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    DINOCAP

    EXPLANATION

         Dinocap was previously evaluated by the JMPR in 1969 and 1974
    and a toxicological monograph was published in 1969 (Annex 1,
    FAO/WHO, 1970a, 1975a).  An ADI was not established during these
    evaluations due to the lack of the following:  studies to
    investigate cararactogenicity, a chronic toxicity in a non-rodent
    species, metabolic studies, specifications, information on mechanism
    of action on cellular respiration, reproduction studies and data on
    residues.  Dinocap is a fungicide-miticide consisting of 2,4- and
    2,6-dinitrooctylphenyl crotonates where the octyl moiety is either
    1-methylheptyl, 1-ethylheptyl or 1-propylpentyl.  The previous
    monograph has been incorporated into this monograph.

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    BIOLOGICAL DATA

    Biochemical aspects

    Absorption, distribution and excretion

         A study of distribution and excretion of 14C-labelled
    (uniformly on the aromatic ring) dinocap was undertaken by dosing
    one male and one female adult albino rat (strain not reported) with
    approximately 62 mg/kg bw (730 microcuries/g) of test material
    incorporated into the diet for 7 days (Graham, 1970).  Animals were
    fed untreated diet for 7 days after the cessation of dosing.  Urine,
    feces, exhaled CO2, cage washes and various tissues were collected
    and analysed for radioactivity.

         A larger proportion of test material was eliminated in the
    urine of male rats (50.8%) than in female rats (38.4%).  A total of
    63.5% and 49.5% of radioactivity was found in the feces of female
    and male rats, respectively.  Minor amounts (<.3%) were found in
    exhaled CO2, cage washes and tissues.

         A comparison of the pharmacokinetics of dinocap after oral,
    dermal and intravenous administration was undertaken in New Zealand
    White rabbits using 14C-2,4-dinitro-6-(1-methylheptyl)phenyl
    crotonate as the surrogate for the mixture of dinocap isomers
    (DiDonato & Longacre, 1985).  Peak plasma levels of 0.29, 1.26 and
    14.5 ppm were found up to 3 hours after oral dosing with 0.5, 3 and
    25 mg/kg bw.  Dermal application of 25, 100 and 220 ppm of test
    material (2.15, 8.31 and 18.3 mg/cm2, respectively) of test
    material resulted in peak plasma concentrations of 0.28, 0.47 and
    1.51 ppm up to 24 hours after dosing.  The elimination of radiolabel
    was biphasic.  The alpha phase half-lives were 2.23-3.76 hrs after
    oral administration and 7.89 to 21.80 hrs after dermal
    administration.  The half-lives for the beta-phase were 33.3 to
    55.1 hrs after oral administration and 118 to 369 hrs after dermal
    administration.  The area under the plasma/time concentration curve
    was proportional to the dose for both routes of administration and
    all doses, suggesting that saturation of absorption or excretion
    does not occur at the dose levels studies.  The absorption ranged
    from 4 to 9% after dermal exposure and 60 to 69% after oral
    exposure.

    Biotransformation

    Rats

         A study of distribution, excretion and metabolism was
    undertaken by administering by gavage 12.5 and 11.7 mg/day of
    14C-2,4-dinitro-6-(2-octyl)phenyl-crotonate for seven consecutive
    days to one male and one female Wistar rat (Honeycutt & Garstka,
    1976a).  Urine, feces and exhaled carbon dioxide were collected
    during the course of the study and tissues were collected at the
    sacrifice 6 hours after the final dosing.  Urine and feces were
    analysed by thin layer chromatography to identify metabolites.

         Feces accounted for 58% of radioactivity in the male and 52% in
    the female. Gastrointestinal tissues accounted for 2.9% (male) and
    3.8% (female); 2.9% (males) and 3.8% (females) of total administered
    radioactivity was found in other tissues with heart (0.85%) and
    liver (0.32%) containing the highest concentrations.  Approximately
    15% of the radioactivity was excreted in the urine by males and 20%
    by females.  Over twenty different metabolites were found in urine
    and feces.  Most of these constituted between 2-8% of total
    radioactivity. A separate study identified several of the major
    metabolites and they were primarily found to be hydrolysis products
    (Honeycutt & Garstka, 1976b).  The pattern of metabolites of dinocap
    found in feces was similar to that observed in squash and cucumbers. 
    More polar metabolites were observed in urine (Honeycutt & Garstka,
    1976c).  An earlier study found no detectable dinocap or phenol
    hydrolysis products in rat muscle, fat, liver, kidney or brain after
    feeding 500 ppm of technical dinocap to an unspecified number of
    rats for 30 days.  The reported level of detection was 1 ppm
    (Gordon, 1956).

    Effects on enzymes and other biochemical parameters

         Chemicals of the dinitrophenol class, such as dinocap, are
    known inhibitors of oxidative phosphorylation.  Dinocap was compared
    with 2,4-dintrophenol in oxygen consumption studies in rats.  Six
    rats (4 males and 2 females) were given a single oral dose of
    600 mg/kg body weight of dinocap.  Measurements made at various
    intervals showed that a steady increase in oxygen consumption
    occurred in the females, which reached a maximum of 63% of the
    zero-time level after 24 hours.  No increase in oxygen consumption
    occurred during 24 hours in male rats fed dinocap.  A comparable
    study with 6 other rats (two males and four females) given a single
    oral dose of 40 mg/kg body weight of 2,4-dinitrophenol resulted in a
    maximum increase in oxygen consumption of 116% for the females and
    90% for the males after three hours, followed by a gradual decrease
    after three hours (Larson, 1957).

