820K88007                                          August,  198?
                                      BROMACIL
                                  Health Advisory
                              Office  of Drinking Water
                        U.S.  Environmental Protection Agency
I. INTRODUCTION
        The Health  Advisory  (HA)  Program,  sponsored by the Office of Drinking
   Water (ODW),  provides  information on  the  health effects,  analytical method-
   ology and treatment technology that would be useful in dealing with the
   contamination of drinking water.   Health  Advisories describe nonregulatory
   concentrations of drinking water  contaminants at which adverse health effects
   would not be  anticipated  to occur over  specific exposure durations.  Health
   Advisories contain a margin of safety to  protect sensitive members of the
   population.

        Health Advisories serve  as informal  technical guidance to assist Federal,
   State and local  officials responsible for protecting public health when
   emergency spills or contamination situations occur.  They are not to be
   construed as  legally enforceable  Federal  standards.  The HAs are  subject to
   change as new information becomes available.

        Health Advisories are developed  for  one-day,  ten-day, longer-term
   (approximately 7 years, or 10% of an  individual's  lifetime) and lifetime
   exposures based  on data describing noncarcinogenic end points of  toxicity.
   Health Advisories do not  quantitatively incorporate any potential carcinogenic
   risk from such exposure.   For  those substances that are known or  probable
   human carcinogens, according  to the Agency classification scheme  (Group A or
   B),  Lifetime  HAs are not  recommended.   The chemical concentration values for
   Group A or B  carcinogens  are  correlated with carcinogenic risk estimates by
   employing a cancer potency (unit  risk)  value together with assumptions for
   lifetime exposure and  the consumption of  drinking  water.   The cancer unit
   risk is usually  derived from  the  linear multistage model with 95% upper
   confidence limits.  This  provides a low-dose estimate of cancer risk to
   humans that is considered unlikely to pose a carcinogenic risk in excess
   of the stated values.   Excess  cancer  risk estimates may also be calculated
   using the One-hit, Weibull, Logit or  Probit models.  There is no  current
   understanding of the biological mechanisms involved in cancer to  suggest that
   any one of these mrdels is able to predict risk more accurately than another.
   Because each  model is  based on differing  assumptions,  the estimates that are
   derived can differ by  several  orders  of magnitude.

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    Bromacil      (                                                August, 1987

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II. GENERAL INFORMATION AND PROPERTIES

    CAS No;  314-40-9

    Structural Formula
            5-Bromo-6-methyl-3-{1-methylpropyl)-2,4(lH, 3H)-pyrimidinedione

    Synonyms

         0  Borea;  Borocil IV:  Bromazil;  Cynogan; Herbicide 976; Hyvar X-WS;
            Hyvar X;  Hyvar X Weed  Killer; Hyvar X-L; Hyvarex; Krovar II; Nalkil;
            Uragan; Urox HX;  Urox  B;  Weed-Broom (Meister,  1983).

    Uses

         8  Herbicide for general  weed  or brush control in noncrop areas;
            particularly useful against perennial grasses  (Meister, 1983).

    Properties (Windholz et al., 1983)

            Chemical  Formula                CgHijC^^Br
            Molecular Weight                261.11
            Physical  State (at  25C)        White crystalline solid
            Boiling Point
            Melting Point                  158-160C
            Density
            Vapor Pressure (100C)         8 x 10-4 mm Hg
            Specific  Gravity
            Water Solubility  (20C)         815 mg/L
            Log Octanol/Water Partition
              Coefficient
            Taste Threshold
            Odor Threshold
            Conversion Factor

    Occurrence

         0  Bromacil  has been found in  Florida ground water; a typical positive
            was 300 ppb (Cohen  et  al.,  1986).

    Environmental Fate

         0  Bromacil  in aqueous solution  was stable when exposed to simulated
            sunlight  for 6 days (Moilanen and  Crosby, 1974).  Only one minor
            (<4%) photolysis  product  (5-bromo-6-methyluracil) was identified.  An
            aqueous solution  of bromacil  at 1  ppm lost all herbicidal  activity

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     Bromacil                                                       August,  1987

                                          -3-


             after exposure to UV light for 10 minutes,  but at 10 ppm and 15
             minutes'  irradiation herbicidal activity was still present (Kearney
             et al.,  1964).  However,  brocnacil in an aqueous solution CpH 9.4)
             containing the photosensitizer methylene blue was rapidly degraded
             under direct sunlight with a halflife of <1  hour (Acher and Dunkelblum,
             1979).

