DIPHENAMID

          Health Advisory
      Office  of  Drinking Water
U.S.  Environmental  Protection Agency
                                                                August,  1987
                                                           DRAFT
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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    Diphenamid
                                                              August,  1987
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II. GENERAL INFORMATION AND  PROPERTIES

    CAS No.  957-51-7

    Structural Formula
                                  HC-C-N(CH,)2
                      N,N-dimethyl-alpha-phenyl-benzeneacetamide

    Synonyms

         e  Dymid;  Enide  (Meister,  1983).

    Uses

         0  Pre-emergent  and  selective herbicide  for tomatoes, peanuts, alfalfa,
            soybean,  cotton and other crops  (Meister, 1986).
                                          C16H17ON
                                          239.30
                                          White crystalline solid

                                          135C



                                          260 mg/L
Properties  (Windholz et al.,  1983)

        Chemical Formula
        Molecular Weight
        Physical State (at 25C)
        Boiling Point
        Melting Point
        Density
        Vapor Pressure (25C)
        Specific Gravity
        Water Solubility (27c)
        Log Octanol/Water Partition
          Coefficient
        Taste Threshold
        Odor Threshold
        Conversion Factor

Occurrence
         0  Diphenamid has  not been  found  in any of the water samples collected
            and analyzed from 567  ground water  locations  (STORET, 1987).

    Environmental Fate
            Diphenamid is  stable  to  hydrolysis at pH 5, 7 and 9 for 7, 12 and
            10 days,  respectively, at elevated temperature  (49C or 120F)
            (NOR-AM,  1986).

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     Diphenamid                                                     August,  1987

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          0   Diphenamid  is  intermediately mobile  (class  3)  on  silt loam and silty
             clay loam soil TLC plates;  on  sandy  loam, it is in class  5, indicating
             that it would  leach readily in this  soil  (Helling and Turner,  1968).
III. PHARMACOKINETICS

     Absorption

             No  information was  found in the  available literature on the absorption
             of  diphenamid.

     Distribution

          0   No  information was  found in the  available literature on the distri-
             bution of diphenamid.

     Metabolism

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

     Excretion

          0   No  information was  found in the  available literature on the excretion
             of  diphenamid.


 IV. HEALTH EFFECTS

     Humans

          0   No  information was  found in the  available literature on the health
             effects of diphenamid in humans.

     Animals

        Short-term Exposure

          0   RTECS (1985) reported the acute  oral LD5o values in the rat, mouse,
             dog, monkey and rabbit to be 60C, 700, 1,000, 1,000 and 1,500 mg/kg,
             respectively.

        Dermal/Ocular Effects

          0   Weddon and Brown (1976) applied  a 90% wettable powder formulation of
             diphenamid to intact or abraded  skin of New Zealand rabbits (two/sex/
             dose) for 24 hours  at 0, 200,  1,000 or 2,000 mg/kg.  No adverse
             responses were observed in any of the exposed animals.

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Diphenamid                                                    August, 1987

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   Long-term Exposure

     e  Woodard et al.  (1966b)  administered technical diphenamid (purity
        not specified)  in the feed to beagle dogs (three/sex/dose)  at dose
        levels of  0,  3,  10 or 30 mg/kg/day for 103 weeks.   No pathological
        effects were  reported at 3 mg/kg/day for clinical  chemistry, hematology,
        urinalysis, gross pathology and histopathology.   Liver weights were
        slightly increased in the 10- and 30-mg/kg/day dosage groups of both
        sexes, and there were slight increases in numbers  of portal macrophages
        and/or fibroblasts when compared to untreated controls.  Liver enzyme
        levels were normal in all treated groups, except for elevation of
        serum glutamic-oxaloacetic transaminase (SCOT) after 8 weeks in one
        female dosed  with 3 mg/kg/day.  A No-Observed-Adverse-Effect-Level
        (NOAEL) of 3  mg/kg/day and a Lowest-Observed-Adverse-Effect-Level
        (LOAEL) of 10 mg/kg/day were identified by this  study.

