IPCS INCHEM Home

    IPRODIONE

    First draft prepared by A. Clevenger
    Office of Pesticide Programs
    US Environmental Protection Agency
    Washington DC USA

    EXPLANATION

         Iprodione was previously evaluated by the Joint Meeting in 1977
    (Annex 1, reference 28) when an ADI of 0-0.3 mg/kg bw was
    established. The data reviewed in 1977 consisted of studies of
    pharmacokinetics, short-term toxicity in rats and dogs, long-term
    toxicity in mice and rats, and special studies on developmental
    toxicity, reproduction, and mutagenicity. The present review
    evaluates studies made available since the 1977 review. Relevant
    portions of the previous monograph have been incorporated into this
    toxicological monograph.

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    BIOLOGICAL DATA

    Biochemical aspects

    Absorption, distribution, and excretion

    Rats

         The pharmacokinetics of iprodione following oral administration
    was studied using groups (5/sex) of Charles River CD rats. One group
    received a single low dose of 50 mg 14C-iprodione/kg bw (uniformly
    labelled phenyl ring). A second group received a single high dose of
    900 mg 14C-iprodione/kg bw. A third group received multiple doses
    (14 daily doses) of 50 mg iprodione/kg bw/day of unlabelled (99.3%
    purity) followed by a single dose of 14C-iprodione. Blood, urine,
    and faeces were collected for 7 days after treatment at which time
    rats were sacrificed and tissues collected.

         Following a single low dose, 90% of the administered dose was
    eliminated within 4 days primarily in urine. Urinary excretion
    accounted for 67% of the administered dose in males and 53% in
    females whereas faecal excretion accounted for 25% in males and 39%
    in females. Males may have absorbed the dose to a greater extent
    than females based on the greater urinary excretion and the larger
    area-under-the-curve (blood concentration-time curve) for males.
    Peak blood concentrations were reached within 2-4 h. After 7 days,
    tissue residues in both sexes were less than 0.7 ppm in any one
    tissue and collectively accounted for no more than 0.3% of the
    administered dose. Tissue concentrations were highest in the liver
    and intestines. The elimination half-life was estimated to be 9 h
    for males and 7 h for females based on the blood-concentration time
    curves.

         Following a single high dose, 90% of the administered dose was
    eliminated within 2 days in males and 3 days in females. The single
    high dose appeared to be absorbed to a lesser extent than the single
    low dose based on the greater faecal excretion of parent compound
    following the high dose compared to predominantly urinary excretion
    of the single low dose. Faecal excretion accounted for 56% of the
    administered high dose in males and 52% in females whereas urinary
    excretion accounted for 43% in male and 46% in females. The peak
    blood concentration was reached within 6 h and was about three times
    the peak concentration following the single low dose. After 7 days,
    tissue concentrations were less than 10 ppm in any one tissue and
    collectively accounted for no more than 0.2% of the administered
    dose. The elimination half-life of the single high dose was about
    twice that for the single low dose. The high dose elimination half-
    lives were 20 h for males and 13 h for females.

         Following multiple low dose exposures, 90% of the administered
    dose was eliminated within 3 days, primarily in urine. The excretion
    pattern was similar to that for the single low dose. Urinary
    excretion accounted for 75% of the administered dose in males and
    65% in females whereas faecal excretion accounted for 20% in male
    and 28% in females. Tissue concentrations were <1 ppm in any one
    tissue (Hallifax, 1989).

         The dermal absorption of iprodione was 0.65% in 24 h for male
    and female rats. Groups of 3 male and 3 female hairless strain rats
    received a dose of 185 mg 14C-iprodione /kg bw of (uniformly
    labeled phenyl ring) applied to a 12 cm2 area of the back for 24
    h. Ninety to 93% of the dose was recovered from the skin. Of the
    0.65% absorbed, 0.45% of the radiolabel was found in urine and
    faeces and the remaining 0.15% was present mainly in the carcass
    (Laurent  et al., 1983).

    Biotransformation

    Rats

         Following a single application of an oral dose of 200 mg
    iprodione/kg bw, 26% of the administered dose was eliminated in the
    urine and 59% in the faeces within 24 hours after application. The
    major portion of the dose excreted in the faeces was the parent
    compound, whereas only 3% of the administered dose was eliminated
    unchanged in the urine. Besides the principal urinary metabolites
    with a degraded isopropylcarbamoyl group (about 11% of the dose
    administered), metabolites with intact hydroxylated or non-
    hydroxylated aromatic rings were excreted in the urine. The isomer
    of the parent compound accounted for a small proportion of the
    metabolites. Residues in the principal organs and tissues did not
    exceed 1.5% of the administered dose in rats sacrificed 4 days after
    dosage (Laurent and Buys, 1974).

         In a similar study rats were dosed once with 100 mg/kg of 14C
    aromatic ring labelled iprodione; 96 hours after administration 62%
    of the applied dose was eliminated via the urine and 36% via the
    faeces. About 16% was excreted as the parent compound in the faeces;
    the remainig radioactivity was mainly in the urine, in the form of
    the desisopropylated derivative (about 20% of the dose) and the N-
    (3,5-dichloro-4-hydroxyphenylbiuret) (approx. 13%). Tissues sampled
    4 days after dosage contained about 1% of the administered dose
    (Laurent, et al, 1976).

         The metabolism of iprodione was studied in Charles River CD
    rats by analysing the urine and faeces obtained in the
    pharmacokinetics study described above (Hallifax, 1989). Metabolite
    identity was based on comparison of retention times with reference
    compounds by TLC and HPLC. A proposed metabolism scheme is shown in
    Figure 1. Iprodione was extensively metabolized by both males and
    females following single low or high doses or repeated low doses.
    Males and females of all groups eliminated in the urine relatively
    large amounts of a dealkylated metabolite corresponding to reference
    compound 32490 RP. The urine of all male and high dose females also
    contained large amounts of 36114 RP, a hydantoin ring-opened
    metabolite. Two major urinary metabolites, each representing 10-15%
    of the administered dose, were unidentified. Females in all groups
    eliminated a larger portion of the urinary radiolabel as the parent
    compound than males. Most of the extracted radiolabel in the faeces
    was the unchanged parent compound with small amounts of the same
    metabolites identified in the urine. The faeces of the high dose
    group contained relatively more parent compound than the single or
    repeated low dose groups, which is consistent with lower absorption
    of the high dose (Hallifax, 1989).

         Iprodione and three metabolites were identified in hairless
    rats (3/sex) treated dermally with a dose (185 mg/kg bw) of 14C-
    iprodione for 24 h. Iprodione was found unchanged in the urine,
    faeces, and intestines. Metabolite 30228 RP was found in the urine
    of males, 32490 was detected in the urine of males and females, and
    36114 RP was detected in the urine, faeces, and intestines of males
    and females (Laurent  et al., 1983).

    Humans

         Small amounts of the metabolite 32490 RP were detected in the
    urine of 3 of 6 workers involved in mixing and diluting the
    formulation ROVRAL WP(R) (50% w/w iprodione). Unchanged iprodione
    was not detected in the urine (Jones, 1983).

    Toxicological studies

    Acute toxicity studies

         The acute toxicity of iprodione is summarized in Table 1.
    Common signs of toxicity include decreased motor activity, ataxia,
    tearing, and paralysis. Tonic convulsions were noted in one study in
    mice.

