5 -01-7- 1387
            UNITED S1^TB^NMi|0NMfoVAL PROTECTION'AGENCY
                          822K87101
                                                           QfflCt Of
                                                            WATIH
MEMORANDUM                  -/f-  ~


SUBJECT:  Ava-ilability of  &&$'tK&l  Review Draft Health
          Ava-ilability of fJU.eeijal  review Draft Healtt
          Advisories fecal:  $tJM^t6nal Pesticide Sutvey

FROM: P  JcWetmA7\CcVtru\\o/ ;?h.D.,  Director
                                  Division, ODW (WH-550D)

TO:       Addressees
                               .    v  .           ,.
     Attached are the  external', review, draft Hea.lth
for 50 pesticides.  These  p^ta'fcTdf^'.'are pa,rt o^f 'tl,
Pesticide Survey  (NFS)  sponsored b|^' the EPA; ^|f ice -Of. Drinking
Water and Office  of Pesticide "Programs. ' ' t h* ^efriairi^rjg 11   -
pesticide Health  Advisories that are part of r the;'auv.rey
distributed as  final Health Advisories earlier this .
     The 50 Health Advisories distributed today include the
following:                             ,    ,
Aciflurofen                         ,. .Ej^hy^ene thiourea
Ame t r y n                              , :f sena^i pJic?s
Ammonium sulfamate                   %lHui)ineturon
Atrazine                             ' achior
1,3-Dichloropropene                   Pirbpham
Dieldrin                              Propazine
Dimethrin                             Simazine
Dinoseb                               Tebuthiuron
Diphenamid                            Terbacil '
Disulfoton                            Terbufbs
Diuron                                Tri-fluralin
Endothall                             2/4'f'5-T

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                   ?-  -  r   1
   X   .'

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t
                             -2-

     A notice of availability for the 50 NFS Health Advisories
will be published in the Federal Register.  These documents
will be made available as a set from the National Technical
Information Service.  In addition, I would appreciate the
assistance of the Regional Offices in distributing these
advisories to the States within their regions.

     Public comments will be received on these Health Advisories
until December 31, 1987.  Any questions should be directed to
Jennifer Orme, Health Advisory Program Coordinator (202) 382-
7586 or Edward Ohanian, Chief, Health Effects Branch  (202)
382-7571.
         Addresses:

         Jerome Healey,  Reg.  1
         Gerald Levy, Reg.  1
         Walter Andrews, Reg.  II
         John Malleck, Reg. II
         Jon Capacasa, Reg. Ill
         Larry Miller, Reg. Ill
         William Patton, Reg.  IV
         Howell Lucius,  Reg.  IV
         Joseph Harrison, Reg. V
         Phyllis Reed, Reg. V
         Marion Mlay .(WH-550G)
         Tudor Davis (WH-556M)
         William Whittington  (WH-551)
         Henry Longest (WH-548)
         Marcia Williams (WH-562)
         Ronald Brand (WH-562A)
         Reto Engler (TS-769C)
         Jerry Kotas (WH-550)

         Attachments
                                      Thomas Love, Reg. VI
                                      Norman Dyer, Reg. VI
                                      Gerald Foree, Reg. VII
                                      Timothy Amsdon, -Reg. VII
                                      Marc Alston, Reg. VIII
                                      Richard Long, "Reg. VIII
                                      William Thurston, Reg. IX
                                      Rich Vaille, Reg. IX *
                                      Richard Thiei, J*eg. X
                                      Anita Frankel, Reg. X
                                      Gerald Emison  (MD-10)
                                      Douglas Campt  (TS-776C)
                                      Charles Elkins (TS-792)
                                      Ken Sexton  (RD-683)
                                      Peter Preuss (RD-689)
                                      Michael Cook (WH-550)
                                      Penny Fenner-Crisp (TS-796)
                                      Anne Barton  (TS-769C)

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' *"".-
 *'
                                                                                                                                                     r

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                                   ACIFLUORFEN
                                                             August,  1987
DRAFT
                                 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 models 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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      Acifluorfen
                    August, 1987
                                           -2-
  II. GENERAL INFORMATION AMD PROPERTIES

      CAS No.  5094-66-6 (acid)

               62476-59-9 (sodium salt)

      Structural Formula
                                       -o-
             Sodium 5-(2-chloro-4-(trifluoromethyl)-phenoxy)-2-nitrobenzoate

      Synonyms

           *  Blazer*,- Carbofluorfen; RH-6201; Tackle*; Sodium acifluorfen (Meister,
     -        1983).
      Uses
              Acifluorfen is used as a selective pre- and post-emergence herbicide to
              control weeds and grasses in large-seeded legumes including soybeans
              and peanuts (Meister, 1983).
      Properties  (Windholz et al.f 1983; Meister, 1983; CHEMLAB, 1985)

              Chemical Formula

              Molecular Weight

              Physical State (25C)
C14H7C1F3N05 (acid)
C14H6ClF3NNa05 (sodium salt)
361.66 (acid)
383.65 (sodium salt)
Off-white solid (acid), brown crystalline
  powder/white powder (sodium salt)
              Boiling Point
              Melting Point

              Density
              Vapor Pressure (25'C)
              Specific Gravity
              Water Solubility (25C)

              Log Octanol/Water Partition
                Coefficient
              Taste Threshold
              Odor Threshold
              Conversion Factor
124-125C (sodium salt)
  151.5-157C (acid)
>25% (sodium salt) (dimensions not
  specified)
-4.85 (acid) (calculated)
1 _ r c :* o 5
      Occurrence
            0  No information was found in the available literature on the occurrence
              of acifluorfen.

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     Acifluorfen                                                August,  1987

                                          -3-


     Environmental Fate

          0  Acifluorfen is stable to hydrolysis;  no degradation was observed
             in solutions at pH 3, 6 or 9 within a 28-day interval.   Varying
             temperatures (18 to 40C) did not alter this stability.  The half-life
             of the parent compound is 92 hours under continuous exposure to light
             approximating natural sunlight.   The decarboxy derivative of acifluorfen
             was the primary degradate found  in solution.  It is suspected that a
             substantial percentage of the photodegradate parent is  lost from
             solution (through volatilization or other mechanisms)  (Registrant
             CBI data).

            The half-life of acifluorfen in  an aerobically incubated soil was
             found to be about 170 days;  anaerobic degradation was  more rapid
             (half-life about 1 month).  The  dominant residue compounds  after
             6-months aerobic incubation were the parent compound and bound
             materials.  After 2 months under anaerobic conditions,  the  acetamide
             of amino acifluorfen was the major degradate extracted  from soil; the
             amino analog itself was also significant, and denitro acifluorfen was
             also formed (Registrant CBI data).

          0  Acifluorfen applied at 0.75 Ib ai/A to a silt loam in Mississippi
             dissipated with a tentative half-life of 59 days.   Leaching of the
             parent compound below 3 inches in the soil was negligible during the
             179-day study.  The dissipation  of acifluorfen in  two silt  loam soils
             in Illinois receiving multi-residue treatments was somewhat slower;
             half-lives were 101 to 235 days  (Registrant CBI data).

          0  Acifluorfen applied to soil columns at highly excessive rates indica-
             tive of spills (682 Ib ai/A) is  very mobile.  Acifluorfen leached
             from the columns with 10 inches  of water accounted for  79 to 93% of
             the acifluorfen applied.  Aerobic aging of the residues in  the column
             substantially reduced the mobility and pesticide movement was inversely
             proportional to the soil CEC. Results from soil TLC (un-aged residues
             only) predict mobility to be intermediate to mobile. Supplementary
             data from a batch adsorption study indicate that un-agad acifluorfen
             is weakly and reversibly adsorbed (Registrant CBI  data).

