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          aw    $2.0
                                                                         January  1992
                                            FINAL
                               DRINKING WATER CRITERIA DOCUMENT
                                             FOR
                                           DALAPON
                            Health  and  Ecological Criteria Division
                               Office of Science and Technology
                                       Office of Water
                             U.S. Environmental  Protection Agency
                                    Washington, DC  20460
             en
               cvi
HEADQUA:
ENVIRON'-
WASHINi ..
"**\ AGENCY

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                                               January 1992    [j
                 FINAL


    DRINKING  WATER  CRITERIA DOCUMENT


                  FOR


                DALAPON
Health and Ecological Criteria Division
   Office  of  Science and  Technology
            Office of Water
 U.S.  Environmental  Protection  Agency
         Washington, DC  20460
                                                    _- -
                                                    r~
                                                    c~

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                             TABLE OF CONTENTS

                                                                            Page

      LIST OF FIGURES	

      LIST OF TABLES	   viii

      FORWORD	     ix

  I.  SUMMARY	    1-1

 II.  PHYSICAL AND CHEMICAL PROPERTIES'..	-   H-l

      A.  General  Properties	   II-1
      6.  Manufacture and Use	   H-l
      C.  Environmental  Fate and  Stability	   II-1

          1.   Leaching From Soils  	   II'1
          2.   Degradation in the  Environment	   11-3

      D.  Summary	   ^~?

III.  TQXICOKINETICS	III-l

      A.  Absorption   	III-l
      B.  Tissue Distribution  	  III-l
      C.  Metabolism	III-5
      D.  Excretion	IH-5
•:-.  '  E.  Bioaccumulation and Retention  ,	 ..>• ......  MI-5
      F.  Summary	111-6

 IV.  HUMAN EXPOSURE		   IV'1

  V.  HEALTH  EFFECTS IN  ANIMALS   	    V-l

      A.  Short-term Exposure	    V-l

          1.   Acute Toxicity	    V-l
          2.   Subacute Toxicity   	    V-3

      B.  Long-term Exposure 	    V-4

          1.   Subchronic Toxicity  	    v~4
          2.   Chronic Toxicity  	    V-6

      C.  Reproductive/Teratogenic Effects  	   V-ll
      D.  Mutagenicity	    v~16
      £.  Carcinoyenicity	   V-17
      F.  Summary	    V-19

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                            TABLE OF .CONTENTS (continued)

                                                                              Page

  VI.  HEALTH EFFECTS IN HUMANS	      VI-1

       A.  Clinical  Case Studies  .	      VI-1
       B.  Epidemiological Studies  	      VI-1
       C.  High-Risk Populations  	      VI-1
       0.  Summary	      VI-1

 VII.  MECHANISMS UF TUXICITY		    VII-1

       A.  Mechanisms in Animals	    VII-1
       B.  Mechanisms in Plants	  .    VII-1
       C.  Interactions	    VII-1
       D.  Summary	J	   • VII-2

VIII.  QUANTIFICATION UF TUXICOLOGICAL EFFECTS   	  .  	   VIII-1

       A.  Procedures for Quantification  of Toxicological Effects ....   VIII-1

           1.   Noncarcinogenic  Effects  	   VIII-1
           2.   Carcinogenic  Effects	   VI11-4

       B.  Quantification  of Noncarcinogenic  Effects for Dalapon  ....   VIII-6      a

           1.   Une-day Health Advisory  	   VIII-6
           2.   Ten-day Health Advisory	   VIII-6
           3.   Longer-term Healtn  Advisory  	 ,.>.-;..   VIII-8
           4.   Reference  Dose and  Drinking Water Equivalent Level- ....  VI11-11

       C.   Quantification  of Carcinogenic Effects for Dalapon 	  VIII-14
       D.   Existing Guidelines  and Standards  	  VIII-15
       E.   Summary	VIII-15

  IX.   REFERENCES	     IX-1

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                                LIST OF FIGURES





Fiyure No.                                                                  Page



  II-l        Major Metabolic and Degradative Routes of Dalapon 	   II-6
                                     vii

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                                 LIST OF TABLES
Table No.

   II-l


  III-l


  III-2


    V-l

    V-2


    V-3



    V-4


    V-5



    V-6


 VIII-1


 VI11-2


 VIII-3
                                                             Page

 Properties  of  Dalapon  (2,2-Dichloropropionic Acid)
 arid  Its  Salts	     II-2

 Tissue Distribution  of  Dalapon in Dogs Given Daily
 Oral  Doses  for 1  Year	    III-2

 Tissue Distribution  of  Dalapon in Male and Female
 Rats  Receiving Dietary  Dalapon for  2. Years	    III-4

 Acute Oral  LD5Q Values  for Dalapon  Sodium  .......      V-2

 Average  Weights of Various Organs Taken From Dogs
 Receiving Dalapon Sodium  by Capsule for 1 Year .....      V-8

 Average  Weights of Various Organs Taken From Rats
 Maintained  for 2  Years  on Diets Containing Dalapon
 Sodium	     V-10

 Selected Nonneoplastic  Lesions Observed in Mice Fed
 Dowpon M for 2 Years	    V-12

 Summary  of  Results of Reproduction  Study in Three                     ||
 Generations (Two Litters Each) of Rats Fed Diets
 Containing  Dalapon Sodium	 . . • .  .. ,    V-13
Selected Neoplastic Lesions Observed in Mice Fed-
Dowpon M for 2 Years  	
V-18
Summary of Candidate Studies for Derivation of the
Longer-term Health Advisory for Dalapon  	   VIII-9

Summary of Candidate Studies for Derivation of the
DWEL for Dalapon	VIII-12

Summary of Quantification of Toxicological  Effects
for Dalapon  	   VIII-16
                                     viii

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                                   FOREWORD


     Section 1412 (b)(3)(A) of the Safe Drinking Water Act, as amended in 1986,
requires  the  Administrator of the Environmental  Protection  Agency  to publish
Maximum Contaminant Level  Goals (HCLGs) and promulgate National Primary Drinking
Water  Regulations  for  each  contaminant,   which,   in  the  judgment  of  the
Administrator, may have an adverse effect on public health  and which  is known or
anticipated to occur in public water systems.  The  HCLG 1s  nonenforceable and is
set at a level  at which no known or anticipated adverse health effects in humans
occur and which allows for an adequate margin of safety.   Factors considered in
setting the HCLG include health effects data and sources of exposure other than
drinking water.

     This  document  provides  the health  effects   basis   to  be  considered  in
establishing the MCLG.   To achieve this objective,  data  on  pharmacokinetics,
human exposure, acute and  chronic toxicity to animals and humans, epidemiology,
and mechanisms  of toxicity  were evaluated.   Specific  emphasis is  placed  on
literature data providing dose-response information.  Thus, while the literature
search and evaluation performed in support of this document was  comprehensive,
only the  reports considered  most pertinent in the derivation of the MCLG are
cited in the document.  The comprehensive literature data base in  support of this
document includes information published up to April 1987;  however,  more recent
data have been  added  during  the review process and in response  to  public
comments.

     When adequate health  effects data exist, Health Advisory values for less-
than-lifetime exposures (One-day, Ten-day, and Longer-term, approximately 10% of
an individual's lifetime)  are included in this document.   These  values are not
used in setting the MCLG,  but serve as informal guidance to municipalities and
other organizations when emergency spills or contamination situations occur.

                                                                James R.  Elder
                                                                      Director
                                     Office of Ground Water and  Drinking Water

                                                              Tudor T.  Davies
                                                                      Director
                                               Office of Science of Technology
                                       ix

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                                   I.  SUMMARY

      Dalapon Is a herbicide used to control  grasses in a wide variety of crops
 and in a number of noncrop applications,  such as  along drainage  ditches  and
 railroads and in industrial  areas.  It is an  organic acid (2,2-dichloropropionic
 acid) soluble in water,  metnanol, and ethanol,  and  is marketed as  the sodium salt
 or as a mixture of the sodium and magnesium salts.   In the  environment,  it  is
 rapidly degraded in soils  by a variety of microorganisms.   The major  degradation
 product,  pyruvic acid, is  a  normal  intermediate in  the metabolism  of  plants  and
 animals.

      The  absorption  of dalapon from  the gastrointestinal tract of mammals has
 not been  measured  directly.   However,  on  the  basis  of excretory data  in dogs
 and humans,  it  appears that  dalapon  is relatively well  absorbed (at least 50%).
 Studies in dogs  and  rats indicate that orally ingested  dalapon is distributed
 to "most" tissues  of the body  (kidney>liver>muscle>brain>fat), with no marked
 preferential  accumulation  in  any  one tissue.  In dogs,  65 to 70% of an oral
 dose  (500 mg/kg) is excreted  in the urine  (as unchanged dalapon)  within 48
 hours,  in numan subjects, approximately  50% of five  consecutive  daily doses
 of  0.5 mg/kg  of dalapon sodium was excreted in  the urine within an 18-day
                                                                               %
 period.

     Acute toxicity data indicate that dalapon  has a  low order of toxicity in
mammals, witn a range  of 1^50  values of 4 to 9  g/kg.  The dry powder or a concen-
trated solution can be irritating to the eyes  or skin if not removed by washing.
Short-term multiple dose studies suggest that  the  toxicity of the compound is
not cumulative.   Cattle that received a 1-g/kg daily oral  dose for  10  days
showed some signs of toxicity but rapidly  recovered  when dosing ceased.  Slight
                                      1-1

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 cloudy swelling of the convoluted tubules and hypertrophy or swelling of the
 glomerular cells of the kidney  were  the only findings in a bull calf receiving
 1 g/kg/day.  Dogs were dosed  by gavage for an 81-day period, initially with 50
 tny/kg/day, with dosages adjusted upward until the animals were receiving 1,000
 mg/kg/aay.  Vomiting ensued at this high dose level, and the study was terminated
 at 81 days.  Except for vomiting, no other signs of toxicity were evident.
 Extensive hematological and biochemical parameters were all  normal, as were the
 organ-to-body weight ratios.

      In a 97-day rat study, there were no  effects in male rats  fed dalapon in
 the  diet  at dosage  levels  up to 115  mg/kg/day.   In female rats,  there were
 slight, statistically  significant increases  in  average  kidney weights at  the  •
 34.6 mg/kg/day  level.   At  doses of 346 or  1,150  mg/kg/day, both  male
 and  female rats showed growth retardation,  increased liver and  kidney weights,
 and  slight histopathological  changes  in the  liver and kidneys.   This study
 establishes  a No-Observed-Adverse-Effect Level  (NOAEL) of-11.5 mg/kg/day  for
 oral  intake  in  the  rat.

      In a  1-year study with mongrel dogs, significant increases were observed
 in the  average  kidney weight  in  dogs  receiving 100 mg/kg/day but not  in those
 receiving  50  mg/kg/day.  All  other parameters were comparable to controls.   In
"a 2-year rat  study, significant  increases were noted in the kidney weight in
 rats  receiving  50 mg/kg/day,  but not  in those receiving 15 or 5 mg/kg/day.   In
 this  chronic  study, a dose  of  15 mg/kg/day is identified  as the NOAEL.  In a
 2-year mice study, increased  liver weights were  noted at  200 mg/kg/day Dowpon
 M in  the diet.  No associated  lesions were noted upon histologic examination
 of the livers.
                                      1-2

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      There were also increased incidences  of  benign  lung adenomas  and  cystadenomas   j|
 of the harderian gland in male mice fed dalapon  for  2 years.   No tumors  were
 found in  rats  fed dalapon for 2 years.

      In a three-generation  reproduction study in  rats, no reproductive effects
 were  found in  rats administered dalapon in the diet  at levels  up to 3,000 ppm
 (15U  nig/kg/day).   In a rabbit teratogenicity  study,  decreased  body weights
 were  noted  in  pups  from dams  receiving  oral doses of 300 mg/kg/day.  However,
 no  fetal  effects  were  noted at  30 or 100 rag/kg/day.  Similarly, the mean of the
 pup weights was  depressed when  pregnant female rats  received 1,000 or 1,500
 mg/kg/day  in the  diet  from days  6 through Ib of gestation but not wnen they
 received  500 mg/kg/day.   No other effects on tne fetuses were observed.