     0  Hollingsworth et al. (1966) fed technical diphenamid (>98%  pure) to
        rats (30/sex/dose) at dose levels of 0,  3,  10 or 30 mg/kg/day for 101
        weeks.  A  slight increase in the mean absolute liver weights of males
        and the relative liver and thyroid weights of females in the high-
        dose groups was observed.  No other adverse effects were reported
        at 10 mg/kg/day or less in general behavior,  feed  consumption, body
        and organ  weights, hematology, gross pathology and histopathology.
        A NOAEL of 10 mg/kg/day was identified by this study.

   Reproductive Effects

     0  In a three-generation reproduction study, Woodard  et al. (1966a)
        supplied diphenamid to albino rats (10 males and 20 females/dose) at
        dose levels of 0,  10 or 30 mg/kg/day.  No reproductive or pathological
        effects were  observed for the parental generations (Fg, F-UJ, F?]-,)
        at any dose tested.  Weanlings of the F3b generation dosed  with
        30 mg/kg/day  showed reversible liver changes, including slight
        congestion, glycogen depletion and irregular size  of the hepatocytes.
        Based on reproductive end points, this study identifies a NOAEL of
        30 mg/kg/day.  Based on fetal toxicity,  a NOAEL  of 10 mg/kg/day and
        a LOAEL of 30 mg/kg/day are identified.

   Developmental Effects

     0  Woodard et al.  M966a)  reported no developmental effects in rat pups
        at any dose level.  Reversible liver changes were  observed  in weanling
        pups of the F3b generation dosed with 30 mg/kg/day.  A NOAEL based on
        fetotoxicity  of 10 mg/kg/day can be identified.

   Mutagenicity

     0  Moriya et  al. (1983) reported that diphenamid (up  to 5,000  ug/plate)
        did not increase reversion frequency in .  typhimurium or . coli
        test systems, either with or without metabolic activation.

     0  Shirasu et al.  (1976) reported that diphenamid (1%) was not mutagenic
        in a recombination assay utilizing JJ. subtilis or  in reversion assays
        with E. coli  or S. typhimurium.

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   Diphenamid                                                    August,  1987

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      Carcinogenicity

        0  In a 2-year feeding  study in rats by Hollingsworth et al.  (1966),
           diphenamid was administered  to albino rats (30/sex/dose)  at dose
           levels of 0,  3,  10 or 30 mg/kg/day for 101 weeks.   Based  on
           histopathological examination of a variety of tissues and organs,
           the authors reported that the type and incidence of neoplasms  were
           comparable in treated and control rats.

        0  In a 2-year feeding  study in dogs by Woodard et al. (1966b), diphenamid
           was administered in  the feed to beagle dogs (three/sex/dose) at dosage
           levels of 0,  3,  10 or 30 mg/kg/day for 103 weeks.   Histopathological
           examinations  were performed  on a variety of tissues and organs, and
           no evidence of increased tumor frequency was reported.


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 = (NOAEi. or LOAEL)  x (BW) = 	   /L (	 u /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 diphenamid.   It is  therefore
   recommended that the  Drinking Water  Equivalent Level (DWEL), adjusted  for a
   10-kg child (0.3 mg/L,  calculated below), be used at this  time as  a conservative
   estimate of the One-day HA value.

        For a 10-kg child,  the  adjusted DWEL is calculated as follows:

                     DWEL = (0.03 mg/kg/day) (10 kg) = 0>3 mg/L
                                   (1 L/day)

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Diphenamid                                                    August, 1987

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where:

          0.03 mg/kg/day = RfD (see Lifetime Health Advisory Section).

                   10 kg = assumed body weight of a child.

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

Ten-day Health Advisory

     No information was found in the available literature that was suitable
for determination of the Ten-day HA value for diphenamid.  It is therefore
recommended that the DWEL, adjusted for a 10-kg child (0.3 mg/L) be used at
this time as a conservative estimate of the Ten-day HA value.