          0  Greenhouse studies have demonstrated that the uptake of acifluorfen
             by rotational crops decreases with aging of residues in soil (Registrant
             CBI data).
III. PHARMACOKINETICS

     Absorption

          0  No information  was  found  in  the available  literature  on  the  absorption
             of acifluorfen.                                           - :

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    Acifluorfen                                                 August,  1987

                                         -4-


    Distribution

         0  No information was  found  in  the available literature on the distribution
            of acifluorfen.

    Metabolism

         0  No information was  found  in  the available literature on the metabolism
            of acifluorfen.

    Excretion

         *  No information was  found  in  the available literature on the excretion
            of acifluorfen.


IV. HEALTH EFFECTS

    Humans

       Short-term Exposure

         0  No information was  found  in  the available literature on the short-term
            health effects of acifluorfen in  humans.

       Long-term Exposure

         0  No information was  found  in  the available literature on the long-term
            health effects  of acifluorfen in humans.

    Animals

       Short-term Exposure

           The Whittaker Corporation (no date, a) reported that the oral LDso of
            Tackle 2S (a formulation containing 20.2% sodium acifluorfen) in the
            rat (strain not specified) was 2,025 mg/kg for males and 1,370 mg/kg
            for females.

         0  Meister (1983)  reported that the acute dermal LD50 of Blazer*  (tech-
            nical grade, purity unspecified)  in the rabbit is 450 mg/kg.  The
            acute dermal LDso of Tackle* (purity unspecified) in the rabbit is
            2,000 mg/kg.

           Goldenthal et al. (1978a) presented the results of a two-week range-
            finding study in which RH 6201 (a formulation containing 39.4% sodium
            acifluorfen) was administered  to Charles River CD-1 mice (10/sex/dose)
            at dietary concentrations of 0, 625, 1,250, 2,500, 5,000 or 10,000
            ppm.  Assuming that 1 ppm in the diet of mice is equivalent to 0.15
. v  i..    .   mg/kg/day (Lehman,  1959), these doses correspond to about  0, 93.8,
   -.,.-'   187.5, 375.0, 750.0 or 1,500 mg/kg/day.  No changes in general behavior
            or appearance were reported at any dose level.  During the  second
            week of the study,  there was a decrease in body weight and  food

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Acifluorfen                                                August, 1987

                                     -5-                ?
        consumption in animals receiving 10,000 ppm (1,500 mg/kg/day).  Gross
        pathological findings included pale kidneys, yellowish livers and
        reddish foci of hyperemia in the stomachs of several mice at the
        5,000- and 10,000-ppm (750 and 1,500 mg/kg/day) dose levels.  Absolute
        liver weight was increased in all test groups dosed at levels of
        2,500 ppm (375 mg/kg/day) or greater.  The increases were statistically
        significant (p <0.01).  A statistically significant (p <0.01) increase
        in relative liver weight was reported at all dose levels.  Based on
        the results of this study, a Lowest-Observed-Adverse-Effect-Level
        (LOAEL) of 625 ppm (93.8 mg/kg/day) was identified.

     0  Piccirillo and Robbins (1976) administered RH 6201 (a formulation
        containing 39.8% sodium acifluorfen) to Wistar rats (5/sex/dose) for
        4 weeks at dietary concentrations of 0, 5, 50, 500 or 5,000 ppm
        (reported to be equivalent to 0, 0.7, 7.6, 55.4 or 506.4 mg/kg/day
        for males and 0, 0.8, 8.3, 60.6 or 528.2 mg/kg/day for females).
        Assuming that these dietary levels reflect the concentration of the
        test compound and not the active ingredient, corresponding levels
        of sodium acifluorfen are 0, 0.3, 3.0, 22.1 and 201.6 mg/kg/day for
        males and 0, 0.3, 3.3, 24.0 and 210.2 mg/kg/day for females (Lehman,
        1959).  Results of the study indicated that body weight was decreased
        in males at 22.1 and 201.6 mg/kg/day, and food consumption was decreased
        in both males at 201.6 mg/kg/day and females at 210.2 mg/kg/day.
        Biochemical analyses revealed that serum glutamic pyruvic transaminase
        (SGPT) levels were increased in males at 22.1 and 201.6 mg/kg/day;
        in males that received 201.6 mg/kg/day, blood urea nitrogen (BUN)
        was increased and glucose levels were decreased.  Changes in organ
        weights included increased absolute liver and kidney weights in males
        at 201.6 mg/kg/day, increased relative liver and kidney weights in
        males at 201.6 mg/kg/day and females at 210.2 mg/kg/day and increased
        relative liver weight in males only at 22.1 mg/kg/day.  Based on the
        results of this study, a No-Observed-Adverse-Effect-Level (NOAEL) of
        3.0 mg/kg/day was identified.

Dermal/Ocular Effects

     0  In a dermal irritation study (Whittaker Corp., no date, b), Tackle 2S
        (a formulation containing 20.2% sodium acifluorfen) was applied
        occlusively (dose not specified) to the intact and abraded skin of
        rabbits.  Effects observed included slight erythema, slight edema,
        blanching of the skin, and eschar formation.  Sign? of dermal
        irritation at intact and abraded sites were absent by 8 days post-
        application.  The test substance was considered to be a moderate
        dermal irritant at 72 hours.

     0  In a dermal irritation study, Weatherholtz et al. (1979b) applied
        RH 6201 (sodium acifluorfen) to the skin of New Zealand White rabbits
        (five/sex/dose; ten/sex/control).  Three different formulations of
        RH 6201 were used in the study and each formulation was tested at
        1.0 or 4.0 mL/kg/day.  The authors indicated that for all RH 6201
        formulations tested,  the dose levels correspond to 50 or 200 mg/kg/day
        of the active ingredient.  The test material was applied once daily
        for 5 days, followed by 2 days with no applications, over a 4-week

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Acifluorfen                                                August, 1987
                                               ?
                                     -6-
        period (total of 20 applications).  At both dose levels, two of
        the formulations produced slight to well-defined irritation.  At
        200 mg/kg/day, central nervous system depression and a statistically
        significant decrease in body weight gain and food consumption were
        noted.  The third formulation produced essentially the same effects,
        with the addition of "thinness," ataxia, slight tremors and mortality
        (2/5 males).  Microscopic evaluations revealed chronic dermatitis,
        acanthosis and hyperkeratosis at both dose levels for all formulations.

     e  Madison et al. (1981) presented the results of the Buhler test for
        dermal sensitization in Hartley-derived albino guinea pigs.  In this
        study, Tackle* (sodium acifluorfen; purity not specified) was not found
        to be a sensitizer when applied topically at a dose of 0.25 mL under
        occlusive binding.

     0  In an ocular irritation study (Whittaker Corp., no date, c), Tackle 2S
        (a formulation containing 20.3% sodium acifluorfen) was instilled
        into the eyes of rabbits.  Signs of ocular irritation and lesions
        included opacities of the cornea, iritis, redness and chemosis of the
        conjunctiva and discharges from both washed and unwashed eyes.  Four
        of six unwashed eyes and one of three washed eyes exhibited blistering
        of the conjunctiva.  Three of six unwashed and one of three washed
        eyes exhibited pannus where corneal opacity had been.

