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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 R«pt. No.
540/FS -92-220
9. Performing Organization Name and Address
10. Pro|ect/Te«k/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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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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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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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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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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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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