August,  ^987
                                      PICLORAM

                                  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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    Piclofram
                                                                 August,  1987
                                         -2-
II. GENERAL INFORMATION AND PROPERTIES
    CAS No.    1918-02-01
    Structural Formula
                                   NH2


                               It
                              C^L   ^
                                 ^sN^
                                     'Cl
                                       f)
                                     'C-OH
                   (4-amino-3,5,6-trichloropicolinic acid)

Synonyms

     0  Amdon;  ACTP?  Borolin?  K-PIN;  Tordon (Meister,  1987).

Uses

     0  Broad-spectrum herbicide for  the control of broadleaf and woody plants
        in rangelands, pastures and rights-of-way for powerlines and highways
        (Meister,  1987).

Properties  (Meister, 1987)

        Chemical Formula
        Molecular Weight
        Physical State (Room Temp.)
        Boiling Point
        Melting Point
        Density
        Vapor Pressure (25C)
        Specific Gravity
        Water Solubility

        Log Octanol/Water Partition
          Coefficient
        Taste Threshold
        Odor Threshold
        Conveision Factor                ~

Occurrence

     0  Picloram has  been found in 359 of 653 surface water samples analyzed
        and in 5 of 77 ground  water samples (STORET, 1987).  Samples were
        collected at  124  surface water locations and 49 ground water locations,
        and picloram  was  found in 7 states.  The 85th percentile of all
        nonzero samples was  0.13 ug/L in surface water and  1.00 ug/L in
        ground water  sources.   The maximum concentration found was 4.6 ug/L
        in surface water  and 1.00 ug/L in ground water.
                                             241.6
                                             White powder
                                             Decomposes
                                             215C (decomposes)

                                             6.2 x 10~7  mm Hg

                                             0.043 g/100 mL (free acid)
                                             40 g/100 mL (salts)
                                             (Chlorine-like)

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     Picloram                                                     August,  1987

                                          -3-


     Environmental Fate

          0  The main processes  for  dissipation of picloram in the environment are
             photodegradation  and  aerobic  soil degradation.  Field tests conducted
             in Texas with a liquid  formulation of picloram have indicated that
             approximately 74% of  the  picloram originally contained in the test
             ecosystems,  which included  the soil,  water and vegetation,  was
             dissipated within 28  days after application (Scifres et al.,  1977).

          0  Photodegradation  of picloram  occurs rapidly in water (Hamaker, 1964;
             Redemann,  1966; Youngson, 1968; Youngson and Goring, 1967), but is
             somewhat slower on  a  soil surface (Bovey et al./  1970; Merkle et al.,
             1967; Youngson and  Goring,  1967).  Hydrolysis of picloram is very
             slow (Hamaker, 1976).

          0  Laboratory studies  have shown that under aerobic soil conditions, the
             half-life of picloram is  dependent upon the applied concentration,
             and the temperature and moisture of the soil.  The major degradation
             product is CC^; other metabolites are present in insignificant amounts
             (McCall and  Jefferies,  1978;  Merkle et al., 1967; Meikle et al., 1970,
             1974; Meikle, 1973; Hamaker,  1975).  In the absence of light under
             anaerobic soil and  aquatic  conditions, picloram degradation is extremely
             slow (McCall and  Jefferies,  1978).

          0  Following normal  agricultural, forestry and industrial applications
             of picloram, long-term  accumulation of picloram in the soil generally
             does not occur.   In the field, the dissipation of picloram will occur
             at a faster  rate  in hot,  wet  areas compared, to cool, dry locations
             (Hamaker et  al.,  1967).  The  half-life of picloram under most field
             conditions is a few months  (Youngson, 1966).  There is little potential
             for picloram to move  off  treated areas in runoff water (Fryer et al.,
             1979).  Although  picloram is  considered to have moderate mobility
             (Helling,  1971a,b), leaching  is generally limited to the upper portions
             of most soil profiles (Grover, 1977),  Instances of picloram entering
             the ground water  are  largely  limited to cases involving misapplications
             or unusual soil conditions  (Frank et al., 1979).