     0  In an ocular irritation study (Weatherholtz et al., 1979a), 0.1 mL of
        Blazer 2S  (purity not specified) was applied to the corneal surface
        of the eyes of rhesus monkeys.  Corneal opacity and conjunctival
        redness, swelling and discharge were observed in both washed and
        unwashed eyes.  All treated eyes were free of signs of irritation by
        14 days posttreatment.

   Long-term Exposure

     0  Harris et  al. (1978) administered RH 6201 (a formulation containing
        39.4% sodium acifluorfen) in the diet to Sprague-Dawley rats (15/sex/
        dose) for  3 months at dose levels of 0, 75, 150 or 300 mg/kg/day.
        Assuming that these doses reflect levels of the test compound and not
        the active ingredient, corresponding levels of sodium acifluorfen
        would be 0, 29.6, 59.1 or 118.2 mg/kg/day.  At the highest dose level
        (118.2 mg/kg/day), a number of effects were observed in male rats.
        These effects included decreased body weight (13%) and decreased food
        consumption (8%).  Biochemical analyses of blood revealed increased
        alkaline phosphatase levels (32%), decreased total protein  (8%) and
        decreased  albumin (14%).  No such effects were reported for female
        rats.  (These biochemical analyses were performed on control and high-
        dose animals only.)  Increased liver weight and microscopic liver
        changes (enlarged hepatocytes) were observed in male rats that received
        59.1 or 118.2 mg/kg/day.  In terms of the active ingredient, a NOAEL
        of 29.6 mg/kg/day was identified.

     0  Barnett (1982) administered Tackle 2S (a formulation containing
        20.4 to 23.6% sodium acifluorfen) to Fischer 344 rats (30/sex/dose)
        for 90 days at dietary concentrations of 0, 20, 80, 320, 1,250,

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Acifluorfen                                                August, 1987

                                     -7-
        2,500 or 5,000 ppm.  The author indicated that these dietary levels
        correspond to average compound intake levels of 0,  1.5, 6.1, 23.7,
        92.5, 191.8 or 401.7 mg/kg/day for males and 0, 1.8, 7.4,  29.7,
        116.0,  237.1  or 441.8 mg/kg/day for females.  Assuming that these
        levels  reflect test compound and not active ingredient intake,
        corresponding levels of sodium acifluorfen intake are approximately
        0, 0.4, 1.4,  5.6,  21.8, 45.3 or 94.8 mg/kg/day for  males and 0, 0.4,
        1.8,  7.0,  27.4,  56.0 or 104.3 mg/kg/day for females (based on 23.6%
        active  ingredient in test compound).  At 5,000 ppm  the following
        effects were observed:  decreased body weight and food consumption
        in both sexes; decreased red blood cell (RBC) count, hemoglobin and
        hematocrit in both sexes; increased serum cholesterol and serum calcium,
        and decreased serum phosphorous in both sexes; increased alkaline
        phosphatase,  SGPT and BUN levels in males; elevated urobilinogen in
        both sexes; increased liver size and discolored liver and kidneys
        in both sexes; and liver cell hypertrophy and increases in mitotic
        figures and individual cell deaths in both sexes.  At 2,500 ppm the
        following effects were observed:  decreased body weight in males;
        decreased RBC count, hemoglobin and hematocrit in both sexes; increased
        BUN levels in males; elevated urobilinogen in both  sexes;  increased
        liver size in both sexes; and liver cell hypertrophy and increases
        in mitotic figures and individual cell deaths in both sexes.  At
        1,250 ppm, the following effects were observed:  increased liver
        size in males and liver cell hypertrophy in both sexes>  The author
        identified 320 ppm as the NOAEL in this study.  In  terms of active
        ingredient concentration, this corresponds to a NOAEL of 5.6 mg/kg/day
        for males and 7.0 mg/kg/day for females.

     0  Mobil  (1981)  presented the 6-month interim results  of a longer-term
        study in which Tackle 2S (a formulation containing  approximately 75%
        sodium acifluorfen) was administered to beagle dogs (eight/sex/dose)
        at dietary concentrations of 0, 20, 320 or 4,500 ppm.  These dietary
        levels  were reported to be equivalent to 0, 0.7, 9.0 or 160 mg/kg/day.
        Assuming that these levels reflect test compound and not active
        ingredient intake, corresponding levels of sodium acifluorfen intake
        are 0,  0.5, 6.8 or 120.0 mg/kg/day (based on 75% active ingredient in
        the test compound).  Following six months of compound administration,
        two animals/sex/dose were sacrificed.  The study reported a number of
        effects at the highest dose tested.  These effects  included decreased
        body weight and food consumption and increased liver weight in both
        sexes.   Additionally, RBC count and hemoglobin concentration were
        decreased in both sexes.  Clinical chemistry analyses revealed
        depressed serum cholesterol, increased alkaline phosphatase, and
        transient elevation of BUN in both sexes.  Males only showed increased
        levels  of lactic dehydrogenase.  No histopathological examinations
        were conducted.   The NOAEL reported in this study was 320 ppm.  In
        terms of the  active ingredient, this corresponds to a NOAEL of
        6.8 mg/kg/day.

     0  Barnett et al. (1982b) administered Tackle 2S (a formulation con-
        taining 19.1  to 25.6% sodium acifluorfen) to Fischer 344 rats
        (73/sex/dose) for 1  year at dietary levels of 0,  25,  150,  500, 2,500
        or 5,000 ppm.  Assuming that these dietary levels reflect the

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Acifluorfen                                                August, 1987

                                     -8-
        concentrations of the test compound and not the active ingredient,
        corresponding levels of sodium acifluorfen are 0, 6.4, 38.4, 128.0,
        640.0 or 1,280 ppm (based on 25.6% active ingredient in the test
        compound).  Assuming that 1 ppm in the diet of rats is equivalent to
        0.05 mg/kg/day, these levels correspond approximately to 0, 0.3, 1.9,
        6.4, 32.0 or 64.0 mg/kg/day (Lehman, 1959).  No excess moribundity or
        mortality was associated with the ingestion of the test substance.
        At 5,000 ppm, the following effects were observed:  decreased mean
        body weight in both sexes; increased absolute and relative liver
        weight in both sexes; decreased protein production, decreased serum
        glucose, decreased triglyceride levels, increased alkaline phosphatase
        and creatine phosphokinase levels, and sporadic increases in SCOT and
        SGPT in both sexes; a slight increase in the excretion of urobilinogen
        in both sexes; and the presence of acidophilic cells that were
        considered to be evidence of cytotoxic changes in the livers of both
        sexes.  At 2,500 ppm, male rats showed increased absolute and relative
        liver weights.  Based on the information presented in this study, a
        NOAEL of 500 ppm was identified for the test compound.  In terms of
        the active ingredient, this corresponds to a NOAEL of 6.4 mg/kg/day.