    FIGURE 1

    Short-term toxicity studies

    Mice

         Groups (10-20/sex/dose) of CF-1 mice received iprodione (purity
    unspecified) in the diet daily for 28 days at 0, 600, 1900, 6000,
    9500, or 15000 ppm (equal to 130, 390, 950, 1500 or 2300 mg/kg
    bw/day for males and 120, 420, 1000, 1500 or 2400 mg/kg bw/day for
    females). The highest dose produced mortality and depressed body-
    weight gain and food consumption. Exposure to 6000 ppm and above
    produced ataxia and lethargy during the first week of treatment. The
    liver was affected in groups receiving 6000 ppm and above. Absolute
    and relative liver weights were increased, livers had a stippled
    appearance on gross examination, and the incidence of hepatocyte
    vacuolation and focal eosinophilic degeneration was increased. At
    15000 ppm granulomatous inflammation, (possibly in response to a
    foreign body), was observed in the heart, liver, and kidney. The
    NOAEL was 1900 ppm (equal to 390 mg/kg bw/day for males and 420
    mg/kg bw/day for females) based on liver effects at 6000 ppm and
    above (Stevens, 1974).

         Groups of 10 CF-1 Carworth mice/sex received iprodione (purity
    unspecified) in the diet daily for 4 weeks at 0, 600, 1900, 6000,
    9500 or 15000 ppm, (equal to 115, 366, 1090, 1860 or 4030 mg/kg
    bw/day for males - the high dose based on first two weeks only - and
    137, 439, 1310, 2090 or 2590 for females). The high dose produced
    mortality and depressed body-weight. Depression and ataxia were
    observed at 6000 ppm and higher. Relative liver weight was increased
    at 6000 ppm and above. Gross necropsy revealed white foci in the
    liver of mice receiving 1900 ppm and higher, a stippled appearance
    of the liver at 6000 ppm and higher, and liver enlargement at 9500
    and 15000 ppm. White foci and granulomatous inflammation were
    observed in numerous tissues, primarily at the high dose. One
    granulomatous lesion was observed in the liver at 6000 ppm and 5
    were observed in the bladder at 9500 ppm. The presence of
    spindle-shaped clear spaces in tissues and foreign body type giant
    cells suggested a reaction to crystal formation. Liver cell
    hypertrophy was increased at 6000 ppm and above. The NOAEL was 600
    ppm (equal to 115 mg/kg bw/day for males and 137 mg/kg bw/day for
    females) based on gross changes in the liver at 1900 ppm and above
    (Huffman, 1974).


    
    Table 1.  Acute toxicity of iprodione

                                                                                                        
    Species   Strain              Sex   Route                LD50       LC50    Reference
                                                             mg/kg bw   mg/l
                                                                                                        

    Mouse     CD-1                M     oral                 1870               Takehara  et al. (1976b)
                                  F                          2670

              CD-1                M     i.p.                 900                Takehara  et al. (1976b)
                                  F                          625

              CD-1                M     subcutaneous         >6700              Takehara  et al. (1976b)
                                  F                          >6700

    Rat       CD                  M     oral                 >2000              Cummins (1989)
                                  F                          >20002

              CD                  M     oral                 2060               Takehara  et al. (1976a)
                                  F                          1530

              Wistar              M&F   oral                 3700               Babish (1976a)

              CD                  M     i.p.                 1330               Takehara  et al. (1976a)
                                  F                          700

              CD                  M     subcutaneous         >4500              Takehara  et al. (1976a)
                                  F                          >4500

              Sprague-Dawley      M     inhalation                      >3.29   Coombs & Clark (1977)
                                  F     (4-hr exp)                      >3.29

    Table 1 (cont'd)

                                                                                                        
    Species   Strain              Sex   Route                LD50       LC50    Reference
                                                             mg/kg bw   mg/l
                                                                                                        

    Rabbit    New Zeeland white   M     dermal (24-hr exp)   >2000              Plutnick  et al. (1988)
                                  F                          >2000

              ?                   ?     dermal (?-hr exp)    >30 000            Babish (1976b)

    Dog       Beagle              M     oral                 >2000              Pasquet & Mazuret (1974)
                                  F                          >2000              (FAO/WHO, 1978)
                                                                                                        

    1 Purity of technical iprodione was 95.8%
    2 Purity of technical iprodione was 97.9%


    
         The crystal formation in tissues was further evaluated using
    groups of 15 CD-1 mice/sex receiving iprodione (93.5%) in the diet
    daily for 4 weeks at 0, 1900, 6000, 9500 or 15000 ppm (equivalent to
    290, 900, 1400, and 2300 mg/kg bw/day). The two highest dose levels
    produced mortality, clinical signs of toxicity, and depressed weight
    gain and food consumption. At 6000 ppm and above, crystalline
    deposits and effects on the liver were observed. Granulomatous
    lesions surrounding crystal deposits were found frequently in the
    urinary bladder and occasionally in liver parenchyma, myocardium,
    diaphragmatic muscle, and skeletal muscle. It was speculated that
    the crystals contained a major metabolite of iprodione, 32490 R.P.,
    which was identified in the liver. Liver effects included increased
    weight, pale and mottled appearance on gross examination, and
    swelling of hepatocytes to form large homogeneous areas in the
    centrilobular region of the liver. Histopathological changes in the
    testes and spleen were observed at doses levels above 6000 ppm. A
    NOAEL of 1900 ppm (equivalent to 290 mg/kg bw/day) was determined
    based on crystalline deposits in the urinary bladder, liver
    enlargement, and hepatocellular swelling at 6000 ppm and above
    (Ganter  et al., 1979).

         Groups of 10 Crl:CD-1(ICR)BR mice/sex received iprodione (95.7%
    purity) in the diet daily for 13 weeks at 0, 1500, 3000, 6000, or
    12000 ppm, (equal to 260, 510, 1100 or 2100 mg/kg bw/day for males
    and 330, 660, 1300 or 2600 mg/kg bw/day for females). The high dose
    was associated with mortality, clinical signs of toxicity, weight
    loss, and reduced food consumption. The two highest dose levels
    produced crystalline deposits with associated multinucleated cells
    in a number of tissues, particularly in the urinary bladder. At the
    lowest dose level of 1500 ppm, liver and adrenal gland weights were
    increased in females. The incidence and severity of liver cell
    enlargement in males and females showed a dose-related increase
    beginning with the 1500 ppm dose level. Enlargement and vacuolation
    of adrenal cortex cells were increased in treated groups. The
    incidence of vacuolation of zona fasciculata cells was 0/10, 1/10,
    3/10, 6/10, and 4/9 in females receiving 0, 1500, 3000, 6000 or
    12000 ppm, respectively. At 3000 ppm and higher, effects were
    observed in the kidney, uterus, ovary, and spleen. The authors
    determined that dose levels of 6000 ppm or greater were unsuitable
    for a long-term study in mice because of crystal formation and
    accompanying effects in the urinary bladder. A NOAEL was not
    identified in this study. The lowest dose of 1500 ppm was associated
    with enlargement of the liver and adrenal glands and microscopic
    changes in these organs (Fryer  et al., 1990a).

