August,  1987
                       820K88100
                                   CHLOROTHALONIL

                                  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-
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  r Chlorothalonil                                                August,  1987

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II. GENERAL INFORMATION AND PROPERTIES

    CAS No.  1897-45-6

    Structural Formula
                    2,4,5,6-Tetrachloro-1,3-benzenedicarbonitrile

    Synonyms

         e  Tetrachloroisophthalonitrile;  Bravo?  Chloroalonil;  Chlorthalonil;
            Daconil;  Exothern;  Forturf;  Nopcocide N96;  Sweep;  Termil;  TPN;  DAC-2787.

    Uses  (Meister,  1986)

         0  Broad-spectrum fungicide.

    Properties  (Meister,  1986; CHEMLAB,  1985;  Meister,  1983;  Windholz et al.,  1983T

            Chemical Formula               CgN2Cl4
            Molecular Weight               265.89
            Physical State (25°C)           White, crystalline  solid
            Boiling Point                  350°C
            Melting Point                  250 to 251°C
            Density                        —
            Vapor Pressure (40°C)           <0.01  mm Hg
            Specific Gravity               ~
            Water Solubility (25°C)         0.6 mg/L
            Octanol/Water Partition         1.32 (calculated)
              Coefficient
            Taste Threshold
            Odor Threshold                 —
            Conversion Factor              —

    Occurrence

         0  Chlorothalonil has been  found in the  1 surface water sample analyzed
            and in none of the 560 ground water samples (STORET, 1987).  Samples
            were collected at 1 surface water location  and 556 ground water
            locations; and the 1 location where it was  found in Michigan, the
            concentration was 6,500  ug/L.

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Chlorothalonil                                                August, 1987

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Environmental Fate

     0  Ring-labeled !4C-chlorothalonil,  at 0.5 to 1.5 ppm,  was stable to
        hydrolysis for up to 72 days in aqueous solutions buffered at pH 5
        and 7 (Szalkowski,  1976b).   At pH 9,  chlorothalonil  hydrolyzed with
        half-lives of 33 to 43 days and 28 to 72 days  in solutions to which
        ring-labeled 14C-chlorothalonil was added at 0.52 and 1.5 ppm,
        respectively.  After 72 days of incubation,  pH 9-buffered solutions
        treated with chlorothalonil at 1.5 ppm contained 36.4% chlorothalonil,
        48.9% 3-cyano-2,4,5,6-tetrachlorobenzamide (DS-19211) and 11.3% 4-
        hydroxy-2,5,6-trichloroisophthalonitrile (DAC-3701).

     0  The degradate 14C-DAC-3701, at 1°00 PPm» was not hydrolysed in aqueous
        solutions  buffered  at pH 5, 7, and 9 after 72  days of incubation
        (Szalkowski, 1976b).

     0  Ring-labeled 14c-chlorothalonil and its major  degradate,  ring-labeled
        14C-DAC-3701, were  stable to photolysis on two silt  loam and three
        silty clay loam soils,  after UV irradiation for the  equivalent of 168
        12-hour days of sunlight (Szalkowski, 19??).

     0  14c-Chlorothalonil  is degraded with half-lives of 1  to 16, 8 to 31,
        and 7 to 16 days in nonsterile aerobic sandy loam, silt loam and peat
        loam soils, respectively, at 77 to 95°F and 80% of field moisture
        capacity (Szalkowski, 1976a).  When chlorothalonil (WP) was applied
        to nonsterile soils ranging in texture from sand to  silty clay loam,
        at 76 to 100°F and  6% soil moisture,  it was degraded with half-lives
        of 4 to more than 40 days;  increasing either soil moisture content
        (0.6 to 8.9%) or incubation temperature (76 to 100°F) enhanced
        chlorothalonil degradation (Stallard  and Wolfe, 1967).  Soil pH
        (6.5  to 8) does not appear to influence or only negligibly influences
        the degradation rate of chlorothalonil; however, soil sterilization
        greatly reduced the degradation rate.  The major degradate identified
        in nonsterile aerobic soil was DAC-3701, representing up to 69% of the
        applied radioactivity.   Other identified degradates  included DS-19221,
        trichloro-3-carboxybenzanu.de, 3-cyanotrichlorohydroxybenzamide, and
        3-cyanotrichlorobenzamide (Stallard and Wolfe,  1967; Szalkowski, 1976a;
        Szalkowski et al.,  1979).

     0  14C-Chlorothalonil  was immobile (Rf 0.0) and the degradate 14C-DAC-3701
        was found  to have low to intermediate mobility (Rf 0.25 to 0.43) in
        two silt loam and three silty clay loam soils, as evaluated using soil
        thin-layer chromotography (TLC) (Szalkowski, 19??).   Based on batch
        equilibrium tests,  chlorothalonil has a relatively low mobility (high
        adsorption) in silty clay loam (K = 26), silt  (K = 29), and sandy
        loam  (K =  20) soils but is  intermediately mobile (low adsorption) in
        a  sand (K  » 3) (Capps et al., 1982).   Soil organic matter content did
        not appear to influence the mobility  of chlorothalonil in soil.

     0  The chlorothalonil  degradate DAC-3701 is mobile in sand,  loam, silty
        clay  loam  and clay  soils (Wolfe and Stallard,  I968a).  After eluting
        a  6-in soil column  with the equivalent of  5  inches of water,  approxi-
        mately 57,  84, 10 and 84% of the  applied DAC-3701 was recovered in

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      Chlorothalonil                                                August,  1987

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              the leach ate  of  the sand,  loam,  silty clay loam and clay soil  columns,
              respectively.

           e   Chlorothalonil  (4.17 Ib/gal F1C) was degraded with a half-life of
              1  to 3  months in sandy loam and  silt loam soils when applied alone  at
              8.34 Ib ai/A  or  in combination with benomyl  (50% wettable powder) at
              1.35 Ib ai/A  (Johnston, 1981).   The treated  soils were maintained at
              80% of  moisture capacity in a greenhouse.

           0   Under field conditions, the half-life of Chlorothalonil (75% wettable
              powder) in a  sandy loam soil was between 1 and 2 months following the
              last of five  consecutive weekly  applications totaling 15 Ib ai/A
              (Stallard et  al., 1972).   Little movement of Chlorothalonil  (0.01 to
              0.17 ppm) below  the 0- to  3-inch depth occurred throughout the 8-month
              study.   Small amounts  (0.01 to 0.21 ppm) of  the degradate DAC-3701
              were found in soil samples collected up to 5 months post-treatment.
              No Chlorothalonil or DAC-3701 was  detected (less than 1 ppb) in a
              nearby  stream up to 7 months post-treatment, or in ground water
              samples (10-foot depth) up to 8  months post-treatment.  Cumulative
              rainfall over the study period was 26.22 inches.