        Spicer et al. (1983) administered Tackle 2S (a formulation containing
        74.5 to 82.8% sodium acifluorfen) to beagle dogs (eight/sex/dose)
        for 2 years at dietary concentrations of 0, 20, 300 or 4,500 ppm,
        reported to be equivalent to 0, 0.5, 7.3 or >21 mg/kg/day for males
        and 0, 0.5, 8.3 or 154 mg/kg/day for females.  Assuming that these
        dietary levels reflect the concentration of the test compound and not
        the active ingredient, corresponding levels of sodium acifluorfen are
        0, 0.4, 6.0 or 100.2 mg/kg/day for males and 0, 0.4, 6.9 or 127.5
        mg/kg/day for females (based on 82.8% active ingredient in the test
        compound).  At the highest dose, body weight was decreased (not
        statistically significant), and a corresponding (statistically sig-
        nificant) decrease in food consumption was also reported.  Physical
        examination revealed heart anomalies in the high- and mid-dose groups.
        At the high dose, irregular heart rhythms and rapid or slow heart
        rates were reported in one male and four females.  Also at this dose
        level, one male was found to have a systolic murmur.  At the mid-dose
        level, one animal of each sex had an irregular heart rhythm (accompanied
        by rapid heart rate in the male).  At the highest dose tested, a
        number of changes were reported, including a statistically significant
        decrease in erythrocyte count, hemoglobin and hematocrit in both
        rsexes; reductions in albumin and cholesterol; increased absolute ar.i
        relative liver and kidney weights; and histopathological liver changes
        including centrilobular hepatocellular fatty vacuolation, bilirubin
        pigmentation and minimal foci of alteration.  Renal tubules showed
        bilirubin pigmentation at all dose levels (most pronounced at the
        high dose).  The authors concluded that this study showed clear
        evidence of target organ toxicity affecting the liver and possibly
        the kidney at the highest dose level.  The authors identified 300 ppm
        (of test compound) as the NOAEL.  In terms of the active ingredient,
        this corresponds to a NOAEL of 6.0 mg/kg/day.

        Goldenthal (1979) administered RH 6201 (a formulation containing 39.4
        to 40.5% sodium acifluorfen) to Charles River CD-1 mice (80/sex/dose)

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Acifluorfen                                                August, 1987

                                     -9-
        for two years in the diet at concentrations that provided dosage
        levels of 0,  1.25,  7.5 or 45.0 ppm of the active ingredient.  After
        16 weeks of administration,  the 1.25 ppm dose was increased to 270 ppm.
        Assuming that 1  ppm in the diet of mice is equivalent to 0.15 mg/kg/day,
        these levels correspond to about 0, 0.19 (increased to 40.5), 1.13 and
        6.8 mg/kg/day (Lehman, 1959).  Two control groups were used in this
        study.  One group received acetone in the diet (control 1), and the
        other received water in the diet (control 2).  At the 40.5 mg/kg/day
        dose level, the following effects were observed:   slight to marked
        elevations in alkaline phosphatase and SGPT levels, in both sexes,
        beginning after one year of exposure; increased absolute and relative
        liver weight in males; increased absolute liver weight in females;
        increased relative kidney weight in males; decreased absolute heart
        weight in males; cellular alterations in the livers of males consisting
        of focal pigmentation, focal hepatocytic necrosis, focal cellular
        alteration, nodular hepatocellular proliferation and hepatocellular
        carcinoma (the only statistically significant change was the focal
        cellular alteration); and focal pigmentation in the livers of females.
        At the 6.8 mg/kg/day dose level, the following effects were observed:
        occasional increases in alkaline phosphatase and SGPT levels in both
        sexes; decreased absolute heart weight in males;  and focal pigmentation
        in the livers of females.  The author indicated that changes with an
        apparent dose-related distribution included focal pigmentation,
        hepatocellular vacuolation,  focal hepatocytic necrosis and nodular
        hepatocellular proliferation.  The incidence of hepatocellular
        carcinoma in males of all treatment groups was approximately the same.
        A NOAEL of 7.5 ppm (1.13 mg/kg/day) was identified by the author.

   Reproductive Effects

     0  In a three-generation reproduction study, Goldenthal et al. (1978b)
        administered RH 6201 (a formulation containing sodium acifluorfen) in
        the diet to Charles River CD rats.  During the course of the study,
        the test compound was administered at various levels depending on the
        age of the animals.  The FI  generation received dose levels of 2.9,
        17.3 or 104 ppm during the first 2 weeks of the study, and 5, 30 and
        180 ppm for the remaining weeks of the generation (study weeks 3 to
        17) (Time-Weighted Average (TWA) dosage levels 4.8, 28.5 or 171.1 pm).
        The ?2 and Fj generations received dosage levels of 180,
        10 or 60 ppm during the first and second weeks of the generation;
        312, 17.3 or 104 ppm during the third, fourth and fifth weeks of the
        generation; and 540, 30 or 180 ppm for the remaining weeks of the
        generation (TWA for F2 generation 486.0, 27.0 or 162.0 ppm; TWA for
        F3 generation 483.8, 26.7 or 161.3 ppm).  The highest dietary TWA dose
        tested in this study was 486 ppm of active ingredient.  Assuming that
        1 ppm in the diet of rats is equivalent to 0.05 mg/kg/day, this
        corresponds to a dose of 24.3 mg/kg/day (Lehman,  1959).  No effects
        related to compound administration were observed in parents or pups
        in terms of general behavior, appearance or survival.  Parental and
        pup body weights and food consumption were similar to controls.
        Fertility, gestation and viability indices were comparable for controls
        and treated groups.  There were no biologically meaningful teratogenic
        effects in the second or third generation, based on mean number of

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Acifluorfen                                                August, 1987

                                     -10-
        viable fetuses,  post-implantation losses, total implantations and
        corpora lutea per dam,  mean fetal body weight, number of fetal
        anomalies and sex-ratio variations.  No compound-related gross lesions
        were noted in third-generation pups necropsied.  Based on the infor-
        mation presented, a NOAEL of 486 ppm (24.3 mg/kg/day) was identified.
        This NOAEL represents the highest dose tested.

     0  In a two-generation reproduction study, Lochry et al. (1986) admini-
        stered technical grade Tackle (sodium acifluorfen) of unspecified
        purity to rats at levels of 0, 25, 500 and 2,500 ppm.  The compound
        was administered in the diet ad libitum to groups of 35 rats/sex/dose
        beginning at 47 days of age and continuing until sacrifice.  In addi-
        tion, the compound was also administered to groups of 40 rats/sex/dose
        from weaning until sacrifice.  Reproductive parameters, mortality,
        body weight and a number of other end points were measured; in addition,
        both gross and histopathological examinations were conducted.  The
        NOAEL for toxicity to both the parents and offspring was 25 ppm,
        based on mortality and kidney lesions at higher doses.  Assuming that
        1 ppm in the diet of rats is equivalent to 0.05 mg/kg/day, the NOAEL
        of 25 ppm in this study corresponds to 1.25 mg/kg/day (Lehman, 1959).

   Developmental Effects

     0  Lightkep et al. (1980) administered Tackle 2S (a formulation containing
        22.4% sodium acifluorfen) by oral intubation at doses of 0, 3, 12 or
        36 mg/kg/day to New Zealand White rabbits (16/dose) on days 6 to 29
        of gestation.  The authors indicated that the administered doses were
        in terms of the active ingredient.  At 36 mg/kg/day, there was a
        slight (nonsignificant) inhibition of maternal body weight gain and a
        marked (significant) inhibition of maternal food consumption.  At this
        dose level, there was also possible interference with implantation
        and a slight decrease in average fetal body weight; neither of these
        changes was statistically significant.   No gross, soft-tissue or
        skeletal malformations were observed in pups, fetuses or late resorp-
        tions at any dose level.  Based on the information presented in this
        study, a NOAEL of 36 mg/kg/day was identified for maternal toxicity,
        fetal toxicity and teratogenicity.  This NOAEL represents the highest
        dose tested.

