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    BENTAZONE

    First draft prepared by Mr. David Clegg
    Health and Welfare Canada
    Ottawa, Canada

    3-isopropyl-1H-2,1,3-benzothiadiazin-4(3H)-one 2,2-dioxide

    EXPLANATION

         Bentazone was considered for the first time by JMPR in the
    present Meeting.  It is used as a post-emergence herbicide for the
    control of broad-leaved weeds and  Cyperaceae in several crops,
    including dicotyledonous (broad-leaved) crops, e.g.,  Phaseolus
    beans, broad beans, soya beans, peas, potatoes, peanuts.  The main
    uses are on cereal grains, including maize and rice.  It is also used
    as a herbicide in non-edible agricultural crops such as grass seed
    cultures, fibre flax (linseed) and on sports fields, lawns and
    pastures (after pasture use no grazing is allowed for a week or more).

         Bentazone has a contact action on the leaves and to a lesser
    extent an action via the soil.  The active ingredient is mainly
    absorbed by the green parts of the plant, where it acts as a
    photosynthesis inhibitor.

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

    BIOLOGICAL DATA

    Biochemical aspects

    Absorption, distribution and excretion

         Four CFY SD CD rats/sex were administered orally 0.8 mg (10 Ci)
    14C-bentazone in 50% (v/v) aqueous alcohol.  Within 6 hours, 56.6 
    8.7% of the administered dose was excreted in the urine and within 24
    hours, 91.1  1.2% was excreted in urine.  During the 96 hours after
    dosing, less than 1% of the administered dose was excreted in the
    faeces and 0.02% was excreted as carbon dioxide.  Tissue residues
    after 4 days differed slightly, with sex, 0.6-1.2% of the administered
    dose remaining in male tissues, and 0.1-0.2% remaining in tissues of
    females.  Absorption appeared to be mainly in the stomach when whole
    body autoradiography was performed.

         Three male rats with biliary fistulas were similarly dosed in 30%
    aqueous ethanol and showed only minimal biliary excretion.  Urinary
    excretion of radioactive material comprised at least 84% unchanged
    bentazone (Chasseaud  et al., 1972).

         To compare the absorption, distribution and excretion of the
    bentazone acid and its sodium salt, groups of 12 male CFY SD rats were
    dosed with either 4 mg bentazone acid/kg bw/day or 4 mg bentazone acid
    equivalent as the sodium salt/kg bw/day for 7 days, and 14C-labelled
    bentazone or bentazone sodium on the 8th day.  Blood was then taken
    from the tail vein over a 24 hour period following the administration
    of the 14C-labelled material.  Maximum plasma concentrations were
    5.08 and 4.87 acid equivalents/ml, the half life of elimination being
    3.36 and 3.1 hours, for the acid and the sodium salt respectively. 
    Time to maximum plasma concentration was 0.77 and 1.18 hours, which
    were not significantly different.  Bioavailability, based on these
    data, appears to be comparable for the acid and the sodium salt
    (Chasseaud  et al., 1979).

         Using 3 CFY SD rats/sex, single oral doses of equivalent to 4 mg
    acid of the sodium salt kg/bw resulted in 63 and 51% of the
    administered dose being excreted in male and female urine,
    respectively, after 6 hours.  By 24 hours, urinary excretion was 90
    and 91% in males and females, respectively.  Faecal excretion after
    120 hours was 1.8 and 0.95% respectively.  No residues were detected
    in the carcass.  A total of 80-86% of the material excreted in urine
    was unchanged bentazone acid.  No conjugates were detected (Chasseaud
     et al., 1979).

         Three male New Zealand White rabbits were administered 5 mg 14C
    (labelled in the phenyl ring) bentazone by gelatin capsule.  Total
    recovery (by day 6 when animals were killed) was 93.5%.  During the
    first 24 hours after dosing, 89.3% of the administered dose was
    excreted in the urine, and 3% in the faeces.  Blood levels of
    radioactivity peaked at 2.5 hours, and elimination half life in blood
    was 2 hours and 12 minutes (Davies & Rogers, 1974).  GLC of urine
    collected over 0-24, 24-48 and 48-72 hours in this study indicated
    unchanged bentazone to be the major excreted product.  Low levels
    (less than 1% when combined) of 6- and 8-hydroxybentazone were
    detected.  The data were confirmed by radio gas chromatography (Otto,
    1974).

         In a study using C57 mice (numbers and sex not reported), 200 L
    14C- bentazone (labelled in the 10 position) administered
    intravenously in corn oil resulted in 92% of the administered dose
    being eliminated in the urine in 24 hours, and 95% in 48 hours (Booth,
    1974).

         Technical bentazone as the sodium salt was administered orally to
    24 CD rats at a dose level of 4 mg acid equivalent/kg bw.  Groups of
    4 rats were killed 0.5, 1, 2, 4, 10 and 72 hours post-dosing.  The
    majority of urinary excretion (65%) occurred in the first 6 hours,
    with 15% being excreted in the 6-12 hour period and 3% in the 12-24
    hour period.  Urine obtained over the first 24 hours was combined, the
    pH was adjusted with acetic acid to pH 5, and subjected to TLC.  More
    than 90% of the urinary material was unchanged bentazone, with
    approximately 2% of the administered dose appearing as
    6-hydroxybentazone.  The majority of the remainder of the urinary
    material comprised polar material, which remained at the origin in the
    chromatograph.  No 8-hydroxybentazone was detected (Hawkins  et al.,
    1986).

         In a series of studies using >99% purity bentazone, or >97%
    purity bentazone sodium administered to CD rats orally or
    intravenously labelled (43.68 mCi/mg bentazone) or unlabelled
    bentazone was administered at 4 or 200 mg/kg bw.

         Two rats/sex were given a single high dose (200 mg/kg bw) 14C-
    bentazone.  Urine, faeces and expired air were collected over 24 hour
    periods for 5 days.  Urinary excretion over 24 hours accounted for
    93.8% (males) and 89.4% (females) of the administered dose.  Five day
    recovery was 96.9% for males and 94.9% for females comprising 95.3%
    and 92.3% in urine and cage washings, 1.15 and 1.12% on faeces,
    < 0.03% in expired air and 0.5 and 1.5% in the carcass of males and
    females, respectively.

         A single low dose of 4 mg 14C-bentazone administered to 5
    rats/sex yielded similar results to those obtained with the high dose
    administration reported above, with 5 day total recovery being 92%
    (male) and 90.1% (female).  A further single high dose oral study

    using 5 male and 4 female rats confirmed the preliminary study (using
    2 rats/sex) reported above.  Five day recovery in this study was 97.1%
    (males) and 95.8% (females).  The fifth female used in the study was
    excluded from the data, since the 61.4% urinary excretion recorded was
    considered abnormal.

         Following 14 days oral dosing with unlabelled bentazone (4 mg/kg
    bw/day), a single oral dose of 14C-labelled bentazone (also 4 mg/kg
    bw) was administered to 5 rats/sex.  The results were similar to those
    reported in the initial single administration high dose study, with
    total 5 day recoveries of 96.8% (males) and 92.5% (females) of the
    administered dose.

         A single intravenous injection of 14C-labelled bentazone sodium
    equivalent to 4 mg acid kg bw dissolved in sodium chloride given to 5
    male and 4 female rats yielded total recoveries of 95.4% (males) and
    90.2% (females) with similar excretion distribution patterns to those
    in the initial single high dose study.

         Using pooled urine, radioactivity in the urine was composed of 
    bentazone > 92%, a maximum of 8% 6-hydroxybentazone, and 0.2%
    8-hydroxybentazone.  The proportion of metabolites was unaffected by
    sex.  Following enzymatic hydrolytic treatment of urine from rats
    given a single oral low dose,  glucuronidase/sulphatase decreased the
    levels of 6-hydroxybentazone from 6% to 2%.  The only detectable major
    tissue residue in rats following 7 days administration of 4 mg
    14C-bentazone/kg bw/day was unchanged bentazone in liver and kidney
    as measured by HPLC.

