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    BENTAZONE (addendum)       JMPR 1998

    First draft prepared by 
    A. Protzel
    US Environmental Protection Agency
    Washington DC, United States

         Explanation 
         Evaluation for acceptable daily intake
              Biochemical aspects
                   Absorption, distribution, and excretion
                   Biotransformation 
              Toxicological studies
                   Acute toxicity
                   Short-term studies of toxicity
                   Genotoxicity
                   Developmental toxicity
              Studies of metabolites
                   Acute toxicity
                   Short-term studies of toxicity 
                   Genotoxicity 
                   Developmental toxicity
         Comments
         Toxicological evaluation
         References


    Explanation

         Bentazone was first evaluated by the Joint Meeting in 1991 (Annex
    1, reference 62), when an ADI of 0-0.1 mg/kg bw was allocated on the
    basis of a NOAEL of 9 mg/kg bw per day in a long-term study of
    toxicity in rats and a safety factor of 100. Further observations in
    humans, a 90-day feeding study in rats with 6-hydroxybentazone, and
    studies of genotoxicity with 6-hydroxybentazone were identified as
    valuable in the continued evaluation of the compound.


    Evaluation for Acceptable Daily Intake

    1.  Biochemical aspects

     (a)  Absorption, distribution, and excretion

         Male and female CD rats were given a single intravenous dose of
    4 mg/kg bw of [phenyl-U-14C] bentazone as the sodium salt, a single
    oral dose of 4 or 200 mg/kg bw free acid, or a single oral dose of
    4 mg/kg bw free acid after a 14-day pretreatment with unlabelled
    bentazone at approximately 4 mg/kg bw per day. Recovery of radiolabel
    in urine after oral dosing indicated extensive absorption from the
    gastrointestinal tract. By 24 h after the single oral dose, 83-94% of
    the radiolabel appeared in urine. Total recovery of radiolabel 120 h
    after dosing accounted for 90-97% of the dose in the animals treated

    orally and 90-95% of the dose in the animals treated intravenously.
    After oral administration, 88-96% of the dose was eliminated in urine
    and 0.8-2.3% in faeces over the 120-h collection period, most being
    eliminated within the first 24 h. No difference between the sexes or
    among dose groups was seen. Experiments with bile-duct-cannulated rats
    indicated that only 0.24-1.3% of the dose of 4 mg/kg bw and 0.3-1.8%
    of the dose of 200 mg/kg bw was eliminated in the bile over a 48-h
    collection period. 

         In a parallel series of studies, CD rats of each sex were given a
    single dose of 4 mg/kg bw [phenyl-U-14C]-bentazone (sodium salt)
    intravenously or an oral dose of 4 (free acid or sodium salt) or
    200 mg/kg bw (free acid). The area under the curve (AUC) for radioabel
    in plasma per unit dose for animals that received the high dose was
    nearly double that of rats given the low dose, suggesting that a non-
    linear region in disposition was reached at the high dose.
    Additionally, the AUC values for females given the low dose were
    nearly one-half those of females dosed intravenously; the
    corresponding values for males were not significantly different. The
    biological significance of the difference in bioavailability in
    females is unclear in view of the similar, extensive absorption of the
    compound (about 90%) in both males and females, the limited metabolism
    of the compound, and the apparently similar rates of excretion in the
    two sexes. At sacrifice at 120 h, the total radiolabel in carcasses
    represented less than 0.69% of the dose in all groups. Whole-body
    autoradiography indicated steady disappearance of the lail with time.
    Signed and dated statements of compliance with good laboratory
    practice (GLP) (40 CFR 160.35) and quality assurance were provided
    with the study. This study satisfies the FIFRA Subdivision F Guideline
    requirement for an 85-1 study of general metabolism (Hawkins et al.,
    1987).

     (b)  Biotransformation

         In the study of Hawkins et al. (1987), described above, parent
    bentazone was the major excretion product in the urine of treated rats
    during the 24-h collection period, representing 81-91% of the dose in
    males and 77-89% in females. 6-Hydroxybentazone represented up to 6.3%
    of the dose, and the isomeric 8-hydroxybentazone was present in trace
    amounts, 0-0.23% of the dose (Figure 1). Although slightly less parent
    bentazone was excreted in the urine of females and less
    6-hydroxybentazone was excreted by rats treated intravenously (0.98%
    of the dose versus 2.4-6.3% in rats given the low oral dose), there
    were no major dose-dependent differences among the groups. Little or
    no glucuronide or sulfate conjugation was seen.

