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                                      PB92-238492
      Pesticide Fact Sheet Number 237: Oxadixyl
      (New  Chemical Registration)
       (U.S.)  Environmental Protection Agency, Washington, DC
      27 Feb  92
I
I
   U.'S. DepartmeRt-of'Commerce

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  REPORT DOCUMENTATION
          PAGE
                          t. REPORT NO.
                          PB92-238492
  4. Title and Subtitle

    EPA Pesticide Fact Sheets  - Oxadixyl
    No.  237
                *. Report Date
                  February 27,  1992
  7. Author**)
    EPA, Office of Pesticide Prograros,  Registration Division
                8. Performing Organization Rpt. No.
                   540/FS -92-220
  9. Performing Organization Name and Address
                                                                            10. Pro|ect/Tek/Woric Unit No.
    U.S.  Environmental Protection Agency
    Office of  Pesticide Programs
    Registration Division  (H7505C-)
    401  M Street, SW
    Washington,  D.C.   20460
                II. Contract(C) or Grant(G) No.

                (C)

                (G)
  12. Sponsoring Organization Name and Address
    Same as vf9
                                                                            13. Type of Report * Period Covered
  IS. Supplementary Notes
  16. Abstract (Limit: 200 words)

          This document contains up-to-date  chemical  information, including a summary
    of the Agency's regulatory position and rationale, on a  specific pesticide  or
    group of pesticides.   A Fact  Sheet is issued after one of the the  following
    actions has  occurred.

          I.  Issuance or  reissuance of a registration standard,
          2.  Issuance of  each special review document,
          3.  Registration of a significantly changed use pattern,
          4.  Registration of a new chemical, or
          5.  An  immediate need for information to resolve controversial  issues
              relating t:>  a specific chemical or use  pattern.
  17. Document Analysis  a. Descriptors
    Pesticides, regulations,  Chemical Information Fact Sheet,  Use Patterns,
    science  findings.
    ta. Identifiers/Open-ended Terms
    e. COSATI Field/Group
                                  RE PRODUCE DBV
                                  U S DEPARTMENT Of COMMERCE
                                  NATIONAL TECHNICAL INFORMATION SERViCt
                                  SPRINGFIELD VA 22161
  . Availability Stateman;
                  Publicly Available
                                                           1*. Security Class (This Report)
                                                              Unclassified
20. Security Ctem CThls Page)
   Unclassified	
                                                                                      Zl. No. of
                           22. Price

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                   Environmental Protection
                   Agency
Office of P:
Washington, D
       M .,,w VAII. ouonances
        Programs (TS-766C!
        0460
                51KD/PS-. 92-220
                                                      PB92-238492
                   Name of Chemical:
                   Reason for Issuance:
                   Date Issued:
                   Fact Sheet Number:
Oxadixyl
New Chemical Registration


February 27, 1992

237
DESCRIPTION  OF CHEMICAL

Generic Name:  2-methoxy-N-(2-oxo-l,3-oxazolidin-3-yl)-acet-2' ,6'-
                xylidide and its desmethyl (M-3) metabolite

Common Name:    oxadixyl

Trade Name:     Sandofan

EPA Shaughnessy Code:   126701

Chemical Abstracts Service (CAS) Number:  77732-09-3

Year of Initial Registration:  1992

Pesticide Type:  Fungicide

U.S. and Foreign Producers:  Sandoz Crop Protection Corporation

USE PATTERNS AND FORMULATIONS

APPLICATION  SITES:  Seed treatment only.  Seeds of the crop
  groupings  fruiting vegetables (except cucurbits) group, cucurbit
  vegetables group,  leafy vegetables (except Brassica vegetables)
  group, Brassica  (cole) leafy vegetables group, cotton seed, peas,
  soybeans,  sunflower seed, root and tuber vegetables group, cereal
  grains group (except  wheat),  grass forage,  fodder  and hay group,
  and non-grass animal  feeds  (forage, fodder, straw  and hay) group
  for the control of Pythium and suppression of  Phvtophthora caused
  seed and seedling diseases.

METHOD OF APPLICATION:  Application will be made by commercial  seed
  treaters as a water-based slurry through standard application
  equipment.

