
    decreased. The number of runts and litters with runts as well as the
    occurrence of cervical ribs was increased at 500 mg/kg bw/day. No
    teratogenic effects were observed. The NOAEL for maternal and
    embryofetal toxicity in this study was 100 mg/kg bw/day (Salamon,
    1985).

    Rabbits

         Groups of 20 pregnant chinchilla rabbits received 0, 25, 75 or
    150 mg penconazole (purity 91.7%)/kg bw/day orally by intubation
    from day 6 to 18 of pregnancy. Observations included clinical signs,
    body-weight gain, food consumption. Dams were killed on day 28 of
    pregnancy and fetuses were removed by caesarean section. No effects
    were observed on the number of corpora lutea, total implantations,
    early and late resorptions, live and dead fetuses, sex ratio uterus
    and fetal weight, external and visceral examination and skeletal
    malformations.

         At 150 mg/kg bw/day average food consumption was slightly
    reduced and the number of early resorptions was slightly but not
    signficantly increased. At the highest dose,one fetus with
    microphthalmia and one fetus showing microphthalmia associated with
    internal hydrocephaly were seen. The NOAEL for maternal toxicity and
    for embryotoxicity was 75 mg/kg bw/day (Giese & Suter, 1982).

         Groups of 20 pregnant New Zeeland white rabbits were orally
    dosed by gavage with 0, 10, 50 or 200 mg penconazole/kg bw/day from
    days 7 to 19 of gestation. Observation included clinical signs,
    body-weight and food consumption. All dams were killed on gestation
    day 29 and fetuses were delivered by caesarean section. During the
    treatment period decreased defecation and urination were observed in
    high-dose animals and body-weight and food consumption were
    decreased. A significant increase in body-weight and mean food
    consumption was observed from gestation day 20-29. The number of
    early resorptions was slightly increased and the number of viable
    fetuses was slightly lower at the highest dose. At 200 mg/kg bw/day,
    a slightly increased incidence of the number of fetuses with
    unossified hyoid body and/or arches (marginal at 50 mg/kg bw/day)
    and of fetuses with reduced ossification of the skull was observed.
    No teratogenic effects were observed. The NOAEL in this study for

    maternal and/or embryotoxicity was 50 mg/kg bw/day (Nemec  et al.,
    1985).

    Special studies on mutagenicity

         A number of genotoxicity tests have been carried out with
    penconazole. The results are summarized in Table 2.

    Special studies on skin and eye irritation and skin sensitization

         Penconazole (purity 88.4%) produced slight erythema in 3 male
    and 3 female New Zeeland white rabbits when applied under occlusive
    conditions to the shaven intact and abraded skin for 24 hours, which
    disappeared within 48 h (Ullmann & Gfeller, 1980b).

         Penconazole (0.1 mg) was inserted into the conjuctival sac of
    the left eye of nine New Zeeland white rabbits. At 30 seconds after
    treatment, the eyes of 3/9 rabbits were washed with physiological
    saline. In unrinsed eyes slight damage of the cornea and slight
    conjunctival redness and chemosis were observed up to 7 days after
    treatment. Rinsed eyes were normal 4 days after exposure. Two
    rabbits died during the experiment. Bloody exudate in the pleural
    and abdominal cavities was observed at autopsy (Ullmann & Gfeller,
    1980a).

         In a similar study, nine New Zeeland white albino rabbits were
    given doses of 100 mg of undiluted penconazole (purity not given)
    into the conjunctival sac of the left eye. Three of nine eyes were
    washed. Conjunctival redness, chemosis and discharge was observed in
    all animals at one hour after application which lasted up to 7 days
    after treatment. The iris showed swelling but these changes
    disappeared within 24 h. Corneal opacity and positive fluorescein
    staining occurred but did not occur in any animal at 48 h (washed
    eyes) and on day 7 (non-washed eyes) (Kuhn, 1988).

         Penconazole (purity 88.4%) was tested for skin sensitization in
    10 male and 10 female Pirbright white guinea-pigs in an optimization
    test. No sensitization was observed when the guinea-pigs received 10
    intracutaneous injections (0.1 ml of a 0.1% suspension of
    penconazole in propylene glycol) followed 14 days later by a single
    challenge injection (0.1 ml of 0.1% suspension of penconazole in
    propylene glycol) (Ulmann & Gfeller,1980c).