    Rats

         Groups of 15 CD/CRJ rats/sex received iprodione (purity
    unspecified) in the diet daily for 3 months at 0, 300, 1000, or 3000
    ppm, (equal to 21, 70 or 210 mg/kg bw/day for males and 24, 82 or
    240 mg/kg bw/day for females). The high dose of 3000 ppm produced

    clinical signs of toxicity (i.e. piloerection, rough fur), depressed
    food and water consumption, and decreased body-weight (final weight
    reduced 20-40%). A number of absolute and relative organ weights
    were decreased at the high dose including the liver, spleen, thymus,
    kidneys, and heart. Microscopic findings were observed at the high
    dose in the liver, spleen, and thymus. Swelling of the zona
    glomerulosa of the adrenal gland showed a dose-related increase at
    1000 and 3000 ppm in both sexes. The NOAEL was 300 ppm (equal to 21
    mg/kg bw/day for males and 24 mg/kg bw/day for females) based on
    microscopic changes in the adrenal cortex at 1000 ppm and above
    (Itabashi  et al., 1978).

         Groups of 10 Crl:CD (SD) BR rats/sex received iprodione (95.7%
    purity) in the diet daily for up to 13 weeks at 0, 1000, 2000, 3000,
    or 5000 ppm (equal to 78, 150 or 250 mg/kg bw/day for males and 89,
    180 or 270 mg/kg bw/day for females). The high dose group was
    terminated during week 8 due to excessive toxicity which included a
    progressive decrease in food intake and body-weight and the death of
    one male. Upon examination these animals showed abnormalities in the
    liver, adrenal glands, uterus, ovaries, prostate, and seminal
    vesicles. Clinical signs (i.e. hunched posture, piloerection,
    emaciation) occurred in males and females receiving 3000 ppm. Body-
    weight, food intake, and food efficiency were reduced at the 2000
    and 3000 ppm. Ovary weight was decreased at 2000 and 3000 ppm, and
    uterus weight was reduced at 3000 ppm. Seminal vesicles and the
    prostate gland of males receiving 3000 ppm were reported as smaller
    than normal but no histological changes were noted.
    Histopathological changes were in the adrenal glands, uterus, and
    ovaries were increased at 2000 and 3000 ppm. Adrenal gland findings
    included enlarged cells of the  zona glomerulosa in males and
    females and vacuolation of the  zone fasciculata mainly in females.
    The uterus showed signs of atrophy and ovaries contained reduced
    numbers of corpora lutea. A NOAEL of 1000 ppm equal to 78 mg/kg
    bw/day for males and 89 mg/kg bw/day for females was determined,
    based on a reduced body-weight gain and histopathological changes at
    2000 ppm and higher (Fryer  et al., 1990b).

         Groups of 15 male and 15 female caesarean originated, barrier
    sustained, rats were fed 0, 150, 500 or 1000 ppm iprodione in the
    diet for 5 months. No effects were observed on mortaility, food
    consumption, haematology (as judged by haemoglobin, haematocrit,
    erythrocyte count, or total and differential leucocyte count)
    clinical chemistry (as judged by BSP, SGOT, SGPT or SAP) or
    urinalysis. Body weight gain was slightly reduced (especially in
    males) at 500 and 1000 ppm. Absolute (but not relative) heart weight
    was reduced in males at 500 and 1000 ppm, and absolute kidney weight
    was reduced at 1000 ppm. In females, absolute liver and kidney
    weights were significantly reduced at 500 ppm only. Gross and
    histopathology were normal at all dose levels. In a parallel study,
    dichlozoline, a structurally related compound, induced cataracts. No
    such effect was seen with iprodione (Ganter  et al., 1973a).

    Dogs

         Groups of 2 male and 2 female dogs were maintained on a diet
    containing iprodione at dose levels of 0, 800, 2400 or 7200 ppm for
    a period of 3 months. At the top dose level the method of
    administration was altered after 6 weeks, to gelatine capsules. The
    treatment did not affect mortality. The recorded values of
    haematological determinations and urinalyses were within normal
    limits, as judged by haemoglobin, haematocrit, reticulocyte
    erythrocyte count, total and differential leucocyte count and
    prothrombine time, except for signs of mild anaemia in 1 male and 1
    female at 2 months and 1 male at 3 months at the top dose level. At
    7200 ppm a reduction of food consumption was observed, accompanied
    by reduced body-weight gain. Opththalmosopic examination of the
    animals did not reveal any pathological alterations. A transient
    increase in SGOT and SGPT was observed after 1 and 2 months of
    treatment at 7200 ppm. In treated male rats a dose-dependent
    increase of relative liver weights was observed, which was also
    observed in females at 2400 ppm and above. At 7200 ppm reduced
    relative weight of testes was found, but there was no histological
    indication of damage. The histopathological findings did not reveal
    any indication of treatment-related alterations of tissues (Coquet,
    1973c; Gunter & Girard, 1973).

         Groups of 6 beagle dogs/sex received iprodione (96.5% purity)
    in the diet daily for 52 weeks at 0, 100, 600, or 3600 ppm, (equal
    to 4.1, 24.9 or 145 mg/kg bw/day for males and 4.3, 28.3 or 153
    mg/kg bw/day for females). Ophthalmology, haematology, clinical
    chemistry, and urinalysis tests were performed periodically over the
    course of the study. Slight retinal hyperreflection was noted more
    frequently in males receiving 3600 ppm and in females receiving 600
    or 3600 ppm. The severity did not increase over time or with dose
    level and was not seen consistently in the same animals over time.
    Red blood cells were affected at 3600 ppm and possibly at 600 ppm.
    Compared to controls, high dose males showed a slight but consistent
    decrease in erythrocyte count, haemoglobin, and haematocrit over the
    course of the study. Females receiving the high dose showed a less
    consistent pattern of anaemia. Platelet count and partial
    thromboplastin time were increased over the course of the study in
    high dose males and females. The high dose was also associated with
    an increase in frequency and severity of erythrocytes containing
    Heinz bodies. After 52 weeks, 3/6 control males and 4/6 control
    females showed the presence of Heinz bodies compared to all males
    and females receiving the high dose. In control dogs the number of
    affected erythrocytes was 0-2 per field compared to 6-50 or over 50
    per field in dogs receiving the high dose. During the first one-
    third of the study, the incidence and severity of Heinz bodies were
    also increased in males receiving 600 ppm. No treatment-related
    changes were noted in the bone marrow.

         Plasma ALP was consistently increased over control values and
    was above the normal range in high dose males and females. In high
    dose females, serum ALT was transiently elevated early in the study
    and LDH was transiently increased late in the study. Total bilirubin
    and albumin were slightly elevated during the study particularly in
    high dose females. Absolute and relative liver and adrenal gland
    weights were increased at the high dose in males and females.
    Absolute prostate gland weight was decreased 22% at 600 ppm and 41%
    at 3600 ppm. Relative prostate gland weight was also reduced at the
    high dose (39%). Two high dose females had enlarged adrenal glands
    and one high dose male had a swollen liver on gross examination.
    Nematode granulomas were found in various tissues of a number of
    control and treated dogs. Treatment-related microscopic changes were
    observed in the liver, adrenal glands, and urinary bladder of high
    dose males and females. In the urinary bladder, the majority of high
    dose males and females had submucosal granulomas and giant cells
    containing crystals. The majority of high dose males and females had
    fat vacuolation and/or pallid appearance of the adrenal cortex
    compared to an absence or lower incidence in controls. Hepatic
    centriacinar atrophy was observed in 3/6 males and 4/6 females
    receiving the high dose compared to no controls with the lesion.
    Pigmented macrophage agglomerates in the liver were more prominent
    in the high dose groups than in controls. An additional finding in
    females was lipofuscinosis in the proximal convoluted tubules of the
    kidney occurring in 2/6, 0/6, 4/5, and 4/6 in the 0, 100, 600, and
    3600 ppm groups, respectively. No treatment-related histopathologic
    changes were noted in the prostate gland. A NOAEL of 100 ppm, equal
    to 4.1 mg/kg bw/day, was determined, 600 ppm representing a minimal
    toxic effect level with the majority of toxic changes occurring at
    the 3600 ppm dose level (Broadmeadow, 1984).