III.  PHARMACOKINETICS

      Absorption

           0   Ryer (1966) administered 14C-chlorothalonil  (dose not specified)
              orally  to albino rats  (3/sex; strain not specified).  In 48 hours
              post-treatment,  60.21% of  the radioactivity  was detected in the
              feces,  indicating that at  least  40% of the oral dose was absorbed.

           0   Skinner and Stallard  (1967) reported that rats receiving 1.54  mg of
              14c-chlorothalonil in a 500 mg/kg  dose (route not specified)
              eliminated  88%  of the  administered dose unchanged in the feces over
              264 hours, indicating  that 12% was absorbed.

           0   Skinner and Stallard  (1967) reported that mongrel dogs receiving
              a  single oral dose  (by capsule)  of 500 mg/kg of Chlorothalonil,
              eliminated  85%  of the administered dose as the parent compound
              within  24 hours  post-treatment,  indicating that 15% was absorbed.

      Distribution

           e   Ryer (1966) administered 14c-chlorothalonil  (dose not specified)  to
              albino  rats  (3/sex; strain not specified) by oral intubation.   After
              11 days, the  carcasses retained  0.44% of the dose while 0.05%  of the
              dose remained in the  gastrointestinal tract.  The highest residues
              occurred in the  kidneys, which averaged 0.01% of the dose for  the six
              rats.  Lesser amounts  were detected in the eyes, brain, heart, lungs,
              liver,  thyroid  and spleen.

           0   Ribovich et al.  (1983) administered single doses of 14C-chlorothalonil
              by oral intubation  to CD-1 mice  at levels of 0, 1.5, 15 or  105 mg/kg.

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Chlorothalonil                                               August, 1987

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        Twenty-four hours post-treatment, the stomach, liver, kidneys, fat,
        small intestine, large intestine, lungs and heart accounted for less
        than 3% of the administered dose.  The stomach and kidneys had the
        highest concentration at all doses tested.  The compound was
        eliminated from the stomach and kidneys by 168 hours post-treatment.

     0  Wolfe and Stallard (1968b) reported a study in which dogs and rats
        received chlorothalonil in the diet for 2 years at 1,500 to 30,000 ppm.
        The amount of the 4-hydroxy-2,5,6-trichloroisophthalonitrile metabolite
        that was detected in the kidney tissue of dogs was less than 1.5 ppm;
        less than 3.0 ppm was detected in liver tissue from dogs and rats.
        The authors concluded that the metabolite was not stored in animal
        tissue.

Metabolism

     0  In the Wolfe and Stallard (196Sb) study, only a small amount of the
        4-hydroxy-2,5,6-trichloroisophthalonitrile metabolite was detected in
        the kidney tissue of dogs (<1.5 ppm) and in liver tissue from dogs
        and rats (<3 ppm).

     0  Marciniszyn et al. (1983) reported that when Osborne-Mendel rats were
        administered single oral doses of 1 4C-chlorothalonil by intubation at
        levels of 0, 5, 50, 200 or 500 rag/kg, no metabolites of chlorothalonil
        were unequivocally identified in urine.
Excretion
        The Ryer study (1966) revealed that, at the end of 11 days, an average
        of 88.45% of the administered dose was excreted in the feces, 5.14% in
        the urine and 0.32% in expired gases as CC^.

        The Skinner and Stallard study (1967) presented results that demon-
        strated that 88% of a dose (route unspecified) of chlorothalonil was
        eliminated unchanged in the feces.  Only 5.2% was eliminated via the
        urine and negligible amounts were detected in expired air.

        Ribovich et al. (1983) administered single doses of  14c-chlorothalonil
        by oral intubation to CD-1 mice at levels of 0, 1.5, 15 or 105 mg/kg.
        The total recoveries of radioactivity 24 hours post-treatment were
        93% for the low dose, 81% for the mid dose and 62% for the high dose.
        The major route of elimination was the feces and was complete at 24
        hours post-treatment for the low- and mid-dose animals, and by 96
        hours for the high dose animals.

        Marciniszyn et al. (1981) reported a study in which single doses of
        14c-chlorothalonil were administered intraduodenally to male Sprague-
        Dawley rats at 0.5, 5, 10, 50, 100 or 200 mg/kg.  Biliary excretion
        of radioactivity was monitored for 24 hours.  Percent recovery of
        radioactivity was  27.8,  20.7,  16.8,  6.4,  7.8 and 6% for each dose
        level, respectively.

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    Chlorothalonil                                               August,  1987

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            Marciniszyn  et al.  (1983a) administered  14C-Chlorothalonil intra-
            duodenally to  male  Sprague-Dawley  rats  (donor  animals)  at a dose of
            5 mg/kg.  Bile was  collected  for  24 hours  following  administration.
            Some  of  the  collected bile was  administered intraduodenally to recipient-
            rats;  bile was also collected from these animals  for 24 hours.  Data
            from  the  donor rats indicated that 1 to  6% of  the administered radio-
            activity  was excreted in  the  bile  within 24 hours after dosing.
            Approximately  19% of the  radioactivity in  bile administered to recipient
            rats  was  excreted within  24 hours  after  dosing.   These  data suggest
            that  enterohepatic  recirculation  plays a role  in  the metabolism of
            Chlorothalonil in rats.

            Pollock  et al. (1983) administered 14C-chlorothalonil by gavage to
            male  Sprague-Dawley rats  at dose  levels  of 5,  50  or  200 mg/kg.  They
            subsequently determined blood concentrations of radioactivity.  The
            authors  hypothesized that, at 200 mg/kg, an elimination mechanism
            (urinary, biliary and/or  metabolism) was saturated,  since the kinetics
            were  nonlinear at this dose.
IV. HEALTH EFFECTS

         0  The purity of  the administered  Chlorothalonil is assumed to be
            >90% for all studies  described  below,  unless  otherwise noted.
    Humans
            Johnsson et al.  (1983)  reported that Chlorothalonil exposure resulted
            in contact dermatitis  in 14 of 20 workers involved in woodenware
            preservation.   The wood preservative used by the workers consisted
            mainly of "white spirit," with 0.5% Chlorothalonil as a fungicide.
            Workers exhibited erythema and edema of the eyelids,  especially the
            upper eyelids,  and eruptions on the wrist and forearms.  Results of
            a patch test conducted with 0.1% Chlorothalonil in acetone were posi-
            tive in 7 of 14 subjects.  Reactions ranged from a few erythematous
            papules to marked papular erythema with a brownish hue without
            infiltration.
    Animals
       Short-term Exposure

         0  Powers (1965) reported that the acute oral LD^Q of Chlorothalonil
            (75% wettable powder)  in Sprague-Dawley rats was >10 g/kg.

