August, 1987
                                  Health Advisory
                              Office of Drinking Water
                        U.S.  Environmental Protection Agency
        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

        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 tl an another.
   Because each model is  based on differing assumptions, the estimates that are
   derived can differ by  several  orders  of magnitude.

    Glyphosate                                                        August, 1987



    CAS No.  1071-83-6

    Structural Formula
                                           O           0
                                                 I      I
                                                 H      OH

                             Glycine, N-(Phosphonomethyl)


            Rodeo*;  Roundup*.


         0  Herbicide for  control  of  grasses,  broad leaved weeds and woody brush
            (U.S.  EPA, 1986b).

    Properties (Meister, 1983)

            Chemical Formula              C3HgN05P
            Molecular Weight              169.07
            Physical State (25C)          White crystalline solid
            Boiling  Point
            Melting  Point                  200C
            Density                        1.74
            Vapor  Pressure                
            Water  Solubility              10 g/L
            Log Octanol/Water Partition
            Taste  Threshold
            Odor Threshold
            Conversion Factor             


         0  Glyphosate has been  found in none of the :-:urface water samples and
            in only  1 of the ground water samples (in the state of California)
            analyzed from  64 samples  taken at 61 locations (STORET,  1987).

    Environmental  Fate

         0  14c-Glyphosate (94%  glyphosate,  5.9% aminomethylphosphonic acid) and
            aminomethylphosphonic  acid  were stable  in sterile buffered water at
            pH 3,  6, and 9 during  35  days of incubation in the dark  at 5 and 35C
            (Brightwell  and  Malik, 1978).

         0  14c-Glyphosate (94%  glyphosate,  5.9% aninomethylphosphonic acid) was
            adsorbed to  Drummer  silty clay loam, Ray silt,  Spinks sandy loam,

     Glyphosate                                                         August,  1987

             Lintonia  sandy  loam, and Cattail  Swamp sediment with  Freundlich-K
             values  of 62, 90,  70,  22, and  175,  respectively (Brightwell  and
             Malik,  1978).   For each soil preparation,  the  maximum percentages
             of  applied glyphosate  desorbed  were 5.3,  3.7,  3.6,  11.5,  and 0.9%,
             respectively.   At  concentrations  ranging  from  0.21  to 50.1 ppm,
             14c-Glyphosate  was highly adsorbed  to  five soils, with organic  matter
             contents  ranging from  2.40  to  15.50% (Monsanto Company,  1975).
             Adsorption of glyphosate ranged from 71 (Soil  E,  2.4% organic matter,
             pH  7.29)  to 99% (Soil  C, 15.5%  organic matter,  pH 5.35).

          0   14c-Glyphosate  (94% glyphosate, 5.9% aminomethylphosphonic acid)
             was slightly mobile to relatively immobile,  with less than 7% of  the
             applied 14C detected in the leachate from 30-cm silt, sand,  clay,
             sandy clay loam, silty clay loam, and  sandy loam soil columns eluted
             with 20 inches  of  water (Brightwell and Malik, 1978).  Aged  (30 days)
             14c-glyphosate  residues were relatively immobile in silt, clay  and
             sandy clay loam soils  with  less than 2% of the radioactivity detected
             in  the  leachate following elution with 20 inches of water.   Both
             glyphosate and  aminomethylphosphonic acid were detected in the  leachate
             of  aged and un-aged soil columns.



          0   Feeding studies with chickens,  cows and swine  showed  that ingestion
             of  up to  75 ppm glyphosate  resulted in nondetectable  glyphosate
             residue levels  (<0.05  ppm)  in  muscle tissue and fat (Monsanto Company,
             1983).  The duration of exposure  was not reported in  this report.
             Glyphosate residue levels were not  detectable  (<0.025 ppm) in milk
             and eggs  from cows and chickens on  diets containing glyphosate.