     0  Florek et al. (1981) administered Tackle 2S  (a formulation containing
        22.4% sodium acifluorfen) by gav^ge at doses of 0, 20, 90 or 180
        mg/kg/day to Sprague-Dawley rats (25/dose) on days 6 to 19 of gesta-
        tion.  The authors indicated that the administered doses were in
        terms of active ingredient.  At 180 mg/kg/day, dams gained signifi-
        cantly less weight than controls.  At 90 and 180 mg/kg/day, lower
        average fetal body weight and significantly delayed ossification of
        metacarpals and forepaw and hindpaw phalanges were noted.  At 180
        rog/kg/day, there was delayed ossification of caudal vertebrae,
        sternebrae and metatarsals.  Additionally, at the highest dose level
        there was a significantly increased incidence of slight dilation of
        the lateral ventricle of the brain.  The authors stated that the
        fetal effects were indicative of delayed fetal development.  Based
        on the results of this study, a NOAEL of 90 mg/kg/day for maternal

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Acifluorfen                                                August,  1987

                                     -11-
        toxicity,  a NOAEL of 20 mg/kg/day for fetotoxicity and a NOAEL of
        180 mg/kg/day (the highest dose tested)  for teratogenic effects were
        identified.

     0  Weatherholtz and Piccirill.o (1979)  administered RH 6201 (a formulation
        containing 39.8% sodium acifluorfen)  by  gavage at doses of 0,  20, 60
        or 180 mg/kg/day to New Zealand White rabbits on days 7 to 19  of
        gestation.  Maternal toxicity at 180  mg/kg/day included statistically
        significant weight loss and mortality.   At  180 mg/kg/day,  there was
        also evidence of fetal toxicity (mortality).   Due to embryotoxicity
        and maternal toxicity at 180 mg/kg/day,  teratogenic evaluations could
        not be performed at this dose level.   At lower doses, no teratogenic
        effects were observed.  Based on the  results  of this study,  NOAELs
        of 60 mg/kg/day were identified for teratogenic effects, maternal
        toxicity and fetal toxicity.

   Mutagenicity

     0  Schreiner et al. (1980) tested Tackle 2S (purity unspecified)  in an
        Ames assay using Salmonella typhimurium  strains TA 98, 100,  1535, 1537
        and 1538.   The test compound was not found  to be mutagenic,  with or
        without metabolic activation, at concentrations up to 1.8 rag/plate.

     0  Brusick (1976) tested RH 6201 (purity not specified) in a mutagenicity
        assay using Saccharomyces cersvisiae  strain D4 and S_. typhimurium
        strains TA 1535, 1537, 1538, 98 and 100. The compound was not found
        to be mutagenic, with or without metabolic  activation, at concentrations
        up to 500 ug/plate.

     0  Putnam et al. (1981) tested Tackle 2S (purity not specified)  in a
        dominant lethal assay using Sprague-Dawley  rats.  The compound was
        administered by gavage at doses of 0, 80, 360 or 800 mg/kg/day for
        5 consecutive days.  No detectable mutagenic activity, as defined by
        induction of fetal death, was reported.

     0  Myhr and McKeon (1981) conducted a primary  rat (Fischer 344)  hepato-
        cyte unscheduled DNA synthesis (UDS)  assay  using Tackle 2S (purity
        not specified).  The test compound did not  induce a detectable level
        of UDS over a concentration range of  0.10 to 25 ug/mL.  Treatment of
        hepatocytes with 50 ug/mL was almost  completely lethal to the  cells.

     0  Schreiner et al. (1981) tested Tackle 2S (purity not specified) in a
        bone marrow metaphase analysis using  Sprague-Dawley rats.   The animals
        were given the test compound by intubation  at doses of 0,  0.37, 1.11
        or 1.87 g/kg/day for 5 days.  The test compound did not significantly
        increase clastogenic events in the bone  marrow cells.

     0  Schreiner et al. (1980) tested Tackle 2S (purity not specified) in
        a murine lymphoma assay.  The compound was  tested without metabolic
        activation at 0.11  to 1.7 ug/mL,  and  with metabolic activation at
        0.08 to 0.56 ug/mL.  No detectable mutagenic  activity was detected
        either with or without activation.

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Acifluorfen                                                August, 1987

                                     -12-
     0  Jagannath (1981) tested Tackle 2S (29.7% purity)  in a mitotic recombi-
        nation assay using Saccharomyces cerevisiae strain D5.  The compound
        was tested at 0, 2.5,  5.0 or 7.5 uL/plate without metabolic activation,
        and at 7.5,  10.0 and 25.0 uL/plate with metabolic activation.  In the
        absence of metabolic activation, the compound induced a dose-related
        increase in recombination events (significant at  5.0 uL/plate) .  With
        metabolic activation,  a dose of 10.0 uL/plate induced an increase in
        recombination events.   The authors reported that  very few survivors
        were observed at 25.0 uL/plate.

       Bowman et al. (1981) tested Tackle 2S (purity not specified) in
        mutagenicity assays using Drosophila melanogaster.  Assays included
        the Biothorax test of Lewis, a dominant lethal assay, an assay for
        Y-chromosome loss, and a White Ivory reversion assay.  In all cases,
        the test compound was tested at concentrations of 1 5 mg/mL.  Results
        of these assays were negative for somatic reversions of White Ivory
        and the Biothorax test of Lewis and positive for  Y-chromosome loss
        and dominant lethal mutations.

   Carcinogenici ty

     0  Barnett et al.  (1982b) administered Tackle 2S (a  formulation
        containing 19.1 to 25.6% sodium acifluorfen) to Fischer 344 rats
        (73/sex/dose) for one year at dietary levels of 0, 25, 150, 500,
        2,500 or 5,000 ppm.  Assuming that these dietary  levels reflect the
        concentrations of the test compound and not the active ingredient,
        corresponding levels of sodium acifluorfen are 0, 6.4, 38.4, 128.0,
        640.0 or 1,280 ppm (based on 25.6% active ingredient in the test
        compound).  Assuming that 1 ppm in the diet of rats is equivalent to
        0.05 mg/kg/day, these doses correspond to approximately to 0, 0.3,
        1.9, 6.4, 32.0 or 64.0 mg/kg/day (Lehman, 1959).   Histopathological
        examinations revealed no evidence of carcinogenicity at any dose level.

     0  Barnett et al.  (1982a) administered Tackle* (a formulation containing
        24% sodium acifluorfen) to B6C3F^ mice (60/sex/dose) for 18 months at
        dietary concentrations of 0, 625, 1,250 or 2,500  ppm.  (The high dose
        was reported to be the maximum tolerated dose.)  The authors reported
        that the dietary levels corresponded to average compound intake values
        of 0, 118.96, 258.73 or 655.15 mg/kg/day for males, and 0, 142.50,
        312.65 or 710.54 mg/kg/day for females.  Assuming that these levels
        reflect test compound and not active ingredient intake, corresponding
        levels of sodium acifluorfen intake are 0, 28.55, 62.10 or 157.24
        mg/kg/day for males and 0, 34.20, 75.04 or 170.53 mg/kg/day for
        females.  An obvious dose-related depression of body weight was
        reported for all doses.  Beginning in week 52 of  the study and
        continuing with increasing frequency was the appearance of palpable
        abdominal masses.  Gross necropsy revealed a dose-related increase in
        liver masses in both sexes.  Histopathological examinations conducted
        at the 52-week interval revealed that the livers  -of six animals per
        sex of high-dose animals (157.24 mg/kg/day for males; 170.53 mg/kg/day
        for females) showed evidence of acidophilic cells.  Males receiving
        this dose displayed a statistically significant increase in the
        frequency of hepatocellular adenomas.  After 18 months of treatment,

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   Acifluorfen                                                August,  1987

                                       -13-
           all  40 high-dose  males and 27/47 high-dose  females sacrificed were
           found to  have  a single benign hepatoma, multiple benign hepatomas or
           hepatocellular carcinomas.   In the males, the incidence of  single
           benign hepatoma and hepatocellular carcinomas was statistically
           significant.   In  the  females, the incidence of  single  hepatomas was
           statistically  significant.

