820K88129
August, 1987
                                      PARAQUAT

                                  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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    Paraquat
                    August, 1987
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II. GENERAL INFORMATION AND PROPERTIES

         Paraquat, with a chemical name 1,1 '-dimethyl-4,4'-dipyridinium
    ion,  is present mostly as the dichloride salt (CAS No. 1910-42-5) or
    as  the  dimethyl sulfate salt (CAS No. 2074-50-2, molecular weight 408.48)
    (Meister,  1987).  Contents discussed below pertain to paraquat dichloride.

    CAS No.  1910-42-5

    Structural Formula
                            CH,-N
      N-CH,
2CI
                      1,1'-Dimethyl-4,4'-bipyridinium-dichloride
    Synonyms
            o-Paraquat  dichloride, Gramixel, Gramonol, Gramoxone, Gramuron,
            Pathclear,  Totacol, Weedol  (Meister, 1985).
    Uses

         0  Contact herbicide and desiccant used for desiccation of seed crops,
           for noncrop and industrial weed control in bearing and nonbearing
           fruit orchards, shade trees, and ornamentals, for defoliation and
           desiccation of cotton, for harvest aid in soybeans,  sugarcane,  guar,
           and sunflowers, for pasture renovation, for use in "no-till" or before
           planting or crop emergence, dormant alfalfa and clover, directed
           spray, and for killing potato vines.  Paraquat is also effective for
           eradication of weeds on rubber plantations and coffee plantations and
           against paddy bund (Meister, 1985).

    Properties  (ACGIH, 1980;  Meister, 1985;  CHEMLAB, 1985;  TDB,  1985)
           Chemical Formula
           Molecular Weight
           Physical State

           Boiling Point
           Melting Point
           Vapor Pressure
           Specific Gravity
           Water Solubility
           Log Octanol/Water Partition
             Coefficient
           Taste Threshold
           Odor Threshold
           Conversion Factor
C12H14N2.2C1
257.18
Colorless to yellow crystalline
  solid
175 to 180°C

No measurable vapor pressure
1.24  at 20°C/20°C
Very soluble
2.44 (calculated)

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Occurrence

     0  Paraquat was found in only one sample,  at a concentration level of
        20 ug/L,  from 721  ground water samples  analyzed (STORET, 1987).
        Samples were collected at 715 ground water locations,  with paraquat
        found in one location in California. No surface water samples were
        collected for analysis.

Environmental Fate

     0  14c-Paraquat dichloride (>96.5% pure) at 91  mg/L was stable to
        hydrolysis at 25 and 40°C at pH 5,  7 and 9 for up to 30 days (Upton
        et al., 1985).

     0  Uniformly ring-labeled 14c-paraquat (99.7% pure) at approximately
        7.0 ppm in sand did not photodegrade when irradiated with natural
        sunlight for 24 months (Pack, 1982). No degradation products were
        detected at any sampling interval.   After 24 months of irradiation,
        >84% of the applied radioactivity was extractable and <4% was
        unextractable.

     0  Paraquat was essentially stable to photolysis in soil (Day and
        Hemingway, 1981).   Four degradation products, 1-methyl-4,4'-bipyridylium
        ion, 4-(1,2-dihydro-1-methyl-2-oxo-4-pyridyl)-1 -methyl pyridylium
        ion, 4-carboxy-1-methyl pyridylium ion, and an unknown, individually
        constituted <6.0%  of the total radioactivity in either irradiated
        (undisturbed) or dark control soils.

     0  Paraquat (test substance uncharacterized) at 0.05 to 1.0 ppm in water
        plus soil declined with a half-life of  >2 weeks (Coats et al., 1964).
        In water only, paraquat declined with a half-life of approximately
        23 weeks.

     o  14c-Paraquat (test substance uncharacterized) was immobile in silt
        loam and silty clay loam (Rf 0.00), and slightly mobile in sandy loam
        (Rf 0.13) soils, based on soil thin-layer chromatography (TLC) tests
        (Helling and Turner, 1968).

     0  Methyl-labeled 14c-paraquat (test substance uncharacterized) at 1.0
        ppm was stable to  volatilization at room temperature over a 64-day
        period (Coats et al., 1964).