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


          0   No  information  on  the  metabolism  of glyphosate was  found in  the
             available literature.
             After a single oral  or  intraperitoneal dose,  less than 1% of the
             administered  dose  was retained  after 120 hours  of treatment (U.S.  EPA,
             1986b).   In rats fed 1,  10  or 100  ppm of 14C-glyphosate for 14 days,
             a steady-state equilibrium  between intake and excretion of label was
             reached  within about 8  days.  The  amount of  radioactivity excreted
             in the urine  decreased  rapidly  after withdrawal of treatment.   Ten
             days  after withdrawal,  radioactivity was detectable in the urine and
             feces of rats fed  10 or 100 ppm of the test  diet.  Minimal residues

    Glyphosate                                                         August,  1987

            of  0.1 ppm  or  less  remained  in  the  tissues  of  high-dose  rats after
            10  days of  withdrawal.   No single tissue  showed  a  significant
            difference  in  the amount of  label retained.
            No information on  the  health  effects  of  glyphosate  in humans was
            found  in  the  available literature.
       Short-term  Exposure

         0  An oral  LD5Q  of  5,600  mg/kg  in the rat is reported for glyphosate
            (Monsanto  Company,  1982a).

         0  Bababunmi  et  al.  (1978)  reported that daily intraperitoneal admini-
            stration of 15,  30,  45 or 60 mg/kg to rats for 28 days resulted in
            reduced  daily body  weight gain,  decreased blood hemoglobin, decreased
            red blood  cell  count and hematocrit values and elevated levels of
            serum  glutamic-pyruvic transaminase and leucine-amino peptidase during
            the experimental period.  The investigators did not specify the dose
            levels at  which  these  effects were observed.

       Dermal/Ocular Effects

         0  A dermal I^g for glyphosate in the rabbit was reported to be
            >5,000 mg/kg  (Monsanto Company,  1982a).

       Long-term Exposure

         0  In subchronic studies  reported by the Weed Science Society of America
            (1983),  technical-grade glyphosate was fed to rats at dietary levels
            of 20, 60  or  200 mg/kg/day and to dogs at 50, 1 50 or 500 mg/kg/day
            for 90 days.  Mean body weights, food consumption, behavioral reactions,
            mortality, hematology, blood chemistry and urinalysis did not differ
            significantly from controls.  There were no relevant gross or histo-
            patholocical  changes.   No other details or data were provided.

         0  Bio/dynamics, Inc.  (1981a) conducted a study in which glyphosate
            was administered in the diet to four groups of Sprague-Dawley rats
            (50/sex/dose) at dose  levels of 0, 3.1, 10.3 or 31.5 mg/kg/day to
            males or 0, 3.4, 11.3  or 34.0 mg/kg/day to females.  After 26 weeks,
            body weight,  organ weight, organ-to-body weight ratios and hematological
            and clinical chemistry parameters were evaluated.  No significant
            differences between control and exposed animals were observed at any
            dose level.

Glyphosate                                                        August, 1987


   Reproductive Effects

     0  Bio/dynamics,  Inc.  (1981b)  investigated the reproductive toxicity of
        glyphosate in  rats.   The glyphosate (98.7% purity) was administered
        in the diet at dose  levels  of 0,  3, 10 or 30 mg/kg/day to Charles
        River Sprague-Dawley rats for three successive generations.  Twelve
        males and 24 females (the FQ generation)  were administered test diets
        for 60 days prior to breeding.   Administration was continued through
        mating, gestation and lactation for two successive litters (F1a,
        Fit,).  Twelve  males  and 24 females from the Fib generation were
        retained at weaning  for each dose level to serve as parental animals
        for the succeeding generation.   The following indices of reproductive
        function were  measured:  fetal, pup and adult survival; parental and
        pup body weight;  food consumption; and mating, fertility or gestation.
        Necropsy and histopathologic evaluation were performed as well.
        No compound-related  changes in these parameters were observed when
        compared to controls, although an addendum to the pathological report
        for this study reported an increase in unilateral focal tubular
        dilation of the kidney in the male F^ pups when compared to concurrent
        controls.  Based  on  data from this study, the authors concluded that
        the highest dose  tested (30 mg/kg/day) did not affect reproduction
        in rats under  the conditions of the study.

