ewe
   OD3U
     •/
                                          January 1992

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                                               January 1992
                 FINAL
    DRINKING WATER CRITERIA DOCUMENT
                  FOR
            OXAMYL (VYDATE)
Health and Ecological  Criteria Division
   Office  of  Science and Technology
            Office of Water
 U.S.  Environmental Protection Agency
         Washington, DC  20460

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                                TABLE UF CONTENTS


                                                                            Page

      LiST  OF  FIGURES	     vii

      LIST  OF  TABLES	     vii-

      FOREWORD	    viii

      AUTHUHS,  CONTRIBUTORS, AND REVIEWERS  . . .	      ix

  I.   SUMMARY  .«	     1-1

 II.   PHYSICAL A.NO  CHEMICAL  PROPERTIES	    II-l

      A.  General  Properties	 . .    II-l
      B.  Product ion  ana  Use	    II-l
      C.  Environmental  Fate and Effects	    II-3

         1.   Stability-.in Water	    II-3;.
         2.   Mooility in Soil   	    II-4V
         3.   Decomposition  in  Soil	  11-6,
         4.   Metabolic  Faie in Plants	    II-9
         5.   Environmental  Toxicity	   11-10

III.   TOX1CUKIHETICS	   HI-1

      A.  Absorption	   III-l
      B.  Dist-ioution	   III-l
      C.  MstaDOlism	   III-2
      U.  Elimination	   III-o
      E.  Bioaccumulation and  Retention  	   III-7
      F.  Summary	   111-7

 IV.   HUMAN EXPOSURE	    IV-1

  V.   HEALTH  EFFECTS  IN ANIMALS	•	     V-l

      A,  Sno-u-term  Exposure	._	     V-l

          1.   Lethality	'.  .  .     V-l
         2.   Otner Effects  .'	  .     V-3

      B.  Long-term Exposure  	     V-4

         1.   SuDChronic Toxicity	,	     V-4
         2.   Cnronic Toxicity	     V-5

      C.  Teratogenic/Reproauctive Effects   	     V-9

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                             TABLE  OF.CONTENTS  (continuea)
                                                                              Page

   V.  HEALTH EFFECTS  IN  ANIMALS  (continued)

       D.  Mutayenicity	t	     V_15

           1.  Gane Mutation Assays  (Category  1)	     V-16
           2.  Chromosome Aberration Assays  (Category 2)	     V-18
           3.  Other Mutagenic Mechanisms  (Category  3)   	     V-lb

       E.-  Carcinogenicity	     V-19
       F.  Summary	„...*.....     V-21

  VI.  HEALTH EFFECTS  IN HUMANS	".  ."	..'...     VI-1

 VII.  MECHANISMS UF TOXICITY	 .''.. . .   VII-1

VIII.  QUANTIFICATION UF TUXICOLQGICAL EFFECTS	   VIII-1
                                                                                  *
       "A.  Procedures for Quantification of Toxicological Effects ....   VIII-1'
                                                                                  t"
           1.  Noncarcinogenic Effects	   VIII-1
           2.  Carcinogenic Effects	; . . . .   VIII-4    11
                                                                                      r
       B.  Quantification of Noncarcinogenic Effects for Uxamyl	   VHI-6
                                                                                      ;i
           1.  One-day  Health Advisory	  . . . . .   VIII-6    ;
           2.  Ten-day  Healtn  Advisory	-.;..-......   .VIII-6    •;
           3.  Longer-term Healtn Advisory	   VIII-6    ,'.
           4.  Reference Dose  and  Drinking Water Equivalent Level ....    VIII-9    ''

       C.  Quantification of Carcinogenic Effects for Oxamyl	VIII-12    i'
       0.  Summary	."	VI11-13    !
  IX.  KEFERENCES
IX-1

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                                 LIST  OF FIGURES


Figure No.   .   - •  °                  .  .
                 »     *                                   *
  III-l     In Vitro Metabolism  of Uxamyl fay Kat  Liver Microsomes   .  .     III-3




                                  LIST OF TABLES


Table No.

                                                                            II-2
li-l
V-l
v-z .
' V-3.
V-4
V-is
y-e
V-7
V-8
V-9
VIII-1
VIII-2
VIII-3
Summary of Acute Toxi city Values in Laboratory Animals

Mean Maternal Body Weights of Rats Fed Oxamyl During
The Effects of Dietary Administration of Uxamyl on
Mean Maternal Soay Weight Gains in Rai>bi4s~£;ve.n -Ora-l
Summary of Viscaral and Skeletal Findings in Fetuses
Effects of Uxamyl Ingestion on Litter Size and Body
Weignts of Weanlinys in Three Generations of Rats ....
Summary of Histopatnologi cal Findings in Rats Fed
Summary of Tumor Data From Mice Fed Oxamyl for 2 Years . .
Summary of Subcnronic Feeding Stuaies Considered in
the Development of the Longer-term Healtn Aavisory for
Summary of Chronic Feeding Studies Considered in the
Development of the Reference Dose and Drinking Water
Summary of Quantification of Toxicological Effects for
V-2
' V-7
V-10:
*.
V-12*
V-13
V-L5
V-17
V-20
V-22
VIII-7
VIII-10
VIII-14
                                       V11

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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 (MCLGs) and promulgate National Primary Drinking
Water Regulations, for each contaminant, which,-in the judgment of the Administra-
tor,  may have  an  adverse effect  on  public  health and  which  is  known  or
anticipated to occur in public water systems.  The MCLG is 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 MCLG 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
                                      viii

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                                   I.  SUMMARY  •




      •Jxamyl, S-rcetnyl  N' ,N' -dimethyl -N-(methyl caraamcyl oxy)-1-thiooxami -


 miaate,  is  the active  ingredient found in the insecticide/nematicide Vydate


 L*, wnicn contains 2*- oxamyl  in methanol.  Vycate* is widely used for control


 of insects, mites, ana nematodes on field crops,  fruits,  and ornamentals.




      Uxamyl is stable  in  the solid form and relatively stable in aqueous  solu-


 tions at acidic pH. At alkaline pH, however, oxamyl  is  rapidly hydrolyzed


 to an oximino compound.  Exposure to liyht, particularly  at  low concentra-


 tions, results in  rapid and -extensive'decomposition of oxamyl.   Decomposition


 in soils under both aerobic and anaerobic conditions  is  also rapid and extensive.
                   to                          f    .

 Fielc studies indicate tnat the mobility  of oxamyl  in  soil is  limited.          *

                                                                                i

      Uxamyl is rapidly aosorbea, metabolized, and eliminated by rodents.  Rats


 eliminated  greater than aQ* of  an oral  dose of  oxamyl  in  the urine within


 3  days of administration.   Mice yiven an  intraparitoneal  (1p)  injection of  .-


 oxamyl excrsted  more than  87» of the dose in  the  urine witnin  3 days.  Relatively


 small  percentages  of each  dose  were found in  the  feces of rats  or  mice within


 72  nours  postadministration.  There  was little  accumulation  of  oxamyl  in the


 tissues,  altnouyh  appreciable amounts  (7  to 12.5-) were found  in tne skin and


 nair  of  two rats witnin 3  days  of  dosiny.   Oxamyl appears to be  extensively


 metaoolizac after  oral  or  ip administration.  The primary metabolites recovered


 in  urine  of both rats  and  mice were  methyl  N-nydroxy-N1 ,N'-dimetny1-.l-thiooxa-


 minndate  (i»Tu)', N,N-dimethyloxamic  acid  (DMOA),  N-methyloxamic  acid (MOA), and


 metnyl N-nydroxyN'-methyl-l-thiooxamimidate (MTO).  In addition, oxamyl and


 fo,N-dimethyl-lcyanoformamide (DMCF)  were  also found in tne urine of mice.


Oxamyl has been shown to be metabolized by hepatic microsomes via two major


pathways.  Une pathway involves  hydrolysis to DMTO, and the second involves



                                      1-1

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 enzymat-ic conversion via UMCF to DMOA.  A third, minor enzymatic process  results

 in partial cemetnylation of oxamyl and its metabolites.


      Tne major mechanism of toxicity of oxamyl appears-to be cholinesterase

 inhibition.  Acute oral, intraperitoneal., or inhalation exposure to lethal

 aoses of oxamyl  resulted in typical  clinical  siyns of cholinesterase  inhioition

 prior to aeath in rats, mice, racbits, guinea pigs, and doys.  Oxamyl  is

 extremely toxic  via oral, inirapejM toneal, and inhalation routes of administra-
                         t
 tion; oral  LD^y  values  were Z.b  to '3.U mg/kg  in  rats, 2.3 to 3-.3 mg/kg  in mice,
                          A
 and  7 mg/ky in yuinea pigs.  Tne.insecticide  (in solution)  has  only limited

 aDsorption through the  skin as evidenced  by dermal LD^ values  of 7bO and >1,2UO

 mg/ky in  raooits  and rats,  respectively.       '               '                  ^
                                                                                f

      Treatment witn atropine  after aaministrati on  of  lethal  doses  of oxamyl is.

 antiaotal  in  rats  due to its  competitive binding of acetylcholine  receptor sites

 on pcstsynaptic memoranes.



      Oxamyl is also toxic following long-term  oral exposure.  Although clinical

 siuns  of  cnolinesterase  innioition were not observed,  statistically significant

 decreases  in  body weiynt were  noted in male and  female  rats  fed  100 ppm in the

 diet .(b.U my/kg/day) for 90 aays or 2 years.   Serum cnolinesterase activity was

 siynificantly decreased  in  females fed 150 ppm (7.^ mg/kg/day) after 4 days and

 in males fed  IbU ppm (7.3 mg/icy/day) after b days  of exposure to oxamyl.  No

 specific target organs were identified.  Histopathologic examination revealed

 no increased  inciaences of  tumors after inyestion  of up to 150 ppm (7.5 mg/kg/day)

 for 2 years in rats.


     Similar  results were obtained in a 2-year study in mice fed oxamyl  in the

diet at levels up to 75 ppm (11.25 mg/kg/day).  Significant decreases  in body
                                      1-2

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 wei^nts were noted in males and females fed 50 ppm (7,3 mg/kg/'day).  NO increases


 in inciaence or type of neoplastic or nonneoplastic lesions were observed in


 mice fea up to 7b ppm wnen compared to -controls.  From the results of the


 feeciny studies, oxamyl was not carcinogenic in rats fed up to .150 ppm or mice


 fed up to 7b ppm for 2 years.  This is supported by negati-ve results of several


 i_n vitro vjenetic toxicity assays.




      In yo-say ana 2-year feeding studies  in beagles,  dietary levels of oxamyl

 »
 up to IbO ppm (3.a my/ky/day)  did not  elicit any changes  in body weight, food


 consumption, clinical  signs, hematologic and urinary parameters,.or histopath-


 oloyy wnen compared to controls. • Statistically significant increases  in se-rum

                                         V

 alkaline phospnatase activity .and cholesterol  levels  were, observed in  groups   *


 fea IsU ppm after  2 years  of exposure, suggesting  some  effect on the liver.


 This  was not supported oy histopstnologic  findings,  however,



      Altnouyn  maternal  toxicity {significantly  decreased  body weight)  was


 marked  at  1QU  ppm  (5.0  mg/kg/day),  oxamyl  fed to pregnant  rats  at  levels up to


 3uu ppm  (ib  mcj/ky/day)  was  not  teratogenic.  Oral  doses of  up  to 4 mg/ky/cay


 aaministerea to  pregnant  rabbits  were  not  teratogenic,  although  significantly
                                                         6

 decreased maternal  body weiynts were observed at 2 mg/kg/day.




      Developmental  toxicity, as  evidenced  by .decreases  in the  litter size of
                                           .. **"*.? '' ' ••""

 cams  fed cxamyl at  10U ppm  (b.O my/kg/cay) was  demonstrated in both one- and


 tnree-generation reproduction studies  in rats.   Decreased growth  (significantly


decreased oody weiynt) of weanlinys from the yroups fed 10U ppm  was also


noted.   Similarly,  parental toxicity in the  form of significantly decreased


Dody weiynts was observed in both males and females fed 100 ppm.  In this


study, oxamyl did not affect fertility or elicit increases  in the incidences of
                                      1-3

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 variations  or malformations  of  tne offspring  of  dams  fed  up  to ISO ppm  (7.5
 mg/kg/aay).

      No  suitable  data. were  found  in the  literature  for  derivation  of  the One-
 and Ten-day  Health  Advisories  (HAs) for  oxamyl .   A  Longer-term HA  of  200 ug/L
 for a  10-ky  child was  calculated,  based  on  a  No-Observed-Adverse-Effect Level
 (HOAEL)  of  2.5 mg/kg/day  identified in a 90-day  feeding study  with rats.  This
 was substituted as  a  cpnservative  estimate  of both  the  One-  and Ten-day HA
 values.   A Drinking Water Equivalent Level  (UWEL) -of  yuu  uy/L  for  a 70-kg
 adult was .developed, based on a NUAEL of '2.5  mg/kg/day  identified  in  a 2-year
 feeafng  study with  rats.  Oxamyl is classified in Group E:   Evidence  of Non-
 carcinog'enici-ty for 'Humans,  based  on the  results 'of a 2-year feeding  study'
 with rats and a 2-year  feeding study with mice.
          ugh no information on tne exposure to or toxicity of oxamyl in humans
was found in tne literature, the results of animal toxicity studies indicate
tnat acute oral, i ntraperi toneal , or inhalation exposure to lethal doses-of.-
oxamyl  at 2.3 to 7  mg/ky can cause rapid death in laboratory animals.  However,
because of tne "reversiole" nature of oxamyl toxicity owing to its mode of
action and tne rapid .metaoolism and elimination of oxamyl and its metabolites,
tnis insecticide appears to have a wide margin of safety.
                                      1-4

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                      II.  PHYSICAL AND CHEMICAL PROPERTIES

 A.   GENERAL PROPERTIES

      Oxamyl, S-nnetnyl  N' ,N'-aimethyl-N-{methylcarbamoy-loxy}-l-thiooxamimidate

 (CAS No. 23135-22-0),  In its pure state, forms colorless  crystals  with  a  slight

 sulfurlike odor and is  considered extremely  toxic.   The compound was  introduced

 oy E.I.  duPont de Neumours and Company, Inc.,  as  the main active ingredient in

 the pesticide Vydate*.   As a solid,  it is  stable.   In aqueous  solutions,  it

 decomposes slowly.   This process is  accelerated by  aeration, sunlight,  alkali,

 or elevated  temperatures.   A summary of the  physical  and  chemical  properties is

 listed in  Table -II-l (Gosselin,  1981; duPont,  1986;  U.S.  EPA,  1986; Worthing

 ana  Walker,  1963; Kennedy,  1986a).                                .           .l
                                                                               f
 B.    PRODUCTION AND  USE

      E.I.  auPont de  Nemours  and  Company, Inc.,  is the  sole producer of oxamyl.