    
    Table 2. Results of mutagenicity assays on penconazole
                                                                                                                        
    Test system          Test object            Concentration               Purity    Results      References
                                                of penconazole              (%)
                                                                                                                        

    In vitro
    Ames testa,b         S. typhimurium         250-20250 µg/ml in          92.8      negative     Arni & Müller (1980)
                         TA100, TA98            DMSO;a > 6750 µg/ml
                         TA1535, TA1537         toxic, and b 20250
                                                µg/ml toxic


    Ames testa,b         S. typhimurium         100-25600 µg/ml in          91.7      negative c   Deparade & Arni (1984)
                         TA98, TA100            acetone
                         TA1535, TA1537

    Yeast testa,b        S. cerevisiae          0.1-40 µg/ml in DMSO        91.7      negative     Arni & Müller (1983)
    (mitotic gene        D7
    conversion)

    Transformation       mouse                  2.625, 5.25, 10.5,          91.7      negative c   Beilstein & Müller (1984a)
    assay                embryofibroblasts      21.0 and 42.0 µg/ml         
                         BALB/3T3               in DMSO

    Mouse lymphoma       L5178Y mouse           (a):6.75-100 µg/ml,         91.7      negative c   Beilstein & Müller (1984b)
    assay a,b            lymphoma cells         100 µg/ml toxic;
                         (TK+/-)                (b):8.25-110 µg/ml,
                                                > 110 µg/ml toxic;
                                                both in DMSO

    DNA repair           human fibroblasts      0, 0,32, 1.6 and            91.7      negative c   Puri & Müller (1983)
    test                                        40 µg/ml.

    DNA repair           rat hepatocytes        0, 032, 1.6, 8.0,           91.7      negative c   Puri & Müller (1984)
    test                                        40 µg/ml

    Table 2. Results of mutagenicity assays on penconazole
                                                                                                                        
    Test system          Test object            Concentration               Purity    Results      References
                                                of penconazole              (%)
                                                                                                                        

    In vivo
    Host mediated        S. typhimurium         0, 350, 700 and 1400        91.7      negative     Arni & Müller (1984)
    assay (intra         TA98, TA100 and        mg/kg orally
    sanguine)            TA1535
                         in male NMRI mice

    Host mediated        L 5178Y-cells          0, 813 mg/kg bw             91.7      negative     Strasser & Müller (1982)
    assay                in DBA/Bom/SPF         orally
                         mice

    Nucleus anomaly      Chinese hamster        0, 417, 834 and 1668        92.8      negative c   Hool & Langauer (1982)
    test                 bone marrow cells      mg/kg orally in PEG 400
                                                per day on 2 consecutive
                                                days

    Sister chromatid     Chinese hamster        0, 417, 834 and 1668        91.7      negative c   Hool & Arni (1983a)
    exchange assay       bone marrow            mg/kg orally in PEG 400

    Chromosome           NMRI mice              0, 91, 272 and 816 mg/kg    91.7      negative     Hool & Arni (1983b)
    aberration assay     spermatogonia          bw orally in PEG
                                                400 per day on 5
                                                consecutive days; at
                                                816 mg/kg
                                                all mice died

    Dominant lethal      Male NMRI mice         0, 272 and 816 mg/kg        91.7%     negative     Hool & Arni (1983c)
    assay                                       bw orally
                                                                                                                        

    a without metabolic activation
    b with metabolic activation
    c positive controls yielded positive result(s)
    

    COMMENTS

         Penconazole administered orally to mice and rats was rapidly
    absorbed and excreted, predominantly in the urine. Female rats
    eliminated more in the urine and less in the faeces than male rats.
    Very low residues were found in organs and tissues in both males and
    females.

         Numerous metabolites were identified in urine and faeces. The
    major metabolic pathways involved oxidation of the pentyl side chain
    to alcohols and acids with sequential cleavage of the terminal
    carbon. As the oxidation products were conjugated, the resulting
    metabolic patterns were complex. More polar and conjugated products
    were found in female rats. Cleavage of the alkyl bridge between the
    two rings led to the formation of 1,2,4-triazole, which was a major
    metabolic route in male rats.

         Penconazole showed low acute oral toxicity to mice, rats and
    hamsters, but was slightly more toxic to rabbits. The World Health
    Organization has classified penconazole as unlikely to present acute
    hazard in normal use (WHO, 1992).