         The compound 4-isooctyl-2,6-dinitrophenol (a constituent of
    technical dinocap) was found to be 7 to 25 times more potent than
    2,4-dintrophenol in stimulation of respiration of rat-liver
    mitochondria.  It was concluded that the pKa and the lipid
    solubility of the compounds as well as the pH of the media were the
    factors influencing this activity, and that there was no instrinsic
    structure-activity relationship relative to the size of the octyl
    group (Hemker, 1962).

         In an auxiliary study to a two-year dog study (see Weatherholtz
     et al. 1979, below), a NOEL for the reduction of liver
    mitochondrial oxidative phosphorylation was found to be 1.6 mg/kg
    bw/day (Hurwitch & Hill, 1979).

         Acute  in vitro studies of the cytotoxicity of dinocap to
    liver and HeLa cells showed that dinocap was among the most acutely
    toxic insecticides to human cell cultures (Gabliks and Friedman,
    1965a).  Exposure to cell cultures of liver and HeLa for up to 84
    days induced little resistance with inhibition of growth and
    morphological changes observed at levels below the I50 (Gabliks &
    Friedman, 1965b).  An increased resistance to polio virus and
    diphtheria toxin was noted in these cell populations after dinocap
    exposure (Gabliks & Friedman, 1965c).

         Dinocap was reported to inhibit the release of calcium from the
    bones of rats (Oledzka & Pastuszynska, 1974a,b).  The inhibition was
    less when vitamin D was supplemented in the diet.  Sodium fluoride
    also was found to inhibit this effect of dinocap in rats (Oledzka,
    1981).

         A skin irritation study of dinocap technical (purity not
    reported) in rabbits at dose levels of 0.5, 1.0, 2.9 and 3.9 cc/kg
    caused moderate to marked skin irritation at all dose levels
    (Larson, 1956a).

         Skin sensitization and irritation studies have been conducted
    in humans (see Human Observations below).

        Toxicological studies

    Acute toxicity

    TABLE 1.  ACUTE TOXICITY STUDIES ON DINOCAP

                                                                                  

                                 LD50           LC50
    SPECIES   SEX    ROUTE    (mg/kg bw)       (mg/l)        REFERENCE

                                                                                  

    Rat       M      oral          2171           -          Krzywicki
              F      oral          1212           -          1985a
              M      oral          1581           -          1985b
              M      oral          1872           -          1985c
              M      oral          2139           -          1985d
              M      oral          1985           -          1985e
              M      oral     1581-2321           -          1985f
              M      oral           980           -          Haag, 1950
              F      oral          1190           -          Larson et al. 1959
              M      oral           635           -          Shirasu, 1980a
              F      oral           510           -          Shirasu, 1980a
              ?      oral         >5000           -          Swann, 1973
              M      oral          1180           -          Mlodecki, 1975
              F      oral          1108           -          Mlodecki, 1975
              M      oral          1175           -          Ochynska, 1975
              F      oral          1493           -          Ahmedkhodzhaeva et al.
                                                             1984
    Mice      M      oral           180           -          Krzywicki, 1985a
              F      oral           150           -          Krzywicki, 1985a
              M      oral           200           -          DeCrescente, 1981
              M      oral            86           -          Shirasu, 1980b
              F      oral            95           -          Shirasu, 1980b
              M      oral            50           -          Mlodecki, 1975
              F      oral           265           -          Ahmedkhodzhaeva et al.
                                                             1984
    Rabbit    M      oral          2000           -          Haag, 1955a
              M      oral          3000           -          Mlodecki, 1975

    Dog       M&F    oral           100           -          Larson, 1959

    Rat       M      i.v.            23           -          Haag, 1955c

    Rat       M      i.p.           388           -          Toshima et al. 1976
              M&F    i.p.           433           -          DeGroot, 1974
              M      i.p.            48           -          Ochynska, 1975
              F      i.p.            57           -          Ochynska, 1975
                                                                                  

    TABLE 1 (CONTD).

                                                                                  

                                 LD50           LC50
    SPECIES   SEX    ROUTE    (mg/kg bw)       (mg/l)        REFERENCE

                                                                                  
              M      i.p.           200           -          Toshima et al. 1976
              F      i.p.           178           -          Toshima et al. 1976

    Rat       M&F    s.c.         >2000           -          Toshima et al. 1976

    Mice      M      s.c.           520           -          Toshima et al. 1976
              F      s.c.           480           -          Toshima et al. 1976

    Rabbit    M      dermal       >4700           -          Haag, 1950
              ?      dermal       >2000           -          Swann, 1973

    Rat       M&F    inhal.         -        >20.8 mg/l      Kruysse & Engel, 1974
              ?      inhal.         -        <202 mg/l       Swann, 1973
                                                                                  
    
    Short-term studies

    Rats

         Groups containing 10 weanling rats of each sex were fed diets
    containing 0, 10, 50, 250, 1000 and 2500 ppm of technical dinocap
    (purity not reported) for six months.  Growth and survival were
    reduced at the 2500 ppm level and growth rate was reduced at
    1000 ppm at weeks 1 and 2 only in males.  Enlarged spleens occurred
    in the males receiving 2500 ppm.  Hematological and microscopic
    examinations revealed no changes attributable to treatment.  The
    NOAEL was 250 ppm (Larson  et al. 1959).