Longer-term Health Advisory

     No information was found in the available literature that was suitable
for determination of the Longer-term HA value for diphenamid.  It is therefore
recommended that the DWEL value, adjusted for a 10-kg child (0.3 mg/L) be
used at this time as a conservative estimate of the Longer-term HA value.

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 feeding study in dogs by Woodard et al. (1966b) has been selected to
serve as the basis for determination of the Lifetime HA value for diphenamid.
In this study, dogs were administered technical diphenamid (0, 3, 10 or 30
mg/kg/day) in the diet for 103 weeks.  Based on clinical chemistry, hematology,
urinalysis, gross pathology and histopathology, this study identified a NOAEL
of 3 mg/kg/day and a LOAEL of 10 mg/kg/day.  The study by Hollingsworth et al.

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Diphenamid                                                    August, 1987

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(1966), which identified a NOAEL of 10 mg/kg/day in a 101-week experiment in
rats, was not selected, since the rat appears to be somewhat less sensitive
than the dog (the NOAEL in the rat is the same as the LOAEL in the dog).

     Using a NOAEL of 3 mg/kg/day, the Lifetime HA is calculated as follows:

Step 1:  Determination of the Reference Dose (RfD)

                     RfD = (3 mg/kg/day) = 0>03 mg/kg/day
                               (100)

where:

        3 mg/kg/day = NOAEL,  based on absence of organ weight loss, clinical
                      chemistry,  hematology, urinalysis, gross pathology and
                      histopathology in dogs exposed to diphenamid via the
                      diet for 103 weeks.

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

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

           DWEL = (0.03 mg/kg/day) (70 kg) = uo mg/L (1f000 ug/L)
                         (2 L/day)

where:

        0.03 mg/kg/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 = (1.0 mg/L) (20%) = 0.2 mg/L (200 ug/L)

where:

        1.0 mg/L = DWEL.

             20% = assumed relative source contribution from water.

Evaluation of Carcinogenic Potential

     0   No evidence of carcinogenic potential was detected in rats (30/sex/dose)
        fed diphenamid in the diet for 2 years  at a dose level of 30 mg/kg/day
        (Hollingsworth et al., 1966),  or in dogs (three/sex/dose) fed diphenamid
        in the diet for 2 years,  also at a dose of 30 mg/kg/day (Woodward
        et al., 1966b).  These studies are limited by the low doses and  the
        small number of animals employed.

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      Diphenamid                                                     August,  1987

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

           0   Applying the criteria described  in EPA's  guidelines  for assessment
              of carcinogenic risk  (U.S.  EPA,  1986a), diphenamid is  classified in
              Group D:   not classified.   This  category  is  for substances  with
              inadequate animal  evidence  of  carcinogenicity.

  VI.  OTHER CRITERIA,  GUIDANCE AND STANDARDS

           0   Tolerances in or on raw agricultural commodities of  0.01  ppm for milk
              to 2 ppm for peanut hay and forage have been set for diphenamid (U.S.
              EPA, 1985).


 VII.  ANALYTICAL METHODS

           0   Analysis of diphenamid  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
              diphenamid 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

           0   Available data indicate that granular  activated carbon (GAC) adsorp-
              tion will remove diphenamid from water.

           8   whittaker (1980) experimentally  determined adsorption  isotherms for
              diphenamid on GAC.

           0   Whittaker (1980) reported the  results  of  GAC columns operating under
              bench-scale conditions.  At a  flow rate of 0.8 gpm/sq  ft and an empty
              bed contact time of 6 minutes, diphenamid breakthrough (when effluent
              concentration equals  10%  of influent concentration)  occurred after
              500 bed volumes (BV).   When two  bi-solute diphenamid solutions were
              passed over the same  column, diphenamid breakthrough occurred after
              235 BV for diphenamid-propham  solution and after 290 BV for diphenamid-
              fluometuron solution.