         0  Doyle and Elsea (1963) reported that the acute oral LD50 of Chloro-
            thalonil in Sprague-Dawley rats was >10 g/kg.

         0  Rittenhouse and Narcisse (1974) reported that the acute ocal LD50 of
            Chlorothalonil in Sprague-Dawley rats was >17.4 g/kg.

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Chlqrothalonil                                                August, 1987

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   Dermal/Ocular Effects

     0  Doyle and Elsea (1963) reported that the dermal LD50 of DAC-2787
        (technical chlorothalonil) in albino rabbits was >10 gAg«  At dermal
        concentrations of 1, 2.15, 4.64 or 10 g/kg (24-hour exposure), the
        compound produced mild to moderate skin irritation characterized by
        erythema, edema, atonia and desquamation.

     0  Doyle and Elsea (1963) reported that when 3 mg of DAC-2787 (technical
        chlorothalonil) was applied to the eyes of albino rabbits, eye
        irritation was limited to mild conjunctivitis that subsided largely
        or completely within 7 days.

     0  Auletta and Rubin (1981) reported the results of eye irritation
        studies in cynomologus monkeys and New Zealand White rabbits using a
        formulation containing 96% chlorothalonil.  In both species,  0.1  mL
        of the test substance was instilled into the conjunctival sac of one
        eye.  Each species displayed mild and transient ocular irritation as
        evidenced by corneal opacities that were reversed by 4 days post-
        instillation.  The animals also showed slight to moderate iridial
        and conjunctival effects which were also reversible.  Rinsing reduced
        conjunctival and iridial effects and prevented formation of corneal
        opacities.

   Long-term Exposure

     0  Blackmore and Shott (1968) administered technical grade DAC 2787
        (chlorothalonil) to Charles River rats for 90 days at dietary levels
        of 0, 4, 10, 20, 30, 40 or 60 ppm (approximately 0,  0.2,  0.5, 1.0,
        1.5, 2.0 or 3.0 mg/kg/day; Lehman, 1959).  No compound-related effects
        were reported regarding physical appearance,  growth, survival, terminal
        clinical values, organ weights or organ-to-body weight ratios.
        Microscopically, the kidneys exhibited occasional vacuolation and
        swelling of the epithelial cells lining the deeper proximal convoluted
        tubules.  These changes were more numerous and more severe in the two
        highest dose groups.  The authors stated that the difference between
        the two highest dose groups (2.0 and 3.0 mg/kg/day)  and the controls
        was distinct, but the difference between the lower dose groups and
        controls was not clear.  Based on this information,  a NOAEL of 30 ppm
        (1.5 mg/kg/day) is identified.

     0  Wilson et al. (1981) administered chlorothalonil in the diet to
        Charles River CD rats (20/sex/dose) for 90 days at doses of 0, 40,
        80, 175, 375, 750 or 1,500 mg/kg/day.  At doses of 375 mg/kg/day or
        higher, significant decreases in body weight were reported.  Decreases
        in glucose levels, blood urea nitrogen and serum thyroxine were
        attributed by the investigators to body weight effects.  A dose-related
        decrease in serum glutamic-pyruvic transaminase (SGPT)  was noted  in all
        test groups.  Significant increases in kidney weights were also noted
        in males at 40, 80,  175 and 375 mg/kg, while  in females increased
        kidney weights were noted at 80, 175 and 750 mg/kg.   These were
        dose-related increases in kidney-to-body weight ratios  in both sexes
        at all doses.  Focal acute gastritis occurred in some rats of both

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Chlorothalonil                                                 August, 1987

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        sexes at all doses and this effect was inversely related to dose.
        A LOAEL of 40 mg/kg/day (the lowest dose tested) is identified in
        this study.

        Colley et al. (1983)  administered technical-grade chlorothalonil in
        the diet to  Charles River rats  (27 males and 28 females per dose) for
        13 weeks at  concentrations of  0,  1.5,  3.0,  10 or 40 mg/kg/day.
        Histopathological examination  revealed that at a dose of 3.0 mg/kg/day
        or greater,  all males displayed  an increased number of irregular
        intracytoplasmic inclusion bodies in the renal proximal convoluted
        tubules.  A  NOAEL of  1.5 mg/kg/day is identified in this study.

        Shults et al. (1983)  administered technical-grade chlorothalonil to
        CD-1 mice for 90 days at dietary concentrations of 0, 7.5,  15, 50, 275
        or 750 ppm (approximately 0, 1.1, 2.3, 7.5, 33.8 or 112.5 mg/kg/day;
        Lehman, 1959).  No treatment-related effects were noted on survival,
        physical condition, body weight,  food consumption or gross pathology.
        At 750 ppm (112.5 mg/kg/day),  an increase in alkaline phosphatase
        levels was observed in females  only.  Increased kidney weight was
        reported in  males dosed at 750 ppm (112.5 mgAg/day) and in females
        dosed at 275 and 750 ppm (33.8  and 112.5 mg/kg/day).  Histopatho-
        logically, dose-related changes  in the forestomach of mice were
        characterized by hyperplasia and hyperkeratosis of squamous epithelial
        cells.  These changes were observed in the 50-, 275- and 750-ppm dose
        groups.  No  other treatment-related histopathological changes were
        reported.  A NOAEL of 15 ppm (2.3 mg/kg/day) is identified in this
        study.

        Paynter and Murphy (1967) administered DAC 2787 (chlorothalonil) to
        beagle dogs   (4/sex/dose) for 16 weeks at dietary concentrations of 0,
        250, 500 or  750 ppm  (approximately to 0, 6.3. 12.5 or 18.8 mg/kg/day;
        Lehman, 1959).  No effects attributable to chlorothalonil were noted
        in terms of   appearance, behavior, appetite, elimination, body weight
        changes, gross pathology or organ weights.  Hematological, biochemical
        and urinalysis values were generally within accepted limits in treated
        and control animals,  except for slightly elevated protein-bound
        iodine values in treated dogs  (especially high-dose females).  No
        compound-related histopathology was noted.  Based on this, a minimum
        NOAEL of 750 ppm (18.8 mg/kg/day) is identified.