   Developmental Effects

     0  Glyphosate was also  administered to pregnant rabbits (route not
        specified) at  dose levels of 75,  175 or 350 mg/kg/day on days 6
        through 27 of  gestation (Monsanto Company, 1982a).  No evidence of
        fetal toxicity or birth defects in the offspring was observed.
        However, at dose  levels of  350 mg/kg/day, death, soft stools, diarrhea
        and nasal discharge  were observed in the animals.


     0  The Monsanto Company (1982a) reported that glyphosate did not cause
        mutation in microbial test  systems.  A total of eight strains (seven
        bacterial and  one yeast), including five Salmonella typhimurium strains
        and one strain of Bacillus subtilis, Escherichia coli and Saccharomyces
        cerevisiae, were  tested.  No mutagenic effects were observed in any

     0  Njagi and Gopalan (1980) found that glyphosata did not induce reversion
        mutations in Salmonella typhimurium histidine auxotrophs.


     0  Bio/dynamics,  Inc.  (1981b)  conducted a study to assess the oncogenicity
        of glyphosate  (98.7% purity).  The chemical was given in the diet to
        four groups of Sprague-Dawley rats at dose levels of 0, 3.1, 10.3 or
        31.5 mg/kg/day to males or  0, 3.4, 11.3 or 34.0 mg/kg/day to females.
        After 26 weeks, animals were sacrificed and tissues were examined for
        histological lesions.  A variety of benign and malignant tumors were
        observed in both  the treated and control groups, the most common tumor

   Glyphosate                                                         August,  1987

           occurring  in the  pituitary  of both  sexes  and  in  the  mammary  glands  of
           females.   The total  number  of rats  of  both  sexes that  developed
           tumors  (benign and malignant) was 72/100  (low dose), 79/100  (mid
           dose),  85/100 (high  dose) and 87/100 (control).   An  increased  rate  of
           interstitial cell tumors of the  testes was  reported  in the high-dose
           males when compared  to  concurrent controls  (6/50 versus 0/50), but
           this was not considered to  be related  to  compound administration.
           Based on the data from  this study,  the authors concluded that  the
           highest dose level  tested  (31.5  and 34.0  mg/kg/day for males and
           females, respectively)  was  not carcinogenic in rats.

        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 (	   /L)
                        (UF) x (	 L/day)


           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 glyphosate.  It is, therefore,
   recommended that the Ten-day  HA value be used at this time as a conservative
   estimate of the One-day HA value.

   I'en-day Health Advisory

        The teratology study in pregnant rabbits has been selected to serve as
   the basis for determination of the Ten-day HA for the 10-kg child.  In this
   study, pregnant rabbits that received glyphosate at dose levels of 0, 75,
   175 or 350 mg/kg/day on days  6 through 27 of gestation showed effects at
   350 mg/kg/day; however, no treatment-related effects were reported at lower
   dose levels.  The No-Observed-Adverse-Effect-Level (NOAEL) identified in
   this study is, therefore, 175 mg/kg/day.  While a developmental end point may
   not be the most appropriate basis for derivation of an HA for a 10-kg child,
   use of this study provides an extra margin of safety.

Glyphosate                                                        August, 1987

     Using a NOAEL of 175 mg/kg/day,  the Ten-day HA for a 10-kg child is
calculated as follows:

       Ten-day HA = (175 mg/kg/day) (10 kg) = 17.50 mg/L (17,500 ug/L)
                        (100)  (1  L/day)


        175 mg/kg/day = NOAEL,  based  on absence of altered physical changes
                        and mortality in rabbits.

                10 kg = assumed body  weight of a child.