TYPES OF FORMULATIONS:  31% flowable end-use (EUP)  formulation and
  96% technical (MUP)  product for formulating use.
APPLICATION RATES:   Application rates range from 0.25-0.75  ounce

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                               -2-

  active ingredient/100 pou.ids of seed.

USUAL CARRIER:  water.

SCIENCE FINDINGS

Summary Science Statement
     Available acute toxicity studies indicate that oxadixyl is in
toxicity category III  (Caution) for acute oral, acute dermal, acute
inhalation and primary eye irritation.
     Chronic  feeding/oncogenicity studies were  conducted in both
the rat and mouse.  The chronic feeding study in the rat suggests
that the  target organ  for  toxicity is the  liver.   There  was  a
statistically significant increase  in hepatocellular adenomas at
the highest  dose tested  in  both male  and  female rats.   In the
chronic feeding study  on mice, a statistically significant increase
in relative liver weights in male and female  mice was observed but
no carcinogenic effects were seen.
     Oxadixyl   did   not  induce  either  genotoxic   effects  or
chromosomal  aberrations  in  a  series  of  mutagenicity  studies.
Teratology studies  indicated a NOEL of 200  mg/kg body  weight in
rabbits  and  in  rats  the maternal  NOEL was  250 mg/kg/day  and
developmental NOEL was 500 mg/kg/day.
     Environmental fate laboratory data have been reviewed and most
were found to be acceptable.   Oxadixyl is slowly degraded in soil,
with a half-life of about 16  months.   Oxadixyl was mobile in loamy
sand,  intermediate in sandy  loam  and loam  and  low   in  clay.
Oxadixyl has a potential to leach, especially in soils high in sand
content  and/or low  in organic  matter.   Field crop  rotational
studies and  soil dissipation studies have been completed but not
yet submitted for review.  The data base is considered acceptable
to support the seed treatment use, since that use should not result
in significant levels of the chemical entering the environment.
    Use of the product as a seed treatment provides no significant
acute, subacute or chronic risks to non-target organisms, including
endangered or threatened species.
CHEMICAL CHARACTERISTICS

PROPERTY

Color
Physical state
Odor
Bulk density
Specific gravity
pH
Storage stability

TOXICOLOGICAL CHARACTERISTICS
MUP

beige
crystalline solid
odorless
0.5 kg/1

5.6
28 months
EUP

off-white
liquid
slight

1.06
8.0-8.5
>2 years
Acute Effects:

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                               -3-

Acute oral toxicity in rats:
     LD50 - 3,622 mg/kg in males
            1,803 mg/kg in females
     Toxicity category III
Acute dermal toxicity in rats:
     LD50 -  >2,000 mg/kg  (male and female)
     Toxicity category III
Acute inhalation toxicity in rats:
     LC50 - >5.6 mg/l/6hrs
     Toxicity category III
Primary eye irritation in rabbits:
     Toxicity category III
Primary dermal irritation in rabbits:
     Toxicity category IV
Dermal sensitization in Guinea pigs:
     Not a skin sensitizer

Chronic studies:

Rodent Feeding/Oncogenicity:
     1.  A 2-year feeding/oncogenicity study with male and female
rats using dietary  concentrations of 0, 100, 250  and 1,000 ppm,
equivalent to  0,  4.79,  10.9  and 47.9 mg/kg/day,  was conducted.
There was a  statistically significant increase  in hepatocellular
adenomas at the high dose in both males and females.  No evidence
of early onset  of these tumors was  seen  since  no hepatocellular
adenomas or carcinomas were  seen  in  any animals sacrificed at 55
and  81  weeks.     Historical  control data  indicated  that  the
spontaneous rate  for hepatocellular  adenomas was 1.64% for males
and 2.62% for females.  Incidence of this tumor type at the highest
dose tested was much greater than  the historical controls for both
males  and  females.   Survival was  unaffected  in  males and  was
slightly but statistically significantly better  in  females.  Liver
weights were significantly  increased in  males but not females at
the high dose.   Mean body weights  were slightly  increased in males
but 2-10% lower in females at the high dose.
     The HED Peer Review Committee considered the classification of
oxadixyl according to EPA Guidelines for Carcinogen  Risk Assessment
and tentatively classified the chemical  as  a Group  C oncogen since
its administration was associated with  a significantly increased
incidence of benign tumors in male and female rats at high doses.
The committee requested  that the liver slides  from this  test be
submitted for reevaluation.  The basis for this request was that,
although there was a very strong response for liver tumors at the
high doses, all of the tumors were diagnosed as benign.  The only
hepatocellular carcinoma  diagnosed  was found in  a control, male
rat.  The reevaluation of the liver slides indicated a shift from
mostly benign to  mostly  malignant tumors due to  a difference in
classification   schemes   used   by    the   pathologists.     Upon
reconsideration, the Committee felt that a quantification of risk
was warranted in  light of the mostly malignant and strong liver
tumor response seen in both sexes of  rats.  The Committee