         Short-term studies with mice, rats and dogs indicated that the
    liver was the primary target organ. In a special study with male
    rats, induction of microsomal liver enzymes was demonstrated. In a
    13-week study in mice, increased liver weight and liver hyperthrophy
    were observed at 500, 1000 and 2400 ppm. The NOAEL was 300 ppm,
    equivalent to 45 mg/kg bw/day.

         In three 90-days studies performed with rats, liver weight and
    liver histopathology were the main effects, except for the second
    study. In the first study, increase in relative liver weight was
    observed at all dietary levels (30, 300 or 3000 ppm), while in the
    third study (dietary levels of 10, 100, 300, 500, 1000 or 2400 ppm)
    the NOAEL was 300 ppm, equivalent to 15 mg/kg bw/day. In the second
    study (dietary levels of 10, 30 or 100) some biochemical parameters
    were affected at 30 and 100 ppm. The NOAEL was 10 ppm, equal to 0.8
    mg/kg bw/day.

         In a one-year study in dogs, increased liver weights and
    histopathological liver effects were observed at dietary
    concentrations of 500 and 2500/5000 ppm. At the highest dose level
    reduced testis weight and athrophic changes were also observed. The
    NOAEL was 100 ppm, equal to 3.0 and 3.3 mg/kg bw/day for males and
    females, respectively.

         In a two-year feeding study in mice (dietary concentrations of
    0, 5, 75, 150 or 300 ppm) increased liver weight at interim kill was
    seen at 300 ppm. The NOAEL in this study was 150 ppm, equal to 19.3
    mg/kg bw/day for males and 17.2 mg/kg bw/day for females. In a long-
    term study in rats (dietary concentrations of 0, 5, 75, 150 or 300

    ppm) liver weight was increased at 150 and 300 ppm. The NOAEL was 75
    ppm, equal to 3.8 and 4.0 mg/kg bw/day for males and females,
    respectively. Penconazole was not carcinogenic in mice or rats.

         Two two-generation reproduction studies in rats were reviewed.
    In the first study (dietary concentrations of 0, 80, 400 or 2000
    ppm), mortality and delayed parturation were observed, as well as
    decreased body-weight gain of parents and pups and increased
    relative liver weights in parents and pups at 2000 ppm. Hyperthrophy
    of liver cells was found at 400 and 2000 ppm. The NOAEL was 80 ppm,
    equal to 5.5-6.5 mg/kg bw/day for males and 7.5-8.5 mg/kg bw/day for
    females. In the second study (dietary concentrations of 0, 25, 250
    or 2500 ppm), liver weights were not determined. The main effect at
    2500 ppm was reduced body-weight gain of parents and pups and
    mortality of pups during lactation. The NOAEL was 250 ppm,
    equivalent to 12.5 mg/kg bw/day.

         Embryotoxicity/fetotoxicity was observed in three
    teratogenicity studies with rats. In two studies (gavage doses of 0,
    30, 100 or 300 mg/kg bw/day in one study and 0, 300 or 450 mg/kg
    bw/day in the other), maternal toxicity, an increased number of
    resorptions, decreased pup weight and delayed ossification were
    observed at the high doses. Maternal toxicity or embryotoxicity were
    not observed at 30 mg/kg bw/day. In the third study (gavage doses of
    0, 5, 100 or 500 mg/kg bw/day), the NOAEL was 100 mg/kg bw/day. In
    two teratogenicity studies with rabbits (doses of 0, 25, 75 or 150
    mg/kg bw/day in one study and 0, 10, 50 or 200 mg/kg bw/day in the
    other), maternal body-weight and food consumption were reduced and
    the number of early resorptions was increased at the highest doses.
    Overall, the NOAEL was 75 mg/kg bw/day for both maternal toxicity
    and embryotoxicity.

         After reviewing the available  in vitro and  in vivo short-
    term genotoxicity data, the Meeting concluded that penconazole was
    not genotoxic.

         An ADI was allocated on the basis of the NOAEL determined from
    the one-year study in dogs, which was supported by the NOAEL from
    the long-term study in rats. A safety factor of 100 was applied.

    TOXICOLOGICAL EVALUATION

    Level causing no toxicological effect

         Mouse:    150 ppm, equal to 17 mg/kg bw/day (two-year study)

         Rat:      75 ppm, equal to 3.8 mg/kg bw/day (two-year study)

                   80 ppm, equal to 5.5 mg/kg bw/day (two-generation
                        reproduction study

                   30 mg/kg bw/day (teratology study)

         Rabbit:   75 mg/kg bw/day (teratology study)

         Dog:      100 ppm, equal to 3 mg/kg bw/day (one-year study)

    Estimate of acceptable daily intake for humans

         0-0.03 mg/kg bw.