         A second one-year dog study was conducted to determine the
    NOAEL between 100 and 600 ppm. Groups of 6 beagle dogs/sex received
    iprodione (96% purity) in the diet daily for 52 weeks at 0, 200,
    300, 400, or 600 ppm, (equal to 7.8, 12, 18 or 25 mg/kg bw/day for
    males and 9.1, 13, 18 or 26 mg/kg bw/day for females). Eye
    examinations and haematology were performed during weeks 4, 8, 12,
    20, 28, 36, and 52. The adrenal glands, kidneys, and prostate were
    the only organs weighed. Kidneys of females and prostate of males
    were the only tissues examined microscopically. Iprodione treatment
    had no effect on survival, body weight, body-weight gain, food
    consumption, or food efficiency. Most dogs treated with iprodione
    developed skin lesions consisting of redness and scab formation
    occurring primarily in the inguinal, hindlimb, and ventral abdominal
    areas. Skin lesions were less frequent and less severe in controls.
    The majority of lesions had cleared by study termination. Tests for
    mange and fungal infection were negative. It was noted that slight
    irritation of the skin was not uncommon in dogs fed powdered chow.

         Eye examinations revealed no treatment-related abnormalities.
    Haematology parameters were within the normal range for all groups.

    In females receiving 600 ppm, erythrocyte count, haemoglobin, and
    haematocrit were reduced at week 4 (15%) and at week 36 (10%). In
    both males and females receiving 600 ppm, values for these
    erythrocyte parameters were consistently lower than control values
    through week 36, although the differences were not statistically
    significant. Heinz bodies were not observed in any control or
    treated animal at any time point. Organ weights (kidney, adrenal
    glands, prostate) were unaffected, and no treatment-related
    histopathological changes were observed in the kidneys of females or
    prostate of males. Based on slight changes in erythrocyte parameters
    at 600 ppm, the NOAEL was 400 ppm, equal to 18 mg/kg bw/day (Kangas
     et al., 1991).

    Long-term toxicity/carcinogenicity studies

    Mice

         Groups of 60 male and 60 female mice were maintained on a diet
    containing the test compound at 0, 200, 500 or 1250 ppm for 18
    months. No treatment-related effects on body-weight, food
    consumption or mortality were found. The recorded values of the
    haematological, blood chemistry and urinalyses tests, performed
    after 6, 12 and 18 months of the feeding period, were within the
    physiological range. Necropsy findings on mice that died during the
    last 6 months of the test and on those sacrificed at the termination
    date showed an increased number of enlarged lymph nodes in males at
    200 ppm. Organ weight variations occurred sporadically in the
    various dose groups which were considered not to be treatment-
    related. The histopathological observations failed to reveal
    abnormal features. The distribution of neoplastic and non-neoplastic
    findings did not appear to demonstrate any significant dose
    dependence. The most common tumours were lymphosarcomas involving
    the spleen, lymph nodes and thymus (Hastings & Huffmann, 1975).

    Rats

         Groups of 60 male and 60 female rats were maintained on a diet
    containing 0, 125, 250 or 1000 ppm iprodione for 24 months. Slight
    reduction in body weight gain was observed at 1000 ppm. This was
    accompained by some reduction in food intake. The treatment had no
    effect on food consumption, mortality or values of the haematologic,
    blood chemistry or urinalyses determinations. Necropsy findings did
    not reveal any drug-related gross alterations. Variations in organ
    weight did not show a group distribution and did not seem to be
    related to drug administration. Histopathology did not indicate a
    treatment relationship with neoplastic or non-neoplastic findings.
    At 24 months the most common tumours observed were pituitary
    adenomas and adenocarcinomas and fibroadenoma of the mammary glands
    (Hastings  et al., 1976).

    Reproduction studies

    Rats

         Groups of 10 male and 20 female rats were maintained on a diet
    containing iprodione at concentrations of 0, 125, 250 or 1000 ppm
    for the first 5 weeks of each generation and 0, 250, 500 or 2000 ppm
    for the next 8 weeks of treatment. The diet was fed through 3
    generations. The treatment did not affect the growth rate, food
    consumption, mortality or fertility of the parent animals. The
    number of living delivered pups of the females treated with 2000 ppm
    was slightly reduced and the post-natal growth of the pups was
    slightly retarded. There was also a tendancy for growth reduction at
    500 ppm. Autopsy findings and microscopic examination of the major
    organs performed in rats of the third generation did not reveal
    abnormalities (Coquet, 1976).

         The reproductive toxicity of iprodione was studied in two
    successive generations of Crl:CD BR/VAF/Plus rats. The first
    parental (F0) animals were mated twice to produce F1a and F1b
    litters. F1a animals were mated twice to produce F2a and F2b
    litters. Groups (28/sex) received diets containing 0, 300, 1000, or
    3000 ppm of iprodione (96.2% purity) beginning at least 10 weeks
    prior to mating. The high dose of 3000 ppm was reduced to 2000 ppm
    at the time of the first mating of F1a rats because of excessive
    toxicity. The administered doses were equal to 17, 55 or 160 mg/kg
    bw/day for F0 males; 21, 71 or 210 mg/kg bw/day for F0 females;
    20, 68, and 150 mg/kg bw/day for F1 males; and 25, 82 or 190 mg/kg
    bw/day for F1 females. Toxicity in adult rats was observed at 1000
    ppm and above. Body-weight, body-weight gain, and food consumption
    were reduced throughout the treatment period in F0 and F1 males
    receiving 3000 ppm and F0 and F1 females receiving 1000 or 3000
    ppm. Reproductive performance was unaffected by iprodione exposure.
    Offspring toxicity was observed at the high dose. During lactation
    (16-21 days of age), F1a and F1b pups exhibited signs of
    toxicity including unkempt or hunched appearance, slow movement, and
    tremors during the last days of lactation. In both generations,
    litter size number of live pups, and pup weight were decreased at
    the high dose. The NOAEL was 300 ppm, equal to 21 mg/kg bw/day, for
    parental toxicity based on reduced parental body-weight at 1000 ppm
    and higher; for embryofetal toxicity, the NOAEL was 1000 ppm, based
    on clinical signs, reduced litter size, and reduced pup weight at
    3000 ppm (Henwood, 1991).

    Special studies on embryo/fetotoxicity

    Rats

         Groups of 25-30 rats were treated orally with 0, 100, 200 or
    400 mg/kg bw/day iprodione on gestation days 5 to 15. Females at 400
    mg/kg bw/day showed reduced fertility, reduced body weight gain and
    a dose-related reduction in food consumption, especially during the

    treatment period. The number of implantations was also reduced at
    the highest dose level. There was no indication of an embryotoxic or
    teratogenic effect of the test compound (Coquet, 1973a).