        Hastings et al.  (1975) administered chlorothalonil to Wistar albino
        rats (15/sex/dose for treatment groups, 30/sex for controls) for four
        months at dietary concentrations of 0, 1, 2, 4, 15, 30, 60 or 120 ppm
        (approximately 0, 0.05, 0.1, 0.2, 0.8, 1.5, 3 or 6 mg/kg/day; Lehman,
        1959).  No significant differences between treated and control groups
        were seen in body weight, food consumption, mortality or gross patho-
        logical changes.  Histopathological examination of the kidneys
        revealed no demonstrable effects at any dose level.  A minimum NOAEL
        of 120 ppm (6 mg/kg/day) is identified.

        Blackmore et al. (1968) administered DAC 2787 (chlorothalonil) to
        Charles River rats (35/sex/dose) for 22 weeks at dietary concentrations
        of 0,  250, 500,  750 or 1,500 ppm  (approximately 0, 12.5, 25, 37.5 or

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Chlorothalonil                                  t             August, 1987
                                      i
                                     -9-
        75 mg/kg/day;  Lehman,  1959).  At all dose levels,  male rats gained
        less weight from weeks 11  to 22.  Females gained less weight from
        weeks 9 to 22  at 750 and  1,500 ppm (37.5 or 75 mg/kg/day).  Food
        consumption values were similar for all groups.  No differences
        between control and test animals were reported for various hematological
        parameters, urinalysis and plasma and urine electrolytes.  Results of
        gross necropsy revealed that livers and kidneys of males treated at
        750 or 1,500 ppm (37.5 or  75 mg/kg/day) were larger than controls.
        Microscopic examinations  demonstrated dose-related compound-induced
        alterations in the kidneys of both sexes at all doses.  These changes
        were characterized by irregular swelling of the tubular epithelium,
        epithelial degeneration and tubular dilatation.  There was a signifi-
        cant increase  in renal tubular diameter in males at all dose levels.
        Accordingly, a LOAEL of 250 ppm (12.5 mg/kg/day) is identified.

     0  Blackmore and  Kundzin (1969) administered technical-grade DAC 2787
        (chlorothalonil) to rats  (strain not specified) (35/sex/dose) for 1
        year at dietary concentrations of 0, 4, 10, 20, 30, 40 or 60 ppm.
        The authors indicated that these dietary levels correspond to 0, 0.2,
        0.5, 1.0, 1.5, 2.0 or 3.0  mg/kg/day.  No compound-related effects on
        physical appearance, behavior, growth, food consumption, survival,
        clinical laboratory values, organ weights or gross pathology were
        noted.  Microscopically,  there were kidney alterations in both sexes
        at 40 and 60 ppm (2.0 and  3.0 mg/kg/day).  These alterations occurred
        primarily in the deeper cortical tubules and consisted of increased
        vacuolation of epithelial  cells accompanied by swelling or hypertrophy
        of the affected cells, often with the deposition of an eosinophilic
        droplet material in the cytoplasm of the vacuole.   Statistical
        significance was not addressed.  A NOAEL of 30 ppm (1.5 mg/kg/day)
        is identified.

     0  Holsing and Voelker (1970) administered technical-grade chlorothalonil
        to beagle dogs (eight/sex/dose) for 104 weeks at dietary concentrations
        of 0, 60 or 120 ppm (approximately 0, 1.5 or 3 mg/kg/day; Lehman, 1959).
        After 2 years  of administration, compound-related histopathological
        changes were observed in  the kidneys of males fed 120 ppm (3 mg/kg/day).
        Males fed 60 ppm (1.5 mg/kg/day) and females fed both dose levels
        were comparable to controls.  The observed changes included increased
        vacuolation of the epithelium in both the convoluted and collecting
        tubules and increased pigment in the convoluted tubular epithelium.
        Clinical findings, terminal body weight, organ-to-body weight ratios
        and gross pathology revealed no conclusive compound-related trends.
        A NOAEL of 60  ppm (1.5 mg/kg/day) is identified.

     0  Tierney et al. (1983)  administered technical grade chlorothalonil
        to Charles River CD-1  mice (60/sex/dose) for 2 years at dietary
        concentrations of 0, 750,  1,500 or 3,000 ppm.  The authors indicated
        that these dietary levels  were approximately 0, 119.4, 251.1  or
        517.4 mg/kg/day for males  and 0, 133.6, 278.5 or 585.0 mg/kg/day
        for females.  No treatment-related effects on body weight, food
        consumption, physical  condition or hematological parameters were noted.
        A slightly increased mortality rate was noted in males receiving
        3,000 ppm (517.4 mg/kg/day).  Also, kidney-to-body weight ratios and

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Chlorothalonil                                              August, 1987
        kidney-to-brain weight ratios were increased significantly in all
        test groups.  Gross necropsy revealed a number of renal effects
        including kidney enlargement, discoloration, surface irregularities,
        pelvic dilation, cysts,  nodules and masses.  Effects on the stomach
        included an increased incidence in masses or nodules.   In the stomach
        and esophagus, nonneoplastic histopathological effects were noted at
        all dose levels, and included hyperplasia and hyperkeratosis of the
        squamous mucosa.  This was considered to be indicative of mucosal
        irritation.  Other changes in the stomach included mucosal and
        submucosal inflammation,  focal necrosis or ulcers of mucosa and
        hyperplasia of glandular mucosa.  Reported histopathological effects
        on the kidney included an increase in the incidence and severity of
        glomerulonephritis, cortical tubular degeneration and cortical cysts.
        These changes were not dose-related, but they did occur at higher
        incidences in treated animals.  Based on the information presented in
        this study, a LOAEL of 750 ppm  (119.4 mg/kg/day-males; 133.6 mg/kg/day-
        females) is identified.

   Reproductive Effects

     0  In a three-generation reproduction study, Paynter and Kundzin (1967)
        administered a mixture containing 93.6% chlorothalonil to Charles River
        rats (10 males and 20 females per dose) at dietary concentrations of
        0 or 5,000 ppm (approximately 0 or 250 mg/kg/day; Lehman, 1959).  At
        the dose tested, the test material produced significant growth
        suppression in the nursing litters of each generation.  Reproductive
        performance was not affected and pups showed no malformations attrib-
        utable to the test substance.  Body weight gains for exposed male and
        female rats of each generation were lower than controls.

   Developmental Effects

     0  Rodwell et al.  (1983) administered technical grade chlorothalonil by
        gavage at doses of 0, 25, 100 or 400 mg/kg/day to Sprague-Dawley rats
        (25/dose level) on days 6 to  15 of gestation.  No compound-related
        external, internal or skeletal malformations were observed in fetuses.
        At 400 mg/kg/day, maternal toxicity was noted  (as evidenced by changes
        in appearance, three deaths, decreased body weight gain and food con-
        sumption).  A slight increase in the number of early embryonic deaths
        was associated with this maternal toxicity.  Ihis study identifies
        a NOAEL of 400 mg/kg/day for  teratogenic effects and a NOAEL of
        100 mg/kg/day for maternal toxicity.