 Oxamyl is  tne  active ingredient  in the  insecticide/nematicide-Vydate L*.  In

 1982, production of  oxamyl was reported to be  0.4 million pounds/year (0.3

million pounas/year for  use  as the insecticide  and 0.1 million pounds/year for

 use as tne nematicide)  (SRI,  1985).   Vydate* consists  of  24% oxamyl in methanol.

 In tnis form, it is classified as a  poison B, which is defined as:   "a less

 aanue-ous  poison: substance,  liquid,  or solid,  other than Class A or irritating

material,  wnich is Known to  be so toxic to man  as to afford a hazard to health

during transportation or whicn,  in the absence  of adequate data on  Human toxicity,

 is presumed to be toxic to man."  It  is used to control insects, mites,  and/or

nematodes on many field crops, fruits, and ornamentals (O'Bannon and Selhime,

1980; French, 1982;  Timmer and French, 1979).  Application may  be by broadcast or

band to soils, as a transplant water  treatment, or a foliar spray (duPont, 1986;
                                      II-l

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         Table II-l.  Physical and'Chemical Properties of Oxamy]
     Parameters
               Value
 CAS number
 23135-22-0
 Synonyms



 Color/form


 Molecular weignt


 Melting  point


 Vapor  pressure  at  25°C


 Specific gravity  at  2iJ0C


 Svaoility



 Structure
 Thioxamyl;  diovamyl;  duPont  1410;
 DP*  1410; .Vydate*
Clear crystalline solid


219-.3'


108-11U°C


2.3 x 10-4 mmHg


0.98  -
Staole in solid form, and in liquid form
at acidic pH
         0
0
II
                                 (CH3}2-N-C-C=N-0-C-N-CH3

                                           SCH3
Soluoility at 25°C
   water
   Acetone
   Etnanol
   Toluene
280 g/L
670 g/L
330 g/L
 1U g/L
SOURCE:  Adapted from Worthing and Walker  (1983); Kennedy (1986a);
         U.S. EPA (1986); duPont (1986); Gosselin (1981).
                                 II-2

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 19S6; 'Kennedy,  19B6a).   It  is  registered for use on a variety of vegetation for
 preplant,  at  planting,  or  postplant  featments  (Agriculture Research Service,
 1986).  Some  or all  applications may  oe classified by tne U.S. EPA as Restricted
 Use Pesticides  (HUP).

 C.   ENVIRONMENTAL FATE  AND EFFECTS

     Because  oxamyl  is  applied to  a wide variety of crops at different stages
 of cultivation, the  compound inevitaoly comes into contact with soil and water.
 Thus, its  fate in these  media  is important.

 1.   Stability in Water      .         .                      _   •
                                        «                                        i
    'Harvey and Han  (157ba) reported  that in water, oxamyl {1.2UU pom)  was
                                                                 <3              •
 staale for "at least  11  days at pH  5  or lower; but was hydrolyzed rapidly to the
            c
 oxirnino compound at  pH 9.  Peeples (1977) calculated a half-life of approxi-
 mately 3 days for a  1,200-ppm  aqueous solution  of oxamyl at pH 9.1 and a naif-
 life of 14 aays for  tne  same concentration of oxamyl in an aqueous solution
witn a pri of b.9.

     The effect of liyht on tne hydrolysis of oxamyl was also examined.  Harvey
 ana Han (1973a) prepared 1 and 1,000  pom [l*C]oxamyl solutions using either
                                                                 —\
distilled or river water.  A set of samples was exposed to ultraviolet lignt
continuously for 7 days, while control samples were stored in the dark  for 10
days.  Aliquots of ultraviolet-exposed samples were analyzed for total  radio-
activity and composition at U, 3, and 19 hours, and at 2, 4, and 7 days.
Controls were examined only at the end of the 10-day holding period.  In all
 lignt-exposed samples, decomposition  of oxamyl was extensive and rapid.  The
most dramatic effects were seen in the 1-ppm sample from river water, in which
99% of tne raciolaoeled oxamyl  was nydrolyzed within 48 hours of the initiation

                                      II-3

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 of  exposure.   At the end of "l'week,  22 to  61%  of  the  parent  compound persisted
 In  the other  ultraviolet-exposed water samples.   The  pesticide was  converted
 primarily to  the ox:ml no derivative  (18 to 51% of  the total  radioactivity
 recovered)  and Its :somer'-(3% In. l.-ppm sample  In  distilled water;  24 to  36%  In
 all  otners).   A polar fraction N,N-dimetnyl (oxamic acid)  was  present In  high
 concentrations (18 and 23%) In the samples containing 1  ppm  only.   The level  of
 oxamyl  In tnree of the control  samples remained essentially  unchanged; however,
'In   river water samples containing 1,OOU ppm,  16%  of  the  parent compound was
 converted to  the oxlmlno form after  1U days.   Recovery of  at  least  98% of. tne
 original  radioactivity  was  reported  for all samples.

      In  a similar study,  6  gallons  of  river water  spiked  with  1 ppm [-4C]-     -i
 oxamyl were left .outdoors and exposed  to direct sunlight  for  6 weeks (Harvey.   '
 and  Han,  19?8a).   No  oxamyl  remained at tne end of  the study.   The  radiocarbon
 was  present primarily  as  the  oximino derivative (46%  of total  radioactivity
 recovered) and its isorner (34%).   Polar compounds, .including  N,N-dimethyloxamic
 acid and  two  unknown  compounds,  comprised  the  remaining 20%  of the  carbon
 label.   Tne autnors  reported  that  oxamyl was hydrolyzed completely  to the
 oximino  compound oy the end  of  the second  day  of the  study.  This compound was
 gradually converted to  its  syn-anti-isomer until an apparent equilibrium state
 was  reacned.   Following this,  additional degradation  products  were  formed.
 Approximately  17% of the  total  radioactivity was not  accounted  for  during the
 6-week experiment.  This  was  presumably lost as
 2.   Mobility  in  Soil
     Conflicting data exist concerning the mobility of oxamyl in the soil.
Harvey and Han (1978a) reported that, under laboratory conditions, oxamyl
(levels not specified) was fairly mobile in four soils (muck, loamy sand,'and

                                      II-4

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 two types .of silt-loam).  Thin-layer chromatograpnic (TLC) analysis gave
 reference (Rf) values ,.(0.53 to l.OU) reflective of a moderately to nighly
 moDile compound (Harvey and Han, 1978a).  The moDility of oxamyl Increased as
                               
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        ^s of a 2-year field study conducted by Mclntosh et al. (1984)
    that oxamyl probably does not accumulate in liynt-textured soils that
    y irrigated.  In tnis experiment, oxamyl was applied at an approximate
   .U pound ai/acre/montn to sandy desert soils in a southern California
   ve. ' Ten pounds/acre were applied during the first year of the study,
   ids/acre were added to tne soil in tne second year.  Five -eplications
   -e lots were used.  Kater-only areas served as controls.  Samples we-e
   • depths of U to 4, 4 to b, and 8 to 12 incnes, and at each foot between 1
   •et below the surface of tne soil.  Analysis of samples obtained between
   •days posttreatment showed that, under the conditions outlined, oxamyl  • .
                  *                    *                        " •    *
   ienetrate tne soil to depths greater tnan 5 feet.  Uxamyl w'as rapidly
   •to its oximino metabolite in these samples.  Levels of both compounds
            by  21 days  postapplication.  Similar results  regarding
           n and  degradation were obtained  when a single  10-pound (ai)/
  stment (lUx the normal  use rate)  of Vydate® was applied to a previously
  a site.      "           '          •

   field study data  described  above  disagree with laboratory data indicating
  myl  is moaerately  to  nignly  mobile in soil.  Harvey and Han (1978a)
  d that, under practical  conditions,  rapid degradation of  oxamyl  precludes
 ?ment in sell  despite  heavy rainfall.

 :omposition  in Sol 1
gradation and metabolism of oxamyl were examined in three moist soils:
andy loam, and silt loam (Ou and Rao,.1986).  Approximately SOU ug
Dxamyl were added to  1UO g dry soil to give a final pesticide concen-
          .  About 59 to 84% of the original carbon label appeared
2 by day 63 postapplication.  At this time, most of the  remaining

                               II-6

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 radiolaoel  was nonextractable (i .e.,° bound).  The exception was the silt  •
 loam with a high so-il-water tension (33 kPa); in this soil, 24.5% of the
•origi-nal  14c dose appeared as oxamyl,  small  amounts of  N,N-dimethyl-2-(methyl-
 tnio)acetamide oxime,  and polar metabolite.-  As the soil-water tension increased,
 degradation of oxamyl  decreased.  Unchanged  parent compound accounted for 28 to
 47% and 53  to 7y% of the recovered radioactivity at the lowest (10 kPa) and
 highest {1.5 x 103) tension levels, respectively.  Half-lives  (tjy2) for  ex"
 tractable 14C disappearance ranged from 8 to 5U days; tjy2  values'for oxamyl
 disappearance were estimated to be shorter.

      Extensive field studies on the decomposition of  Vydate® in soil  were
'conducted by Harvey and  Han (1978a),  In one investigation,  three types of soil  :
                     *                                                           ' £
 (silt  loam,  loamy-sand,  and fine sand)  were  treated with  [14c]oxamyl  at a  rate   ,
 equivalent  to 6  pounds ai/acre.   All sites'were exposed to  normal  weather  conci-
 tions  and similar  amounts  of rainfall.   Samples were  analyzed  at  1  week,  1
month,  and  3 or  5  months  posttreatment.   In  all  three soils, oxamyl  was rapidly
decomposed;  less than  5% of tne  parent  compound remained  at  the 1-month collec-
tion time.   After  1  month,  volatility losses  (presumably  as  1*C02)  comprised
65.b to 73.0% of the original  14C  application.   The oximino  derivative of
Vydate® and  a  polar  fraction appeared early  in  the  study  (at 1  week)  and in
consideraole amounts.  However,  only trace levels  of  these  radioactive compo-
nents we-e detected  at the  end  of  tne study.  Unextracted residue contained 6.3
to 27.0%  of  the original  radioactivity;  these levels  varied  greatly  w-ith regard
to time ana  soil type.   Five months  after sprayiny, approximately 9%  of the
original  laoel was extracted from  the loamy  sand  residue  and was  distributed :n
the soil  as  follows:  alphahumus,  32%;  soluble  numin, 18%; fulvic acid, 13%;
beta-humus and insoluole  humus,  6% each; hymatomelanic acid, 4%;  and  a volatile
compound  lost during analysis,  21%.  Detailed analysis of the other  soils  was

                                      II-7

-------
 not reported,  leacnate water Detained from loamy sand and'"fine sand, contained
 no raaioacti vity at 1 week and 1 month and only trace amounts ("less than 6% of
 tne original carbon laDel) at the last sampling time.

      Aerated silt loam was treated with [14c]oxamyl (0.98 uCi) at a rate
 equivalent to 4 pounds/acre (Harvey and Han,  iy78a).  The experiment was repeated
 under anaerooic conditions at a level of 6 ppm [l^CJoxamy'l (7.12 uCi).  Both
 soils were placed in metabolic chambers for 42 days.  In the presence of air,
 51% of the labeled chemical was converted to  14CU2,  11* appeared as a polar
 fraction, .and 4% remained unchanged..  Only a  trace amount of the parent com-
 pound was  present as the  oximino  form.  Approximately  26% of the original
 radioactivity was incorporated into normal  soil  organic material.   Nearly
                                                                                 i.
 two-tnirds  of  tnis'residual  radioactivity  was  divided  among  several  soil frac-   ,
 tions:   fulvic acid, 62%;  alpha-humus, 25%; hymatomelanic acid,  6%;  and beta-
 nuraus,  6*.   Aoout 7% of the original  radioactivity  in  tne aerocic  soil  samples
 was not  accounted for.             .                 ..-•-..-

     Under  anaerooic conditions, decomposition of  [l^Cjoxamyl was  almost as
 rapid and extensive  as in  the  aerobic system in  that only 8% of  the  parent  com-
 pound remained  after 42 days  (Harvey  and Han,  1978a).   However,  only 3% of  the
 0,-iyinal racioactivity was  converted  to ^COg, and more than  80% appeared as the
 oximino  compound  and the polar  fraction.  Residual levels  of  radioactivity  were
 low (5%) at  tne 42-day-..mark, indicating a delay  in botn" the  oxidation of oxamyl
 to COj and tne  incorporation of the pesticide into organic matter.