        In a pond treated  with paraquat (test substance uncharacterized) at
        1.14 ppm (Frank and Comes, 1967), paraquat residues (uncharacterized)
        declined from 0.55 ppm 1 day after treatment to nondetectable (<0.001
        ppm) 18 days after treatment.  The dissipation of paraquat residues
        (uncharacterized)  in water was accompanied by a concomitant increase
        of paraquat residues (uncharacterized)  in the soil.  Paraquat (test
        substance uncharacterized) at 0.04 ppm  dissipated in pond water with
        a half-life of approximately 2 days (Coats et al., 1964).  For more
        details,  see Calderbank's chapter on paraquat in Herbicides
        (Calderbank, 1976).

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     Paraquat                                                      August, 1987

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III. PHARMACOKINETICS

     Absorption

          0  In Wistar rats given  single oral doses of 14c-paraquat dichloride or
             dimethyl sulfate by gavage  (0.5 to 50 mg/kg,  purity not stated),
             69 to 96% was  excreted  unchanged, mostly in feces,  and no radioactivity
             appeared in bile (Daniel and Gage, 1966).  Some systemic absorption of
             the degradation products that were produced in the  gut was noted.
             Approximately  30% of  the administered dose appeared in feces in a
             degraded form.

          0  14C-Methyl-labeled paraquat (99.7% purity) was administered orally
             to a cow in a  single  dose of approximately 8 mg cation/kg (Leahey
             et al., 1972).  A total of  95.6% of the dose was excreted in feces in
             the first 3 days.  A  small  amount, 0.7% of the dose, was excreted in
             the urine, 0.56% during the first 2 days.  Only 0.0032% of the dose
             appeared in the milk.

          0  A goat was administered 1 4C-ring-labeled paraquat dichloride (>99%
             purity) orally at 1.7 mg/kg for 7 consecutive days  (Leahey et al.,
             1976a).  At sacrifice,  2.4% and 50.3% of the radioactive dose had been
             excreted in the urine and feces, respectively, and  33.2% was recovered
             in the contents of the stomach and intestines.  The radioactivity was
             associated with unchanged paraquat.

          0  In studies with pigs, 14C-methyl-labeled  (Leahey et al., 1976b) and
             1^-ring-labeled (Spinks et al., 1976) paraquat (>99% purity) at
             dose levels of 1.1 and 100 mg ion/kg/day, respectively, was given
             for,up to 7 days.  At sacrifice, 69 to 72.5% and 2.8 to 3.4% of the
             total radioactive dose had  been excreted in the feces and urine,
             respectively.

     Distribution

          0  Pigs were given oral  doses of 14C-methyl-labeled (Leahey et al.,
             1976b) and 14c-ring-labeled (Spinks et al., 1976) paraquat dichloride
              (>99% purity)  for up  to 7 consecutive days at dose  levels of 1.1 and
             1 00 mg ion/kg/day, respectively.  At sacrifice, radioactivity associated
             mostly with unchanged paraquat was identified in the lungs, heart,
             liver and kidneys, with trace amounts in the brain, muscle and fat.

          0  The distribution of radioactivity was studied in a goat fed 14C-ring-
             labeled paraquat dichloride (1.7 mg/kg/day, 99.7% purity) in the
             diet for 7 consecutive days (Hendley et ai., 1976).  Most of the
             radioactivity was found in the lungs, kidneys and liver.  The major-
             residue was unchanged paraquat.

     Metabolism

          *  Paraquat dichloride or paraquat dimethyl sulfate (radiochemical
             purity:  99.3 to 99.8%), labeled with 14C in either methyl groups or
             in the ring, was poorly absorbed from the gastrointestinal tract of a

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    Paraquat                                                      August,  1987

                                         -5-

            cow (Leahey  et  al.,  1972), goats  (Hendley  et al.,  1976),  pigs  (Leahey
            et al.,  1976b;  Spinks  et  al.,  1976)  and  rats (Daniel and  Gage,  1966),
            and was  excreted  in  the feces  mostly as  unchanged  paraquat.   However,
            after  an oral dose,  there was  microbial  degradation of paraquat in
            the gut.   In one  study with  rats  (Daniel and Gage,  1966), 30%  of a
            dose of  paraquat  appeared in the  feces in  a degraded form.   A  portion
            of these microbial degradation products  can be absorbed and  excreted
            in the urine, whereas  the remainder  is excreted in the feces.
    Excretion
            In  studies  with  a  cow  (Leahey  et  al.,  1972)  and  rats (Daniel and
            Gage,  1966),  about 96% and  69  to  96%,  respectively,  of the administered
            radioactivity (single oral  doses,  14C-labeled) from  paraquat was
            excreted  in the  feces within 2 to 3  days  as  unchanged paraquat.