III. PHARMACOKINETICS

     Absorption

          0  Picloram is  readily absorbed  from the gastrointestinal (GI) tract of
             rats (Nolan  et al., 1980).  Within 48 hours after dosing rats with
             1400 rag/kg body weight  (bw),  80 to 84% of the dose was found in
             urine.

          0  A  500-kg Holstein cow was administered 5 mg/kg picloram in the feed
             for 4 days (approximately 0.23 mg/kg/day).  Ninety-eight percent of
             the total  dose was  excreted in the urine, demonstrating nearly
             complete absorption (Fisher et al., 1965).

          0  Similar results were  observed in three male Fischer CDF rats  receiving
             14c-picloram (dose  not  specified), where 95% of the dose was  absorbed
             (Dow, 1983).

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Picloram                                                     August, 1987

                                     -4-


Distribution

     0  Picloram appears to be distributed throughout the body,  with the
        highest concentration in the kidneys (Redemann,  1964).   In rats
        (strain, age and sex not specified)  administered a single 20 mg/kg
        dose of 1^C-labeled picloram in food, radioactivity was  found in
        abdominal fat,  liver, muscle and kidneys with maximum levels occurring
        2 to 3 hours after dosing.

     0  Hereford-Holstein steers fed picloram at daily doses of  3.2 to 23 mg/kg
        for 2 weeks had tissue concentrations of 0.05 to 0.32 mg/kg in
        muscle, 0.06 to 0.45 mg/kg  in fat, 0.12 to 1.6 mg/kg in  liver, 0.18
        to 2.0 mg/kg in blood and 2 to 18 mg/kg in kidney (Kutschinski and
        Riley, 1969).

     0  In a similar study, two steers (strain not specified) fed 100 or 200 mg
        picloram (3 or 6 mg/kg bw/day) for 31 days had picloram  concentrations
        of 4 or 10 mg/kg, respectively, in the kidneys,  while concentrations
        in other tissues (muscle, omentum fat, heart, liver, brain) were less
        than 0.5 mg/kg  (Leasure and Getzander, 1964).

Metabolism

     8  Picloram administered to rats or cattle was excreted in  the urine in
        unaltered form  (Fisher et al., 1965; Nolan et al., 1980; Dow, 1983),
        and no ^ ^CO^ was detected in expired air of rats given ' ^-carbon-
        labeled picloram (Redemann, 1964; Nolan et al.,  1980; Dow, 1983).
        These studies indicate that picloram is not metabolized  significantly
        by mammals.
Excretion
        Picloram administered to rats is excreted primarily in the urine
        (Redemann, 1964; Nolan et al., 1980; Fisher et al., 1965).

        Male (F344) rats that were administered a single oral dose of picloram
        at 1,400 mg/kg bw, within 48 hours excreted 80 to 84% of the dose in
        the urine, 15% in the feces, less than 0.5%. in the bile and virtually
        no measurable amount as expired CC>2 (Nolan et al., 1980).

        One Holstein cow administered 5 ppm picloram in feel for 4 consecutive
        days excreted more than 98% of the dose in the urine (Fisher et al.,
        1965).

        In male F344 rats administered picloram at 10 mg/kg bw orally, clearance
        of picloram from the plasma was biphasic, showing half-lives of 29 and
        228 minutes.  When administered the same dose intravenously, biphasic
        clearance occurred with half-lives of 6.3 and 128 minutes  (Nolan
        et al., 1980).

        Cattle excrete picloram primarily in the urine (Fisher et al., 1965),
        although small amounts may appear in the milk (Kutschinski and Riley,
        1969).  In Holstein cows fed picloram for 6 to 14 days at doses of

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    Picloram
August, 1987
                                        -5-
            2.7 mg/kg/day  or  less, no  picloram  could  be  found  in  the milk,  while
            cows  fed picloram at doses of  5.4 to  18 mg/kg/day  had milk  levels  up
            to 0.28 mg/L.   This corresponds  to  0.02%  of  the  ingested dose.   When
            picloram feeding  was discontinued,  picloram  levels in milk  became
            undetectable within 48 hours.