         Plasma levels following single oral doses of 4 mg 14C
    bentazone/kg bw to 5 rats/sex peaked after 0.5 hours at 5.5 g/ml in
    males and after 0.25 hours at 5.2 g/ml in females.  The elimination
    half lives were 2.1 and 1.2 hours in males and females, respectively. 
    At high doses (200 mg/kg bw) given orally,  plasma concentrations one
    hour post-dosing were 240 (male) and 280 (female) g/ml and
    elimination half life was about 7.8 hours (males) and 2.2 hours
    (females).  Using the sodium salt, following oral low dose
    administration, peak plasma concentrations were 6.5 g/ml (both sexes)
    at 0.25 hours and elimination half-life was 2 hours (males) and 1.3
    hours (females).  The area under the plasma concentration/time curve
    showed that high oral doses of free acid gave significantly larger
    values for both sexes.  In females only, low doses of bentazone or the
    sodium salt showed reduced values compared to i.v. administration.  No
    differences were observed at low oral doses.

         Biliary excretion following low single oral doses was, after 24
    hours, 1.3% and 0.2% (males and females, respectively) of the
    administered doses.  After high dose administration, 1.8% and 0.8% of
    the administered dose was detected in bile after 24 hours in males and
    females, respectively.  There was no evidence of accumulation of

    bentazone in rat tissues following either single or multiple doses
    (Hawkins  et al., 1987).

         A rat dermal absorption study using dose levels 0.002, 0.02, 0.2,
    and 2.0 mg 14C-sodium bentazone/cm2 (equivalent to 0.12, 1.2, 12,
    and 120 mg acid/kg bw) applied to 24 male rats/dose level, with
    sacrifices at 0.5, 1, 2, 4, 10 and 72 hours post dosing indicated that
    most radioactivity was still on the skin at 10 and 72 hours.  Based on
    excretion of bentazone and on blood plasma levels, the amount absorbed
    was 1.23 (< 2.9), 1.9 (< 2.3), 1.46 (< 1.8) and 0.79 (< 1.2)% of
    the applied doses of 0.002, 0.02, 0.2 and 2.0 mg sodium bentazone/cm2
    (Hawkins  et al., 1985).

    Toxicological studies

    Acute toxicity

         Bentazone has a relatively low acute toxicity in rats, guinea
    pigs and rabbits.  The LD50 values are given in Table 1.

         Signs of toxicity included, after oral dosing, dyspnoea, apathy,
    staggering gait, prostration and, in cats and dogs, vomiting.  In
    cats, convulsions were also observed.

         Acute inhalation studies included a study on saturated air
    containing bentazone volatiles at about 1.2 mg/l at 20 C.  An 8 hour
    exposure of rats did not result in any mortality (Hofmann & Zeller,
    1970).

         In a dust inhalation study, 10 rats (Wistar SPF:Chbb:THOM)/sex
    were exposed to an actual concentration of 5.1 mg (97.8% purity
    bentazone)/l air.  The respirable particles constituted 69.5%.  Body
    weight gain was slightly retarded.  Necropsy did not reveal any
    abnormalities.  Signs of toxicity seen on day 1 consisted of a reddish
    crust on orbital margins, and noisy respiration.  No deaths occurred
    (Klimisch  et al., 1986).

         Application of a 50% (w/w) formulation of bentazone for 24 hours
    to intact and abraded skin (2.5 x 2.5 cm) at 0.5 g/dose (3
    rabbits/sex), resulted in a primary irritation index of 1, slight
    erythema clearing by day 8 post dosing (Hildebrand & Kirsch, 1983a).

         Eye irritation was investigated using 3 White Vienna rabbits/sex
    given 0.1 ml (ca 33 mg bentazone) in the conjunctival sac of one eye. 
    Eyes were not washed.  Corneal opacity, iris congestion, conjunctival
    redness, chemosis and discharge were observed, clearing by day 15
    post-dosing.  Irritation index was 35 (moderately irritating)
    (Hildebrand & Kirsch, 1983b).


    
    Table 1.  Acute toxicity of bentazone, bentazone sodium salt, and anthranilic acid

                                                                                            

    Species              Sex       Route         LD50              Reference
                                              (mg/kg bw)
                                                                                            

    Bentazone

    Rat                 m & f      oral       1220 (1056-1409)     Hofman, 1973
    Rat

    Rat                   m        oral       ca. 1780             Hildebrand & Kirsch (1982)
    Rat                   f                   1470 (1080-1990)

    Rat                   m        oral       2340 (2208-2480)     Toyoshima  et al. (1978b)
                          f                   2470 (2058-2964)

    Rabbit              m & f      oral       750*                 Zeller & Bernstiel (1969)

    Cat                 m & f      oral       ca. 500*             Zeller & Magoley (1970)

    Dog                 m & f      oral       > 100*               Zeller & Magoley (1970)

    Guinea pig          m & f      oral       ca. 1100*            Kirsch & Hofmann (1974)

    Mouse                 m        s.c.       655 (585-734)        Toyoshima et al. (1978a)
                          f                   580 (550-673)

    Mouse                 m        i.p.       494 (437-558)        Toyoshima et al. (1978a)
                          f                   505 (447-571)

    Rat                   m        s.c.       970 (705-1329)       Toyoshima et al. (1978b)
                          f                   975 (813-1170)
                                                                                            

    Table 1 (contd).

                                                                                            

    Species              Sex       Route         LD50              Reference
                                              (mg/kg bw)
                                                                                            

    Bentazone (contd)

    Rat                   m        i.p.       403 (336-443)        Toyoshima et al. (1978b)
                          f                   407 (363-456)

    Rat                   m        i.p.       ca. 383              Kirsch & Hildebrand (1983)
                          f                   > 316 < 383

    Bentazone Sodium Salt

    Rat                   m        oral       1480 (1253-1748)     Hofman (1974)
                          f                   1336 (1148-1601)
                                              acid

    Guinea pig            m        oral       ca. 1100             Kirsch (1974)
                          f                   1000 acid

    Anthranilic Acid

    Mouse                 f        oral       ca. 1400*            Hoffmann (1972)

    Rat                 m & f     dermal      > 5000               Toyoshima  et al. (1978e)
    Rat                 m & f     dermal      > 2500               Zeller (1970)
                                                                                            

    *  Approximate median lethal dose (ALD50)
    m  male
    f  female
    

         Sensitization tests in guinea pigs using the Magnusson and
    Kligman Maximization Test (Kieczka & Kirsch, 1986) and the Open
    Epicutaneous Test (Kieczka & Hildebrand, 1986) indicated bentazone to
    have sensitizing potential.

    Short-term studies

    Rats

         Four groups of 10 Wistar KFM-Ham rats/sex/dose level,
    approximately 8 weeks old, were fed diets containing 0, 400, 1200 or
    3600 ppm (97.8% purity) bentazone.  A further 10 rats/sex were
    included in the control and 3600 ppm groups which were retained 28
    days beyond the final dose.  Mean bentazone concentrations in prepared
    diets were 99.1 (89-109)%, 85.4 (83.4-86.6)% and 91.5 (88.3-93.0)% of
    nominal values at 400, 1200 or 3600 ppm.  Homogeneity ranged from - 8%
    to 49% over 3 samples (top, middle and bottom), and 21 day stability
    in the diet was demonstrated.  Mean test material intake was 25.3,
    77.8 and 243.3 mg/kg bw/day for males, and 28.9, 86.1 and 258.3 mg/kg
    bw/day for females.  No clinical signs were observed.  One male and
    one female were found dead.  In the male, kidney haemorrhage was
    noted.  Data on the female could not be assessed due to marked
    autolysis.  A second 3600 ppm female died during terminal anaesthesia. 
    Congestion was noted in most organs.  Food consumption was comparable
    in all groups.  Body weight was slightly, but statistically
    significantly reduced in females at 3600 ppm.  During the recovery
    period, weight gain was comparable between controls and 3600 ppm
    females.  No treatment-related ophthalmologic effects were noted, but
    no data are provided beyond the description of the comprehensive
    examination undertaken.  Prolonged thrombo-plastin time (PT) and
    partial thromboplastin time (PTT) were observed in males at 3600 ppm
    at 13 weeks, but recovered during the withdrawal period.  Platelet
    counts were increased, not significantly, in 3600 ppm males at 13
    weeks returning to normal by 17 weeks.  In females, platelet counts
    were significantly increased at 3600 ppm after 13 weeks with some
    recovery by 17 weeks.  No increase in PT and PTT was observed in
    females.  Other haematological parameters were comparable to controls.