        0   Goldenthal  (1979)  administered RH 6201  (a formulation  containing 39.4
           to 40.5%  sodium acifluorfen) to Charles River CD-1 mice (80/sex/dose)
           for  two years  in  the  diet at concentrations that provided dose
           levels of 0, 1.25, 7.5 or 45.0 ppm of  the active ingredient.  After
           16 weeks  of administration,  the 1.25 ppm dose was increased to  270 ppm.
           Assuming  that  1 ppm in the diet of mice is  equivalent  to 0.15 mg/kg/day,
           these doses correspond to approximately 0,  0.19 (increased  to 40.5),
           1.13 or 6.8 mg/kg/day (Lehman, 1959).  Two  control groups were  used
           in this study. One group received acetone  in the diet (control 1)
           and  the other  received water in the diet  (control 2).   In males
           receiving the  highest dose there was a nonstatistically significant
           increase  in the incidence of nodular hepatocellular proliferation and
           hepatocellular carcinoma, which indicated to the authors that these
           changes were dose-related.

        0   Coleman et  al. (1978) administered RH  6201  (a formulation containing
           39.8% sodium acifluorfen) to Charles River  Outbred albino CD COBS
           rats (approximately 75/sex/dose) for 2 years at changing dietary
           concentrations.   Mean sodium acifluorfen  intake values over the
           course of the  study were 0,  1.25, 7.54 and  17.56 mg/kg/day  for  males
           and  0, 1.64, 9.84 and 25.03  mg/kg/day  for females.

        0   Acifluorfen is structurally  similar to nitrofen [2,4-dichloro-1-(4-
           nitrophenoxy)  benzene; CAS No. 1836-75-7].   Nitrofen has been shown
           to be carcinogenic in Osborne-Mendel rats and B6C3F1 mice  (NCI, 1978,
           1979; both  as  cited in NAS,  1985).
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  th following formula:

                 HA = (NOAEL or  LOAEL)  x  (BW)  , 	   /L  (	  /L)
                        (UF) x (    L/day)
   where:
           NOAEL or LOAEL = No- or  Lowest-Observed-Adverse-Effeet-Level
                            in mg/kg  bw/day.

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

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Acifluorfen                                                August, 1987

                                     -14-
                    UF - uncertainty factor (10,  100 or 1,000), in
                         accordance with NAS/OCW  guidelines.

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

One-day Health Advisory

     No data were found in the available literature that were suitable for
determination of a One-day HA value for acifluorfen.  It is therefore recom-
mended that the Ten-day HA value for a 10-kg child (2 mg/L, calculated below)
be used at this time as a conservative estimate of the One-day HA value.

Ten-day Health Advisory

     The study by Florek et al. (1981) has been selected to serve as the
basis for determination of the Ten-day HA for a 10-kg child.  In this study,
Tackle 2S (a formulation containing 22.4% sodium  acifluorfen) was administered
by gavage at doses of 0, 20, 90 or 180 mg/kg/day  to Sprague-Dawley rats
(25/dose) on days 6 to 19 of gestation.  The authors indicated that the
administered doses were in terms of active ingredient.  At 180 mg/kg/day,
dams reportedly gained significantly less weight than controls.  At 90 and
180 mg/kg/day, lower average fetal body weight and significantly^delayed
ossification of metacarpals and forepaw and hindpaw phalanges were noted.  At
180 mg/kg/day, there was delayed ossification of  caudal vertebrae, sternebrae
and metatarsals.  Additionally, at the highest dose level there was a signifi-
cantly increased incidence of slight dilation of  the lateral ventricle of the
brain.  The authors stated that the fetal effects were indicative of delayed
fetal development.  No effects on implantations,  litter size, fetal viability,
resorption or fetal sex ratio were reported.  Based on the results of this
study, a NOAEL of 20 mg/kg/day for fetotoxicity was identified.

     The Ten-day HA for the 10-kg child is calculated as follows:

          Ten-day HA =  (20 mg/kg/day)  (10 kg) = 2 mg/L (2,QOO ug/L)
                          (100)  (1 L/day)
where:
         20 mg/kg/day = NOAEL, based on absence of fetal toxicity in rats
                       exposed to aciflucrfen via gavage during days 6 to 19
                       of gestation.

               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.

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Acifluorfen                                                August, 1987

                                     -15-


Longer-term Health Advisory

     The study by Harriett (1982) had been selected to serve as the basis
for determination of the Longer-term HA.  In this study, the NOAEL was
5.6 mg/kg/day based on an increase in the size of the liver in male rats.
However, a lower NOAEL, 1.25 mg/kg/day, was recently identified in a two-
generation rat reproduction study by Lochry et al. (1986).  Since the NOAEL
in the Lochry et al. (1986) study is numerically identical to the value on
which the Lifetime HA is based and since a two-generation reproduction study
is suitable for calculating a Longer-term HA, it was determined that it is
appropriate to base the Longer-term HA on the Lifetime HA.

     The Longer-term HA for a 10-kg child is calculated as follows:

       Longer-term HA = (1.25 mg/kg/day) (10 kg) = 0.13   /L (130 ug/L)
                            (100) (1 L/day)

where:

        1.25 mg/kg/day - NOAEL (see Lifetime Health Advisory below).

                 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 the 70-kg adult is calculated as follows:

       Longer-term HA = (1.25 mg/kg/day) (70 kg) = Q.44 mg/L (440 ug/L)
                            (100) (2 L/day)

where:

        1.25 mg/kg/day = NOAEL (see Lifetime Health Advisory below).

                 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

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Acifluorfen                                                August,  1987

                                     -16-
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.

     A 2-year Charles River CD-1 mouse dietary study by Goldenthal (1979) was
originally selected to serve as the basis for determination of the Lifetime
HA for acifluorfen.  In this study,  a NOAEL of 1.13 mg/kg/day was identified.
More recently, however, a two-generation rat reproduction study by Lochry et
al. (1986) was identified that strongly supports the results of the Goldenthal
(1979) study and identifies a NOAEL of 1.25 mg/kg/day.

     Using the NOAEL of 1.25 mg/kg/day, the Lifetime HA for acifluorfen is
calculated as follows:

Step 1:  Determination of the Reference Dose (RfD)

                  RfD = (1.25 mg/kg/day) = 0.0125 mg/kg/day
                             (100)

where:

        1.25 mg/kg/day = NOAEL, based on the absence of mortality and kidney
                         lesions in rats.

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

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

          DWEL = (0.0125 mg/kg/day) (70 kg) = 0.437 mg/L (437 ug/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.

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Acifluorfen                                                August, 1987

                                     -17-


Step 3:  Determination of the Lifetime Health Advisory

            Lifetime HA = (0.437 mg/L) (20%) . 0<009 mg/L (9 ug/L)
                                 (10)

where:

        0.437 mg/L = DWEL.

               20% = assumed relative source contribution from water.

                10 = additional uncertainty factor per ODW policy to account
                     for possible carcinogenicity.