         A summary report of a 90-day study in rats discussed the oral
    toxicity of dinocap technical (purity not reported) at dose levels
    of 0, .55, 5.5, 55.5 mg/kg bw/day administered by daily gavage 6
    days per week (Mlodecki  et al. 1976).  The control group consisted
    of 15 males and 15 females;  the two other dose levels consisted of
    30 males and 30 females per dose level.  Decreased body weight gain
    was observed at the high dose level; and increases of GOT, GPT and
    AP and "distinct focal, and degenerative necrotic changes of the
    stomach, liver and kidneys" at both dose levels.  Individual animal
    data was not presented.

         A published report of a 32-day study in Wistar rats was
    available (Ochynska & Ochynska, 1984).  A total of 14 male and 14
    female rats were given increasing doses of dinocap (purity not
    specified) to reach a dose level of 443 mg/kg bw/day in females and
    513 mg/kg bw/day in males.  The cumulative lethal dose (the dose
    estimated to result in 50% mortality over the course of the study)
    was found to be 344 and 356 mg/kg bw/day for males and females,
    respectively.

    Rabbits

         A summary report was available for a 90-day study in male
    rabbits (strain not specified).  Ten animals served as controls, 10
    received 150 mg/kg bw/day by gavage and 10 received 30 mg/kg bw/day. 
    The low dose level was reported to be without toxicologic effect
    (Szadowska  et al. 1977).

    Dogs

         Groups, each containing three mongrel dogs of unspecified sex
    and age, were fed diets containing 10, 50, 100, 250 or 1000 ppm of
    technical dinocap (purity not specified) for one year.  One dog in
    the 250 ppm group died within six weeks, another was sacrificed
    after marked weight loss and the third was transferred to control
    diet.  Decreased body weight gain was reported at dose levels of
    100 ppm and greater.  Histopathological changes ("acute diffuse

    necrosis" or "acute massive necrosis" of the liver) were reported at
    dose levels of 250 and 1000 ppm (Larson, 1956b).

         Four male and 4 female beagle dogs per dose level were fed
    either 0, 15, or 60 ppm of dinocap technical (78% purity) for 107
    weeks (Weatherholtz  et al. 1979).  A fourth group was initially
    fed 240 ppm during the first week; due to toxicity dose levels were
    reduced to 0 ppm during weeks 2-3, 120 ppm during weeks 4-30,
    240 ppm during weeks 31-32 and 180 ppm during weeks 33-61.  The high
    dose level animals were sacrificed after 62 weeks.  A variety of
    toxicological effects were observed in the high dose group including
    weight loss, ataxia, gross and microscopic myocardial changes, and
    retinal atrophy.  Discoloration and decreased reflectiveness of the
    tapetum lucidum and reduced vascularity of the retina and optic disk
    were also observed at the high dose level.  Ocular changes similar
    to those observed in high dose animals were observed in 7 of 8 mid
    dose dogs.  No other treatment-related effects were observed in mid
    or low dose animals.  The NOAEL was 15 ppm, equivalent to 0.4 mg/kg
    bw/day.

    Long-term/carcinogenicity studies

    Mice

         Dinocap was among the 120 pesticides that were screened for
    carcinogenicity in hybrid mice (Innes  et al. 1969).  Maximum
    tolerated doses (1 mg/kg bw/day) were administered to 18 male and 18
    female C57BL/6 x C3H/Anf mice and to 18 male and 18 female C57BL/6 x
    AKR mice for 18 months by gavage starting at day 7 after birth and
    continuing by dietary incorporation after day 21.  Survival after 18
    months ranged from 13-15 animals/sex/strain.  No significant
    increase in any tumour type at any site examined was observed
    compared to control animals.  Total number of tumour-bearing animals
    did not exceed 5 in any group.  The most common tumour type was
    reticulum cell sarcoma type A which occurred in 3 male and 2 females
    of the B6C3F1 hybrid strain.

    Rats

         Groups containing 10 weanling rats of each sex were fed diets
    containing 0, 10, 50, 250 and 1000 ppm of technical dinocap for two
    years.  There was decreased weight gain during the first year only
    in the male rats fed 1000 ppm, but the effect on body weight during
    the second year was not reported.  No other effect of treatment,
    either gross or histopathological was noted at any of the dose
    levels studied (Larson  et al. 1956c).

         A summary report was available which reported effects observed
    after the long-term dietary administration of dinocap (purity not
    specified) to Wistar rats (Mlodecki  et al. 1956c).  After two
    years' exposure, animals were fed control diet for 12 weeks prior to

    final sacrifice.  Thirty males per group received doses of either 0,
    0.15, 1.42 or 13.89 mg/kg bw/day.  Females received doses of 0, 0.9,
    0.92 or 8.87 mg/kg bw/day.  Decreased body weight gain was reported
    for both the mid and high dose animals.  No effects of dinocap on
    mortality, behaviour, clinical chemistry, hematology or gross or
    microscopic pathology were reported.  No clear reversal of the
    decreased body weight gain in mid and high dose animals was
    apparent.