         Clinical chemistry data indicate a slight increase in total
    cholesterol in 3600 ppm females, with recovery after 4 weeks
    withdrawal, increased sodium levels (all doses) in treated females,
    increased chloride levels in 3600 ppm females, changes in protein
    electrophoresis in males at 1200 and 3600 ppm (increased albumin and
    A/G ratio, and increased globulin (all doses) in females.  All
    observed changes showed recovery during the withdrawal period. 
    Urinalysis data for males indicated increased 18 hour volume and
    decreased specific gravity at 3600 ppm.  Increased 18 hour urine
    volume and decreased specific gravity were observed at all dose levels
    in females.  Recovery occurred during the 4 week withdrawal period. 
    Male absolute and relative, and female relative kidney weights were
    increased at 3600 ppm, as were male absolute adrenal weight and female

    relative liver weight.  Again all organ absolute and relative weights
    were comparable to control values after the 4 week withdrawal period. 
    Gross and histopathology are comparable in all groups.  The NOAEL is
    400 ppm (equal to 25.3 and 28.9 mg/kg bw/day, respectively) (Tennekes
     et al., 1987).

         Five groups of 20 Sprague Dawley rats/sex/dose level were fed 0,
    70, 200, 800 or 1600 ppm technical bentazone for 90 days.  Additional
    groups of 10 rats/sex were fed 0, 70, or 1600 ppm for 90 days, and
    then returned to normal diet for a 42 day period prior to sacrifice. 
    Haematology and clinical chemistry for 10 rats/sex/dose level were
    performed after 4, 7 and 11 weeks.  Urinalysis was performed at 3 and
    9 weeks.  It is stated that no clinical signs were observed.  Food
    consumption was comparable in all groups.  Female body weight was
    reduced at 1600 ppm after about 6 weeks on diet.  Body weight gain was
    comparable between controls and 1600 ppm females during the withdrawal
    period.  No adverse effects were noted on haematological parameters
    (which included prothrombin time), nor in clinical chemistry
    parameters (SGPT, SAP, and urea only).  Urinalysis data did not
    indicate any dose or compound related effects.  Absolute and relative
    (to body weight and to heart weight) organ weight data showed no
    changes in absolute weight of heart, liver or kidney (only organs
    weighed).  In males, heart and kidney/body weight ratios were
    increased at 1600 ppm and in females, kidney/bw ratios were increased
    at 800 and 1600 ppm.  Organ/heart weight ratios were decreased for
    liver and kidney in 1600 ppm males and kidney/heart weight ratio was
    increased in 70, 800 and 1600 ppm females.  At termination of the
    withdrawal period, only female kidney/bw ratio remained elevated at
    1600 ppm.  Gross pathology was stated to be comparable in all groups. 
    Histopathology indicates isolated seminiferous tubule and/or
    testicular degeneration in 2/20 and 1/20 rats at 200 and 1600 ppm at
    90 days, and in 1/10 at 1600 ppm after the withdrawal.  These changes
    were not considered to be compound-related.  An NOAEL of 800 ppm is
    indicated based on decreased body weight gain.

    Rabbits

         Four groups of five New Zealand White rabbits/sex/dose level were
    exposed daily for 21 days to a volume of 4 ml/kg bw to give dose
    levels of 0 (solvent control of 0.5% CMC), 250, 500 or 1000 mg
    bentazone (purity 97.8%)/kg bw/day.  Stability and homogeneity in the
    0.5% CMC was satisfactory.  Solution concentration analyses showed
    actual values were comparable to, or slightly exceeded, nominal
    values.  Exposure was for 6 hours/day on at least 10% of the body
    surface (intact shaved skin), under a semi-occlusive dressing.  The
    exposed skin was washed after each exposure.  Following each weekly
    weighing, solution concentrations required to give a constant dose
    level were recalculated.

         Mortality occurred in 1/5 control and 2/5 1000 mg/kg bw/day
    females.  Deaths were preceded by markedly reduced food intake and
    body weight loss.  In males, food intake and body weight were
    comparable to controls at all dose levels.  In females, food intake
    tended to be reduced at days 7 and 14 at 1000 mg/kg bw/day.  A similar
    pattern was noted for female body weights.  The incidence of clinical
    signs of toxicity was increased in females at 1000 mg/kg bw/day.  No
    statistically significant changes in haematological parameters were
    reported and only a slight increase in male serum albumin at 1000
    mg/kg bw/day was statistically significant in the clinical chemistry
    parameters.  Absolute and relative liver weights were variable,
    especially in females.  Kidney, adrenal and testicular absolute and
    relative weights were generally comparable between groups.  The main
    pathological finding was chronic proliferative cholangitis, diagnosed
    as being caused by coccidia.  Hyperaemia of the intestines associated
    with mucosal and submucosal subacute inflammation was also noted in
    all groups, indicated to have been associated with coccidial
    infection.

         The observed changes in females (i.e. mortality, changes in body
    weight and food intake, and incidence of occurrence of clinical signs)
    at 1000 mg/kg bw/day may have been due to coccidiosis.  However, at
    day 7 food and body weight reductions were not confined to animals
    with coccidiosis.  Consequently, a NOAEL of 500 mg/kg bw/day appears
    to be appropriate (Schilling  et al., 1988).

    Dogs

         Five groups of 10-12 month old beagle dogs in groups of
    3/sex/dose level were fed diets containing 0, 100, 300, 1000 or 3000
    ppm bentazone (purity not specified) for 13 weeks.  No data are
    available on diet analyses.  One male and 2 female dogs at 3000 ppm
    died after 7-12 weeks on diet.  Coma and probably agonal spasms
    preceded death.  No signs of toxicity were observed at 100 or 300 ppm. 
    At 1000 ppm, one male dog showed a sedative effect during the 12th and
    13th week on diet.  At 3000 ppm all dogs showed toxic signs, beginning
    with sedation (weeks 2-4) and proceeding to ataxia and prostration. 
    Vomiting probably reduced the actual absorbed dose in the 3000 ppm
    group.  Occasional vomiting occurred in all groups, especially at 1000
    ppm.  Food intake was reduced at 3000 ppm.  Based on body weight
    (which was severely depressed at 3000 ppm) and food intake, actual
    compound intake was calculated to be 4, 12, 39.6 and 113.8 mg/kg
    bw/day.  Haematological parameters were comparable to controls at dose
    levels of 100, 300 and 1000 ppm.  At 3000 ppm, prothrombin time,
    "bleeding time", erythrocyte sedimentation rates, and reticulocyte
    count were increased.  Platelet counts, haemoglobin, erythrocyte
    counts and packed cell volume were decreased.  Clinical chemistry data
    were comparable in all groups up to and including 1000 ppm.  At 3000
    ppm, BUN, SGOT, SGPT, SAP, total bilirubin, BSP retention time, and
    globulin were all increased, while total protein, A/G ratio, albumin
    and globulin were decreased in both sexes.  Urinalyses were comparable

    in all groups except for a non dose related increase in sodium ions
    after 6 weeks on diet at 300, 1000 and 3000 ppm and increased
    incidence of ketonuria at 3000 ppm.  Electrocardiograph data were
    comparable in all groups at 0, 6 and 13 weeks.  Ophthalmological
    examination indicated slight bilateral haemorrhagic conjunctivitis in
    all 3000 ppm dogs.  Based on "a simple sound test" (not described)
    hearing was stated to be normal at all dose levels.  Gross pathology
    indicated an ulcerated left hind leg in 1/6 dogs at 1000 ppm.  At 3000
    ppm cachexia, conjunctivitis and pale livers were noted in all dogs,
    pale kidneys in 5/6 dogs, swelling in the thoracic region (3/6 dogs,
    1/sex) gastric ulcer in 1/3 males, and skin ulceration (1/3 males). 
    Histopathology (limited to liver, kidney, adrenal, bone marrow and 16
    other tissues) showed prostatitis or suppurative prostatitis with
    areas of abscess formation in 1, 1 and 3 dogs at 300, 1000 and 3000
    ppm respectively, marked signs of maturation deficiency with
    polynuclear spermatospores and empty epididymal ducts in 1/3 males at
    1000 and 3000 ppm.  Three of 6 dogs at 3000 ppm showed necrotic
    congestion of the liver and 3/6 dogs showed albuminous swelling of the
    kidney.  Fatty degeneration of the myocardium is reported in 1/3 males
    and 2/3 females and splenic extramedullary haematopoiesis in 1/3 males
    and 2/3 females at 3000 ppm.  Organ and organ to body weight ratio
    data are limited to the relative data which indicate at 3000 ppm
    increased liver, kidney, adrenal and thyroid weights.  These are
    probably related to the decreased body weight at 3000 ppm.  The NOAEL
    for this study is 300 ppm (equal to 12 mg/kg bw/day) (Leuschner
     et al., 1970).