      Dalapon was  not mutagenic  in a variety of organisms including Salmonella
 typhimurium, Escherichia  coli,  T4 bacteriophage, Streptomyces coelicolor,
 Saccharomyces  cerevisiae, and AsDergil_lu,s_ nidulans.  In one study (technical
 details not provided), dalapon was found to increase chromosomal aberrations in
mice  at doses  of  2UU mg/kg or more.
      No reports of adverse effects in individuals who manufacture or utilize
dalapon were found.  In addition, no human toxicity data or epidemiological
studies were found for this compound.
      In liver mitochondria, dalapon exerts a mild inhibition of pyruvate uptake.
 In plant tissues, dalapon has been found to inhibit several  enzyme  systems that
utilize pyruvate.  The role of enzyme inhibition in the  herbicidal  activity  of
dalapon is not clear.
     No acute oral exposure data were found that were suitable  for  calculation
of a One-day Health Advisory (HA).  A maternal NGAEL  of  30  mg/kg/day,  based  on
                                      1-3

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a teratogenicity study in  rabbits, was  selected to calculate the Ten-day HA of
3000 ug/L for a 10-kg child.  This value is considered to be appropriate as a
conservative estimate of the One-day HA value for a 10-kg child as well.  A
NOA£L of 15 mg sodium dalapon/kg/day, based on a 2-year feeding study in
rats, was used to calculate a Longer-term HA of 300,ug/L for a 10-kg child and
9UO jjg/L for a 70-kg adult.  The same study was also used to calculate a
Reference Dose (RfD) of 27 ug/kg/day ahd a Drinking Water Equivalent Level
(DWEL)  of 900 ug/L for a 70-kg adult.   (All the Health Advisory, RfD and DWEL
values  were referring to the active ingredient dalapon acid).  No sensitive
subpopulations or other special  considerations are recognized regarding the risk
of dalapon exposure.
                                     1-4

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                     II.  PHYSICAL AND CHEMICAL PROPERTIES

A.  GENERAL PROPERTIES

     Dalapon (2,2-dichloropropionic acid) is a carboxylic acid that is soluble
In water, methanol, and ethanol.  The chemical and physical properties of
dalapon are shown in Table II-l.

B.  MANUFACTURE AND USE
     Dalapon formulations are registered for selective use in controlling
grasses in a wide variety of crops, including specified fruit trees,  beans,
coffee, corn, cotton, peas, beets, and sugarcane.   It is also registered  for
use in noncrop areas such as lawns, industrial areas, ditches, and  along  rail-
road tracks.  Dalapon is marketed as the sodium salt or as a mixture  of the
sodium and magnesium salts (Kenaga, 1974).
C.  ENVIRONMENTAL FATE AND STABILITY         .     --.;.   •       •            ...."
1.  Leaching From Soils
     Since botn dalapon and its salts are water soluble, they tend  to follow
waterflow in the environment.  Warren (1954) reported that dalapon  was  readily
leached from four types of soil.  Smith et al. (1972) studied the leaching of
dalapon in a soil column (8.5-inch) of sandy loam.  Dalapon was  present at a
level  of application of 1 Ib/acre.  Nine acre-inches of water applied in
O.b-inch increments leached 99.4% of the dalapon from the column.   On the basis
of soil tnin-layer chromatography (TLC) of 40 different pesticides, Helling
(1971) classified dalapon in the group with the greatest mobility.
                                      II-l

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            Table II-l.  Properties  of Dalapon  (2,2-Dichloropropionic
                         Acid)  and Its Salts
              Property
         Value
 Physical  appearance

  Acid
  Sodium  salt
  Magnesium salt .

 Melting point

  Sodium  salt
  Magnesium salt

 Molecular weight

  Acid
  Sodium  salt
  Magnesium salt

 Density

 Solubility  (g/lUO 9 solvent)

  Water    '    '""
  Methanol
  Ethanol

 Partitioning coefficient
 • (n-octanol/water)

pKa
Colorless liquid
White solid
White-tan solid
Decomposes at 193 to 197°C
Decomposes at 193°C
143
165
308.5
1.389 g/mL

Acid    Na salt
>80.0
 18.5
 82.7

5.?a
1.74
 90.0-
 17.9
<18.5
Mg salt

 >80.0
  35.9
.  25.5
 Taken from Kenaga (1980).

SOURCE:  Adapted from Kenaga (1974)
                                      II-2

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      Miller and Uetzendaner (1973) sampled  soils  taken  from  a  number  of  areas
 of the United States  at various time intervals  up to  1  year  after the applica-
 tion of dalapon.  At  one sample site,  no  residues were  found in the top  6
 inches of soil  after  40 days,  regardless  of the rate  of application.  At another
 site,  residues  of  dalapon  in the  top 6  inches of  soil after 7 days were 2.0 to
 2.2 ppm;  at  14  days,  0.11  to 0.28 ppm;  at 28 days, 0..06 ± 0.15 ppm; and at 42
 days,  <0.025  ppm.  No dalapon  at  any site was detected  in the 6- to 12-inch
 soil  layer.   Thus, although dalapon  moves rapidly in the environment, it appears
 that  it is.also  rapidly degraded.

      Oalapon  was found  in  one  of  the surface water or ground water samples
 analyzed  from 14 samples taken at  14 locations  (STORE!, 1987).

 2.   Degradation  in the  Environment

      The  sodium  salt  of  dalapon hydrolyzes  slowly in water to produce pyruvic
 acid  arid  chloride ion;  the  rate of hydrolysis .increases with increasing tempera-
 ture.   After  175 hours, the extent of hydrolysis  at 25°C for 1, 5, and 18%
 dalapbn solutions was U.41, 0.61,  and 0.8%, respectively (Brust, 1953).

     Hydrolysis of solutions of either dalapon or dalapon  sodium salt  is  accel-
 erated  at alkaline pH.  For example, hydrolysis of dalapon sodium salt at 60°C
 was 20% complete in 30 Hours,  at which time the equilibrium pH  was  2.3.   In
 contrast, hydrolysis  was 50% complete in 30 hours when the pH was  maintained  at
 12 during the study (Tacey and  Bellinger,  1958).  Photodegradation  of  dalapon
to pyruvate may also  occur, and the pyruvate may then  be further converted  at a
 slower rate to acetaldehyde and carbon dioxide (Tanaka and Wien,  1972).

     Although laboratory studies indicate  that dalapon is  a highly  mobile
compound {Warren, 1964;  Helling, 1971,  Kenaga,  1974)  and should be  readily
                                      II-3

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 Teachable from soils, field data show that under many  practical  conditions
 dalapon does not get below the top 6-inch layer of soil.   This  is  probably
 because microbial  action proceeds at a faster  rate than leaching under  favor-
 aole conditions (Kenaga, 1974).  Microbial  degradation is  by  far the most
 important process  affecting the fate of  dalapon  in soil.   Other processes,
 which are of lesser importance, are  leaching and  runoff, chemical  degradation,
 adsorption,  and volatilization.  Kenaga (1974)  indicated that photodegradation
 may not be a major degradative pathway in the  environment.  Based  on the light
 absorption characteristics  of  aqueous solutions  of sodium  salts of dalapon,
 photodecomposition of dalapon  in field applications  is improbable  (Kearney et
 al.,  1965).

      Microbial  degradation  in  soil has been well  estaolished.  Thiegs (1955)
 found that the  concentration of dalapon  (59 ppm)  in  autoclaved soil did not
 change after incubation  at  100°F for 1 week, whereas in nonautoclaved soil
 dalapoh  disappeared  in 4 to -5  weeks  after one  application of 50 ppm and in 1
 week  after a second  application.

      A laboratory  study  (Holstun  and  Loomis, 1956) showed that dalapon degrada-
 tion  in  soil  was very sensitive to temperature.   Little.or no degradation .
 occurred wnen soil  temperature  was below  15°C,  but decomposition at a concentra-
 tion  of  120  ppm (12 mg/kg)  in soil was essentially complete (<15 ppm)  after 2
 weeks  at 30°C.  The  rate  of degradation was inhibited by lack of moisture,  low
 pH, and  tne  addition of  large quantities  of organic matter, suggesting that
 bacterial decomposition  of dalapon was taking place.  Jensen (1957) found a
 group of bacteria that decomposed dalapon in soil after an  initial  incubation
period of 4 weeks.   Magee and Colmer  (1959) found eight species  of  soil
bacteria that, when grown on agar plates, were  able to  decompose up to  5,QUO
                                      II-4

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 ppm dalapon.  Six of these were tentatively identified as Agrobacter and two as
 Pseudomonas; however, other unidentified bacteria, molds, and actinomycetes
 were also present.

      Hirsch and Alexander (1960) found that 89 to 100% of the chlorine  in
 dalapon was released in 3 weeks by soil cultures of Nocardia  and  Pseudomonas
 microorganisms.  In  laboratory tests, decomposition of 50 ppm dalapon in
 California soil  samples ranged from complete disappearance in 2 weeks to one-
 third  disappearance  in  8 weeks {Day et al.,  1963).   The degradation of dalapon
 in these soils  was unrelated to soil  type,  texture, cation  exchange capacity,
 or total  organic  matter, but evidently was  related  to  the  various microbial
 populations  in  the samples.   Kaufman  (1964)  reported that  under greenhouse
 conditions,  dalapon  disappeared in  4  to 8 days  in muck  soil,  in 8 to 16 days in
 loam and  silty  loam  soils, in  16 to 32 days  in  sandy loam  soil, and in 32 to 64
 days in  silty clay soil.  This  appeared to  be primarily  a  consequence of bac-
 terial degradation,  although  other  soil microorganisms  were present.

     Kearney et al.  (1964) identified  the following microbial  genera capable of
 liberating chloride  ion  from dalapon:   Pseudomonas, Bacillus,  Alcaligenes,
 Agrobacterium, Arthrobacter, and Nocardia.  A suspension from  an Arthrobacter
 species,  presumably  containing  only free enzymes, was also capable of
 denalogenating organically bound chlorine from dalapon and converting dalapon
 to pyruvaze.  Foy  (-1961) identified monochloropropionate as a  degradation
 product of dalapon in a stock solution  contaminated by a fungus that was
not identified.

     A summary of degradative reactions of dalapon in the environment  is  shown
 in Figure II-l.   The  major degradation product, pyruvic acid,  and  its  breakdown
products are all normal  metabolic intermediates in mammalian metabolism.
                                       II-5

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                      fungi
                                 CH3CC12COOH*
                                    Dalapon
                             mlcrobial
        hydrolysis
       CH3CHC100H*

  alpha-Chloropropionic
  acid
[CH3CC10HCOOH]
                   phocodegradation
[CH3CC1COOH]
                               CH3COCOOH* + CV

                                 Pyruvic acid
  Energy cycles of
  cells (Krebs, lactic
  acid, etc.)
                                 CH-CHO + C02

                                 Acetaldehyde
                                      I
                                   CH^COOH*

                                 Acetic acid
                                      I
Figure II-l.  Major metabolic and degradative routes of dalapon.  (Starred
              acids will be in equilibrium with their anions, with the position
              of the equilibrium depending on pH and the specific cations in a
              particular environment, and the compounds in brackets will  be
              transient.)
SOURCE:  Adapted from Kenaga (1974).
                                      II-6

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D.  SUMMARY

     Dalapon (2,2-dichloropropionic acid) is a herbicide  that  is  commercially
available as formulations of the sodium and magnesium salts.   It  is  utilized
to control grasses in crops, drainage ditches, along railroads, and  in  indus-
trial areas.  Dalapon is water soluble and tends to follow waterflow.   In  the
environment, it is rapidly degraded in soil  by a variety  of microorganisms.
The major metabolic product, pyruvic acid, may be further degraded to yield
acetaldehyde and acetate.  These degradative products  are normal  intermediates
in mammalian metabolism.
                                     II-7

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                               III.  TOXICOKINETICS

A.  ABSORPTION

     No direct data on the absorption of dalapon were found in the literature.
leasure (1964) reported that dalapon fed to animals is quickly excreted in the
urine, but no data were provided.  Hoerger (1969) found that 65 to 70% of an
oral dose (5UU mg/kg) administered to dogs was excreted in the urine within 2
days, and that humans ingesting 0.5 mg/kg of dalapon sodium on each of 5 con-
secutive days excreted approximately 50* in the urine over the subsequent
18-day period.  These results  indicate that dalapon is well absorbed from the
gastrointestinal (GI) tract of animals and humans.

