x                        August,  1987
                                                                          t
                                     PRONAMIDE

                                  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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    Pronamide
                                                               August,  1987
                                         -2-
II.  GENERAL INFORMATION AND PROPERTIES

    CAS No.   23950-58-5

    Structural Formula
                                          0 H CH3
                                          C-N-C-CsCH
                                                 I
                                                 CH3
                   3,5-Dichloro(N-1,1-dimethyl-2-propynyl)benzamide

    Synonyms

         8  Kerb*;  Kerb*  SOW;  Propyzamide; RH315  (Meister,  1983).

    Uses

         0  Pronamide is  used  as  an herbicide  for pre-  or  postemergence weed  and
            grass  control in small,  seeded legumes  grown for  forage  or  seed,
            southern turf,  direct seeded  or  transplanted lettuce,  endive,  escarole,
            woody  ornamentals,  nursery  stock and  Christmas trees  (Meister,  1983).
                                           C12HnCl2ON
                                           256.14
                                           White crystals
                                            154  to  156°C
                                            8o5  x 10-5  mm  Hg
                                            0.48 gm/cc
                                            0.015 mg/L
                                            3.05 to 3.27
Properties   (NIOSH,  1985; TDB,  1985)

        Chemical  Formula
        Molecular Weight
        Physical  State  (25°C)
        Boiling Point
        Melting Point
        Vapor Pressure  (25°C)
        Specific  Gravity
        Water Solubility
        Log Octanol/Water Partition
          Coefficient
        Taste Threshold
        Odor Threshold
        Conversion Factor

Occurrence
         0  Pronamide has been found in 18 of 258 ground water samples analyzed
            (STORET, 1987).  No surface water samples were collected,  and samples
            were collected from 252 ground water locations.   Pronamide was found
            only in California.  The 85th percentile of all  nonzero samples was
            1  ug/L, and the maximum concentration found was  1  ug/L.

    Environmental Fate

         •  14c-Pronamide (100% radiopurity)  at 1.5 ppm hydrolyzes very slowly
            (10% of applied material) in sterile, deionized  water buffered to

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             pH 5,  ~l,  and 9 and  incubated  at 20°C for 28 days  in the dark (Rohm
             and Haas  Bristol  Research  Laboratories,  1973).   The following minor
             hydrolysis products were identified:  RH-24,644 (2-(3,5-dichlorophenyl)-
             4,4-dimethyl-5methyleneoxazoline);  RH-24,580 (3,5-dichloro-N-(l,l-
             dimethylacetonyl) benzamide);  and  RH-25,891 (2-(3,5-dichlorophenyl)-
             4,4-dimethyl-5-hydroxymethyl-oxazoline).  Similar results were obtained
             in other  hydrolysis studies  (Rohm  and Haas Bristol Research Laboratories,
             1970).

          0  Pronamide has a half-life  of  10 to 120 days in  aerobic  soils (Fisher,
             1971;  Walker, 1976; Walker and Thompson, 1977;  Walker,  1978; Hance,
             1979;).  Complete experimental conditions and purity were not specified,
             and/or a  formulated product was applied.  The degradation rate does
             not appear to depend upon  soil texture.   However, increasing soil
             temperature, and  to a lesser  extent, soil moisture and  pH enhance
             pronamide degradation.  The major  degradates are RH-24,580 and
             RH-24,644.  Soil  sterilization greatly reduced  the degradation rate
             of pronamide.  Pronamide  (at  a recommended application  rate of 0.5 to
             2 Ib/A) does not  inhibit the  growth or CC>2 evolution of bacteria and
             fungi  (Lashen, 1970).

          0  Pronamide is moderately mobile in  soils  ranging in texture from loamy
             sand to clay based  on preliminary  soil column and adsorption/desorption
             tests  (Walker and Thompson, 1977;  Rohm and Haas Company, 1971; Fisher
             and Satterthwaitte, 1971). The two major degradates of pronamide
             (RH-24,580 and RH-24,644)  are mobile in  sand and  clay soils (Fisher,
             1973).  The mobility of pronamide  and its two major degradates tends
             to decrease as the  organic matter  content, clay content and cation
             exchange  capacity of the soil increases.