    •Tne rate of  aerooic and anaerobic decomposition of 6 ppm [l^Cjoxamyl in
   «
 loamy sand, fine sand, and silt loam was investigated  by  Harvey ana Han  (1978a).
Soil samples were analyzed for radioactivity and composition at 0, 7, 14, and
28 days after treatment.  Uxamyl concentrations declined  steadily in both

                                       II-8

-------
 aercoic.and anaerobic samples;  after  23 days, approximately 28% of the parent

 compound  remained in aerated  sands, and only 2% persisted  in the silt loam

 deprived  of oxygen,  unaer aerooic conditions, tne half-life of oxamyl was 15

 days for  the fine sandy soil  and  11 days for the loamy sand samples.  In the

 aos'ence of oxygen, tne naif-life  of oxamyl was approximately 6 days.  Un the

 basis of  results from a 2-year  field  study, Mclntosh et al. (1984) reported a

 half-life of 1 to 4 days for  oxamyl when the compound was applied at a -ate of

 1 pound ai/acre/month to1 irrigated, sandy desert soils.  In a field study conducted

 oy Harvey and Han {1978a), e-1,200 ft2 area of silt loam was treated with 5.65
                      9                 •            '          '
 pourias a:/acre.'' Soi-1 samples reaching'depths of  3U inches were analyzed on U,
          •a
.2, o, 9, lt», 23, 30,  and 6U days after oxamyl. application.  The half-life of
             a

 Vydate* unaer the conditions  of this study was  8  days.                         ,

                                                                                t
 4.   Metabolic  Fate  in  Plants


      Tne metaoolic patnway of L-*C]oxamyl  was studied in  peanut and  tobacco

 seedlings  treated with  2  and  6 pounds  ai/acre,  respectively (Harvey,  1973).   In-

 extracts of  young peanuts, peanut hay  and  seedlings,  and  mature tobacco,  the

 majority of  -aaioactivity  (73 to 1UO%) was  detected  in a  "polar fraction."  At

 'i  to  6 weeks  postspraying, this polar  fraction  consisted  primarily of  a  gluco-

 siae  conjugate  of a hyarolyzed oximino compound.  Demethylation gradually

 occurred,  producing a monomethyl oximino glucoside witnin  1  to  2  months  and

 an IS-aeme.nylated oximino  glucosiae several months after  exposure to the  nemati-

 cide.  Smell amounts  of oxamyl  and its oximino  derivative  were  found-in  the

 plant extracts  at various  stages of harvesting.  N,N-dimethyloxamic acid  was

 also aetectea in  tobacco raised  in  growth  chambers.   Below are  the chemical

 structures for  tnese compounds.   The author.sugyested that the  presence of this

 compound may represent a minor or alternate metabolic  pathway for oxamyl.
                                       II-9

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              COMPC'JND  . '  " '       NAME
OXAUYL     UFTHY1. N1, N1—OIMETKY1—N1 [METHYLCAfl.
         BAMOYU) OXYJ—I-THIOOXAMIUICATE
                                                             0

                                                          ,f NOCNMCK,
                       QXIUINOUETABOUTE                CMv
                       USTHYl N—HYDRO*—N'. N'—DIMETHYL—1—
                       TKOCXAMIMIOATt                 „„ /
                                      ,  II   /
                                      N-0-«C
                                                           NOH
                                                  CtV
                       N. N—OIUETHMOXAUlC ACID
                                                     N-C— "COOH
                                                 CM,

      In  anotner study, a 1% solution  (w/v) of  [l^Cloxamyl  in U.2% aqueous Tween


2u was spotted  on the surface of  green  tomatoes  (Cv. Bonny Best) being grown  in

a greenhouse  (Harvey, 1976). 'A total of 0.37  mg  oxamyl  was applied to each


tomato.   Fruit  was allowed to' ripen  and'was  harvested.in pairs at 7, 11, 14,
   •  '                                                           

(13%) and  its glucose conjugate (5%).   Approximately 4% of the radioactivity

was associated  witn N,N-aimethyl-l-cyanot'ormamiae  (UHCr).   The remainder of

the radiocarbon (19%) was present as  a  mixture of -polar or natural products.

Comparable levels  of  oxamyl and its metabolites were found at 21 days, altnough

a steady decline  in oxamyl  and an increase in  the  oximino  compound were observed


during the 3-week  harvesting time.



5.   £nvi"onmenta1  Toxicity

                      <3
                  4
     Technical  grade  (93.5% pure) or  1% granule oxamyl  was dissolved in water

at concentrations  of  13.5,  18, 24, 32, 42, or  56 ppm (Watanabe,  1975).  A

75-ppm solution of  tne granular formulation  was also included in the study.

Tne solutions were  t-ansferred to 50-L tanks,  and  10 carp  (approximately 6.1 cm

long and weigning  bt>  y)  were placed in each  tank for 48  hours for the purpose of

evaluating tne  acute  toxicity of  Vydate®.  No  fish  survived the highest concen-

tration level  of either  type of  oxamyl.  All animals survived exposure to the



                                       11-10

-------
 13. b- and 13-ppm solutions, and 1U to 9U% of  the carp-. were  still  alive  after
 swimming In waters containing Intermediate concentrations  of  oxsmyl .  "Op  to 50%
 of the flsn were found turning slaeways while In -the  treated  water; the bodies
 of many flsn were bent In a U-snape following exposure to  the' chemical .  Fish
 that died during tne study, had enlarged gall  ol adders, 'hematocel la, and anemia
 In tne gills.  Bent bodies did not return to  normal  after  carp  were placed  back
 Into fresn water.  Forty-eight hour median tolerance  limit  (Tl_m)  values we~e '
 29 ppm'Ui) and 3b ppm (ai) for carp exposed  to  1% granule  and  technical  grade
 oxamyl, respectively,  indicating  that granule Vydate® is slightly  more-  toxic to
 ca~p tnan is the technical  grade.  The authors  concluded that,  at  the
                                      o                                      " "
 concentrations  investigated,  botn forms  of oxamyl  could do  consideraole harm
 to fish.
                                                                               i
      Tadpoles  (kana  temporaria) exposed  to  oxamyl  exhibited slowed growth,
 delayed  development, and  physical  deformities.   In this field study (Cooke,
      , eignt cayes of 4U tadpoles each .vere maintained for 6U to 8U days
                                               <3
adjacent to sugar oeet, barley, and potato fields that had been sprayed .with
the pesticiae (exposure levels not noted).  No other chemicals were used during
tne experiment.  In cages kept Detwesn fields of barley and potatoes, mortality
was nigh, development and growth were slow, deformities particularly vertical
curvature and tail  tip,, were also found.  However, cages kept between barley and
sugaroeet, survival was good, development was rapid, and growth was satisfactory.
Deformities occurred late in the study showing lateral kinks.  Cages kept between
sugaroeet and potatos showed high mortality during the first month but leveled
for tne rest of the study.  Lateral curves and tail  tip deformities were also
observed.  A cage kept in a nature reserve pond served as  a control; all
parameters measured were normal, except for a few lateral  kinks.  In a parallel
laboratory study, approximately 9U% of tadpoles exposed to 1UU ppm oxamyl  for

                                     11-11

-------
 1 hour, developed vertical curvature deformities similar to those seen in the

 field (Cooke, 1981).  No tail tip defects developed in the 100-ppm oxamyl-treated

 tadpoles.  Tne deformities observed under laboratory conditions appeared to be

 related to abnormal posturing, unlike those found in the field wnich appear to

 be of muscular origin.  Experimental evidence therefore did not prove conclusively

 that oxamyl caused tne harmful effects observed in field tadpoles.  It did indicate

 however, that oxamyl  warrants further consideration.


      A significant increase in the mortality  rate for bees was observed  after

 oxamyl  was sprayed over alfalfa fields (Atkins  et al .,  1974).   Early morning-^

 fol'iar  applications of Vydate® (U.S'and 1.0'pound/acre)  suppressed bee foraging

 for  at  least 4 days.   More than 9b% of the  bees exposed  directly  to either
                                                                                 i
 concentration of  the  pesticide dieo within  24 hours;  of  tne bees  placed  in the  ^
                                                                                 I
 field 1  nour after spraying  either u.b or l.U pound/acre,  only 29  and  12% died

 during  the next 24 nours,  respectively. Approximately  3%  of control  bees  ciie^

 under similar exposure conditions  and  times.  The  overall  hazard  of  Vydate® \

 to Dees  was  moderately  nigh  at  tne 1.0-pound/acre  level  and  moderate  for the

 U.i-pouna/acre concentration.


      Under  laboratory  conditions,  oxamyl was  toxic to one type  of  earthworm,

 the night  crawler  (Lumbricus  terrestris) (Ruppel  and  Laugnlin,  1977).  In  this

 study, Vyaate* was mixed with ary  potting soil  at  rates  equivalent to 0, 2, 4,

 8, 16, and 32 pounas ai/acre.  Ten active niynt crawlers were  added to eacn test

 soil.  A -eiatively nigh level of  tne pesticide, 13.U6 pounds  ai/acre, was

 required to cause death in bu% of  the niynt crawler population.  According to

the autnors, tnese data support evidence of high night crawler mortality rates

 ooserved in fields sprayed with oxamyl.
                                     11-12

-------
     Tne effect of ID ppm oxamyl on bacterial growth was studied in three types
of soil:  fine sand, silt loam,  and sandy loam (Peeples, 1977).  Dilution plate
counts were used to determine soil microbial  populations at 1, 2, 4, and 8
weeks after treatment.  CC>2 evolution was used to measure microbial activity.
Oxamyl had no adverse effects on either fungal or bacterial population or on
microoial respiration in any of  the soil types.
                                      11-13

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                               III.  TUXICOKINETICS   -                *


A.   ABSORPTION


     Seventy-two Hours  after two male Charles  River-CU  rats were  given  a

single  oral dose of  1.0 mg (3:74 or 5.6 uCi)  [l-Hc]oxamyl, about 55%  of the

original  radioactivity  was recovered in the  urine  (Harvey  and  Han,  1978&).

About 19% of the radiocaroon was found in  the  hide  (skin and nair), the carcass,

and  various tissues  (including  plasma, but  excluding the gastrointestinal tract}

at t-ie  time, of sacrifice (72 hours postdosing).  Plasma-levels  of radioactivity

accounted-for only 1.55 and 2.13% of the original  1*C dose at  72  hours.  These

data suyyest'that at  least 74%  of-the dose is  absorbed  from the gastrointestinal
                                                           c *
tract following oral  administration.'                                           *
                                                                                r

     Chang and Knowles  (1979) gave 2U  male Swiss-Webster mice  a single intra-

yeritones! (ip) dose  of  1.16 my/kg (0.13 uCi)  [l-14c]oxamyl.  Within 96 hours
                                                                              9
after oeing injected  with  the pesticide, mice  excreted  88.7 and 7.7% of the

radioactive label in  the urine  and feces,  respectively.  More  than 75% of the

original  radioactive  dose  was eliminated during the  first 6 hours of the

study, with the majority (72.7%)  appearing in  the urine.  At 96 hours after

injection, tne 14c concentration in  the  plasma was  only 30.5 ppb; plasma
 • •      •           f
radioactivity levels  were  not measured at  any  other  time.


B.   DISTRIBUTION

     Tissue levels of radioactivity  were generally  low  following  administration

of radiolaoeled oxamyl.  About  22% of  a  single oral dose of 1.0 mg [l-14c]oxamyl

(3.74 or  5.6 uCi) retained  by two  male Charles River-CD rats was  distributed

among 13  body fractions  3  days  after administration  (Harvey and Han, 1978b).

Approximately 6.98 and  12.55% of  the original  radiocarbon were  recovered in the


                                      III-l

-------
 rVide  (skin  and  hair),  6.34 and 4.18% were retained  in the  carcass,  4-.76  and
 1.32% were  found in the gastrointestinal tract, and 1.5b and 2.13% were  present
 in tne olood.  The.liver of one animal  contained  1.^8% of  the original  radio-
 activity, wnile tne hepatic 1*C level in the second rat was  only 0.2U%.   Other
 tissues  contained  no more than U.36% of tne  original  14c label  (Harvey  and  Han,
 1978D).

      In  the  study  conducted by Chang and Knowles  (iy7y), radiocarbon  residues
 in  tissues of 2U Swiss-Webster male  mice given  single intraperitoneal injections
 of  1.16  mg/kg (U.13  ud)  [1-14C]  oxamyl  were  very low.   Residue  levels ranged
 from  11.U ppb in tne testes to 37.U  ppb  in the  liver  96  hours  after dosing.

 C.   METABOLISM                          .                                       k

     Uxamyl   is metabolized  extensively  in rats  and  mice.  Urine  and feces
 collected from two male Charles River-CD  rats given a  single  oral dose of
 l.U my [l-14c]oxamyl were  analyzed 72 hours9after dosing; more than 70% of the
 recovered radioactivity appeared  as  conjugates  of the  oximino-metabolite of
 oxamyl (metnyl N-hydroxy-N'a,N'-dimethyl-l-thiooxamimidate, OMTO; Fig. III-l-I)   •
 and N,N-dimethyloxamic acid  (DM(JA; Fig.  IiI-1-III), and as the monomethyl
                                   o
 derivatives  metnyl  N-hydroxy-N'.-methyl-l-thiooxamimidate (MTO; Fig. III-l-II)
 and N-metnyloxamic acid (MUA).  The  percent distribution of these four metabolii
was "ougnly  equivalent in both urine and feces, although the urine contained
 approximately bb% of the original radioactivity and feces contained about 15%.
 No oxamyl or other organosoluble  metabolites, including N,N-dimethyl-l-cyano-
formamiae (UMCF), were found in urine, feces, or tissues.  Approximately 43 and
 61% of tne radioactivity recovered,  respectively, In the plasma and hide of
 rats was incorporated into  various ami no acids  (Harvey and Han, 1978b).   In the
                                          tes  :»
II1-2

-------
                                                                  -COOK
Figure III-l.  In vitro metabolism  of  oxamyl  by  rat  liver  microsomes.
               •   I:  DMTO
                II:  Metnyl  N-hydroxy-N'-methyl-1-thiooxamimidate  (MTO)
               III:  DMOA
                 V:  DMCF
                VI:  Metnyl  N'-methyl-N-[(methylcarbamoyl)oxy]-l-thio-
                     oxaraimidate  (DM0).

SOURCE:  Adapted from Harvey and  Han  (1978b).
                                      III-3

-------

-------
 skin and hair, 14C was associated primarily with glycine, trypt-ophan, leucine,


 phenylalanine, and aspartic acid; leucine, glutamic acid, lysine, arginine, and


 tryptopnan contained the greatest proportions' of radiocarbon recovered in the


 blood.




      The metabolic profile of urine collected from 2U male Swis»s-Weoster mice


 yiven single ip injections  of 1.16 my/kg [l-l^Joxamyl  was similar to that in


 rats (Chang and Knowles, 1979).  The major urinary metabolite was DMTO,  which


 accounted for an average, of 43.5% of the radioactivity  excreted  by the animals'


 during tne 96-hour postdose collection period.   Urinary DMOA ranged from 8.9
    6

 to 27.2% of the recovered radioactivity, with the highest concentrations  appearing


 early in the study.   MOA levels increased steadily from 2.3  to 9.9% during the
                                                                                i   * °
                                                                                ••
 96 hours after dosing,  and  MTU levels,  which  peaked at  15% after 2 days,  dropped
                                                                                (

 to 6.9% during the last interval  of  the study (72 to 96 hours after dosing).