         In a previous study, adult male CD rats received 14C-bentazone,
    presumably [phenyl-U-14C]-labelled, as a single oral dose of 4 mg/kg
    bw of the sodium salt (expressed as the free acid), and metabolites in
    the urine were analysed by thin-layer chromatography. Parent bentazone
    represented 65, 15, and 3.2% of the dose in urine collected 0-6, 6-12,
    and 12-24 h after dosing, respectively, for a total of 83% of the
    dose; 6-hydroxybentazone represented 1.7, 0.4, and 0.1% of the dose at

    FIGURE 1

    those times. 8-Hydroxybentazone was not detected. Polar radioactive
    compounds at the origin represented 2.1% of the dose in the 0-24-h
    period (Hawkins et al., 1986).

    2.  Toxicological studies

     (a)  Acute toxicity

         Bentazone is more acutely toxic to rats by the oral route than
    its 6-hydroxy or 8-hydroxy metabolites. The LD50 values for
    technical-grade bentazone (purity unspecified) suspended in aqueous
    carboxymethyl cellulose in Wistar rats were 1800 mg/kg bw for males,
    1500 mg/kg bw for females, and 1600 mg/kg bw for males and females
    combined. The LD50 value for males was estimated from deaths at four
    doses, with no statistical analysis; the values for females and for
    males and females combined were determined by probit analysis.
    Dyspnoea and apathy were noted at doses of 825 mg/kg bw and higher,
    and staggering occurred at the highest dose, 2610 mg/kg bw per day.
    Animals at this dose that died had bloody ulcerations in the stomach
    and intestinal contents mixed with blood (Hildebrand & Kirsch, 1982).

     (b)  Short-term studies of toxicity

     Rats

         Groups of 10 Wistar KFM-Han, outbred SPF quality rats of each sex
    received technical-grade bentazone (purity, 97.8%) at a dietary level
    of 0, 400, 1200, or 3600 ppm for 13 weeks, equal to doses of 0, 25,
    78, and 240 mg/kg bw per day in males and 0, 29, 86, and 260 mg/kg bw
    per day in females. Twenty additional rats were used for a 28-day
    recovery experiment. Ten rats received 3600 ppm bentazone for 13 weeks
    and were then given regular diet and observed for an additional 28
    days; 10 rats served as untreated controls in the recovery experiment.
    The animals were observed for clinical signs, deaths, body weight, and
    food consumption; ophthalmic, urinary, haematological, and clinical
    chemical parameters; organ weights; and gross and histopathological
    alterations. 

         One male and two females at the high dose died, one of the
    females under anesthesia; no signs of toxicity were reported. The body
    weights of females at this dose were statistically significantly lower
    than those of controls from week 10 onwards; there were no effects on
    the body weights of males, and no statistically significant
    differences in body weights were seen during the recovery period. The
    food consumption of males at the high dose was slightly increased and
    became statistically significantly greater than that of controls from
    week 7 onwards; the food consumption of females was generally not
    affected. No ophthalmological effects were reported. Statistically
    significant increases in prothrombin time and partial thromboplastin
    time were seen in males at the high dose, whereas females at all doses
    had statistically significantly depressed prothrombin time and the
    partial thromboplastin time was not affected. The values for certain
    clinical chemical parameters were statistically significantly

    different from those of controls in males at the high dose, but they
    were generally within the historical control values and returned to
    normal during the recovery period; the values for females were within
    the historical control range. 