         Four groups of 6 beagle dogs/sex/dose level were fed diets
    containing 0, 100, 400 or 1600 ppm (97.8% purity) bentazone for 52
    weeks.  Average test article intake was 0, 3.04, 13.07 and 49.72 mg/kg
    bw/day for males and 0, 3.29, 13.20 and 54.83 mg/kg bw/day for females
    at 0, 100, 400 and 1600 ppm,  respectively.  There was no mortality at
    1600 ppm.  Decreased body weight gains were noted sporadically in
    males up to week 8 in all but one animal.  After week 8, weight gain
    tended to stabilize.  One animal showed consistently reduced body
    weight.  In 4/6 females at 1600 ppm body weight gain was reduced
    during the first 6 weeks.  Terminal mean body weights in all groups
    were comparable.  Food consumption was comparable in all animals
    except for 1 female at 1600 ppm in weeks 3-7, which suffered from
    gastroenteritis during this period.  Clinical signs at 1600 ppm in
    males included emaciation and dehydration in the animal showing
    consistently reduced body weight, bloody diarrhoea and subsequent
    anaemia, which recovered after 1 week on normal diet (week 7) and a
    third dog with transient skin lesions.  No treatment related effects
    were noted on clinical chemistry parameters, ophthalmological and
    hearing tests, organ weights and gross pathology.  At 1600 ppm, in
    week 13, one female showed reduced erythrocyte and haemoglobin levels,
    accompanied by increased thromboplastin (PT) and partial
    thromboplastin times (PTT).  The reduced erythrocyte count and
    haemoglobin levels were also noted in this dog at 26 weeks, but PT and
    PTT were normal.  At week 13 only, two other females also showed

    increased PT and PTT.  As already noted, 1 male dog at 1600 ppm became
    anaemic in the first 6 weeks of the study.  Even after withdrawal from
    treated diet for 1 week, by week 13 haemoglobin was still slightly
    reduced, and PT and PTT were increased.  These effects were not
    apparent at 26 weeks.  A second 1600 ppm male dog showed increased PT
    and PTT at weeks 26 and 52.  Histopathological examination did not
    reveal any compound related effects except for reduced spermiogenesis
    in two dogs at 1600 ppm (one bilateral and one unilateral).  The NOAEL
    for the study was 400 ppm (equal to 13.07 mg/kg bw/day) (Allen
     et al., 1989).

    Long-term/carcinogenicity studies

    Mouse

         Four groups of 50 Swiss Webster mice/sex/dose level were fed
    diets containing 0, 100, 350 or 1600 ppm bentazone (purity not
    specified) for 18 months (equal to mean average intakes of 0, 13.3,
    46.5, 155.3 mg/kg bw/day for males, and 0, 16, 56.6, 260.4 mg/kg
    bw/day for females) (Cannon  et al., 1974)  No data are available for
    gross or histopathology of intentional sacrifices, except data on
    tumour incidence.  The pathology data are therefore considered to be
    inadequate.

         A second study in mice (Hunter  et al., 1978) utilized four
    groups of 40 CFLP mice/sex/dose level fed diets containing 0, 100,
    350, or 1600 ppm bentazone acid (purity not given).  No overt signs of
    toxicity were observed in any group of mice.  Survival, however,
    tended to be adversely affected in both sexes during the latter stages
    of the study at 1600 ppm, although statistical significance was not
    achieved.  Food consumption was comparable in all groups.  No
    consistent adverse effects were noted on body weight or body weight
    gains.  Food utilization was comparable in all groups. 
    Histopathological examination was limited to gross lesions, lymph
    nodes, liver, spleen, thyroid, pituitary and ovaries.  This is
    insufficient to permit an assessment of carcinogenicity, although the
    available data do not indicate any bentazone related tumour induction
    on the tissues examined.

         A third mouse study utilized groups of 50 B6C3F1 mice/sex/dose
    level fed diets containing 0, 100, 400 or 2000 ppm bentazone technical
    (purity 93.9%) in the diet for 24 months.  Additional satellite groups
    of 10 mice/sex/dose level were maintained for interim sacrifice at 6
    and 12 months.  Dietary levels were adjusted to take into account the
    purity of the bentazone technical.  Dietary analyses (performed every
    3 months) indicated mean average percentages of 102.3% (range
    96.3-112.4%), 102.4% (range 88.9-133.1%) and 98.7% (range 87.9-106.3%)
    of nominal values at 100, 400 and 2000 ppm.  The available data did
    not permit an assessment of homogeneity.  Daily average intake over
    the 104 weeks of the study was 12, 47, and 242 mg/kg bw/day for males,
    and 12, 48 and 275 mg/kg bw/day for females.  Mortalities at 2 years

    were 28, 28, 30 and 40% for males, and 20, 18, 26 and 30% for females. 
    These mortality rates are not statistically significantly different. 
    Clinical signs at termination were limited to an abdominal inflation
    (6/35 cf. 0/40 in controls) in female mice.  Body weight in 2000 ppm
    males was intermittently significantly reduced.  Water intake in males
    was also significantly reduced during weeks 52-65 at 2000 ppm.  No
    adverse compound- or dose-related ophthalmological effects were
    observed at 6, 12, or 24 months.  Prothrombin time was prolonged in
    male mice at 400 and 2000 ppm.  This effect was considered a toxic,
    bentazone-related effect, since in a preliminary dose range finding
    study, haemorrhagic lesions (severe) were noted at 5000 and 10000 ppm. 
    Other haematological observations included increased haemoglobin and
    haematocrit in 24-month 2000 ppm males.  Other effects were not
    compound-related.  Clinical chemistry did not show any consistent dose
    or compound-related effects on BUN, SGPT, SGOT, total cholesterol,
    total protein, albumin, and A/G ratios.  Urinalysis similarly showed
    no consistent time, dose, or compound-related effects.  Organ weights
    and organ/body weights varied sporadically.  The only possible dose
    related effect was in males, where pituitary absolute and relative
    weights were increased at 2000 ppm at 6 months and at 400 and 2000 ppm
    at 24 months.  There were no data for pituitary weights at 12 months. 
    Gross pathology indicated several incidences of abdominal retention of
    blood (possibly due to liver rupture) in moribund or dead males at 100
    and 2000 ppm.  Incidence of liver masses in male mice was slightly but
    not significantly increased (6 in controls v 9 at 2000 ppm). 
    Non-neoplastic histopathological changes included calcification of the
    tunica albuginea testes and peripheral interstitial vessels at 400 and
    2000 ppm (dose-related), increased incidence of liver and heart
    haemorrhages in males at 2000 ppm and increased hyperplasia of the
    islets of Langerhans in males at 400 and 2000 ppm (dose-related). 
    With respect to neoplastic lesions, three different pathological
    reports have been submitted.  The original report of the study
    indicates an increased incidence of hepatocellular carcinomas in male
    mice (6, 10, 13 and 21 at 0, 100, 400 and 2000 ppm) and of neoplastic
    nodules in female mice (3, 4, 4, 11 at 0, 100, 400 and 2000 ppm)
    (Takehara  et al., 1985) .  The slides were re-evaluated by Butler
    (1985b), who using the criteria of Vesselnovitch  et al. (1978),
    indicated an incidence of 9, 7, 8 and 10 hepatocellular carcinomas in
    males, at 0, 100, 400 and 2000 ppm.  A third examination of the slides
    was performed by Carlton, Butler and Yamate (1987).  Carlton reported
    8, 7, 10 and 11 hepatocellular carcinomas in males, Butler, 10, 7, 10
    and 10 and Yamate, 9, 7, 10 and 11 at 0, 100, 400 and 2000 ppm
    respectively.  In none of the reports is there evidence of induction
    of liver carcinogenicity.  The NOEL for this study is determined to be
    100 ppm based on decreased prothrombin times at 400 and 2000 ppm and
    changes in male pituitary weight at similar dose levels (Takehara
     et al., 1985).