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recommended chat the quantification of risk be performed using the
original ccisfcined  benign and malignant liver tumor numbers since
the total number of tumors would not change significantly.
     The systemic NOEL in rats was 250 ppm and the systemic LEL was
1,000  ppm based  on decreased  body weight  gain  in  females  and
increased  liver weights in  males.   Hepatocellular adenomas were
present in both male and female rats at the 1,000 ppm level.
     2.  A 2-year chronic feeding/oncogenicity  study in mice was
conducted using dietary concentrations of 0,  40, 100  and 400 ppm,
equivalent to 0, 6, 15 and 60 mg/kg/day.   In this study, the only
effect of treatment seen was an increase in relative liver
weights which was statistically significant in male  and female mice
at 97 weeks.  There was  no evidence of tumor formation at 400 ppm
(highest  dose  tested) .   The systemic NOEL  was 100  ppm  and  the
systemic  LEL was  400  ppm  (HDT) based on relative  liver weight
increases  in both  male and female mice.
     3.  A 13-week feeding study in rats using doses of 0, 100, 250
and 1,000 ppm resulted in a NOEL for males of  6.6 mg/kg/day.  Based
on decreased hemoglobin, mean corpuscular hemoglobin, total blood
protein and blood  calcium, the LEL  (males) was equivalent to 16.5
mg/kg/day.   For females, the NOEL was 8.2 mg/kg/day.   Based on
decreased total blood protein, albumin, calcium and chloride, the
LEL for females was 21.5 mg/kg/day.

Non-rodent Feeding Studies:
     A 1-year feeding study  using male and female beagle dogs was
conducted  at  levels of  0,  25,  50  and 500 ppm  (equivalent  to 0,
0.625, 1.25 and 12.5 mg/kg/day).   There were no definitive toxic
effects  in dogs fed at  the highest dose  tested.   A significant
decrease in mean thyroid weight was observed in all  dosed groups of
females but no effects  were  noted in males. This was  considered an
incidental  finding in  the  absence  of further supporting  data.
Based  on  the lack of  systemic effects  at any dose  tested,  the
systemic NOEL was  considered to  be greater than or equal to 12.5
mg/kg/day.

Teratology:
     1.    A  teratology  study  was  conducted  in  rabbits  by
administering dosage rates of 0,  50,  100  and 200 mg/kg body weight
by gavage.   The maternal NOEL was 50 mg/kg  and the  LEL was 100
mg/kg based on increased resorptions.  The teratogenic NOEL was 200
mg/kg  (highest  dose tested).
     2.    A  teratology  study  using  rats was   conducted  by
administering levels of  0, 250, 500 or 1,000 mg/kg/day by gavage.
The maternal NOEL  in this test was 250 mg/kg/day and the maternal
LEL  (decreased body  weight gain)  was  500  mg/kg/day.    The
developmental   NOEL  was  500 mg/kg/day  and the   LEL was  1,000
mg/kg/day  based on decreased fetal body  weight gain,  increased
resorptions,  increased  incidence of retardation of  fetal kidney
development and increased incidence of skeletal variations.

