Un:;ec btates uince 01
Env rcnmental Protection and Toxic Substances
Age.-c> (H7501C) 540/FS-89-047
Pesticide
Fact Sheet
Name of Chemical:
Reason for Issuance: New Chemical - First Food Use
Date Issued: April 13, 1989
Fact Sheet Number: 200
1. Description of Chemical
Generic Name: Trans-5-(4-chlorophenyl)-4-inethyl-2-oxo-3-thiazolidine-
carboxamide
Cannon Name: Hexythiazox
Trade Name: Savey®
Other Proposed Names: N/A
Code Number: DPX-Y5893, NA-73
EPA Shaughnessy Code: 128849
Chemical Abstracts Service (CAS) Number: 78587-05-0
Year of Initial Registration: 19S9
Pesticide Type: Acaricide
U.S. and Foreign Producers: E.I. du Pont de Nemours & Company, Inc.
2. Use Patterns and Formulations
Application Sites: Pears (foliar)
Types and Methods of Application: Ground Application: Use sufficient
water, 150 to 800 gallons per acre (gal/A) for dilute application,
50 to 150 gal/A for concentrate applications.
Application Rates: Apply the lower rates (4.0 oz/A) formulated
product (form) on low mite egg infestation levels and the high
rates (6.0 oz form/A) on moderate to high mite egg infestation
levels or to larger trees. Apply only one application per growing
season.
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Type of Formulation: 50% wettable powder.
Limitations:
o Use only in conmercial plantings; do not use in home plantings.
o Re-entry Statement - Do not treat areas while unprotected humans
or domestic animals are present in the treatment areas.
Do not allow re-entry into treated areas without protective
clothing until sprays have dried.
o Do not graze or feed livestock on cover crops growing in
treated areas.
o Do not apply more than a total of 6 oz. form/A per growing season
o Do not apply within 28 days of harvest.
o Do not apply more than once per growing season.
o Do not apply this product through any type of irrigation system.
3. SCIENCE FINDINGS
Summry Science Statement;
The EPA Peer Review Cortmittee completed its evaluation of hexythiazox
with respect to its oncogenLc potential, anil co-icluded that the data
available for hexythiazox provide limited evidence of oncogenicity
for the chemical in mice. According to EPA Guidelines for Carcinogen
Risk Assessment (Federal Register September 24, 1986) the Committee
classified hexythiazox as a Category C oncogen (possible human
carcinogen with limited evidence of carcinogenicity in animals).
The decision supporting a Category C classification (rather than a
Category B classification) was based primarily on the fact that
only one species was affected (mouse), mutagenicity assays did not
support upgrading to a B classification and the structure-activity
relationship of hexythiazox to other compounds supported a C
classification.
In classifying hexythiazox as a Category C oncogen, the Agency
concluded that a quantitative estimation of the oncogenic potential
for humans should be calculated because of the increased incidence
of malignant and combined benign/malignant liver tumors in the
female mouse. Thus, a Q-^* of 3.9 x 10 (mg/kg/day) in human
equivalents has been calculated. Dietary oncogenic risk to the
general population based on the highly conservative assumption
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that all pears are treated with hexythiazox and would bear residues
at the proposed tolerance level is estimated to be 10~6. Non-
dietary oncogenic risk to the mixer/loader, applicator based on
a denial absorption factor of 2%, use of protective clothing and
one application per year is estimated to be 1CH>.
Technical hexythiazox exhibits low mammalian acute toxicity. The
results of the technical acute toxicity data show a very mild eye
irritant. It is not a sensitizer, nor considered to be mutagenic,
nor teratogenic. Hexythiazox is readily absorbed by mammals, and
the majority of the residue is largely excreted in the feces and
urine by 24 hours. The results of the acute toxicity on the
end-use formulation (50% WP) indicates that it is of low toxicity
(Toxicity Category III and IV).
Sufficient data are available to characterize hexythiazox for pear
use from an environmental and ecological effects standpoint. The
results of acute testing indicates that hexythiazox is practically
non-toxic to birds on both an acute oral and dietary basis. Hexy-
thiazox is moderately to highly toxic to aquatic invertebrates.