         A more recent chronic rat feeding study was conducted in SPF
    Wistar rats (Maita  et al. 1980).  Test material (77.5% purity) was
    incorporated into the diet and fed at dose levels of 0, 20, 200 and
    2000 ppm for 30 months.  Eighty animals of each sex were started on
    test at each dose level and 8 animals/sex/dose level were sacrificed
    after 13, 26 and 52 weeks.  Body weight was recorded weekly;
    behaviour, food and water consumption were recorded daily. 
    Urinalysis, clinical chemistry and hematology were examined prior to
    the sacrifice of the satellite groups.  Gross examinations were
    conducted for all animals sacrificed or dying during the course of
    the study and weights of major organs recorded.  The following
    tissues were examined histologically: lungs, pancreas, salivary
    glands, stomach, duodenum, jejunum, ileum, caecum, urinary bladder,
    seminal vesicles, prostrate, uterus, sternum, bone marrow of the
    femur, sciatic nerve and grossly observable lesions.

         A significantly reduced mortality was observed in both sexes
    primarily at the high dose.  This was apparent from week 56 in
    females and week 89 in males. Group mean body weight gains were also
    reduced in both sexes at the high dose level from initiation of the
    study to termination.  Yellowing of the urine and fur was observed
    at the high dose level.  Both males and females at that dose level
    showed decreased hematocrit, hemoglobin and RBC counts during the
    first year of the study;  no significant effects on these parameters
    were observed at final sacrifice.  Decreased fat deposition was
    noted in the 2000 ppm dose groups.  Other differences in both
    neoplastic and non-neoplastic observations (including cataract
    incidence) in the high dose groups could be attributed to the
    increased survival of animals at this dose level and older average
    age at sacrifice.  The NOAEL in this study is 200 ppm (equal to
    6.41 mg/kg bw/day for males and 8.05 mg/kg bw/day for females).

    Reproduction studies

    Rats

         A summary report of a preliminary study of the effects of
    dinocap (purity unspecified) on reproduction was available (Fraczek,
    1979).  Ten rats of each sex (age not specified) were reported to
    receive 0.5% of the LD50 for 12 weeks.  Animals were mated and
    reproductive parameters examined.  The authors reported decreased
    survival and lactation indices in dinocap-treated offspring.

    Decreased parental body weight gain was also noted in treated
    animals.

         A three generation reproduction study with a teratology phase
    was reported in rats (Mulligan, 1976).  Dinocap technical (82%
    active ingredient) was incorporated into the diet of 10 male and 20
    female Sprague-Dawley rats at dose levels of 0, 1, 20 and 200 ppm. 
    Parental animals of each generation were fed either control or
    treated diets for at least 9 weeks prior to mating.  The P1
    parental animals were mated once, the two following generations were
    mated twice.  The first litter of each mating was used as the
    subsequent parental generation and the second litter was sacrificed
    on day 19 of gestation and examined for developmental toxicity. 
    Litters were culled to equal numbers at weaning.  Ophthalmoscopic
    examinations were conducted on all animals prior to mating. 
    Histopathological examinations were not conducted for parental or
    filial animals.

         Two males and one female were paired for 21 days for each
    mating.  Males were allowed to cohabit with different females after
    each week.  Vaginal smears were conducted daily to ascertain mating. 
    Body weights were recorded on days 0, 7, 14 and 19 of gestation. 
    Two-thirds of the second litters of second generation and one-third
    of the second litter of the third generation was stained and
    examined for skeletal anomalies.  The remaining fetuses were
    viscerally examined using the technique of Wilson.

         Findings which appeared to be due to compound administration
    were not observed in the parental or filial animals.  Body weights,
    behaviour, reproduction indices and the incidences of developmental
    anomalies were similar in control and treated groups for all
    generations.  The NOAEL was therefore 200 ppm, equivalent to
    6.4 mg/kg bw/day.

        Special studies on genotoxicity

    TABLE 2.  RESULTS OF GENOTOXICITY ASSAYS OF DINOCAP

                                                                                  

    TEST SYSTEM       TEST OBJECT          RESULTS       REFERENCE

                                                                                  

    Ames test         Salmonella           Negative      Lohse, 1982b
                      typhimurium
                      TA1538, TA98,
                      TA100

    Ames test         S. typhimurium       Positive      Shirasu, 1979, 1982
                      TA1538, TA98

    Ames test         S. typhimurium       Positive      Moriya et al. 1983
                      TA100, TA1535,
                      TA1537, TA1538

    Ames test         S. typhimurium       Positive      Melly et al. 1981
                      TA1538

    Ames test         S. typhimurium       Negative      Melly, 1982a
                      TA1538

    Ames test         S. typhimurium       Negative      Lohse, 1982b
                      TA1538

    Ames test         S. typhimurium       Negative      Byers, 1982
                      TA1538

    Ames test         S. typhimurium       Positive      Higganbotham et al.
                      TA1538                             1984
                                                                                  

    TABLE 2 (CONTD).