            Goats  (Hendley et  al., 1976) and  pigs  (Leahey et al., 1976b;  Spinks
            et  al.,  1976) that received single oral doses of 14c-labeled paraquat
            (1.7 and  1.1  or  100 mg ion/kg/day, respectively) for up to 7 days
            excreted  50 and  69%, respectively, of  the total  administered dose  in
            feces  unchanged.
IV. HEALTH EFFECTS
 s  ————————

    Humans
       Short-term Exposure

         0  The Pesticide Incident  Monitoring  System (U.S.  EPA,  1979)  indicated
            numerous cases  of  poisoning  from deliberate or  accidental  ingestion
            of paraquat or  by  dermal  and inhalation exposure from spraying,
            mixing and loading operations.  Generally,  the  concentrations of the
            ingested doses  or  of  amounts inhaled or spilled on the skin were not
            specified.  Symptoms  reported following these exposures included
            burning of the  mouth, throat, eyes and skin. Other effects noted
            were nausea,  pharyngitis,  episcleritis and  vomiting.   No fatalities
            were reported following dermal  or  inhalation exposure.  Deliberate
            and accidental  ingestion  of  unspecified concentrations of  paraquat
            resulted in respiratory distress and subsequent death.  See also
            Cooke et al.  (1973).

       Long-term Exposure

         0  No information  was found  in  the available literature  on long-term
            human exposure  to  paraquat.
    Animals
       Short-term Exposure
            Acute oral  LD50  values  for paraquat  (99.9%  purity)  were reported  as
            112,  30,  35 and  262  mg  paraquat  ion/kg  in the rat,  guinea  pig,  cat
            and hen (Clark,  1965).   Signs  of toxicity included  respiratory  distress

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        and cyanosis among rats and guinea pigs, blood-stained droppings
        among the hens,  and muscular weakness, incoordination and frequent
        vomiting.of frothy secretion among the cats.

     0  Acute (4-hour)  inhalation LC50 values for paraquat ranged from 0.6 to
        1.4 mg ion/m3 paraquat (McLean Head et al.,  1985).

   Dermal/Ocular Effects

     0  Acute dermal LD50 values for rabbits (Standard Oil, 1977) were
        59.9 mg/kg and 80 to 90 mg paraquat ion/kg for rats (FDA, 1970).

     0  Paraquat concentrate 3 (34.4% paraquat ion)  was applied  (0.5 mL or
        172 mg paraquat ion) to intact and abraded skin of six male New
        Zealand White rabbits for 24 hours (Bullock,  1977).  Very slight,
        moderate or severe erythema and slight edema were noted during the
        7-day observation period for both intact and abraded skin.

     0  Paraquat concentrate 3 (0.1 mL, 34.4% paraquat ion) was instilled
        into the conjunctival sac of one eye in each of six male New Zealand
        White rabbits (Bullock and MacGregor, 1977).  Untreated eyes served
        as controls.  Unwashed eyes were examined for 14 days.  Complete
        opacity of the cornea was reported in three of six rabbits.  Roughened
        corneas, severe pannus, necrosis of the conjunctivae, purulent discharge,
        severe chemosis of the conjunctivae and mild iritis were also reported.

   Long-term Exposure

     0  Beagle dogs  (three/sex/dose) were fed technical o-paraquat  (32.2%
        cation) in the diet for 90 days at dose levels of 0, 7, 20, 60 or
        120 ppm (Sheppard, 1981).  Assuming that 1 ppm is equivalent to
        0.025 mg/kg/day, these levels correspond to doses of 0, 0.18, 0.5,
        1.5 or 3 mg paraquat ion/kg/day (Lehman, 1959), respectively.
        Increased lung weight, alveolitis and alveolar collapse were observed
        at 60 ppm.  The No-Observed-Adverse-Effect-Level  (NOAEL) identified
        for this study was 20 ppm  (0.5 mg paraquat ion/kg/day).