Hexythiazox is highly toxic to fish. Although technical hexythiazox
is toxic to aquatic biota, the application rates and physical/
chemical properties of the end-use product minimize potential
adverse effects for the pear use. Hexythiazox is relatively
non-toxic to non-target insects such as honeybees.
No effects to endangered/threatened species are expected, as the
trigger for endangered species concern has not been exceeded (the
•estimate.'! environmental concentration (EEC) is less than 1/20 the
Adequate data are sufficient to define the fate of hexythiazox in
the environment. Hexythiazox is very stable to hydrolysis, with
an estimated T 1/2 exceeding 50 days at environmentally expected
temperatures and pH values. Hexythiazox undergoes slow photo lytic
degradation under sunlight, with T 1/2 of 16.6 days in water and
116 days in soil. Hexythiazox degrades in soil under laboratory
conditions. The T 1/2 in aerobic soils ranged from 17 to 35 days.
Hexythiazox and its soil aged residues do not leach significantly
in soil due to its low solubility in water, high soil adsorption
characteristics, and slight vertical movement in soils tested.
Hexythiazox is not likely to persist in the field, with T 1/2
ranging from 5 to 15 weeks. No crop rotation study is required
for this orchard crop use. Both accumulation and depuration of
hexythiazox will occur in bluegill sunfish. Bioconcentration
factors of approximately 1300X were calculated in the bluegill
sunfish flowthrough study. During 28 days of depuration, 97% of
the radiolabeled material was eliminated.
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Chemical/Physical Characteristics of the Technical Grade Product
Physical State: Crystalline solid
Color: Pale yellow
Odor: Odorless
Melting Point: 105 to 107.5 °C
108 to 108.5 °C for analytical grade
Vapor Pressure: 2.54 x 10~8 innttg (20 °C)
IVblecular Weight: 352.5
Solubility: Chloroform 137.9 (g/100 mL)
Acetone 16.0
n-^fexane 0.39
Methanol 2.06
Xylene 36.2
Acetonitrile 2.86
Water 0.5 ppm
Specific Gravity: d420 1.289
Bulk Density: 0.50 to 0,70 g/mL
Octanol/Water Partition Coefficient: 340
pH: Stability to Hydrolysis
(t 1/2 of 0.25 ppm at 22 °C) pH 5 > 7 x 10* (hours)
7 > 7 x 104
9 1.21 x 104
Stability to Temperature: Stable after 3 months at 50 °C
Storage Stability: 100% active ingredient stable at room
"eitperat iro arU at 50 °C cor 180 days
Toxicology Characteristics of the Technical Grade:
o Acute Oral Toxicity - Rat: LD5Q > 5000 mg/kg
Toxicity Category IV
o Acute Dermal Toxicity - Rat: LD50 > 5000 mg/kg
Toxicity Category III
o Acute Inhalation LCso > 2.0 mg/L
Toxicity Category III
o Primary Dermal Irritation - Rabbit: Not a primary skin
irritant. Toxicity Category IV
o Primary Eye Irritation: Very mild eye irritant.
Toxicity Category III
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o Dental Sensitization: Non-sensitizer
o 1-Year Feeding - Dog: NOEL = 100 ppm (2.5 mg/kg/day)
o 2-Year Feeding/Oncogenicity - Rat: NOEL (Systemic) = 430
(21.5 mg/kg/day); oncogenicity-negative at 3000 ppm (HOT)
o 2-Year Feeding/Oncogenicity - Mouse: NOEL (Systemic) =250
ppm (37.5 mg/kg/day); Oncogenic in female mouse liver at
1500 ppm (225 mg/kg/day) HOT
o Reproduction (2 generation) - Rat: Reproductive NOEL > 2400
ppm (120 mg/kg/day); Maternal NOEL = 400 ppm (20 mg/kg/day)
o Teratology - Rabbit: NOEL > 1080 mg/kg/day for developmental
toxicity (HOT). Maternal toxicity NOEL > 1080 mg/kg/day
(HOT)
o Teratology - Rat: Maternal NOEL = 240 mg/kg/day; Fetotoxic
NOEL = 240 mg/kg/day; Teratogenic NOEL > 2160 mg/kg/day
(HOT)
o Mutagenicity: Negative in a battery of mutagenicity
studies.