          0  More than 26 soil fungi  representative of several taxonomic groups,
             including Fungi Imperfecti,  Ascomycetes and Zygomycetes, were capable
             of metabolizing bromacil  as  their sole carbon source (Wolf et al.,
             1975; Torgeson, 1969; Torgeson and Mee, 1967; Boyce Thompson Institute
             for Plant Research,  1971).

          0  Data from soil metabolism studies indicate that bromacil at 8 ppm  had
             a half-life of about 6 months in aerobic loam soil incubated at 31 C
             (Zimdahl  et al., 1970).   However, 10% of applied bromacil at approximately
             3 ppm was slowly degraded to CC>2 in an aerobic sandy loam soil after
             330 days  at 22C (Wolf,  1974; Wolf and Martin, 1974).  In anaerobic
             sandy loam soil, bromacil at approximately 3 ppm had a calculated
             half-life of approximately 144 days.  No CC>2 evolved from the sterilized
             soil treated with bromacil within 145 days,  indicating that degradation
             was microbial.

          0  Bromacil  is mobile in soil.   Phytotoxic residues of bromacil leached
             19 cm in  clay and silty  clay loam soils eluted with the equivalent of
             4.3 acre-inches of water  (Signori et al., 1978).  In mucky peat, loam
             and loamy sand soils eluted  with the equivalent of 13 to 15 cm of  water,
             bromacil  leached to  10-,  25-, and to >30-cm depths, respectively  (Day,
             1976).  Utilizing soil thin-layer chromatographic techniques 1 4c-
             bromacil  was evaluated to be mobile (Rf 0.7) in a silty clay loam
             soil (Helling, 1971). Bromacil is not adsorbed by montmorillonite,
             illite, or humic acid to any great extent [Freundlich K (adsorption
             coefficient) 10 at  25C]; however, at 0C bromacil was adsorbed
             (Freundlich K 126) to humic  acid (Haque and Coshow, 1971; Volk,
             1972).  Adsorption appeared  to increase with decreasing temperatures.

          0  Data from field dissipation studies showed that bromacil phytotoxic
             residues  persisted in soils  ranging in texture from sand to clay for
             >2 years  following a single  application of bromacil at i2.6 Ib ai/A
             (active  ingredient/acre)  (Bunker et al., 1971; Stecko,  1971).


III. PHARMACOKINETICS

     Absorption

          0  Workers who were exposed  to  bromacil during production,  formulation
             and packaging excreted unchanged bromacil and the 5-bromo-3-sec-butyl-
             6-hydroxymethyluracil metabolite in the urine (DuPont,  1966b).
             Unchanged bromacil and the metabolite were also detected in the urine
             of rats fed bromacil in  the  diet (DuPont, 1966a).   Although these
             data indicate that bromacil  is absorbed, sufficient information was
             not available to quantify the extent of absorption.

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    Bromacil                                                       August,  1987

                                        -4-


    Distribution

         8  No  information was found  in  the available literature on  the distribu-
           tion of bromacil.

    Metabolism

         0  Workers at a bromacil production plant excreted unchanged bromacil
           and the 5-bromo-3-sec-butyl-6-hydroxymethyluracil metabolite, present
           as  the glucuronide and/or sulfonate conjugate, in urine  (DuPont,  1966b)t

         0  Gardiner et al.  (1969)  fed rats  (age and strain not specified)  food
           containing 1,250 ppm bromacil  for  4 weeks.  Assuming 1 ppm equals
           0.05 mg/kg/day in the older  rat  (Lehman, 1959), this dietary  level
           corresponds to about 62.5 mg/kg/day.  Analysis of the urine of  these
           rats revealed the presence of  unchanged bromacil and the 5-bromo-3-
           sec-butyl-6-hydroxymethyluracil metabolite  (primarily as the
           glucuronide and/or sulfonate conjugate).  Five other minor metabolites
           were also detected! 5-bromo-3-(2-hydroxy-1-methylpropyl)-6-methyluracil;
           5-bromo-3-(2-hydroxy-1-methylpropyl)-6-hydroxymethyluracil; 3-sec-butyl-
           6-hydroxymethyluracil;  5-bromo-3-(3-hydroxyl-1 -methylpropyl)6-methyluracil;
           and 3-sec-butyl-6-methyluracil.  An unidentified bromine-containing
           compound with a  molecular weight of 339 was also detected.
    Excretion
            In humans  exposed  to  bromacil  during  its  formulation  and  packaging,
            urinary excretion  products  included 0.1 ppm parent compound  and
            6.3 ppm 5-bromo-3-sec-butyl-6-hydroxymethyluracil, present mostly  as
            a conjugate (DuPont,  1966b).