         In a dose range-finding study in CD pregnant rats, treatment
    with 400 and 800 mg/kg bw/day resulted in mortality, weight loss,
    and pronounced clinical signs. Treatment with 240 mg/kg bw/day
    reduced weight gain and produced clinical signs, and 120 mg/kg
    bw/day occasionally produced clinical signs (i.e. flaccid muscles).
    The lowest dose of 40 mg/kg bw/day had no effect on maternal health.
    It was concluded that dose levels should not exceed 240 mg/kg bw/day
    in a definitive developmental toxicity study (Tesh  et al., 1986a).

         In the definitive study, iprodione (94.2%) was administered by
    oral gavage to groups of 25 mated female CD rats at doses of 0, 40,
    90, or 200 mg/kg bw/day. Controls received the vehicle (aqueous
    methylcellulose). Rats were treated days 6-15 of gestation and
    sacrificed on day 21. The administered doses had no adverse effect
    on maternal health as assessed by mortality, clinical signs, body-
    weight, and food consumption. In the offspring, the incidence of
    space between body wall and organs was slightly increased at the
    high dose. The incidences were 4.3%, 5.3%, 5.8%, and 11.2% on a
    fetal basis and 15%, 20%, 20%, and 32% on a litter basis at 0, 40,
    90 and 200 mg/kg bw/day, respectively. The majority of affected
    fetuses were small in size. It was noted that this observation was
    associated with fetuses of low body-weight in previous studies and
    was indicative of slight immaturity. The incidence of small fetuses
    (<2.7g) in this study was 2.9%, 5.1%, 4.9%, and 8.0% (fetal basis).
    Group mean fetal body-weights were 3.27, 3.18, 3.16, and 3.15 g. The
    findings collectively were suggestive of a slight effect on fetal
    developmental at the high dose despite the fact that none of the
    differences were statistically significant and values at the high
    dose were within the historical control range. A NOAEL for maternal
    toxicity of 200 mg/kg bw/day and a NOAEL for embryo-fetal toxicity
    of 90 mg/kg bw/day were determined, based on slightly delayed fetal
    development at 200 mg/kg bw/day. There was no evidence of
    teratogenic potential at the highest dose tested (200 mg/kg bw/day)
    (Tesh  et al., 1986b).

    Rabbits

         Groups of 15-17 New Zeeland white rabbits were intubated on
    gestation days 6-16 inclusive with 0, 100, 200 or 400 mg/kg bw/day
    iprodione. Body-weight gain, over the period of treatment, was
    slightly reduced at 100 mg/kg bw/day, and a dose-related weight loss
    occurred at 200 and 400 mg/kg bw/day. Food intake was reduced at 200
    mg/kg bw/day and above. At 400 mg/kg bw/day 9 of 17 females died,
    and only one of the four remaining pregnant animals carried to term.
    Fetal loss was increased at 200 mg/kg bw/day, and the fetal weight
    was reduced at 200 mg/kg bw/day and above. Multiple malformations
    occurred in 1 of 68 living fetuses at 200 mg/kg bw/day. Minor
    malformations were noted in all groups (Coquet, 1973b).

         The developmental toxicity of iprodione was studied in New
    Zeeland white rabbits. Iprodione (95.0% purity) was administered by
    oral gavage to groups of 18 artificially inseminated females at
    doses of 0, 20, 60, or 200 mg/kg bw/day. The control group received
    the vehicle (aqueous methylcellulose). Rabbits were treated on days
    6-18 of gestation and sacrificed on day 29. Maternal toxicity was
    produced at 60 and 200 mg/kg bw/day. The high dose group experienced
    weight loss and reduced food consumption during the entire treatment
    period. Clinical signs associated with the high dose included hair
    loss, diarrhoea, and decreased urination and defecation. The group
    receiving 60 mg/kg bw/day experienced slight body-weight loss during
    the first six days of treatment compared to positive weight gain by
    controls. Seven of 18 females receiving the high dose aborted
    compared to 1/18, 0/18, and 1/18 for the 0, 20, and 60 mg/kg bw/day
    groups. Ten does receiving the high dose delivered litters, two of
    which had totally resorbed litters (compared to 1/13 controls)
    resulting in only 8 viable litters at the high dose. A NOAEL of 20
    mg/kg bw/day was determined based on depressed maternal weight gain
    at 60 mg/kg bw/day and above. The high dose of 200 mg/kg bw/day was
    considered an excessive dose for a teratology evaluation. Some
    skeletal variations appeared increased at the high dose, but the
    incidences were within the historical control range. The NOAEL for
    maternal toxicity was 20 mg/kg bw/day based on depressed weight gain
    at 60 mg/kg bw/day. The NOAEL for embryo-fetal toxicity was 60 mg/kg
    bw/day based on increased abortions and post-implantation losses at
    200 mg/kg bw/day (Keets  et al., 1985).

    Special studies on eye and skin irritation and hypersensitivity

         Technical iprodione caused mild, transient eye irritation in
    rabbits. The irritation was lessened by washing the eye immediately
    after exposure (Babish, 1976c; Bonnette, 1991a).

         Technical iprodione is not a dermal irritant in rabbits
    (Babish, 1976d; Bonnette, 1991b) or a dermal sensitizer in guinea-
    pigs (Trimmer  et al., 1988).

    Special studies on genotoxicity

         The results of genotoxicity studies are summarized in Table 2.
    Iprodione has been consistently negative in assays for point
    mutation, chromosomal aberration, and sister chromatid exchange. A
    questionable positive result was reported for DNA damage in
     Bacillus subtilis.

    Observations in humans

         No data available.



        Table 2.  Results of genotoxicity assays on iprodione
                                                                                                                                                
    Test system                   Test object                  Concentration of                     Purity  Results   Reference
                                                               iprodione
                                                                                                                                                

    Ames test (1)                 S. typhimurium               1-5000 µg/plate dissolved in DMSO    96.2%   Negative  Lawlor & Valentine (1990)
                                  TA98, TA100, TA1535,
                                  TA1537, TA1538

                                  S. typhimurium               25-200µg/plate dissolved in DMSO     95.1    Negative  Bouanchaud & Cartier
                                  TA98, TA100, TA1535,                                              99.3%             (1982a,b)
                                  TA1537, TA1538

                                  S. typhimurium               12.5-250 µg/plate dissolved in DMSO  ?       Negative  Benazet & Cartier (1979)
                                  Ta98, TA100, TA1535,
                                  TA1537

    E. coli mutation assay (1)    E. coli K12, GY 5057         0.05-1000 µg/ml dissolved in DMSO    95.1    Negative  Bouanchaud & Cartier
                                  strain                                                            99.3%             (1982a,b)

                                  E. coli, W3110 (pol A+),     12.5-200 µg/plate dissolved in DMSO  95.1    Negative  Bouanchaud & Cartier
                                  p3478 (pol A-)                                                    99.3%             (1982a,b)

    B. subtilis mutation          B. subtilis rec. exc.        20-1670 µg/ml dissolved in DMSO      96.8%   Positive  Felkner (1985a)
    assay (1)                     pol strains (19 strains)                                                  (3)

    Saccharomyces cerevisiae      Saccharomyces cerevisiae D7  62.5-500 µg/ml dissolved in DMSO     99.3%   Negative  Bouanchaud & Cartier
    mutation assay (1)            strain                                                                              (1982a,b)

    (2)                           Saccharomyces cerevisiae D7  250 µg/ml dissolved in DMSO          ?       Negative  Benazet & Cartier (1979)
                                  strain