 In contrast to rats,  mice excreted both unchaged  oxamyl.and  OMCF,  wnich  comprised


 up to 18.3.and 3,U%  of  the  total  radioactivity  recovered in  the  urine, respectively.


 Six unknown compounds we.^e  also excreted by mice.   Results from  this  study


 indicate tnat  demetnylation of oxamyl  and  its metabolites  occurs  with  time.


 The data also  suggest that,  altnough tne metabolism of  oxamyl varies  sligntly


 oetween  rats and mice,  oxamyl  degradation  in  these  two  species is  generally


 similar  to  that in plants and  in  tne environment  (see Chapter II,  Pnysical and


 Chemical P-operties).



      In  anotner experiment  by  Harvey  and Han  (iy78b), one rat dosed with  1.1 mg


 (1U.7 uCi)  [l-14c]DMCF  (rather than  oxamyl) excreted conjugates of DMOA and MOA


 (lb and  7%, respectively,-of the  total  radioactivity) in the urine over a


 72-hour  period after  dosing.   An  additional 27% of  the  radiocarbon recovered in


the urine was associated with  amino  acids.  The authors postulated that the
                                     III-4

-------
 remaining'l^C-was prooably Incorporated Into other natural constituents.
 Tissues, carcass, and blood from the [l-14C]DMCF-treated rat contained very low
 levels of radioactivity; 23 to B9% of the 1*C residues from these fractions
 appeared as amlno acids.  7-3 absence of DMCF In rat urine and the similarities
 In metabolites from oxamyl- and DMCF-treated rats suggests that DMCF Is only an
 Intermediate In the metabolism of oxamyl  In  the rat.

      In vj_tr_o oat a support In vl^vo metabolism studies In rats and mice.  In a
 stady conducted by Harvey and Han (1973b), three levels of [l-l*C]oxaniyl  (0.3,
 1.0,  and 2.U 119)  were Incubated for 2 hours  with mlcrosomalt and/or soluble
 (cytosollc)  fractions obtained from the livers  of Charles River-CD rats:' A
 control  system containing 1.0  mg  of [l"4C]oxamyl 'but no hepatic  mlcrosomal
 fraction accompanied  each test system.   In addition  to oxamyl,  DMTO,  DMCF,  and   ,
 DMOA  were present  In  substantial  amounts  at  the  end  of the 2-hour reaction
 period.   Tnese four compounds  comprised  93.b  to  96.8% of the  total  radioactivity.
 Small  amounts  of the  monomethyl derivatives  of  oxamyl  and Its  oxlmlno compound..
 (DMTO) were  also present  In  the  Incubation medium.   The  control medium contained
 only DMTO In approximately tne same  concentration  as In  the  test samples,
 suggesting tnat hydrolysis of-oxamyl  Is Independent  of the liver microsomal
 fraction.
             B
     After a 2-hour In vitro Incubation period with  [l-l^joxamyl (200,000 dpm)
 and mouse liver suocellular  fractions, the primary metabolite formed was DMTO
 ;iZ.5 to 24.u% of the total  recovered radiocarbon) {Chang and Knowles, 1979).
 Oxamyl  as parent compound represented approximately  70 to 8U% of the total
 radioactivity.  DMCF, DMOA, MOA,  methyl  N1-methyl-M-[(methylcarbomoyl)oxy]-l-
tniooxamimlaate (DM0), and several unknown compounds  were also present, but in
very low concentrations.
                                     III-5

-------
      Un tne oasis' of In vivo and supporting in vitro data, Harvey and Han

 (1978b) postulated that oxamyl metabolism occurs by two major pathways:  by

 hydrolysis .to DMTO ana by enzymatic conversion via DMCF to DMOA. 'Superimposed

 on tnese two pathways is another slower enzymatic process that results in

 partial demethylation of the dimethyl carbamoyl  group.  The proposed vn vitro

 metasolism of oxamyl  by rat liver microsome (Harvey and Han, 1978b)  appears in

 Figure III-l.  Tne authors did not comment on the metabolic'incorporation of

 14C into tne various  amino acids, nor did they report the position(s) of the

 carbon label  associated with radiolabeled amino  acids.
   *•                                                                    *

      Oxamyl  metabolism in  vitro and in vivo is very similar.  The two path-
                                                                     e>
 ways  share  tnree  major products:   DMTO,  DMOA,  and MTU.   Rats and. mice also      •

 excrete MOA  following either oral  or ip  dosing.   Demethylation has been

 demonstrated  in Doth  in  vivo and  in  vitro  studies.   Differences  in oxamyl

 metabolism oecome  evident  when  comparing species.   DMCF  is  considered  a

 metabolic intermediate  only  in  rats,  but the compound is  actually excreted  in

 the urine of mice.  Unchanged oxamyl  is  completely  metabolized by orally  dosed

 *ats and by microsomes  isolated from  rat hepatocytes, wnereas the urine  of

 ip-aosed mice contained up to 18.3% of the unchanged parent  compound  (Harvey

 and Han, IS/BD}.


 D.   ELIMINATION


     Oxamyl  is rapidly eliminated following ingestion in rats and ip dosing in

mice.   In ooth species, elimination occurs primarily via the urine.  -Two Charles

River-CD rats treated  with a single oral  dose (1.0 mg) of [l-14C]oxamyl excreted

an average of 55 and 15% of the original  radiocarbon in the urine and feces,

repectively,  duriny the 72-hour period that followed dosing (Harvey  and Han,

198D).   Little radioactivity (less than 0.3%) appeared in expired air of dosed


                                     111-6

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F.   SUMMARY

     Oxamyl is rapidly aosorbed, metabolized, and eliminated.  In orally treated
-3-5, mo.-e tnan half  (54.3%) of an oxamyl dose was eliminated in the urine and
about 15% in the faces within 3 days after ingestipn.  Mice excreted approxi-
mately 87% of an ip dose of oxamyl in the urine and 7.2% in the feces Dy 4 days
postaaministration.
     Due to -apid elimination of a large proportion of administered
aoses, individual tissue levels of radioactivity remain low in ip-dosed mice.
Oxamyl, or its metabolites, did not accumulate to any appreciable amount in any
 rats.  In- a study witn 20 male Swiss-Webster mice, 88 and 7% of a 1.16-my/k-g
 ip-aose of [^Cjoxamyl appeared in the urine and feces, respectively, by 72 hours;  ij
 more than 75% of the dose was eliminated in the urine (72.7%)  and feces  (3.U%)
 during the initial  6 hours after administration (Chang'Snd Knowles,  1979).

 E.    3IUACCUMULATION AND RETENTION

      No information on tne bioaccumulation or retention of oxamyl  following
 repeated  dosing was found in the 'available literature.   Due to the rapid excre-
 tion and  metabolism'of the compound,  and low ttssue  levels in  20  ip-dosed mice,
 significant  accumulation and retention of the pesticide are not expected.   How-
 eve.-,  tne presence  (at 72 hours  postadministrati on)  of  approximately  19% of  an
 oral  aose of  1.0 mg [l—4c]oxamyl  in  each of the bodies  of two rats given the
                                                                                 f
 cnemical  suyyests tnat oxamyl  or its  metabolites may  accumulate in or be  retained
 oy  various body  fractions,  such  as  the skin, hair, carcass,  liver, and Dlood.
 Incorporation  of  i*C  from the  tagged  parent  compound  into  natural  constituents
 ^e.g., amino  acics) also  points  to  retention of  oxamyl  by  the  body.
                                     III-7

-------
tissue in mat'species, although in two orally dosed rats,  7 to 12.B* of the

original 1*C was recovered in the hide (skin and hair) 3 days after dosing, and

a total of 19% was retained by the whole body.


     Uxamyl was extensively metabolized following oral administration to rats

and ip administration to mice.  The primary urinary metabolites excreted by

both species were DMTO, OMOA, MOA, and MTO.  Unlike rats, mice excreted the

unchanged parent compound as well as DMCF.  In vitro studies demonstrate that
                                                                         3
oxamyl is metabolized by hepatic microsomes via two major pathways; the first

involves hydrolysis to UMTU, and the seco'nd involves enzymatic conversion via
          •     *                      .                           a
DMCF to DMUA.  A minor enzymatic process,'which results in  partial demethylation.

of oxamyl and its metabolites, was also noted.                    .      '     -f

                                                                         *'       4

     Based on the" above findings, accumulation and retention of oxamyl in the

body is not expected, altnough radiolabfil  from the oxamyl moiety [14C] has  been

found in amino acids.
                                     III-8

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                               IV.  HUMAN EXPOSURE
     To be provided by Science and Technology Branch, Office of Drinking
Water.
                                     IV-1

-------
                           V.  HEALTH EFFECTS IN ANIMALS


  A.   SHORT-TERM EXPOSURE


  1.    Lethality
                     ...               '  t

       Uxamyl  has  been  snown to be extremely  toxic when administered orally to

  laboratory  animals.   Kennedy (1986a) reported  acute oral  LD5Q values  of 2.5. to

  3.1  mg/kg for  fasted  rats,  2.3  to 3.3  trig/kg for mice, and  7.0 mg/kg for guinea

  pigs.   Typical signs  of cholinesterase inhibition such as  tremors, salivation,
                                    B
  and  lacrimati.on  were  noted 'immediately after dosing {Kennedy,  1986a).
           »
      , Qxamyl  is also extremely toxic  after intraperitoneal  injection.  An  LD5Q   i
                                              o
,...i.n .-rats of 4.U mg/kg  w,as  reported by Kennedy (1986a).   Single  intraperitoneal   •
i
  injections of  oxamyl  in saline  resulted  in  mortality  within '2  hours in  mice

  yiven doses  of 2.3 m^/ky  or  greater  and  in  guinea pigs  given  doses  of 5.1

 mg/kg or greater (Kennedy, 1986a).   Oxamyl  is  less  toxic via -the: dermal route;

 LDjj values  of 750 and  >1,200 mg/kg  were reported in  rabbits and rats,  respec-

 tively.  From these results,- oxamyl  appears  to  be only  partially absorbed

 througn tne  SKin.  However,  clinical signs  of  cholinesterase inhibition were

 noted in animals given  dermal doses -of oxamyl  (Kennedy, 1986a).


      Tne 1-hour LC^Q  for  rats exposed  to oxamyl  via inhalation (head-only

 exposure)  were 0.17 mg/L  for males and 0.12 mg/L  for females.  The 4-hour LCgQ

 was  U.U54  mg/L for  male rats.  Clinical signs  noted during exposure included

 exopnthalmos, salivation, lacrimation, and  gasping  (Kennedy, 1986a).
A summary of the
and
                                     values of oxamyl is presented in Table V-l
                                       V-l

-------
Taole V-l.  Summary of Acute Toxicity Values in Laboratory Animals
            After Exposure to Oxamyl

Species (Sex)
Rat (M)
Rat (F)
Rat (M)
Rat (F)
Mouse (M)
Mouse (F)
Guinea yiy (M)
Rat
Rat .
Raooit
Rat (M)
Rat (F)
Exposure
route
oral
oral
oral
oral
oral
oral
oral
*P
aermal . . -
dermal
inhalation
inhalation
Acute
LU50:
LL)5U:
LU50:
LDsJi
LD50:
'LD5U:
LD5U:
LD50:
LCsS:
toxicity value
3.1 mg/kg
2.5 mg/kg
4.0 my/kg
2.8 mg/kg
3.3 mg/kg
2.3 mg/kg
7.0 mg/kg
4.0 mg/kg
>1200 mg/kg
740 mg/kg
0.17 mg/L (1-hr)
U.12 my/L {1-hr}
Reference
Kennedy (l'yb6a)
Reinhart (iy?l)
Kennedy (1986a)
Kennedy (1986a)
Kennedy (1986a)
Kennedy (1986a)
Kennedy (1986a)
Kennedy (iy86a)
Rat (M)
            innalation
U.064 mg/L (4-nr)     Kennedy (1986a)
                               V-2

-------
2.  Uther Effects     •                  .         •  -


     Tne ability of oxamyl to innioit serum cholinesterase activity was studied •


in 10 rats given a single oral dose of 4.86 my/kg oxamyl approximately 90% of


LDjg.  Tnis dose resulted in an approximately 40% decrease in serum choli nesterase


activity (decreased from a mean pretreatment value of 4.3 to a posttreatment


value of 2.b umol substrate hyarolyzed/ml/5 min) 5 minutes after exposure and a


6U% decrease (1.8 _+ 0.7 um substrate hyarolyzed/mL/5 min) 4 hours after


administration.  Activity returned to normal level of 5.7 24 hours after


aaministrati on  (Kennedy, 1986a).  Little or no cholinesterase innibition was


observed whfen atropine sulfate (bO mg/kg) was admini'stered by ip injection
                                          *3                                    '    "

immediate-ly after oxa'myl administration.  No mortality occurred when atropine


was injected after a dose of pxamyl tna't normally would kill 50% of tne rats; •  ' •  • -.
                                                                                t

however, fasciculations were noted in rats'receiving the oxamyl/atropine
                                                     «


comoination (Kennedy, 1986a).
                                                    p



     Rats  (six  males) given repeated oral doses  of 2.4 mg/kg of oxamyl 5 days/


week for 2 weeks exhioited mild fasciculations that  lasted 2 to 4 hours during


tne first wee*  ana 1 to 2 hours during tne second week.  Slight decreases in


oody weignt were noted.  The  author  stated that  rats exhibited salivation and


sliynt pai lor after the first two doses, but no  clinical signs were noted tnereafter


(Kennedy,  1986a).  Hence, it  appears that the  rats developed a slight  tolerance


to oxamyl  after 1 week of oral dosing.




     uxamyl appears to be less toxic to aogs after oral  administration.  Male


oeagles were given single oral doses of 5, 10,  15, or  3U mg/kg and observed  for


21 days.   All the oxamyl-treated  dogs  exhibited  clinical signs of  cholinesterase


inhibition, and one dog  given 3U  mg/kg died  (Kennedy  19b6a).
                                       V-3

-------
      Repeated application of 50 or  lUO my/kg of oxamyl in a dimethylformamiae
 (DMF) vehicle to the abraded or intact skin of groups of five male and five female!
 rabbits, 6 nours/day for 15 days, resulted in fasciculations, irregular breathing,!
 reduced coordination, and salivation after each dose.  These effects lasted       •
 approximately 4 nours (Kennedy, 19b6a).  No effects were reportedly noted in
 controls-exposed to DMF only.  In a similar study, minimal  effects were noted     ;|
 in groups of six male rabbits after application of 50 or 100 mg/kg oxamyl  in an
 aqueous methanol vehi-cle to intact or abraded skin.'  Apparently, tne dimethyl-
•formamiae vehicle increased the absorption of oxamyl  through the skin,  resulting
 in greater  toxicity.