            Rats were  fed  bromacil  (1,250  ppm  in  the  diet) for 4  weeks;  urine
            was collected  daily during  weeks  3 and  4  of the  study.  Analysis of
            the urine  revealed the  presence of 20 ppm unchanged bromacil and
            146 ppm of the 5-bromo-3-sec-butyl-6-hydroxymethyluracil  metabolite
            (conjugated and unconjugated form) (DuPont, 1966a; Gardiner  et al.,
            1969).
IV. HEALTH EFFECTS
    Humans
            No information was located in the available  literature on the health
            effects of bromacil in humans.
    Animals
            Most of the animal data available are from unpublished  studies identified
            prior to the published  report by Sherman  and  Kaplan  (1975).   These
            authors stated that an  80% wettable bromacil  powder  was used in all
            tests discussed in their report except for eye  irritation  studies  in
            which a 50% wettable bromacil powder was  used.   All  dosages  and

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Bromacil                                                       August, 1987

                                     -5-
        feeding levels, unless otherwise stated,  were based on the active
        ingredient,  bromacil.

   Short-term Exposure

     8  The oral LD50 value for male ChR-CD rats  was calculated to be 5,200
        mgAg (Sherman and Kaplan, 1975).  Clinical signs of toxicity included
        rapid respiration, prostration and initial weight loss.

     0  In male mongrel dogs, a single oral dose  of 5,000 mg/kg caused nausea,
        vomiting, fatigue, incoordination and diarrhea (Sherman and Kaplan,
        1975).  It was not possible to estimate a lethal oral dose for bromacil
        in dogs because vomiting occurred almost  immediately, even at doses
        of 100 mg/kg.

     0  Sherman and Kaplan (1975) administered bromacil to groups of six male
        ChR-CD rats by gastric intubation at dose levels of 650, 1,035 or
        1,500 mg/kg/day, 5 days/week for 2 weeks  (10 doses).  Four of six
        animals died at the high dose.  Five of six survived exposure to
        1,035 mg/kg/day, but showed gastrointestinal and nervous system
        disturbances, and there was focal liver cell hypertrophy and hyper-
        plasia.  All animals survived the low dose with similar, but less
        severe, pathological changes.  The 650-mg/kg/day dose is identified as
        the Lowest-Observed-Adverse-Effect-Levels (LOAEL) in this study.

     0  Palmer (1964) reported that sheep that received bromacil at oral
        doses of 250 mg/kg for five days developed weakness in the legs and
        incoordination.  Recovery from these symptoms usually took several
        weeks.  Administration of 100 mg/kg/day for 11 days induced an 11%
        weight loss but no observable clinical symptoms.

   Dermal/Ocular Effects

     0  Bromacil (applied as a 50% aqueous solution of the 80% wettable
        powder) was only mildly irritating to the intact and abraded skin of
        young guinea pigs exposed for periods of  up to 3 weeks.  It was more
        irritating to the skin of older animals.   Bromacil did not produce
        skin sensitization (DuPont, 1962).

     0  Sherman and Kaplan (1975) reported that when bromacil was applied
        dermally to rabbits the lethal dose was greater than 5,000 mg/kg,
        the maximum feasible dose.  No clinical signs of toxicity and no
        gross pathological changes were observed.

     0  Bromacil, as a 50% aqueous suspension, was mildly irritating to the
        skin of young guinea pigs, but only slightly more irritating to the
        skin of older animals.  It was not a skin sensitizer (Sherman and
        Kaplan, 1975).

     0  Sherman and Kaplan (1975) reported that bromacil (0.1 mL of a 10%
        suspension in mineral oil) resulted in only mild temporary conjuncti-
        vitis in both the washed and unwashed eyes of rabbits.  No corneal
        injury was observed when a dose of 10 mg  dry powder was applied
        directly to the eye.