            Nolan et al.  (1983) investigated the  excretion of  picloram  in humans.
            Six male volunteers  (40- to 51-years  old)  ingested picloram at 0.5 or
            5 mg/kg in approximately 100 mL  of  grape  juice.  Seventy-six percent
            of the dose was excreted unchanged  in the urine  within 6 hours (half-
            life  of 2.9 hours).  The remainder  was eliminated  with an average
            half-life of 27 hours.  The authors did not  report observations, if
            any,  of adverse effects.   Thus,  excretion of picloram in humans was
            biphasic as had been demonstrated in  rats by Nolan et al. (1980).
IV. HEALTH EFFECTS

    Humans
            No  information  on the  health  effects  of  picloram  in humans was found
            in  the  available literature.   In  the  excretion  study by Nolan et al.
            (1983), described above,  the  authors  did not address the presence of
            toxic effects in human volunteers  ingesting  picloram at 0.5 or 5 mg/kg.
    Animals
       Short-term  Exposure

         0   The  acute  oral  toxicity of  picloram is  low.   Lethal doses have been
            estimated  in  a  number  of species,  with  LD50  values ranging from
            2,000  to 4,000  mg/kg (NIOSH,  1980; Dow, 1983).

         0   In a 7- to 14-day study .by  Dow (1981),  beagle dogs (number per group
            not  specified)  were administered picloram (79.4% Tordon)  at dose
            levels of  0,  250,  500  or 1000 mg/kg/day.   Based on 79.4%  active
            ingredient, actual doses administered were 200, 400 or 800 mg/kg/day.
            The  No-Observed-Adverse-Effect-Level  (NOAEL) was determined to be
            200  mg/kg/day,  the lowest dose tested,  based on the absence of reduced
            food intake.

         0   In a 9-day feeding study by Dow (1980a),  picloram was fed to dogs
            (one/dose)  at dose levels of  400,  800 or  1,600  mg/kg bw/day.  Picloram
            was  acutely toxic to female dogs at the higher  doses and  not toxic
            at 400 mg/kg/day (the  lowest dose  tested), which was identified as
            the  NOAEL.

         0   In a 32-day feeding study by  Dow  (1980b), picloram was administered
            to mice at dose levels of 0,  90, 270, 580, 900  or 2,700 mg/kg/day.
            The  NOAEL  was 900 mg/kg/day,  and the Lowest-Observed-Adverse-Effect-
            Level  (LOAEL) was 2700 mg/kg/day,  based on increased liver weight.

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Picloram                                                     August, 1987

                                     -6-


   Dermal/Ocular Effects

     0  Most formulations of picloram have been evaluated for the potential
        to produce skin sensitization reactions in humans.   Dow (1981) reported
        in summary data that Tordon 22K was not a sensitizer following an
        application as a 5% solution.  A formulation of Tordon 101 containing
        6% picloram acid and 2,4-D acid was not a sensitizer as a 5% aqueous
        solution in humans (Gabriel and Gross,  1964).   However, when the
        triisopropanolamine salts of picloram and 2,4-D (Tordon 101) were
        applied as a 5% solution, sensitization occurred in several individuals;
        however, when applied alone, the individual components were nonreactive,

   Long-term Exposure

     0  Subchronic studies with picloram have been conducted by Dow (1983)
        using three species (dogs, rats, mice)  over periods of 3 to 6 months.
        A 6-month study was conducted with beagle dogs that received picloram
        at daily doses of 0, 7, 35 or 175 mg/kg/day (six/sex/dose group)
        (Dow, 1983).  Increased liver weights were observed at the highest
        dose (175 mg/kg/day) for males and females, and at the intermediate
        dose (35 mg/kg/day) for males.  Therefore, the 7-mg/kg/day dose level
        was considered to be a NOAEL.

     0  In a 13-week feeding study, CDF Fischer 344 rats (1 5/sex/dosage group)
        were fed picloram in their diet at dose levels of 0, 15, 50, 150, 300
        or 500 mg/kg/day (Dow, 1983).  Liver swelling was observed in both
        sexes at the 150- and 300-mg/kg/day dose levels.  The NOAEL in this
        study was identified as 50 mg/kg/day.