         Bentazone had a diuretic effect in animals of each sex. In both
    males and females, the urine volume was increased in a dose-related
    manner, becoming significantly different from that of controls at
    3600 ppm. The specific gravity was decreased in animals of each sex;
    the decrease was dose-related in males and was statistically
    significantly different from that of controls at the high dose; in
    females, the decrease was significantly different from that of
    controls at all doses but did not decrease monotonically. The mean
    absolute and relative kidney weights were statistically significantly
    greater than those of controls in males at 3600 ppm; in females,
    although both the mean absolute and relative kidney weights were
    greater than those of controls, the values reached statistical
    significance only for absolute weights. The only change in liver
    weights was a statistically significantly increase in relative liver
    weight in females at 3600 ppm. Gross examination revealed lung thrombi
    in 1/10 controls and 3/10 females at the high dose and dilated uterine
    horns in 1/10 controls and 3/9 females at the high dose. No
    statistically significant histopathological findings were made. The
    NOAEL for systemic toxicity was 1200 ppm, equal to 78 mg/kg bw per
    day, and the LOAEL was 3600 ppm, equalto 240 mg/kg bw per day, on the
    basis of statistically significant decreased body weights of females
    throughout the latter part of treatment, increased prothrombin time
    and partial thromboplastin time in males, increased urinary output
    with decreased specific gravity in animals of each sex, and some
    degree of kidney hypertrophy in both males and females (Tennekes et
    al., 1987). 

         Groups of five male and five female New Zealand white rabbits
    received repeated dermal applications of bentazone (purity, 97.6%) in
    Tylose CB in 0.5% aqueous suspension under semiocclusion for 6 h once
    a day for 21 days at a dose of 0, 250, 500, or 1000 mg/kg bw per day.
    No deaths or clinical signs were seen in animals of either sex at any
    dose, and no adverse effects were seen on treated skin. The NOAEL was
    1000 mg/kg bw per day, the highest dose tested (Kirsch, 1993).

     (c)  Genotoxicity 

         Bentazone was considered not to be genotoxic  in vitro or
     in vivo in the previous evaluation. It has been tested only as a
    compound of 96.7% purity for reverse mutation in  Salmonella 
     typhimurium strains TA98, TA100, TA1535, TA1537, and TA1538, at
    concentrations of 20-5000 g per plate, in the presence and absence of
    an exogenous metabolic activation system. Negative results were
    obtained (Gelbke & Engelhardt, 1983). 

     (d)  Developmental toxicity

     Rats

         In a study of developmental toxicity, pregnant Wistar/HAN rats
    (Kfm: WIST, outbred, SPF quality) received technical-grade bentazone
    (purity, 97.8%) mixed with 4% carboxymethyl cellulose in distilled
    water by gavage at a dose of 0, 40, 100, or 250 mg/kg bw per day on
    days 6-15 of gestation. The dams were observed for mortality, clinical
    signs, body weight, and food consumption;  post mortem, the uterus
    was removed, weighed, and opened for internal examination. The fetuses
    were examined for sex, weight, and gross external abnormalities, and
    underwent visceral (slice technique) and skeletal examinations. No
    signs or symptoms of compound-related toxicity were reported, and
    there were no effects on body weight, body-weight gain, or food
    consumption. The litter incidence of fetal resorptions was increased
    in dams at 250 mg/kg bw per day as compared with controls, and the
    difference in total number was statistically significant (0 in
    controls and 44 at the high dose). There was a small but statistically
    significant decrease in mean fetal weight at the high dose (4.8 g in
    controls versus 4.3 g). The rate of ossification in the phalangeal
    nuclei of fore- and hindlimb digits, the fifth sternebra, and cervical
    vertebrae was decreased, and the litter incidence of phalangeal nuclei
    with delayed ossification was statistically significant at the high
    dose (chi2,  p < 0.05). The NOAEL for maternal toxicity was
    250 mg/kg bw per day, the highest dose tested, and that for
    developmental toxicity was 100 mg/kg bw per day on the basis of
    statistically significantly decreased mean fetal weights and delays in
    tissue ossification at the high dose (Becker at al., 1986). 

    3.  Studies of metabolites

     (a)  Acute toxicity 

         The acute oral LD50 values for 6-hydroxy- and 8-hydroxybentazone
    suspended in aqueous carboxymethyl cellulose in male and female Wistar
    rats were > 5000 mg/kg bw. The 6-hydroxy compound was > 98%, and
    the 8-hydroxy compound was > 98.5% pure. Two males that received 5000
    mg/kg bw 8-hydroxybentazone died, but no deaths occurred among females
    at any dose (2150, 3830, or 5000 mg/kg bw) or among any of the animals
    given the 6-hydroxy metabolite. Necropsy of the rats that died after
    intake of 5000 mg/kg bw 8-hydroxybentazone showed general congestion
    (Kirsch & Kieczka, 1987). No lesions were found at necropsy in animals
    given 5000 mg/kg bw 6-hydroxy-bentazone (Kirsch & Kieczka, 1986). 