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Bromacil                                                       August,  1987

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   Long-term Exposure

     0  Zapp (1965)  discussed a study,  also reported  by Sherman and Kaplan
        (1975),  in which 10 male and 10 female ChR-CD rats  were fed dietary
        levels of 0, 50, 500 or 2,500 ppm bromacil for 90 days.  This
        corresponds  to doses of about 0, 2.5,  25 or 125 mg/kg/day, assuming
        1  ppm equals 0.05 mg/kg/day in an older rat (Lehman,  1959).  Because
        no signs of  toxicity were observed at  any dose, the high dose was
        increased to 5,000 ppm (about 250 mg/kg/day)  after  6 weeks; to
        6,000 ppm (about 300 mg/kg/day) after  10 weeks; and to 7,500 ppm
        (about 375 mg/kg/day) after 11  weeks.   This dosing  pattern resulted
        in reduced food intake and mild histological  changes in thyroid and
        liver.  No compound-related effects on weight gain, hematology,
        urinalysis or histology were detected  at the  two lowest doses;  25
        mg/kg/day was identified as the No-Observed-Adverse-Effect-Level
        (NOAEL)  in this study.

     0  Sherman et al. (1966, also reported by Sherman and  Kaplan, 1975) fed
        groups of 36 male and 36 female ChR-CD rats food containing 0,  50,
        250 or 1,250 ppm bromacil for 2 years.  This  corresponds to doses
        of about 0,  2.5, 12.5 or 62.5 mg/kg/day, assuming 1 ppm equals 0.05
        mg/kg/day in older rats (Lehman, 1959).  Females at the highest
        dose showed decreased weight gain (p <0.001).  No other toxic effects
        were observed in a variety of parameters measured,  including mortality,
        hematology,  urinalysis, serum biochemistry, gross pathology, organ
        weight or histopathology, except for a slight thyroid hyperplasia at
        the high dose.  This study identified  a NOAEL of 12.5 mg/kg/day.

     0  Beagle dogs  (three/sex/dose level) were fed a nutritionally complete
        diet containing 0, 50, 250 or 1,250 ppm bromacil for 2 years (Sherman
        et al.,  1966; also reported by Sherman and Kaplan,  1975).  This
        corresponds to doses of about 0, 1.25, 6.25 or 31.2 mg/kg/day,  assuming
        1 ppm equals 0.025 mg/kg/day in the dog (Lehman, 1959).  No nutritional,
        clinical, hematological, urinary, blood chemistry or histopathologic
        evidence of toxicity was detected in any group.  This study identified
        a NOAEL of 31.2 mg/kg/day.

     0  Kaplan et al.  (1980) administered bromacil (approximately 95% pure)
        to CD-1  mice (80/sex/dose) for 78 weeks at dietary  levels of 0, 250,
        1,250 or 5,000 ppm.  Based on information presented by the authors,
        these dietary levels correspond to doses of 0, 39.6, 195 or 871
        mg/kg/day for males and 0, 66.5, 329 or 1,310 mg/kg/day for females.
        During the first year of the study, a compound-related decrease in
        body weight gain was observed in male mice receiving 5,000 ppm and in
        female mice receiving 1,250 ppm.  The treatment and control groups
        exhibited no significant (p <0.05) differences in food consumption.
        Mortality in the 5,000-ppm females was significantly (p <0.05)  greater
        than in the controls.  Liver changes noted in treated mice consisted
        of increased mean and relative weights in the 1,250-ppm females and
        the 5,000-ppm males; an increased incidence of diffuse hepatocellular
        hypertrophy in  the  1,250- and 5,000-ppm males and in the  5,000-ppm
        females; an increased incidence of centrilobular vacuolation in 250-ppm
        males; an increased incidence of scattered hepatocellular necrosis in

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Bromacil                   ,                                   August, 1987
        5,000-ppm males;  and the presence of extravasated erythrocytes in
        the hypertrophied hepatocytes of the 1,250- and 5,000-ppn males.  The
        authors felt that centrilobular vacuolation and hypertrophy were
        probably related  to enzyme induction.  The toxicological significance
        of extravasated erythrocytes in the hypertrophied hepatocytes was
        unclear.  Compound-related changes in the testes of mice consisted of
        an increased incidence of spermatocyte necrosis, sperm calculi and
        mild interstitial-cell hypertrophy/hyperplasia in the 1,250- and
        5,000-ppm males and a dose-related increase in the incidence of testi-
        cular tubule atrophy in all male treatment groups.  Based on changes
        in testes, a LOAEL of 250 ppm (39.6 mg/kg/day) is identified for male
        mice.  A NOAEL of 250 ppm (66.5 mg/kg/day) was identified for female
        mice.