B.  TISSUE DISTRIBUTION
     Paynter et al. (1960) reported on the tissue distribution of dalapon in
dogs receiving 0, 15, 50, or 100 mg/kg/day of dalapon sodium.  Twelve mongrel
dogs were divided into four groups of two males and one female per group.  The
        \
compound was administered by capsule, 5 days a week for 52 weeks.  Body weight
was recorded weekly.  Food was offered once a day, and water was available
ad libitum.

     At termination of the study, the dogs were necropsied, tissues were imme-
diately frozen at dry-ice temperature, and then kept at 0°C or below until
analyzed.  Dalapon  was extracted and measured by the method of Smith et al.,
(1957).  Tissue distribution data are shown in Table III-l.  No consistent  sex
differences were noted in the distribution of the compound in the tissues
examined.  The pattern of tissue distribution was kidney>liver>muscle>brain>fat,
                                     III-l

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               Table  III-l.   Tissue Distribution  of  Dalapon  in  Dogs
                             Given Daily Oral  Doses  for  1  Year

Tissue

Kidney

Liver

Muscle

Brain

Fat

Sex

M
F
M
F
M
F
M
F
M
F

15
b
23
17
- 27
17
15
12
11
7
2
1
Dosage (mg/kg/day)
50

21
32
16
27
13
27
9
13
2
4
a
1UU

78
60
48
57
51
35
25
18
15
5

aOral dose of dalapon sodium, 5 days/week.
DData are expressed as mg 2,2-dichloropropionic acid per kg tissue,

SOURCE:  Adapted from Paynter et al. (1960).
                                     III-2

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      In a related study, Paynter et al. (1960)  reported on  the  analysis  of
 tissue from rats maintained for 2 years on a  diet containing  dalapon  at  several
 different dosage levels.  Four groups of 24 male albino rats, Carworth Farm
 strain, received dalapon sodium in their diet at levels of  0, U.01, 0.03, or
 u.1%,  approximating  0,  5,  15,  or 50 mg/kg/day,  respectively, according to the
 authors.   At  termination of the study,  tissues  were immediately removed, frozen
 at dry-ice temperature,  and kept frozen until analyzed. The tissue distribution
 in male and female  rats  after  2 years on diets  containing dalapon is  shown in
 Table  III-2.  The pattern  of distribution was similar to that seen in dogs
 (i.e.,  kidney>liver>rauscle>brain>fat);  no dalapon  was detected in the muscle,
 brain,  fat, and  milk  at  the low dose.  Dalapon  has  also been detected in the
 milk of lactating female dogs  given dalapon for  an  unspecified length of time
 (Dow,  1962b).  Samples of  milk  were collected,  frozen,  and then analyzed by gas
 chromatography with electron-capture detection.  The concentrations found were
 10.1 and  11.5 ppm in  the milk of dogs at  the 50-mg/kg dose level and 15.1. ppm
 in dogs at the 100-mg/kg level.
     Fertig and  Schreiber  (1961) studied  dalapon levels in cow's milK.  Dairy
 cattle  (6  Jerseys, 16 Holsteins, 6 Guernseys, and  6 Brown Swiss) were fed
 dalapon at a level equivalent to 300 ppm  in the  diet (corrsponding to about 9.0
                                                                               >,
 my/kg/day).  The dalapon was mixed  with  a  grain  concentrate and fed just prior
 to  milking.  The total study period included 1 week of  standardized prefeeding,
 3 weeks of dalapon feeding, and  1 week of postdalapon feeding.  Duplicate milk
 samples were taken morning and  evening from each cow and analyzed for  dalapon
 by  the method of Kutschinski (1961).  Milk levels reached maximum at about 7
days and remained essentially constant (1.08 to 1.46 mg/kg)  over the total
 3-week feeding period.  There were  no differences in response  among  the  four
breeds.
                                     III-3

-------
      Table  III-2.  Tissue  Distribution of Dalapon  in Hale and Female Rats
                    Receiving  Dietary  Dalapon for 2 Years

Tissue
Kidney
Liver
Muscle
Brain
Fat
Milkc
Dosage (mg/kg/day)a
5 15
4.0° 9.7
1.0 . 3.5
2.9
- - 2.6
0.5
6.0

50
28.2
10.7
7.5
5.4
1.4
19.1

aEstimated by the authors from dietary levels of 0.01, 0.03,  and 0.1%.
bData are expressed as mg 2,2-dichloropropionic acid per kg tissue.
cFrom third-generation lactating females; milk level in rats  maintained  on
 diets containing 3,000 ppm (150 mg/kg) was 29.3 mg/kg.

SOURCE:  Adapted from Paynter et al. (1960).
                                     III-4

-------
 C.  METABOLISM

      Leasure (1964)  found that 65 to 70% of  a  single  oral dose of 500 mg  of
 dalapon sodium administered to dogs was excreted  unchanged in the urine within
 48 hours.   Redemann  and Hamaker (1959)  reported that  in a cow fed 36C1 -labeled
 dalapon, only  two  labeled products were found  in  the  milk.  These were dalapon
 and chloride ion,  indicating that dehalogenation  of dalapon had occurred to
 some extent in the cow.  No further details  of this study were available.

 D.   EXCRETION
      Hoerger (1969)  fed a single  oral dose (500 mg/kg) of dalapon sodium to
 dogs.   The  animals excreted 65 to 70% of the dose in  the urine as unchanged   .
 dalapon within 48  hours.   When the animals were fed repeated daily doses of 50
 or  100  mg/kg for a 611-day period, total  recovery of dalapon in the urine ranged
 from 25 to  53%.  Hoerger  (1969) also studied dalapon  excretion in human sub-
 jects who consumed five successive daily oral doses of 0.5 mg/kg- of dalapon
 sodium.  Approximately  50% of  the dose  was found in the urine over the subse-
 quent 18-day period.  No  other studies  of the excretory rate for dalapon were
 found in tne literature.
E.
    BIOACCUMULATION AND RETENTION
     No studies were found that 'provided direct estimates of half-lives of.
dalapon in oody tissues.  However, the long-term studies by Paynter et al .
(I960) (see Section II. 8, Distribution) indicate that there is no significant
accumulation of dalapon in tissues of either dogs or rats after 1 to 2 years of
exposure at doses ranging from 5 to 100 mg/kg/day.   Fertig and Schreiber (1961)
found that in dairy cattle receiving 9.0 mg/kg/day, dalapon levels reached  a
steady-state level (1.08 to 1.46 mg/kg milk) in 7 days,  and this did not
                                     III-5

-------
Increase over a period of 3 weeks.  When dalapon feeding was discontinued, milk     ||
levels decreased to 0.115 mg/kg in 3 days and to 0.045 mg/kg in 7 days.  Resi-
dues in tissues were not investigated.

F.  SUMMARY

     Few studies of dalapon toxicokinetics were found in the literature.   On
the basis of excretory data in dogs and humans, it appears that dalapon is
relatively well absorbed when ingested orally (at least 50 to 70%}.   Tissue
distribution studies in dogs and rats show that orally ingested dalapon
distributes to most tissues of the body (kidney>liver>muscle>brain>fat),  with
no marked preferential accumulation in any one tissue.  In dogs,  65  to  70% of
an oral dose (500 mg/kg) is excreted in the urine (as unchanged dalapon)  in 48
hours.  In human subjects, it was found that approximately 50% of five  consecu-
tive daily doses of 0.5 mg/kg of dalapon sodium'is  excreted in the urine  within
an 18-day period.
                                     III-6

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                                         IV. .  HUMAN EXPOSURE




               This section will be provided  by the Science and Technology Branch, ODW,



          EPA, at a later date.
                                                IV-1
I

1

-------
                          V.  HEALTH EFFECTS  IN  ANIMALS
 A.  SHORT-TERM EXPOSURE
 1.  Acute  Toxicity

      Paynter et  al.  (I960)  studied the  acute oral toxicity of dalapon sodium
 in rats, mice, guinea  pigs, rabbits,  and  chicks.  The technical-grade 'material
 used in the  acute studies  contained 83  to 85% dalapon sodium salt; 6% related
 chloropropionic  acid,  sodium salt; 1% pyruvic acid  sodium salt; 8% sodium
 chloride;  and 2% unidentified.  The animals were administered single doses of
 dalapon ranging. from 1,000 to 15.80U  rug/kg body weight.  The acute oral LDsg
 values were  calculated for the five species by tne  "Moving Average" method of
 Thompson (1947), and the results are  shown in Table V-l;  The acute oral LDgQ
 values for these five  species ranged  from 3,860 mg/kg for the female rabbit and
 female guinea pig to 9,330  mg/kg for  the male rat.
     Kochkin  (1967) reported  that the acute oral LDso value of dalapon sodium
was 7,100 mg/kg for the albino mouse and 4, 700. mg/kg for the white rat.  These
values are vary similar to those reported by Paynter et al. (1960).  As part of
a study of 57 pesticides, Gaines and Linder (1986) determined the dermal LDsg
value of dalapon applied in aqueous solution to be greater than 5,000 mg/kg in
botn male and female Sherman  rats, and the oral LDso to be 7,126 mg/kg in males
and 6,936 in females.

     Very slight dermal toxicity was observed in rabbits treated with concen-
trated solutions of dalapon (Paynter et al., 1960), and no dermal  effects were
observed in a calf, hog, or in three sheep treated with dalapon spray (Goldstein
and Long, 1960).  Slight to moderately severe cornea! injury and conjunctiva!
irritation were observed in rabbits treated with dalapon powder or 10% dalapon

                                      V-l

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Table V-l.  Acute Oral LDsg Values for Dalapon Sodium

Species
Rat


Mouse

Guinea pig
Rabbit
Chick
Sex
M
F
N/S
M
F
N/S
F
F
F
M/F
LD50 (mg/kg)
9,330
7,570
4,700
7,126
6,936
7,100
>4,600
3,860
3,860
5,660
Reference
Paynter et al .
Kochkin (1967}

(1960)

Gaines and'linder (1986)
Kochkin (1967)
Paynter et al .
Paynter et al .
Paynter et al.
Paynter et al .

(1960)
(1960)
(I960)
(1960)
                       V-2

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 solution, but these effects were diminished by washing the eye and were fully
 reversible  (Paynter et al., 1960).

 2.   Subacute Toxicity
                 i
     Paynter et al. (1960) intubated a heifer (weighing 252 kg) and a bull
 suckling calf (weighing 59.1 kg) with 1.0 g/kg of dalapon, sodium dissolved in  .
 water on each of 10 consecutive days. , During the latter part of the study, the
 heifer showed signs of general lassitude, diarrhea, roughness of coat, loss of
 appetite, slight loss of weight, slowed pulse rate, mild cyanosis of the mucous
 membranes, and some discharge from the eye.  Four days after the last dose, the
 heifer appeared to have recovered and was in good condition.  The slowed pulse
 rate was still present, and some discharge from the eyes remained.  At this
 time, the animal was sacrificed and necropsied.  During the course of the
 study, the nursing  bull calf showed no signs of toxicity and gained 6.8 kg in
 weignt.  Twenty-four hours after the last dose, the calf was sacrificed and..
 necropsied.   Sections of the rumen, reticulum, omasum, abomasum, lymph nodes,
 adrenals, tnyroid,  heart, kidneys, liver, spleen, pancreas, lung, bladder, and
 gallbladder of both animals appeared normal  on microscopic  examination.  Tne
 kidneys showed slight cloudy swelling of the convoluted tubules and hypertrophy
 or swelling  of the  glomerular cells with decreased glomerular spaces.

     Palmer  and Radeleff (1964) reported the effects of feeding commercial
 dalapon sodium to sheep,  predominantly of the Delaine breed, and a mixed dairy
breed of cattle (one animal per dose level).  No apparent effects were noted in
the sheep receiving  10 daily doses  of 250 or 500 mg/kg or in the cattle
 receiving 10 daily  doses  of 250 mg/kg or 8 daily doses of 5UO mg/kg.   However,
parotid swelling was observed  in the cow receiving 500-mg/kg/day doses.  No
                                      V-3

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 control  animals  were used.   One sheep  was  continued  on  a chronic  regimen  of  481
 daily doses of 100 my/kg with no signs of  toxicity  reported.