          0  The dissipation rate of pronamide  from terrestrial field sites is
             quite  variable, with half-lives ranging  from 10 to 90 days (Benson,
             1973;  Walker, 1976; Hance  et  al.,  1978a; Hance  et al.,  1978b; Kostowska
             et al., 1978; Walker, 1978; Zandvoort et al., 1979).  Data are insuf-
             ficient to determine the effect, if any, of meteorological conditions
             or the role leaching may play in pronamide dissipation.

          0  The environmental fate of  pronamide is the subject of several unpub-
             lished, undated reports  (Cummings  and Yin; Fisher and Cummings; Rohm
             and Haas; Satterthwaite and Fisher; Yin).


III. PHARMACOKIN ETICS

     Absorption

          0  No information on the absorption of pronamide was found ir. the
             available literature.

     Distribution

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

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   Metabolism

         0  About 54 and 0.6% of the radioactivity was recovered as unmetabolized
           Kerb* in the feces and urine, respectively, of rats treated orally  with
           (14c-carbonyl)-pronamide (dose not specified)  (Yin and Swithenbank,
           undated).  The major metabolite in the feces was 2-(3,5-dichlorophenyl)-
           4,4-dimethyl-5-hydroxymethyloxazoline  (15%), and the major metabolites
           in the urine were  <*-(3, 5-dichlorobenzamido) isobutyric acid  (22.4%),
           B-(3,5-dichlorobenzamido)-a-hydroxy-8 methyl-butyric acid  (19.2%),  and
           two unknown metabolites (24.1 and 16.7%).

         •  Unmetabolized Kerb* did not appear in the urine of cows treated  orally
           with (14C-carbonyl) Kerb*; the major metabolite was  6-(3,5-dichloro-
           benzamido)-o-hydroxy-B-methyl-butyric acid (71.4%)(Yin and Swithenbank,
           undated).
    Excretion
           After oral  ingestion of radiolabeled Kerb*  by  rats,  unmetabolized
           Kerb* accounted  for 54 and  0.6% of  the radioactivity recovered  in
           feces and urine, respectively.  In  the cow,  oral  ingestion of Kerb®
           produced no unmetabolized Kerb* in  the urine (Yih and Swithenbank,
           undated).
IV.  HEALTH EFFECTS

    Humans
            No information on the  health  effects of pronamide in humans was found
            in the available literature.
    Animals
       Short-term Exposure

         0  The acute oral LD50 in rats for pronamide (technical)  is in the range
            of 8,350 mg/kg bw (Meister, 1984)  to 16,000 mg/kg bw (Powers,  1970a).

       Dermal/Ocular Effects

         0  Pronamide is not a primary dermal irritant to albino rabbits.   In two
            separate studies, an aqueous paste of 500 mg pronamide  [50% active
            ingredient (a.i.)] was applied to the skin of six rabbits for 24 hours
            (Powers, 1970c; Regel, 1972).  No signs of irritation were observed
            by Powers (1970c).  Twenty-four hours after exposure,  Regel (1972)
            observed erythema, which subsided at 72 hours.

         0  Powers (1970b) administered 100 mg of Kerb* (50% a.i.) in the con-
            junctival sac of 12 rabbits.  Eye irritation and chemosis were noted
            at 24 hours but disappeared by day 7, as confirmed by fluorescein
            examination.

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   Long-term Exposure

     8  Rats (10/sex/dose)  were fed a diet containing 0,  50,  150, 450, 1,350
        or 4,050  ppm pronamide (100% a.i.) for 3 months (Larson and Borzelleca,
        1967a).   This  corresponds to 0,  2.5,  7.5,  22.5, 67.5  or 202.5
        nig/kg/day,  assuming 1  ppm in feed is  equivalent to 0.05 mg/Jcg/day
        (Lehman,  1959).   Significant body weight depression was observed at
        the 4,050 ppm  dose  level.  Initial significant body weight depression
        also occurred  in  the rats fed 1,350 ppm, but disappeared on continued
        feeding.  At the  150 ppm dose, absolute and relative  liver weights in
        females were-significantly higher than in controls; no histological
        lesions were seen,  and no dose-related trend was  observed for this
        increase  in relative liver weight. Individual data were not presented
        for organ weights and several other parameters, clinical observations
        were not  presented  and analytical determination of the test compound
        was not reported.  The No-Observed-Adverse-Effect-Level (NOAEL)
        identified  in  this  study was 2.5 mg/kg/day.