     0  Wazeter et al.  (1976) administered DTX-75-0016 (chlorothalonil;
        purity not specified) by oral intubation at doses of 0, 1, 2.5 or
        5 mg/kg to Dutch Belted rabbits (10/dose) on days 6 to 18 of gestation.
        No compound-related changes in  general behavior or appearance were
        reported at the 1 or 2.5 mg/kg  dose level.  Occasional hypothermia
        and hyperactivity were noted  at a dose of 5 mg/kg.  Maternal body
        weight was not  affected at any dose.  No signs of toxicity were
        reported regarding the number of implantation sites, numbers of live
        or dead fetuses, live fetal weight, sex ratio or structural development)
        However, an increase in the number of females with dead or resorbed

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Chlorothalonil                                              August, 1987

                                     -11-
        fetuses (nine) and in the number of females aborting (four, two died
        during the study) were seen at 5 mg/kg.  Based on this information,
        this study identifies a NOAEL of 2.5 mg/*.g/3ay for maternal/fetal
        toxicity and a NOAEL of 5 mgAg/day for teratogenic effects.

     0  Shirasu and Teramoto (1975) administered chlorothalonil by gavage to
        Japanese white rabbits (eight controls, nine per dose) at doses of
        0, 5 or 50 mgAg/day on days 6 to 18 of gestation.  At 50 mg/kg/day,
        four of the nine does aborted.  No compound-related growth retardation
        or malformations were noted in offspring in any test group.  This
        study identifies a NOAEL of 50 mg/kg/day for teratogenic effects and
        a NOAEL of 5 mgAg/day for maternal toxicity.

   Mutagenicity

     8  Qiinto et al. (1981) reported that chlorothalonil (concentrations not
        specified) was not mutagenic, with or without metabolic activation,
        in five tester strains of Salmonella typhimurium.

     0  Wei (1982) reported that chlorothalonil, at concentrations up to
        764 ug/plate, was not mutagenic in S. typhimurium strains TA 1535,
        1537, 1538, 100 or 98, with or without liver or kidney activation
        systems.

     0  Kouri et al. (1977c) reported that DTX-77-0035 (chlorothalonil) at
        concentrations up to 6.6 ug/plate did not induce point mutations in
        S. typhimurium strains TA 1535, 100, 1537, 1538 or 98, with or without
        S-9 activation.

     0  Shirasu et al. (1975) reported the results of a reverse mutation test
        using j>. typhimurium strains TA 1535, 1537, 1538, 98 and 100 and
        Escherichia coli WP2 hcr+ and WP2 her-.  Chlorothalonil failed to pro-
        duce an effect without activation at concentrations up to 500 pg/plate;
        negative results also were obtained with activation at chlorothalonil
        concentrations up to 100 pg/plate.

     0  Kouri et al. (1977b) reported the results of a DNA repair assay using
        —• typhircurim" strains TA 1978 and 1538.  Chlorothalonil, dissolved
        in dimethylsulfoxide at 1 mg/mL and tested at 2, 10 and 20 uL of the
        stock solution per plate, was found to be active in both strains with
        or without metabolic activation.

     0  DeBertoldi et al. (1978) reported that chlorothalonil (2,500 ppm) did
        not induce mitotic gene conversions in Saccharomyces cerevisiae in the
        presence or absence of metabolic activation systems.  In tests on
        Aspergillus nidulans using both-resting and germinating conidia,
        chlorothalonil (up to 200 ppm) did not induce mitotic gene conversions.

     0  Shirasu et al. (1975) reported that, at concentrations up to 200
        ug/disk, chlorothalonil was negative in a rec-assay using Bacillus
        subtilis strains H17 and M45.

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Chlorothalonil                                               August, 1987

                                     -12-
     0  Kouri et al. (1977a)  exposed Chinese hamster cells (V-79) and mouse
        fibroblast cells (BALB/3T3) in vitro to chlorothalonil at concentra-
        tions of 0.3 ug/mL (for V-79 cells) or 0.03 ug/mL (for mouse fibroblast
        cells).  The V-79 cells were tested without metabolic activation; the
        BALB/3T3 cells were tested with and without metabolic activation.
        Chlorothalonil was not mutagenic in either cell type.

     0  Mizens et al. (1983a) reported the results of a micronucleus test in
        Wistar rats, Swiss CFLP mice and Chinese hamsters.  Rats were dosed at
        0, 8, 40, 200, 1,000 or 5,000 rag/kg; mice and hamsters received 0, 4,
        20, 100, 500 or 2,500 mg/kg.  All animals were dosed by gavage and all
        received two doses, 24 hours apart.  Chlorothalonil did not induce
        bone marrow erythrocyte micronuclei in any of the species tested.

     0  Legator  (1974) reported the results of an in vivo cytogenetic test on
        chlorothalonil in mice (strain not specified) using the micronuclei
        procedure.  The test compound was administered by gavage for 5 days
        at a concentration of 6.5 mg/kg/day.  At this concentration,
        chlorothalonil did not increase the number of cells with micronuclei.

     0  Legator  (1974) presented the results of a host-mediated assay using
        male Swiss albino mice and S. typhimurium strains G-46, TA1530, C-207,
        TA1531,  C-3076, TA1700, D-3056 and TA1724.  Mice  (10/dose) received
        chlorothalonil by gavage for 5 days at 6.5 mg/kg/day.  The compound
        did not produce any measurable mutagenic response when initially
        evaluated in vitro against the eight tester strains of S. typhimurium.
        When the tester strains were inoculated into treated mice, no increase
        in mutation frequency was observed.

     0  Legator  (1974) presented the results of a dominant lethal assay in
        which male mice (strain not specified) were dosed with chlorothalonil
        for five days at 6.5 mg/kg/day.  These mice were mated with untreated
        females, and the number of early fetal deaths and preimplantation
        losses were measured.  There was no significant difference in the
        fertility rates between test and control animals during weeks 1 to 7.
        At week  8, there was a significant decrease in fertility in the test
        group.

     0  Mizens et al.  (1983b) presented the results of a chromosomal aberration
        test in  Chinese hamsters.  The test animals received two doses of
        chlorothalonil, 24 hours apart, by gavage at concentrations of 0, 8,
        40, 200,  1,000 or 5,000 mg/Kg.  At 5,000 mg/kg» a statistically
        significant increase in bone marrow chromosomal abnormalities was
        observed.  However,  the authors concluded that this effect could not
        be attributed to chlorothalonil because the animals exhibited toxic
        responses to dosing.