     (b)  Short-term studies of toxicity

         Groups of 10 Wistar rats of each sex received 8-hydroxybentazone
    (99.9% active ingredient) in the diet at 0, 400, 1200, or 3600 ppm for
    three months, equal to doses of 0, 28, 85, and 260 mg/kg bw for males
    and 0, 34, 100, and 300 for females. No compound-related effects were
    seen on mortality, clinical signs, body weight, food consumption,
    haematological, clinical chemical, or urinary parameters, organ

    weights, or gross or histopathological appearance. In particular,
    there was no significant effect on thromboplastin time at 45 or 94
    days. The NOAEL was 3600 ppm, equal to 260 mg/kg bw per day, the
    highest dose tested (Mellert et al., 1993) 

     (c)  Genotoxicity

         Studies on the genotoxicity of metabolites of bentazone are
    summarized in Table 1. The 6- and 8-hydroxy isomers of bentazone also
    gave negative results in assays for reverse mutation, with and without
    microsomal activation (Gelbke & Engelhardt, 1987a,b).
    8-Hydroxybentazone gave negative results in an assay for gene mutation
    at the  hprt locus in Chinese hamster V79 cells, with and without
    metabolic activation (Mullerschon, 1992) and in an assay for
    micronucleus formation in mice treated  in vivo (Gelbke, 1993).

     (d)  Developmental toxicity

         In a range-finding study for developmental toxicity, groups of
    nine or 10 pregnant Wistar (Chbb:THOM SPF) rats received
    8-hydroxybentazone (purity unspecified) in 0.5% aqueous carboxymethyl
    cellulose (Tylose CB 30 000) at a dose of 0 or 300 mg/kg bw per day on
    days 6-15 of gestation. Maternal toxicity was observed, consisting of
    significant decreases in body-weight gain (89%) and food consumption
    during days 6-8 of gestation. The frequency of post-implantation loss
    (12.6%) was greater than that in concurrent controls (4.6%), but this
    finding was within the range for historical controls (4.5-15.7%)
    (BASF, 1992).

         In a study of developmental toxicity, groups of 25 pregnant
    Wistar (Chbb:THOM SPF) rats received 8-hydroxybentazone (purity,
    99.9%) in 0.5% aqueous carboxymethyl cellulose (Tylose CB 30,000) at a
    dose of 0, 40, 100, or 250 mg/kg bw per day on days 6-15 of gestation.
    The dams were observed for deaths, clinical signs, body weight, and
    food consumption;  post mortem, the uterus was removed, weighed, and
    opened for internal examination. The fetuses were observed for sex,
    weight, and gross external abnormalities, and underwent visceral
    (slice technique) and skeletal examinations. There was no maternal or
    developmental toxicity. The NOAEL for both maternal and developmental
    toxicity was 250 mg/kg bw per day, the highest dose tested (Hellwig &
    Hildebrand, 1993).

    Comments

         After oral administration to rats, [phenyl-U-14C]-bentazone was
    extensively absorbed and rapidly excreted in the urine. In rats given
    a single dose, 83-94% appeared in the urine by 24 h and 90-97% by
    120 h after dosing, with less than 0.7% in the residual carcase.
    Biliary excretion of the compound amounted to less than 2% of the
    dose. Bentazone undergoes very limited biotransformation in rats.
    Bentazone was the major compound identified in urine, representing
    81-91% of the dose in males and 77-89% in females. 6-Hydroxybentazone
    was present in amounts up to 6.3% of the dose, and isomeric


        Table 1. Results of assays for the genotoxicity of the 6-hydroxy and 8-hydroxy metabolites of bentazone  

                                                                                                                                

    End-point                  Test object              Concentration              Purity     Results     Reference
                                                                                   (%)
                                                                                                                                

    6-Hydroxybentazone
    Reverse mutation           S. typhimurium TA98,     20-5000 g/plate           > 98       Negative    Gelbke & Engelhardt 
                               TA100, TA1535, TA1537     S9                                              (1987a)