   Reproductive Effects

     0  Sherman et al. (1966; also reported by Sherman and Kaplan,  1975)
        reported the effects of bromacil on reproduction in a three-generation
        study in rats.  Twelve male and twelve female weanling ChR-CD rats were
        fed bromacil in the diet at 0 or 250 ppm.  This corresponds to doses
        of about 0 or 12.5 mg/kg/day, assuming 1  ppm in the diet equals
        0.05 mg/kg/day for older rats (Lehman, 1959).  Animals were bred
        after 12 weeks, and the FI& and the ?2b generations were maintained on
        the same diets as their parents.  No evidence of adverse effects on
        reproduction or lactation performance was observed.  Examination of
        the F2b generation revealed no evidence of gross or histopathological
        effects.  This study identified a minimum NOAEL of 12.5 mg/kg/day.

   Developmental Effects

     0  Paynter (1966; also reported by Sherman and Kaplan, 1975) administered
        bromacil to New Zealand White rabbits (8 or 9 per dosage) at dietary
        levels of 0, 50 or 250 ppm on days 8 through 16 of gestation.  Assuming
        1 ppm equals 0.03 mg/kg/day in the rabbit (Lehman, 1959), these
        dietary levels correspond to about 0, 1.5 or 7.5 mg/kg/day.  No
        significant differences between the conception rates of the control
        and test groups were observed.  Control and test group litters were
        comparable in terms of litter size, mean pup length, mean litter
        weight, number of stillbirths and number of resorption sites.  No
        gross malformations were observed in any animals.  Skeletal clearing
        revealed no abnormalities in bone structure- in any animals.  Based
        on reproductive and teratogenic end points, a NOAEL of 250 ppm
        (7.5 mg/kg/day) was identified.

     0  Pregnant rats (strain not specified) were exposed to aerosols of
        bromacil (165 mg/n>3) on days 7 to 1 4 of gestation.  No prenatal
        changes or teratogenic effects were observed (no further details were
        provided) (Dilley et al., 1977).

   Mutagenicity

     0  In a sex-linked recessive lethal test (Valencia,  1981),  Drosophila
        melanogaster (Canton-S wild-type stock)  were exposed to bromacil in

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Bromacil                   .                                    August, 1987
                >

                                     -8-
        food at levels of 2,  3,  5 or 2,000 ppm.  Bromacil was found to be
        weakly mutagenic at the  2,000-ppm dose level.

     0  Riccio et al. (1981)  reported that bromacil (tested concentrations
        not specified) was not mutagenic with or without metabolic activation
        in assays conducted using Saccharomyces cerevisiae strains D3 and D7.

     0  Siebert and Lemperle (1974)  reported that bromacil was not mutagenic
        when tested at a concentration of 1,000 ppm using J5. cerevisiae
        strain D4.

     0  Simmon et al. (1977)  reported that bromacil was not mutagenic in an
        in vivo mouse dominant-lethal assay and the following in vitro assays?
        unscheduled DNA synthesis in human fibroblasts (WI-38 cells); reverse
        mutation in Salmonella typhimurium strains TA1535, 1537, 1538 and
        100, and in Escherichia  coli WP2; mitotic recombination in _S_. cerevisiae;
        and preferential toxicity assays in _E. coli (strains W3110 and p3478)
        and Bacillus subtilis (strains H1 7 and M45).

     0  In a modified Ames assay (Rashid, 1974), bromacil was not mutagenic
        in . typhimurium strains TA1535 and 1538 when tested at
        concentrations up to 325 ug/plate.

     0  In an assay designed to  test for thymine replacement in mouse DNA
        (McGahen and Hoffman, 1963), Swiss-Webster white mice received bromacil
        by oral intubation at 100 mg/kg twice daily for 2 days, followed by
        50 mg/kg twice daily for 8 days.  Under the conditions of the assay,
        bromacil was not recognized as a thymine analog by the mouse.

     0  Bromacil did not show any signs of mutagenicity in a variety of
        microbial test systems (Jorgenson et al., 1976; Woodruff et al., 1984).

     0  In the Ames test, bromacil (5% concentration) induced revertants in
        three of six Salmonella  strains tested  (Njage and Gopalan, 1980).