     0  Beagle dogs (10 months old; one/sex/dose)  were fed a  diet containing
        0, 450, 1350 or 4050 ppm pronamide (100% a.i.) for 3  months (Larson
        and Borzelleca, 1967b).  This corresponds to approximate doses of
        0, 10, 30 or 90 mg/kg/day, assuming 1 ppm in feed is  equivalent to
        0.025 mg/kg/day (Lehman, 1959).   A decrease in weight gain and food
        consumption and an  increase in serum  alkaline phosphatase, liver
        weight and  liver-to-body weight  ratios, as compared to controls,
        were seen in the  animals dosed at 4,050 ppm.  No  histological changes
        were seen in the  livers.  The hematological and urinalysis findings
        were within normal  ranges.  The  NOAEL identified  in this study was
        30 mg/kg/day.

     0  In a 2-year feeding study in beagle dogs (four/sex/dose) the addition
        of pronamide  (97% a.i.) to the diet at dose levels of 0, 30, 100 or
        300 ppm  (0, 0.75, 2.5 or 7.5 mg/kg/day, assuming 1 ppm in feed is
        equivalent  to  0.025 mg/kg/day; Lehman, 1959) caused no adverse effects
        at any of the  doses tested (Larson and Borzelleca, 1970b).  A NOAEL
        of 7.5 mg/kg/day  (the highest dose tested) was identified in this
        study.

     0  Smith (1974) administered Kerb*  (97%  a.i.) to 6-week-old (C57 BL16 x
        C3H Anf)Fi  male  and female mice (100/sex/dose),  for  78 weeks at
        dietary concentrations of 0, 1000 or  2000 ppm (0, 150 or 300 mg/kg/day,
        assuming  1  ppm in feed is equivalent  to 0.15 mg/kg/day; Lehman, 1959)
        pronamide.  Male  and female mice that ingested 2000 ppm gained sig-
        nificantly  less weight (p <0.05); males also exhibited adenomatous
        hyperplasia, degeneration, hyperplasia, intrahepatic  cholestasis,
        necrosis  and/or fatty changes of the  liver.  Liver weights were
        significantly  increased over controls for males and females in both
        treatment groups.  Based on this information, a Lowest-Observed-Adverse-
        Effect-Level (LOAEL) of 1,000 ppm (150 mg/kg/day) was identified.

     0  Newberne  et al.  (1982) administered pronamide (94% a.i.) to male
        B6C3F1 mice at dose levels of 0, 20,  100,  500 or  2,500 ppm (0, 3,
        15, 75 or 375  mg/kg/day, assuming 1 ppm in feed is equivalent to

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        0.15 mg/kg/day:  Lehman,  1959)  for up to 24 months.  Another group was
        fed 2,500 ppm (375 mg/kg/day)  pronamide for 6 months.   The mean body
        weight of the mice fed 2,500 ppm was significantly depressed at 14 days
        and thereafter throughout the study.  At the 24-month  sacrifice, the
        mean body weight of this group was approximately 70% of the control
        group.  Survival of the mice was unaffected.  The highest dose level
        (2,500 ppm)  resulted in liver lesions including bile duct hyperplasia,
        parenchymal  cell hypertrophy,  parenchymal cell necrosis, hyperplasia
        and cholestasis  at all time periods examined.  Based on this infor-
        mation, a NOAEL of 500 ppm (75 mg/kg/day) was identified.

   Reproductive Effects

     0  In a teratogenicity study in New Zealand White rabbits (18/dose),
        pronamide was administered at levels of 0, 5, 20 or 80 mg/kg/day
        (technical,  97%  pure)  during gestation days 7 to 19 (Costlow and
        Kane, 1985).  Five abortions were observed in the 80 mg/kg/day group.
        There were no compound-related effects on the incidence of implantations,
        resorptions, fetal deaths or on fetal body weight at any dose tested.
        Maternal toxicity (anorexia, vacuolation of hepatocytes) was observed
        in the 20-mg/kg/day group.  A NOAEL of 20 mg/kg/day was identified
        based upon the absence of developmental/reproductive effects and a
        NOAEL of 5 mg/kg/day was identified based upon the absence of maternal
        toxicity.

