820K88004
                                   FLUOMETURON

                                 Health Advisory
                             Office of Drinking Water
                       U.S. Environmental  Protection Agency
  August, 1987
DRAFT
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 models is able to predict risk more accurately than another.
   Because each -nodel is based on differing assumptions, the estimates that are
   derived can differ by several orders of magnitude.

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    Fluometuron
                                                    Auqust, 1987
                                         -2-
II. GENERAL INFORMATION AND PROPERTIES
    CAS No.    2164-17-2
    Structural Formula
                           0
                           II
                                 H-N-C-NCCH,),
                   N,N-DiTnethyl-N-(3-(trifluoromethyl)phenyl)-urea

    Synonyms

         0  C 2059;  Cotoron;  Cottonex;  Lanex (Meister,  1983).

    Uses

         0  Herbicide (Windholz  et al.f  1983).

    Properties  (Windholz et  al.,  1983;  CHEMLAB,  1985;  TDB, 1985)
                                            C1oH11ON2F3
                                            232.21
                                            White crystals

                                            163-164.5C

                                            5 x 10~7  rrtn Hg

                                            80 mg/L
                                            1.88 (calculated)
Chemical Formula
Molecular Weight
Physical State (25C)
Boiling Point
Melting Point
Density
Vapor Pressure (20C)
Specific Gravity
Water Solubility (25C)
Octanol/Water Partition
  Coefficient
Taste Threshold
Odor Threshold
Conversion Factor
    Occurrence

           Fluometuron was not found in any of 31 ground water samples analyzed
            from 29 locations (STORET, 1987).  No surface water samples were
            tested.

    Environmental Fate

         o  14c-Fluometuron (test substance not characterized) was intermediately
            mobile (Rf = 0.50)  in a silty clay loam soil (2.5% organic matter)
            based on thin-layer chromatography (TLC) tests of soil (Helling, 1971;
            Helling et al., 1971).

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     Fluometuron                                                 August,  1987

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          0  14c-Fluometuron (test substance not characterized),  at various concen-
             trations,  was very mobile  in  a  Norge loam soil (1.7% organic matter)
             with a Freundlich-K of 0.31 (Davidson and McDougal,  1973).   Freundlich-K
             values,  determined in soil:water slurries (5-10 g/100 mL)  treated with
             14c-fluometuron (test substance not characterized) at 0.05  to 10.0 ppm,
             were 0.37  for Uvrier sand  (1% organic matter), 1.07  for Collombey sand
             (2.2% organic matter), 1.66 for Les Evouettes loam  (3.6% organic matter),
             3.16 for Vetroz sandy clay loam (5.6% organic matter),  and  1.36 for
             Illarsatz  high organic soil (22.9% organic matter)  (Guth,  1972).

          0  Fruendlich-K values were positively correlated with  the organic matter
             content of the soil.  Fluometuron (test substance not characterized),
             at 10 to 80 uM/kg,  was adsorbed at 10 to 51%  of the  applied  amount to  a
             loamy sand soil (1.15% organic  matter) and 16 to 67% of the  applied to a
             sandy loam soil (1.9% organic matter) in water slurries during a test
             period of  1 minute to 7 days, with adsorption increasing with time
             (LaFleur,  1979).  Approximately 22% of the applied fluometuron desorbed
             in water from the loamy sand  soil and 15% desorbed from the  sandy loam
             soil during a 7-day test period.

          0  Fluometuron (50% wettable  powder,  WP) dissipated from the 0- to 5-cm
             depth of a sandy clay loam soil (3.2% organic matter) in central
             Europe with a half-life of less than 30 days  (Guth et al., 1969).
             Fluometuron residues (not  characterized) dissipated  with a half-life
             of 30 to 90 days.


III.  PHARMACOKINETICS

     Absorption

          0  Boyd and Foglemann (1967)  reported that fluometuron  is  slowly absorbed
             from the gastrointestinal  (GI)  tract of female CFE rats (200 to 250 g).
             Based on the radioactivity recovered in the urine and feces  of four
             rats given 50 mg 14Olabeled  f luometuron after a 2-week pretreatment
             with 1,000 ppm unlabeled fluometuron [estimated as 100 mg/kg/day,
             assuming 1 ppm equals 0.1  mg/kg/day in the young rat (Lehman, 1959)],
             the test compound appears  not to have been fully absorbed within 72
             hours.  Of an orally administered dose (50 mg/kg), up to 15% was
             excreted in the urine and  49% in the feces.