    Rats

         Four groups of 50 Sprague-Dawley rats/sex/dose were fed diets
    containing bentazone (purity not stated) at concentrations of 0, 100,
    350 or 1600 ppm for up to 2 years.  In the absence of any reports on
    histopathological examination of animals dying during the study, and
    the absence of any reported tumours in the available histopathology on
    scheduled sacrifices, the limited data available can not be adequately
    assessed (Cannon  et al., 1974).

         Four groups of 50 Fischer 344 Du/Cri SPF rats/sex/dose level plus
    two supplemental groups of 10 rats/sex/dose level for 6 and 12 month
    interim sacrifice were fed 93.9% pure bentazone at dietary levels to
    give a concentration of 0, 200, 800 or 4000 ppm bentazone active
    ingredient, for 2 years.  Dietary analyses indicated diets achieved
    mean percentages of nominal values (based on 8 assays performed at 3
    monthly intervals) of 102.5% (range 95.1-108), 100.4% (range
    96.2-106.3) and 102.9% (range 96.4-109.1) for the 200, 800 and 4000
    ppm dose levels.  Average daily compound intake over the 2 year period
    was, for males, 9, 35 and 180 mg/kg bw/day, and for females, 11, 45
    and 244 mg/kg bw/day.  Homogeneity could not be assessed from the data
    provided.  Mortality was comparable between groups with 2 year male
    survival of 60, 56, 72 and 70% and female survival of 62, 58, 70 and
    54% at 0, 200, 800 and 4000 ppm.  No compound-related clinical signs
    were observed.  Body weight in both sexes was depressed at 4000 ppm
    with significant depressions of body weight from weeks 5 and 6
    onwards.  At 800 ppm, body weight was depressed in males during weeks
    19-36, and in females during weeks 60-65.  The effects at 800 ppm were
    transient.  Food intake was significantly reduced at 33 weeks,
    randomly distributed throughout the study, in males at 4000 ppm.  In
    females at 4000 ppm, food intake was significantly increased in 6
    weeks of the study, and significantly decreased in 9 weeks of the
    study.  At 800 ppm food intake in males was significantly increased in
    4 weeks of the study, and decreased in 16 weeks of the study.  In
    females,  food intake was increased in 10 weeks and decreased after 5
    weeks of the study.  Food efficiency was generally comparable to
    controls throughout the study in both sexes.  Water intake was
    increased in both sexes at 800 ppm (males, week 29-77, sporadic,
    females week 29 onwards) and at 4000 ppm (males from week 6 onwards,
    and females from week 17 onwards).

         Examination of the eyes of treated rats at 6 months did not
    indicate any difference from controls.  At 12 months one male rat
    showed a unilateral cataract and, in the other eye, a whitish zone in
    the fundus at 4000 ppm.  A similar whitish zone was observed in the
    fundus of one eye at 800 ppm and in one eye of another rat at 4000
    ppm.  In females, a unilateral cataract was noted in one rat at 200
    ppm.  At 24 months, cataract incidence was 7, 1, 4 and 18 in males,
    and 1, 2, 2, 5 in females at 0, 200, 800, and 4000 ppm.  Whitish
    zones, or pallor in the fundus was observed in 5, 9, 5 and 1 male, and
    5, 5, 7 & 2 females.  Keratitis of the anterior part of the eyeball

    was noted in 1 control male rat, and in 7 male rats at 4000 ppm.  A
    subsequent review of the original Takehara  et al. report by Butler
    (1985a) concludes that, because of differences in preservation (some
    eyes in Bouin's fluid and some in formalin),  it is not possible to
    form an opinion on the incidence of cataracts based on
    histopathological examination.  Further, he indicates that cataracts
    are commonly observed with widely variable incidence in Fischer 344
    rats and that all but one of the cataracts observed at
    ophthalmological examination were unilateral, whereas compound-induced
    cataracts would be expected to be bilateral, and that in studies on
    cataractogenicity, young rats have been shown to be more susceptible
    to chemically induced cataracts than old rats (Grant, 1974; Gehring,
    1971).  Based on these indications, Butler concluded that the high
    incidence of cataracts in males at 4000 ppm is unlikely to be compound
    related.  Optic nerve atrophy was observed in 9 male rats (8
    unilateral) at 24 months, and in 1 male rat at 12 months in the 4000
    ppm group.  A subsequent report (Takehara & Kudow, 1986) indicates
    that in 6 of 9 rats with cataracts and optic nerve atrophy, distal
    optic nerve attached to the eyeball was removed and examined. 
    Degenerative changes and proliferation of glial cells were observed in
    all 6 optic nerves.  However, 4 of 6 rats with cataracts, but no
    reported optic nerve atrophy, also showed similar degenerative
    changes.  Optic nerve atrophy co-existed with other (unspecified)
    abnormalities in the eyeball suggesting the possibility of an
    association with lesions other that cataracts, but this remains to be
    elucidated.  It should be noted that the optic tracts in the brain
    show no evidence of histological change in animals with gross optic
    nerve degeneration.

         Urinalyses indicated light coloured urine at 4000 ppm at all time
    intervals (6, 12 & 24 months) except in 24-month males.  At 800 ppm,
    increased incidence of light coloured urine occurred in 12-month males
    and 24-month females, the same groups showing a slight increased
    incidence at 200 ppm.  Urine volume was increased in all groups except
    24-month females where it was decreased and 24-month males (comparable
    to controls) at 4000 ppm.  At 800 ppm in 6-month males and females,
    and 24-month males, urine volume was slightly increased.  Specific
    gravity was decreased at 4000 ppm in all groups, at 800 ppm in 6-month
    males and females, 12-month males, and 24-month females and at 200 ppm
    in 6-month females.  Protein was decreased in all groups except
    24-month males at 4000 ppm, in both sexes at 6 months and in males at
    12 months.  Slight decreases were noted at 200 ppm in both sexes.  The
    results may be related to increased water intake, but again there is
    some inconsistency, e.g., reduced specific gravity in 200 ppm females
    at 6 months, with no increase in urinary volume.  The only consistent
    effects on haematological parameters were, however, limited to
    coagulation times.  In males, PTT was increased at all time intervals
    at 4000 ppm and at 800 ppm at 12 months, PTT was increased at 4000 ppm
    at 6 and 12 months.

         In females, data were erratic, with increased PTT at 800 and 4000
    ppm at 12 months, but decreased PTT at 800 ppm at 24 months.  PTT was
    increased in females at 800 ppm only, at 24 months.  Compound-related
    haemorrhagic effects may therefore be present in males at 4000 ppm. 
    Clinical chemistry investigations indicated BUN to be statistically
    significantly increased (dose- related) at all dose levels in males,
    and in females at 4000 ppm (6 and 12 months), and 800 ppm (12 months). 
    Glucose was decreased in 200 and 800 ppm males at 6 months, in 4000
    ppm males at 12 months, and at 200 and 4000 ppm in both sexes at 24
    months.  A/G ratios in 4000 ppm males at 6 months, and 4000 ppm
    females at 12 months.  A decreased A/G ratio was noted at 12 months in
    200 ppm males.  Total cholesterol was decreased in males at 6 and 24
    months at 4000 ppm, and slightly (not statistically significant)
    decreased in females at 24 months at 4000 ppm.  Other changes noted
    are not considered to be related to compound administration.

         Kidney absolute and relative (to body weight) weights were
    increased significantly in both sexes at 4000 ppm at 6 months.  At 12
    months absolute weight (females) and relative weight (both sexes) were
    increased, and at 24 months, female relative weights were increased. 
    At 24 months, male absolute and relative weights were significantly
    decreased at 800 ppm.  Liver absolute weights were decreased in males
    at all time intervals at 4000 ppm, and at 800 ppm at 24 months.  Male
    relative liver weights were decreased at 800 and 1000 ppm at 24
    months.  Male absolute spleen weights were also decreased at all time
    intervals at 4000 ppm, and relative spleen weights were decreased at
    6 and 24 months.  Male thyroid absolute relative weights were
    decreased at 800 and 4000 ppm at 6 and 12 months.  Female absolute
    thyroid weights were significantly decreased at 4000 ppm after 12
    months.