     0  Osborne-Mendel rats receiving picloram at 370 or 740 mg/kg/day in the
        diet for 2 years had renal disease resembling that of the natural
        aging process (NCI, 1978).   Increased indices of parathyroid hyperplasia,
        polyarteritis, testicular atrophy and thyroid hyperplasia and adenoma
        were observed.  Polyarteritis may be indicative of an autoimmune
        effect.

     0  Ten male and female B6C3F-J mice were administered picloram in their
        diet at dose levels of 0, 1,000, 1,400 or 2,000 mg/kg/day for 13 weeks
        (Dow, 1983).  Liver weights were increased significantly  (p values not
        reported) in females and males at all dose levels tested.

   Reproductive Effects

     0  As described above in the 2-year feeding study by NCI  (1978), testicular
        atrophy was observed in male Osborne-Mendel rats receiving picloram at
        370 or 740 mg/kg/day.

     0  Groups of 4 male and 1 2 female rats were maintained on diets containing
        0, 7.5, 25 or 75 mg/kg/day of Tordon (95% picloram) through a -three-
        generation  (two litters per  generation) fertility,  reproduction,
        lactation and teratology study  (McCollister et al., 1967).  The rats
        were 11-weeks old at the start of the study and were maintained on
        the test diets for 1 month prior to breeding to produce the F-|a

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Picloram                                                     August, 1987

                                     -7-
        generation.   Records were kept of numbers of pups born live, born
        dead or killed by the dam;  litter size was culled to eight pups after
        5 days.  Lactation continued until the pups were 21-days old, when
        they were weaned and weighed.  After a 7- to 10-day rest, the dam was
        returned for breeding the FIJ., generation.  The second generation (?2a
        and F3b) was derived from F2b animals after 110 days of age.  Two
        weanlings per sex per level of both litters of each generation were
        observed for gross pathology.  Gross pathology was also performed on
        all parent rats and all females not becoming pregnant.  Five male and
        five female weanlings from each group of the F^ litter were selected
        randomly for gross and microscopic examination (lung, heart, liver,
        kidney, adrenals, pancreas, spleen and gonads).  Picloram reduced
        fertility in the 75 mg/kg/day dose group.  No other effects were
        noted.  Based on these results, a NOAEL of 25 mg/kg/day was identified.

   Developmental Effects

     0  In the McCollister et al. (1967) study described above, the F1c, F2c
        and F3c litters were used to study the teratogenic potential of
        picloram.  The dams were sacrificed on day 19 or 20 of gestation, and
        offspring were inspected for gross abnormalities, including skeletal
        and internal structures, and placentas were examined for fetal death
        or resorptions.  None were observed at any dose level.  Picloram
        reduced fertility in the 75-mg/kg/day dose group.  Based on these
        results, a NOAEL of 25 mg/kg/day was identified.

     0  Thompson et al.  (1972) administered picloram in corn oil to pregnant
        Sprague-Dawley rats on days 6 to 15 of gestation.  Four groups of 35
        rats  (25 for the teratology portion and 10 for the postnatal portion
        of the study) received picloram at 0, 500, 750 or 1,000 mg/kg/day by
        gavage.  Rats were observed daily for signs of toxicity.  Prebreeding
        and gestation day 20 body weights were obtained on teratology rats
        and prebreeding and postpartum day 21 body weights were obtained for
        signs of maternal toxicity, while rats given 750 or 1,000 mg/kg/day
        developed hyperesthesia and mild diarrhea after 1 to 4 days of treatment;
        and 14 maternal deaths occurred between days 8 and 17 of gestation in
        these dose groups.  Evidence of retarded fetal growth, as reflected
        by an increase in unossified fifth sternebrae, was observed in all
        treatment groups but not in a dose-related manner; i.e., the occurrence
        of bilateral accessory ribs was increased significantly in fetuses of
        dams given 1,000 mg/kg for 10 days during gestation.  At this dose
        level, there was maternal toxicity and, therefore, no NOAEL was
        determined.   The LOAEL was 500 mg/kg, the lowest dose tested.