 B.   LONG-TERM EXPOSURE
 1.   Subchrom'c  Toxicity
      Kochkin (1967)  reported  the results of a 2-mbnth dietary study in albino
 rats.  Two  dose  levels  (one-twentieth  and  one-fifth  of  the LDsg)  were employed
 (equivalent to 235  and  940  mg/kg/day,  on the basis of the LDgo of 4,7UO mg/kg
 reported  by the  author). The following parameters were studied:  blood count,
 prothrombin time, whole  blood catalase and cholinesterase activity, serum -SH
 levels, tissue respiration, weights  of internal organs, vitamin C content of
 adrenals, and  the -SH content  of  homogenized liver.  No details of methods were
 provided.   None  of the animals  died  during the 2-month  feeding period, although
 the animals  receiving 940 mg/kg/day  had decreased weight gain.  Tnis group also
 nad decreased  serum  -SH  levels  (p  <0..002) and increased.organ-to-body weight -  .
 ratios for  liver, kidney, spleen,  thyroid, pituitary, and adrenals.  Tnere was
 "irregular  thickening of the  stomach submucosa due to edema, swelling of the
 basal cells  and  inflammatory  cellular  infiltration.  In the lumen of the small
 intestine there  was  profuse desquamation of the glandular epithelium and defor-
 mation of the  papules, due to  infiltration by inflammatory-cellular elements."
 No histological  changes  were  reported  in other organs.
     Paynter et al.  (1960) maintained groups of 10 male and 10 female rats
 (Wistar-Dow strain)  for  97 days on diets containing 0.0, 0.0115,  0.0346,  0.115,
 0.346, or 1.15% dalapon  sodium.  These dosages are equivalent to  0.0,  11.5,
 34.6, 115, 346, or 1,150 my/kg/day, respectively,  according to the authors.   No
effects were found in male rats ingesting  up to 115 mg/kg/day.  In female  rats,
                                      V-4

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 there were statistically significant increases  (no p value  given)  in  average
 kidney weights at the 34.6- and 115-rag/kg/day dose levels,  but  no  other  differ-
 ences from the controls.  No histopathological  changes  were found  that correlated
 with the increased kidney weights.   Toxic effects  were  noted at the higher  doses
 (346 and 1,150 mg/kg/day),  including growth  retardation, increases in average
 weight of the liver and kidneys, and slight  histopathological changes (not
 specified) in the liver and kidneys of  both  sexes.   There were  no  dose-related
 changes in mortality, food consumption, hematological data,  average body weights,
 or microscopic lesions  of the spleen, lung,  or  heart.   An NOAEL of 11.5 mg/kg/day
 was identified, based on increased  kidney weights  in females rats  receiving
 3.4.6 mg/kg/day.
      Paynter et al.  (196U)  administered dalapon  sodium  orally by capsule to
 one male and one female mongrel  dog,  5  days/week for 80 days.   Dogs were weighed
 weekly, and doses were  adjusted for weight gain.   During the first 2 weeks,
.each dog received a  dose containing bO  mg/kg/day dalapon;sodium.  The dose was
 then adjusted upward weekly until a maximum  of  1,000 mg/kg was  reached.  During
 the 10th and llth weeks, the dose was divided into  two  500-mg daily doses in an
 attempt to prevent vomiting.  The following  parameters  were monitored both
 prior  to and at  termination (day 81)  of the  study:   complete blood counts, cell
 volumes,  blood  urea  nitrogen (BUN), bromsulphalein  (8SP) liver  function tests,
 and urinalyses.   At  81  days, the animals  were killed  and necropsied.  Gross
 examination revealed  no specific findings in either dog that appeared to be
 compound  related.  Organ-to-body weight  ratios of the liver, kidneys, spleen,
 and testes  for  both dogs  were  within  normal  limits as were hematological  and
 biochemical  measurements.   Since only two animals were  used in this study,
 increasing  doses were administered  during the study, and no control animals
 were included, the toxicological effects  could not be adequately assessed.
 No  NOAEL  or LOAEL was identified.
                                      V-5

-------
      Kochkin (1967)  administered perorally  to  albino  rats, at  1,  10, and  200
 mg/kg, dalapon sodium in aqueous solution six  times/week for 5 months.  The
 number of animals and sex, weight,  and strain  of  rats were not given.  After 4
 months, the serum -SH levels  were depressed  in the 200-mg/kg dose group
 (p <0.05),  while  a decrease occurred  in the  10-mg/kg dose group after 5 months
 on the diet (p  <0.01),   Animals  at  the  10-mg/kg dose level also showed a slowing
 of conditioned  reflexes.  During the  fifth month, the frequency of cessations
 of the conditioned reflexes and  the number of  phasic reactions increased
 (p <0.01}.   There was an increase in  the organ-to-body weight ratio of the
 thyroid of  rats at the 2UO-mg/kg level.  Microscopic examination of the thyroid
 of the animals  in this group  showed marked vasodilation and hyperemia, which
 the authors  considered to  be  effects  of dalapon.  This effect was not noted 10 ._
 the 10-mg/kg dose level  animals.  No  effects were reported in the 1 mg/kg group.
 Very  few details  on the  methods  including the  number, sex, and strain of animals
 used  as  well as results were  reported for this study (Russian translation).
 Therefore,  the importance  of  the  effects noted could not be adequately assessed--
 and  a  NOAEL was not identified.

 2.   Chronic Toxicity

     Paynter et al. (1960)  studied the long-term effects of dalapon sodium in
 mongrel  dogs.  Twelve healthy mongrel  dogs were divided  into four groups  of
 two females and one male per  yroup.   Each  group received either 0, 15,  50, or
 100 mg/kg/day of dalapon sodium administered by capsule,  5 days a week  for
 52 weeks.  The following parameters  were monitored for each dog initially  and
at weeks 13, 26, and  52:   complete blood count, BUN  level,  BSP  liver  function
test, and urinalysis.  At necropsy,  the heart,  lungs,  liver,  spleen,  kidneys,
and testes were weighed.   Sections from the  thyroid,  lungs, heart,  liver,
kidneys, adrenals, pancreas, spleen, lymph nodes,  bone marrow,  urinary  bladder,
                                      V-6

-------
and  gonads of each animal were  examined microscopically.  All dogs showed
normal  behavior,  gained weight,  and  exhibited no evidence of adverse effects
attributable to the compound.  There were no significant alterations in the
nematological or  biochemical parameters.  Average organ-to-body weight ratios
were essentially  normal, except  for a statistically significant increase
{p <0.05) in average kidney weight in the dogs that received 100 mg/kg/day.
The organ-to-body weight ratios  are shown in Table V-2.  Histopathological
examination of tissues showed no abnormalities,  even in the heavier kidneys
from the high-dose group.  A NOAEL of 50 mg/kg/day based on increased kidney
weights at 10U mg/kg/day was identified.

     Paynter et al. (I960) also  carried out a 2-year feeding study in albino
rats (Carworth Farm strain) given levels of 0.01, 0.03, and 0.1% dalapon sodium
in the diet.  The authors calculated these dietary levels to approximate 5, 15,
and 50 mg/kg/day, respectively.  Groups of 24 male rats were fed at each dose
level; groups of  20 female rats  were fed at all  but the 0.1%. level.  Complete ...
blood counts and hemoylobin determinations were carried out on animals from
each group at the following intervals:  initially, five males and five females;
at 14 weeks, three males and three females; at 26 weeks, two males and two
females; at 52 weeks, three males and three females; and at 104 weeks, three
males and three females.  Interim sacrifices and histological examination were"1
performed at 26 weeks on two male and two female rats from each group and at 52
weeks on two males from each group.  At 104 weeks, the remaining animals were
sacrificed and necropsied, and appropriate tissues were taken for histological
examination from representative-males and females from each group (number not
specified).
     Growth,  food consumption,  survival, and hematological  findings were compar-
able  for dalapon sodium-treated male and female  rats as compared to controls.
                                      V-7

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                                                       a
          Table V-2.   Average Weights of Various Organs  Taken from Dogs
                      Receiving Dalapon Sodium by Capsule for 1 Year

Dosage
(nig/kg/day)
Control

15

50

100

Weight
(kg)
9.33
+0.82
9.87
±1.85
8.43
+1.79
9.60
+1.21 •
Lungs
(%)
0.67
+0.12
0.70
+0.18
0.62
+0.06
0.73
.+0.15
Heart
(%)
0.64
+0.05
0.77
+0.07
0.88
j+0.23
0.85
+0.22
Liver
(%)
2.51
+0.22
2.91
+0.24
2.80
+0.09
2.83
+0.15
Spleen
(*)
0.15
±0.02
0.20
±0.03
0.20
+0.07
0.23
±0.05
Ki dneys
(*)
0.42
+0.03
0.43'
+0.02
0.46
+0.01
0.56
+0.03
Testes
(%)
0.17
±°-03
0.16
jKI.OO
0.18
+Q.OQ
0.21
+0.00

a
 As percent of terminal body weights +_ SO.


SOURCE:  Adapted from Paynter et al. (1960)
                                      V-8

-------
 The average kidney weight of the'male rats receiving the 5U-mg/kg/day dose
 showed a statistically significant increase (p <0.05) as compared to the male
 controls at the end of the 2-year period (Table V-3).  Microscopic evaluation
 of the tissues revealed no evidence of adverse effects.  At dietary levels of 5
 and 15 mg/kg/day,  all  parameters measured were comparable to  controls.   A NOAEL
 of 15  mg/kg/day was identified  for this  study.

      In a chronic  dietary study conducted by  Dow Chemical  Company  (1983),
 groups of BSCSF^ mice  (96 control/sex  and 50/sex in each  treatment  group)  were
 fed Dowpon M (a mixture of 72.1% 2,2-dichloropropionate,  sodium salt, and
 13.8%  2,2-dichloropropionate, magnesium  salt)  at levels  equivalent  to 0,  2, 60,
 or 2UU mg/kg/day for 24 months.  An additional  10 animals  of  each  sex were
 maintained on  the  same  treatment regimen  and  sacrificed  after 12 months on the
 diets.  The parameters  studied  included mortality,  clinical signs of toxicity,
 body weight, food  consumption,  clinical chemistry,  hematology, urinalysis,
 gross  pathology, organ  weights,  and histopathology.  -At the 1-year  interim-
 sacrifice,  a slight, nonsignificant increase  in  liver weights was observed in
 the nigh-dose  group (2UO  mg/kg/day).   Histological  examination of the liver did
 not reveal  any  lesions  associated  with the weight  increase.. Red blood cell
 (RBC)  count, hemoglobin,  and packed  cell  volume were significantly elevated
 (p  <0.U5)  in all males  in the treatment groups when compared to controls, but
 the increases were not dose related.  At the 2-year terminal sacrifice,  the
 slight increase in liver weight  still persisted in the high-dose group.
 Elevations in RBC count, hemoglobin, packed cell volume, and serum glutamic-
 pyruvic transaminase (SGPT) for males in the high-dose group were  attributed by
the authors to  a disproportionate number of hepatocellular carcinomas in the
 10 high-dose males  sampled.  However, the total numbers  of liver tumors  in the
treated groups  were not significantly different from that of the control  group.
                                      V-9

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    Table V-3.   Average Weights of Various Organs  Taken From Rats Maintained
                for 2 Years on Diets Containing  Dalapon Sodium

Dietary
Level (%)
Control
0.01
0.03
0.10
Control
0.01
0.03
Number
Sex of rats
M 15
M 16
M 15
M 15
F 12
F 15
F 13
Body
weights (g)
488
±60
491
±65
463
±94
473
±58
336
±39
326
±66
353
±64
Liver (%)
2.88
• ±0.37
2.79
±0.38
2.59
±0.33
2.91
±0.25
3.54
±0.46
3.35
±0.43
. 3.51
±o.io
Kidneys (S)
0.64
±0.06
0.66
±0.10
. 0.68
±0.14
0.71*
±0.20
0.68
±0.09
0.80
±0.27
0.70
±0.14
Testes {*)
0.73
±0.10
0.64
±0.15
0.60
±0.15
0.69
±0.10
—
--
—

a
 As percent of terminal body weights ± SD.
*Significantly different from controls at p <0.05.