    Carcinogenic!ty

     0  NCI  (1980) reported  the results of a study in which technical-grade
        chlorothalonil was administered to Osborne-Mendel rats  (50/sex/dose)
        for 80 weeks at Time-Weighted Average (TWA) dietary doses for both
        males and females of 5,063 or 10,126 ppm, respectively.  These dietary

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Chlorothalonil                                              August, 1987

                                     -13-
        doses have been calculated to correspond to approximately 253 and
        506 mgAg/day (Lehman, 1959).  Matched controls consisted of groups
        of 10 untreated rats of each sex;  pooled controls consisted of the
        matched controls combined with 55  untreated male or female rats from
        other bioassays.  An observation period of 30 to 31 weeks followed
        dosing.  Clinical signs that appeared with increased frequency in
        dosed rats included hematuria and, from week 72 on, bright yellow
        urine.  Adenomas and carcinomas of renal tubular epithelium occurred
        with  a significant (p = 0.03, males;  p = 0.007, females) dose-related
        trend.  The frequency of renal tumors was statistically greater in
        the high-dose males (p * 0.035) and high-dose females (p = 0.016)
        than in corresponding controls (males:  pooled controls, 0/62; low
        dose, 3/46; high dose, 4/49; females:  pooled controls, 0/62; low
        dose, 1/48; high dose, 5/50).  The observed adenomas and carcinomas
        were  considered to be histogenically related.  Results of this study
        were interpreted as sufficient evidence of carcinogenic!ty in
        Osborne-Mendel rats.

     0  NCI (1980) also reported a study in which technical-grade Chlorothalonil
        was administered to B6C3F1 mice (50/sex/dose) for 80 weeks at TWA
        dietary doses of 2,688 or 5,375 ppm for males and 3,000 or 6,000 ppm
        for females.  These dietary doses  have been calculated to correspond
        to approximately 403.2 or 806.3 rag/kg for males and 450 or 900 mg/kg
        for females (Lehman, 1959).  Matched controls consisted of 10 untrea1?ed
        mice of each sex; pooled controls  consisted of the matched controls
        combined with 50 untreated male or female mice from other bioassays.
        An observation period of 11 to 12  weeks followed dosing.  Since the
        dosed female mice did not show depression in mean body weights or
        decreased survival compared with the controls, they may have been
        able  to tolerate a higher dose. No tumors were found to occur at a
        greater incidence among dosed animals than among controls.  It was
        concluded that, under the conditions of this bioassay, Chlorothalonil
        was not carcinogenic in B6C3Fi mice.

     0  Tierney et al. (1983) administered technical-grade Chlorothalonil
        (97.7% pure) to Charles River CD-I mice (60/sex/control and dose groups)
        for 2 years at dietary concentrations of 0, 750, 1,500 or 3,000 ppm.
        The authors indicated that these dietary levels were equivalent to
        0, 119, 251 or 517 mg/kg/day for males and 0, 133,  278 or 585 mg/kg/day
        for females.  Increased incidences of squamous cell tumors of the
        forestomacb were noted in all treatment groups.  These tumors consisted
        principally of carcinomas, although papillomas were also seen.  This
        increased incidence was statistically significant in females dosed
        at 1,500 ppm (279 mg/kg/day).  No  clear dose-related trend in the
        incidence of these tumors was observed.  A slight increase in the
        incidence of tumors of the glandular epithelium of the fundic stomach
        was observed in dosed animals; this increase was neither statistically
        significant nor dose-related.  When the numbers of animals with
        epithelial tumors of the fundic or forestomach were combined, the
        incidence of these tumors showed a statistically significant increase
        in the 1,500- and 3,000-ppm female dose groups (279 and 585 mg/kg/day).
        No treatment-related renal neoplasms  were seen in any female dose
        group.  Increased incidences of adenomas and carcinomas in renal

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   Chlorothalonil                                                 August, 1987

                                        -14-
           cortical  tubules  were noted  in  all  treated  groups  of  male mice.
           These  changes  did not show a dose-response  relationship;  the increased
           incidence was  statistically  significant  only  in  the 750 ppm (251
           mg/kg/day)  group.  The authors  concluded that the  administration of
           chlorothalonil caused an  increase in  the incidence of primary gastric
           tumors and an  increase in the incidence  of  renal tubular  neoplasms.

           Wilson et al.  (1985)  gave chlorothalonil (98.1%  pure  with less than 0.03s
           hexachlorobenzene)  to Fischer 344 rats  (60/sex/dose)  in their diet at
           dose levels of 0, 40, 80  or  175 mg/kg/day.  Males  were treated for
           116 weeks,  while  females  received the chemical for 129 weeks.  Survive]
           among  the various groups  was comparable.  In  both  sexes,  at the high-
           dose level, there were significant  decreases  in  body  weights.  In
           addition, there were  also significant increases  in blood  urea nitrogen
           and creatinine, while there  were decreases  in serum glucose and
           albumin levels.  In both  sexes, there were  dose-dependent increases
           in kidney carcinomas  and  adenomas at  doses  above 40 mg/kg/day.  In
           the high-dose  females, there was also a  significant increase in
           stomach papillomas.  The  data show  that, in the  Fischer 344 rat,
           chlorothalonil is a carcinogen.
V. QUANTIFICATION OF TOXICOLOGICAL EFFECTS
                                                                  V
        Health Advisories (HAs)  are generally determined for one-day, ten-day,
   longer-term (approximately 7  years) and lifetime exposures if adequate data
   are available that identify a sensitive noncarcinogenic end point of toxicity.
   The HAs for noncarcinogenic toxicants are derived using the following formula:

                 HA = (NOAEL or  LOAEL) x (BW) . 	   /L {	   /L)
                        (UF) x (	 L/day)

   where:

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

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

                       UF = uncertainty factor (10, 100 or 1,000), in
                            accordance with NAS/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 information was found in the available literature that was suitable
   for determination of a One-day HA for chlorothalonil.  Accordingly, it is
   recommended that the Ten-day HA value  (250 ug/L, calculated below) for a
   10-kg child be used at this time as a conservative estimate of the One-day
   HA value.

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Chlorothalonil                          «                     August,  1987

                                     -15-


Ten-day Health Advisory

     The rabbit teratology study by Wazeter et al. (1976) has been chosen to
serve as the basis for the calculation of the Ten-day HA.  Animals received
0, 1, 2.5 or 5 mg/kg Chlorothalonil by gavage on days 6 through 18 of  gestation.
No adverse effects were observed at either of the two lower treatment  doses.
At 5 mg/kg, an increase in the number of females with dead or resorbed fetuses
and in the number of females aborting was observed.  The NOAEL for maternal/
fetal toxicity is 2.5 mg/kg/day.