      Minimal  effects  were noted after instillation of oxamyl  (10 mg)  into  the  "
                 - '  .        '                                                  i
 eyes  of  rabbits.  Slight constriction of  the  pupils,  minimal  congestion  of  the  -
 iris,  and mild  reaness  and  swelling  of  tne conjunctiva were  reported  (Kennedy
 lyBoa).  Eyes were  essentially  normal  oy  24 hours  postadministrati on.  Kennedy
 (1936a)  reported that one of  four  rabbits  exhibited reduced  muscular  co-
 ordination  in the hind  limbs  20 minutes postdose;  therefore,  it  appears that
 some  absorption  of  oxamyl occurred after ocular exposure.

 B.   LONG-TERM EXPOSURE

 1.   SUPi chronic  Toxicity  .

     Haskell Laboratory  conducted a  study  in wnich groups of  1U weanling
 C.-1:CD rats of each sex  were fed diets containing  0, 50, 100, or  150 ppm
 of oxamyl (>9b% purity)  for 90  days.  These were comparable to dose levels of
 app-oximately U, 2.5, b.O, and  7.5 mg/kg/day.  Initially, for the first 4 days
of feeding,  the high-dose group actually received  500 ppm of oxamyl in the
                                      V-4

-------
  diet.   Thi-s  aose  caused  Immediate,  excessive weight  loss,  as well  as  fascicuia-


  tlon,  ruffled  fur,  and  mild diarrhea In male rats.   The  males- and  females  fed


.  the  nigh  dosaye were  then  placed  on control diets  for  3  days.   From day 8  to


  termination  of tne  study,  the  nigh-dose group  received IBU'ppm In  the  diet.


  fne  only  obvious.sign of toxlclty que  to  oxamyl  administration  was In  body


  weignt.   Body weights were  significantly  lower  (p  y5*  purity}  in  tne  diet


 (equivalent  to  dose  levels  of approximately U,  1.2, 2.b,  and 3.8 myAg/aay,


 respectively).   No compound-related  changes in  body weight  gain, food  consump-
                                                                                   .
 tion, clinical  siyns,  nematology,  clinical  chemistry,  or  pathologic findings      •


 were  noted in ooth the control  and compound-treated dogs.  Only one control


 male  aoy  lost 1.1  kg weignt;  the rest maintained  or gained  weight.  -Ine

 autivfrr reuo-teo i-nfrequent,  sporadic incidences  of  bloody mucoid diarrnea,  eye

"c.  *
discharge, inflammation,  aenydration, thinning  nair  on  cnest, and cysts in  aogs

receiving  oxamyl,  but  these  were  not considered to  be  related to oxamyl adminis-

tration  (Kennedy, 19afab).
                                      V-b

-------
  2.   Chronic Toxicity



      Tnree  long-term feeding  studies with oxamyl nave been reported (Kennedy,



  1986b).   In trie first-study conducted^ at Haskell Laboratory, groups of 35



 weanling CM:CD rats of each  sex were yiven 0, 50, 1UO, or 150 ppm of oxamyl



  (95% purity) in the aiet for  2 years, corresponding to doses of approximately



 Q, 2.3, 5.0, and 7.5 my/kg/day.  An additional control group of 36 male and 36



 female rats was-fed a diet containing 0 ppm oxamyl.  A-three-generation repro-



 duction study was conducted simultaneously using 16 male-and 16 female rats



'from'each test group and one control group. "Animals were mated after 12 weeks



 of exposure to test diets.   Further details on the reproduction study' will  be

  *

 given in  tne following  section.  Cholinesterase activity in the whole blood    .
                                                                     •           *.


 (umol acetyltniocholine  hydrolyzed in 5  min/mL blood)  from control  animals,  and,



 animals fed 1UU or  150  ppm  was measured  periodically during the study.  Signif-



 icant decreases  (p £0.05) in  cholinesterase  activity  were  noted in  females


 receiving .tne  hign  dose  (approximately 20%  inhibition)  after  4  cays  and  in  males



 receiving  tne  nigh  oose  (approximately 33%  inhibition)  after  8  days  on study.



However, after  1 month,  cnolinesterase activity retur-ed to normal and remained



within  normal  range  tnroughout the  remaining 2 years  of exposure to  150 ppm  of



oxamyl.  Body weights were  decreased in  a dose-related manner with significant



reductions  (p £U.05) noted  in  tne  groups fed 100 and  150 ppm  (males and females)



compared to  controls throughout the study (Taole V-2).  Females fed 50 ppm



oxamyl  snowed no change  in  body weight tnroughout the study except at.  24 months



when  mean oody weignt was significantly  reduced  (P  <0.05).  Slignt decreases in



food  consumption of tne  group  fed  IbO ppm compared  to the  control group were



reported.  No clinical signs of toxicity attributable to oxamyl administration



were noted, and mortality rates were comparable between control and test groups.



Slight decreases in absolute organ  weights (liver,  spleen,  kidneys) were noted
                                      V-6

-------
    "                       '                 »
Table V-2.  Mean Body Weights of Rats Fed Uxarny] for  2  Years

Months
on study

0
1 •
3
6
12
18
24 .

0

140
343
.'.so?
614
744
762
"799
Dietary
0
Males', (weight
142
• • 341
507 •
•601
738
778
806
Females (weight
0
1 . • •
3
6
12
18
24
118
208'
'287
343
- 446
569
640
119
211)
293
348
469
562
63b
level
50
In gr
142
326
492
584
725
782
744
(pom)
100
ams)
140
304*
474*
565
697*
754
750

150

139
282*
442*
511*
626*
768*
675*
in grams)
121
206
254
338
440
555
588*
119
186*
252*
290*
345*
.432*
460*
119 i
183* • •
248*
282*
328*
389*
415*
-- - , ,
'Significantly  different from control  value (p _
-------
  in  males  and  females  fed  1UU  or  1SU  ppm  of  oxamyl,  but  tnese  changes were not-


  statistical ly significant.  Organ-to-body weight  ratios were  comparable between


  controls  and. test.groups.   Therefore,  tne organ weight  changes we~e attributed

                     *  ^  4
  to  decreased  body  weight.   Histopatnologic  examination  revealed no_compound-


  related abnormalities.  Tumor  incidences were comparable between controls and


  test groups.   The  NOAEL for this study was  identified as 5U ppm (2.5 -^/kg/day)


  of  oxamyl.



                           0
      A second  chronic study was  conducted at WIL  Research Laboratory (1981).


  Groups of 80 .male  and 80 female  CD-I mice were fed  0, 25, 50, or 75 ppm of

                                                   Q
  oxamyl (y?.l%  purity) in the aiet for  2 years.  These dietary levels'were


  equivalent to  mean doses of U, 3.75, 7.5, and 11.25 mg/kg/day.  Initially,     *


  tne nigh-dosage group received 1UO ppm of oxamyl.   However, excessive mortality'


  occurred at this dietary level (10 males and 8 females in the first montn on


 study); therefore, the high dosage was reduced to 75 ppm at week 6.  The only


-clinical  signs attributable to oxamyl administration were noted in animals  .   .


 dying prior to terminal  sacrifice.  These included emaciation, lethargy, and


 moriDundity.  Slight, sporadically significant decreases (p £0.05)  in  body


 weights were noted in animals  from the groups fed 50 or 75 ppm, particularly


 in the first 6 months of tne study.   Several hematoloyic parameters (hemo-


 glooin, hematocrit, and  red cell  count) were significantly reduced (p  <0.01)


 in tne males fed the nigh  dose compared with controls  at week  4.   These  para-


 meters  were within  normal  ranges  from week  13 to study terminat-ion. Histo-


 patnological  examination revealed no  lesions attributable  to oxamyl administra-


 tion.   Chronic nephritis was noted in a number of animals  at terminal sacrifice.


 However,  increased  incidences  were noted  in  control  animals  compared to  other


 groups;  control males had  an incidence of 52% compared with  23, 20, and  13%  for


 the  males  fed oxamyl  at  25,  5U, and  75 ppm,  respectively.   The incidence  of



                                       V-8

-------
chronic nephritis in control fema.les was 15% compared wltn 6, 10, and 3% for
females fed oxamyl at 25, 50, and 75 ppm, respectively.'  Tumor incidences were
similar for control and test groups (WIL, 1981; Kennedy, 1986b).  The NOAEL for
tnis study was 25 ppm (3.75 my/kg/day).
     Kennedy  (1986b) aVso reported the results of a 2-year feeding study in
beadle dogs conducted at Haskell Laboratory.  Groups of four dogs of each sex
were fed diets containing U, 50, 100, or 150 ppm of oxamyl for 2 years.  These
dietary levels were equivalent to approximately 0, 1.3, 2.5, and 3.8 mg/kg/day,
respectively.  No mortalities occurred during the study.  Body'weights, food
consumption,  clinical observations, and hematological and urinalysis parameters
                                                             *
•were comparable between control's and test groups.  Serum alkaline phospha£ase  \
                    '                        *
activity and  cholesterol levels were increased (2 standard deviations above
pretest values for all  groups) in animals fed 150 ppm compared to all other
aose groups including controls (significance was not reported).  Histopatnologic
findings were observed  with equal frequency in all groups including controls.
Tnere were no increases in  incidences  of lesions that could  be attributed to
the inyestion of  oxamyl.

C.   TEKATUGENIC/REPROUUCTIVE EFFECTS
     Kenneay  (1986o) reported the results of  a teratogenicity  study  in  rats
conducted  oy  Haskall Laboratory  (1971).  rive groups  of at  least 22 timed-
pregnant Crl:CD  rats were  fed diets  containing 0,  50,  1UO,  150,  or 300  ppm of
oxamyl on  days 6  to  15  of  gestation,  corresponding to  doses  of 0, 2.5,  5.0,
7.5, and ib mg/kg/day,  respectively.   Although not significantly different,
body weights  of  dams fed oxamyl  were  decreased in  a  dose-related manner.  An
approximately 42% decrease  in body  weight gain was observed  during the  study
in  dams fed 3UU  ppm  of  oxamyl compared to controls  (Taole V-3).   A corresponding
                                       V-9

-------
     Table V-3.  Mean Maternal Body Weights of Rats Fed
                 Oxamyl  During Gestation

Mean body weights (g) during
Dietary
level
(ppm)
0
50
10U
150
3UU
gestatl

6
a
218
221
218
214 .
216
on days:

16
295
289
264
25U
'228


20
362
358
334 •
—324'
3UO

 Standard deviations were not reported.

SOURCE':   Adapted from Haskell Laboratory (1971).
                            V-1U

-------
 dose-related decrease In food consumption was observed In dams fed oxamyl. 'No


 significant differences were noted-In number of Implantation sites, live fetuses,


 or resorptions between test groups and controls (Table V-4).   Fetal growth,  as


 measured by Dody weight and crown-to-rump length, was comparable between control


 and test groups.  The Incidences and types of soft tissue and.skeletal  abnor-


 malities were similar in fetuses from dams fed either control  or test diets.


 In tnis study, oxamyl was not teratogenic in rats.



      In.a teratogenicity study with raboits  conducted at  Hazleton Laboratories


 (Snyaer, iy»U; Kennedy,  iyb6o),  groups of 17 artificially inseminated New

                                                          o                     »
 Zealand White  rabbits were  given oral  doses  of  0,  1,  2, or 4 mg/kg/day  of


 oxamyl  (97.1%  purity) on days 6  to 19  of  gestation.   Two  rabbits died during  ?

                                                                               *
 tne study (one each  from tne control and  30U-ppm  groups),  but  these deaths were


 probaoly  due to technical errors in dosing.   Significant  decreases  (p <0.05)  in


 body weight gain were noted  in dams administered  2 and 4  mg/kg/day  during the


 treatment period (days 6 to  19 of gestation) compared to  controls. (Table Vr5),-


 Th=~e was  a corresponding decrease  in  food consumption in  the  rabbits adminis-


 tered 2 and 4  mg/ky/day  during the  treatment period.  After tne  dosing  reyimen


 enaea,  nowever,  the  rabbits  appeared to recover:   body weight  gains  of  dams


 aaministereo 2  and 4 mg/kg/day exceeded those of controls  during days 19


 to  29 of  gestation,  and  body  weight gains  for the  entire  study were  comparable


 between controls and  all test  groups.  Mean  numoer of implantations  and live


 fetuses,  and sex ratios  were  comparable between controls  and all test groups.