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

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

Longer-term Health Advisory

     No information was found  in the  available literature that was suitable
for determination of the Longer-term  HA value for glyphosate.   It is, therefore,
recommended that the adjusted  DWEL for a 10-kg child 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 ky 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 Bio/dynamics (1981b) has been selected to serve as the
basis for determination of the Lifetime HA value for glyphosate.  In this
study, the reproductive toxicity of glyphosate in rats was investigated over

Glyphosate                                                        August, 1987


three generations.  Even though no compound-related changes in the reproductive
indices were observed when compared to controls at a dose level of 30 mg/kg/day,
there were pathological changes of renal focal tubular dilation in male F3b
weanling rats at this level.   Therefore, the lower dose level of 10 mg/kg/day
was identified as the NOAEL.

     Using a NOAEL of 10 mg/kg/day, the Lifetime HA is calculated as follows:

Step 1:  Determination of the Reference Dose (RfD)

                     RfD = (10 mg/kg/day) = 0>1 mg/kg/day


        10 mg/kg/day = NOAEL,  based on absence of renal focal tubular
                       dilation in rats.

                 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 = (0.1 mg/kg/day) (70 kg)  = 3.5 mg/L (3,500 ug/L)
                          (2  L/day)

        0.1 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 = (3.5 mg/L) (20%)  = 0.70 mg/L (700 ug/L)


        3.5 mg/L = DWEL.

             201* = assumed relative source contribution from water.

Evaluation of Carcinogenic Potential

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

     0  The evidence of carcinogenicity in  animals is considered equivocal by
        the Science Advisory  Board (Pesticides), and has been classified in
        Category D [Office of Pesticide Programs has requested the manufacturer
        to conduct another study in animals (U.S. EPA, 1986)].

      Glyphosate                                                        August, 1987



           0  No other criteria,  guidelines or standards were found in the available
              literature pertaining to glyphosate.

           0  Tolerance of 0.1 ppm has been established for the combined residues
              of glyphosate and its metabolite in or on raw agricultural commodities
              (U.S.  EPA,  1985a).


           0  Analysis of glyphosate is by a high-performance liquid chromatographic
              (HPLC)  method applicable to the determination of glyphosate in water
              samples  (U.S. EPA,  1985B).  In this method, a known volume of sample
              is applied to a Bio-Rad prefilled AG 50W-X8 column.  The column
              effluent is injected via an auto injector onto a primary column
              packed  with a cation exchange resin, but used in an anion-exclusion
              mode to  eliminate interferences.  The effluent from this column flows
              onto a  strong anion-exchange column where the analytical separation
              is accomplished.  Detection and quantitation are made with a spectro-
              photometer at 570 run.  The method detection limit for glyphosate is
              5 ug/L.


           0  No information was  found in the available literature on treatment
              technologies capable of effectively removing glyphosate from contami-
              nated water.

    Glyphosate                                                      August, 1987



    Bio/dynamics,  Inc.*  1981a.   Lifetime feeding study of glyphosate (Roundup
         Technical).  Project No. 77-2062 for Monsanto Co., St. Louis, MO.  EPA
         Accession Nos. 246617 and 246621.  (Unpublished report)

    Bio/dynamics,  Inc.*  1981b.   A three-generation reproduction study in rats
         with glyphosate.  Project No. 77-2063 for Monsanto Co., St. Louis, MO.
         EPA Accession Nos.  245909 and 247793.  (Unpublished report)

    Brightwell, B., and J.  Malik.  1978.  Solubility, volatility, adsorption and
         partition coefficients,  leaching and aquatic metabolism of MON 0573 and
         MON 0101:  Report  No. MSL-0207.

    Meister, R.T., ed.  1983.  Farm chemicals handbook.  Willoughby, OH:  Meister
         Publishing Company,  p.  C117.

    Monsanto Company.  1975.  Residue and metabolism studies in sugarcane and
         soils.  Montsanto  Agricultural Products Company, 800 Lindbergh Blvd.,
         St. Louis, MO.

    Monsanto Company.  1982a.  Material safety data sheet, glyphosate technical.
         800 N. Lindbergh Blvd.,  St. Louis, MO.  MSDS No. 107-83-6.