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

         Observations in humans.

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    Basle, Switzerland.

    Hiles, R.A. (1987c) 90-Day subchronic dietary toxicity and kinetic
    study in albino rats with CGA-71818 technical. Unpublished report
    HLA 6117-120 dated 14-04-1987 from Hazleton Laboratories America,
    Inc. Madison, Wisconsin 53704. Submitted to WHO by Ciba-Geigy Ltd.,
    Basle, Switzerland.

    Hool, G. & Arni, P. (1983a) Sister chromatid exchange study CGA
    71818 Chinese hamster. Unpublished report dated 2-06-1983 project
    No. 811523 from Ciba-Geigy Ltd, Protection of Health and
    Environment, Toxicology, Basle, Switzerland. Submitted to WHO by
    Ciba-Geigy Ltd., Basle, Switzerland.

    Hool, G. & Arni, P. (1983b) Chromosome studies in male germinal
    epithelium CGA 71818 mouse. Unpublished report dated 17-06-1983
    project No. 811520 from Ciba-Geigy Ltd, Protection of Health and
    Environment, Toxicology, Basle, Switzerland. Submitted to WHO by
    Ciba-Geigy Ltd., Basle, Switzerland.

    Hool, G. & Arni, P. (1983c) Dominant lethal test, mouse 8 weeks CGA
    71818. Unpublished report dated 2-12-1983 project No. 811519 from
    Ciba-Geigy Ltd., Protection of Health and Environment, Experimental
    Pathology, Basle, Switzerland. Submitted to WHO by Ciba-Geigy Ltd.,
    Basle, Switzerland.

    Hool, G. & Langauer, M. (1982) Nucleus anomaly test in somatic
    interphase nuclei. CGA 71818 Chinese hamster. Unpublished report
    dated 20-1-1982 experiment No. 800551 from Ciba-Geigy Ltd,
    Protection of Health and Environment, Toxicology, Basle,
    Switzerland. Submitted to WHO by Ciba-Geigy Ltd., Basle,
    Switzerland.

    Kobel, W. (1981) Acute oral LD50 in the rabbit of technical CGA
    71818. Unpublished report dated 4-3-1981, project No. 800554 from
    Ciba-Geigy Ltd., Exp. Toxicology Sisseln, Switzerland, Submitted to
    WHO by Ciba-Geigy Ltd., Basle, Switzerland.

    Kuhn, J.O. (1988) Primary eye irritation study in rabbits EPA
    guidelines No. 81-4. Unpublished report dated 31-03-1988 project
    no.: 5303-88 from Stillmeadow Inc. Houston, Texas, USA. Submitted to
    WHO by Ciba-Geigy Ltd., Basle, Switzerland.

    LeVan, L.W. (1987) Acute kinetic study with CGA-71818 technical in
    albino rats. Unpublished report dated 2-03-1987 project No. HLA
    6117-123 from Hazleton Laboratories America Inc. Madison, Wisconsin,
    USA. Submitted to WHO by Ciba-Geigy Ltd., Basle, Switzerland.

    Murphy, R.T. & Capps, T.M. (1988a) CGA-71818 Metabolism in hens - a
    summary. Unpublished report No. ABR-88009 dated 20-05-1988 from
    Ciba-Geigy Corp. Greensboro, NC, USA. Submitted to WHO by Ciba-Geigy
    Ltd., Basle, Switzerland.

    Murphy, R.T. & Capps, T.M. (1988b) CGA-71818 Metabolism in goats - a
    summary. Unpublished report No. ABR-88008 d.d.20-05-1988 from Ciba-
    Geigy Corp. Greensboro, NC, USA. Submitted to WHO by Ciba-Geigy
    Ltd., Basle, Switzerland.

    Nemec, M.D. & Keets, S.A., Leist, P.L. & Mercieca, M.D. (1985) A
    teratology study (segment II) in albino rabbits with CGA-71818
    technical. Unpublished report No. WIL-82004 dated 31-07-1985 from
    WIL Research Laboratories Inc., Ashland, Ohio, USA. Submitted to WHO
    by Ciba-Geigy Ltd., Basle, Switzerland.