                                                                                  

    TEST SYSTEM       TEST OBJECT          RESULTS       REFERENCE

                                                                                  

    Ames test         S. typhimurium       Negative      Higganbotham, 1985
                      TA1538

    Reverse           E. coli              Negative      Shirasu, 1979, 1982
    mutation          WP2 hcr

    Reverse           Saccharomyces        Positive      Guerzoni, 1976
    assay             cervisiae

    Mouse lymphoma    L5178Y               Negative      Cifone, 1981
    cells

    Micronucleus      Mouse bone           Negative      Sasaki et al. 1982
                      marrow

    Cytogenetic       Mouse                Negative      Pilinskaya et al.
                                                         1980

    DNA damage        B. subtilis          Negative      Shirasu, 1979

    Unscheduled       Hepatocytes          Negative      Muller & Byers, 1985
    DNA synthesis     from Fischer
                      344 adult
                      males
                                                                                  
    
    Special studies on teratogenicity

    Mice

         Dose levels of 0, 6, 12 and 25 mg/kg bw/day (84% purity) were
    administered by oral gavage to CD-1 mice (resulting in 22, 7, 28 and
    15 litters) on days 7 to 16 of gestation (Gray  et al. 1986, 1988). 
    Maternal toxicity was not observed at any dose level.  Increased
    incidences of pup mortality and decreased fetal weights were
    observed at the mid and high dose levels.  Postnatal torticollis
    consistent with malformations of the inner ear (missing otoliths)
    was found in pups of the 12 (6%) and 25 (24%) mg/kg bw/day by 30
    days of age.  Swimming ability was adversely affected in each of the
    pups with complete agenesis of the otoconia.  The NOAEL for
    embryo/fetotoxicity was 6 mg/kg bw/day.

         In another mouse teratology study, CD-1 mice were dosed at
    levels of 5, 10, 20, 40, 80 and 120 mg/kg bw/day (84% purity) on
    days 7-16 of gestation, day 1 being the day of identification of the
    vaginal plug or of semen in the vagina (Rogers  et al. 1986).  All
    fetuses died at the highest dose level.  Decreased maternal body
    weight gain and increased maternal mortality was observed at
    80 mg/kg bw/day.  Fetal body weight and gravid uterine weights were
    decreased at all dose levels.  An increased incidence of cleft
    palate was observed at dose levels of 20 mg/kg bw/day and greater. 
    The NOAEL for embryo/fetotoxicity was therefore 10 mg/kg bw/day.

    Rats

         No effects on perinatal development were observed after dosing
    Sprague-Dawley rats with dinocap (84%) and 100 mg/kg bw/day by
    gavage on days 2-20 of gestation (Gray  et al. 1986).  Reduced
    maternal weight gain was observed at this dose level.  A second
    study reported that Sprague-Dawley rats were dosed at 0, 100, 150
    and 200 mg/kg bw/day on gestation days 7-20 (Rogers  et al. 1988). 
    Fifteen sperm positive rats were dosed in the control group and 18
    in each group were dosed with dinocap.  Fetal weight and maternal
    weight gain were both reduced at the two highest dose levels.  No
    increase in malformations was observed.  The NOAEL was 100 mg/kg
    bw/day in these two rat studies.

         A teratology examination was conducted during the course of the
    3 generation rat reproduction study (see Reproduction studies
    above).  No teratogenic effects were observed.

    Hamsters

         Five groups of 10 mated female Syrian golden hamsters were
    dosed with 0, 25, 50, 100 or 200 mg/kg bw/day of dinocap technical
    on days 8-11 of gestation (10, 10, 9, 9 and 9 were pregnant).  The
    females were allowed to deliver and pups were weighed and examined

    on days 1 and 5.  Prior to parturition, 1 female each died at 100
    and 200 mg/kg bw/day and total litter weight was reduced at all dose
    levels on days 1 and 5 (Gray  et al. 1986).  No other toxicity was
    observed.

         Dinocap was administered by gavage to Syrian golden hamsters at
    dose levels of 0, 12.5, 25, 50, 75, 100 or 200 mg/kg bw/day (Gray
     et al. 1988).  A total of 29, 12, 11, 32, 17, 15 and 7 sperm
    positive pregnant animals were gavaged at each dose level. 
    Decreased maternal weight gain was observed at dose levels of
    50 mg/kg bw/day and greater.  Mean fetal weights were decreased at
    dose levels of 25 mg/kg bw/day and greater.  The authors reported
    that kidney dilatation and fetuses classified as hydronephrotic were
    increased at dose levels of 25 mg/kg bw/day and greater.  The NOAEL
    is 12.5 mg/kg bw/day.

    Rabbits

         Two oral gavage teratology studies of dinocap were conducted
    which followed the same protocol but which had overlapping dose
    levels (Costlow & Kane, 1984a,b).  Dose levels in these studies were
    established on the basis of a range-finding study which dosed 6
    animals each at levels of 0, 10, 31.6, 100, 215, 464 and 1000 mg/kg
    bw/day of technical dinocap (84% active ingredient); fetotoxicity or
    embryotoxicity were observed at dose levels of 31.6 mg/kg and
    greater and maternal toxicity at doses of 100 mg/kg and greater
    (Costlow, 1984). In the primary studies, dinocap technical was
    administered by oral gavage to pregnant New Zealand White rabbits on
    days 7 through 19 of gestation.  Eighteen animals per dose level
    were administered 0, 3, 12, 48 or 64 mg/kg bw/day in the first study
    and 0, 0.1, 0.5 or 48 mg/kg bw/day in the second study.  Animals
    were periodically weighed and appearance and behaviour were recorded
    on a daily basis.  All females were sacrificed on day 29 of
    gestation and fetuses examined for external, skeletal and visceral
    abnormalities.