    8-Hydroxybentazone
    Reverse mutation           S. typhimurium           20-5000 g/plate           > 98.5     Negative    Gelbke & Engelhardt 
                               TA98,TA100, TA1535,       S9                                              (1987b)
                               TA1537

    Gene mutation              Chinese hamster          Trial 1:                    99.9      Negative    Mullerschon (1992)
                               V79 cells, hprt locus    55-2002 g/ml -S9
                                                        495-5005 g/ml +S9
                                                        Trial 2:
                                                        300-3000 g/ml -S9
                                                        500-5000 g/ml +S9

    Micronucleus formation     NMRI mouse in vivo       625, 1250, 2500 mg/kg bw    99.9      Negative    Gelbke (1993)
                                                                                                                                
    

    8-hydroxybentazone was present in trace amounts (0-0.23% of the dose).
    There were no major differences among the groups. Glucuronide or
    sulfate conjugation was either negligible or nonexistent; 6- and
    8-hydroxybentazone are also metabolites of bentazone in plants.

         Bentazone is more acutely toxic to rats than are its two
    hydroxylated metabolites when given by the oral route. The acute oral
    LD50 of technical-grade bentazone was estimated to be 1800 mg/kg bw
    in males and 1500 mg/kg bw in females. The acute oral LD50 value for
    6- and 8-hydroxybentazone was 5000 mg/kg bw.

         WHO has classified bentazone as slightly hazardous (WHO, 1996).

         The two studies described below indicate that 8-hydroxybentazone
    does not have the anticoagulant and diuretic effects of bentazone at
    the doses tested and has less systemic toxicity than the parent
    compound under the test conditions. No data were available on the
    short-term toxicity of 6-hydroxybentazone.

         Rats received technical-grade bentazone in the diet at
    concentrations of 0, 400, 1200, or 3600 ppm for 13 weeks. The body
    weights of females were decreased and were statistically significantly
    different from those of controls at 3600 ppm from week 10 onward.
    Examination of haematological parameters indicated statistically
    significant increases in prothrombin time and partial thromboplastin
    time in males at 3600 ppm in comparison with controls. Bentazone had a
    diuretic effect in animals of each sex, reaching statistical
    significance at 3600 ppm. The NOAEL for systemic toxicity was 1200 ppm
    (equal to 78 mg/kg bw per day) on the basis of statistically
    significant decreased body weights in females throughout the latter
    part of the treatment, increased prothrombin time and partial
    thromboplastin time in males, increased output of urine with decreased
    specific gravity in animals of each sex, and some degree of kidney
    hypertrophy in both males and females at 3600 ppm, equal to 240 mg/kg
    bw per day. 

         Rats received 8-hydroxybentazone in the diet at concentrations of
    0, 400, 1200, or 3600 ppm for three months. No compound-related
    effects were observed on body weights, clinical signs, food
    consumption, haematological, clinical chemical, or urinary parameters,
    clotting time, organ weights, or gross or histopathological
    appearance. The NOAEL was 3600 ppm (equal to 260 mg/kg bw per day),
    the highest dose tested.

         The following two studies of developmental toxicity indicate that
    bentazone has effects at doses below a maternally toxic dose, whereas
    8-hydroxybentazone had no developmental or maternal toxicity at any of
    the doses tested.

         Pregnant rats received technical-grade bentazone by gavage at 0,
    40, 100, or 250 mg/kg bw per day on days 6-15 of gestation. The NOAEL
    for maternal toxicity was 250 mg/kg bw per day, the highest dose
    tested. The NOAEL for developmental toxicity was 100 mg/kg bw per day
    on the basis of significantly decreased mean fetal weights and delays
    in tissue ossification, which reached statistical significance on a
    litter basis at the highest dose. 

         No developmental toxicity was observed in pregnant rats that
    received 8-hydroxybentazone by gavage at 0, 40, 100, or 250 mg/kg bw
    per day on days 6-15 of gestation. The NOAEL for developmental
    toxicity was 250 mg/kg bw per day, the highest dose tested.

         Bentazone, 6-hydroxybentazone, and 8-hydroxybentazone did not
    induce reverse mutation in bacteria, and 8-hydroxybentazone did not
    induce gene mutation in mammalian cells or micronucleus formation in
    mice  in vivo. The Meeting concluded that neither bentazone nor its
    metabolites are genotoxic.