 Boih Snyaer and  Kennedy  reported  a  slight  increase (not significant)  in the


 incidence of resorptions in the yroup  administered 4 mg/kg/day (mean incidence


 of  resorptions was 10.4  and 24.8  for control and high-dose groups,  respectively),


 indicating a slignt embryotoxic effect.  Fetal oody weights and crown-to-rump


measurements were similar in control and test groups.  Slight increases (not



                                      V-ll

-------
           TaDle  V-4.   Effects  of  Dietary Administrat-ipn of  Oxamyl  on  Pregnant
                       Rats  and Their Offspring  .'       : •  •          ,,
. • . • • • •• .11
Dietary level (ppm) •
Parameter
Femal
femal
es preynant/
e on study
0
22/26

50
26/27 .
No. of implantations/
litter
Live
Litre
fetuses/1
rs with
•> ft of
. UUw^

resorptions (%)
Total numoer of
res or
Fetal
ptions (»
body wei
)
ynt (g)
10.6
10.0

9
13
3.8
i 1.8
± 2-2

(41)
(6)
jf 0.4
10.8
10.2

11
'. 17
4.0
i 2.2
±2.1

(42)
(6)
^ 0.3
100
150
•
: 25/28., ' 26/28
•^
11.3^1.9 10.3
10.8 i 2.0 9.8

9 (36) 9
12 (4) 14
3.9 jf 0.3 4.0

± 2-5
i 2.5

(35)
(5)
•*• 0.4
•.!
i!
300 i
i
1 *

23/28
*
' 10.8 i!
10. ri *_
f
«••**'
2.c

10 (ji£^
P
16 (ci)
3.8 ^||0.4
!l
SOURCE:  Adapted from Kennedy (1986b).
                                          V-12

-------
    Table V-5.  Mean Maternal Body Weight Gains in Rabbrts Given
                Oral Doses of Qxamyl During Gestation

Dose level
(my/ kg/day)
0
1
2
4
Body
0-6
58. U
66.0
59.7
113.1
weight gain'
6-19
169.5
154.4
65.2*
55.6*
(g) on oestation
19-29'
138.4
' 144.1
0
157.1
218.6 '.
day:
.0-29
36b.9
368.7
282.0
387.3
6 . «
*Significant1y different from controls at p 
-------
 significant) were observed in the number of visceral and skeletal  abnormalities
•(variants and anomalies) in. litters from dams administered 1 mg/kg/day'compared
 to otner groups including controls (Table V-6).  These increased incidences did
                                                         *
 not occur in a dose-related manner and were not statistically significant.
 Therefore, they were considered to be incidental occurrences.  The author
 concluded tnat oxamyl  was not teratogenic in rabbits under the conditions of
           .•*•-'                                           .          '  *
 tnis" study.     .  -                    .                "                     '

      A  one-yeneration  reproduction study-was conducted  by  Haskell  Laboratory
 (Kennedy, 1986b).   Groups of six Crl:CD rats of each sex were fed  diets  con-
 taining  oxamyl  at  levels  of  U,  5U, 1UU,  or  150  ppm  (equivalent to  doses  of  0,
 2.5,  o.O,  and  7.5  my/kg/day)  continuously  for -31 to 95  days  and mated  to produce
                                                                                j£
 two  litters  (Fia-and FID).   This study was  run  concur-ently  with a  90-day feeding
 study (see Section  V.B.I.).   Body  weights were  significantly  decreased (p £0.05)
 in  parental  males  fed  100 or  150 ppm  starting 28 days after  initiation of
tne  study.   Decreases  were also  ooserved in  parental females  from, the  groups
fed  100  and  150 ppm, but  significant  changes were sporadic.   Fertility did  not
appear to  oe affected  by  ingestion of  oxamyl.   The  number  of  Fia pups delivered
to flams  from the 1UO-  and 150-ppm  groups, and the number of  F^J  PUPS delivered
to clams  fed  IbO ppm  of oxamyl, were slightly decreased  compared  to controls.
Survival of pups was not  affected  during lactation.  Significant decreases
(p £U,Ob)  were observed in the body weights  of  weanlings from  both F}a and  F^b
litters  in the groups  fed 50, 100,  and  150 ppm  compared to controls..

     A suosequent tnree-generation reproduction  study in rats was conducted con-
currently with a 2-year feeding  study  (Section  V.3.2.).  After approximately
12 weeks of ingestation of oxamyl  at dietary levels  of 0, 50, 100,  or 150 ppm,
16 male  and 16 female Crl:CD rats  from each  group were paired  (Fg parental
                                      V-14

-------
     Table V-6.   Summary  of Visceral  and  Skeletal  Findings  in Fetuses
                 of Rabbits Given Oxamyl  During  Gestationa

Dosage levels (mg/kg/day)
Observation
No. examined

Variants: -. '
Intermediate lobe of lung
absent
Very small stomach
Slightly dilated renal pelves
Anomalities,;
Hydrocephaly
Cleft palate
Ectopic kidney

Variants:
Angulated hyoid wing
Fused sternebrae
Fused rios
0 1
113 90
Visceral


0 3
U 2bc
1 2
.
0 2bc
0 1C
0 • 1
Skeletal

3 3
0 2
0 2 .
, 2
89
Examination


1 .
U
1

0
0
. o
Examination

1
1
1
4
75


,
0
0
0

0
0
U


0
0
0

 aNumoers represent the number of pups arfected in
bcihe same superscripts indicate tne same pup.

SUURCE:   Adapted from Synder (1980).
                                      V-15

-------
"  generatio'n^ to  produce two litters"(Fla  and  Flb  generations).  The"Flb and F2b

  generations  we.-e  mated at  approximately  111)  days of age to produce F2 and f^

  generations  (two  litters  each),  respectively.  Reproductive indices such

  as  fertility  index,  gestation  length,  pup viability, and lactation index were

  comparaole between control  and test  groups for all generations.  .Litter size

  and mean body weights  of weanlings from 'dams ingesting the 1UO- or 15U-ppm

 -levels of oxamyl  were  significantly  decreased (p <0.05) in the majority of

  generations compared to controls  (TaDle V-7).  Histopathological'examination of

 animals from each generation (parents  and offspring) revealed no abnormalities

 attributable to oxamyl ingestion  (Kennedy, 1986b).
                                                             e

 D.   MUTAuENICITY                                          •                    ;
                                                                                j

      Limited  information was available in the literature on the mutagenicity  of

 oxamyl.                  '


 1.   Gene  Mutation Assays  (Category 1)                                   ......


      a.  Gene mutation in  prokaryotej


      Moriya et al. (1983)  reported the evaluation of oxamyl  in  the mammalian/

microsome  "everse  mutation assay  (Ames test). Sa1 mone 11 a typhrimyriurn,

strains 7A100..TA98,  TA1535, .TA1537,  and  TA1538,  and Escnerichia coli, strain

WP2  ncr, were  exposed  to concentrations of up to  5.UOO ug/plate of oxamyl with

or without activation  (rat  liver  S9 mix).  Results were  negative, indicating

that oxamyl is not mutagenic  to _S.  typnimurium or IE. coli.  Negative results

were also reported oy  Shirasu et  al.  (1976) following a  reverse mutation assay

conducted in S_. typnimurium  strains TA1535, TA1537, TA1538, TA98, and TA100,

and £. coli strain WP2  her.  Concentrations of 10 to 1,000 ug/plate of oxamyl
                                      V-16

-------
 Table V-7.   Effects  of Uxamyl  Ingestion on Litter Size and Body Weights
           .  of Weanlings In Three Generations of Rats

Dietary
level
(ppm) Gene.-ation
0 Fla
50
100
150
0 Flb
50
100
150
0 F2a
50.
100
150
0 F2b
bO
100
150
y p^
50
100
IDO
U F3b
50
100
150
Mean
litter size3
12.3
10.9
10.2*
10.4
13.6
12.3
11.3*
11.1*
11.9 .
12.3
10.6
10.4*
12.9
12.5
11.0*
11.0*
12.4
12.2.
10.2*
9.9*
12.6
13.1
12.2
10.3*
Mean weanli ng
body weight
(g.)
53
52
44*
39*
57
55
47*
• 42*
53
49
41*
36* . '
57
52
42*
37*
52
48
43*
37*
52
50
39*
37*

     er of pups per litter.
*Significantly different from control value (p £0.05).

SOURCE:  Adapted from Kennedy (1986b).
                                      V-17

-------
 in  the  absence  or  presence -of an activation  system  (rat  liver  S9 mix) were not


 mutagenic.


                                ' *-    '        *.    '   "
      D.   In  vi t ro  gene  mutati ons  "      -       .



      No mutagenic  response was  obtained  in a host-mediated assay-with S_.


 typnimurium,  strain  G 46  hys, after oral  administration  of oxamyl  at total


 doses of  2 or 4 my/kg to  male ICR  mice (two equal doses were administered over


 a 24-hour period)  (Snirasu et al.,  1976).



     The  mutagenic potential  of  oxamyl was tested in Chinese hamster V79 target


 cells with fcr without activation (irradiated Syrian hamster fetal  cells).
           «•                                  . a

 Treatment with oxamyl (concentrations not specified) for 72 hours, with or


 without activation,_  hacLno..significant effect on mutagenic frequency (Wojciechowski


 and Kaur, 1980).



 2.   Chromosome Aberration Assays  (Category 2)             -.
                                                                                   !i
     NO chromosome aberration studies with oxamyl were found in the available


 literature.    •  />          o
3.   (finer Mutaoenic Mechanisms  (Category 3)
                                                          V
     The evaluation of tne'effect"of oxamyl (94% purity) on DNA-damage/repair
                                                    a

capaoility was evaluated using Bacillus subtil is strains H-17 Rec+ and M-45

Rec-.  Concenta.tions of 2U to 2,UUO ug/disk did not preferentially inhibit the

repair-deficient strain (M-45 Rec-) compared to the repair-competent strain


(H-17 Rec^} (Shirasu et al., 1976).
                                      V-18

-------
E..   CARCINOGEN 1CITY          .  '

     Two chronic feeding studies In rodents have been conducted and were

described earlier (see Section V.B.2.)  In the feedlny study conducted with

rats at Haskell Laboratory (Sherman et al., 1972), groups of 36 male and  36

female Crl:CU rats were fed oxamyl at 0, bO, 100, or 150 ppm for 2 years  (equi-

valent to mean doses of U, 2.5, b'.U, and 7.b mg/kg/day, respectively.  Significant

decreases In body weight were observed In both males and females fed 100 or 15U

ppm compared to controls.  A summary of the histopathological  findinys Is

presented In Taole V-8.  The Incidence of mammary tumors was 67% In control

females ana 33% In females fed IbO ppm; no mammary tumors occurred In males.

Pituitary tumors occurred In incidences of 23 (one of the control groups) to
             . 9
33% in males- fed Ibtl. ppm and b7 (one of the control groups) to 37% in treated   ?

female's."  After reanaljcsis of the  statistics, there appeared to be a significant
  :  .   -           o .  . .  .  »    p
increase (p <0.u5) in the incidence of liver microgranulomas in both males and
       ' '       a                                    *
females fed 15U°ppm compared to controls.  This lesion is characterized by a
                                        »...  •
granular cnanae in tne liver and considered nohneoplastic.  Tumor Jjictqences
                                                         „
were comparaole between the control group and the hign-dose group.   In this

study, oxaffiyl aid not induce a carcinogenic response in rats (Kennedy, 1986b).

It should De noted, however, that  several deficiencies existed in this study.

Adequate numoers of animals were not tested or examined histopathologically

(36/sex/group).  Possible target organs such as the liver or reproductive

organs were apparently not histologically examined in all dose groups.   In

addition, tumors observed, i.e., tnose found in mammary and pituitary tissue,

were not aaequately descrioed in the report.


     In tne second feeding study,  groups of 8U CD-I mice of each sex were fed

diets containing oxamyl at U, 25,  5U,  or 7b ppm for 2 years, corresponding to

mean dosayes of U, 3.7b,  7.5, and  11.25 my/kg/day.  Decreases  in  body weight


                                       V-19

-------





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V-20

-------
 (sporadically significant) in the 5U- and 75-ppm groups  were  noted  (see  Section
 V.B.2.)  Histopathological examination revealed no significant  increases  in
 tumor incidence in. test groups compared to controls.   A  summary  of  the tumor
 data is presented in Table V-9.  Tumors observed were those commonly  found in
 aging animals and were not considered to be  attributable to oxamyl  administration.
 The incidences of hepatomas were 11 and 25%  for control  males and males  fed
 150 ppm, respectively, for mice surviving to terminal  sacrifice; no hepatomas
 were observed in females.   Lung adenomas occurred at  incidences  of  22 and 23%
 for control  males and males fed 150 ppm,  respectively, and 0 and 3% in control
 and high-dose females, respectively, for mice  surviving  to termination of the
 study.   There were no significant  increases  in  tumor.incidence in test groups   .
                                                                                V
 compared to  controls.  Oxamyl  was  not carcinogenic  in  mice under tne  conditions
 of  tnis  study.

 F.    SUMMARY

      Uxamyl has  been  shown  to  be extremely toxic  to laboratory animals following
 acute oral, intraperitoneal,  or inhalation exposure.   Acute 1$$$ values in rats
 ranged from 2.5  mg/kg for  oral  ingestion  to  4.0 mg/kg  after ip injection.
 Mortality occurred immediately  after dosing, and  signs of cholinesterase inhioi-
 tion  such as  salivation, fasciculation, and  tremors were observed prior to
 death.   No delayed  deaths  occurred.   Cholinesterase innibition appears to be
 the major mechanism of  toxicity  following oxamyl  administration.  Administration
 of atropine after  treatment with lethal doses of  oxamyl prevented mortality and
cholinesterase inhibition in rats.   Dermal absorption of  oxamyl  (in  solution)
appears to be limited.  The acute dermal LDso for rabbits was  740 mg/kg.   Clinical
signs of cholinesterase inhibition were observed  prior to death, and mortalities
                                      V-21

-------













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V-22

-------
 usually occurred  witnin 4.5 hours  postadministration.   Histopatholoy-ical examina-

 tion of tissues  did not reveal  any abnormalities after acute  exposure.


      Oxamyl  is also hiyhly toxic to rats  and  mice following  lony-term oral

 exposu-e.  Kats  fsa 1UU ppm (6.U to 7.0 mg/kg/aay)  for 91)  days  exnioited

 significant  decreases in Dody weight gains  compared to controls.   Decreases  in

 Dody weiynt  occurred in 28 days  for male  rats  inyesting  oxamy'l  at  1UO or

 IbU  ppm {t>.U and  7.6 my/ky/day).   In this study,  clinical  signs of crriinesterase

 innibition and severe weiynt loss  were observed  in  rats  fed  500 ppm  for 2 days.

 No target organs  were ioentified.   Histopathological examination of  tissues  did  •

 not  reveal any abnormalities attributable to  oxamyl  ingestion.


      Similarly, decreases  in body  weight yain  were  observed in  rats  fed 1UO  or
                                                                               i
 IbU  pum (b.U and  7.6 my/kg/day)  of  oxamyl for  2  years.   Rats  inyesting 150 ppm'
                                                                               t
 aid  not  exnibit overt  clinical signs of cnolinesterase inhibition.   However,

 cnolinesterase activity  in  blood was lower  in  females  after 4 days and in males

 after 8  days of exposure to oxamyl  at 151) ppm.   The  type,  onset, and distribution

 of neoplastic and nonneoplastic  lesions were unaffected  &y inyestion of .oxamyl.