   Mutagenicity

     0  The mutagenic activity of picloram has been studied in a number of
        microbial systems.  Ames tests in several Salmonella typhimurium
        strains indicated that picloram was not mutagenic with or without
        activation by liver microsomal fractions (Andersen et al., 1972;
        Torracca et al., 1976; Carere et al., 1978).

     0  One study using the same system as above found picloram to be weakly
        mutagenic (Ercegovich and Rashid,  1977).

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Picloram                                                     August, 1987

                                     -8-
     0  Picloram was shown to be negative in the reversion of bacteriophage
        AP72 to T4 phenotype (Andersen et al., 1972), but positive in the
        forward mutation spot test utilizing Streptomyces coelicolor  (Carere
        et al., 1978).

     0  Irrespective of a weak mutagenic response in the Salmonella typhimurium
        test (Ercegovich and Rashid, 1977) and a positive forward mutation,
        the authors take the position that picloram is not mutagenic.  This
        view is supported by studies in male and female Sprague-Dawley rats
        fed picloram at dose levels of 20, 200 or 2,000 mg/kg/day in which no
        cytological changes in bone marrow cells were observed (Mensik et
        al., 1976).

   Carcinogenicity

     0  Picloram (at least 90% pure) was administered by diet to Osborne-
        Mendel rats and B6C3F1 mice (NCI, 1978; also reviewed by Reuber,
        1981).  Pooled controls from carcinogenicity studies run in the same
        laboratory (and room, at the Gulf South Research Institute) and over-
        lapping this study by at least 1 year were used.  Fifty male  rats
        were dosed with picloram at 208 or 417 mg/kg/day and 50 female rats
        were dosed at 361 or 723 mg/kg/day.  During the second year,  rough
        hair coats, diarrhea, pale mucous membranes, alopecia and abdominal
        distention were observed in treated rats.  In addition, a relatively
        high incidence of follicular hyperplasia, C-cell hyperplasia  and
        C-cell adenoma of the thyroid occurred in both sexes.  However, the
        statistical tests for adenoma did not show sufficient evidence for
        association of the tumor with picloram administration.  An increased
        incidence of hepatic neoplastic nodules  (considered to be benign tumors)
        was observed in treated animals.  In male rats, the lesion appeared
        in only three animals of the low-dose treatment group and was not
        significant when compared to controls.  However, the trend was signifi-
        cantly dose-related in females (p = 0.016).  The incidence in the
        high-dose group was significant (p = 0.014) when compared with that
        of the pooled control group.  The incidences of foci of cellular
        alteration of the liver were:  female rats - matched controls 0/10,
        low-dose 8/50, high-dose 18/49; male rats - matched controls  0/10,
        low-dose 12/49, high-dose 5/49.  Thus, there is evidence that picloram
        induced benign neoplastic nodules in the livers of rats of both
        sexes, but especially those of the females.  Subsequent laboratory
        review by the National Toxicology Program  (NTP) has questioned the
        findings of this study because animals with exposure to known carcinogens
        were placed in the same room with these animals and cross-contamination
        might have occurred.  In the same study, NCI  (1978), 50 male  and
        50 female mice received picloram at 208 or 417, and 361 or 723 mg/kg/day,
        respectively.  Body weights of mice were unaffected, and no consistent
        clinical signs attributable to treatment were reported during the
        first  6 months of the study, except isolated incidences of tremors
        and hyperactivity.  Later, particularly in the second year, rough
        hair coats, diarrhea, pale mucous membranes, alopecia and abdominal
        distention occurred.  No tumors were found in male or female  mice or
        male rats at incidences that could be significantly related to treatment.
        It was concluded that picloram was not a carcinogen for B6C3F-) mice.