     0  Alderley Park beagle dogs  (six/sex/dose) were fed diets containing
        technical paraquat (32.3%) cation daily for 52 weeks at dietary  levels
        of 0, 15,  30 or 50 ppm (Kalinowski et al., 1983).  Based on actual
        group mean body weights and food consumption, these values correspond
        to doses of  0,  0.45, 0.93  and  1.51 mg/kg/day for male dogs and 0,
        0.48, 1.00 or 1.58 for females.  Clinical and behavioral abnormali-
        ties, food consumption, body weight, hematology, clinical chemistry,
        urinalysis, organ weights, gross pathology and histopathology were
        comparable for  treated animals and controls at 15 ppm  (the lowest
        dose tested).  An increased severity and extent of chronic pneumonitis
        occurred at  30 ppm in both sexes, but especially in the males.   Based
        on the results of this study, the NOAEL identified was 15 ppm  (0.45 mg
        paraquat cation/kg/day).

     0  Technical paraquat dichloride  (32.7% paraquat ion) was fed to Alderley
        Park mice  (60/sex/dose) for 97-99 weeks at levels of 0,  12.5, 37.5

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        and 100/125 ppm (100 ppm for the initial 35 weeks and then 125 ppm
        until termination of the study)  (Litchfield et al., 1981).  Based on
        the assumption that 1  ppm in the diet of mice is equivalent to 0.15
        ing/kg/day (Lehman,  1959), these  levels correspond to doses of 0,
        1.87, 5.6 and 15/18.75 mg/kg.  The animals were observed for toxic
        signs, and body weights, food  consumption and utilization, urinalysis,
        gross pathology and histopathology were evaluated.  Renal tubular
        degeneration in the males and  weight loss and decreased food intake
        in the females, were the only  effects observed, and occurred in the
        37.5-ppm dose group.  Based on these findings, a NOAEL of 12.5 ppm
        (1.87 mg/kg/day) was identified.

     0  Fischer 344 rats (70/sex/dose) were fed diets containing 0,  25, 75
        or 150 ppm of technical paraquat (32.69% cation) for 113 to 117 weeks
        (males) and 122 to  124 weeks (females) (Woolsgrove et al., 1983).  Based
        on the assumption that 1 ppm in  the diet is equivalent to 0.05 mg/kg/day
        (Lehman, 1959), these levels correspond to doses of 0, 1.25, 3.75 or
        7.5 mg/kg/day.  Clinical signs,  food and water consumption,  clinical
        chemistry, urinalysis, hematology, ophthalmoscopic effects,  gross
        pathology and histopathology were evaluated.  Increased incidences of
        slight hydrocephalus were noted  in the female rats dying between week
        53 and termination  of the study; these incidences were 5/60, 8/30,
        9/27 and 9/30 rats  in the control, low, mid and high dose, respectively.
        Also, increased incidences of  spinal cord cysts and cystic spaces
        were noted in the male rats dying between week 53 and termination of
        the study.  These incidences were 0/53, 6/36 and 4/35 rats at the
        control, low and mid-level doses, respectively; no incidence was
        reported at the high dose.  Eye  opacities, cataracts and nonneoplastic
        lung lesions (alveolar macrophages and epithelialization, and slight
        peribronchiolar lymphoid hyperplasia) were observed at 75 ppm and
        above.  Similar eye lesions occurred at 25 ppm (the lowest dose
        tested).  These effects did not  appear to be biologically significant,
        since they were either minimal or occurred after 104 weeks of treatment
        and appeared, therefore, to be only an acceleration of the normal
        aging process.  Based on these results, an approximate NOAEL of
        25 ppm (1.25 mg/kg/day) was identified.