         Gross pathology in 3 males dosed at 4000 ppm which died within 18
    months showed haemorrhagic lesions, which were probably bentazone
    related. In histopathological examination at 6 months, no lesions were
    observed.  At 12 months, two males dosed at 4000 exhibited testicular
    Leydig cell adenomas, another male exhibited a urinary bladder
    transitional cell papilloma, and one female at 800 ppm had a
    mesenchymal tumour in the thoracic cavity.  At 24 months, the
    incidence of Leydig cell adenomas was high, but comparable in all
    groups (30/30, 28/28, 38/41, and 32/34 at 0, 200, 800, and 4000 ppm). 
    There was no evidence of bentazone related tumour induction or of
    induced non-neoplastic histopathological changes.  The NOAEL was 200
    ppm (equal to 9 mg/kg bw/day for males, and 11 mg/kg bw/day for
    females (Takehara  et al., 1984).

    Reproduction studies

         Four groups of 20 Sprague-Dawley rats/sex/dose level were fed
    diets containing 0, 20, 60 or 180 ppm.  These dietary levels were
    maintained at a constant level throughout the study.  The F0 parents

    were bred after 8 and 18 weeks on diet, F1 parents at 18 and 29 weeks
    on diet and the F2 parents at 18 and 28 weeks on diet.  From the F3b
    litters, 20 animals/sex/dose level were maintained during a
    developmental period of 9 weeks, and then subjected to
    histopathological examination.  Rats used as parents were selected at
    random.  This implies sibling matings may well have occurred.  No data
    on homogeneity, stability or dietary concentrations are available. 
    Pairings were on a 1:1 basis, males were changed every 7 days for up
    to 4 weeks if mating had not occurred.  Day 0 of gestation was
    considered to be the day on which semen was detected in the vagina. 
    Parental animals for the 2nd and 3rd generation were drawn from b
    litters.  Animals not required as parents or for microscopic
    examination were killed at 4 weeks of age (end of lactation) and
    examined macroscopically.

         Fertility in males, assessed by the number of animals
    successfully mating during first 7 days, was unaffected.  Numbers of
    females failing to successfully mate in 28 days were also comparable
    between groups.  Viability and lactation indices were comparable.

         Neither clinical signs nor parental mortality was observed during
    the entire study.  Food intake was comparable between groups and water
    intake was stated to be comparable (no data).  Actual average compound
    intake ranged from 1.6-2.5 mg/kg bw (20 ppm), 4.7-7.3 mg/kg bw (60
    ppm) and 14.1-21.9 mg/kg bw (180 ppm) across the various generations
    and breedings.  Body weights were generally comparable between groups. 
    Ophthalmoscopy of parental animals at sacrifice was normal.  No
    macroscopic or microscopic abnormalities were observed in F3b pups. 
    Neither were macroscopic changes observed in parental animals, except
    for non-compound related pulmonary changes.  Litter size, incidence of
    stillbirths, incidence of abnormal pups, pup birth weight, and pup
    survival to weaning were comparable in all groups of each mating.  The
    NOAEL was 180 ppm (Leuschner  et al., 1973).

         Wistar/HAN rats were fed diets containing either 0, 200, 800, or
    3200 ppm of bentazone technical in a two generation (one litter)
    reproduction study.  The F0 generation (25 rats/sex/dose level) was
    treated for 70 days before mating.  Each male was cohabited with a
    single female.  Litters were randomly culled to 8 pups on day 4.  Each
    litter was weaned on day 21 of lactation and 25 animals/sex/dose level
    were chosen for the F2 generation from the F1 generation. 
    Reproductive organs and gross lesions from F0 and F1 control and
    high dose animals were examined microscopically.

         Body weights during the premating periods were consistently lower
    than controls in high-dose males and females of each generation. 
    Maternal body weights of high-dose animals were generally lower than
    control animals during lactaction.  Mean food consumption was
    decreased early (days 1-29) in the premating period for high-dose F1
    females.  Histological examinations of tissues were unremarkable.

    Reduced pup body weight was observed on days 4, 7, 14 and 21 for each
    generation at the mid-and high-dose levels.  Pup body weights of
    low-dose animals during lactation were similar to those of controls. 
    No other compound-related effects on reproduction were observed.  The
    NOAEL in this study is 200 ppm (equal to 15 mg/kg bw day) based upon
    decreased pup body weight during lactation at dose levels of 800 ppm
    (equal to 62 mg/kg bw/day) and greater.

    Special studies on embryo/fetotoxicity

    Rat

         Four groups of 25 11 week old Wistar/HAN rats/group were
    administered 0, 40, 100 or 250 mg bentazone (97.8% purity)/kg bw on
    days 6 through 15 of pregnancy.  The day of positive vaginal smear or
    presence of vaginal plug was designated day 0.  The test material was
    stable for at least 2 hours in the 4% CMC vehicle (which was also
    administered to the 0 (control) group).  Analyses indicated test
    solutions to have acceptable homogeneity.  Mean concentrations of
    suspensions, as a % of nominal values ranged from 88.2 to 95.6% in low
    and mid-dose groups, and 75.6-99.8% in the high-dose group.  Females
    were paired overnight on a 1 male:1 female basis.  On day 21 of
    pregnancy, females were killed and subject to caesarian section.

         Group size of pregnant females was 24, 22, 24, and 25 at 0, 40,
    100 and 250 mg/kg bw.  No clinical signs nor mortalities were
    observed.  There were no dose-nor compound-related effects on body
    weight.  Mean corrected body weight reduction in the 100 mg/kg bw
    group was attributed to the increased number of pups/dam seen in this
    group.  Food intake was slightly reduced at 250 mg/kg bw on days 6-11,
    but was slightly increased on day 11-16.  No adverse effects were
    observed with respect to implantation incidence, numbers of live or
    dead fetuses, sex ratio, embryonic (early) resorptions or abortion. 
    However, at 250 mg/kg bw, incidence of late resorptions (with a
    consequential increase in post implantation losses) was increased. 
    Pup body weight at this dose level was decreased (4.3 g v 4.8 g in
    controls).

         No external malformations were observed in the 261 control, 232
    low dose, 272 mid-dose or 238 high-dose pups examined.  Neither were
    any soft-tissue malformations observed in the 129 control, 117
    low-dose, 129 mid-dose or 118 high-dose pups examined.  The incidence
    of incomplete ossification of vertebrae and/or sternebrae was slightly
    increased (9/120 pups in 7 litters) as was the incidence of unossified
    phalangeal nuclei and calcanea in the 250 mg/kg bw group and this was
    probably attributable to delayed maturation, indicated by the reduced
    pup body weights at this dose level (Becker  et al., 1987).  NOAELs
    were determined to be 100 mg/kg bw for maternal and fetotoxicity,
    based on possible decreased maternal food intake, reduced pup weights,
    increased late resorption incidence, and delayed pup ossification.

    There was no evidence of teratogenic activity even at the high dose of
    250 mg/kg bw (Becker  et al., 1987).

         Four groups of Charles River CD (SD) rats were fed diets
    containing 0 (22 pregnant females), 2000 (21 pregnant females), 4000
    (23 pregnant females) or 8000 (23 pregnant females) ppm bentazone
    (dose corrected for 93.9% purity) from day 0 (day of observed semen in
    vagina, or of detection of copulatory plug) to day 21 (day of
    sacrifice) of gestation.  Dietary analyses indicated that the
    percentage of nominal values ranged from 77.8 to 119.9% (10 analyses)
    at 2000 ppm, 85.4 to 110.2% (10 analyses) at 4000 ppm and 93.0 to
    106.7% (5 analyses) at 8000 ppm.  Calculated intake, based on food
    consumption and body weights was 0, 162, 324, and 631 mg/kg bw/day.