         8-Hydroxybentazone was less toxic than the parent compound, and,
    on the basis of the structural similarities between the 6- and
    8-hydroxy isomers, the Meeting concluded that the 6-hydroxy isomer is
    also less toxic than the parent. Therefore, the Meeting maintained the
    ADI of 0-0.1 mg/kg bw for bentazone.

         Because this was a limited review, data were not evaluated that
    would permit the establish-ment of an acute reference dose. 

    Toxicological Evaluation

     Levels that cause no toxic effect
     Bentazone

         Mouse:    100 ppm, equal to 12 mg/kg bw per day (toxicity in a
                   two-year study of toxicity and carcinogenicity)

         Rat:      200 ppm, equal to 9 mg/kg bw per day (toxicity in a
                   two-year study of toxicity and carcinogenicity)
                   1200 ppm, equal to 78 mg/kg bw per day (13-week study
                   of toxicity)
                   250 mg/kg bw per day (maternal toxicity in a study of
                   developmental toxicity)
                   100 mg/kg bw per day (developmental toxicity)

         Dog:      400 ppm, equal to 13 mg/kg bw per day (one-year study
                   of toxicity)

     8-Hydroxybentazone

         Rat:      3600 ppm, equal to 260 mg/kg bw per day (three-month
                   study of toxicity)
                   250 mg/kg bw per day (maternal and developmental
                   toxicity in study of developmental toxicity)

     Estimate of acceptable daily intake for humans

         0-0.1 mg/kg bw

     Estimate of acute reference dose

         Not considered

        List of end-points relevant for comparing the toxicities of bentazone, 6-hydroxybentazone 
    and 8-hydroxybentazone
                                                                                                 

     Absorption, distribution, excretion and metabolism in mammals

    Rate and extent of oral absorption        83-94% rapidly absorbed (bentazone)
    Dermal absorption                         No data
    Distribution                              Extensive
    Potential for accumulation                Little or none for bentazone; no data on metabolites
    Rate and extent of excretion              Rapid excretion: 83-94% of a dose excreted in urine 
                                              within 24 h (bentazone)
    Metabolism in animals                     Very little biotransformation: 81-91%of a dose 
                                              excreted untransformed. Metabolites are 
                                              6-hydroxybentazone (6.3% of dose) and 
                                              8-hydroxybentazone (0-0.23% of dose)
    Toxicologically significant compounds     Bentazone
    (animals, plants and environment)

    Acute toxicity

    Rat LD50 oral                             Bentazone: 1500 mg/kg bw 
                                              6-Hydroxybentazone: > 5000 mg/kg bw 
                                              8-Hydroxybentazone: > 5000 mg/kg bw

    Short-term toxicity

    Target/critical effect                    Bentazone: decreased body weights in females, 
                                              increased clotting times (prothrombin time and 
                                              partial thromboplastin time) and increased output 
                                              of urine with decreased specific gravity
                                              6-Hydroxybentazone: no data
                                              8-Hydroxybentazone: no effect up to highest dose 
                                              tested
    Lowest relevant oral NOAEL                Rat: Bentazone: 90 days, 78 mg/kg bw per day
                                              6-Hydroxybentazone: no data
                                              Rat: 8-Hydroxybentazone: 260 mg/kg bw per day, 
                                              highest dose  tested 
    Lowest relevant dermal NOAEL              Bentazone: 1000 mg/kg bw per day (highest dose 
                                              tested)
                                              6-Hydroxybentazone: no data
                                              8-Hydroxybentazone: no data
    Lowest relevant inhalation NOAEL          No data

    Genotoxicity                            Bentazone and its metabolites are not genotoxic

    Long-term toxicity and carcinogenicity
    Target/critical effect                    No data
    Lowest relevant NOAEL                     No data
    Carcinogenicity                           Bentazone: no carcinogenicity
                                              6-Hydroxybentazone: no data
                                              8-Hydroxybentazone: no data