   Reproductive Effects

     0  Lindsay et al. (1982)  fed Alderley Park rats technical paraquat
        dichloride (32.7% cation w/w)  in unrestricted diet for three genera-
        tions at dose levels of 0, 25, 75 or 150 ppm paraquat ion.
        Based on the assumption that 1 ppm in the diet of
        rats is equivalent  to 0.05 mg/kg/day (Lehman, 1959), these levels
        correspond to doses of 0, 1.25,  3.75 or 7.5 mg/kg/day.  No adverse
        reproductive effects were reported at 150 ppm (the highest dose
        tested) or less. An increased incidence of alveolar histiocytosis in
        the lungs of male and  female parents (Fg, FI and F2) was observed in
        the 75- and 150-ppm dose groups.  Based on these results, a reproductive
        NOAEL of >150 ppm (7.5 mg/kg/day,  the highest dose tested) and a
        systemic NOAEL of 25 ppm (1.25 mg/kg/day, the lowest dose tested)
        were identified.

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Paraquat                                                      August,  1987
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                                     -8-


   Developmental  Effects^

     0  Young adult Alderley  Park  mice (number not stated)  were administered
        paraquat  dichloride (100%  purity)  orally by gavage  at dose levels of
        0,  1, 5 or 10 mg paraquat  ion/kg/day on days 6 through 15 of gestation
        (Hodge et al.,  1978a).   No teratogenic responses  were reported at
        10  mg ion/kg/day (the highest dose tested) or lower.   Partially
        ossified  sternebrae in  26.3% of  the fetuses in the  high-dose group
        (10 mg ion/kg/day)  and  decreased maternal weight  gain in  the 5-mg
        ion/kg/day dose group were observed.   Based on these  results,  the
        developmental NOAEL identified for this study was 5 mg/kg/day, while
        the maternal NOAEL  was  1 mg/kg/day.

     0  Hodge et  al. (1978b)  dosed Alderley Park rats (29 or  30/dose)  by
        gavage with paraquat  dichloride (100% purity) on  days 6 through
        15  of gestation at  dose levels of  0,  1, 5 and 10  mg paraquat ion/kg/day.
        No  teratogenic effects were reported at 10 mg ion/kg/day  (the highest
        dose tested).  Maternal body weight gain was significantly decreased
        (p_
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   Paraquat                                                      August, 1987

                                        -9-
           125 ppm until termination of  the study)  (Litchfield  et al.,  1981).
           Based on the assumption  that  1  ppm in food  in  mice is equivalent to
           0.15 mg/kg/day (Lehman,  1959),  these levels correspond to doses of 0,
           1.87, 5.6 and 15/18.75 mg/kg.   The study appeared  to have been conducted
           properly, except that hematological and  organ  weight determinations
           were not performed.  The absence of these parameters do not compromise
           the results, since the occurrence of certain toxicological end points
           (e.g., leukemia) detected by  these tests are rare  in mice.  The
           results, therefore,  provide evidence that paraquat is not oncogenic
           at the dose levels tested.

        0  Woolsgrove et al. (1983) fed  Fischer 344 rats  (70/sex/dose)  diets
           containing technical paraquat (32.69%) for  113 to  117 weeks (males)
           and 122 to 124 weeks (females)  at dietary levels of  0,  25, 75 and
           1 50 ppm.  Based on the assumption that 1  ppm in the  diet of rats is
           equivalent to 0.05 mg/kg/day  (Lehman, 1959),  these levels correspond
           to doses of 0, 1.25, 3.75 and  7.5 mg paraquat  cation/kg/day.  The
           predominant tumor types  noted  in this study were tumors of the lungs,
           endocrine glands (pituitary,  thyroid and adrenal) and of the skin and
           subcutis.  Both the  lung and  endocrine tumors  occurred at a frequency
           similar to the incidence of these kinds  of  tumors in the historical
           control.  Only the squamous cell neoplasia  of  the skin and subcutis
           were determined to be treatment-related.  The  squamous cell carcinoma
           was a predominant tumor  in the  head region  of  the male and female
           rats.  This uncommon tumor occurred in 51.6% of all  rats with skin and
           subcutis tumors in the head region.  The incidence of these tumors in
           this study was 2, 4, 0 and 8%  in the control,  low-,  mid- and high-dose
           male groups, respectively and  0, 0, 4 and 3% in the  control, low-,
           mid- and high-dose female groups, respectively.  When these incidences
           were compared with incidences  in historical controls (0 to 2.0% in
           males and 1.9 to 4.0% in females) the high-dose male group reflected a
           significant increase (p  = 0.01).  Also when squamous cell carcinoma and
           papilloma (including those of  the head region) were  combined, only
           the tumor incidence  in the high-dose male group exceeded the historical
           and concurrent controls  (U.S.  EPA, 1985  and 1986a).