    CHO/HGPRT mutation assay (1)  Chinese hamster ovary cells  5-1500 µg/ml dissolved in DMSO       ?       Negative  Godek  et al. (1985)
                                  (CHO-K1-BH4)

    In vitro cytogenetics (1)     Chinese hamster ovary        15-400 µg/ml dissolved in DMSO       ?       Negative  San Sebastian  et al. (1985
                                  cells (CHO-K1-BH4)

    Table 2 (cont'd)
                                                                                                                                                
    Test system                   Test object                  Concentration of                     Purity  Results   Reference
                                                               iprodione
                                                                                                                                                

    In vitro sister chromatid     Chinese hamster ovary cells  5-400 µg/ml dissolved in DMSO        ?       Negative  Felkner (1985b)
    exchange (1)                  (CHO-K1-BH4)

    Dominant lethal assay         CF-1 mice                    0, 1500, 6000 ppm X 49 days          ?       Negative  Hastings  et al. (1974)
                                                                                                                      (WHO, 1978)
                                                                                                                                                

    (1) Both with and without metabolic activation.
    (2) Without metabolic activation.
    (3) Positive at highest and lowest doses without metabolic activation. Problem with precipitation of test material, inadequate negative
        and positive controls.


    
    COMMENTS

         Iprodione is extensively absorbed from the gastrointestinal
    tract. It was extensively metabolized and rapidly excreted,
    primarily in the urine, although relative faecal excretion of the
    parent compound increased at high doses. Higher doses (for example
    900 mg/kg bw) appeared to be absorbed to a lesser extent and
    eliminated at a slower rate than lower doses (for example 50 mg/kg
    bw). The elimination half-life was 7-9 h following a single low dose
    and 13-20 h following a single high dose. The metabolic pathways
    elucidated in rats involve dealkylation on the isopropyl carbamoyl
    chain, hydroxylation of the aromatic ring and rearrangement and
    opening of the hydantoin ring.

         Iprodione had low acute toxicity by all routes of exposure. The
    oral LD50 was greater than 1500 mg/kg bw in mice, rats, and dogs.
    The World Health Organization has classified iprodione as unlikely
    to present acute hazard in normal use (WHO, 1992).

         In three 4-week studies in mice at dietary concentrations of 0,
    600, 1900, 6000, 9500, or 15000 ppm, the lowest NOAEL was 600 ppm,
    equal to 115 mg/kg bw/day, based on macroscopic hepatic changes at
    1900 ppm. At 6000 ppm and above, the test material crystallized in
    the tissues. In a 3-month study in mice at dietary concentrations of
    0, 1500, 3000, 6000, or 12000 ppm (equal to 260, 510, 1100, and 2100
    mg/kg bw/day) an increase in liver and adrenal gland weights and
    hypertrophy and/or vacuolation of hepatocytes and adrenal cortical
    cells were observed in all treated groups.

         In a 3-month study in rats at dietary concentrations of 0, 300,
    1000, or 3000 ppm, the NOAEL was 300 ppm, equal to 21 mg/kg bw/day.
    Higher doses produced swelling in the zona glomerulosa of the
    adrenal cortex. In another 3-month study in rats at dietary
    concentrations of 0, 1000, 2000, 3000, or 5000 ppm, the NOAEL was
    1000 ppm, equal to 78 mg/kg bw/day, based on reduced body-weight
    gain and histopathological changes in the adrenal glands, ovaries
    and uterus at 2000 ppm and higher.

         In a one-year study in dogs at dietary concentrations of 0,
    100, 600, or 3600 ppm, the NOAEL was 100 ppm, equal to 4.1 mg/kg
    bw/day, based on the detection of Heinz bodies in erythrocytes and
    decreased prostate gland weight at 600 ppm and higher. In a second
    one-year study at dietary concentrations of 0, 200, 300, 400, or 600
    ppm, the NOAEL was 400 ppm, equal to 18 mg/kg bw/day, based on
    decreased erythrocyte values at 600 ppm.

         In a two-generation reproduction study in rats at dietary
    concentrations of 0, 300, 1000, or 3000/2000 ppm, the NOAEL was 300
    ppm, equal to 21 mg/kg bw/day, based on depressed body-weight at
    1000 ppm and above. Reproductive performance was unaffected.
    Offspring survival and growth were reduced at 3000/2000 ppm.

         In a teratology study in rats using gavage doses of 0, 40, 90,
    or 200 mg/kg bw/day, the NOAEL for maternal toxicity and
    teratogenicity was 200 mg/kg bw/day. The NOAEL for embryofetal
    toxicity was 90 mg/kg bw/day, based on slightly delayed fetal
    development at 200 mg/kg bw/day. In rabbits administered 0, 20, 60,
    or 200 mg/kg bw/day by gavage, the NOAEL for maternal toxicity was
    20 mg/kg bw/day based on depressed weight gain at 60 mg/kg bw/day.
    The NOAEL for embryofetal toxicity was 60 mg/kg bw/day based on
    increased abortions and post-implantation loss at 200 mg/kg bw/day.
    No teratogenic effects were found.

         After consideration of the available genotoxicity data, the
    Meeting concluded that iprodione was not genotoxic.

         The former ADI, based on a multi-generation reproduction study
    in rats, was revised. The new ADI was based on the results of
    several studies, including the reproduction study in rats, the
    teratology study in rabbits, and the one-year study in dogs. A
    safety factor of 100 was applied to the NOAELs from these studies.

    TOXICOLOGICAL EVALUATION

    Level causing no toxicological effect

         Mouse:    600 ppm in the diet, equal to 115 mg/kg bw/day (four-
                        week study)

         Rat:      300 ppm in the diet, equal to 21 mg/kg bw/day
                        (two-generation reproduction study)

                   500 ppm in the diet, equivalent to 25 mg/kg bw/day
                   (reproduction study reviewed by the 1977 Joint
                   Meeting)

         Rabbit:   20 mg/kg bw/day (teratology study, maternal toxicity)

         Dog:      400 ppm in the diet, equal to 18 mg/kg bw/day (one-
                        year study)

    Estimate of acceptable daily intake for humans

         0-0.2 mg/kg bw/day

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

         1.   Ongoing toxicological studies.

         2.   Observation in humans.

    REFERENCES

    Babish, J.C. (1976a). Acute oral toxicity in rats. Unpublished
    report from Food and Drug Research Laboratories, Inc., Waverly, New
    York, USA. Submitted to WHO by Rhône-Poulenc Agrochimie S.A., Lyon,
    France.

    Babish, J.C. (1976b). Acute dermal toxicity in rabbits. Unpublished
    report from Food and Drug Research Laboratories, Inc., Waverly, New
    York, USA. Submitted to WHO by Rhône-Poulenc Agrochimie S.A., Lyon,
    France.

    Babish, J.C. (1976c). Eye irritation test in rabbits. Unpublished
    report from Food and Drug Research Laboratories, Inc., Waverly, New
    York, USA. Submitted to WHO by Rhône-Poulenc Agrochimie S.A., Lyon,
    France.

    Babish, J.C. (1976d). Primary skin irritation study with rabbits.
    Unpublished report from Food and Drug Research Laboratories, Inc.,
    Waverly, New York, USA. Submitted to WHO by Rhône-Poulenc Agrochimie
    S.A., Lyon, France.

