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hexythiazox (Savey) Chemical Profile 4/89

Name of Chemical:  Hexythiazox
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-methyl-2-oxo-3-thiazolidine-
              carboxamide
Common 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: 1989 
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.
Type of Formulation:  50% wettable power.
Limitations:
-- Use only in commercial plantings; do not use in home plantings.
-- 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.
-- Do not graze or feed livestock on cover crops growing in treated areas.
-- Do not apply more than a total of 6 oz. form/A per growing season
-- Do not apply within 28 days of harvest.
-- Do not apply more than once per growing season.
-- Do not apply this product through any type of irrigation system.
                        3. SCIENCE FINDINGS
Summary Science Statement:
     The EPA Peer Review Committee completed its evaluation of hexythiazox 
with respect to its oncogenic potential and concluded 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 
Qsubl* of 3.9 x 10(-2) (mg/kg/day)(-1) in human equivalents has been 
calculated. Dietary oncogenic risk to the general population based on the 
highly conservative assumption that all pears are treated with hexythiazox 
and would bear residues at the proposed tolerance level is estimated to be 
10(-6). Nondietary oncogenic risk to the mixer/loader, applicator based on 
a dermal absorption factor of 2%, use of protective clothing and one 
application per year is estimated to be 10(-6).
     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. Hexythiazox 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 estimated 
environmental concentration (EEC) is less than 1/20 the LC50).
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 photolytic 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.
Chemical/Physical Characteristics of the Technical Grade Product:
Physical State:  Crystalline solid
Color:  Pale yellow
Odor:  Odorless
Melting Point:  105 to 107.5 degrees C
                108 to 108.5 degrees C for analytical grade
Vapor Pressure:  2.54 x 10(-8) mmHg (20 degrees C)
Molecular Weight:  352.5
Solubility:  Chloroform        137.9 (g/100 mL)
             Acetone            16.0
             n-Hexane            0.39
             Methanol            2.06
             Xylene             36.2
             Acetonitrile	   2.86
             Water               0.5 ppm
Specific Gravity:  d(4)20 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 degrees C) pH 5  > 7 x 10(4) (hours) 
                                            7  > 7 x 10(4)
                                            9  1.21 x 10(4)
Stability to,Temperature:  Stable after 3 months at 50 degrees C
Storage Stability:  100% active ingredient stable at room temperature and
                    at 50 degrees C for 180 days.
Toxicology Characteristics of the Technical Grade:
-- Acute Oral Toxicity - Rat:  LD50 > 5000 mg/kg.  Toxicity Category IV
-- Acute Dermal Toxicity - Rat:  LD50 > 5000 mg/kg.  Toxicity Category III
-- Acute Inhalation LC50 > 2.0 mg/L.  Toxicity Category III
-- Primary Dermal Irritation - Rabbit:  Not a primary skin irritant.
   Toxicity Category IV
-- Primary Eye Irritation:  Very mild eye irritant.  Toxicity Category III
-- Dermal Sensitization:  Non-sensitizer
--1-Year Feeding - Dog:  NOEL = 100 ppm (2.5 mg/kg/day)
-- 2-Year Feeding/Oncogenicity - Rat:  NOEL (Systemic) = 430 
   (21.5 mg/kg/day); oncogenicity-negative at 3000 ppm (HDT)
-- 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) HDT
-- Reproduction (2 generation) - Rat:  Reproductive NOEL > 2400 ppm 
   (120 mg/kg/day); Maternal NOEL = 400 ppm (20 mg/kg/day)
-- Teratology - Rabbit: NOEL > 1080 mg/kg/day for developmental toxicity
   (HDT). Maternal toxicity NOEL > 1080 mg/kg/day (HDT)
-- Teratology - Rat:  Maternal NOEL = 240 mg/kg/day; Fetotoxic NOEL = 240
   mg/kg/day; Teratogenic NOEL > 2160 mg/kg/day (HDT)
-- Mutagenicity:  Negative in a battery of mutagenicity studies.
End-Use Formulation:
The stated results for the following acute studies are for the 50 percent 
wettable powder formulation:  
  Oral (rat), (dermal (rat), inhalation (rat), primary dermal irritation
  (rabbit), and primary eye irritation (rabbit) and dermal sensitization
  (guinea pig).
-- Acute Oral - Rat:  LD50 > 5000 mg/kg (male [M] and female [F]) 
   Toxicity Category III
-- Acute Dermal Toxicity - Rat:  LD50 > 5000 mg/kg (M&F) 
   Toxicity Category III
-- Acute Inhalation - Rat: LC50 > 2.8 mg/L (M&F) 
   Toxicity Category III
-- Primary Dermal Irritation - Rabbit:  Negative (N) Toxicity Category IV
-- Primary Eye Irritation - Rabbit:  Reddened conjunctivae, maximum score
   of 2, maximum duration 6 days. Chemosis ended by day 3 (M); Toxicity
   Category III
-- Dermal Sensitization - Guinea Pig:  Not a sensitizer
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 degrees C. At pH 9 at 
22 degrees C, hexythiazox hydrolyzed very slowly with an estimated half-
life of 416 days.
     14(C)-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 10(4). After 14 days of depuration, about 97 percent of the 
accumulated radioactivity was removed.  Residue analysis of the 28-day fish 
samples showed that about 52 to 88 percent of the (14)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
-- Avian Oral Toxicity: > 2510 mg/kg (mallard duck LD50).
-- Avian Dietary Toxicity (8 days):  > 5620 ppm (bobwhite quail LC50) and 
   > 5620 ppm (mallard duck LC50).
-- Freshwater Fish Acute Toxicity:  (96-hr LC50:  0.53 mg/L (bluegill) and
                                    > 1 mg/L (rainbow trout).
-- Freshwater Invertebrate Acute Toxicity (43-hr LC50 - Grade:
   1.22 mg/L (Daphnia crinata); (48-hr EC50):  0.74 mg/L.
-- Invertebrate Life Cycle:  NOEL 0.5 mg/L (Daphnia magna).
-- Honeybee LC50:  >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 l-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 10(-6).
     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 RAC 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 of 1 to 7 ai/A whereas the 
proposed use on pears is for 0.2 lb 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 registration 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.
                         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
Phone: (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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