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   Picloram                                    ,                August, 1987

                                        -9-
           Dow (1986) retested picloram (93% pure) in a 2-year chronic feeding/
           oncogenicity study in Fisher 344 rats.  Rats (50/sex/dose) were fed
           20, 60 or 200 mg/kg/day.   Oncogenic effects above those of controls
           were absent in this study.
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 =        or LOAEL )  x (BW) = _ mg/L ( _ Ug/L)
                        (UP) 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, 1 00 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 the One-day HA value for picloram.  It is, therefore,
   recommended that the Ten-day HA value for a 10-kg child (20 mg/L, calculated
   below) be used at this time as a conservative estimate of the One-day HA value,

   Ten-day Health Advisory

        The 7- to 14-day study in dogs  by Dow (1981) has been selected to serve
   as the basis for the Ten-day HA value for picloram because dogs appear to be
   the most sensitive species.  Ooses of 200, 400 or 800 mg/kg/day were used and
   the dose of 200 mg/kg/day was identified as the NOAEL for short-term exposures
   based on reduced food intake.  Other short-term studies include a 9-day study
   in dogs by Dow (1980a) with a NOAEL of 400 mg/kg/day and a 32-day study in
   mice by Dow (1980b) with a NOAEL of  900 mg/kg/day.

        Using a NOAEL of 200 mg/kg/day, the Ten-day HA for a 10-kg child is
   calculated as follows:

              Ten-day HA = (200 mg/kg/day )  (10 kg) = 2Q mg/L (20,000 ug/1)
                             (100) (1 L/day)

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Picloram                                  ,                  August,  1987

                                     -10-
where:

        200 mg/kg/day  NOAEL based on the absence of reduced feed intake in
                        beagle dogs exposed to picloram for 7 to 14 days.

                1 0 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 study by Dow (1983) has been selected to serve as the basis for the
Longer-term HA value for picloram because dogs have been shown to be
the species most sensitive to picloram.  In this study, picloram was fed for
6 months to beagle dogs (six/sex/group) in the diet at dose levels of 0, 7,
35 or 175 mg/kg/day.  At 175 mg/kg/day, the following adverse effects were
observed in both male and female dogs:  decreased body weight gain, food
consumption and alanine transaminase levels, increased alkaline phosphatase
levels, absolute liver weight and relative liver weight.  At 35 mg/kg/day,
increased absolute and relative liver weights were noted in males.  No
compound-related effects were detected in females at 35 mg/kg/day or in males
or females at 7 mg/kg/day.  Based on these data, 7 mg/kg/day was identified
as the NOAEL for dogs for a 6-month exposure.

      Using this study, the Longer-term HA for a 10-kg child is calculated as
follows:
          Longer-term  HA  =  ^ffiffl*^1)0* -  0.7 "g/L  (700  ug/L)


 where:

         7 mg/kg/day =  NOAEL, based on the absence of  relative  and  absolute
                       liver  weight changes.

               10 kg =  assumed  body weight of a child.

                100 =  uncertainty factor, chosen in accordance with  NAS/OCW
                       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 = (7 mg/kg/day)  (70) = 2.45 mg/L  (2,450 ug/L)
                            (100)  (2 L/day)
 where:
         7  mg/kg/day  =  NOAEL,  based  on  the  absence of  relative and absolute
                       liver  weight  changes.

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Picloram                                                     August, 1987

                                     -11-


              70 kg * assumed body weight of an adult.

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

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

Lifetime Health Advisory

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

     The study by Dow (1983), chosen for the Longer-term Health Advisory has
also been chosen to calculate the Lifetime HA value for picloram.  In this
study, picloram was fed for 6 months to beagle dogs (six/sex/group) in the diet
at dose levels of 0,  7,  35 or 175 mg/kg/day.  At 175 mg/kg/day, the following
adverse effects were observed in both male and female dogs:  decreased body
weight gain, food consumption and alanine transaminase levels, increased
alkaline phosphatase levels,  absolute liver weight and relative liver weight.
At 35 mg/kg/day, increased absolute and relative liver weights were noted in
males,  io compound-related effects were detected in females at 35 mg/kg/day
or in males or females at 7 mg/kg/day.  Based on these data, 7 mg/kg/day was
identified as the NOAEL for dogs for a 6-month exposure.  Therefore, the
Lifetime HA for picloram is determined as follows:

Step 1:  Determination of the Reference Dose (RfD)

                    RfD = (7  mg/kg/day) = 0<07 mg/kg/day
                             (100)
where:
        7 mg/kg/day =  NOAEL,  based on the absence of relative and absolute
                      liver  weight changes.