     0  Bromacil did not induce sex-linked recessive lethals in D_. melanogaster
        (Gopalan and Njage,  1981).

   Carcinogenic!ty

     0  Sherman et al.  (1966) fed Toups of 36 male and 36 female weanling
        ChR-CD rats bromacil in the diet for 2 years.  Dietary levels were
        0, 50, 250 or 1,250 ppm  (about 0, 2.5, 12.5 or 62.5 mg/kg/day, based
        on Lehman, 1959).  There was no effect on mortality, and the only
        treatment-related lesion detected by histological examination was a
        slight increase in the incidence of light-cell and follicular-cell
        hyperplasia in  the thyroid at the high dose.  One high-dose female
        was found.to have follicular-cell adenoma.  The authors stated that
        these observations suggest a compound-related effect.

      0  Kaplan et al. (1980) administered bromacil  (approximately 95% pure)
        to CD-1 mice  (80/sex/dose) for 78 weeks at dietary levels of 0, 250,
        1,250 or  5,000 ppm.  Based on information presented by the authors,

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   Bromacil                                                       August,  1987

                                        -9-
           these dietary levels correspond to compound intake levels of 0, 39.6,
           195 or 871  mg/kg/day for males and 0,  66.5, 329 or 1,310 mg/kg/day
           for females.   In males, the combined incidences of hepatocellular
           adenomas plus carcinomas/number of animals examined were 10/74,
           11/71, 8/71 and 19/70 (p <0.05) at 0,  250, 1,250 and 5,000 ppm,
           respectively.  Hepatocellular carcinoma incidences were 5/74, 4/71,
           4/71  and 9/70 (p >0.05) at 0, 250, 1,250 and 5,000 ppm, respectively.
           These tumors  were found predominantly in mice that survived to terminal
           sacrifice.   No effect on liver tumor incidence was observed in females.


V. QUANTIFICATION OF TOXICOLOGICAL EFFECTS

        Health Advisories (HAs) are generally determined for one-day, ten-day,
   longer-term (approximately 7 years) and lifetime exposures if adequate data
   are available that identify a sensitive noncarcinogenic end point of toxicity.
   The HAs for noncarcinogenic toxicants are derived using the following formula:

                 HA = (NOAEL or LOAEL) x (BW) = 	 mg/L (	 Ug/L)
                        (UF) x (	 L/day)

   where:

           NOAEL or LOAEL = No- or Lowest-Observed-Adverse-Effect-Level
                            in mg/kg bw/day.

                       BW * assumed body weight of a child (10 kg) or
                            an adult (70 kg).

                       UF = uncertainty factor (10, 100 or 1,000), in
                            accordance with NAS/ODW guidelines.

                	 L/day = assumed daily water consumption of a child
                            (1 L/day) or an adult (2 L/day).

   One-day Health Advisory

        No studies were located which are suitable for derivation of a One-day HA
   for bromacil.  The Ten-day HA, derived below,  of 4.6 mg/L for a 10-kg child
   is proposed as a conservative One-day HA.

   Ten-day Health Advisory

        The 2-week oral study in rats by Sherman and Kaplan (1975) has been
   selected as the basis for the Ten-day HA for bromacil.  Animals were
   dosed by gavage for 10 days over a period of 2 weeks.  The lowest dose tested
   (650 mg/kg/day) produced mild pathological changes in the liver, and this
   value was identified  as a LOAEL.

        Using a LOAEL of 650 mg/kg/day, the Ten-day HA for a 10-kg child is
   calculated as follows:

         Ten-day HA = (650 mg/kg/day) (5/7) (10 kg) = 4>6   /L (4 600 ug/L)
                            (1,000) (1  L/day)

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Broraacil                                                       August, 1987

                                     -10-
wheres

        650 mg/kg/day = LOAEL,  based on mild liver pathology in rats
                        exposed by gavage to bromacil for 2 weeks.

                  5/7 = correction for dosing 5 days per week.

                10 kg = assumed body weight of a child.

                1,000 = uncertainty factor chosen in accordance with NAS/ODW
                        guidelines for use with a LOAEL from an animal studyc

              1  L/day  assumed daily water consumption of a child.

Longer-term Health Advisory

     The 90-day study by Zapp (1965) has been selected to serve as the basis
for the Longer-term HA for bromacil.  Rats were fed diets containing up to
500 ppm without any adverse effects.  This study identified a NOAEL of
500 ppm (about 25 mg/kg/day).