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 = -ig"«*n  or LOAEL)  x  (BW)  = 	 mg/L  (	 ug/L)
                        (UF)  x  (	 L/day)

   where:

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

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

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

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

One-day Health Advisory

     No suitable information was found in the available literature for the
determination of the One-day HA value for paraquat.  It is therefore recommended
that the Ten-day HA value for the 1 0-kg child of 0.1 mg/L (100 ug/L), calculated
below, be used at this time as a conservative estimate of the One-day HA value.

Ten-day Health Advisory

     The rat developmental study  (Hodge et al., 1978b) has been selected to
serve as the basis for the determination of the Ten-day HA value for paraquat.
In this study, Alderley Park rats were administered paraquat (100% purity)
during gestation days 6 through 15 at dose levels of 0, 1, 5 or 10 mg paraquat
ion/kg/day.  There was a statistically significant  (p^_0.001; p = 0.05)
decrease in maternal and fetal body weight gain at  the 5-mg paraquat ion/kg/day
dose; also at 5 mg/kg/day, there was a slight retardation in ossification.
The fetotoxic and maternal NOAEL identified in this study was 1 mg paraquat
ion/kg/day.  An adequate study of comparable duration reported a NOAEL that
was higher than that in the study selected for derivation of the Ten-day HA.
A NOAEL of 5 mg/kg/day was identified for developmental effects, while the
maternal NOAEL was similar (1 mg/kg/day)  (Hodge et  al., 1978a).

     Using a NOAEL of 1 mg/kg/day, the Ten-day HA for a 1 0-kg child is
calculated as follows:
where:
          Ten-day HA =  (1 m?Ag bw/day)  (10 kg)  _  0.1 mg/L  (100 ug/L)
                           (100)  (1 L/day)
         1 mg/kg/day = NOAEL, based on the absence of  fetotoxic and maternal
                      effects in rats exposed to paraquat by gavage on days
                      6 through 15 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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Paraquat                                                      August, 1987

                                     -1 1-


Longer-term Health Advisory

     No studies were found in the available literature that were suitable for
deriving the Longer-term HA value for paraquat.  The 90-day oral study of dogs
(Sheppard, 1981) reported a NOAEL (0.5 mg ion/kg/day) which is similar to the
NOAEL (0.45 mg ion/kg/day) of the 52-week oral dog study (Kalinowski et al.,
1983) used to derive the Lifetime HA.  It is, therefore, recommended that the
Drinking Water Equivalent Level (DWEL) of 0.16 mg/L  (160 ug/L), calculated below,
be used for the Longer-term HA value for an adult, and that the DWEL adjusted
for a 10-kg child, 0.045 mg/L (45 ug/L), be used for the Longer-term HA value
for a child.

Ldfetime 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, 1986b), then caution should be exercised in
assessing the risks associated with lifetime exposure to this chemical.

     The study by Kalinowski et al.   (1983) has been selected to serve as the
basis for the Lifetime HA value for  paraquat.  In this 52-week feeding study
in beagle dogs, a NOAEL of 15 ppm (0.45 mg paraquat ion/kg/day) was identified
based on the absence of hematological, biochemical, gross pathological and
histclogical effects as well as the absence of any significant changes in
food consumption, or in body and organ weights for treated and control groups.
Adequate studies of comparable duration reported NOAELs higher than those of
the critical study selected for derivation of the Lifetime HA.   A lifetime
oral study in rats (Woolsgrove et al., 1983) reported a NOAEL of 25 ppm
(about 1.25 mg/kg/day); a NOAEL of 12.5 ppm (about 1.87 mg/kg/day) was
identified for mice (Litchfield et al., 1981).