    Puri, E. & Müller, D. (1983) Autoradigraphic DNA repair test on
    human fibroblast CGA 71818 . Unpublished report dated 2-12-1983
    project No. 811657 from Ciba-Geigy Ltd.,Protection of Health and
    Environment, Toxicology, Basle, Switzerland. Submitted to WHO by
    Ciba-Geigy Ltd., Basle, Switzerland.

    Puri, E. & Muller, D. (1984) Autradiographic DNA repair test on rat
    hepatocytes. CGA 71'818 ( in vitro test for DNA-damaging
    properties). Proj. No.: 811522. Unpublished report dated 30 January
    1984 from Ciba-Geigy Ltd., Basle, Switzerland. Submitted to WHO by
    Ciba-Geigy Ltd., Basle, Switzerland.

    Salamon, C.M. (1985) CGA-71818 technical teratology study in rats.
    Unpublished report No. 450-2087 dated 16-09-1985 from American
    Biogenics Corp., Decatur, Illinois, USA. Submitted to WHO by Ciba-
    Geigy Ltd., Basle, Switzerland.

    Sarasin, G. (1980) Report on acute oral LD50 in the mouse of CGA
    71818 technical. Unpublished report No. 800552 dated 20-10-1980 from
    Ciba-Geigy Ltd., Basle, Switzerland. Submitted to WHO by Ciba-Geigy
    Ltd., Basle, Switzerland.

    Schardein, J.L. (1987) Two-generation reproduction study in albino
    rats with CGA 71818. Unpublished report No. 382-119 dated 14-08-1987
    from International Research and Development Corp., Mattawan,
    Michigan, USA. Submitted to WHO by Ciba-Geigy Ltd., Basle,
    Switzerland.

    Seiffert, G., Komarek, J., Zak, F., Malik, C. & Zakova, N. (1983)
    CGA 71818 21 day repeated dose dermal toxicity study in rabbits.
    Unpublished report dated September 1983, project No. 820206 from
    Ciba-Geigy Ltd., Basle, Switzerland. Submitted to WHO by Ciba-Geigy
    Ltd., Basle, Switzerland.

    Strasser, F.F. & Müller, D. (1982) Point mutation assay with mouse
    lymphoma cells. Host-mediated assay with CGA 71818. Unpublished
    report project No. 811355 dated 5-01-1982 from Ciba-Geigy Ltd.,
    Basle, Switzerland. Submitted to WHO by Ciba-Geigy Ltd., Basle,
    Switzerland.

    Ullmann, L. & Gfeller, W. (1980a) Report on eye irritation in the
    rabbit after single application of technical CGA 71818. Unpublished
    report project No. 800557 dated 28-05-1980 from Ciba-Geigy Ltd.,
    Basle, Switzerland.Submitted to WHO by Ciba-Geigy Ltd., Basle,
    Switzerland.

    Ullmann, L. & Gfeller, W. (1980b) Report on skin irritation in the
    rabbit after single application of technical CGA 71818. Unpublished
    report project No. 800558 dated 28-05-1980 from Ciba-Geigy Ltd.,
    Basle, Switzerland. Submitted to WHO by Ciba-Geigy Ltd., Basle,
    Switzerland.

    Ullmann, L. & Gfeller, W. (1980c) Report on skin sensitizing
    (contact allergenic) efect in guinea-pigs of technical CGA 71818.
    Unpublished report project No. 800560 dated 12-06-1980 from Ciba-
    Geigy Ltd., Basle, Switzerland. Submitted to WHO by Ciba-Geigy Ltd.,
    Basle, Switzerland.

    Van Dijk, A. (1987) (U-14C) phenyl CGA 71818: Absorption,
    distribution, excretion and metabolism after single oral and
    repeated oral administration to the rat. Unpublished report project
    No. 075666 dated 11-06-1987 from RCC Umweltchemie AG, Itingen,
    Switzerland. Submitted to WHO by Ciba-Geigy Ltd., Basle,
    Switzerland.

    Waechter, F., Bentley, P. & Stäubli, W. (1985) The effect of
    penconazole on drug metabolizing enzymes in the livers of male rats
    and mice. Unpublished report dated April 1985 from Ciba-Geigy Ltd.,
    Basle, Switzerland. Submitted to WHO by Ciba-Geigy Ltd., Basle,
    Switzerland.

    WHO (1992). The WHO recommended classification of pesticides by
    hazard and guidelines to classification 1992-1993 (WHO/PCS/92.14).
    Available from the International Programme on Chemical Safety, World
    Health Organization, Geneva, Switzerland.


    See Also:
       Toxicological Abbreviations