 Tumor incidences  and types  were  comparable  between  controls and mice fed 150 ppm.


     Mice fed oxamyl  at  5U  ppm (B.7  to 10.8 my/kg/day) for 2 years exhibited
     o
 decreases in ooay weight yain, particularly in the  first 6 months of study.

 In tnis  stuay, excessive mortality  and aecreases  in  body weight were observed

 in mice  fed 1QU ppm  du-ing  the first month  of  study. 'This necessitated reduction

of tne  luu-ppm dietary level  to  7sj  ppm.  Histopathological findings-were com-

paraole  between control and  test groups.  There  were no  compound-related

increases in incidence or type of neoplastic or  nonneoplastic lesions.


     Uogs fed diets  containing up to 16'0 ppm of  oxamyl for 90 days did not

exnioit  any signs of toxicity compared to control animals.  Uogs fed 150 ppm of
                                      V.-23

-------
 oxamyl .for 2 years- exhibited increases in serum alkaline  phosphatase  activity

 and cholesterol  levels, suggesting some effect  on  the l:ver;  however,  histo-

 patnoloyical  examination of the liver and otner tissues did not  reveal  any

 aDno~malities.   No differences in body weights, food  consumption, clinical

 siyns, or  hematological  parameters were observed in doys  investing up  to  15U

 ppm of oxamyl.


      Ingestion of  up  to 15p ppm of oxamyl  for 2 years  did not affect the

 longevity  of  rats, mice,.or doys.  Oxamyl  was not  considered to  be carcinogenic

 in  rats  or mice  following  cnronic exposure to 15U  -or  7b ppm of oxamyl,  respec-

 tively,  in the diet.   This is  supported by the  negative results  of several j_n_
                         (
 vitro mutayenicity assays.


     Tne teratogeniciry  and  reproductive  toxicity  of oxamyl were studied in

 rats and raboits.   A  teratogenicity  study  in rats  revealed that, although

 ma~ernal  toxicity  eviaenced  by  decreased  body weight gain was observed  in

 pregnant rats.fed  oxamyl at  1UU  ppm  (8.2 mg/kg/day), -no increase in fetal

 variations or malformations  were  noted  in oxamyl-treated  groups  fed up  to 3UU

 ppm  (2U.b mg/kg/day)  compared to  controls.  Similarly, in pregnant rabbits

 given oral  doses  of oxamyl at 2 my/kg/cay, decreases in maternal  body weight

 gain were noted during the treatment  period (day 6-15 .of gestation).   No

compound-related  effects on  tne  fetuses were noted.  Tnerefore, oxamyl  is. not

 consiaered to be teratogenic in  rats  or raooits.


     Developmental  toxicity of oxamyl was demonstrated in both one- and tnree-

 generation reproduction studies in rats by decreases in the litter size of

dams fed  oxamyl  at  1UU ppm (6.2 to 7 mg/kg/day).   In addition, reductions were

observed  in tne body weignts of weanlings from  dams fed 1UO ppm of oxamyl.
                                      V-24

-------
Parental • toxicity was apparent at  luu ppm, as evidenced by decreases in body  ..
weight gain of both males'and females.  Oxamyl-did  not affect  fertility of rats
fed up to 15U ppm (9.3'to lu.l mg/kg/day}, and no increases  in  incidences of
variations or malformation i-n pups  from the 15U-ppm group were  observed.
                                      V-2b

-------

-------
                         VI.  HEALTH EFFECTS IN HUMANS





     No studies *ere found in the available literature on the effects of



oxamyl  exposure in humans.
                                      VI-1

-------
                                                                                    i
                            VII.  MECHANISMS UF TQXICITY
                                           * "
      Specific., studies  on  the mode  of .action of oxamyl were not found in tne
 availaole literature.  However, the results of tne acute animal toxicity
 studies  (ci-ted in.Chapter  V) indicate .that the primary mechanism of .toxicity
 of oxamyl, as is the case witn otner caroamate insecticides, is cholinesterase
 innio.ition.  Tnis is evidenced oy  the typical  clinical signs of cholinesterase
 inhioition sucn as salivation, lacrimation, tremors, and fasciculations.

      Carbamate insecticides appear to interfere witn the cholinesterase trans-
 mission of nerve impulses across nerve synapses  (Kuhr and Dorough, 1976).
 Specifically, caroamates enter the synapse, reacting with or inhibiting acetyl-
 cnolinesterase (ACnE), thus preventing the cleavage of tne normal  suostrate,   i
 acetylcndline.  There is an accumulation of acetylene line in the  nerve          «
 synapse causing continued depolarization of  tne  postsynaptic membrane,  wnich  .
 results in  eventual  failure of the peripheral  nerve or effector tissue  due ^o
 prolonyed stimulation.   Since  peripheral cholinesterase synapses  control  vital  --  ||
 functions sucn as  heartbeat and respiration,  acute' exposure to  lethal concen-  ,.«-.-.[••.
 trations  of  oxamyl  causes  rapid mortality in  animals.                              i
                                                                                    il
      The  following  equations illustrate  the  reaction of an N-metnylcarbamate       il
 insecticide  with ACh£.   Tnis is also  the mechanism for aimethyl carbamate  and      \
-oryanopnospnorus insecticides  (Kuhr and  Dorougn,  1976).                             [!
Steo 1:
               U                     U
                     <	
     HAChS + XUCNHCH^ 	> HAChE XUCNHCH3
Steo 2:
             U                      0
             ii                      ii
                 H	> HOX •»•
                                     VII -1

-------
Steo 3:
     H.,0 + ACnECNHCH^ ---- > HACnt +



     Tne enzyme couples with tne insect-ici'de to form an intartneaiate complex

(Step i)., wnich can dissociate or decompose into a staole carsamylated enzyme
                                r»
(Step 2) plus a leaving yroup (the parent pnenol , naphthal. or oxime).  The


caroarnylated enzyme then nydrolyzes to generate free enzyme and methyl carbamic

acid (Step 3).  Tnus, the reaction _aes not result in destruction of ACnE.


However, hydrolysis of tne  insecticide molecule occurs.  Normally (without tne

presence of the insecticide), AChE cleaves acetylcnoline according to tne


aoove reaction, very rapidly.  In the presence of tne insecticide (ouriny
                                                                               «,
poisoniny), nowever, there  is competition between tne insecticide and
                                                                               t

acetylcholine for an active site on tne enzyme.  Studies on the kinetics of

eitner reaction have snown  that caroamates in yeneral have yreater affini-y for
                                                                         »         *
AChE tnan acatylcholine (O'Brien et al., 1966; Reiner and Aldridge, 1967).

unce attachment occurs, tne insecticide "ties up" .or inni^ts the- enzym§"t, s-ince

                                                              .''..«..           •
tne reactions in Steps 2 and 3 are much' slower for the enzyme-insecticide

complex tn&n for tne acetylcnoline-enzyme complex.  The half-life for

aecarDamylction is approximately 30 to 40 minutes  (Reiner and Aldridge, 1967).
                                      VII-2

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

      The quantifier-:"on of -toxicoloyical  effects of a chemical  consists  of  an
 assessment  of  noncarcinogenic and carcinogenic  effects.  Chemicals  that  do  not
 produce carcinogenic effects are,believed  to have a threshold  dose  below wnich
 no adverse,  noncarcinogenic health effects occur,  whereas  carcinogens  are
 assumed to  act  without  a  threshold.

 A.    PROCEDURES  FOR  QUANTIFICATION OF  TOXICOLOGICAL EFFECTS

 1.    Noncaj'ci nogeni c Effects

      In  the  quantification  of  noncarcinogenic effects,  a Reference Dose  (RfD),
                                                                               i
 formerly called  the  Acceptaole Daily  Intake  (ADI),  is calculated. .The. RfD is  '
                                                                               f
 an  estimate  of a daily  exposure of the  human population that is likely to be
 without  appreciable  risk  of  deleterious health effects, even if exposure occurs
 over  a  lifetime.  The RfD is derived from  a No-Observed-Adverse-Effect Level
 (NOAEL), or  Lowest-Observed-Adverse-Effect Level  (LOAEL), identified from a
 suocnronic or chronic study, and divided by an uncertainty factor (UF).  The
 RfD "s calculated as follows:
       RfD =  (NOAEL or LOAEL 1
             Uncertainty factor
= 	 mg/kg bw/day
     Selection of the uncertainty factor to be employed in the calculation of
the RfD is based on professional judgment while considering the enti're data
base of toxicological effects for the chemical.  To ensure that uncertainty
factors are selected and applied in a consistent manner, the Office of Dr-'nking
Water (ODW) employs a modification to the guidelines proposed oy the National
Academy of Sciences (NAS, 1977, 198U) as follows:
                                     VIII-l

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      o  An uncertainty factor of 10 is generally  uSed when-good  chronic  or


         subchronic human exposure data identifying a NOA&L are' available and


         are supported by good chronic or subchronic toxicity  data  in  other


         spec'es.



      o  An uncertainty factor of 100 is generally  used when good chronic


         toxicity  data identifying"a .NOAEL are  available  for one  or more  animal

                                                                      •5
         species  (and human  data  are not available),  or when good chronic or

                                                       
-------
     DWEL =
_  Rr'D x (body weight in    _
Drink:ng water volume In L/oey
mg/L (	ug/L)
               Body weight = assumed to be 70 kg for an adult.
     Drinking water volume - assumed to be 2 I per day for an adult.

     In addit'on to the RfD and the DWEL,  Health Advisories (HAs)  for exposures
of shorter duration {One-day, Ten-day, and Longer-term HAs) 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 a similar equation to the RfD and DWZL; however,  tne NOAELs
                                                                                *.
or LOAELs are identified from acute or subcnronic studies.  The HAs  are  derived
as follows:
     HA - (NQAEL or LQAEL) x (bw) =
       •     (     L/aayJ. x .(     "
                             mg/L  (	 ug/L)
     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 cnemical 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
is generally derived from a study of less than 30 days'  duration.  A Longer-
term HA ^s derived for both a 10-kg child and a 70-kg adult and  assumes an

                                     VIII-3

-------
 exposure period of approximately 7 years (or 10% of an individual's  lifetime).
                                                                9

 A Longer-term HA is generally der'ved from ;a _st'Jdy of subchrcmic  duration


• (exposure for 10% of an animal's lifetime).



 2.    Carcinogen*c 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:   Known Human Carcinogen.  Sufficient evidence  exists  from


                   epidemiology studies  to support a causal  association between


                   exposure to the chemical  and  human cancer.



      o  Group B:   Probable'Human Carcinogen.   Sufficient  evidence of care:no-  '
                 ,                                                              t

                   genicity in animals with  limited (Group Bl) or inadequate


                   (Group 32)  evidence 'n 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 whicn no data


                   are available.



      o  Group  •:   Evidence of Noncarcinogenicity  for Humans.  No evidence of


                   carcinogenicity in  at  least two adequate animal tests in


                   different species or  in both  adequate epidemi ologic and


                   animal  studies.



      If  toxicological evidence  leads  to  the classification of the contaminant


as a  known, probanle, or  possible human  carcinogen,  mathematical models are
                                     VIII-4

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 used to calculate the estimate  of  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  anima-l data,  animal  doses must be  converted to equivalent human
 doses,   This  conversion  includes correction'for  noncontinuous 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  rmit estimate and,  in fact,  may be lower.   Excess cancer risk estimates
 may also be calculated using other models such as the one-hit, Wei bull, logit,
 and probit.   There is- little basis  in the current understanding of the  biolog"!-
 cal mechanisms involved  in cancer to suggest that any one of these models is
 able to predict risk more  accurately than any others.   Secause 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
random errors in scientific measurement.  In most cases, only  studies using
                                     VIII-5

-------
 laDoratory animals nave been performed.  Thus,  there is uncertainty  when  tne
                  0

 data are extrapolated to humans.  When developing cancer risk  rate  levels,

 several  otner areas of uncertainty exist,  such  as the incomplete  knowledge

 concerning the healtn effects of contaminants  in'drinking water;  the impact of

 tne laboratory 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

 laboratory 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.
                                                                               «,

 8.    QUANTIFICATION OF  NONCARC INOGEN 1C  EFFECTS  FOR  OXAMYL           •     ...


 1.    One-clay  Health Advisory


      No  suitaole  data were  found  in  tne  literature  for  calculation of-the One-

 aay  HA for oxarnyl.  Therefore,  a  conservative estimate  of the-One-day HA of 200

 uy/L, tne  Lonyer-term HA for a  10-kg child, was substituted as the One-day HA.


 2.   Ten-cay  Health Advisory


     .No cata  found  in tne literature were  appropriate for  calculation of tne

Ten-uay HA.  Therefore, the  Longer-term  HA for  a  10-kg  child of 20U ug/L can be

substituted as a conservative  estimate of  tne Ten-day HA.


3.   Longer-term Health Advisory


     Two subchronic feeding studies were considered for derivation of the  Longer-

term HA (Taole VIII-1).  In  a 90-aay feeding study conducted by Haskell  Laboratory

(Kennedy, 1986b; Sherman et al., 1972) in which Crl:CD rats were fed diets


                    ' .  •            • VIII-6

-------
    Table VIII-1.  Summary of Subchronic-feeding Studies Considered in the
                   Development of  the  Longer-term'Health Advisory for Oxamyl

'
Reference
Kennedy (1986b)a




Kennedy (1986b)


Species
(sex)
Rat
(M/F)



Dog
(M/F)

Duration Dose
Route (days) (ppm)
dietary 90 50
1UO

150

dietary 90 50
100
150

Effects
NUAEL
Decreased body
weight
Decreased body
weight
NOAEL



^Previously reported by Sherman et al. (1972). .
                                     VIII-7

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 containing  U,  oi),  1UO,  or 150 ppm of  oxamyl  at  equivalent doses of 'approximately
 2.5,  3.0, ana  7.b  mg/kg/day  (U.S.  EPA,  1987), the  NUAEl was  bO ppm (approximately
 2.5 mg/ky/cay),'oased on  decreases  In body weight  of males and females 'fed 100
 or 15U  ppm  of  oxamyl.   In the second  9U-day  feeding study conducted at Hazleton
 Laooratorles  (Kennedy,  19865),  oeagles  were  fed  diets  containing U, 50, 100, or
 15U ppm  (approximately  equivalent  to  doses of 1.3, 2.b, or 3.8 mg/kg/day).
 The NQAEL for  tnls study  was  identified  as 3.8 mg/kg/day, tne nighest dose
 tested,  based  on  lack of  cnange in  any  parameter measured including body weight,
 food  consumption,  hematology, clinical  cnemistry,  or histopathological examination.