     0  In a three-generation reproduction study, 20 to 25 albino CD rats were
        fed a diet containing pronamide (RH-315; purity not stated) at dose
        levels of 0, 30, 100 or 300 ppm (Larson and Borzelleca, 1970c).
        Assuming 1 ppm in the diet is equivalent to 0.05 mg/kg/day, this
        corresponds  to doses of 0, 1.5, 5 or 15 mg/kg/day (Lehman, 1959).
        The authors  reported no adverse reproductive effects in parents or
        pups, but individual animal data were not available to validate the
        above conclusions.  Based on this information a NOAEL  of 300 ppm (15
        ing/kg/day, the highest dose tested) was identified.

   Developmental Effects

     0  In a teratogenicity study in New Zealand White rabbits (18/dose),
        pronamide was administered at levels of 0, 5, 20 or 80 mg/kg/day
        (technical,  97% pure) during gestation days 7 to 19 (Costlow and
        Kane, 1985).  An increased incidence of gross and microscopic liver
        lesions, one materna^. death, five abortions and a significant
        (p <0.05) decrease in the maternal body weight gain were observed at
        the 80-mg/kg/day dose.  At the 20-mg/kg/day dose, rabbits exhibited
        anorexia, vacuolation of hepatocytes and a slight decrease in body
        weight gain.  There were no compound-related effects on the incidence
        of implantations, resorptions, fetal deaths or on fetal body weight
        at any dose tested.  The NOAEL in this study was 5 mg/kg/day based
        on maternal effects, and 80 mg/kg/day based on developmental effects.

     0  In a study designed to evaluate fetal development, adult female rats
        (FDRL) were administered 0, 7.5 or 15 mg/kg/day pronamide by gavage
        in corn oil from days 6 through 16 of gestation (Vogin, 1972).  No

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        adverse effects were reported for the mean number of implantation
        sites,  the number of live or dead fetuses or the mean fetal weight.
        The authors concluded that pronamide administered orally to rats at
        doses up to 15 mg/kg/day was not teratogenic, but individual animal
        data were not available to validate these conclusions.  Based on this
        information a NOAEL of 15 mg/kg/day (the highest dose tested) was
        identified.

   Mutagenicity

     0  In a cytogenetic study, pronamide (Kerb®, analytical) administered
        by intragastric intubation at dose levels of 5, 50 or 500 mg/kg to
        rats did not produce any aberrations of the bone marrow chromosomes
        (Fabrizio, 1973).

   Carcinogenicity

     0  In a study evaluating the carcinogenic potential of Kerb®, 6-week-old
        (C57 BL16 x C3H Anf)F1 male and female mice (100/sex/dose) were fed
        pronamide (97% a.i.) in the diet at doses of 0, 1,000 or 2,000 ppm
        (0, 150 or 300 mg/kg/day, assuming 1 ppm in feed is equivalent to
        0.15 mg/kg/day; Lehman, 1959) for 78 weeks (Smith, 1974).  Male and
        female mice that ingested 2,000 ppm gained significantly less weight
        (p <0.05); the animals also gained slightly less weight at the 1,000-ppm
        level,  but the change was not significant.  No increase in tumors was
        observed for female mice treated with pronamide over controls.  For
        male mice, a total of 35 of the 99 animals in the high-dose group,
        21 of the 100 animals in the low-dose group and 7 of the 100 animals
        in the control group developed hepatic neoplasms, of which 24, 18
        and 7 were carcinomas in the high-dose, low-dose and control groups,
        respectively.  A total of 28 of 99 male mice that ingested 2,000 ppm
        exhibited intrahepatic cholestasis, but did not have carcinomas of
        the liver.