     Distribution

          0  Boyd and Foglemann (1967)  detected radioactivity in  the liver,  kidneys,
             adrenals,  pituitary, red blood  cells, blood plasma and  spleen 72 hours
             after oral administration  of  14C-labeled fluometuron at dose levels of
             50 or 500  mg/kg in rats.   The highest concentration  was detected in
             red blood  cells.

     Metabolism

          0  Boyd and Foglemann (1967)  concluded that,  by  thin-layer chromatographic
             analysis,  the urine of rats in  their study contained m-trifluoromethyl-
             aniline, desmethyl-fluometuron,  demethylated  fluometuron, hydroxylated

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   Fluometuron                                                 August, 1987

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           desmethyl-fluometuron, hydroxylated demethylated fluometuron, and
           hydroxylated aniline.

           Lin et al. (1976) reported that after incubation of 14CF3-labeled
           fluometuron with cultured human embryonic lung cells for up  to 72
           hours, 95% of the compound remained unchanged.  Human embryonic  lung
           cell homogenate metabolized small amounts of fluometuron through
           oxidative pathways to N-(3-trifluoromethylphenyl)-N-formyl-N-methylurea,
           N-(3-trifluoromethylphenyl)-N-methylurea, and N-(3-trifluoromethylphenyl)
           urea.
    Excretion
           Boyd and Foglemann  (1967) reported  that urinary excretion  of  radio-
           active  label peaked at  24 hours after administration  of  14c-fluometuron
            (50 mg/kg)  and decreased during the remaining 48 hours.  Seventy-two
           hours after oral  administration of  the radioactive  label,  up  to  15%
           of the  administered dose was  eliminated in  the urine.

            In the  study by Boyd and Foglemann  (1967),  fecal excretion of fluometuron
           peaked  by  48 hours  postdosing and decreased over the  remaining 24 hours.
           Forty-nine percent  of  the administered dose (50 mg/kg) was eliminated
           in the  feces.
IV. HEALTH EFFECTS
    Humans
            No information was found in the available literature on the health
            effects of fluometuron in humans.
    Animals
       Short-term Exposure

         0  NIOSH (1985) reported the acute oral LD5Q values of fluometuron as
            6,416, 2,500, 900 and 810 mg/kg in the rat,  rabbit, mouse and guinea
            pig, respectively.
         0  Sachsse and Bathe (1975) reported an acute oral LD^Q value of
            4,636 mg/kg for both male and female Tif RA1 rats.

         0  Foglemann (1964a) reported the acute oral LD50 values for CFW albino
            mice as 2,300 mg/kg in females and 900 mg/kg in males.

       Dermal/Ocular Exposure

         0  Siglin et al. (1981) conducted a primary dermal irritation study in
            which undiluted fluometuron powder  (80%) was applied to intact and
            abraded skin of six young adult New Zealand White rabbits for 24
            hours.  The test substance was severely irritating, with eschar
            formation observed at 24 and 72 hours.

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Fluometuron                                                 August,  1987

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     0  Foglemann (1964b)  exposed the skin of eight albino rabbits (four/sex)
        to a 10% aqueous  suspension of fluometuron (applied under rubber
        dental damming)  for 6 hours/day for 10 days.   No  contact sensitization
        developed during  the exposure period.  Weight depression at day 130
        was evident in the treated group.

     0  Galloway (1984)  reported no sensitizing reactions in Hartley albino
        guinea pigs exposed to undiluted fluometuron on alternate days for
        22 days and on day 36.