         An increased incidence of hydrocephaly and neural tube defects,
    as well as post-implantation losses, were observed at dose levels of
    3 mg/kg bw/day and greater.  A NOAEL for embryo/fetotoxicity and
    teratogenicity was established as 0.5 mg/kg bw/day in this study.

         A dermal range-finding study in New Zealand White rabbits was
    conducted using dose levels of 0, 20, 50, 200 and 200 mg/kg bw/day
    of dinocap Wettable Dust and 20, 50, 100, 200 mg/kg bw/day dinocap
    Liquid Concentrate and 200 mg/kg bw/day dinocap technical (Costlow &
    Lutz, 1985a).  Formulation blanks not containing dinocap was also
    tested.  Severe skin irritation was observed at dose levels of
    20 mg/kg and greater with LC formulation, 100 mg/kg and greater with
    the WD formulation and with 200 mg/kg of the technical material.  An
    increased incidence of resorptions and/or abortions or reduced fetal
    weight was observed only at dose levels of 200 mg/kg.

         In the primary dermal teratology study, 18 New Zealand White
    rabbits per dose level were treated with either 0, 25, 50 or
    100 mg/kg of dinocap technical (87.8% purity) (Costlow & Lutz,
    1985b).  Test material was applied to the shaved backs of the
    animals on days 7 though 19 of gestation.  The site of application
    was alternated to reduce dermal irritation.  Animals were observed
    daily, periodically weighed and sacrificed on day 29 of gestation. 
    Dams were examined for corpora lutea, resorption sites and live and
    dead fetuses.  All fetuses were weighed and examined for external,
    visceral and skeletal abnormalities.

         Dermal irritation was observed in all dinocap-treated animals. 
    Frank maternal toxicity was observed only at 100 mg/kg bw/day. 
    Slight increases in delayed ossification and skull abnormalities
    (accessory skull bone) were observed at the 100 mg/kg bw/day dose
    level.  However, these increases did not reach statistical
    significance.  A NOAEL for embryo/fetotoxicity is estimated as being
    approximately 100 mg/kg bw/day for this study.

    Special studies on cataractogenicity

         Summary reports of a series of 3 studies of the
    cataractogenicity of dinocap technical and 2,4-ditronitrophenol in
    Pekin ducks were available (Larson, 1958). Dosing for up to 12 weeks
    found that dinocap induced cataract formation at dose levels of
    50 ppm and greater.

         A summary report of a second cataractogenicity study in Pekin
    ducks found no cataract induction at dose levels of up to 2500 ppm
    (Larson, 1965).

         A summary report of a third cataractogenicity study in Pekin
    ducks confirmed that no cataract induction occurred at dose levels
    of up to 2500 ppm (Larson, 1966).

         Cataract induction was observed in a study in New Zealand White
    rabbits at gavage dose levels of 27 and 81 mg/kg bw/day administered
    for 30 days (Mathason & O'Hara, 1981).  Mortality and reduced body
    weight gain were also observed at those dose levels.  A NOAEL was
    identified at 9 mg/kg bw/day.

    Observations in Humans

         A fatal poisoning with a mixture of dodine, monocrotophos and
    dinocap was followed by a forensic analysis of liver, brain, kidney,
    lung, blood and gastric contents (Gelbke & Schlicht, 1978).  Dinocap
    could not be detected in the tissues that were analysed.  A total of
    20 mg of dinocap was found in gastric contents.  The authors
    concluded that the primary cause of death was probably
    monocrotophos.

         Patch tests were performed on the forearms of 50 human subjects
    using dinocap formulated either as an emulsion or as a wettable
    powder.  Exposure was for 48 hours.  Moderate irritation resulted
    from the emulsion in 11 subjects and from the powder in three. 
    Similar results occurred when the opposite forearms were patched 12
    days later, 25 subjects reacting to the emulsion and nine to the
    powder.  Intensified reactions resulted during succeeding days in
    three subjects (Larson  et al. 1959).

    COMMENTS

         Dinocap was moderately well absorbed after oral administration. 
    The elimination of dinocap was found to be biphasic in the rabbit,
    with plasma half-lives of about 3 and 33-55 hours after oral
    administration.  Males excreted dinocap in approximately equal
    amounts in the urine and feces; females excreted slightly more in
    the feces.  Although the metabolic pathway has not been well
    defined, the metabolites appear to be mainly hydrolysis products.

         Dinocap has a low acute toxicity in the species examined.

         No increase in any tumour type appeared to be associated with
    dinocap in a mouse oncogenicity study.  However, only one dose level
    (1 mg/kg bw/day) and 18 animals/sex/dose level/strain were used in
    the study.

         Increased survival of treated animals was observed in a
    long-term feeding study in rats.  Decreased fat deposition and an
    increased incidence of cataracts in the high-dose group were
    considered to be associated with increased longevity.  The NOAEL was
    200 ppm, equal to 6.4 mg/kg bw/day.

         Dinocap is a member of the dinitrophenol class of chemicals
    which inhibit oxidative phosphorylation.  Cataract induction has
    been observed in ducks and rabbits.  The NOAEL in rabbits, in which
    dinocap was administered by gavage, was 9 mg/kg bw/day.