Evaluation of Carcinogenic Potential

     8  Four studies that evaluated the carcinogenic potential of sodium
        acifluorfen were identified.  The results of one of these studies
        (Barnett et al., 1982a) indicated that sodium acifluorfen was car-
        cinogenic in B6C3F-| mice.  The results of the other three studies
        (Goldenthal, 1979; Coleman et al., 1978;  Barnett et al., 1982b)
        provided no evidence of carcinogenicity in two strains of rats and
        one strain of mice.  However, due to deficiencies in the three negative
        studies, the results of these studies are not sufficient to contradict
        the results of the positive study.  Each of these studies is discussed
        briefly below.

        -  In the positive study {Barnett et al., 1982a), B6C3Fi mice received
           sodium acifluorfen in the diet for 18 months.  At the end of the
           study, the high-dose (157.24 mg/kg/day) male mice displayed a
           statistically significant increase in the incidence of single
           benign hepatomas and hepatocellular carcinomas.  A statistically
           significant increase in the incidence of single hepatomas was
           observed in high-dose (170.53 mg/kg/day) females.

        -  In one of the studies with negative results (Goldenthal, 1979)
           Charles River CD-1 mice received sodium acifluorfen in the diet for
           two years at doses of 0, 0.19 (increased to 40.5 after 16 weeks),
           1.13 or 6.8 mg/kg/day.  Although no evidence of carcinogenicity was
           observed in this study, the dose levels tested were considerably
           lower than the level that produced positive results in the 18-month
           mouse feeding study (157.24 mg/kg/day) (Barnett et al., 1982a).

        -  In the second study with negative results (Coleman et al., 1978),
           Charles River outbred albino CD COBS rats received sodium acifluorfen
           for two years at dietary levels up to 25.03 mg/kg/day (females) or
           17.56 mg/kg/day (males).  Although it is difficult to make cross-
           species comparisons, these levels are considerably lower than the
           level that produced positive results in the 18-month mouse feeding
           study (157.24 mg/kg/day) (Barnett et al., 1982a).  In addition,
           no adverse effects were observed at any dose level used in this
           study, indicating that the maximum tolerated dose was not used.

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     Acifluorfen                                                August,  1987

                                          -18-
             -  In the third  study  with  negative results  (Barnett  et al.,  1982b),
                Fischer 344 rats  received  sodium acifluorfen  for 1  year  at dietary
                concentrations  of 0,  0.3,  1.9,  6.4,  32.0  or 64.0 mg/kg/day.
                Although the  results  of  this  study were negative,  a study  duration
                of 1  year is  not  sufficient for assessing carcinogenic potential.

             Acifluorfen is structurally similar to  nitrofen  [2,4-dichloro-1-(4-
             nitrophenoxy)  benzene; CAS  No. 1836-75-7].   Nitrofen  has been shown
             to be carcinogenic in  Osborne-Mendel rats and B6C3Fi  mice  [NCI,  1978,
             1979; both as  cited  in NAS  (1985)].  Although data on nitrofen cannot
             be used  to conclude  that sodium  acifluorfen  is carcinogenic,  these data
             do,  to some extent,  support the  positive results of Barnett et al.
             (1982a).

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

             Applying the criteria  described  in EPA's guidelines for assessment
             of carcinogenic  risk (U.S.  EPA,  1986a), acifluorfen is classified  in
             Group Cs  possible human carcinogen. Category C is for substances
             with limited evidence  of carcinogenicity in  animals in the  absence
             of human data.
 VI. OTHER CRITERIA,  GUIDANCE AND STANDARDS

          0  The U.S.  EPA has established  residue  tolerances  for  sodium  acifluorfen
             in or on  raw agricultural  commodities that  range  from  0.01  to 0.1  ppm
             (CFR, 1985).

          0  The EPA  RfD Workgroup has  concluded that an RfD  of 0.013 mg/kg/day
             is appropriate for  acifluorfen.


VII. ANALYTICAL METHODS

          0  Analysis of acifluorfen is by a  gas chromatographic  (GC) method
             applicable to the determination  of certain  chlorinated acid pesticides
             in water samples (U.S.  EPA,  1986b).   In  this  method, approximately
             1  liter  of sample is acidified.   The  compounds are extracted with
             ethyl ether using a separatory funnel.   The derivatives are hydrolyzed
             with potassium hydroxide,  and extraneous organic  material is removed
             by a solvent wash.   After  acidification, the  acids are extracted and
             converted to their  methyl  esters using diazomethane  as the  derivatizing
             agent.  Excess reagent  is  removed, and the  esters are determined by
             electron capture GC. The  method detection  limit has not been deter-
             mined for this compound, but  it  is estimated  that the detection
             limits for analytes included  in  this  method are  in the range of 0.5
             to 2 ug/L.

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      Acifluorfen     *                                          August,  1987?

                                           -19-
VIII. TREATMENT TECHNOLOGIES

           0  Reverse osmosis (RO)  is  a  promising  treatment method for pesticide-
              contaminated water.   As  a  general  rule,  organic compounds with
              molecular weights  greater  than  100 are candidates  for removal  by RO.
              Larson et al.  (1980)  report  99% removal  efficiency of chlorinated
              pesticides by  a thin-film  composite  polyamide membrane operating at a
              maximum pressure of  1,000  psi and  at a maximum temperature of  113F.
              More operational data are  required,  however,  to specifically determine
              the  effectiveness  and feasibility  of applying RO for the removal of
              acifluorfen from water.  Also,  membrane  adsorption must be considered
              when evaluating RO performance  in  the treatment of acifluorfen-
              contaminated drinking water  supplies.

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    Aeifldbrfen                                                August, 1987

                                         -20-


IX. REFERENCES

    Barnett,  J.*  1982.   Evaluation of ninety-day subchronic toxicity of Tackle*
         in Fischer 344  rats.   GSRI Project No. 413-971-40.  Rhone-Poulenc
         Agrochemie No.  372-80.   Unpublished study.  MRID 0122730.

    Barnett,  J., L. Jenkins and R.  Parent.*  1982a.  Evaluation of the potential
         oncogenic and toxicological effects of long-term dietary administration
         of Tackle* to B6C3FI  mice.  GSRI Project No. 413-984-41.  Final Report.
         Unpublished Study. MRID 00122732.

    Barnett,  J., L. Jenkins and R.  Parent.*  1982b.  Evaluation of the potential
         oncogenic and toxicological effects of long-term dietary administration
         of Tackle* to Fischer 344 rats:   GSRI Project No. 413-985-41.  Interim
         report.  Unpublished  study.  MRID 00122735.

    Bowman, J., C. Mackerer, S.  Bowman, D.C. Jessup,  R.C. Geil and B.W. Benson.*
         1981.  Drosophila mutagenicity assays of Mobil Chemical Company compound
         MC 10109 (MRI 533).   Study No. 009-275-533-9.  Unpublished study.
         MRID 00122737.

    Brusick,  D.*  1976.   Mutagenicity evaluation of RH-6201.  LBI Project No. 2547.
         Unpublished study. MRID 00083057.

    CFR.  1985.  Code of Federal Regulations.  July 1, 1985.  40 CFR  180.383.
         p. 336.

    CHEMLAB.   1985.  The Chemical Information System, CIS, Inc.  Baltimore, MD.

    Coleman,  M.E., T.E.  Murchison,  P.S. Sahota et al.*  1978.  Three and twenty-four
         month oral safety evaluation study of RH-6201 in rats.  DRC 5800.  Final
         Report.  Unpublished  study.  MRID 00087478.