     0  Technical fluometuron was not found to be an eye  irritant in rabbits
        (Foglemann, 1964c).

   Long-term Exposure

     0  Foglemann (1965a)  conducted a 90-day feeding study in which CFE rats
        (15/sex/dose) were administered technical fluometuron (purity not
        specified)  in the diet at dose levels of 100, 1,000 or 10,000 ppm
        (reported as 7.5,  75 or 750 mg/kg/day).  Following exposure, various
        parameters including hematology, clinical chemistry and histopathology
        were evaluated.   Enlarged, darkened spleens were  observed grossly in
        male rats given 75 mg/kg/day.  At the highest dose level, a depression
        in body weight and congestion in the parenchyma of the spleen, adrenals,
        liver and kidneys were evident.  A mild deposition of hemosiderin in
        the spleen was also evident.  Spleens were large  and dark; livers
        were brownish and muddy colored; and kidneys were small with discolored
        pelvises in high-dose males.  Histopathological findings were confined
        to mild congestion in various organs and mild hemosiderin deposits
        in the spleens of high-dose rats.   No effects were evident in rats
        given the 7.5 mg/kg/day dose level for any parameter measured.  This
        dose level was identified as the No-Observed-Adverse-Effect-Level
        (NOAEL) for this  study.

     0  Foglemann (1965b) administered technical fluometuron (purity not
        stated) in feed to three groups of beagle pups (three/sex/dose) at
        dose levels of 40, 400 or 4,000 ppm (reported as  1.5, IS or 150
        mg/kg/day)  for 90 days.  At 150 mg/kg/day, mild inflammatory-type
        reactions and congestion in the liver and kidneys and mild congestion
        and hemosiderin deposits in the spleen were observed.  Also at this
        high dose,  the spleen to body weight ratio was slightly increased.
        No adverse systemic effects were observed in dogs administered 1.5 or
        15 mg/kg/day (NOAEL).

     0  In the NCI (1980) study, B6C3F.] mice and F344 rats (10 of each sex)
        were given fluometuron (>99% pure) in the diet for 90 days to estimate
        1,000, 2,000, 4,000, 8,000, and 16,000 ppm.  Decreased body weight gain
        (>10%) was apparent with doses above 2,000 ppm.  Treatment-related
        splenomegaly was  found in rats with doses above 1,000 ppm.  Microscopic
        examination was done on spleens only from rats given more than 2,000
        ppm, and this assessment indicated dose-related changes including
        hyperemia of red  pulp with atrophy of Malpighian  corpuscles and
        depletion of lymphocytic elements.  Body weight gain was reduced
        (>10%) in male and female mice given more than 2,000 ppm.  Assuming

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Fluometuron                                                 August,  1987

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        that 1  ppm in the diet equals 0.10 mg/kg/day in the young rat and
        0.15 mg/kg/day in the mouse (Lehman, 1959), 1,000 ppm (NOAEL)
        corresponds to 100 mg/kg/day in rats and 2,000 ppm (NOAEL) corresponds
        to 300 mg/kg/day in mice.

     0  Hofmann (1966) administered 0,  3,  10, 30 or 100 mg/kg technical
        fluometuron (Cotoron = C-2059,  purity not specified) as a suspension
        in 1% Mulgafarin six times per  week for 1  year by pharnyx probe to
        four groups of Wistar rats (25/sex/dose) .   Following treatment,
        general behavior, mortality, growth, food consumption, clinical
        chemistry, blood, urine, and histopathology were evaluated.  Males
        dosed with 30 or 100 mg/kg/day  and females dosed with 100 mg/kg/day
        showed significant  (p <0.05) reductions in body weight at the end of
        the study compared  to controls.  No toxicological effects were observed
        in rats administered 3 or 1 0 mg/kg/day  (NOAEL).

      0  In the NCI (1980) study, F344 rats  (10 of each sex) were given
        fluometuron (>99% pure) at dietary levels of 250, 500, 1,000, 2,000
        and 4,000 ppm in a repeat of the 90-day study to examine splenic
        effects more closely.  Splenomegaly in all treated groups was noted.
        A dose-related increase in spleen weights and a dose-related decrease
        in circulating red blood cells was observed in females fed 250 ppm
        and higher.  Increased spleen weights were evident in males given
        doses above 500 ppm.  However,  statistical analysis of the data was
        not done.  Stated in the report without presentation of data is the
        observation of a dose-related increase  in red blood cells with
        polychromasia and anisocytosis in male and female rats and congestion
        of red pulp with corresponding decrease of white pulp in spleen.
        Assuming  that 1 ppm equals 0.10 mg/kg/day in the young rat (Lehman,
        1959), a  Lowest-Observed-Adverse-Effect-Level  (LOAEL) of 250 ppm  (25
                  ) is suggested in this study.
      0  No noncarcinogenic effects  (survival, body weight and pathological
        changes) in B6C3Fi mice and F344 rats were found in the NCI (1980)
        bioassay discussed under Carcinogenicity.