         Ocular toxicity in the form of discolouration, decreased
    reflectiveness of the  tapetum lucidum and reduced vascularity of
    the retin and optic disk were observed in a two-year dog study.  The
    NOAEL was 15 ppm, equal to 0.4 mg/kg bw/day.

         No effects associated with dinocap were found in a combined rat
    reproduction (2 generations with 2 litters per generation)/
    teratology study.  The highest dose tested was 200 ppm, equal to
    6.4 mg/kg bw/day.

         Teratology studies were conducted in mice, rats, hamsters and
    rabbits.  a variety of forms of embryo/fetotoxicity and terata were
    observed, with the apparent order of species sensitivity being
    rabbits > mice > hamsters > rats.  In rats, the NOAEL was
    100 mg/kg bw/day, since body weights were decreased at the higher
    doses.  In the hamster, indications of hydronephrosis were observed
    at dose levels of 25 mg/kg bw/day and greater;  the NOAEL was
    12.5 mg/kg bw/day. In the mouse, the NOAEL was 6 mg/kg bw/day, based
    on a variety of malformations at higher dose levels.  The most
    sensitive species tested was the rabbit.  Neural tube and skull
    defects were observed at a dose level of 3 mg/kg bw/day; the NOAEL
    was 0.5 mg/kg bw/day by the oral route.  Because of concerns about
    teratogenic effects, a safety factor greater than 100 was applied.

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

    TOXICOLOGICAL EVALUATION

    Level causing no toxicological effect

         Rat:      200 ppm, equal to 6.4 mg/kg bw/day
         Rabbit:   0.5 mg/kg bw/day (based on teratology)
         Dog:       15 ppm, equal to 0.4 mg/kg bw/day.

    Estimate of acceptable daily intake for humans

         0-0.001 mg/kg bw.

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

         Observations in humans.
         Oncogenicity study in a second species.

    REFERENCES

    All reports indicated by (*) have been submitted to WHO by Rohm and
    Haas, Inc., Philadelphia, Pennsylvania, USA.


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    *Byers, M.J. (1982)  Karathane Technical Microbial Mutagen Test. 
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    *Costlow, R.D. & Kane, W.W. (1984a)  Teratology study with Karathane
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    *Costlow, R.D. & Kane, W.W. (1984b)  Teratology study with Karathane
    in rabbits.  Rohm and Haas Report No. 83R/113, March 30, 1984.

    Costlow, R.D., Kane, W.W. & Black, D.L. (1984c)  Range-finding study
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    *Costlow, R.D. & Lutz, M.F. (1985a)  A range-finding teratology
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    *Gabliks, J. & Friedman, L. (1965c).  Responses of cell cultures to
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    *Gardner, G.A. (1977)  Cataractogenic study of Karathane in rabbits. 
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    *Gehring, P.J. & Buerge, J.F. (1969)  The cataractogenic activity of
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    *Graham, W.H. (1970)  A material balance study in rats using
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    Gray, L.E., Rogers, J.M., Ostby, J.S., Kavlock, R.J., Ferrell, J.M.
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    *Guerzoni, M.E., Del Cuplo, L. & Ponti, L. (1976)  Mutagenic
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    *Haag, H.B. (1954b)  Six-month study on the effect of adding
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    *Haag, H.B. (1955a)  Acute oral toxicity of Karathane to rabbits. 
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    May 31, 1955.

    *Haag, H.B. (1955b)  Acute oral toxicity of Karathane to dogs. 
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    *Haag, H.B. (1955c)  Acute oral toxicity of Karathane to rats. 
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    *Hemker, H.C. (1962)  Lipid solubility as a factor influencing the
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    1984.

    *Higginbotham, C. & Byers, M.J. (1984b)  Karathane Technical
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    November 29, 1984.

    *Higginbotham, C. & Byers, M.J. (1985)  Microbial mutagenicity
    assay:  Karathane Technical.  Rohm and Haas Report No. 85R-039,
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    *Honeycutt, R.C. & Garstka, T.A. (1976a)  Rat feeding and metabolism
    study with 14C-2,4-dinitro-6-2(2-octyl)phenyl crotonate.  Rohm and
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    *Honeycutt, R.C. & Garstka, T.A. (1976b)  The identification of
    metabolites of 2,4-dinitro-6-(2-octyl)phenyl crotonate in rat urine
    and feces.  Rohm and Haas Technical Report No. 3423-76-29, August
    17, 1976.

    *Honeycutt, R.C. & Garstka, T.A. (1976c)  Comparative thin layer
    chromatography of metabolites of 2,4-dinitro-6-(2-octyl)phenyl
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    *Hurwitch, J. & Hill, J.T. (1979)  The effect of Karathane
    (Technical) on oxidative phosphorylation in canine hepatic liver
    mitrochondria.  Final Report. Hazleton Laboratories America, Inc.
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    *Innes, J.R.M., Ulland, B.M., Valerio, M.G., Petrucelli, L.,
    Fishbein, L., Hart, E.R. & Pallotta, A.J. (1969)  Bioassay of
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    National Cancer Institute Report No. NCI-DCCP-CG-1973-1-1, August
    1968, appended.

    *Kruyzsse, A., Engel, C. (1974)  Acute inhalation toxicity study in
    rats.  Central Institute for Nutrition and Food Research.  Rohm and
    Haas Report No. 74RC-1087, October, 1974.