    Florek, M., M. Christian,  G. Christian and E.M. Johnson.*  1981.  Terato-
         genicity study  of TACU 06238001 in pregnant rats.  Argus Project 113-004.
         Unpublished study. MRID 00122743.

    Goldenthal, E.I., D.C. Jessup,  R.G. Geil and B.W. Benson.*  1978a.  Two week
         range finding study in mice:  285-016.  Unpublished study.  MRID 00080568.

    Goldenthal, E.I., D.C. Jessup and D. Rodwell.*  1978b.  Three generation
         rtproduction study in rats:  RH-6201, 285-014a.  Unpublished study.
         MRID 00107486.

    Goldenthal, E.I., D.C. Jessup,  R.G. Geil and B.W. Benson.* 1979.  Lifetime
         dietary feeding study in mice:  285-01 3a.  Unpublished study.
         MRID 00082897.

    Harris, J.C., G. Cruzan and W.R. Brown.*  1978.  Three month subchronic rat
         study.  RH-6201.  TRD-76P-30.  Unpublished study.  MRID 00080569.

    Jagannath, D.*  1981.  Mutagenicity of 06238001 lot LCM 266830-7 in the mitotic
         recombination assay with the yeast strain D5.  Genetics Assay No. 5374.
         Final Report.  Unpublished study.  MRID 00122740.

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Acifluorfen                                                August, 1987

                                     -21-


Larson, R.E., P.S. Cartwright, P.K. Eriksson and R.J. Petersen.  1982.
     Applications of the FT-30 reverse osmosis membrane in metal finishing
     operations.  Paper presented at Tokohama, Japan.

Lehman, A.J.  1959.  Appraisal of the safety of chemicals in foods, drugs and
     cosmetics.  Association of Food and Drug Officials of the United States.

Lightkep, G., G. Christian et al.*  1980.  Teratogenic potential of TACU
     06238001 in New Zealand white rabbits (Segment II Evaluation).  Argus
     Project 113-003.  Unpublished study.  MRID 00122744.

Lochry, E.A., Hoberman, A.M. and Christian, M.S.*  1986.  Two-generation Rat
     Reproduction Study, Argus Research Laboratories, Inc.  Study No.218-002.

Madison, P., R. Becci and R. Parent.*  1981.  Guinea pig sensitization study.
     Buhler test for Mobil Corporation.  Tackle 2S.  FDRL Study No. 6738.
     Unpublished study.  MRID 00122729.

Meister, R., ed.  1983.  Farm chemicals handbook.  Willoughby, OH:  Meister
     Publishing Company.

Mobil Environmental and Health Science Laboratory.*  1981.  A study of the oral
     toxicity of Tackle 2S in the dog.  Mobil Study No. 1091-80.  Six-month
     status report.  Unpublished study.  MRID 00122733.

Myhr, B., and M. McKeon.*  1981.  Evaluation of 06238001 in the primary rat
     hepatocyte unscheduled DNA synthesis assay.  MEHSL Study 1022-80.  Final
     Report.  Unpublished study.  MRID 00122742.

NAS.  1985.  National Academy of Sciences.  Drinking Water and Health.  Vol. 6.
     Chapter 9:  Toxicity of Selected Contaminants.  Washington, DC.  National
     Academy Press.

NCI.  1978.  National Cancer Institute.  Biloassay of nitrofen for possible
     carcinogenicity.  Technical Report Series No. 26.  DHEW Publication No.
     (NIH) 78-826.  U.S. Department of Health, Education and Welfare.
     Washington, DC.  101 pp.  Cited in:  NAS.  1985.  National Academy of
     Sciences.  Drinking Water and Health.  Vol. 6.  Chapter 9:  Toxicity of
     Selected Contaminants.  Washington, DC.  National Academy Press.

NCI.  1979.  National Cancer Institute.  Bioassay of nitrofen for possible
     carcinogenicity.  Technical Report Series No. 184.  DHEW Publication No.
     (NIH) 79-1740.  U.S. Department of Health, Education and Welfare.
     Washington, DC.  57 pp.  Cited in:  NAS.  1985.  National Academy of
     Sciences.  Drinking Water and Health.  Vol. 6.  Chapter 9:  Toxicity of
     Selected Contaminants.  Washington, DC.  National Academy Press.

Piccirillo, V.J., and T.L. Robbins.*  1976.  Four week oral range finding
     study in rats.  RII-6201.  Unpublished study.  MRID 00071892.

Putnam, D., L. Schechtman and W. Moore.*  1981.  Activity of T1689 in the
     dominant lethal assay in rodents.  MA Project No. T1689.116.  Final Report,
     Unpublished study.  MRID 00122738.

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Acifluorfen                                                August, 1987

                                     -22-
Schreiner, C.A. ,  M.A.  McKenzie and M.A. Mehlmaru*  1980.  An Ames Salmonella/
     mammalian microsome mutagenesis assay for determination of potential
     mutagenicity of Tackle 2S MCI0978.  Study No. 511-80.  Unpublished
     study.  MRIO 00061622.

Schreiner, C., K. Skinner and M. Mehlman.*  1981.  Me ta phase analysis of rat
     bone marrow cells treated in vivo with Tackle 2S.  Study No. 1041-80.
     Unpublished  study.  MRID 00122741.

Spicer, E. , L. Griggs, F. Marroquin, N.D. Jefferson and M. Blair.* 1983.  Two
     year dietary toxicity study in dogs.  (Tackle*) 450-0395.  Unpublished
     study.  MRID 00131162.

U.S. EPA.  1986a.  U.S. Environmental Protection Agency.  Guidelines for
     carcinogenic risk assessment.  Fed. Reg.  51 (1 85) : 33992-34003.
     September 24.

U.S. EPA.  1986b.  U.S. Environmental Protection Agency.  U.S. EPA Method #3 -
     Determination of Chlorinated Acids in Ground Water by GC/ECD, January
     1986 draft.   Available from U.S.  EPA's Environmental Monitoring and
     Support Laboratory.  Cincinnati, OH.

Weatherholtz, W., S. Moore and G. Wolfe.*  1979a.  Eye irritation study in
     monkeys.  Blazer 2S.  Project No. 417-396.  Final Report.  Unpublished
     study.  MRID 00140887.

Weatherholtz, W., K. Peterson, M. Koka and R.W. Kapp.* 1 979b.  Four-week
     repeated dermal study in rabbits.  RH-6201 formulations.  Project No.
     417-386.  Final Report.  Unpublished study.  MRID 00140889.

Weatherholtz, W., and V. Piccirillo.*  1979.  Teratology study in rabbits
     (RH-6201 LC).  Final Report.  Project No. 417-374.  Unpublished study.
     MRID 00107485.
Whittaker Corporation.*  No date, a.  Acute oral LDso rats.  Study No. 410-0249.
     Unpublished study.  MRID 00061625.

Whittaker Corporation.*  No date, b.  Primary dermal irritation  rabbit:
     Study No. 410-0286.  Unpublished study.  MRID 00061629.

Whittaker Corporation.*  No date, c.  Primary eye irritation  rabbits.
     Study No. 410-C252.  Unpublished study.  MRID 00061628.

Windholz, M., S. Budavari, R.F. Blumetti and E.S. Otterbein, eds.  1983.
     The Merck Index, 10th ed.  Rahway, NJ;  Merck and Co., Inc.
 *Confidential Business Information submitted to the Office of Pesticide
  Programs.

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