      The yo-day feeding study in  rats was selected for calculation of the Longer-
 term  HA  because it was  of  appropriate duration,  dose levels  appeared to be
 adequately  cnosen, and  the study  was  adequately  conducted.
                                                                                 i
      The Longer-term HA for a lU-kg child is calculated as follows:

      (2.b nu/kg/oay) (10  ky)  =  u.2b my/L (rounded  to. 20U ug/L)
         U L/aay) (I'M)        •                   "''  "  ": "	"\	
wnere:
        2.3 my/kg/day = NUAEL, oased on the absence of decreases in booy weight
                        of rats.
                lu ky = assumed body weignt of a child,
              1 L/day = assumed daily water consumption of a child.
                  10U * uncertainty factor, chosen in accordance with NAS/
                        ODW guidelines for use with a NOAEL from an animal
                        study.

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

      (2.S mg/ky/day) (70 kg) = 0.87b mg/L (rounded to 900 ug/L)
         (2 L/day) (1UO)
                                     VIII-8

-------
 wnere:
        -2.3 mg/ky/aay = NOAEL, based on tne  absence of decreases  In  body  weight
                         of rats.
                 7u ky ~ assumed &.ocy weiyht  of an aault.
               2  L/oay * assumed daily water  consumption of an  adult.
                   10U = uncertainty factor,  cnosen in accordance  with  NAS/
                         OUW guidelines for use with a NQAEL from  an  animal
                         study.

 4.    Reference Dose and Drinking  Hater Equivalent Level

      Tnree-cnronic feeding studies  were considered for derivation of the
 Reference  Dose (Rfu")  ana Drinking Water Equivalent Level  (DWEL)  {Taole VIII-2).
 In  a  study  conducted  by Haskell  Laooratory (Kennedy,  19866;  Sherman  et al., 19/2),
 Crl:CU  rais  were fed  diets containing 0,  50,  100, or  150 ppm of oxamyl for 2
 years.  Tnese  levels  were  approximately equal  to  doses  of  0, 2.5, 5.0, and 7.5
my/kij/aay (U.S. tPA,  lya7).  Significant  decreases  (p _
-------
     Table VIII-2.   Summary of Chronic Feeding Studies Considered in the
                    Development of the Reference Dose and Drinking Water
                    Equivalent Level  for Oxamyl

Reference
Kennedy (lybbo)a
Kennedy (19b6o)
Kennedy (19B5o)
Species Duration Dose
(sex) Route (years) (ppm)
Rat ' dietary 'i 5U '
(M/F)
1UO
150
Mouse dietary 2 25
(M/F)
bU
75
• Dog • dietary 2 bO
(M/F)
100
150
Effects
NQAEL
Decreases in
body weight
Decreases in
body weight
NOAEL
Decreases in
body weight
Decreases in
body weignt,
decreases .in
. hematological
parameters
NOAEL
Decreases in
serum alkaline
phosphatase
activity and
cholesterol
levels

apreviously reported oy Sherman et al.  (1972).
                                    VIII-10

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 phosphatase activity and cholesterol  levels were increased in dogs at the
 150-ppm dose level compared to controls.  The NOAEL for this study was 100 ppm'
.'(2.5 rng/kg/day) (Kennedy, 1986b).

      CD-I mice were fed diets' containing 0, 2b,  50, or 75 ppm (equivalent to
 doses of 0, 3.5, and 11.2b mg/kg/day, respectively).  Significant decreases-.
 (p £O.U6) in the body weights of animals fed 50  or 75 ppm of oxamyl were spor-
 adically noted only in the first 6 months of exposure, after which body weights
 of mice in the 50- and 75-ppm groups were comparable to controls.  Hemoglobin,
 hematocrit levels,  and  red  blood call counts were signficantly  decreased
 (p <0.01)  compared  to controls after 4 weeks of  exposure.   However, these
 values  were within  normal  range  for the remainder of the  study.   The NOAEL  for i
 tnis  study was  25-ppm (3.5  mg/kg/day).

      The  rat feediny  study  conducted at Haskell  Laboratory  was  selected for
 calculation  of  the  RfD  and  DWEL  because Jt  was a comprehensive,  adequately.run
 study of appropriate  duration.   In  addition,  tne NOAEL for  this  study  (2.5  mg/
kg/day) was  supported by  NOAEL values of  2.5  and  3.5 mg/kg/day identified in
the cnronic  dog  and mouse studies,  respectively.
     The DWEL for a 70-kg adult  is  calculated as  follows:
Step 1:  Determination  of the RfD

     RfD =  (2-5 mg/kg/day)  = u>025  mg/kg/day  (25  ug/kg/day)

where:
     2.5 my/kg/day

               100
NOAEL, based on absence of changes in body weight
in rats.
uncertainty factor, chosen in accordance with NAS/OOW
guidelines for use with a NOAEL from an animal study.
                                    VIII-11

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Step 2:  Determination of the DUEL
     DWEL = (0.025 my/kq/day) (7U kg)  = 0.875 mg/L (900 ug/L)
                    -
where:
     0.025 my/kg/day = HfD.
               70 kg = assumed body weight of an adult.
             2 I/day = assumed daily water consumption of an adult.

C.   QUANTIFICATION OF CARCINOGENIC EFFECTS FOR OXAMYL

     Two studies were considered for derivation of carcinogenic risk estimates
for oxamyl.   In a 2-year feeding study in which Crl:CD rats were fed oxamyl at
.levels of 0, 60, 100, or IbO ppm (equivalent to daily doses of 0, 2.5, 5.0, and
7.5 my/kg/day) systemic toxicity in the form of reduced  body weights was noted
in males and  females  fed 100 or 150 ppm of oxamyl.  Histopathologic evaluation
of tissues  from control and high-dose animals  revealed no increases in incidence
of neoplastic  or nonneoplastic  lesions attributable to oxamyl ingestion  (see
Section V.E.  and Table V-8)  (Kennedy, 1986b; Sherman  et  al., 1972).  A few
deficiencies  were noted in this study.  Numbers of animals  tested  and examined
histoloyically (36/sex/dose) were  not adequate according to current standards.
 In addition,  possible target  organs such  as  the liver and reproductive organs
were  apparently  not  examined  histologically  in all groups.

      Similar results  were  obtained in a 2-year feeding study  in  CD-I mice  fed
 0,  25,  50,  or 75 ppm of oxamyl  (equivalent  to  daily doses of  0,  3.5, 7.5,  and
 11.25 mg/kg/day,  respectively).  Decreases  in  body weight were noted in  males
 and  females fed 50  or 75  ppm of oxamyl, particularly  in  the first  6 months of
 study.   As  in the  rat study,  ingestion  of up to 75 ppm (11.25 mg/kg/day) of
                                     VIII-12

-------

-------
oxamyl did not result in increased incidences in type or frequency of  tumors  in


mice {see Section V.E. and Taole V-9)  (Kennedy, 1986b; Snyder, 198U}.




     The available aata suggest that orally ingested oxamyl  is not carcinogenic


to laboratory animals.  Therefore, no calculation of excess  cancer risk was


performed.




D.   SUMMARY




     Taole VIII-3 summarizes the HA and-DUEL  values for oxamyl.




     Oxamyl  may be classified in Group E:   Evidence of Noncarcinogenicity  for


Humans,  based on the results of at least  two  adequate animal  tests ui  different"
                                                                   ts

species  in which no evidence of carcinogen!city  was obtained  (U.S. EPA,  1987).
                                    VIII-13

-------
 Table VIII-3.  Summary  of  quantificat:on of Toxicoloyical Effects  for Oxamyl
       Value
Drinkingwater concentration

          (uy/L)
  Keference
One-day HA for lU-kg  child

Ten-day HA for lU-kg  cnild

Longer-term HA for lu-Kg child

Lonyer-tertn HA for 70-kg adult

UWEL (1UUS from drinking
       water)

Excess cancer risk (lu~6)
              a

              a
           9UU

           900

        '   9UU
Kennedy (1986D)

Kennedy (1S86D)

Kennedy (19B6o)
3Thsse numbers were based on the Longer-term HA because of lack of appropriate  ,
 daia for derivation of the One- and Ten-day HAS,
 The Longer-term HA value is recommenced as a conservative estimate of "he
 Une-aay and Ten-day HA values.
                                    VIII-14

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                                 IX.   REFERENCES
 Agricultural  Research Service.   1986.  Guidelines for the Control  of  Plant
 Diseases  and  Nematoaes.   Agriculture Handbook =556,  pp.  195-214.

 Atkins  EL,  Grey'wooG-Hale EA,  Macdonald RL,  Ferguson  DT.   1974.   Effect  of
 pesticide on  apiculture, [unpuolisned material]  Riverside,  CA:  University
 of  California.   Submitted to  £.1. duPont de Nemours  ana  Company,  Inc.   U.S.
 EPA Accession No.  095326.

 Chang K-M,  Knowles CO.   1979.   Metabolism of oxamyl  in mice and twospottecl
 spider  mites.  Arch.  Environ. Contain. Toxicol. 3:499-508.

 Cooke AS.   1981.   Tadpoles as indicators of harmful  levels  of pollution  in
 the field.  Environ.  Pollut.  25:123-133.

 E.I. duPont de Nemours  and Company,  Inc.  1986.   Material Safety Data Sheet  for
 Vydate  L.  Wilmington, DE.

 French  V.  1982.   Evaluation  of Vendex 4L and Vydate L for  suppression  of
 citrus  rus> mite.   J. Rio Grande Val. Hortic. Soc. 35:121-125.                 f-

 Gosselin  RE,  Smitn RP, Hodge  HC.   1981.   Clinical Toxicology of Commercial
 Products, 5th Ed.   Baltimore, MD:  Williams  and Wilkins.

 Harvey  0  Jr.  1973.   Additional  studies  on  the metabolism and biodegraciation of
 oxamyl  in plants,  [unpuolished  material] E.I. duPont de  Nemours and Company,
 Inc.  Wilmington,  DE.  U.S. EPA Accession No. 096301.  .--.-. .
                                                                 6
 Harvey  J  Jr.  1976.   Metabolism of oxamyl  in  tomato  fruit,  [unpublished      y
 material] E.I. duPont de Nemours  and Company, Inc.   Wilmington,:DE.  U.S. EPA
 Accession No. 095326.

 Harvey  J  Jr., Han  J C-Y.   1978a.   Decomposition  of oxamyl in soil  and water.
 J. Agric. Food Chem.  26:539-541.

 Harvey  J  Jr., Han  J C-Y.  "1978b.   Metaoolism  of  oxamyl and  selected metabolites
 in the  rat.  J. Agric. Food Chem.  25:902-910.

 Haskell  Laboratory.   1971.  Teratogenic  study in  rats  with  s-methyl-1-dimethyl
 carsamoyl-N-[(methylcarbamoyl)oxyl]thioformimidate (IND-1410).  Report No.
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 Kennedy GL.   1986a.  Acute toxicity  studies with  oxamyl.  Fundam. Appl.  Toxicol.
 6:423-429.

Kennedy  GL.  1986b.  Chronic toxicity, reproductive,  and teratogenic studies
with oxamyl.  Fundam. Appl. Toxicol.  7:106-118.

Kuhr RJ, Dorough  HW.  1976.  Carbamate Insecticides:   Chemistry, Biochemistry,
and Toxicology.  Cleveland, OH:  CRC  Press,  pp. 41-70.
                                      IX-1

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 Mclntosh CL, Jenkins JP,  Burgoyne DL,  Ferguson DT.  1984.  A two-year field
 study to determine the fate of oxamyj  in  soil during  f-lood irrigation.  J.
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 Moriya M, Ohta T, Watanabe K,  Miyazawa T,  Kato K, Shirasu Y.  1983.  Further
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 NAS.  1980.  National  Academy  of  Sciences. -Drinking  water a-nd health, Vol. 3.
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 O'Bannon JH, Selhime AG.   1980.  Evaluation of multiple foliar applications of
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 O'Brien  RD, Hilton BD,  Gilmour L. 1966.  The reaction of carbamates with
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 Reiner E, Aldridge UN.  1967.   Effects of pH on  inhibition and spontaneous
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Sherman H, Barnes JR, Aftosmis   JG.  1972.   Long-term feeding  study in rats
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Accession No. 66912.

Snirasu Y, Moritani M, Watanabe K.  1976.   Oxamyl mutagenicity study  using
bacteria.  Mutat. Res. 40:19-30.

Snyder FG.  1980.  Teratology study in rabbits--oxamyl.  Final report.  Hazleton
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                                      IX-2

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SRI  International.'  1985.  Directory of chemical procedures:  United States of
America.  Menlo Park, CA.           '       .'    .        "

Timmer LW, French JV.  1979.  Control of Tylenchulus semipenetranj^ on citrus
with aldicarb, oxamyl, and U8CP.  J. Nematol.  11:387-394.

U.S. Environmental Protection Agency..  1986.   Catalog of pesticide cnemical
names and their synonyms.  Office of Pesticide Programs.  Washington, DC.
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of Drinking Water.  Washington, DC.

Watanabe Y.  1975.  Toxicity evaluation of Vydate* (oxamyl) on carp, [unpub-
lished material] Osaka Japan.  Mie  Innerwater  Fishery Experimental Station.
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U95326.

WIL Research Laboratories, Inc.  1981.  Long-term feeding  study in mice with
oxamyl.  Project No. WIL-77033.  U.S. EPA Accession Nos. 070136-07U143.

Wojciechowsfci  JP, Kaur P.  198U.  Cel 1-mediated  mutagenesis of V79 cells with
four caroamates.  In Vitro.  16:235-236.

Worthing CK,  Walker Sts.   1983.  -The Pesticide  Manual, 7th  Ed.   Great Britain:
The British Crop Protection Council.
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