End-Use Formulation
The stated results for the following acute studies are for the 50
percent ^ettable fx>/d-ar formulation: Oral (rat), dermal (rat),
inhalation (rat), primary dermal irritation (rabbit), and primary
eye irritation (rabbit) and dermal sensitization (guinea pig).
o Acute Oral - Rat: LD50 > 5000 mg/kg (male (M) and female (F)
Toxicity Category III
o Acute Dermal Toxicity - Rat: LE^Q > 5000 mg/kg (M&F)
Toxicity Category III
o Acute Inhalation - Rat: I/^Q > 2.8 mg/L (M&F)
Toxicity Category III
o Primary Dermal Irritation - Rabbit: Negative (N)
Toxicity Category IV
o Primary Eye Irritation - Rabbit: Reddened conjunctivae,
maximum score of 2, maximum duration 6 days. Chemosis
ended by day 3 (M); Toxicity Category III
o Dermal Sensitization - Guinea Pig: Not a sensitizer
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Physiological and Biochemical Characteristics:
Foliar Absorption: N/A
Translocation: Not translocated.
Mechanism of Pesticide Action: Neurotoxicity Characteristic -
Controls mites through ovicidal/chemosterilant activity when
spray mist comes in contact with mite eggs or female mites.
Environmental Characteristics;
The environmental fate data indicate that hexythiazox and its
soil-aged residues did not have significant vertical mobility
and thus are not likely to leach and contaminate ground water.
Field data also indicate that hexythiazox dissipates with half-
life of 5 to 26 weeks. Hexythiazox underwent slower photolytic
degradation on soil than in aqueous solution with a half-life
of 116 days. Hexythiazox did not undergo any noticeable
hydrolysis under acidic to neutral conditions at 22 °C. At pH
9 at 22 °C, hexythiazox hydrolyzed very slowly with an estimated
half -life of 416 days.
14C-DPX-Y5893 (labeled at C-5 of thiazole moiety) was bioaccumulated
in bluegill sunfish under flow-through conditions with a biological
concentration factor (BCF) range of 1000 to 1600 at peak on the
basis of whole fish. The highest accumulation occurred in viscera
with a BCF range of 1.3 to 1.7 x 1Q4. After 14 days of depuration,
about 97 percent of: the aocu.Ttulate.l radioactivity was removed.
Residue analysis of the 28-day fish samples shewed that about 52
to 88 percent of the l^C-residue was present as polar material ( s ) ,
5 to 23 percent as parent DPXY5893, 2 to 15 percent as cyclohexane-
hydroxylated metabolites of parent, 4 to 7 percent as conjugated
material, and 2 to 4 percent as tissue bound residues.
Ecological Characteristics;
Technical Formulation
o Avian Oral Toxicity: > 2510 mg/kg (mallard duck 11)50).
o Avian Dietary Toxicity (8 days): > 5620 ppm (bobwhite quail
and > 5620 ppm (mallard duck
o Freshwater Fish Acute Toxicity: (96-hr LC5Q: 0.53 mg/L
(bluegill) and > 1 mg/L (rainbow trout).
o Freshwater Invertebrate Acute Toxicity (48^-ir LC^Q - Grade:
1.22 mg/L (Daphnia crinata); (48-hr EC50): 0.74 mg/L.
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o Invertebrate Life Cycle: NOEL 0.5 mg/L (Daphnia magna).
o Honeybee T-C$Q: >1000 ppm
Tolerance Assessment
A Section 408 tolerance under the Federal Food Drug and Cosmetic Act
has been established for residues of hexythiazox in/on the following
raw agricultural commodity (40 CFR 180.448)
Commodity Part Per Million
Pears 0.3
The acceptable daily intake (ADI), based on a NOEL of 2.5 mg/kg/day
from a 1-year dog feeding study and a safety factor of 100 is
0.025 mg/kg/body weight/day. The TMRC from the proposed tolerance
is 0.000037 mg/kg body weight/day. This is equivalent to about
7.4 percent of the ADI
The nature of the residue in pears (pome fruit) is adequately defined.