    Reproductive toxicity

    Reproduction target/critical effect       No data
    Lowest relevant reproductive NOAEL        No data
    Developmental target/critical effect      Bentazone: developmental effects (decreased fetal 
                                              weights and delayed ossification) below maternally 
                                              toxic dose
                                              6-Hydroxybentazone: no data
                                              8-Hydroxybentazone: no developmental toxicity at highest dose tested
    Lowest relevant developmental NOAEL       Rat: Bentazone: 100 mg/kg bw per day
                                              6-Hydroxybentazone: no data
                                              Rat: 8-Hydroxybentazone: 250 mg/kg bw per day

    Neurotoxicity / Delayed neurotoxicity     No data

    Other toxicological studies               No data

    Medical data                              No data

    Summary                  Value               Study                        Safety factor
    ADI                      0-0.1 mg/kg bw      Long-term toxicity, rats     100
    Acute reference dose     Not considered
                                                                                                 
    
    References

    BASF (1992) Results of a range-finding prenatal toxicity study with
    8OH-bentazon in rats after oral administration (gavage). Unpublished
    study dated January/February 1992. Project No. 10R0437/91061 from BASF
    Aktiengesellschaft, Department of Toxicology, Ludwigshafen/Rhein,
    Germany. Submitted to WHO by BASF Aktiengesellschaft, Ludwigshafen,
    Germany.

    Becker, H., Frei, D., Vogel, W. & Terrier, C. (1986) Embryotoxicity
    (including teratogenicity) study with bentazone technical in the rat.
    Unpublished report, BASF RZ-Report No. 86/421 dated 30 December 1986
    from RCC Research and Consulting Company AG, Itingen, Switzerland, RCC
    Report No. 064530. Submitted to WHO by BASF Aktiengesellschaft,
    Ludwigshafen, Germany.

    Gelbke, H.P. (1993) Cytogenetic study in vivo of 8-OH-bentazon in mice
    micronucleus test single oral administration. Unpublished document No.
    BASF 93/10424 dated 6 May 1993 from BASF Aktiengesellschaft,
    Department of Toxicology, Ludwigshafen/Rhein, Germany, Project
    No.26M0437/914319. Submitted to WHO by BASF Aktiengesellschaft,
    Ludwigshafen, Germany.

    Gelbke, H.P. & Engelhardt, G. (1983) Report on the study of Reg. No.
    51 929 (bentazone) (ZNT test substance No. 83/3) in the Ames test
    (standard plate test with  Salmonella typhimurium). Unpublished
    document No. BASF 83/222 dated 10 June 1983 (original German report)
    and 26 October 1983 (English translation) from BASF
    Aktiengesellschaft, Department of Toxicology, Ludwigshafen/Rhein,
    Germany. Submitted to WHO by BASF Aktiengesellschaft, Ludwigshafen,
    Germany.

    Gelbke, H.P. & Engelhardt, G. (1987a) Report on the study of
    6-hydroxy-bentazon (ZNT test substance No. 86/244) in the Ames test
    (standard plate test and preincubation test with  Salmonella 
     typhimurium). Unpublished document No. BASF 87/023 dated 15 January
    1987 from BASF Aktiengesellschaft, Department of Toxicology,
    Ludwigshafen/Rhein, Germany, Project No.40/1M0244/86. Submitted to WHO
    by BASF Aktiengesellschaft, Ludwigshafen, Germany.

    Gelbke, H.P. & Engelhardt, G. (1987b) Report on the study of
    8-hydroxy-bentazon (ZNT test substance No. 86/391) in the Ames test
    (standard plate test and preincubation test with  Salmonella 
     typhimurium). Unpublished document No. BASF 87/0168 dated 14 May
    1987 from BASF Aktiengesellschaft, Department of Toxicology,
    Ludwigshafen/Rhein, Germany, Project No.40/1M0391/86. Submitted to WHO
    by BASF Aktiengesellschaft, Ludwigshafen, Germany.

    Hawkins, D.R., Elsom, L.F. & Girkin, R. (1986) Report on the urinary
    metabolites of bentazone in the rat. Unpublished report, document No.
    BASF 86/090 dated 31 January 1986 from Huntingdon Research Centre Ltd,
    Huntingdon, United Kingdom. Submitted to WHO by BASF
    Aktiengesellschaft, Ludwigs-hafen, Germany.