Step 1;   Determination of the Reference Dose (RfD)

                RfD = JO.45 mc^ion/kg/day) = 0.0045 mg/kg/day

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Paraquat                                                      August,  1987

                                     -12-


where:

        0.45 mg ionA9/day = NOAEL,  based on the absence of  biochemical,
                             hematological,  gross pathological and histo-
                             pathological effects in dogs fed paraquat in
                             the diet for 52 weeks.

                       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 = (0.0045 mgAg/day) (70 kg) , 0>16  mg/L (160 ug/L)
                          (2 L/day)

where:

        0.0045 mgAg/day = RfD.

                   70 kg = assumed body weight of an adult.

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

Step 3:  Calculation of the Lifetime Health Advisory

            Lifetime HA = (0.16 mg/L) (20%)  = 0.003  mg/L (3  ug/L)
                                10

where:

        0.16 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

      0  In studies with mice, technical paraquat dichloride  (32.7% paraquat
        ion) did not induce significant oncogenic responses  at dose levels of
        0, 12.5, 37.5 or 100/125 ppm (0, 1.87, 5.6 or 15/18.75 mgA9»  respec-
        tively)  (Litchfield et al.,  1981).  The oncogenic potential of paraquat
        has been determined in studies in which rats were fed technical
        paraquat for 113 to 124 weeks at dose levels of 0, 25, 75 and  150 ppm
        (0, 1.25, 3.75 and 7.5 mgAg/day), respectively.  The incidences of
        pulmonary, thyroid, skin and adrenal tumors  were not clearly associated
        with treatment; however, the incidence of skin carcinomas was  signifi-
        cantly increased  (p = 0.01) in the high-dose males (Woolsgrove et al.,
        1983).

      0  The International Agency for Research on Cancer has  not evaluated the

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      Paraquat                    i                                  August, 1987

                                           -13-
              Applying the criteria described in EPA's guidelines for assessment
              of carcinogenic risk (U.S. EPA, 1986b), paraquat may be classified in
              Group C:  possible human carcinogen.  This group is used for substances
              with limited evidence of carcinogenicity in animals in the absence of
              human data.
  VI. OTHER CRITERIA, GUIDANCE AND STANDARDS

           0  The Office of Pesticide Programs (OPP) has established tolerances on
              raw agricultural commodities for paraquat ion derived from either the
              bis(methyl sulfate) or dichloride salt ranging from 0.01 to 5 ppm
              (U.S. EPA, 1984).  The tolerances are based on an ADI of 0.0045
              mg/kg/day derived from a 1-year feeding study in dogs, with a ,NOAEL
              of 0.45 mg/kg/day and a safety factor of 100.

           0  The National Academy of Sciences (NAS, 1977) has a Suggested-No-
              Adverse-Response-Level (SNARL) of 0.06 mg/L.  This was calculated-
              using an uncertainty factor of 1,000 and a NOAEL of 8.5 mg/kg/day
              identified in the 2-year rat study by Chevron Chemical Company (1975),
              with an assumed consumption of 2 L/day of water by a 70-kg adult, with
              the assumption that 20% of total intake of paraquat was from water.

           0  American Conference of Governmental Hygenists has presented a threshold
              limit value of 0.1  mg/m^ for paraquat of respirable particle sizes
              (ACGIH, 1980).
 VII. ANALYTICAL METHODS

              There is no standarized method for the determination of paraquat in
              water samples.   A method has  been reported for the estimation of para-
              quat residues on various crops (FDA,  1979).   In this method,  paraquat
              is reduced by sodium  dithionite to an unstable free radical that has
              an intense blue color and also a strong absorption peak at 394 run.


VIII. TREATMENT TECHNOLOGIES

              Weber et al.  (1986) investigated the  adsorption of paraquat and other
              compounds by  charcoal and cation and  anion exchange resins and their
              desorption with water.   They  developed Freundlich adsorption-desorption
              isotherms for paraquat  on charcoal.   When  250 mg of charcoal  was added
              to paraquat solutions,  it exhibited the following adsorptive  capacities:
              37.3 and  93.2 mg paraquat/g charcoal  at concentrations  of  0.373 mg/L
              and 37.3  mg/L,  respectively.   Paraquat was also adsorbed by IR-120
              exchange  resins (H+ and  Na+ forms).   The IR-120-H resin showed more
              affinity  towards paraquat than the IR-120-Na  resin.   When  665 mg of
              paraquat  in solution  was  added  to 15  mg of resin,  IR-120-H adsorbed
              70% of paraquat while the IR-120-Na adsorbed  66% of  paraquat.