     Using a NOAEL of 25 mg/kg/day, the Longer-term HA for a 10-kg child is
calculated as follows:

        Longer-term HA = (25 mg/kg/day) (10 kg) , 2.5 mg/L (2,500 ug/L)
                            (100)  (1 L/day)

where:

        25 mg/kg/day = NOAEL, based on the absence of any pathological evidence
                       of toxicity in rats exposed to bromacil via oral feeding
                       for 90 days.

               10 kg = assumed body weight of child.

                 100  uncertainty factor, chosen in accordance with NAS/ODW
                       guidelines  for use with a NOAEL from an animal study.

             1 L/day = assumed daily water consumption of a child.

     Using a NOAEL of 25 mg/kg/day, the Longer-term HA for a 70-kg adult is
calculated as follows:

       Longer-term HA = (25 mg/kg/day) (70 kg) = 8.7 mg/L (8,700 ug/L)
                            (100)  (2 L/day)
where:
         25 mg/kg/day = NOAEL, based on absence of any toxic effects in rats
                       exposed to bromacil via oral feeding for 90 days.

               70 kg  assumed body weight of an adult.

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Bromacil                                                       August, 1987

                                     -11-


                 100 = uncertainty factor,  chosen in accordance with NAS/ODW
                       guidelines for use with a NOAEL from an animal study.

             2 L/day = assumed daily water consumption of an adult.

Lifetime Health Advisory

     The Lifetime HA represents that portion of an individual's total exposure
that is attributed to drinking water and is considered protective of noncar-
cinogenic adverse health effects over a lifetime exposure.   The Lifetime HA
is derived in a three-step process.   Step 1 determines the Reference Dose
(RfD), formerly called the Acceptable Daily Intake (ADI).  The RfD is an esti-
mate of a daily exposure to the human population that is likely to be without
appreciable risk of deleterious effects over a lifetime, and is derived from
the NOAEL (or LOAEL), identified from a chronic (or subchronic) study, divided
by an uncertainty factor(s).  From the RfD, a Drinking Water Equivalent Level
(DWEL) can be determined (Step 2).  A DWEL is a medium-specific (i.e., drinking
water) lifetime exposure level, assuming 100% exposure from that medium, at
which adverse, noncarcinogenic health effects would not be expected to occur.
The DWEL is derived from the multiplication of the RfD by the assumed body
weight of an adult and divided by the assumed daily water consumption of an
adult.  The Lifetime HA is determined in step 3 by factoring in other sources
of exposure, the relative source contribution (RSC).  The RSC from drinking
water is based on actual exposure data or,  if data are not available, a
value of 20% is assumed for synthetic organic chemicals and a value of 10%
is assumed for inorganic chemicals.   If the contaminant is classified as a
Group A or B carcinogen, according to the Agency's classification scheme of
carcinogenic potential (U.S. EPA, 1986), then caution should be exercised in
assessing the risks associated with  lifetime exposure to this chemical.

     The chronic feeding study in rats by Sherman et al. (1966) has been
selected to serve as the basis for the Lifetime HA.  This study identified a
dietary LOAEL of 1,250 ppm and a NOAEL of 250 ppm, based on weight gain and
mild thyroid hyperplasia.  This NOAEL corresponds to about 12 mg/kg/day.  The
same NOAEL is evident in a three-generation reproduction study in rats by
Sherman et al. (1966).  The long-term feeding studies in dogs by Sherman
et al. (1966) and mice by Kaplan et  al. (1980) were not selected, since the
demonstrated NOAEL was the lowest in the rat study.

     Using a NOAEL of 12 mg/kg/day,  the Lifetime HA is derived as follows:

Step 1:  Determination of the Reference Dose (RfD)

                    RfD = (12 mq/kg/day) = 0.12 mg/kg/day
                              doo)                  y
where:
          12 mg/kg/day = NOAEL,  based on absence of hepatic effects in rats
                         exposed to bromacil via the diet for 2 years.

                   100 = uncertainty factor, chosen in accordance with NAS/ODW
                         guidelines for  use with a NOAEL from an animal study.

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    Bromacil                                                       August,  1987

                                        -12-


    Step 2:   Determination of the Drinking Water  Equivalent Level  (DWEL)

              DWEL =  (0.12 mg/kg/day)  (70 kg)  .  4<2   /L  {4 2QQ   /L)
                            (2 L/day)

    where:

            0.12 mg/kg/day  RfD.

                    70 kg = assumed body weight  of an adult.