    Hawkins, D.R., Mayo, B.C., Pollard, A.D., Green, S.L., Biggs, S.R. &
    Whitby, B.R. (1987) The biokinetics and metabolism of 14C-bentazon in
    rats. Unpublished report, document No. BASF 87/0429 dated 16 September
    1987 from Huntingdon Research Centre Ltd, Huntingdon, United Kingdom.
    Submitted to WHO by BASF Aktiengesellschaft, Ludwigshafen, Germany.

    Hellwig, J. & Hildebrand, B. (1993) Study of the prenatal toxicity of
    8-OH-bentazon in rats after oral administration (gavage). Unpublished
    report, document No. BASF 93/10572 dated 9 June 1993 from BASF
    Aktiengesellschaft, Abteilung Toxicologie, Ludwigshafen/Rhein,
    Germany, report No. 30R0437/91081. Submitted to WHO by BASF
    Aktiengesellschaft, Ludwigshafen, Germany

    Hildebrand, B. & Kirsch, P. (1982) Report on the study of the acute
    oral toxicity in rats of Reg. No. 51 929 -- bentazone. Unpublished
    document No. BASF 83/114 dated 30 November 1982 (original in German);
    English translation dated 21 June 1983 from BASF Aktiengesellschaft,
    Department of Toxicology, Ludwigshafen/Rhein, Germany. Submitted to
    WHO by BASF Aktiengesellschaft, Ludwigshafen, Germany.

    Kirsch, P. (1993) Study of the dermal toxicity of Reg. No. 51 929
    (bentazone) in white rabbits: Application to the intact skin over 3
    weeks. Unpublished report, document No. BASF 93/10760 dated 9 June
    1993 from BASF Aktiengesellschaft, Department of Toxicology,
    Ludwigshafen/Rhein, Germany, Project No. 41H0243/91042. Submitted to
    WHO by BASF Aktiengesellschaft, Ludwigshafen, Germany.

    Kirsch, P. & Kieczka (1986) Report on the study of acute oral toxicity
    on the rat based on OECD and EPA (FIFRA). Unpublished report, document
    No. BASF 87/002 dated 29 December 1986 from BASF Aktiengesellschaft,
    Department of Toxicology, Ludwigshafen/Rhein, Germany, Project.
    Submitted to WHO by BASF Aktiengesellschaft, Ludwigshafen, Germany.

    Kirsch, P. & Kieczka (1987) Report on the study of acute oral toxicity
    on the rat based on OECD and EPA (FIFRA). Unpublished report, document
    No. BASF 87/030 dated 21 January 1987 from BASF Aktiengesellschaft,
    Department of Toxicology, Ludwigshafen/Rhein, Germany, Project.
    Submitted to WHO by BASF Aktiengesellschaft, Ludwigshafen, Germany.

    Mellert, W., Deckardt, K., Kuttler, K. & Hildebrand, B. (1993)
    Subchronic oral toxicity study with 8-OH-bentazon in Wistar rats.
    Administration in the diet for 3 months. Unpublished report No. BASF
    93/11011 dated 13 September 1993 from BASF Aktiengesellschaft,
    Department of Toxicology, Ludwigshafen/Rhein, Germany, Project No.
    31S0437/91060. Submitted to WHO by BASF Aktiengesellschaft,
    Ludwigshafen, Germany.

    Mullerschon (1992) Gene mutation assay in Chinese hamster V79 cells in
    vitro with 8-OH bentazone. Unpublished report No. BASF 92/11329 dated
    20 October 1992 from CCR Cytotest Cell Research GmbH & Co. KG,
    Germany. BASF Project No. 50M0437/919018. Submitted to WHO by BASF
    Aktiengesellschaft, Ludwigshafen, Germany.

    Tennekes, H., Horst, K., Luetkemeier, H., Wilson, J., Vogel, W. &
    Terrier, C. (1987) Report on the 13-week oral toxicity (feeding) study
    with bentazone technical in the rat. Unpublished report, document No.
    BASF 87/0173 dated 12 May 1987 from RCC Research and Consulting
    Company AG, Itingen, Switzerland. Submitted to WHO by BASF
    Aktiengesellschaft, Ludwigshafen, Germany.

    WHO (1996)  The WHO Recommended Classification of Pesticides by 
    Hazard and Guidelines to Classification 1996-1997 (WHO/PCS/96.3),
    International Programme on Chemical Safety, Geneva.
    


    See Also:
       Toxicological Abbreviations