     0  In a 2-year study in male B6C3F-J mice (Newberne et al., 1982),
        pronamide was fed to the animals (63 animals/dose) at dose levels of 0,
        20, 100, 500 or 2,500 ppm (0, 3, 15, 75 or 375 mg/kg/day, assuming 1
        ppm in feed is equivalent to 0.15 mg/kg/day; Lehman, 1959).  Another
        group was fed 2,500 ppm ('375 mg/kg/day) pronaaide for 6 months.  The
        mean body weight of mice fed 2,500 ppm was significantly depressed at
        14 days and thereafter throughout the study.  At the 24-month sacrifice,
        the mean body weight of this group was approximately 70% of the con-
        trol group.  Survival of the mice was unaffected.  The highest dose
        (2,500 ppm) resulted in liver lesions, including bile duct hyperplasia,
        parenchymal cell hypertrophy, parenchymal cell necrosis, hyperplasia
        and cholestasis at all time periods examined.  At 18 months, the
        2,500-ppm dose group had increased parenchymal cell neoplasms, but
        this was not statistically different from the controls.  At 24 months,
        there was a statistically significant increased incidence of hepatic
        adenomas and carcinomas in the 500- and 2,500-ppm dose groups.  The
        incidence of hepatic carcinomas was 5/63, 9/63, 12/63, 18/63 and
        14/61 in the control, 20-ppm, 100-ppm, 500-ppm and 2,500-ppm groups,
        respectively.  Thus, the liver appears to be the target organ for

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           neoplasia.  According to the authors, hypertrophy and hyperplasia
           are not uncommon in untreated older mice of this strain.  However,
           pronamide tended to shift the onset of these lesions to an earlier age.

      0    Pronamide in the diet at dose levels of 0, 30, 100 or 300 ppm  (0,
           1.5,  5 or 15 mg/kg/day,  assuming 1  ppm in feed is equivalent to
           0.05 mg/kg/day;  Lehman,  1959) fed to rats (30/sex/group) for 2 years
           did not produce  any carcinogenic effects (Larson and Borzelleca,
           1970a).  However,  doses  used in this study were too low to assess the
           carcinogenic potential of pronamide.


V. QUANTIFICATION OF TOXICOLOGICAL  EFFECTS

        Health Advisories (HAs) are generally determined for one-day, ten-day,
   longer-term (approximately 7 years) and lifetime exposures if adequate data
   are available that identify a sensitive noncarcinogenic end point of toxicity.
   The HAs for noncarcinogenic toxicants are derived using the following  formula:

                 HA = (NOAEL or LOAEL) x (BW) = 	 mg/L (__ ug/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 the One—day HA value for pronamide.  It is therefore
   recommended that the Lifetime HA value of 0.052 mg/L  (52 ug/L) be used at
   this time as a conservative estimate of the One-day HA value for pronamide.

   Ten-day Health Advisory

        Little information is available on the acute toxicity of pronamide.
   Toxicity from acute exposure to pronamide has been assessed in three
   reproduction/teratology studies, but it is not possible to evaluate the
   most sensitive end point for acute toxicity from these studies.  No effects
   were observed in rats exposed to pronamide via gavage (Vogin, 1972) or in
   feed  (Larson and Borzelleca, 1967b) at doses as high as 15 mg/kg/day.  No
   higher doses were tested in the rat, but higher doses have been tested in the
   rabbit  (Costlow and Kane, 1985).  In this study, New Zealand White rabbits

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were administered pronamide during gestation days 7 through 19 at dose levels
of 0, 5, 20 or 80 mg/kg/day.  Toxic effects observed at the highest dose
include a statistically significant decrease in maternal body weight gain
and an increased incidence of gross and microscopic liver lesions.  Less
significant effects on body weight and liver toxicity were observed at the
20-mg/kg/day dose, and a NOAEL of 5 mg/kg/day was identified.  This value
is similar to the NOAEL identified from a 2-year feeding study in dogs
(7.5 mg/kg/day; Larson and Borzelleca, 1970b), which is used as the basis
for the Lifetime HA.  Considering the limitations of the database on pronamide,
it is therefore recommended that the Lifetime HA value of 0.052~mg/L (52 ug/L),
calculated below, be used at this time as a conservative estimate of the
Ten-day HA value for pronamide.

Longer-term Health Advisory

     Liver toxicity has been observed after acute, subchronic and chronic
administration of pronamide to experimental animals.  Adverse effects on the
liver have been observed after acute exposure of rabbits to 80 mg/kg/day via
gavage (Costlow and Kane, 1985), subchronic exposure of rats and dogs to
7.5 mg/kg/day and 90 mg/kg/day, respectively (Larson and Borzelleca, 1967a,b),
and chronic feeding of 300 and 375 mg/kg/day to mice (Smith, 1974; Newberne
et al, 1982).  In contrast to the subchronic rat feeding study, a NOAEL of
15 mg/kg/day was identified in a 2-year rat feeding study (Larson and-
Borzelleca, 1970a); however, this study was invalidated (U.S. EPA, 1985).
Both rat studies suffer similar deficiencies, which make them unsuitable to
serve as the basis for HA values (U.S. EPA, 1985a).  Considering the limita-
tions of the database on pronamide and the potential for this compound to
cause liver damage, it is therefore recommended that the Lifetime HA value
of 0.052 mg/L  (52 ug/L) be used at this time as a conservative estimate of
the Longer-term HA value for pronamide.