                  2 L/day = assumed daily water  consumption of an adult.

    Step 3:   Determination of the Lifetime Health Advisory

                Lifetime HA =  (4.2 mg/L)  (20%) = 0.08 mg/L (80 ug/L)
                                    10

    where:

            4.2 mg/L = Lifetime HA at  100% contribution  from drinking water.

                20%  assumed relative source  contribution from water.

                  10 = additional uncertainty factor per ODW policy  for  use with
                      a Group C carcinogen.

    Evaluation of  Carcinogenic Potential

         0   Bromacil has not been determined  to be  carcinogenic, although  an
            increased  incidence of hepatocellular adenomas plus carcinomas  was
            observed in male CD-1 mice fed bromacil in the diet at a dose  level
            of 871 mg/kg/day for 78 weeks  (Kaplan et al.,  1980).

         0   The  International Agency for Research on Cancer has not  evaluated the
            carcinogenic potential of  bromacil.

         0   Applying the criteria described in  EPA's guidelines for  assessment of
            carcinogenic risk (U.S. EPA, 1986), bromacil is classified in  Group Ci
            possible human carcinogen.   This  category is for substances  with
            limited  evidence of carcinogenicity in  animals in  the absence  of
            human  data.

         0   The  U.S.  EPA has not published excess lifetime cancer risks  for this
            material.


VI. OTHER CRITERIA,  GUIDANCE AND STANDARDS

         0   The  NAS  (1977) has  calculated  an  acceptable  daily  intake (ADI)  of
            0.0125 mg/kg/day, based on a chronic  NOAEL of  12.5 mg/kg/day in rats a
            an uncertainty factor of  1,000.   A  suggested-no-adverse-response level
            (SNARL)  of 0.086 mg/L was  calculated  based on  an assumed water consumption
            of 2  L/day by a 70-kg adult, with 20% contribution from  water.

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      Bromacil                                                       August,  1987

                                           -13-
           0  The U.S. EPA Office of Pesticide Programs (EPA/OPP) previously
              calculated an ADI of 62.5  ug/kg/day,  based on a NOAEL of 6.25 mg/kg/day
              in a 2-year feeding study  in dogs (Sherman et al.,  1966) and an
              uncertainty factor of 100.   This was  updated to 130 ug/kg/day based
              on a 2-year rat feeding study using a NOAEL of 12.5 mg/kg/day and a
              100-fold uncertainty factor.

           0  A tolerance of 0.1 ppm bromacil in or on citrus fruits and pineapples
              has been set by the EPA/OPP (CFR, 1985).  A tolerance is a derived
              value based on residue levels, toxicity data, food  consumption levels,
              hazard evaluation and scientific judgment, and it is the legal maximum
              concentration of a pesticide in or on a raw agricultural commodity or
              other human or animal food (Paynter et al.,  undated).

           0  The American Conference of Governmental Industrial  Hygienists (ACGIH,
              1984) has recommended a threshold limit value (TLV) of 1 ppm, and a
              short-term exposure limit  (STEL) of 2 ppm.


 VII. ANALYTICAL METHODS

           0  Analysis of bromacil is by a gas chromatographic (GC) method applicable
              to the determination of certain organonitrogen pesticides in water
              samples (U.S. EPA, 1985).   This method requires a solvent extraction
              of approximately 1 L of sample with methylene chloride using a
              separatory funnel.  The methylene chloride extract  is dried and
              exchanged to acetone during concentration to a volume of 10 mL or
              less.  The compounds in the extract are separated by GC, and measure-
              ment is made with a thermionic bead detector.  The  method detection
              limit for bromacil is 2.38 ug/L.


VIII. TREATMENT TECHNOLOGIES^

           0  No information was found in the available literature on treatment
              technologies used to remove bromacil  from contaminated water.

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    Bromacil                                                        August, 1987

                                         -14-


IX. REFERENCES

    ACGIH.   1984.   American Conference of Governmental Industrial Hygienists.
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    Acher,  A.J., and  E.  Dunkelblum.   1979.   Identification of sensitized
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    Boyce Thompson Institute for Plant Research.   1971.   Interaction of herbicides
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                                     -15-
Haque, R., and W.R. Coshow.  1971.  Adsorption of isocil and bromacil  from
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                                     -16-
Riccio, E.,  G. Shepherd, A. Pomeroy, K. Mortelmans and M.D. Waters.*   1981.
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                                     -17-
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