    *Krzywicki, K.M. & Hazleton, G.A. (1985a)  Karathane Technical:
    Acute oral LD50 toxicity study in male rats and mice.  Rohm and
    Haas Report No. 85R-47, July 23, 1985.

    *Larson, P.S. (1956a)  The effects of the continued application of
    Karathane Technical (30% in dimethylphthalate) to the skin of
    rabbits.  Medical College of Virginia.  Rohm and Haas Report
    No. 56RC-1013, October 10, 1956.

    *Larson, P.S. (1956b)  One-year study on the effect of adding
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    *Larson, P.S. (1956c)  Toxicologic studies on the effect of adding
    Karathane to the diet of rats for a two-year period.  Medical
    College of Virginia.  Rohm and Haas Report No. 56RC-1011, December
    28, 1956.

    *Larson, P.S. (1957)  Studies on the effect of Karathane on oxygen
    consumption in the rat.  Rohm and Haas Report No. 57RC-1022, January
    2, 1957.

    *Larson, P.S. (1958)  Effect on cataract formation by adding
    Karathane and 2,4-dinitrophenol to the diet of ducks.  Medical
    College of Virginia.  Rohm and Haas Report No. 58RC-1017, February
    13, 1958.

    *Larson, P.S., Finnegan, J.K., Smith, R.B. Jr., Haag, H.B.,
    Hennigar, G.R., Patterson, W.M. (1959)  Acute and chronic toxicity
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    *Larson, P.S. (1965)  Preliminary study of the potential
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    *Larson, P.S. (1966)  Toxicologic and potential cataractogenic
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    Medical College of Virginia, May 5, 1966.

    *Lohse, K.L. (1982a)  Karathene Technical Microbial Test.  Rohm and
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    *Lohse, K.L. & Byers, M.J. (1982b)  Dinitrooctyl phenol Microbial
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    *Maita, K., Tsuda, S., Saito, T.  et al. (1980)  Chronic toxicity
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    *Mathason, H.B. & O'Hara, G.P. (1985)  Karathene technical
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    *Melly, J.G. & Scribner, H.E. (1981)  Karathene Technical Microbial
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    *Melly, J.G. (1982a)  Karathane Technical Microbial Mutagen Test. 
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    *Melly, J.G. (1982b)  Karathane Technical Microbial Mutagen Test. 
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    *Mlodecki, H., Fortak, W., Szadowska, A., Fraczek, S., Graczyk, J. &
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    *Mlodecki, H., Fortak, W. & Fraczek, S. (1976)  Toxicity studies on
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    *Mlodecki, H., Fraczek, S. & Lukaszek, S. (1978)  Toxicity studies
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    *Moriya, M., Ohta, T., Watanabe, K., Miyazawa, T., Kato, K. &
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    *Morrison, R.D. & Hazleton, G.A. (1985b)  Karathane Technical: Acute
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    *Morrison, R.D. & Hazleton, G.A. (1985d)  Karathane Technical: Acute
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    *Morrison, R.D. & Hazleton, G.A. (1985e)  Karathane Technical: Acute
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    *Morrison, R.D. & Hazleton, G.A. (1985f)  Karathane Technical: Acute
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    *Muller, G. & Byers, M.I. (1985)  Karathene Technical.   In vitro
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    *Mulligan, T. (1976)  Three generation reproduction study-rats. 
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    *Ochynska, J., Bronisz, H. & Ochynska, J. (1975)  Analytical and
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    *Ochynska, J. & Ochynska, J. (1985)  Analytic and toxicologic
    studies on dinocap.  Part III.  Cumulative toxicity of dinocap. 
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    *Oledzka, R., Pastuszynska, J. (1981a)  Role in bone metabolism of
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    *Oledzka, R., Pastuszynska, J. (1981b)  Alterations in bone
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    *Oledzka, R. & Pawlak-Bieniek, J. (1974a)  Influence of dinocap on
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    Rogers, J.M., Barbee, B., Burkhead, L.M., Rishin, E.A., Kavlock,
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    *Shirasu, Y., Ebihara, K., Saito, T. (1980a)  Karathane acute oral
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    *Shirasu, Y., Ebihara, K., Saito, T. (1980b)  Karathane acute oral
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    *Shirasu, Y., Moriya, M., Tezuka, H., Teramoto, S., Ohta, T. &
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    *Swann, H.E. Jr. (1973)  Karathane technical toxicity screen tests. 
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    *Szadowski, A., Fortak, W., Graczyk, J. (1977)  Toxicity studies on
    dinocap.  Part III.  Studies on subacute toxicity of dinocap in
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    *Toshima, S., Saita, H. & Ishikawa, A. (1976)  Acute toxicity of
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    *Weatherholtz, W.D., Kundzins, W., Alsaker, R.A., Marshall, P.M.,
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    - Karathene Technical. Hazleton Laboratories America, Inc., Vienna,
    Virginia.  Rohm and Haas Report No. 79RC-45, August 6, 1979.


    See Also:
       Toxicological Abbreviations
       Dinocap (FAO/PL:1969/M/17/1)
       Dinocap (WHO Pesticide Residues Series 4)
       Dinocap (JMPR Evaluations 1998 Part II Toxicological)