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

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                                     -10-
carcinogenic potential (U.S. EPA, 1986a), then caution should be exercised in
assessing the risks associated with lifetime exposure to this chemical.

     Two-year chronic pronamide feeding studies have been performed in three
species:  the rat (Larson and Borzelleca, 1970a), dog (Larson and Borzelleca,
1970b), and mouse (Newberne et al., 1982).  For the rat and dog studies, only
low doses were used and no toxic effects were observed.   The highest doses
tested, 15 mg/kg/day (rat) and 7.5 mg/kg/day (dog), were identified as NOAELs
for these studies.   Because of various deficiencies in the rat study, this
study was not validated (U.S. EPA, 1985), and is therefore not acceptable as
the basis for the Lifetime HA value.  The 2-year study performed on mice
(Newberne et al., 1982) was rejected as the basis for the Lifetime HA because
of the relative insensitivity of mice to pronamide compared to other species.
The NOAEL of 75 mg/kg/day identified in this study was higher than doses
causing liver toxicity in subchronic feeding studies in both the rat and dog
(Larson and Borzelleca, 1967a,b).  Taking all of these studies into consid-
eration, the 2-year feeding study in dogs (Larson and Borzelleca, 1970b) was
selected as the basis for determination of the Lifetime HA for pronamide.
In this study, beagle dogs fed a diet containing pronamide at dose levels of
0, 30, 100 or 300 ppm (0, 0.75, 2.5 or 7.5 mg/kg/day) for 2 years showed no
adverse effects at any of the doses tested.  A NOAEL of 7.5 mg/kg/day (the
highest dose tested) was identified in this study.

     Using a NOAEL of 7.5 mg/kg/day, the Lifetime HA is calculated as follows:

Step 1:  Determination of the Reference Dose (RfD)

                   RfD =  (7'5 mg/kg/day) = 0.075 mg/kg/day
                              (100)

where:

        7.5 mg/kg/day » NOAEL, based on the absence of adverse effects in
                        dogs administered pronamide in the diet for 2 years.

                  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 = (0.075 mg/kg/day)  (70 kg) , 2.6 mg/L  (2,600 ug/L)
                          2 L/day

where:

        0.075 mg/kg/day = RfD.

                  70 kg = assumed body weight of an adult.

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

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     Pronamide                                                       August, 1987

                                          -11-


     Step 3:  Determination of the Lifetime Health Advisory
                 Lifetime HA = (2'6 mg/D (20%) = 0.052 mg/L (52 ug/L)
                                     (10)

     where:

             2.6 mg/L = DWEL.

                  20% = assumed relative source contribution from water.

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

     Evaluation of Carcinogenic Potential

          0  Applying the criteria described in EPA's final guidelines for assess-
             ment of carcinogenic risk (U.S. EPA, 1986a), pronamide has tentatively
             been classified in Group C:  possible human carcinogen.  This category
             is for substances with limited evidence of carcinogenicity in animals
             in the absence of human data.


 VI. OTHER CRITERIA, GUIDANCE AND STANDARDS

          0  A Provisional Acceptable Daily Intake (PADI) of 0.0750 mg/kg/day and
             a calculated Theoretical Maximum Residue Concentration (TMRC) of
             0.0409 mg/day that utilizes 0.91% of the PADI has been established
             (U.S. EPA, 1985a).

          8  Residue tolerances have been established for pronamide and its metabo-
             lites in or on raw agricultural commodities that range from 0.02 ppm
             to 10.0 ppm (U.S. EPA,  1985b).


VII. ANALYTICAL METHODS

          0  Analysis of pronamide is by a gas chromatographic (GC) method appli-
             cable to the determination of certain nitrogen-phosphorus containing
             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 a nitrogen-phosphorus
             detector.  The method detection limit has not been determined for
             pronamide, but it is estimated that the detection limits for analytes
             included in this method are in the range of 0.1 to 2 ug/L.