    Benazet, F. & Cartier, J.R. (1979). Iprodione (26 019 R.P.): In-
    vitro mutagenicity study in  Salmonella typhimurium (Ames' strains)
    and in  Saccharomyces cerevisiae (Zimmermann's strain D7).
    Unpublished report No. RP/RD/CNG 20 177-E from Rhone-Poulenc, Vitry-
    sur-Seine, France. Submitted to WHO by Rhône-Poulenc Agrochimie
    S.A., Lyon, France.

    Bonnette, K.L. (1991a). Primary eye irritation study in rabbits with
    iprodione. Unpublished report No. 3147.109 from Springborn
    Laboratories, Inc., Spencerville, Ohio, USA. Submitted to WHO by
    Rhône-Poulenc Agrochimie S.A., Lyon, France.

    Bonnette, K.L. (1991b). Primary skin irritation study in rabbits
    with iprodione. Unpublished report No. 3147.108 from Springborn
    Laboratories, Inc., Spencerville, Ohio, USA. Submitted to WHO by
    Rhône-Poulenc Agrochimie S.A., Lyon, France.

    Bouanchaud, D.H. & Cartier, J.R. (1982a). Iprodione (26 019 R.P.):
    Supplementary studies of mutagenesis in microorganisms. Unpublished
    report No. CRV/CNG 21 465 from Rhône-Poulenc, Vitry-sur-Seine,
    France. Submitted to WHO by Rhône-Poulenc Agrochimie S.A., Lyon,
    France.

    Bouanchaud, D.H. & Cartier, J.R. (1982b). Iprodione (26 019 R.P.),
    technical grade compound:  In vitro mutagenesis in microorganisms.
    Unpublished report No. CRV/CNG 21 466 from Rhône-Poulenc, Vitry-sur-
    Seine, France. Submitted to WHO by Rhône-Poulenc Agrochimie S.A.,
    Lyon, France.

    Broadmeadow, A. (1984). Iprodione: 52-week toxicity study in dietary
    administration to beagle dogs. Unpublished report No. 84/RH0022/179
    from Life Science Research, Suffolk, England. Submitted to WHO by
    Rhône-Poulenc Agrochimie S.A., Lyon, France.

    Coombs, D.W. & Clark, G.C. (1977). RP 26019 technical: acute
    inhalation toxicity-four hour LC50 in rats. Unpublished report No.
    RNP 75/775 from Huntingdon Research Centre Ltd., Cambridgeshire,
    England. Submitted to WHO by Rhône-Poulenc Agrochimie S.A., Lyon,
    France.

    Coquet, B. (1973a) Recherche du pouvoir teratogène chez le rat OFA
    par voie orale du produit 26019 R.P. Unpublished report from Centre
    de Recherche et d'Elevage des Onoins, No. 731016.

    Coquet, B. (1973b) Recherche du pouvoir teratogène chez le lapin par
    voie orale du produit 26019 R.P. Unpublished report from Centre de
    Recherche et d'Essais biologiques, Les Onoins, No. 730925.

    Coquet, B. (1973c) Essai de toxicité chronique (3 mois) chez le
    chien par voie orale du produit 26019 R.P. Unpublished report from
    Centre de Recherche et d'Elevage des Onoins, No. 731008.

    Coquet, B. (1976) Influence du produit 26019 R.P. sur la
    reproduction du rat (essai sur 3 générations). Unpublished report
    from Institut Français de Recherches et Essais biologiques, No.
    760435 submitted by Rhône-Poulenc.

    Cummins, H.A. (1989). Iprodione: acute oral toxicity study in the
    rat. Unpublished report No. 89/RHA255/0391 from Life Science
    Research, Suffolk, England. Submitted to WHO by Rhône-Poulenc
    Agrochimie S.A., Lyon, France.

    Felkner, I.C. (1985a). DNA damage in  Bacillus subtilis with
    iprodione technical. Unpublished report No. 2214 from Borriston
    Laboratories, Inc., Temple Hill, Maryland, USA. Submitted to WHO by
    Rhône-Poulenc Agrochimie S.A., Lyon, France.

    Felkner, I.C. (1985b).  In vitro sister chromatid exchange in
    Chinese hamster ovary cells (CHO). Unpublished report No. PH 319-BO-
    001-84 from Borriston Laboratories, Inc., Temple Hill, Maryland,
    USA. Submitted to WHO by Rhône-Poulenc Agrochimie S.A., Lyon,
    France.

    Fryer, S.E. (1990a). Iprodione: sub-acute toxicity to mice by
    dietary administration for 13 weeks. Unpublished report No. RNP
    323/90667 from Huntingdon Research Centre Ltd., Cambridgeshire,
    England. Submitted to WHO by Rhône-Poulenc Agrochimie S.A., Lyon,
    France.

    Fryer, S.E. (1990b). Iprodione: sub-acute toxicity to rats by
    dietary administration for 13 weeks. Unpublished report No. RNP
    322/90767 from Huntingdon Research Centre Ltd., Cambridgeshire,
    England. Submitted to WHO by Rhône-Poulenc Agrochimie S.A., Lyon,
    France.

    Ganter, P., Pasquet, J., Spicer, E., Girard, P., & Myon, J. (1979).
    Iprodione (26 019 R.P.): one month toxicity study in mice by dietary
    administration. Unpublished report No. RP/RD/CNG 19 950 from Rhône-
    Poulenc, Vitry-sur-Seine, France. Submitted to WHO by Rhône-Poulenc
    Agrochimie S.A., Lyon, France.

    Ganter, P., Julou, L., Pascal, S., Pasquet, J., Populaire, P.,
    Delesque, M., LeBail, R. & Myon, J. (1973). Produit No. 26019 R.P.
    Toxicité à terme (5 mois) chez le rat par voie orale, en comparaison
    avec la dichlozoline (Selex, N.D. Sumitomo = 23319 R,P). Unpublished
    report from Laboratoires de Recherches de la Société des Usines
    Chimiques Rhône-Poulenc, No. D.S.Ph. No. 17124 submitted by Rhône-
    Poulenc.

    Ganter, P. & Girard, P. (1973). Produit No. 26019 R.P. Examen
    histologique de la toxicité oculaire du 26019 R,LO, chez le chien
    après un traitement de 3 mois. Unpublished report from Laboratoires
    de Recherches de la Société des Usines Chimiques Rhône-Poulenc, No.
    D.S.Ph. No. 17131 submitted by Rhône-Poulenc.

    Godek, E.G., Naismith, R.W., & Matthews, R.J. (1985). CHO/HGPRT
    mammalian cell forward gene mutation assay. Unpublished report No.
    PH 314-BO-001-84 from Borriston Laboratories, Inc., Temple Hill,
    Maryland, USA. Submitted to WHO by Rhône-Poulenc Agrochimie S.A.,
    Lyon, France.

    Hallifax, D. (1989). Iprodione: absorption, distribution, metabolism
    and excretion study in the rat. Unpublished report No.
    89/RPM005/1013 from Life Science Research, Suffolk, England.
    Submitted to WHO by Rhône-Poulenc Agrochimie S.A., Lyon, France.

    Hastings, S.E., Huffman, K.W., & M.A. Gallo (1974). RP 26019:
    Dominant lethal mutagenicity in mice. Unpublished report No. SEH
    74:69-CH-47 from Hess & Clark, Ashland, Ohio, USA. Submitted to WHO
    by Rhône-Poulenc Agrochimie S.A., Lyon, France.