   Reproductive Effects

      0  No information was found in the available literature on the effects
        of fluometuron on reproduction.

      0  A reproduction study with technical fluometuron in rats is in progress
        to satisfy U.S. EPA Office  of Pesticide Programs (OPP) data requirements.

   Developmental Effects

      0  Fritz  (1971) reported a teratology study in rats in which dams were
        given  C-2059 suspension in  carboxymethylcellulose during days 6
        through 15 of gestation.  Offspring were removed on day 20 of ges-
        tation for examination.  The NOAEL was indicated as 100 mg/kg/day,
        and higher doses reduced fetal body weight.  However, this study was
        invalidated by the U.S. EPA OPP because of inadequate reporting.

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Fluometuron                                                 August, 1987

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     8  A teratology study in which pregnant Spf New Zealand rabbits were
        given technical fluometuron (purity not specified) by gavage at dose
        levels of 50,  500, and 1,000 mg/kg/day during gestation days 6 through
        19 was reported by Arhur and Triana (1984).   Does were examined for
        body weight, food consumption and pathological and developmental
        effects, and laparohysterectomy was done on gestation day 29 for
        pathological evaluation of fetuses.  Increased liver weights and
        increased mean number of resorptions were found with all doses
        (p <0.05 at the low and mid doses;  insufficient number of fetuses for
        statistical analysis at the high dose).  A LOAEL of 50 mg/kg/day was
        identified.  Reductions in body weights and food consumption occurred
        in does given 500 and 1,000 mg/kg/day.  Deaths, abortions and perforated
        stomachs were observed in does given 1,000 mg/kg/day.

   Mutagenicity

     0  In bacterial assays (Dunkel and Simmon, 1980), fluometuron (6.6 mg/plate)
        was not mutagenic in Salmonella strains TA 1535, TA 1537, TA 1538,
        TA 98 and TA 100, either with or without metabolic activation.

     0  Seiler (1978)  reported that fluometuron (2,000 mg/kg bw) given as a
        single oral dose of an aqueous suspension by gavage resulted in a
        strong inhibition of mouse testicular DNA synthesis in mice killed
        3.5 hours after treatment.  Results were inconclusive in a subsequent
        micronucleus test.

     0  In yeast assays (Seibert and Lemperle, 1974), a commercial formulation
        of fluometuron was ineffective in inducing mitotic gene conversion
        in Saccharomyces cerevisiae strain D4 without exogenous metabolic
        activation.

   Carcinogenicity

     0  In a long-term bioassay (NCI, 1980), fluometuron was administered in
        feed to F344 rats and B6C3Fi mice.   Groups of rats (50/sex/dose) were
        fed diets containing 125 or 250 ppm fluometuron for 103 weeks.  Mice
        (50/sex/dose) were fed 500 or 1,000 ppm for an equivalent period
        of time.  Assuming that 1 ppm equals 0.05 mg/kg/day in the older rat
        and 0.15 mg/kg/day in the'mouse (Lehman, 1959), 125 and 250 ppm
        equaled 6.25 and 12.5 mg/kg/day in rats and 500 and 1,000 ppm equaled
        75 and 150 mg/kg/day in mice.  Results based on survival, body weights,
        and nonneoplastic pathology  (including spleen) were negative in rats.
        Following treatment, there were no significant increases in tumor
        incidences in male or female F344 rats or in female B6C3Fi mice com-
        pared to controls.  In male B6C3F-)  mice, an increased incidence
        of hepatocellular carcinomas and adenomas was noted.  The incidences
        were dose-related and were marginally higher than those in the corre-
        sponding matched controls or pooled controls from concurrent studies
        [matched control, 4/21 or 19%; low dose, 13/47 or 28%; high dose,
        21/49 or 43% (p = 0.049); pooled controls, 44/167 or 26%].  NCI (1980)
        concluded that additional testing was needed because of equivocal
        findings for male mice and because both rats and mice may have been

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   Fluometuron                                                    August, 1987

                                        -8-
           able to tolerate higher doses.   The NOAELs identified for rats and
           mice are 12.5 and 75 mg/kg/day,  respectively.