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                               -5-

Reproduction:
     In a  3-generation  rat reproduction  study,  dose levels of 0,
100,  250  and  1,000  ppm in  feed resulted in a NOEL of  250  ppm
(equivalent to 22 mg/kg/day  for  dams) for effects on reproduction
and development  up to lactational  day  21 and an LEL of 1,000 ppm
(88 mg/kg/day  for dams)  for weight loss  on lactational day 21 in
Fla and F2a pups.  The NOEL for other systemic effects was 250 ppm
(22 mg/kg/day)  and  the  LEL was 1,000 ppm  (88  mg/kg/day)  for a
marginal body weight loss and food consumption increase  in females
prior to mating,  at conception and during  lactation.  Potassium and
glucose levels were significantly increased in males  at the highest
dose tested in 2 of  the  3  generations tested.

Mutagenicity:
     Oxadixyl was negative for mutagenicity in the Ames Salmonella
assay for point mutations,  mouse micronucleus assay,  Saccharomyces
cerevisiae   reverse   mutation   induction   assay,   Saccharomvces
cerevisiae mitotic  induction assay, UDS in  rat hepatocytes,  and
transformation in Balb/C-3T3 cells.

ENVIRONMENTAL FATE

     Based on available  data submitted to support registration of
both  seed  treatment  and terrestrial  crop  use,   oxadixyl  is
persistent and mobile in the environment.  In laboratory studies,
oxadixyl was  stable  to hydrolysis  at pH 5 and  7.   At  pH 9,  the
chemical undergoes   a minor hydroLytic  reaction with  half-lives
between 7 and 52 days at 70  and  50 C respectively.   The chemical
is not susceptible to photolysis in water or on  soil.  Aerobic and
anaerobic soil metabolism is apparently similar with  oxadixyl being
slowly degraded with a half-life of  16 months.  Volatilization or
degradation to C02  or other volatile products is not a significant
dissipation pathway.  Leaching studies demonstrate that the parent
compound is especially  mobile  in soils with a high  percentage of
sand and/or a low organic matter content.  There are no acceptable
field dissipation studies  that confirm these laboratory findings.
The properties and  characteristics that  oxadixyl demonstrated in
laboratory studies are similar to  those  associated with chemicals
detected in ground water.  Also,  the chemical could be transported
in runoff during a rain  event to surface water.   However, the use
of  oxadixyl  in  commercial seed treatment operations  should not
result  in  significant  levels  of  the  chemical  getting  into  the
environment.    As  such, the  impact to  surface or  ground water
should be minimal.

ECOLOGICAL CHARACTERISTICS

     Effects  on  terrestrial  organisms:    The  available  data
indicated that the maximum proposed seed  treatment rate should not
have acute effects on non-target birds and mammals.   Although the
maximum terrestrial EEC exceeds the reproductive  and  systemic NOELs
for mammalian toxicity tests, potential  chronic effects to birds

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                                          -6-

           and mammals would  be  minimal due  to  low application  rate,  low
           toxicity,  method of application  (planting),  low bioaccumulation
           potential   and   adequate  labeling   to  ensure  proper  planting
           techniques.
                Effects on aquatic organisms:  Based on available data, it was
           concluded that no acute or subacute effects should occur to aquatic
           organisms  at  the proposed  application  rates.   Chronic  effects to
           fish  and   aquatic   invertebrates  appear  unlikely  ue  to  low
           application rates,  low toxicity and the method of application.
                Endangered  species considerations:   The  maximum te-rrestrial
           EEC is  just  slightly  above 1/10 LC50  for both  maliaxd  duck and
           bobwhite quail and  for small wild mammals.  Because the EEC
           represents  the worst case  (all seeds exposed)  and labeling
           statements  ensure proper planting,  the effects to  endangered and
           threatened  terrestrial  species  appears  minimal.    The  maximum
           aquatic  EEC  is  well  below the 1/20  LC50 for rainbow  trout so
           application should pose no hazard to endangered freshwater aquatic
           organisms.