           0   GAC adsorption appears  to be  the most  effective treatment technique
              for the removal of diphenamid  from contaminated water.  However,
              selection of individual or  combinations of technologies to attempt
              diphenamid removal from water  must be  based on a case-by-case technical
              evaluation, and an assessment of the economics involved.

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    Diphenamid                                                    August, 1987
IX. REFERENCES

    Helling,  C.S.,  and B.C.  Turner.   1968.    Pesticide mobility:  Determination
         by soil TLC.   Science.   16:562-563.

    Hollingsworth R.L.,  M.W. Woodard and G.  Woodard.*  1966.  Diphenamid safety
         evaluation by dietary feeding to rats for 101 weeks.  Final Report.
         Unpublished study.   MRID 00076381.

    Meister,  R.T.,  ed.  1986.  Farm Chemicals Handbook.  Willoughby, OH:  Meister
         Publishing Co.

    Moriya, M.,  T.  Ohta,  K.  Watanabe,  T. Miyazawa, K. Kato and Y. Shirasu.  1983.
         Further mutagenicity studies on pesticides in bacterial reversion assay
         systems.  Mutat. Res.  116:185-216.

    NOR-AM.  1986.   NOR-AM Chemical Company.  Diphenamid:  Hydrolysis study (ground
         water data call-in).  Wilmington,  DE.  Unpublished study submitted to the
         Office  of  Pesticide Programs.

    RTECS.   1985.  Registry  of Toxic Effects of Chemical Substances.  National
         Institute  for Occupational Safety and Health.  Washington, DC.  National
         Library of Medicine On-Line File.

    Shirasu,  Y., M. Moriya,  K. Kato, A. Furuhashi and T. Kada.  1976.  Mutagenicity
         screening  of pesticides in the microbial system.  Mutat. Res.  40:19-30.

    STORET.  1987.

    TDB.  1985.   Toxicology  Data Bank.  MEDLARS II.  National Library of Medicine's
         National Interactive Retrieval Service.

    U.S. EPA.  1985.  U.S. Environmental Protection Agency.  Code of Federal
         Regulations.   40 CFR 180.230.

    U.S. EPA.  1986a.   U.S.  Environmental Protection Agency.  Guidelines for
         carcinogen risk assessment.  Fed.  Reg.  51(185):33992-34003.  September 24.

    U.S. EPA.  1986b.   U.S.  Environmental Protection Agency.  U.S. EPA Method #1
         - Determination of  nitrogen and phosphorus containing pesticides in
         ground  water by GC/NPD, January 1986 draft.  Available from U.S. EPA's
         Environmental Monitoring and Support Laboratory, Cincinnati, OH.

    Weddon T.E., and P.K. Brown.*  1976.  Enide 90 WDermal LD50 and skin
         irritation evaluation in New Zealand rabbits.  Technical Report No.
         124-9610-MWG-76-6.   Unpublished study.  MRID 00054611.

    Whittaker, K.F.   1980.   Adsorption of selected pesticides by activated carbon
         using isotherm  and  continuous flow  column systems.  Ph.D.  Thesis, Purdue
         University.

    Windholz, M., S.  Budavari,  R.F.  Blumetti and E.S.  Otterbein,  eds.  1983.  The
         Merck Index,  10th ed.   Rahway,  NJ:   Merck and Co., Inc.

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Diphenamid                                                    August, 1987
                    i           '
                                     -10-
Woodard M.W., G. Woodard and M.T.  Cronin.*  1966a.  Diphenamid:  three-genera-
     tion reproduction study in rats.  Unpublished study.  MRID 00076383.

Woodard M.W., G. Woodard and M.T.  Cronin.*  1966b.  Diphenamid safety evaluation
     by dietary feeding to dogs for 103 weeks.  Final Report.  Unpublished
     Study.  MRID 00076382.
 Confidential Business Information submitted  to  the Office of Pesticide
  Programs.

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