         No deaths occurred at any dose level.  Reported clinical signs of
    toxicity (haematuria in 4 females from day 19 onwards) occurred only
    at 8000 ppm.  Mean body weight was depressed (statistically
    significant) on days 3, 12-15 and 20, 21, at 8000 ppm.  Food intake
    was reduced at 8000 ppm on days 2, 18, 20 and 21 (statistically
    significant), and water intake was statistically significantly
    increased at 4000 and 8000 ppm on most days of gestation.  Necropsy
    findings were limited to one animal at 8000 ppm which was emaciated
    and had a haemorrhage of the left uterine horn.  Uterine weight, total
    fetal weight, and placental weight were comparable in all groups, but
    weight of amniotic fluid was statistically significantly increased at
    4000 and 8000 ppm.  Non-statistically significant changes at 8000 ppm
    included increased implantation rate (13.9 in control v 15.0 at 8000
    ppm), increased incidence of early resorptions (0.8 v 1.3), increased
    incidence of dead fetuses (8.4% v 11.4%) and decreased pup weight
    (males, 5.37 v 5.06, females 5.07 v 4.81 g).  The incidence of "small
    pups" was markedly increased (6 in controls v 48 at 8000 ppm).  These
    effects probably reflect maternal toxicity at this dose level.  There
    was no evidence of teratogenic activity of bentazone at any dose
    level, as assessed by external, soft tissue and skeletal examination. 
    The incidence of variants did not show any correlation with dose or
    compound administration.  The NOAEL for maternal toxicity was 2000
    ppm, based on increased water intake and increased amniotic fluid
    weight at higher doses.  The NOAEL for teratogenicity was greater than
    8000 ppm (Itabashi  et al., 1982).

         Five groups of Sprague-Dawley rats were dosed (by gavage) on days
    6-15 of pregnancy (day of positive vaginal smears, day 0) with 1% CMC
    (28 rats) 22.2 (26 rats), 66.7 (29 rats), or 200 (27 rats) mg
    bentazone (92.5% purity)/kg bw/day.  The final group (27 rats) was
    untreated.  Pregnant females were obtained from 4 female:1 male
    pairings.  Body weight and body weight gain were comparable at all
    intervals (0-6, 0-11, 0-15 and 0-20 days) between all groups.  It is
    stated that there were no clinical signs of toxicity.  There was no
    mortality.  Average numbers of corpora lutea/dose level, average
    number of implants, incidence of viable implantations, dead
    implantations, resorptions and dead fetuses were comparable in all

    groups.  Mean pup weights and litter weights as well as mean pup
    length were comparable in all groups.  Mean placental weight was
    comparable to the 1% CMC control.  No abnormalities were noted in
    gross examinations (all pups), skeletal examinations (2/3 of pups), or
    soft tissue (1/3 of pups) examinations.  Incidence of anomalies (wavy
    ribs, vertebral anomalies), variants (accessory ribs, sternal
    ossification, unilateral renal pelvis enlargement) or retardations
    (general; incomplete skull bone ossification) were comparable in all
    groups.  The NOAEL for the study is > 200 mg/kg bw/day (Hofmann &
    Merkle, 1978).

    Rabbits

         Four groups of 16 mated (1 f: 1 m) Chinchilla rabbits were
    administered doses of 0, 75, 150 or 375 mg 97.8% purity technical
    bentazone/kg bw on days 6-18 post-coitum (day of mating considered to
    be day 0)  Administered suspensions were in aqueous 4% CMC, and were
    stable for at least 2 hours.  Homogeneity was acceptable.  Mean actual
    concentration as percentage of nominal values ranged from 93-97%
    (low-dose), 86-105% (mid-dose) to 87-103% (high-dose).  Group sizes of
    pregnant animals at term (day 28) were 16, 16, 16, and 14 at 0, 75,
    150 and 375 mg/kg bw respectively.  At the top dose, 1 rabbit failed
    to conceive and a second aborted placentae on day 22.  This abortion
    was considered to be compound-related, since dose range-finding
    studies (not available) are stated to have indicated 11.1 and 70%
    post-implantation losses at 300 and 450 mg/kg bw.  It is noted that
    the same male rabbit was mated to these high-dose females, which had
    no pups at day 28.  However, this male also successfully impregnated
    2 low-dose females, although one of these low-dose females had an
    unusually small litter (4 pups v 7.4 - 8.4 average).

         Food intake was reduced by 6.2% during the 6-18 day period of
    pregnancy in the high-dose group.  However, in the low-dose group,
    post-dosing, decreases in food intake were noted of up to 19%,
    compared to controls.  In mid-dose animals food intake was comparable
    to controls.  Hence the reduced intake at the high-dose may not be due
    to bentazone administration.  Body weight gain was unaffected by
    bentazone treatment in pregnant animals.  There were no mortalities. 
    Excluding the females without pups at day 28, there were no effects on
    numbers of implantations, pre-implantation losses, post-implantation
    losses, numbers of live or dead fetuses, resorption rates, fetal
    weights or sex ratio.

         No external malformations were noted in the 118 (control), 114
    (low-dose), 129 (mid-dose) or 114 (high-dose) fetuses examined.  No
    abnormalities of abdominal or thoracic soft tissues, or of the skull
    skeletal structures were observed.  A single fetus at 150 mg/kg bw
    exhibited hydrocephaly.  In the absence of any dose effect
    relationship, this observation is not considered to be
    compound-related.  Skeletal variants were observed in a number of

    fetuses, but there was no evidence of a dose or compound relationship
    in their incidence.  A NOAEL of 150 mg/kg bw was determined based on
    the total litter loss occurring in 1 female at 375 mg/kg bw.  There is
    no evidence of teratogenicity at dose levels up to 375 mg/kg bw
    (Becker  et al., 1987).

         Five groups of 15 Himalayan ChBB:HM artificially inseminated
    rabbits were dosed by gavage with 0 (untreated), 0 (CMC - 0.5%), 50,
    100 or 150 mg 92.5% purity bentazone technical/kg bw (based on the
    initial pre-dosing weight of the rabbits) on days 6-18 post
    insemination.  The day of insemination was considered to be day 0. 
    Administration volume was 10 ml/kg bw.  Sacrifice was on day 28
    post-insemination.  Conception rates resulted in 15 pregnant animals
    in both control groups and 14 in each test group.  Food intake
    compared to untreated controls was reduced in all groups during days
    13-18 post-insemination.  Compared to CMC controls, test group food
    intake was comparable.  Body weight was slightly higher in untreated
    controls on days 12-20, but was comparable (as was body weight gain)
    with the CMC control group.  One control (untreated) and 2 at 100
    mg/kg bw aborted.  One each at 100 and 150 mg/kg bw showed vaginal
    haemorrhage, and died within 24 hours.

         Numbers of corpora lutea were comparable between groups of
    pregnant animals. Implantation rates were slightly reduced at 50 and
    150 mg/kg bw as was the number of live fetuses per pregnant animal. 
    However, the percentage of implantations resulting in live pups was
    comparable between all groups.  There was no dose effect relationship
    with respect to resorption incidence at any time interval.  The only
    malformations (cleft palate and kidney hypoplasia) were noted in the
    control group.  Fetal weights were slightly increased at 100 and 150
    mg/kg bw and placental weights were increased at 150 mg/kg bw. 
    Incidence of variations and retardations in skeletal and soft tissues
    (determined by X-ray) i.e., sternal variations, rib variations, and
    retinal folds are comparable.  No other variants are reported. 
    Bentazone does not appear to be teratogenic at doses up to and
    including 150 mg/kg bw in this study.  Based on the observation of
    vaginal haemorrhages and subsequent deaths at 100 and 150 mg/kg bw, a
    NOAEL of 50 mg/kg bw is indicated (BASF, 1978).


        Special studies on genotoxicity

    Table 2.  Genotoxicity testing of bentazone

                                                                                                                          

    Test system         Test organism                Concentration          Results      Reference

                                                                                                                          

    Rec. Assay          B. subtilis                  20-2000 g/disc        Negative     Shirasu et al. (1976)

    Reverse             S. typhimuriuma              10-1000                Negative     Shirasu et al. (1976)
    mutation            TA98, TA100, TA1535,         g/disc
                        TA1537, TA1538
                        E. coli WP 2 her

    Host mediated       Mouse                        0-200 mg/kg bw         Negative     Shirasu et al. (1976)
                        S. typhimurium
                        G46 i.p.

    Ames test           S. typhimurium               3.1-2000 g/plate      Negative     Oesch (1977)
                        TA98, TA100, TA1537

    CHO/HGPRT for       CHO (Hamster)a               0.1-10 mg/ml           Negative     Gelbke & Jackh (1985)
    point mutation      Substrain K4a
                        Weakly positive

    CHO/HGPRT for       CHO (Hamster)a               1.25-15 g/ml          Negative     den Boer, 1985
    point mutation      Substrain Ka
                        subclone BH4

    Micronucleus        Mouse                        200-800 mg/kg bw       Negative     Gelbke & Engelhardt (1985)
    (bone marrow)

    Unscheduled DNA     Mouse (primary)              2.51-502 g/ml         Negative     Cifone & McKeon (1985a)
    synthesis           hepatocytes)
                                                                                                                          

    Table 2 (contd).