           0   MacCarthy and Djebbar (1986)  evaluated  the use of  chemically  modified
              peat for  removing paraquat from aqueous  solutions  under a  variety of

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Paraquat                                                      August, 1987

                                     -14-
        experimental  conditions.   Paraquat sorption isotherms on treated
        Irish peat were determined by equilibrating 100-mL volumes of 3.66 mg/L
        paraquat with 0.1  g  of  peat at ambient conditions.   Tests indicated
        that equilibrium for paraquat was achieved after 6 days.  Peat exhib-
        ited the following paraquat sorption capacities:   40, 55 and 60 mg
        paraquat/g peat at concentrations of 2,  4 and  6 mg/L, respectively.
        The effects of pH, ionic  strength and flow rate on paraquat removal
        efficiency were also investigated.  When 45 mL of 16-mg/L paraquat
        solution was  gravity fed  to a column with a diameter of 6 mm that had
        been packed with 700 mg treated peat, 95 to 99% paraquat removal
        efficiency was reported without a significant  effect by variations in
        pH, ionic strength or flow rate.

        In summary, several  techniques for the removal of paraquat from water
        have been examined.   While data are not unequivocal, it appears that
        adsorption of paraquat by charcoal, ion exchange and modified peat are
        effective treatment  techniques.  However, selection of individual or
        combinations  of technologies for paraquat removal from water must be
        based on a case-by-case technical evaluation and an assessment of
        the economics involved.

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    Paraquat                                                      August, 1987

                                         -15-


IX. REFERENCES

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    Bullock,  C.H.*  1977.  The skin irritation potential of ortho paraquat 3 Ibs/
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    Bullock,  C.H.  and J.A.  MacGregor.*  1977.  The eye irritation potential of
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    Calderbank, A.  1970.  The fate of paraquat in water.  Outlook Agric.
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    Calderbank, A.  1976.  In  Herbicides:   Chemistry, degradation and mode of
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    CHEMLAB.   1985.   The  Chemical Information System, CIS,  Inc, Bethesda, MD.

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    Clark,  D.G.,  T.S. McElligott and E.W. Hurst.  1966.  The toxicity of paraquat.
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    Clay, P.  and M.  Thomas.*  1985.  Paraquat dichloride (technical liquor):
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    Coats,  G.E.,  H.H. Funderburk, Jr.  and J.H. Lawrence et al.*  1964.  Persistence
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    Cooke,  N.J., D.C. Flenley and H. Matthew.  1973.  Paraquat poisoning.  Serial
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         England.   Report No. CTL/P/1374, September 17.  MRID GS 0262-009.

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                                     -16-
Daniel, J.W. and J.C. Gage.*  1966.  Absorption and excretion of diquat and
     paraquat in rats.  Imperial Chemical Industries Limited, England.  Brit.
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FDA.  1979.  Food and Drug Administration.  Pesticide analytical manual,
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Hodge, M.C.E., S. Palmer, T.M. Wright and, J. Wilson.  1978a.  Paraquat
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Howard, C.A., J.  Wildgoose, P. Clay  and C.R. Richardson.   1985.  Paraquat
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Kalinowski, A.E., J.E. Doe, I.S. Chart, C.W. Gore,  M.J. Godley, K. Hollis,
     M. Robinson  and B.H. Woollen.   1983.  Paraquat:  One-year feeding study
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Leahey, J.P., R.J.  Hemingway, J.A. Davis and R.E. Griggs.   1972.  Paraquat
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Leahey, J.P., C.A.  Spinks, D. Neal and P.K. Carpenter.  1976a.  Paraquat
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Leahey, J.P., P.  Hendley and  C.A. Spinks.  1976b.   Paraquat metabolism and
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           r
                                       -17-
  Lehman, A.J.  1959.   Appraisal of the safety of chemicals in foods, drugs and
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                                     -18-
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                                                         *

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 •Confidential Business Information  submitted  to  the  Office  of  Pesticide
  Programs.

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