        0  Chronic feeding studies with technical fluometuron in rats and mice
           are ongoing to satisfy OPP data  requirements.


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) = 	   /L (	   /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/OEW guidelines.

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

   One-day Health Advisory

        No information was found in the available literature that was suitable
   for determination of the One-day HA value for fluometuron.  The teratology
   study by Arhur and Triana  (1984) was not selected because a NOAEL was not
   identified.   It is therefore recommended that the Longer-term HA value for a
   10-kg child (1.5 mg/L, calculated below) be used at this time as a conservative
   estimate of the One-day HA value.

   Ten-day Health Advisory

        No information was found in the available literature that was suitable
   for determination of the Ten-day HA value for fluometuron.  The teratology
   study by Arhur and Triana  (1984) was not selected because a NOAEL was not
   identified.   It is therefore recommended that the Longer-term HA value for a
   10-kg child (1.5 mg/L, calculated below) be used at this time as a conservative
   estimate of the Ten-day HA value.

   Longer-term Health Advisory

         The 90-day feeding study in dogs by Foglemann (1965b) has been selected
   to serve as the basis  for  the Longer-term HA value for fluometuron.  In this

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Fluometuron                                                 August,  1987

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study, dogs given technical fluometuron at dose levels of 0,  1.5,  15 or 150
ing/kg/day in the diet for 90 days showed pathological effects in spleen,
liver and kidney at the highest dose and no observable effects at the lower
doses.  The 90-day feeding studies with rats by Foglemann (1965a)  and NCI
(1980) were not selected because the 15 mg/kg/day NOAEL in the Foglemann
(1965b) study was below the lowest doses of 75 mg/kg/day in the Foglemann
(1965a) and 25 mg/kg/day (estimated) in the NCI (1980) repeat 90-day study
where effects were noted.  Additionally, pathological changes in spleen found
with the lowest dose (250 ppm) in the repeat NCI (1980) study in rats were
not found with this dose in the initial 90-day study and in the 2-year bioassay
in rats by the NCI (1980).  Because 7.5 mg/kg/day in the Foglemann (1965a)
study and 12.5 mg/kg/day (estimated) in the NCI (1980) carcinogenicity bioassay
were NOAELs, it is concluded that 15 mg/kg/day would be consistent with a
NOAEL in these 90-day studies in rats.  The study by Hofmann (1966) in which
rats were given technical fluometuron as a suspension by gavage at dose
levels of 0, 3, 10, 30 and 100 mg/kg, six times per week for 1 year, was  not
selected because feeding the substance in the diet is preferred over giving
it as a suspension by gavage for estimating exposure from drinking water,
although the 10 mg/kg NOAEL in this study approximates the 15 mg/kg/day NOAEL
in the Foglemann (1965b) study.  The 90-day feeding study in mice by NCI
(1980) was not selected because the NOAEL of 300 mg/kg/day (estimated) is
above the effect levels in the other studies considered.  The 15 mg/kg/day
dose level in dogs was, therefore, identified as the NOAEL.

     Using a NOAEL of 15 mg/kg/day, the Longer-term HA for a 10-kg child is
calculated as follows:

       Longer-term HA =  (15 mg/kg/day)  (10 kg) = 1>5 mg/L (1,500 ug/L)
                            (100)  (1 L/day)
where:
        15 mg/kg/day = NOAEL, based on absence of pathological changes in the
                       spleen, liver and kidneys of dogs exposed to the test
                       substance in the diet for 90 days.

               10 kg = assumed body weight of a 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.