                                                                                                                          

    Test system         Test organism                Concentration          Results      Reference

                                                                                                                          
    Chromosomal         CHO cells                    1.7-5.0 mg/ml          Negative     Taalmann, 1987
    aberrations

    Dominant lethal     m Rat (SD)                   20-180 ppm in diet     Negative     Leuschner, 1971
                                                     (13 weeks)

    Dominant lethal     m Mouse (NMRI)               195 mg/kg bw           Negative     Hofmann & Pek (1975)
                                                     (single dose)

    Ames test           S. typhimurium               20-5000 g/plate       Negative     Gelbke & Engelhardt (1983b)
                        TA100, TA1535, TA1537,
                        TA1538, TA98

    Ames test           S. typhimuriumaa             20-5000 g/plate       Negative     Gelbke & Engelhardt (1983b)
                        TA1535, TA100, TA98,
                        TA1537, TA1538
                        E. coli WP2 uvra

    Reverse mutation                                 20-5000 g/plate       Negative     Gelbke & Engelhardt (1983b)

    Ames test           S. typhimuriuma              500-10 000 g/plate    Negative     Gelbke & Engelhardt (1985)
                        TA1535, TA100, TA98,
                        TA1537, TA1538

    Mitotic gene        Saccharmyces cerevisiae      100 ppm                Negative     Giebert & Lemperle (1974)
    conversion          diploid strains
                        D4) MA20: d, gal 2,
                        ade 2-2,try 5-12-leul
                        D4) MD20: a, +, ade 2-1,
                        try 5-27 - +
                                                                                                                          

    Table 2 (contd).

                                                                                                                          

    Test system         Test organism                Concentration          Results      Reference

                                                                                                                          

    Ames test           S. typhimurium               Up to 5000 g/plate    Negative     Moriya et al. (1983)
                        TA100, TA98, TA1535,
                        TA1537, TA1538

    Reverse mutation    E. coli WP2 her              Up to 5000 g/plate    Negative     Moriya et al. (1983)
                                                                                                                          

    a    With and without activation
    m  male
    

    COMMENTS

         After oral administration bentazone is rapidly absorbed, mainly
    via the stomach, and rapidly excreted, largely unchanged, in the
    urine.  Only 1-2% appeared in faeces over the first 96 hours.  Two
    metabolites have been identified in animals, 6-hydroxy- and
    8-hydroxy-bentazone, at very low levels.  Residues in plants, which
    are present at very low levels, comprise mainly 6-hydroxy metabolite. 
    Absorption and excretion in rats and in rabbits were not affected by
    sex, dose level, or repeated dosing.

         Bentazone has a relatively low acute toxicity in rats,
    guinea-pigs and rabbits.  WHO has classified bentazone as slightly
    hazardous.

         There were two short-term studies in rats.  The first indicated
    a NOAEL of 400 ppm, equal to 25.3 and 28.9 mg/kg bw/day for males and
    females respectively, using dietary concentrations of 0, 400, 1200, or
    3600 ppm for 13 weeks.  The primary toxic effects observed were
    changes in serum electro-phoretic patterns and, at higher doses,
    increased prothrombin time (PrT), increased partial thromboplastin
    time (PTT) and decreased body-weight gain.  In the second study, using
    dietary concentrations of 0, 70, 200, 800 or 1600 ppm, 800 ppm
    (equivalent to 40 mg/kg bw/day) was accepted as a NOAEL, the changes
    in testicular histopathology noted at 200 and 1600 ppm being
    non-dose-related in incidence and occurring in very few animals. 
    Further, no signs of testicular effects occurred in rats even in the
    long-term studies at doses up to 4000 ppm.  The limiting toxicological
    effects were decreased body-weight gain.

         A 90-day study in dogs, using dietary concentrations of 0, 100,
    300, 1000 or 3000 ppm, indicated a NOAEL of 300 ppm, equal to 12 mg/kg
    bw/day, based on sedation at 1000 ppm,, and a maturational arrest in
    the testes (polynuclear spermatocytes and empty epididymal tubules) in
    one animal at 1000 ppm and in one animal at 3000 ppm.  A later study,
    lasting one year and using dietary concentrations of 0, 100, 400 or
    1600 ppm, indicated a NOAEL of 400 ppm, equal to 13 mg/kg bw/day.  At
    1600 ppm, various clinical signs were observed in males, and increased
    PrT and PTT were observed in both sexes.  At 1600 ppm two dogs showed
    reduced spermiogenesis.

         Three teratology studies in rats failed to demonstrate
    teratogenic potential, as did two teratology studies in rabbits.  The
    NOAELs in the rat studies were 100 mg/kg bw/day for maternal and
    embryo/fetotoxicity in the first study (dose levels of 0, 40, 100 or
    250 mg/kg bw/day) the next dose causing decreased maternal food intake
    and reduced pup weight; 2000 ppm (equal to 162 mg/kg bw/day) in the
    second study (dietary concentrations of 0, 2000, 4000 or 8000 ppm) and
    200 mg/kg bw/day (the highest dose) in the third study (dose levels 0,
    22, 67 or 200 mg/kg bw/day).  In rabbits the NOAELs were 150 mg/kg
    bw/day (dose levels 0, 75, 150 or 375 mg/kg bw/day) and 50 mg/kg

    bw/day (dose levels of 0, 50, 100 or 150 mg/kg bw/day) in two
    different studies.  In these studies abortion and vaginal haemorrhage
    were the limiting factors.

         Two multigeneration studies in rats were provided.  In the first,
    using dietary concentrations of 0, 20, 60 or 180 ppm, no effects were
    observed at the highest dietary level of 180 ppm, equal to 14 mg/kg
    bw/day.  The second study indicated a NOAEL of 200 ppm, equal to 15
    mg/kg bw/day, the higher dietary concentrations (800 and 3200 ppm)
    resulting in reduced pup weights and reduced maternal weights during
    lactation.

         Three long-term/carcinogenicity studies in mice were reviewed. 
    Two of these studies were unacceptable by present day standards.  The
    third study (dietary concentrations of 0, 100, 400 or 2000 ppm)
    indicated a NOAEL of 100 ppm, equal to 12 mg/kg bw/day, based on
    increases in prothrombin time and changes in the male pituitary
    weight.  The majority view of the three pathological reviews of
    hepatocellular neoplasia was accepted, i.e., that there was no
    evidence of tumour induction.

         Two long-term/carcinogenicity studies in rats were reviewed.  One
    of these was unacceptable by present standards.  The second study
    (using dietary concentrations of 0, 200, 800 or 4000 ppm) indicated a
    NOAEL of 200 ppm (equal to 9 and 12 mg/kg bw/day for males and females
    respectively) based upon changes in urine volume and colour, PTT in
    males and clinical chemical parameters occurring at 800 ppm.  The
    occurrence of cataracts noted in this study was determined not to be
    related to compound administration.

         After reviewing the available  in vitro and  in vivo
    genotoxicity data, it was concluded that there was no evidence of
    genotoxicity.

         The ADI was determined using a 100-fold safety factor applied to
    the long-term study in rats.  The ADI was supported by NOAELs in mice
    and dogs.  The 3-month study in dogs, even though it indicated a lower
    NOAEL, was not used since the number of animals (3/sex/dose) was low.

    TOXICOLOGICAL EVALUATION

    Level causing no toxicological effect

         Mouse:    100 ppm equal to 12 mg/kg bw/day (both sexes)
         Rat:      200 ppm equal to 9 (males) or 11 (females) mg/kg bw/day
         Dog:      400 ppm equivalent to 10 mg/kg bw/day

    Estimate of acceptable daily intake for humans

         0-0.1 mg/kg bw.

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

         -    Further observations in humans.

         -    90-day feeding study in rats of 6-hydroxy-bentazone.

         -    Genotoxicity tests on 6-hydroxy-bentazone.

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    Zeller, H., & Magoley, J. (1970).  Acute oral toxicity of
    3-isopropyl-1H-2,1,3-benzothiadiazin-4(3H)-one-2,2-dioxide to
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    Limburgerhof, Germany.


    See Also:
       Toxicological Abbreviations
       Bentazone (HSG 48, 1990)
       Bentazone (ICSC)