VIII. TREATMENT TECHNOLOGIES

             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.

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                                     -12-
        Larson et al. (1982) report 99% removal efficiency of chlorinated
        pesticides by a thin-film composite polyamide membrane operating at a
        maximum pressure of 1,000 psi and at a maximum temperature of  113°F.
        More operational data are required, however, to specifically determine
        the effectiveness and feasibility of applying RO for the removal of
        pronamide from water.  Also, membrane adsorption must be considered
        when evaluating RO performance in the treatment of pronamide-contami-
        nated drinking water supplies.

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    Pronamide                                                        August,  1987

                                         -13-


IX. REFERENCES

    Benson, N.R.   1973.  Efficacy, leaching and persistence of herbicides  in
         apple orchards.  Bulletin 863.  Washington State University, College  of
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    Costlow, R.D., and W.W. Kane.*  1985.  Teratology study with Kerb technical  (no
         clay) in rabbits.  Unpublished study no. 83R-026 prepared and submitted
         by Rohm and Haas Company, Spring House, PA.  Accession no.  256590.

    Cummings, T.L., and R.Y. Yih.  Undated.  Metabolism of Kerb (3,5-dichloro-N-
         (l,l-dimethyl-2-propynyl)benzamide) in different types of soil.
         Unpublished report prepared by Rohm and Haas Co., Philadelphia, PA.
         Memorandum Report No. 52.

    Fabrizio, P.O.A.*  1973.  Final report:  Cytogenetic study:  Kerb analytical.
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         Kensington, MD for Rohm and Haas Company, Philadelphia, PA.  April  16.
         MRID 00038031.

    Fisher, J.D.   1971.  Dissipation and metabolism study of Kerb in soil  and  its
         effects on microbial activity.  Unpublished report prepared by Rohm and
         Haas Co., Philadelphia, PA.  Lab. 11 Research Report No. 11-229.

    Fisher J.D.  1973.  Soil leaching study with Kerb degradation products RH-24,
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         Philadelphia, PA.  Tech. Report No. 3923-73-4.

    Fisher, J.D., and T.L. Cummings.  Undated.  Biodegradation study of carbonyl-
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         sludge test.  Unpublished study prepared by Rohm and Haas Co, Philadelphia,
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    Fisher, J.D., and S.T. Satterthwaite.  1971.  Leaching and metabolism  studies
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    Hance,  R.J.  1979.  Effect of pH on the degradation of atrazine, dichlorprop,
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    Hance,  R.J.,  P.O. Smith, T.H. Byast and E.G. Cotterill.  1978a.  Effects of
         cultivation on the persistence and phytotoxicity of atrazine and  propy-
         zamide.   Proc. Br. Crop Prot. Conf. Weeds.  14(2):541-547.

    Hance,  R.J.,  P.O. Smith, E.G. Cotterill and D.C. Reid.  1978b.   Herbicide
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    Kostowska, B., J. Rola and H. Slawinska.  1978.  Decomposition dynamics  of
         propyzamide in experiments with winter rape.  Pamiet. Pulawski.
         70:199-205.

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                                     -14-
Larson, P.S., and J.F. Borzelleca.*  1967a.  Toxicologic study on  the  effect
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Larson, P.S., and J.F. Borzelleca.*  1967b.  Toxicologic study on  the  effect of
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Larson, P.S., and J.F. Borzelleca.*  1970b.  Toxicologic study on  the  effect
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Larson, P.S., and J.F. Borzelleca.*  1970c.  Three-generation reproduction  studyt
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Larson, R.E., P.S. Cartwright, P.K. Eriksson and R.J. Petersen.   1982.
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Lashen, E.S.  1970.   Inhibitory effects of Kerb and Kerb transformation
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NIOSH.  1985.  National Institute for Occupational Safety and  Health.  Registry
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                                                   ?
                                     -15-
Powers, M.B.*  1970a.  Final Report (Study 1) - Acute Oral - Rats.   Unpublished
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Powers, M.B.*  1970c.  Final Report (Study 4) - Primary Skin - Rabbits.
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                                     -16-
U.S. EPA.  1985b.  U.S. Environmental Protection Agency.  Code of Federal
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