SUURCE:  Adapted from Paynter et al. (1960).
                                      V-lu

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 The  clinical  chemistry  and  heraatology  parameters were comparable  between  control
 and  high-dose females.   It  should  be noted  that the  females from  all  groups
 exhibited  fibrous  osteodystrophy  (Table  V-4), a diffuse bone disorder that
 caused elevations  in  alkaline  phosphatase values.  There was also a significant
 increase (p  <0.05) in the incidence  of extramedullary hematopoesis in the mid-
 and  high-dose females when  compared  to controls.  The authors considered this  .
 to be coincidental and  of no toxicological importance.  An increase in the
 incidences of benign  lung tumors and cystadenomas of the harderian gland was
 noted in the  high-dose males but the increase was within the range of historical
 controls and  therefore, was not attributed to dalapon administration.  A NOAEL
 of 60 mg/kg/day was identified from  this study.

 C.   REPRODXTIVE/TERATOGENIC EFFECTS
     Paynter  et al. (1950) carried out a three-generation reproduction study
 in rats administered 0, 0.03, 0.1, or 0.3% dalapon sodium in the diet (approxi-
 mately U, 15,  50, or 150 mg/kg/day,  respectively).  Groups of young albino rats
 (4 males and  12 females; strain not  specified) were started on the diets at 90
 days of age.   At 110 days of age, the animals were placed together in breeding
 cages.  The FQ generation and all descendent animals were maintained on the
 dalapon sodium diets throughout the  study.  All  tne pups from the F]a litter
 were discarded, and the females were returned to the breeding cages after 10
 days.  The resultiny FIJJ litters were maintained on their respective diets for
 selection of 4 males and 12 females to be mated when 110 days  old to produce
the Fga and ?2b generations.  This process was repeated  to produce the subsequent
 generation.  Indices  of  fertility,  gestation, viability, and lactation were
 recorded, and these data are summarized in Table V-5. The data show that
dalapon sodium in the diet through three generations of  two litters  each had no
effect on reproduction parameters,  even at dietary levels  of 0.3% (3,000 ppm).

                                      V-ll

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       Table  V-4.   Selected  Nonneoplastic  Lesions Observed  in Mice Fed Dowpon M for 2 Years

Dietary Level (mq/kg/day)
Males
Organ/Lesion
Liver
Aggregates of retlculo-
endothelial cells
Foci of altered hepatocytes
Soleen
Extramedullary hemato-
poiesis
Pancreas
Cyst
Bone
»—
fibrous osteodystrophy
Kidneys
luouiar atrophy, multi focal
Cortical cyst
Tubular dilation, multifocal
0
(86)a

28
2
(86)

10
(86)
2
(86)
0

52
9
4
2
(*0)

9 '
2
(50)

4
(50)
1
(50)
0

34
1
3
60
(bO)

15
2
(50)

3
(49)
0
(50)
0

28
0*
2
200
(bO)

15
4
(50)

11
(50)
1
(50)
0

27
1
5
0
. (85)

65
3
(86)

5
• (86)
1
(86)
75

5
0
1
Females
2
(t>Q)

27*
1
(50)

6
(50)
1
(50)
44

2
1
0
60
(=0)

35
2
(50)

9*
(49)
0
(50)
45

7
0
0
200
(DO.

33
1
(so;

ii'
(50
3
(50.
45

3
0
U

aNumbers in parentheses represent the number of tissues examined.
*Significantly different from controls at p <0.0b.

SOURCE:   Adapted from Dow (1983).
                                                 V-12

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   Table  V-5.   Summary of  Results  of Reproduction  Study  in Three  Generations

               (Two Litters Each)  of Rats  Fed  Diets  Containing  Dalapon Sodium

Dietary
levels (%)
Control
0.01
0.1
0.3
Control
0.03
0.1
0.3
Control
0.03
0.1 .
0.3


Generati on
FO
FO
F0
FO
Fib
. Flb
Fib
Fib '
F2b
P2b
P2b
'»


Fertility
index*
100
86
100
100
100
100
96
100
100
95
100
100


Gestation
index0
100
100
100
100
100
100
100
100
96
95
100
1UO


Vi abi 1 i ty
i ndexc
96
• 95
95
93
88
86
86
89
87
69
81-
85


Lactation
i ndexd
95
86
96
94
92
100
98
99
82
95
99
99

apercantage of females achieving two pregnancies.
bPercentage of pregnancies yielding live births.
cPercentage of rats born that survived for 5 days.
^Percentage of rats alive at 5 days that survived the 21-day  lactation period.

SOURCE:  Adapted from Paynter et al. (I960).
                                      V-13

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 Body weight measurements at weaning and at weekly intervals  (for exposed rats
 that were allowed to mature) were also comparable to those of controls.

      In a teratogenicity study conducted by Hazleton Laboratories Deutschland
 (BASF,  1987),  groups of inseminated New Zealand White female  rabbits  (16/group
 in  the  0-, 30-,  and 100-mg dose groups; 19 in the 300-mg dose group)  were  given
 0,  30,  100,  or 300 mg/kg/day dalapon (Na/Mg salt, purity 9.9.3%)  by oral  gavage
 on  days 6 through 18 of gestation.  Three high-dose animals aborted between
 days 21 and  25 of gestation.  Pregnancy was terminated on day 28 of gestation.
 The parameters examined included behavioral change and general observations,
 body weight,, and food consumption of each inseminated female  rabbit.  Upon
 sacrifice on day 28, each  animal  was examined macroscopically for structural  or
 pathological changes.   All  fetuses were examined  for external  malformations.
 The pre  and  postimplantation loss, sex ratio  of fetuses, and  incidence of fetal
 anamolies  were comparable  between dalapon-treated and control  groups.  The
 results  of administration  of three doses  of dalapon can  be summarized as follows:
 adminstration  of  dalapon at  300 mg/kg/day  elicited  maternal toxicity and
 ambryotoxicity.   There  were  significant decreases in  maternal  body weight gain
 and  in food  and water consumption.  Five  animals  showed  an enlarged spleen.
 The  mean  fetal weight was  significantly lower than  i.n the control group.  Admin-
 istration  of dalapon at 100  mg/kg/day  elicited  maternal  toxicity but did not
 elicit emoryotoxicity or teratogenicity.   The  body  weight gain and food consump-
 tion were-significantly lower than in  the  control group.  Administration of
dalapon at 30 mg/kg/day did  not elicit  any  adverse  effects.  Therefore,  the
dose of 3U my/kg/day was considered the NOAEL for this study.
     In a teratological range-finding  test, Thompson  et  al. (1971) administered
dalapon sodium as an aqueous solution  by gavage to  pregnant Sprague-Dawley  rats
                                      V-14

-------
 from days 6 through 15 of  gestation.  Five treatment groups, each consisting of
 6 females, were administered  250, 500, 1,000, 1.5UO, or 2,000 mg/kg/day,
 respectively.  A control group of six rats received water as the vehicle.
 Clinical signs of maternal toxicity consisted of soft stools and slight appetite
 depression in the 2,000-mg/kg dosage group.   One rat from the 1,500-mg/kg group
 had  diarrhea.  At 1,5UO and 2,000 mg/kg,  weight  gain of  the  pregnant  dams was
 depressed.  The fetal  resorption rate was increased at  both  the 1,500- and
 2,000-mg/kg dose levels but was not significantly different  from that of con-
 trols.   At 2,000 mg/kg, pup weights were  significantly  less  than those of
 controls.   No effects  were noted at 1,000, 500,  or 250 mg/kg/day.  Based on
 clinical signs  of  toxicity, a NOAEL  of  1,000  mg/kg/day is  identified  from this
 study.

     Emerson  et al.  (1971)  reported  on  the effects  of daily  administration by
 gavage  of  an  aqueous solution of  dalapon  sodium  (500, 1,000,  or  1,500 mg/kg/day}
 to groups  of  25 pregnant  Sprague-Oawley rats  from  days 6-through  15 of  gestation.
 Animals were  sacrificed on  day 20 of  gestation, and  fetuses were  removed  by
 cesarean section.  The  following  parameters were  recorded:  maternal   body
 weight on days  0, 6, 15,  and  20;  number of viable fetuses, resorptions,  and
 corpora lutea;  individual fetal weights and sex; external  appearance  of  pups;
 and frequency of skeletal and  visceral aonormalities.  Mean weight gain.in
 dams  receiving  500 or 1,500 mg/kg/day and mean daily food  consumption in the
 1,500- mg/kg/day group were significantly less for the dalapon-treated animals
 than  for comparable controls  over the dosing period  (days  6 to 15 of  gestation
 only).  Mean pup weights were  significantly less than those of controls in the
 1,000- and 1,500-mg/kg/day  groups.  An increased incidence of delayed  ossifi-
 cation of sternabrae and the hyoid was observed in the fetuses of dalapon-
treated dams.   The authors  associated this delayed ossification with  the
                                      V-15

-------
 decrease In fetal- weights.   Spontaneous major visceral  abnormalities consisted
 of microphthalmia in one fetus each in the 500-  and 1,000-mg/kg/day groups.   No
 major dose-related skeletal  or visceral abnormalities were  observed in the
 fetuses treated with dalapon sodium and,  other than decreased pup weights at
 the two higher dose levels,  the authors assessed that no  adverse effects were
 noted.  However, delayed ossification is  considered developmental toxicity, and
 since an increased incidence was noted in fetuses from  dams in the 500-, 1,000-,
 and l,5UU-mg/kg/day groups compared to controls,  a  fetal  NOAEL was .not obtained
 in this  study.   Based  on maternal weight  gains,  a LOAEL of 500 rag/kg/day is
 identified  from this  study.
      In  a breeding study with  dogs  (Dow,  1962a),  dalapon  was administered to
 female beagles  at  50  (six dogs),  100 {three dogs),  or 200 (one dog) mg/kg
 before and'during  pregnancy  for periods ranging  from 2 to 6 months.  The dog
 given  the 2UO-mg/kg dose produced a small, weak  litter.   No adverse effects on
 either reproduction or  lactation were noted at the  other  dose levels in which
 12 litters were  produced from  10 females.  A maternal NOAEL of 100 mg/kg/day
 is  identified  from this  study.
 0.   MUTAGENICITY
     Dalapon was not mutagenic  in a  variety of organisms  including Salmonella
 typhimurium, Escherichia coli,  T4 bacteriophage,  Streptomyces coelicolor,
 Saccharomyces cerevisiae, and Asperg1l_l_us nidulans  (Siebert and Lemperle, 1974;
 U.S. EPA, 1984).
     Moriya et al.  (1983) determined  dalapon to be  negative in  the S^.  ty_ph1mu-
 rium assay in strains TA98 and TA100, tested according to Ames  et al.  (1975),
with or without metabolic activation.
                                      V-16

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     Carere et al.  (1978)  reported dalapon sodium to be nonmutagenic when
 tested  for induction of  point mutations in four strains of S_. typhimurium
 (TA1535, TA1536, TA1537, and TA1538) in the presence or absence of rat liver
 microsomal fractions, according to Ames et al. (1973).  Dalapon sodium was also
 found to be nonmutagenic in a test for the induction of resistance to low
 concentrations of streptomycin in the filamentous bacterium^, coelicolor.

     Kurinnyi et al. (1982) reported that dalapon, tested at 40, 2UO, or 1,000
 mg/kg,  increased chromosomal aberrations in mice at the two high doses.  The
 inadequate technical details presented, however, preclude an evaluation of this
 study.