The residue of concern is the parent and its hydroxylated
cyclohexane ring metabolites.
There are no animal feed items with pear orchard use therefore the
nature of the residue in animals is not relevant. Since there
are no feed items involved with pears and the label includes the
restriction "Do not graze or feed livestock or cover crops growing
In treated areas", no secondary residues (meat, milk) are anticipated
from this proposed use.
No processing data have been submitted however none are required
since residue levels in pear juice and nectar will not exceed the
tolerance level on the raw agricultural commodity pears.
There are no Canadian or Mexican tolerances and no Codex Maximum
Residue Limits (MRLS) have been established for hexythiazox and its
metabolites in/on pears. Therefore, no compatibility problem exists.
Reported Pesticide Incidents; None
4. Summary of Regulatory Position and Rationale
A full review of the data indicates that although hexythiazox is an
oncogen in mice the dietary and nondietary risks would be extremely
small from the proposed use on pears. Estimated dietary oncogenic
risk to the general population based on the highly conservative
assumption that all pears are treated with Savey and would bear
residues at the proposed tolerance level is estimated to be
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The Agency believes that actual exposure and risk would be lower.
The basis for this is that the risk of 10"6 reflects a worst-case
dietary exposure because it assumes that 100 percent of the United
States pear crop is treated with Savey and that all quantities of
the food consumed will bear residue levels as high as the proposed
tolerance. In reality, the Agency knows that all pears would not
be treated with this pesticide. Based upon an analysis of the
market penetration of currently registered acaricides, the Agency
expects the percent of crop treated with Savey in a typical year
would be about 30 percent. Likewise, the Agency believes that
residue levels in pear juice and nectar will not exceed the
established tolerance of 0.30 ppm in or on the RAG pears, since
the maximum residue level in pear juice is less than 50 percent
of the residue level in whole fruit. In addition, since there
are no animal feed items involved with pears and the petitioner
has included the label restriction "Do not graze or feed livestock
or cover crops growing in treated areas," no secondary residues
in meat or milk are expected.
Estimated non-dietary oncogenic risk to the mixer/loader applicator
based on a dermal absorption factor of 2%, the use of protective
clothing and 1 application of per year is 10~6. The Agency believes
that this estimate is an overestimation of the lifetime cancer risk
and that actual exposure and risk would be much lower since the
surrogate data base for calculating exposure reflected application
rates qf 1 to 7 ai/A whereas the proposed use on pears is for 0.2
Ib ai/A. An estimated risk of less than 1 X 10~5 is considered to
be an acceptable risk relative to mixer, loaders and applicators.
Thus, based on the above risk assessment the Agency has characterized
the risk posed to the general public and to pesticide applicators
from the proposed use of Savey as extremely small.
The Agency has determined, based on the available data and use pattern,
that endangered/threatened species would not be adversely affected.
Hexythiazox is not likely to leach and contaminate ground water.
The Agency has reviewed all relevant data and has determined that no
additional data are necessary to make the determination required
by FIFRA sec 3(c)(5). Thus, the Agency is approving this registra-
tion under FIFRA sec 3(c)(5).
The Agency has determined that the product will perform its intended
function without unreasonable adverse effects on the environment,
and that when used in accordance with the label directions, the
product will not generally cause unreasonable adverse effects
on the environment.
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The Agency has determined that all necessary tolerances have been
issued under FIFRA sec. 408.
5. Sumnary of Data Gaps
None
6. Contact Person at EPA
George T. LaRocca
Product Manager (15)
Insecticide-Rodenticide Branch
Registration Division (H7504C)
Office of Pesticide Programs
Environmental Protection Agency
401 M Street S.W.
Washington, DC 20460
Office location and telephone number:
Room 204, Crystal Mall #2
1921 Jefferson Davis Highway
Arlington, VA 22202
Pnone: (703) 557-2400
DISCLAIMER: The information presented in this Pesticide Fact Sheet is
for informational purposes only and may not be used to fulfill data
requirements for pesticide registration and reregistration.
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