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

         Ten-day HA = (2.5 mg/kg/day) (10 kg) = 0.25 mg/L (250 ug/L)
                          (100) (1 L/day)
where:

        2.5 mg/kg/day » NOAEL, based on absence of maternal or fetal toxicity
                        in rabbits exposed to Chlorothalonil via gavage on
                        days 6 to 18 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.

Longer-term Health Advisory

     The studies by Colley et al.  (1983), Blackmore and Kundzin (1969) and
Blackmore and Shott (1968) have been selected to serve as the basis for the
Longer-term HA for Chlorothalonil.  In the study by Colley et al., technical-
grade Chlorothalonil was administered in the diet to Charles River rats for
13 weeks at concentrations of 0, 1.5, 3.0, 10 or 40 mg/kg/day.  Histopatho-
logical examinations revealed that at doses of 3.0 mg/kg/day or greater, male
rats displayed an increased number of intracytoplasmic inclusion bodies in
the proximal convoluted renal tubules.  Blackmore and Shott (1968), gave
technical-grade Chlorothalonil in the diet to Charles River rats for 90 days
at doses of 0, 0.2, 0.5, 1.0, 1.5, 2.0 or 3.0 mg/kg/day.  At the two highest
dose levels, the kidneys exhibited occasional vacuolation and swelling of
the epithelial cells lining the deeper proximal convoluted tubules.  In the
Blackmore and Kundzin (1969) study, technical-grade Chlorothalonil was admin-
istered in the diet to rats for 1  year at doses of 0, 0.2, 0.5,  1.0,  1.5, 2.0
or 3.0 mg/kg/day.  At the 2 higher doses, there were alterations in the deeper
convoluted renal tubules in both sexes.   Each of the studies identified a
NOAEL of 1.5 mg/kg/day.

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

       Longer-term HA = (1>5 mg/kg/day)  (10 kg) = 0.15 mg/L (150 uq/L)
                            (100)  (1  L/day)

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Chlorothalonil   ,          *                                 August, 1987

                                     -16-
where:

        1.5 mg/kg/day - NOAEL, based on absence of kidney effects in rats
                        exposed to Chlorothalonil in the diet for 13 weeks.

                10 kg « assumed body weight of a child.

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

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

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

       Longer-term HA = (1
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Chlorothalonil                                               August, 1987

                                     -17-
     The study by Holsing and Voelker (1970) has been selected to serve as
the basis for the Lifetime HA for chlorothalonil.  In this study, technical-
grade Chlorothalonil was administered to beagle dogs (eight/sex/dose) for 104
weeks at dietary concentrations of 0, 60 or 120 ppm (0, 1.5 or 3.0 mg/kg/day).
The results following 2 years of administration revealed compound-related
histopathological changes in the kidneys of males fed 120 ppm (3 mg/kg/day).
Males fed 60 ppm (1.5 mg/kg/day) and females fed both dose levels were
comparable to controls.  The observed changes included increased vacuolation
of the epithelium in both the convoluted and collecting tubules and increased
pigment in the convoluted tubule epithelium.  From these results, a NOAEL of
1.5 mg/kg was identified.

     Using this NOAEL, the Lifetime HA is derived as follows:

Step 1:  Determination of the Reference Dose (RfD)

                   RfD = (1»5 mg/kg/day) = 0.015 mg/kg/day
                              (100)

where:

        1.5 mg/kg/day = NOAEL, based on absence of histopathological changes
                        in dogs fed chlorothalonil for one year.

                  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 = (0-015 mg/kg/day)  (70 kg) = 0>525 mg/L (525   /L)
                           2 L/day

where:

        0.015 mg/kg/day = RfD.

                  70 kg = assumed body weight of an adult.

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

Step 3:  Determinetion of the Lifetime Health Advisory

     The estimated excess cancer risk associated with lifetime exposure to
drinking water containing chlorothalonil at 525 ug/L (the DWEL) is 3.5 x 10~4.
This estimate represents the upper 95% confidence limit from extrapolations
prepared by OPP and ODW using the linearized, multistage model.  The actual
risk is unlikely to exceed this value, but there is considerable uncertainty
as to the accuracy of risks calculated by this methodology.

Evaluation of Carcinogenic Potential

     a  In an NCI bioassay (1980), technical grade chlorothalonil was
        administered in the diet at 253 or 506 mg/kg/day to Osborne-Mendel

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      Chlorothalonil                                                August,  1987

                                          -18-
              rats  for  80 weeks.  A statistically  significant  increase  in the
              frequency of renal tumors was observed  in high-dose males  and  females.

           0   NCI  (1980) reported that chorothalonil  was  not carcinogenic in B6C3F-)
              mice  when administered in the diet,  at  403  or 806  mg/kg and 450 or
              900 mg/kg for  males and females, respectively, for 80  weeks.   However,
              Tierney et al.  (1983) concluded  that chlorothalonil was carcinogenic
              in Charles River CD-1 which received the compound  (0,  119,  251  or
              517 mg/kg/day  for males and 0, 134,  279 or  585 mg/kg/day  for  females)
              in the diet for 2 years.  Increased  incidences of  squamous cell
              papilloma and  carcinoma of the forestomach  were  noted  in  all  treatment
              groups.   This  increase was statistically significant only  in  the mid-
              dose  females.   Increased incidences  of  adenoma and carcinoma  of the
              renal cortical tubules were observed in all treatment  groups.   Again,
              no dose-response was noted, since  these increases  were statistically
              significant only in the mid-dose males.

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

           0   Applying  the criteria described  in EPA's guidelines for assessment of
              carcinogenic risk  (U.S. EPA, 1986a), chlorothalonil is classified in
              Group B2: probable human carcinogen.   This category is for chemicals
              for which there is inadequate evidence  from human  studies  and  sufficient
              evidence  from  animal studies.

           0   From  the  Wilson et al. (1985) data,  OPP calculated a q-| *  of 2.4 x
              10-2  (mg/kg/day)-1.  The 95% upper limit lifetime  dose in  drinking water
              associated with a  10-6 excess risk level is 1.5  ug/L.  Corresponding
              levels  for 10-5 an(j 1 o~4 are 15  and  150 ug/L, respectively.  While
              recognized as  statistically alternative approaches, the range of
              risks described by using any of  these modelling  approaches has little
              biological significance unless data  can be  used  to support the selection
              of one  model over  another.   In the interest of consistency of approach
              and  in  providing  an upper bound  on the  potential cancer risk,  the
              Agency  has recommended use of the  linearized multistage approach.
              However,  for completeness, the 10"^  risk numbers for other models
              will  be given.  These values, at the 10-6  level,  are:  multihit -
              9 ug/L;  one hit -  2 ug/L; probit - 51 ug/L; logit  - 0.8 ug/L;  and
              Weibel  -  0.6 ug/L.