           BENEFITS

                The oxadixyl end-use product will be used at low use rates for
           control  of  seed and  seedling  diseases  caused by Pvthium  and
           Phytophthora which affect a large number of economically important
           crops.  Seed treatment may eliminate the need  for more costly early
           season foliar sprays to control diseases caused by these organisms,
           resulting in lower cost and  reduced pesticide usage.  This chemical
           would be an alternative to currently registered pesticides which
           are prone  to  development of resistance in fungi.  Alternation of
           chemicals  would  slow  development  of  resistance since different
           modes  of  action are  involved.   Oxadixyl also has a favorable
           environmental toxicity profile  and  low solubility  in water which
           would reduce  chances for off-target movement.

           TOLERANCE ASSESSMENT

                Tolerances  are established  for the combined residues of the
           fungicide oxadixyl,  [2-methoxy-N-(2-oxo-l,3-oxazolidin-3-yl) -acet-
           2',6'-xylidide]  and  its desmethyl or M-3 metabolite, [2-hydroxy-N-
           (2-oxo-l,3-oxazolidin-3-yl)-acet-2',6'-xylidide],   expressed  as
           oxadixyl in or on the following raw agricultural commodities:  0.10
           ppm for the fruiting vegetables (except cucurbits) group, cucurbit
           vegetables  group, leafy vegetables  (except  Brassica vegetables)
           group, Brassica  (cole)  leafy vegetables group, cotton seed, peas,
           soybeans,  sunflower seed, root and tuber vegetables group, cereal
           grains group  (except wheat),  grass  forage,  fodder  and hay group,
           and non-grass animal feeds  (forage,  fodder, straw and hay) group.
                The nature  of  the  residue  is  adequately understood and the
           Agency concluded that the pesticide is  useful  for the purposes for
           which  tolerances  are  sought  and  that  establishment  of  the
           tolerances  will  protect the public health.

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                               -7-

     The Reference Dose (RfD)  based on the 2-year rat feeding study
 (NOEL of 10.9 mg/kg body weight) and using an uncertainty factor of
 100,  is  calculated  to  be  0.11  mg/kg  body  weight/day.    The
 anticipated  residue  contribution  (ARC) of the proposed tolerances
 is 0.000034 mg/kg body weight/day and utilizes 0.031 percent of the
 RfD for the total population and the percents  of the RfD are 0.074
 and 0.058 percent for non-nursing infants and  children ages 1-6,
 respectively.  Since chronic exposure estimates are less than 1% of
 the Reference Dose,  the  risk of  toxic  effects  other  than cancer
 appears to be negligible.
     Oxadixyl has been classified as a  Group C (possible human)
 carcinogen  with  a  carcinogenic  potency  factor   (Q,*)  of  0.053
 (mg/kg/day)" .  The upper  bound carcinogenic risk estimate
 (1.8 x 10" ) , defined with  anticipated residues, may  slightly exceed
 the level generally considered negligible by the Agency.  However,
 the risk estimate is based on the assumption that 100% of the crop
 that is grown  in the U.S.  will be treated with this product.  This
 assumption   is  unrealistic  since   alternative  pesticides  are
 available and disease  situations requiring the pesticide will not
 occur  everywhere.   A true estimate  of  the  actual  use  of  this
 chemical is not possible,  but  realistically, the use level would be
 less than  100%.   Therefore, the carcinogenic risk estimate would
 reasonably be less than that  calculated.

 SUMMARY OF MAJOR  DATA  GAPS

     There  are no data gaps  for the use of oxadixyl as  a seed
 treatment.  A  field dissipation study must be  submitted to support
 any future  registrations  for  the  use of this chemical for foliar
 applications  and  field crop rotational  data must  be  submitted if
 label restrictions regarding  rotational crops  are to be  removed
 from the label.

 CONTACT PERSON AT EPA

 Susan T. Lewis,
 Product Manager  (PM) 21,
Registration  Division  (H-7505C),
 Environmental  Protection  Agency,
 401 M St., SW,
Washington, DC 20460.

Office location and telephone number:
Rm. 227, CMI2,
 1921 Jefferson Davis Highway,
Arlington, VA 22202.
 (703)  305-1900.

DISCLAIMER:   The information in  this  Pesticide Fact Sheet  is a
summary only and is not to be used to satisfy data requirements for
pesticide registration and  reregistration.

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