 E.   CARCINOGENICITY

     Paynter et at. (1960) performed a 2-year study in rats fed doses of 0, 5,
 15, or  50 mg/kg/day dalapon sodium and a 1-year study in dogs given oral doses
 of 0, 15, 50, or 100 mg/kg/day.  No tumors were found.  However, the details on
 the histologically findings from these two studies were not reported, and a
 dog study of 1 year's duration was not considered to be of sufficient lengtn to
 draw conclusions about the carcinogenic potential of dalapon.  Dow Chemical
Company (1983) conducted a 2-year feeding study in which B6C3Fi mice were fed
 levels  equivalent to 0, 2, 60, or 200 mg/kg/day Dowpon M (see Section V.8).  A
"list of selected neoplastic lesions observed in this study is presented in Table
 V-6.  Male mice receiving 2 and 200 mg/kg/day Dowpon M, had a statistically
 significant increase (p <0.05) in the number of animals with two benign hepatic
 adenomas when compared to controls.  However, there were no increases in the
 number  of mice with benign liver tumors, malignant liver tumors or total liver
 tumors.  Therefore, the study authors considered this finding to be coincidental.
 The authors also reported a significant trend (p <0.05) towards development of
                                      V-17

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Table V-6.  Selected Neoplastic Lesions  Observed in  Mice Fed  Dowpon M  for  2  Years
Dietary Level {mg/kg/day)
Males
Organ/Lesion
Liver
Adenomas, benign (2)
Adenoma, benign (1)
Carcinoma, malignant
Lymphosarcoma
Pituitary
Adenoma, anterior, benign
•b
Adenoma., alveolar, benign •
Adenocarcinoma, alveolar
malignant
Harderian Gland
Cystadenoma, benign
Mesenteric Lymph Node
Lymphosarcoma
0
(86)
0
10
11
0
(81)
1
(86)
, 7 .
2
(86)
6
5
2
(50)
4*
7
4
0
(45)
0
(50)
IOC
1
(50)
5
3
60
(50)
0
3
3
0
(47)
0
(50)
.IOC-
0
(50)
6
2
200
(50)a
3*
9
9
0
(43)
0
(50)
-..., • 9-.-- :•
0
(50)
11*
5
0
(85)
0
11
0
0
(79)
14
(86)
:8 .
0
(77)
4
13
Females
2
(50)
0
5
1
2
(43)
11
(49)
0
0
(48)
1
10
60
(50)
1
5
2
3
(47)
9
(50)
5
1
(44)
1
2
200
(50)
2
1
0
2
(46)
4
(50)
6
0
(49)
6
11

aNumbers in parentheses represent the
. bThe study authors reported a positive
for males only.
• -Significantly different from controls
: 'Significantly different from controls
number of tissues examined.
linear trend at p <0.05 (Cochran-Armitage Trend
at p <0.05 as calculated by the reviewers.
at p <0.05 as calculated by the study authors.
test)
, SOURCE: Adapted from Dow (1983).
i
•'
.
_•
i •








V-18

-------
i
i

-------
 benign lung tumors  in male mice.  Reevaluation of the data by  the  reviewers  did
 not reveal  a significant trend using the Cochran-Armitage Trend  test,  although
 significant increases (p <0.05) in the incidence of benign lung  tumors  at  the
 low- and mid-dose levels were found.  There was a significant  increase  (p  <0.05)
 in the incidence  of  benign cystadenomas  of  the harderian  gland in  high-dose
 male mice.   The incidence was 22% compared  to  7% in control males.  The study
 authors  attributed this  increase to improved examination  methods stating that
 the historical  incidence had  increased after implementation of these new procedures.
 Historical  control incidences reportedly ranged from 10-18% in males, and  7-9%
 in females  at  27  months.

 F.   SUMMARY

   '   Dalapon has  a relatively low order  of  toxicity  to mammals.  Acute oral
 LDbU values in  several species  of rodents range  from 3,900 to 9,300 mg/kg.  A
 heifer that received  10 daily doses  of 1,000 mg/kg  dalapon.showed mild signs
 of toxicity but rapidly  recovered within 4  days  after the  last dose.  Histo-
 logical  examination of a  calf  receiving  1,000  mg/kg/day revealed only a slight
 cloudy swelling of the proximal  convoluted  tubules  and hypertrophy or swelling
 of  tne glome.-ular cells with  reduced  glomerular  space.  No toxic effects were
 observed in sheep or  cattle fed  250  or 500 mg/kg/day  for 10 days.  In a sub-   ^"->*H
 chronic study, dogs were dosed  initially with  50 mg/kg/day, with the dose then
 adjusted upward until the  animals were receiving 1,000 mg/kg/day.  Vomiting
 ensued at tnis hign dose level,  and the  study  was terminated at 81 days.
 Except for the vomiting, no other signs  of toxicity  were evident.  Extensive
 hematological and  biochemical  parameters were  all normal, as were organ-to-body
weight ratios.
                                      V-19

-------
     In rats fed.dalapon in the diet for 97 days at doses of approximately 0,
11.5, 34.6, 115, 346, or 1,150 mg/kg/day, no adverse effects were observed in
male rats at dose levels up to 115 mg/kg/day.  In female rats, there were sig-
nificant increases in average kidney weights at 34.6 and 115 mg/kg/day.   At the
highest dose levels (346 and 1,150 mg/kg/day),  both males and females showed
growth retardation, increased average liver and kidney weights, and slight
histopathological changes in the liver and kidneys.  At 346 mg/kg/day, minimal
histopathological changes were seen in the liver and kidneys, while at 34.6 and
115 mg/kg/day, there was an increase in kidney  weights of female rats; no micro-
scopic kidney lesions were found.  Based on the increased kidney weights, a
NOAEL of 11.5 mg/kg/day is established for rats dosed for the 97-day period.
     In a 5-month study, rats administered dalapon sodium in the drinking water
at a level of 200 rag/kg/day showed an increase  in weight and histopathological
changes of the thyroid.  At the next lower dose level (10 mg/kg/day), rats
                                                            >,
showed a decreased -SH level in the serum and a slowing of conditioned reflexes.
No individual data and very few details of the  study were presented.

     In a 1-year feeding study with mongrel dogs, significant kidney weight
increases occurred in dogs receiving 100 mg/kg/day but not in animals receiving
50 mg/kg/day.  Hematological and biochemical parameters, as well as histologi-
cal appearance of tissues, were comparable to controls at all dietary levels.
In a 2-year feeding study in rats, a significant increase in kidney weight was
observed in animals receiving 50 mg/kg/day.  At dose levels of 5 or 15 mg/kg/
day, no effects were noted.  In this chronic study, 50 my/kg/day can be  con-
sidered a LOAEL and 15 my/kg/day a NOAEL.  Increased liver weights were  noted
                                               »
in mice fed dalapon (Dowpon M) at a level equivalent to 200 mg/kg/day for 2
years.
                                      V-20

-------
      Dalapon was  nonmutagenic  in  assays with  Salmonella  typhimurium  strains
 TA98, TA100, TA1535,  TA1536, TA1537,  and  TA1538 with or  without  metabolic
 activation; Esch_erj_c_M_a  coli,  T4  bacteriophage,  Saccharomyces  c_erevisi_ae.,
 Streptomyces coelicolor, and Aspergillus  nidulans.   One  study, for which
 technical  details were not  available,  reported  an increase in metaphase
 chromosomal aberrations  in  the  bone marrow of mice  at a  dose level of 200 tug/kg
 or above.

      Tnere were significant increases  in  incidences  of benign lung adenomas in
 male  mice at 2, 60, and  200 mg/kg/day  and benign cystadenomas of the harderian
 gland in male mice at 20U mg/kg/day.   No  tumors were reported in rats fed
 dalapon  for 2 years. -In-a three-generation  study  in rats, no effects on
 reproductive parameters  were found at  dose levels up to  3,000 ppm in the diet
 (15U mg/kg/day}.  In a rabbit teratogenicity  study, the  only fetal effect noted
was decreased body weights of pups from dams given oral  doses of .300 mg/kg/day
dalapon on days 6 though 18 of  gestation.  No fetal effects were noted at 30 or
 1UU mg/kg/day.   Similarly, mean pup weights were significantly less than that
of controls when pregnant rats  received 1,000 or 1,500 mg/kg/day from days  6
tnrouvjn 15 of gestation  but not when fed 500 mg/kg/day over the same period.
No oiner effects on  the fetuses were considered to be dose related.
                                      V-21

-------
                          VI.   HEALTH  EFFECTS IN HUMANS
 A.   CLINICAL CASE STUDIES
     No  clinical case studies  reporting the effects of dalapon in humans were
 found.
B..  EPIDEMIOLOGICAL STUDIES                     .     .

     No epidemiological reports concerning dalapon exposure were found in the
literature.

C.   HIGH-RISK POPULATIONS

     No data identifying high-risk populations were, found in the literature.

0.   SUMMARY
     Few data are available on the health effects of  dalapon in  humans.   No
reports of adverse effects in individuals who manufacture or apply  dalapon
were found.  In an experimental study in humans,  only the excretion of the
compound in the urine was  discussed.
                                     VI-1

-------
0.  SUMMARY

     Because of the structural relationship of dalapon (2,2-dichloropropionic
acid) to pyruyic acid and the fact that pyruvate is a major degradative product
of tnis compound in the environment, several  investigators  have examined the
effects of dalapon on pyruvate-utilizing enzymes in plants  and animals.

     In rat liver mitochondria,  dalapon exerts a weak inhibition of  pyruvate
uptake.  In plant tissues, dalapon inhibits several enzyme  systems that utilize
pyruvate.  It was suggested that this innibition may play a role in  the toxic
response of plants to dalapon.
                                    VII-2

-------
                          VII.  MECHANISMS OF TOXICITY

A.  MECHANISMS  IN ANIMALS

     Paradies and Papa  (1977) measured the effect of several halogenated mono-
carboxylic acids on the  rate of uptake of pyruvate into rat liver mitochondria
In vitro.  Pyruvate uptake  into mitochondria was inhibited only 15% by 2 mM
dalapon, with a Kj of 5.60  mM.  This is in contrast to the 42.5% inhibition
caused by 2-chloropropionate, with  a KJ of 0.59 mM.  These inhibitory effects
were of a purely competitive type.  No other information was found on the
mechanism of dalapon action in animal species.

B.  MECHANISMS IN PUNTS
     Redemann and Meikle (1955) investigated the innibitory role of dalapon on
three enzyme systems involving pyruvic acid:  pyruvate oxidase in whole cells
°f Streptococcus faecal is; pyruvate oxidase prepared from•Proteus vulgarls
X-19; and commercially available yeast carboxylase.  Pyruvate oxidase from S_.
faecalls was found to be inhibited by dalapon in a complex  manner somewhat
resembling noncompetitive inhibition.  Yeast carboxylase and pyruvate oxidase
from _P_. vulgaris X-19 both appeared to be competitively as  well  as  noncompeti-
tively inhibited.  The authors suggested that dalapon could lead to appreciable
inhibition of pyruvate-utilizing enzyme systems in plants.   The  role of such a
mecnanism in the overall toxicity of dalapon to plants is  unclear.

C.  INTERACTIONS
     No reports  of synergistic or antagonistic effects were found in the
literature.
                                     VII-1

-------
                  VIII.  QUANTIFICATION OF TOXICOLOGICAL EFFECTS

      The quantification of toxicological effects of a chemical consists of
 separate assessments of noncarcinogenic and carcinogenic effects.  Chemicals
 that do not produce carcinogenic effects are believed to have a threshold dose
 below which no adverse, noncarcinogenic health effects occur, while carcinogens
 are assumed to act without a threshold.                   .

 A.   PROCEDURES FOR QUANTIFICATION OF TOXICOLOGICAL EFFECTS

 1.   Noncarci nogenic Effects

      In the quantification of noncarcinogenic effects, a Reference Dose (RfD,
 formerly called the Acceptable Daily Intake (ADI))  is calculated.  The RfD is   '
 an estimate (with an uncertainty spanning perhaps an order of magnitude)  of a
 daily exposure of the human population (including sensitive  subgroups) that is
. likely to be without an appreciable risk  of deleterious  health effects during
 a lifetime.  The RfD is derived from a No-Observed-Adverse-Effect Level  (NOAEL),
 or Lowest-Observed-Adverse-Effect Level  (LOAEL),  identified  from  a subchronic
 or cnronic  study,  and divided by an uncertainty factor(s).  The RfD is calculated
 as follows:

        RfD  *   (NQAEL or  LQAEL)      = 	 mg/kg bw/day
             Uncertainty  factorys)

      Selection  of the  uncertainty  factor  to  be  employed  in the  calculation  of
 the  RfD  is  based on  professional  judgment while considering  the entire  data
 base  of  toxicological  effects  for the chemical.   To  ensure that uncertainty
 factors  are selected  and  applied  in a consistent  manner, the  Office of Drinking
 Water (ODW)  employs  a modification  to the guidelines  proposed  by  the National
 Academy  of  Sciences  (NAS,  1977,  19BO) as  follows:
                                      VIII-1

-------
      o  An uncertainty factor of 10 is generally used when good chronic  or
         subchronic human exposure data identifying a NOAEL are available and
         are supported by good chronic or subchronic toxicity  data  in  other
         species.

      o  An uncertainty factor of 100 is  generally  used when good chronic
         toxicity data identifying a NOAEL are  available for one or more  animal
         species  (and  human  data  are not  available),  or when good chronic  or
         subchronic toxicity data identifying a  LOAEL in humans are available.

      o  An uncertainty factor of 1,000 is  generally  used when limited or
                                                 i
         incomplete chronic  or subchronic  toxicity  data  are available, or when
         good chronic  or  subchronic  toxicity data identifying a LOAEL, but.not -
         a  NOAEL,  for  one or more animal species are  available.