VI.   OTHER CRITERIA,  GUIDANCE AND STANDARDS

           0  WHO  Temporary  Acceptable Daily Intake = 0.005 mg/kg/day  (Vettorazzi
              and  Van den Hurk,  1985).

           0  EPA/OPP has calculated a PADI of 0.015  mg/kg/day based on the NOAEL
              of  1.5  mg/kg/day  identified  in the 2-year  dog study  (Holsing and and
              Voelker,  1970) and an uncertainty factor of 100  (U.S.  EPA, 1984a).

           0  U.S.  EPA established tolerances  in or on raw agricultural commodities
              residue levels of  0.1 to 5 ppm  (40 CFR  180.275,  1985).

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       Chlorothalonil                                                August, 1987

                                            -19-


VII.   ANALYTICAL METHODS

            0  Analysis  of chlorothalonil  is  by  a  gas  chromatographic (GC)  method
               applicable  to the determination of  certain  chlorinated pesticides in
               water  samples (U.S.  EPA,  1986b).  In  this method,  approximately
               1  liter of  sample is extracted with methylene  chloride.   The extract
               is concentrated  and  the  compounds are separated  using capillary
               column GC.   Measurement  is  made using an electron  capture detector.
               The method  detection limit  has not  been determined for chlorothalonil,
               but it is estimated  that the detection  limits  for  analytes included
               in this method are in the range of  0.01 to  0.1 ug/L.


 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.  (1982)  reported  99% removal efficiency  of chlorinated
               pesticides  by  a  thin-film composite polyamide  membrane operating  at
               a  maximum pressure of 1,000 psi and a maximum  temperature of  113°F.
               More operational data are required, however, to  specifically  determine
               the effectiveness and feasibility of applying  RO for  the  removal  of
               chlorothalonil from water.  Also, membrane adsorption must beXconsid-
               ered when evaluating  RO performance in  the treatment  of chlorothalonil-
               contaminated drinking water supplies.

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    Chlorothalonil                                                August, 1987

                                         -20-


IX. REFERENCES

    Auletta,  C.S., and L.F.  Rubin.*  1981.   Eye irritation studies in monkeys and
         rabbits with Bravo  500:   Report DS-2787.  Unpublished study.  MRID 00077176,

    Blackmore, R.H.,  and L.D.  Shott.*  1968.  Final report:  three-month feeding
         study—rats.  Project No. 200-205.  Unpublished study.  MRID 00087316.

    Blackmore, R.H.,  L.D.  Shott,  M. Kundzin et al.*  1968.  Final report:
         four-month feeding  study—rats (22 weeks).  Project No. 200-198.
         Unpublished study.   MRID 00057701.

    Blackmore, R.H.,  and M.  Kundzin.*  1969.  Final report:  12-month feeding
         study—rats. Project No. 200-205.   Unpublished study.  MRID 00087358.

    Capps, T.M., J.P. Marciniszyn, A.F. Markes, and J.A. Ignatoski.*  1982.
         Document No. 555-4EF-81-0261-001,  Section J, Vol. VI.  Submitted by
         Diamond Shamrock Corporation.

    CFR.  1985.  Code of Federal  Regulations.  40 CFR 180.275.  July 1, 1985.

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

    Colley,  J., L. Syred,  R. Heywood et al.*  1983.  A 13-weeV subchronic toxicity
         study of T-117-11 in rats (followed by a 13-week withdrawal period).
         Unpublished study.   MRID 00127852.

    DeBertoldi, M., R. Barale, and M. Giovannetti.  1978.  Mutagenicity of
         pesticides evaluated by  means of gene conversion in S. cerevisiae and A.
         nidulans.  Environ. Mut. 2:359-370.

    Doyle, R.L., and J.R.  Elsea.*  1963.  Acute oral, dermal and eye toxicity and
         irritation studies  on DAC-2787:  N-107.  Unpublished study.  MRID 00038909.

    Hastings, T.F., M. Dickson, W.M. Busey et al.*  1975.  Four-month dietary
         toxicity study—rats chlorothalonil.  Project No. 24-201.  Unpublished study.
         MRID 00040463.

    Holsing,  G., and R. Voelker.*  1970.  104-week dietary administration—dogs:
         Daconil 2787 (Technical).  Project No. 200-206.  Unpublished study.
         MRID 00114304.

    Johnsson, M., M. Buhagen, H.L. Leira and S. Solvang.  1983.  Fungicide-induced
          contact dermatitis.  Contact Dermat.  9:285-288.

    Johnston, E.F.*  1981.  Soil  disappearance studies with Benlate fungicide and
         Bravo 500 fungicide, alone and in combination:  Document No. AMR-06-81.
         Unpublished study submitted by E.I. du Pont de Nemours and Co.,
         Wilmington, DE.

    Kouri, R.E., R. Joglekar and  D.P.A. Fabrizio.*  1977a.  Activity of
         DTX-77-0034 in an _in_ vitro mammalian cell point mutation assay.
         Unpublished study.   MRID 00030289.

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Chlorothalonil                                              August,  1987

                                     -21-
Kouri, R.E., A.S. Pannar, J.M. Kuzava et al.*   1977b.  Activity of DTX-77-0033
     in a test for differential inhibition of repair deficient and repair
     competent strains of Salmonella typhimurium.  unpublished study.
     MRID 00030288.

Kouri, R.E., A.S. Pannar, J.M. Kuzava et al.*   1977c.  Activity of DTX-77-0035
     in the Salmonella/microsomal assay for bacterial mutagenicity.  Unpublished
     study.  MRID 00030290.

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Chlorothalonil                                               August,  1987

                                     -22-
Pollock, G., J. Marciniszyn, J. Killeen et al.*   1983.  Levels of  radioactivity
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                                     -23-
Szalkowski, M.B.*  1976a.  Effect of microorganisms upon the soil
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     technical Chlorothalonil in rats:  Document No. 099-5TX-80-0234-008.
     Unpublished study prepared by ADS Biotech Corp.  2269 p.  MRID 00146945.

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                                     -24-
Windholz, M., S. Budavari, R.F. Blumetti and E.S. Otterbein, eds.  1983.
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Wolfe, A.L., and D.E. Stallard.*  1968a.  The fate of DAC-3701 (4-hydroxy-
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 Confidential Business Information submitted to the Office of Pesticide
  Programs.

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