    Monsanto Company.  1982b.  Rodeo herbicide for aquatic vegetation management.
         Technical manual.   800 N. Lindbergh Blvd., St. Louis, MO.  82-L01.

    Monsanto Company.  1982c.  The health and environmental safety aspects of
         Roundup herbicide:   An overview.  800 N. Lindbergh Blvd., St. Louis, MO.
         Roundup Herbicide  Bulletin No. 3.

    Monsanto Company.  1983.  Rodeo herbicide:  Toxicological and environmental
         properties.  800 N. Lindbergh Blvd., St. Louis, MO.  Rodeo Herbicide
         Bulletin No.  1.

    NAS.   1977.  National Academy of Sciences.  Drinking water and health.  Vol.  I.
         Washington, DC:  National Academy of Sciences.

    NAS.   1980.  National Academy of Sciences, National Research Council.  Drinking
         water and health.   Vol. 3.  Washington, DC: National Academy Press.
         pp. 77-80.

    Njagi,  G.D.E., and H.N.B. Gopalan.  1980.  Mutagenicity testing of some
         selected food preservatives, herbicides and insecticides.  Bangladesh
         J.  Bot.  9:141-146.  (abstract only)

    Olorunsogo, 0.0.   1981.   Inhibition of energy-dependent transhydrogenase
         reaction by N-(phosphonoznethyl)glycine in isolated rat  liver mitochondria.
         Toxicol. Lett.  10:91-95.

    Olorunsogo, O.O.,  and E.A. Bababunmi.  1980.   Inhibition of  succinate-linked
         reduction of  pyridine nucleotide  in  rat liver mitochondria "in vivo" by
         N-(phosphonomethyl)glycine.  Toxicol. Lett.  7:149-152.

Glyphosate                                                        August,  1987

Olorunsogo, O.O., E.A. Bababunmi and 0. Bassir.  1977.  Toxicity of glyphosate.
     Proceedings of the 1st International Congress on Toxicology.  G.L. Plaa
     and W.A.M. Duncan, eds.  New York:  Academic Press,  p. 597.  (abstract

Olorunsogo, O.O., E.A. Bababunmi and O. Bassir.  1979a.  Effect of glyphosate
     on rat liver mitochondria in vivo.  Bull. Environ. Contain. Toxicol.

Olorunsogo, O.O., E.A. Bababunmi and 0. Bassir.  1979b.  The inhibitory effect
     of N-(phosphonomethyl)glycine in vivo on energy-dependent, phosphate-
     induced swelling of isolated rat liver mitochondria.  Toxicol. Lett.

Rueppel, M.L., B.B. Brightwell, J. Schaefer and J.T. Marvel.   1977.  Metabolism
     and degradation of glyphosate in soil and water.   J. Agric. Food  Chem.

Seiler, J.P.  1977.  Nitrosation in vitro and in vivo by sodium nitrite, and
     mutagenicity of nitrogenous pesticides.  Mutat. Res.  48:225-236.

Shoval, S., and S. Yariv.   1981.  Infrared study of the fine structures of
     glyphosate and Roundup.  Agrochimica.  25:377-386.

STORET.  1987.

U.S. EPA.  1985a.  U.S. Environmental Protection Agency.  Code of Federal
     Regulations.  40 CFR 180.364.  July 1.

U.S. EPA.  1985b.  U.S. Environmental Protection Agency.  U.S. EPA Method 140
     - Revision A - Glyphosate.  Fed Reg.  50:40701.  October  4, 1985.

U.S. EPA.  1986a.  U.S. Environmental Protection Agency.  Guidelines for
     carcinogen risk assessment.  Fed. Reg.   51(185):33992-34002.  September 24.

U.S. EPA.  1986b.  U.S. Environmental Protection Agency.  Guidance for the
     registration of pesticide products containing glyphosate  as the active
     ingredient.  Case No.  0178, June, 1986.

Weed Science Society of America.  1983.  Herbicide handbook, 5th ed.
     Champaign, IL:  Weed Science Society of  America, pp. 258-263.
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