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   Picloram                                                     August,  1987

                                        -12-


                  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 = (0.07 mg/kg/day) (70) .  2.45   /L (2450   /L)
                             (2 L/day)

   where:

            0.07 mgAg/day = RfD.

                     70 kg - assumed body weight of an adult.

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

   Step  3:  Determination of the Lifetime Health Advisory

                Lifetime HA = (2.45 mg/L)  (20%) = 0.49 mg/L  (490 ug/L)

   where:

            2.45 mg/L = DWEL.

                  20% = assumed relative  source contribution from water.

   Evaluation  of Carcinogenic Potential

         0   The National Cancer Institute  conducted studies on the carcinogenic
            potential of picloram in rats  and mice  (NCI, 1978; this study
            was also reviewed by Reuber, 1981).  In the study with mice,  there
            was no indication of an oncogenic response from dietary exposure
            which  included  levels of more  than  5,000 ppm picloram  (723 mg/kg/day)
            for the  greater part of their  lifetime.  The rat study, however, was
            negative for oncogenic effects in males, while female rats exhibited
            a  statistically significant increase in neoplastic nodules in the
            liver.   On a time-weighted average, exposures ranged up to 14,875  ppm
            (743 mg/kg/day) picloram in the diet.

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

         0   Applying the criteria described in  EPA's guidelines for assessment
            of  carcinogenic risk  (U.S. EPA, 1986b), picloram may be classified
            in  Group D:  not classified.   This  group is generally used for sub-'
            stances  with inadequate human  and animal evidence of carcinogenicity
            or  for which no data are available.


VI.  OTHER CRITERIA,  GUIDANCE AND STANDARDS

         0   The U.S. EPA Office of Pesticide Programs has set an RfD  for  picloram
            at 0.07  mg/kg/day  (U.S. EPA, 1986b).

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      Picloram                                                     August, 1987

                                           -13-
           *  Tolerances have been established for picloram in or on raw agricultural
              commodities (U.S.  EPA,  1986c).

           0  The National Academy of Sciences (HAS,  1983) has calculated a chronic
              Suggested-No-Adverse-Response-Level (SNARL) of 1.05 mg/L for picloram.
              An uncertainty factor of 1,000 was  used because the issue of carcino-
              genicity had not yet been resolved  and  also because the Johnson (1971)
              study used by NAS does  not provide  enough information for a complete
              judgment of its adequacy.


 VII. ANALYTICAL METHODS

           0  Analysis of picloram is by a gas chromatographic (GC) method applicable
              to the determination of certain chlorinated acid pesticides in water
              samples (U.S.  EPA, 1986d).  In this method, approximately 1 liter of
              sample is acidified.  The compounds are extracted with ethyl ether
              using a separatory funnel.  The derivatives are hydrolyzed with
              potassium hydroxide and extraneous  organic material is removed by a
              solvent wash.   After acidification, the acids are extracted and
              converted to their methyl esters using  diazomethane.  Excess reagent
              is removed, and the esters are determined by electron-capture gas
              chromatography.  The method detection limit has not been determined
              for picloram.


VIII. TREATMENT TECHNOLOGIES

           0  The manufacture of this compound has been discontinued (Meister,
              1987).  No information  was found on treatment technologies capable of
              effectively removing picloram from  contaminated water.

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    Picloram                                                     August,  1987

                                         -14-


IX. REFERENCES

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Picloram                             .                        August, 1987
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Picloram                r                                 August,  1987

                                     -16-
Meister, R.,  ed.   1987.   Farm chemicals handbook.  Willoughby, OH:  Meister
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Picloram                                                  August, 1987

                                     -17-
Torracca, A.M., G.  Cordamone,  V.  Ortali, A. Carere, R. Raschette and G. Ricciardi.
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Confidential Business Information submitted to the Office of Pesticide
 Programs.

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