      Tne uncertainty  factor used for  a specific risk  assessment is based prin-
 cipally  on  scientific  judgment rather  than scientific fact and accounts .for  ...
 possible intra- and interspecies  differences.  Additional considerations, which
 may necessitate the use  of  an  additional uncertainty factor of 1 to 10, not
 incorporated in the NAS/ODW  guidelines for selection of an uncertainty factor
 include the use of a less-than-lifetime study for deriving an  RfD,  the signifi-
 cance of the adverse health effect, pharmacokinetic factors, and the  counter-
 balancing of beneficial effects.
     From the RfD, a Drinking Water Equivalent  Level  (DWEL)  can be  calculated.
The DWEL represents a medium-specific (i.e.,  drinking water) lifetime  exposure,
at which adverse, noncarcinogenic health effects are not anticipated to  occur.
The DWEL assumes  100% exposure from drinking  water.  The DWEL  provides the non-
carcinogenic health effects  basis for establishing  a  drinking  water standard.
                                     VIII-2

-------
 For ingestion data,  the DUEL is derived as  follows:

      DWEL •    RfD x (body weight in kg)     _  [	mg/L  (	ug/i_}
             Uriniong water volume in L/day

 where:

                Body  weight = assumed to be  70 kg for an adult.      .
      Drinking water  volume * assumed to be  2 L per  day for an  adult.

      In  addition to  the RfD and the  DWEL, Health Advisories (HAs) for exposures
 of  shorter  duration  (One-day,  Ten-day,  and  Longer-term) are determined.
 The HA values are  used  as  informal guidance to municipalities  and other organi-
 zations  when  emergency  spills  or contamination situations occur.  The HAs are
 calculated  using an  equation similar to the RfD and DWEL; however, the NOAELs
 or  LOAELs are identified from  acute  or  subchronic studies.  The HAs are derived
 as  follows:

      HA  = (NOAEL or  LQAEL)  x (bw)  =	mqn  /	ug/Lj
             (UFJ x (     L/aayJ

      Using the  above  equation,  the following drinking water HAs are developed
 for  noncarcinogenic  effects:
      1.  One-day HA  for  a  10-kg  child ingesting 1 L water..per day.
      2.  Ten-day HA  for  a  10-kg  child ingesting 1 L water per day.
      3.  Longer-term HA  for  a 10-kg  child ingesting 1 L water per day.
      4.  Longer-term HA  for  a 70-kg  adult ingesting 2 L water per day.

     The One-day HA calculated for a 10-kg child assumes  a single acute expo-
sure to the chemical  and is  generally derived from a study of less than 7  days
duration.  The Ten-day HA assumes a  limited  exposure period of 1  to  2 weeks  and
                                     VIII-3

-------
is generally derived from a study of less than 30 days duration.  The Longer-
term HA is derived for both a 10-kg child and a 70-kg adult and assumes an
exposure period of approximately 7 years (or 10% of an individual's lifetime).
The Longer-term HA is generally derived from a study of subchronic duration
(exposure for 10% of an animal's lifetime).

2.   Carcinogenic Effect^

     The EPA categorizes  the carcinogenic potential  of a chemical, based  on
the overall weight of evidence, according to the following scheme:

     o  Group A:   Human Carcinogen.  Sufficient evidence exists from epidemiology
                  studies to support,a causal  association between  exposure to
                  the chemical  and human cancer.

     o  Group 8:   Probable Human Carcinogen.  Sufficient  evidence  of  carcino-
                  genic! ty in  animals with limited  (Group  Bl) or. inadequate
                  (Group  82)  evidence  in humans.
     o   Group C:   Possible Human Carcinogen.  Limited  evidence  of  carcinogeni-
                  city  in  animals  in the absence of  human  data.
     o   Group D:   Not Classified as to  Human Carcinogenicity.   Inadequate  human
                  and'animal evidence of carcinogenicity or for which no data
                  are available.
    o  Group E:   Evidence of Noncarcinogenicity for Humans.  No evidence of
                  carcinogenicity  in at  least two adequate animal tests in
                  different species or in both adequate epidemiologic and
                  animal studies.
                                    VIII-4

-------
      If toxicological evidence leads to the classification of the contaminant
 as a known, probable, or possible human carcinogen, mathematical  models are
 used to calculate the estimated excess cancer risk associated with the inges-
 tion of the contaminant in drinking water.  The data used in these estimates
 usually come from lifetime exposure studies in  animals.   To  predict the risk
'for humans from animal data, animal doses must  be converted  to equivalent  human
 doses.   This conversion includes  correction for noncontiguous exposure, less-
 than-lifetime studies, and for differences in size.  The  factor that  compen-
 sates for the size difference is  the cube root  of the ratio  of the animal  and
 human body weights.  It is assumed that the average adult human body  weight  is
 70 kg,  and that the average water consumption of  an adult human is 2  liters  of
 water per day.

      For contaminants with a carcinogenic potential,  chemical  levels  are cor-
 related with a  carcinogenic risk  estimate by  employing a  cancer potency (unit
 risk) value together with the assumption for  lifetime-exposure via ingestion of
                       *
 water.   The cancer unit  risk is usually derived from a linearized  multistage
 model with a 95% upper confidence limit providing a low dose estimate;  that  is,
 the  true risk to humans,  while not identifiable,  is not likely to  exceed the
 upper limit estimate and,  in fact,  may  be  lower.   Excess  cancer risk  estimates
 may  also be calculated using other models  such  as the  one-hit,  Weibull, logit,
 and  probit.  There is  little basis  in the  current  understanding of the  biologi-
 cal  mechanisms  involved  in  cancer to  suggest  that  any  one of tnese models is
 able  to  predict  risk more  accurately  than  any others.  Because  each model is
 based on differing assumptions, the estimates that  are derived  for each model
 can differ  by several  orders  of magnitude.

     The scientific data base  used to calculate and support the setting of
 cancer risk rate levels has an inherent uncertainty due to the systematic and
                                     VIII-5

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 random errors in-scientific measurement.  In most cases, only studies  using
 experimental animals have been performed.  Thus, there is uncertainty  when the
 data are extrapolated to humans.  When developing cancer risk rate levels,
 several other areas of uncertainty exist, such as the incomplete knowledge
 concerning the health effects of contaminants in drinking water;  the impact of
 the experimental  animal's age, sex, and species; the nature  of the target  organ
 system(s)  examined;  and the actual  rate of  exposure of the internal targets in
 experimental  animals or humans.   Dose-response data usually  are available  only
 for high levels  of  exposure,  not for the lower levels  of  exposure closer to
 where  a standard  may be set.   When  there is  exposure to more than one contami-
 nant,  additional uncertainty  results from a  lack of information about possible
 synergistic  or antagonistic effects.

 B.   QUANTIFICATION  OF  NQNCARCINOGENIC  EFFECTS  FOR  DALAPON
 1.   One-day  Health  Advisory.

     Since no studies found in the  literature were  suitable  for the determina-
tion of a One-day HA  value for dalapon,  U.S.  EPA (1987) recommended that the
Ten-day HA value for a  10-kg child  (3.0  mg/L, calculated below) be used as  a
conservative estimate of the One-day HA  value.
                                                                               i
2.   Ten-day Health Advjsor^                                   ?
     The rat teratology study by Emerson et al.  (1971) had been considered to
serve as the basis for determination of  the Ten-day HA for a  10-kg child.
However, in this study, tne chemical purity  was  not specified, and the  lowest
dose administered (500 mg/kg/day, LOAEL) had maternal toxicity.  A recent
teratology  study with rabbits  (BASF, 19B7) was selected to serve as the
basis for the'10-day HA.  This study specified the purity of  the chemical
and provided a lower LUAEL (100 mg/kg/day),  and  a NOAEL of 30 mg/kg/day.
                                     VIII-6

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 In this study, groups of inseminated New Zealand white rabbits were given oral
 closes of U, 30-, 10U- and 3UU mg/kg/day dalapon (Dowpon M:  Na/Mg salt, purity
 99.3%) on days 6 through 18 of gestation.   Significant decreases in maternal
 body weight, in food and water consumption were noted in the mid- and high-
 aose groups.  Fetal  body weight from dames given the high-  dose was also -
 decreased.  However, no adverse effects were noted in the low- dose group,
 and a NGAEL of 30 mg/kg/day was identified.  Standards  for  dalapon are
 commonly expressed in terms of the acid rather than the salt.  Thus, it  is
 necessary to convert the NOAEL for the Na/Mg salt, 3U mg/kg/day to the
 equivalent value for the acid.  It is assumed that Oowpon M was
 approximately  5:1 mixture of sodium and magnessium salts.
      The NOAEL for dalapon  as  acid = (30 mg/kg/day)  (143) (7)  = 26.5 mg/kg/day
                                      (165)  (5)  + (308.6)  (1)
 where:
         30 mg/kg/day =  NOAEL for  the Na/Ka  salt
                  143 =  formula weight  of dalapon as  acid        _              .
                  165 =  molecular  weight of  sodium  dalapon
                308.5  *  molecular  weight of  magnesium  dalapon
                   7  =  total number  of  dalapon acid moiety  in Dowpon M
                   5  *  number  of  sodium dalapon in Dowpon M
                   1  »  number  of  magnesium  dalapon in Dowpon M
                        (each magnesium  binds 2 dalapon acid moieties)
     Tne Ten-day HA  for a lu-kg child is .calculated as follows:
         Ten-day HA = (26.5 mg/kg/day)(10 kg) =2.7 mg/L {3,UOO ug/L)
                          (100)(1  L/day)
where:
     26.5 mg/kg/day = NOAEL of dalapon as acid based on body weight
                      decreases in dams
                                     VIII-7

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 3.
          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
     Table VIII-2 summarizes the studies considered for the Longer-term HA for
dalapon.  The two oral toxicity studies on rats by Kochkin (1967) were not
selected  because very few details of the studies were available and the effects
observed  could not adequately  be assessed.  Therefore, the NOAEL and LOAEL could
not be identified.  The 80-day oral toxicity study with dogs {Paynter et al.,
1960} was not selected because it was based on only two animals, and increasing
doses were used over an 80-day period.