    Hastings, S.E. & Huffman, K.W. (1975). Chronic toxicologic and
    carcinogenic study with RP 26019 in mice. Unpublished report from
    Rhodia, Inc., Hess and Clark Division, No. SEH 75:223. Submitted to
    WHO by Rhône-Poulenc.

    Hastings, S.E., Winbigler, J.C., & Kiggins, E.M. (1976). Chronic
    toxicologic and carcinogenic study with RP 26019 in rats.
    Unpublished report from Rhodia, Inc., Hess and Clark Division, No.
    76:57. Submitted to WHO by Rhône-Poulenc.

    Henwood, S.M. (1991). Two-generation reproduction study with
    iprodione technical in rats. Unpublished report No. HLA 6224-154
    from Hazleton Laboratories America, Inc., Madison, Wisconsin, USA.
    Submitted to WHO by Rhône-Poulenc Agrochimie S.A., Lyon, France.

    Huffman, K.W. (1974). Subacute toxicity, RP 26 019, mice.
    Unpublished report No. KWH 74:43 from Hess & Clark, Ashland, Ohio,
    USA. Submitted to WHO by Rhône-Poulenc Agrochimie S.A., Lyon,
    France.

    Itabashi, M., Hayashi, K., Kudo, S., Maruyama, Y., Takahara, K., &
    Tajima, M. (1978). Three-month dietary oral toxicity study of 26.019
    in rats. Unpublished report from Nippon Institute for Biological
    Science, Japan. Submitted to WHO by Rhône-Poulenc Agrochimie S.A.,
    Lyon, France.

    Jones, A.G. (1983). Fungicides: Iprodione. Exposure of personnel
    mixing ROVRAL WP. Unpublished report No. 428 from May & Baker, Ltd.,
    Essex, England. Submitted to WHO by Rhône-Poulenc Agrochimie S.A.,
    Lyon, France.

    Kangas, L. (1991). A 52-week dietary toxicity study of iprodione in
    the beagle dog. Unpublished report No. 84296 from Bio-Research
    Laboratories Ltd., Senneville, Quebec, Canada. Submitted to WHO by
    Rhône-Poulenc Agrochimie S.A., Lyon, France.

    Keets, S.A., Leist, P.L., Mercieca, M.D., & Clevidence, K.J. (1985).
    A teratology study in rabbits with iprodione. Unpublished report No.
    WIL-21028 from WIL Research Laboratories, Inc., Ashland, Ohio, USA.
    Submitted to WHO by Rhône-Poulenc Agrochimie S.A., Lyon, France.

    Laurent, M. & Buys M. (1974) Etude du métabolisme chez le rat.
    Unpublished report from Société des Usines chimiques, Rhône-Poulenc.

    Laurent, M., Brunie, B., Buys, M., Heusse, D. & Chabassol, Y. (1976)
    Etude du métabolism chez le rat à l'aide du produit marqué au 14C.
    Unpublished report from Rhône Poulenc, Direction des Recherches et
    du Développement, Centre de Recherches Nicolas Grillet, Vitry-sur-
    Seine, C.N.G. An. No. 18548, submitted by Rhône Poulenc.

    Laurent, M., Bredenbac, J., Chabassol, Y., & Marlard, M. (1983).
    Iprodione. Percutaneous metabolism in the rat. Unpublished report
    No. CNG-An 4675-E from Rhône-Poulenc Research, Vitry-sur-Seine,
    France. Submitted to WHO by Rhone-Poulenc Agrochimie S.A., Lyon,
    France.

    Lawlor, T.E. & Valentine, D.C. (1990). Mutagenicity test on
    iprodione (technical) in the  Salmonella/mammalian-microsome
    reverse mutation assay (Ames test) with confirmatory assay.
    Unpublished report No. HLA 11092-0-401R from Hazleton Laboratories
    America, Inc., Kensington, Maryland, USA. Submitted to WHO by Rhône-
    Poulenc Agrochimie S.A., Lyon, France.

    Pasquet, J. & Mazuret, A. (1974). 26 019 R.P.: acute toxicity and
    local tolerance. Unpublished report No. SUCRP-DSPh 17 746 from
    Rhône-Poulenc, Paris, France. Submitted to WHO by Rhône-Poulenc
    Agrochimie S.A., Lyon, France.

    Plutnick, R.T. & Kapp, R.W. (1988). Iprodione (technical) - acute
    dermal limit test in the rabbit. Unpublished report No. 209806 from
    Exxon Biomedical Sciences, Inc., East Millstone, New Jersey, USA.
    Submitted to WHO by Rhône-Poulenc Agrochimie S.A., Lyon, France.

    San Sebastian, J.R., Naismith, R.W., & Matthews, R.J. (1985).  In
     vitro chromosome aberration analysis in Chinese hamster ovary
    cells (CHO). Unpublished report No. PH 320-BO-001-84 from Borriston
    Laboratories, Inc., Temple Hill, Maryland, USA. Submitted to WHO by
    Rhône-Poulenc Agrochimie S.A., Lyon, France.

    Stevens, K.R. (1974). Subacute toxicity, RP 26 019. Unpublished
    report No. KRS 74:3 from Hess & Clark, Ashland, Ohio, USA. Submitted
    to WHO by Rhône-Poulenc Agrochimie S.A., Lyon, France.

    Takehara, K., Itabashi, M., Hayashi, K., Kudow, S., Kawakubo, A., &
    Tajima, M. (1976a). Acute toxicity of Rovral (26019RP). I. Oral,
    intraperitoneal and subcutaneous administration in rats. Unpublished
    report from Nippon Institute for Biological Science, Japan.
    Submitted to WHO by Rhône-Poulenc Agrochimie S.A., Lyon, France.

    Takehara, K., Itabashi, M., Hayashi, K., Kudow, S., Kawakubo, A., &
    Tajima, M. (1976b). Acute toxicity of Rovral (26019RP). II. Oral,
    intraperitoneal and subcutaneous administration in mice. Unpublished
    report from Nippon Institute for Biological Science, Japan.
    Submitted to WHO by Rhône-Poulenc Agrochimie S.A., Lyon, France.

    Tesh, J.M., McAnulty, P.A., & Deans, C.F. (1986a). Iprodione
    (technical grade): effects of oral administration upon pregnancy in
    the rat. 1. Dosage range-finding study. Unpublished report No.
    85/RHA063/752 from Life Science Research, Suffolk, England.
    Submitted to WHO by Rhône-Poulenc Agrochimie S.A., Lyon, France.

    Tesh, J.M., McAnulty, P.A., Lambert, E.P., Wilby, O.K., & Tesh, S.A.
    (1986b). Iprodione (technical grade): teratology study in the rat.
    Unpublished report No. 85/RHA064/765 from Life Science Research,
    Suffolk, England. Submitted to WHO by Rhône-Poulenc Agrochimie S.A.,
    Lyon, France.

    Trimmer, G.W. (1988). Iprodione (technical) - dermal sensitization
    test in the guinea-pig (Buehler method). Unpublished report No.
    209821 from Exxon Biomedical Sciences, Inc., East Millstone, New
    Jersey, USA. Submitted to WHO by Rhône-Poulenc Agrochimie S.A.,
    Lyon, France.

    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
       Iprodione (Pesticide residues in food: 1977 evaluations)
       Iprodione (Pesticide residues in food: 1980 evaluations)
       Iprodione (Pesticide residues in food: 1995 evaluations Part II Toxicological & Environmental)