      The Longer-term HA for  a 70-kg adult is calculated as follows:

       Longer-term HA =  (15  mg/kg/day) (70 kg) = 5>3 mg/L (5/30o ug/L)
                             (100)  (2 L/day)
 where:
         15 mg/kg/day = NOAEL, based on absence of pathological changes in the
                       spleen, liver and kidneys of dogs exposed to the test
                       substance in the diet for 90 days.

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Fluometuron                                                 August, 1987

                                     -10-


               70 kg = assumed body weight of an adult.

                 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 NCI  (1980) carcinogenicity bioassay in F344 rats has been selected
to serve as the basis for determination of the Lifetime HA value for fluo-
meturon.   Rats were exposed to dose levels of 0, 125 and 250 ppm fluometuron
in the diet (estimated as 6.25 and 12.5 mg/kg/day) for 103 weeks.  No observable
effects were evident in this study.  Although pathological changes in spleens
of rats given 250 ppm fluometuron in the diet (estimated as 25 mg/kg/day)
were noted in the repeat 90-day study in rats by NCI  (1980), it appears that
splenic lesions were either not evident or were able to reverse in the rats
given the  250-ppm dietary level for 2 years  (only one rat died by  1 year into
the bioassay).  Furthermore, pathological changes in the spleen were not
evident with doses below 2,000 ppm in the initial 90-day study in F344 rats
by NCI  (1980).  The 90-day and 1-year studies discussed under Longer-term
Health Advisory have not been selected for calculation of a Lifetime HA
because of their short duration compared to the 103-week NCI (1980) bioassay
and because, although not as many end points were assessed in the NCI  (1980)
bioassay compared to these studies, major effects observed in these studies
 (pathology, body weight) were evaluated in the NCI  (1980) bioassay.  The NCI
 (1980) bioassay in B6C3Fi mice was not considered because higher dose levels
 (500 and 1,000 ppm, estimated as 75 and 150 mg/kg/day) were used.

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Fluometuron                                                 August, 1987

                                     -1 1-


     Using the NCI (1980) bioassay in rats with a NOAEL of 12.5 mg/kg/day,
the Lifetime HA is calculated as follows:

Step 1:  Determination of the Reference Dose (RfD)

                   RfD = (12'5 nig/kg/day) = 0.0125 mg/kg/day
                             (100X10)

where:

        12.5 mg/kg/day = NOAEL,  based on absence of observable effects in rats
                         exposed to fluometuron in the diet for 103 weeks.

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

                    10 = additional uncertainty factor used by U.S. EPA OPP
                         to account for data gaps (chronic feeding studies in
                         rats and dogs,  reproduction study in rats, teratology
                         studies in rats and rabbits).

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

          DWEL = (0.0125 mg/kg/day) (70 kg) , 0.438   /L (438   /L)
                         (2 L/day)

where:

        0.0125 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 = (0.438 mg/L)  (20%) = 0.09 mg/L (90 ug/L)

where:

        4.38 mg/L = DWEL.

              20% = assumed relative source contribution from water.

Evaluation of Carcinogenic Potential

        NCI (1980) determined that fluometuron was not carcinogenic in male
        and female F344 rats and female mice (B6C3F-|).  The marginal increase
        in the incidence of hepatocellular carcinomas and adenomas in male
        B6C3F-|  mice was concluded to be equivocal evidence in the NCI (1980)
        report on its bioassay.

     0   IARC (1983) has classified fluometuron in Group 3:   This chemical
        cannot be classified as  to its  carcinogenicity for humans.

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      Fluometuron                                                  August,  1987

                                           -12-
           0  Applying  the  criteria described in EPA's guidelines  for  assessment  of
             carcinogenic  risk  (U.S. EPA,  1986),  fluometuron may  be classified in
             Group D:  not classified.  This category is used for substances  with
             inadequate animal  evidence of carcinogenicity.


  VI.  OTHER CRITERIA, GUIDANCE AND STANDARDS

           0  The  U.S.  EPA/OPP previously calculated  an ADI of 0.008 mg/kg/day
             based on  a NOAEL of 7.5 mg/kg/day in a  90-day feeding study  in rats
              (Foglemann,  1965a) and an uncertainty factor of  1,000 (used  because
             of data gaps).  This has been updated to 0.013 mg/kg/day, based  on  a
              2-year feeding  study in rats  using a NQAEL of 12.5 mg/kg/day and an
             uncertainty  factor of  1,000.