     In a subchronic oral toxicity study by Paynter et al. (1960), a 97-day
exposure  of rats to various levels of sodium dalapon (65% pure) in the diet
resulted  in an increase in kidney weight of the females at 34.6 mg/kg/day and
higher exposure levels, but not at 11.5 mg/kg/day.  A dose-response relation-
snip was  observed.  A number of hematological, biochemical, and histological
parameters were monitored.  From this study,  11.5 mg/kg/day is indicated to be
a NOAEL in rats.  Since the increase in kidney weight observed in female rats
receiving 34.6 mg/kg/day or higher doses might be an early sign of an adverse
effect on the kidneys, this dose is taken as  the LOAEL.  Similarly, in a 2-year
rat chronic dietary  study, sodium dalapon exposure (65% pure)  resulted in an
increase in male kidney weight at 50-mg/kg/day but not at  15  mg/kg/day (NOAEL).
Considering both Paynter et al. (1960) rat dietary studies together, the highe-r
of NOAEL 15-mg/kg/day for sodium dalapon was  chosen to calculate both a
Longer-term HA and a Lifetime HA.
                                     VIII-8

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Table VIII-1.  Summary of Canidate Studies for Derivation of
               the Longer-terra Health Advisory for Dalapon

Reference Species Route
Kochkin Rat Diet
(1967)
Exposure
Duration
2 months
Endpoints
Blood count,
enzyme activ-
NOAEL LOAEL
(mg/kg/day) (mg/kg/day)
<235
(salt)
                                ity, organ
                                •weights,
                                weight gain,
                                histopathology
Kochkin Rat
(1967)


Paynter et Rat
al. (1960)



Paynter et Rat
al. (1960)

Paynter et Dog
al. (1960)




Oral 5 months
(6 times/
week)

Diet 97 days




Diet 2 years


Oral 80 days





Organ weights,
conditioned
reflexes, vaso-
dilation
Organ and body
weights, histo-
pathology,
growth, food
consumption
Histology,
tissue weights,
body weight
Gross examina-
tion, blood
chemistry,
urinalysis,
organ and
body weights
>1 (salt)



11.5
(salt)
6.5
(acid)

15 (salt)
8 (acid)

__





—



34.6
(salt)



50 (salt)
28 (acid)

__






                            VIII-9

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      It  is  customary  to  express  dalapon standards  in terms of the acid  rather
than  the  salt.   The NOAEL  used to  derive the  Longer-term HA is based on  studies
(Paynter  et al.,  1960) in  which  rats were exposed  to sodium dalapon that was
65% pure.   Thus,  a NOAEL for  dalapon as the pure acid must be calculated:
      The  NOAEL for dalapon as pure acid =
      (15 mg/kg/day)(0.65)(143) = 8 mg'/kg/day
                 165
where:
     15 mg/kg/day
             0.65
              143
              165
NOAEL for 65% pure sodium dalapon,
purity of sodium dalapoh used in determining NOAEL.
molecular weight of dalapon as acid.
molecular weight of sodium dalapon.
     The Longer-term HA for a 10-kg child is calculated as follows:
     Longer-term HA = (8 mg/kg/day)(10 kg) =0.3 mg/L .(300 i^g/L) .
                      (3)(1UO)(1 L/day)
where:
     8 my/kg/day * NOAEL, based on kidney weight increases in male rats.
           10 kg = assumed body weight of a child.

             100 = uncertainty factor, chosen in accordance with NAS/ODW
                   guidelines for use with a NOAEL from animal study.
         1 L/day « assumed daily water consumption of a child.
               3 - additional uncertainty factor, chosen to account for the
                   possible inadequacy of the available animal data.

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

     Longer-term HA * (8 mg/kg/day)(70 kg) = 0.9 mg/L (900 ug/L)
                    - (3)(1UO)U L/day)

                                    VIII-10

-------
 where all  factors are the same except:
        70 kg = assumed body weight of an  adult.
      2 L/day * assumed daily water consumption of  an  adult.

 4.    Reference Dose and Drinking Water Equivalent  Level

      Table VI11-3 summarizes the studies  considered for  derivation  of the DWEL
 for dalapon.  The study by Paynter et ai,  (1960),  involving  a  1-year exposure
 of  dogs to three doses of dalapon in the  diet, was not selected  because  of  its
 shorter duration.  In  this study, a NOAEL  of  50  mg/kg/day  is based  on a
 statistically  significant increase in average kidney  weight  in dogs receiving
 100 mg/kg/day.  The study by Kochkin (1967) involving a  5-month  exposure of
 rats to three  doses of dalapon in the diet has not been  selected because
 very few details  of the study (a Russian translation) were available regarding
 methods  or results,  and the importance  of  the effects observed (decreased
 serum sulfhydryl  levels  and slowed  reflexes) could not be adequately assessed.
 In  a 2-year  dietary study in mice by Dow  (1983), a slight increase in liver
 weights  was  noted at 200 mg/kg/day.   A  NOAEL of  60 mg/kg/day was identified.

     The  study  by  Paynter et al.  (1960), involving  a 2-year exposure of rats to
 tnree levels of dalapon  in  the diet,  has been selected to serve  as the basis for
 calculation  of the  RfD  and  DWEL  because rats appear to be the most sensitive
 species  to dalapon  toxicity.   In  this "study (Table VIII-3), a slight statistically
 significant  increase in  kidney weights was noted at 50 mg/kg/day.  Although no
 histopathological findings  were  observed in the  heavy kidneys,  changes  in organ
weights may be an early  indicator of  an adverse effect and a conservative
approach was adopted for  identifying the NOAEL which was  15 mg/kg/day  for this
study.
                                    VIII-11

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                        Table VI11-2.  Summary of Candidate Studies for
                                       Derivation of the DWEL for DaUpon
                                        Exposure
          Reference  Species   Route    Duration   Endpoints
                                             • NOAEL       LOAEL
                                           (mg/kg/day)  (mg/kg/day)
          Paynter
          et al.
          (196U)

          Dow
          (1983)

          Paynter
          et al.
          (1960)

          Kochkin
          (1967)
Dog
Diet     1 year     Kidney weight   50 (salt)    100  (salt)
Mice    Diet     2 years    Liver weight    60  (salt)   200  (salt)
Rat
Rat
Diet
Diet
2 years.    Kidney  weight   15  (salt)    50  (salt)
                            8  (acid)    28  (acid)
5 months   Decreased
           serum
           sulfhydryl
           levels;  slowed
           reflexes
>1 (salt)
                                                                                              i
i
                                             VIII-12

-------
     Since the NOAEL used to derive the RfD is  based on sodium dalapon  that was
65% pure, it is necessary to convert the NOAEL  for dalapon  as  pure  acid.
The NOAEL for dalapon as pure acid *
     (IS mg/kg/day)(0.65)(143) = 8 mg/kg/day
                165
where:
     15 mg/kg/day « NOAEL for 65% pure sodium dalapon.
             0.65 = purity of sodium dalapon used in determining NOAEL.
              143 = molecular weight of dalapon as acid.
              165 = molecular weight of sodium dalapon.

     The additional uncertainty factor appears warranted because the majority of
studies within the extensive database were conducted prior to 1960 and may be
inadequate according to present standards, although the validity cannot be
assessed using the available data.
     The RfD and OWEL for a 7U-kg adult are calculated as follows:

Step 1:  Determination of the Reference Dose  (RfD)

     RfD = (8 mg/kg/day) = 0.027 mg/kg/day
              UOOK3)
where:
      8 mg/kg/day = NOAEL for 100% dalapon as  acid.
              100 « uncertainty  factor, chosen  in  accordance with NAS/ODW
                   guidelines  for use with  a  NOAEL  from an animal study.
                3 = additional  uncertainty factor, chosen to account  for the
                   possible  inadequacy  of the available animal  data.
                                     VIII-13

-------
Step 2:  Determination of the Drinking Water Equivalent Level (DWEL)
     DUEL = (0.027 mg/kg/day)(70 kg) • U.9 mg/L (900 ug/L)
                  ( 2 L/day)
where:
     0.027 mg/kg/day = RfD.
              70 kg - assumed body weight of an adult.
            2 L/day = assumed daily water consumption of an adult.

     This DWEL calculation assumes that 100% of the human exposure is derived
from drinking water.  The DWEL may be modified upon the availability of rela-
tive source contribution data providing estimates of human exposure from food,
air, and possibly the occupational environment.  The ultimate goal is to estab-
lish a DWEL so that human exposure from all  sources does not exceed the RfD.
C.   QUANTIFICATION OF CARCINOGENIC EFFECTS  FOR DALAPON
     The data on the carcinogenic potential  of dalapon are equivocal.  No
tumors were reportedly found in Carsworth rats after ingestion of approximately
5, 15 or 50 mg/kg/day for 2 years (Paynter et al., I960),  However, in a 2-year
dietary study in B6C3Fi mice reported by Dow {1983}, increased incidences of
benign lung adenomas were obtained in male mice fed 2, 60 or 20U mg/kg/day
(increases were significant at the low- and  mid-dose levels).  In addition,
significantly increased incidences of benign cystadenomas of the harderian
gland were observed in male mice fed 200 mg/kg/day.  No increased incidences
of tumors were noted in female mice.  Therefore, this study may provide
limited evidence of carcinogenicity in that  dalapon ingestion resulted in
significantly increased incidences of benign lung and harderian gland tumors
in male mice.  The lack of historical  control  data, however, makes it difficult
                                    VIII-14

-------
to evaluate the toxicological  significance of the increased occurance of benign
•harderian gland tumors.  This  chemical has not been classified for human
carcinogenic potential by the  U.S. EPA.

0.   EXISTING GUIDELINES AND STANDARDS

     The U.S. EPA criterion for the oral exposure of dalapon is based on
noncarcinogenic risk  (IRIS, 1988, fron^ Paynter et al.( I960).  The American
Conference of Governmental Industrial Hygienists (ACGIH, 1987) recommends a
Time-Weighted Average-Threshold Limit Value (TWA-TLV) of 1 ppm (6 mg/m3).

E.   SUMMARY
     Table VIII-4 summarizes the HA and DUEL values (calculated on the basis
of noncarcinogenic endpoints).  No high-risk populations have been identified,
and no synergistic or antagonistic interactions  of dalapon with other chemicals
are recognized.  No beneficial  effects of dalapon in mammals are  recognized.
Dalapon, however, is an effective herbicide with low environmental  persistence
and a relatively low order of toxicity.
                                    VIII-15

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Table VIII-3.  Summary  of  Quantification of Toxicological Effects for Dalapon

Value
One-day HA for 10-kg child
Ten-day HA for 10-kg child
Longer-term HA for 10-kg child
Lonyer-term HA for 70-kg adult
DWEL (70-kg adult}
Drinking water
concentration
(ug/L)
a
3,000
300
900
900
Reference
—
BASF (1987)
Paynter et al .
Paynter et al .
Paynter et al .



(I960)
(1960)
(I960)

The Ten-day HA value for a 10-kg child is recommended as a conservative estimate
of the One-day HA value.
                                   VIII-16

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                                 IX.  REFERENCES
 ACGIH.  1987.  American Conference of Governmental  Industrial  Hygienists.
 Threshold limit values and biological  exposure  indices  for  1987-1988,  p. 18.

 Ames 8N, Durston WE, Yamasaki  E, Lee FD.  1973.  Carcinogens are  mutagens:  A
 simple test system combining liver homogenates  for  activation  and bacteria  for
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 Ames 8N, McCann J, Yamasaki  E.   1975.   Methods  for  detecting carcinogens and
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 BASF Corporation.  1987.   Oalapon:  Oral  (gavage)  teratogenicity study  in the
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 Brust, H.   1953.  Hydrolysis of  dalapon  sodium  salt  solutions.  E.G. Britton
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 Carere A,  Ortali  VA,  Cardamone G, Torracca AM,  Raschetti R.  1978.  Microbio-
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 Day  BE,  Jordan  LS,  Russell RC.   1963.  Persistence  of dalapon  residues in
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 Dow.   1962a.  The  Dow  Chemical Co.  Biocnemical  Research Laboratory,. Midland,
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 Dow.   1962b.  The  Dow  Chemical Co.  Agricultural  Chemical  Research Labs,
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 Dow.  1983.   The Dow Chemical Co. Biochemical Research Laboratory, Midland,  MI.
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 Emerson  JL, Thompson DJ, Gerbig CG.  1971.  Results of teratological  studies in
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 Fertig SN, Schreiber MM.  1961.   Effect of dalapon ingestion on performance  of
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 Foy CL.  1961.  Absorption, distribution and  metabolism of 2,2-dichloropropionic
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dalapon in plants.  Plant Physiol. 36:698-709.
                                      IX-1

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Tanaka FS, Wien RG.  1972.  Photolysis of 2,2-dichloropropionlc acid in  aqueous
solution.  U.S. Dept. of Agriculture.  (Cited in Kenaga,  1974.)

Thieys BJ.  1955.  The stability of dalapon in soils.   Down  to Earth,  fall
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Thompson WR.  1947.  Use of moving averages and interpolation  to estimate
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Thompson DJ, Gerbig CG, Emerson JL.  1971.   Results  of  tolerance study of
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U.S.' EPA.  1984.  U.S. Environmental Protection Agency.   Draft health  and
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Warren GF.  1954.  Rate of leaching and breakdown of several herbicides  in
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                                      IX-4

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Leasure JK.  1964.  Metabolism of herbicides.   The halogenated  aliphatic  acids.
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Magee LA, Colmer AR.  1959.  Decomposition of  2,2-dichloropropionic  acid  by
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Miller PW, Getzendaner ME.  1973.  Residues of dalapon  in  soil  treated with
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Moriya M, Ohta T, Watanabe K, Miyazawa  T, Kato K,  Shirasu  Y.   1983.  Further
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MAS.  1977.  National Academy of Scientes.  Drinking water and  health.
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