           0  Tolerances have been established for negligible  residues of  fluometuron
             in or on  cottonseed and sugar cane at 0.1 ppm  (U.S.  EPA, 1985a). 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).


 VII.  ANALYTICAL METHODS

           0  Analysis  of  fluometuron is by a high-performance liquid  chromatographic
              (HPLC) method applicable to the determination of certain carbamate
              and  urea  pesticides in water  samples (U.S.  EPA,  1985b).   This method
              requires  a solvent extraction of approximately 1 liter of sample with
             methylene chloride using a separatory funnel.  The methylene chloride
              extract is dried and concentrated  to a  volume of 10  mL or less.  HPLC
              is  used  to permit  the  separation of  compounds, and measurement is
              conducted with a UV detector. The method detection  limit for
              fluometuron  is 11.1 ug/L.


VIII.  TREATMENT TECHNOLOGIES

           0   Available data indicate  that  granular activated  carbon  (GAC) adsorption
              will remove  fluometuron from  water.

           0   Whittaker (1980)  experimentally determined  adsorption isotherms for
              fluometuron  on GAC.

           0   Whittaker (1980) reported  the results of  GAC columns operating under
              bench-scale  conditions.  At a flow rate of  0.8  gpm/sq ft and an empty
              bed  contact  time  of  6  minutes,  fluometuron  breakthrough  (when effluent
              concentration equals  10% of influent concentration)  occurred after
              1,640 bed volumes  (BV).   When a bi-solute  solution  of fluometuron
              diphenamide  was passed over  the  same column,  fluometuron breakthrough
              occurred  after 320 BV.

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Fluometuron                                                 August, 1987

                                     -13-
        GAC adsorption appears to be the most promising treatment technique
        for the removal of fluometuron from contaminated water.  However,
        selection of individual or combinations of technologies to attempt
        fluometuron removal from water must be based on a case-by-case
        technical evaluation,  and an assessment of the economics involved.

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    Fluometuron                                                     August,  1987

                                        -14-


IX.  REFERENCES

    Arhur,  A., and V. Triana.*  1984.  Teratology  study  (with  fluometuron)  in
         rabbits.  Ciba-Geigy Corporation.  Report No. 217-84.   Unpublished
         study.  MRID 842096.

    Boyd,  V.F.,  and R.W. Foglemann.*  1967.  Metabolism  of  fluometuron  (1,1-dimethyl-
         3-(alpha, alpha,  alpha-trifluoro-m-tolyl)  urea)  in the  rat.  Ciba
         Agrochemical Company.  Research Report CF-1575.  Unpublished study.
         MRID 00022938.

    CHEMLAB.  1985.  The chemical  information  system.  CIS,  Inc.,  Bethesda,  MD.

    Davidson, J., and J. McDougal.  1973.   Experimental  and predicted movement
         of three herbicides in a  water-saturated  soil.   J.  Environ. Qual.
         2(4):428-433.

    Dunkel, V.C., and V.F.  Simmon.  1980.   Mutagenic  activity  of chemicals
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         bioassay.  PROGRAM.  IARC.   Sci.  Publ.  27:283-302.

    Foglemann, R.W.*  1964a.  Compound C-2059  technical    acute oral  toxicity 
         male and female mice.  AME Associates for CIBA  Corporation.   Project No.
         20-042.  Research Report  CF-735.   Unpublished study.  MRID 00019032.

    Foglemann, R.W.*  1964b.  Compound C-2059  80 WP-repeated rabbit dermal  toxicity.
         AME Associates for CIBA Corporation.  Project No.  20-0242. Research
         Project CF-740.   Unpublished study.   MRID 00018593.

    Foglemann, R.W.*  1964c.  Compound C-2059  Technical    Acute eye irritation 
         Rabbits.  AME Associates  for CIBA Corporation.   Project No. 20-042.
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    Foglemann, R.W.*  1965a.  Cotoran  90-day feeding  rats.  AME Associates for
         CIBA Corporation.  Project No. 20-042.  Unpublished study. MRID 00019034,

    Foglemann, R.W.*  1965b.  Subacute toxicity  90 day administration -- dogs.
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    Fritz, H.*   1971.   Reproduction  study:  Segment II.   Preparation C-2059:
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    Galloway, D. *   1984.   Guinea pig  skin  sensitization.  Project No.  3397-84.
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    Guth, J.A.   1972.   Adsorption  and elution  behavior of plant  protective agents
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         pflanzenschutzmitteln  in  boeden.   Schriftenreihe des vereins  fuer wasser,
         boeden, and  lufthygiene,  Berlin-Dahlem  (37):143-154.

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             Fluometuron                                                    August, 1987

                                                  -15-
             Guth,  J.  A.,  H.  Geissbuehler and L.  Ebner.  1969.  Dissipation of urea
                  herbicides  in soil.   Meded. Rijksfac. Landbouwwet.  XXXIV(3):1027-1037.

             Helling,  C.S.  1971.   Pesticide mobility in soils:   II.  Applications of soil
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             Helling,  C.S.,  D.D.  Kaufman and C.T. Dieter.  1971.  Algae bioassay detection
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             Hofmann,  A.*  1966.   Examinations on rats of the chronic toxicity of preparation
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             IARC.   1983.   International Agency  for Research on Cancer.  Vol. 30. _ IARC
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             LaFleur,  K.   1979.  Sorption of pesticides by model soils and agronomic
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             Lehman, A.J.   1959.   Appraisal of the safety of chemicals in foods, drugs,
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             Lin,  T.H., R.E.  Menzer and H.H. North.  1976.  Metabolism in human embryonic
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             Meister,  R.,  ed.  1983.  Farm chemicals handbook.  Willoughby, OH:  Meister
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             NCI.   1980.   National Cancer Institute.  Bioassay of fluometuron for possible
                  carcinogenicity.  NCI-CG-TR-195.  Bethesda, MD.

             NIOSH.   1985.  National Institute for Occupational Safety and Health.  Registry
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             Paynter,  O.E.,  J.G.  Cummings and M.H. Rogoff.  Undated.  United States
                  Pesticide  Tolerance  System.  U.S. EPA Office of Pesticide Programs.
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             Sachsse,  K.,  and R.  Bathe.*  1975.   Acute oral LD5Q of technical fluometuron
                  (C-2059) in the  rat.  Project No. Siss. 4574.   Unpublished study.  MRID
                  00019213.

             Seiler, J.P.   1978.   Herbicidal phenylalkylurea as possible mutagens.  I.
                  Mutagenicity tests with some urea herbicides.   Mutat. Res.  58:353-359.

             Siebert,  D.,  and E.  Lemperle.  1974.  Genetic effects of herbicides:  Induction
                  of mitotic  gene  conversion in Saccharomyces cerevisiae.  Mutat. Res.
                  22:111-120.

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Fluometuron                                                  August, 1987

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Siglin, J.C., P.J. Becci and R.A. Parent.*  1981.  Primary skin irritation in
     rabbits (EPA - FIFRA):  FDRL:  Study No. 6817A.  Food and Drug Research
     Laboratories for Ciba-Geigy.  Unpublished study.  MRID 00068040.

STORET.  1987.

TDB.  1985.  Toxicology Data Bank.   Medlars II.  National Library of Medicine's
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U.S. EPA.  1985a.  U.S. Environmental Protection Agency.  Code of Federal
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U.S. EPA.  1985b.  U.S. Environmental Protection Agency.  U.S. EPA Method 632
     - Carbamate and urea pesticides, Fed. Reg.  50:40701.  October  4.

U.S. EPA.  1986.  U.S. Environmental Protection Agency.  Guidelines  for
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Whittaker, K.F.  1980.  Adsorption of selected pesticides by activated carbon
     using isotherm and continuous flow column systems.  Ph.D. Thesis, Purdue
     University.

Windholz, M., S. Budavari, R.F. Blumetti and E.S.  Otterbein, eds.  1983.
     The Merck Index -- an encyclopedia of chemicals and drugs, 10th ed.
     Rahway, NJ:  Merck and Company, Inc.
 Confidential  Business  Information  submitted  to the Office of Pesticide
  Programs.

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