Document ID: EPA-HQ-OPP-2005-0309-0005
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2008-05-28T04:00Z

SEQ CHAPTER \h \r 1 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

	OFFICE OF

	PREVENTION, PESTICIDES

	AND TOXIC SUBSTANCES

MEMORANDUM

Date:		14-February-2008

Subject:	Hexythiazox - Human-Health Risk Assessment for the Section 3
Registration for Application to Field Corn.  

Petition #:	5F6953	DP #:	345087

Decision #:	357936	PC Code	128849

From:		Tom Bloem, Chemist

		P.V. Shah, Ph.D., Toxicologist

		Registration Action Branch 1 (RAB1)/Health Effects Division (HED)
(7509P)

		Mark Dow, Ph.D., Biologist

		Risk Integration, Minor Use & Emergency Response Branch (RIMUERB)

		Registration Division (RD; 7505P)

Thru:		Dana Vogel, Branch Chief

		RAB1/HED (7509P)

To:		George Larocca/Olga Odiott (RM 13)

		RD (7505P)

The HED of the Office of Pesticide Programs (OPP) is charged with
estimating the risk to human health from exposure to pesticides.  The RD
of OPP has requested that HED evaluate hazard and exposure data and
conduct dietary, occupational, residential, and aggregate exposure
assessments, as needed, to estimate the risk to human health that will
result from all registered/proposed hexythiazox uses.  

A summary of the findings and an assessment of human risk resulting from
the registered/proposed hexythiazox uses are provided in this document. 
The risk assessment, residue chemistry review, and dietary risk
assessment were provided by Tom Bloem (RAB1), the hazard
characterization by P.V. Shah (RAB1), the occupational/residential
exposure (ORE) assessment by Mark Dow (RIMUERB), and the drinking water
assessment by Mark Corbin of the Environmental Fate and Effects Division
(EFED).



Table of Contents

  TOC \o "1-3" \h \z \u    HYPERLINK \l "_Toc191173564"  1.0  EXECUTIVE
SUMMARY	  PAGEREF _Toc191173564 \h  3  

  HYPERLINK \l "_Toc191173565"  2.0  PHYSICAL/CHEMICAL PROPERTIES
CHARACTERIZATION	  PAGEREF _Toc191173565 \h  7  

  HYPERLINK \l "_Toc191173566"  3.0  HAZARD CHARACTERIZATION	  PAGEREF
_Toc191173566 \h  8  

  HYPERLINK \l "_Toc191173567"  3.1  FQPA Considerations	  PAGEREF
_Toc191173567 \h  8  

  HYPERLINK \l "_Toc191173568"  3.2  Dose-Response Assessment	  PAGEREF
_Toc191173568 \h  9  

  HYPERLINK \l "_Toc191173569"  3.3  Endocrine Disruption	  PAGEREF
_Toc191173569 \h  9  

  HYPERLINK \l "_Toc191173570"  4.0  EXPOSURE ASSESSMENT	  PAGEREF
_Toc191173570 \h  12  

  HYPERLINK \l "_Toc191173571"  4.1  Summary of Registered Uses	 
PAGEREF _Toc191173571 \h  12  

  HYPERLINK \l "_Toc191173572"  4.2  Summary of Proposed Uses	  PAGEREF
_Toc191173572 \h  12  

  HYPERLINK \l "_Toc191173573"  4.3  Dietary Exposure/Risk Pathway	 
PAGEREF _Toc191173573 \h  13  

  HYPERLINK \l "_Toc191173574"  4.3.1  Food Residue Profile	  PAGEREF
_Toc191173574 \h  13  

  HYPERLINK \l "_Toc191173575"  4.3.2  Water Residue Profile
Exposure/Risk Pathway	  PAGEREF _Toc191173575 \h  17  

  HYPERLINK \l "_Toc191173576"  4.4  Dietary Exposure Analyses	  PAGEREF
_Toc191173576 \h  18  

  HYPERLINK \l "_Toc191173577"  4.5  Residential Exposure/Risk Pathway	 
PAGEREF _Toc191173577 \h  19  

  HYPERLINK \l "_Toc191173578"  5.0  AGGREGATE RISK ASSESSMENTS AND RISK
CHARACTERIZATION	  PAGEREF _Toc191173578 \h  19  

  HYPERLINK \l "_Toc191173579"  6.0  CUMULATIVE RISK	  PAGEREF
_Toc191173579 \h  20  

  HYPERLINK \l "_Toc191173580"  7.0  OCCUPATIONAL EXPOSURE	  PAGEREF
_Toc191173580 \h  20  

  HYPERLINK \l "_Toc191173581"  7.1  Occupational Handler Exposure and
Risk	  PAGEREF _Toc191173581 \h  20  

  HYPERLINK \l "_Toc191173582"  7.2  Post-application Exposure and Risk	
 PAGEREF _Toc191173582 \h  22  

  HYPERLINK \l "_Toc191173583"  7.3 Cancer Assessment	  PAGEREF
_Toc191173583 \h  23  

  HYPERLINK \l "_Toc191173584"  7.4 Restricted Entry Interval	  PAGEREF
_Toc191173584 \h  24  

  HYPERLINK \l "_Toc191173585"  8.0  DATA NEEDS/LABEL REQUIREMENTS	 
PAGEREF _Toc191173585 \h  24  

  HYPERLINK \l "_Toc191173586"  8.1  Toxicology	  PAGEREF _Toc191173586
\h  24  

  HYPERLINK \l "_Toc191173587"  8.2  Residue Chemistry	  PAGEREF
_Toc191173587 \h  24  

  HYPERLINK \l "_Toc191173588"  8.3  Occupational/Residential	  PAGEREF
_Toc191173588 \h  24  

 1.0  EXECUTIVE SUMMARY

Background:   Hexythiazox possesses ovicidal and larvicidal activity
against tetranychid mites.  Hexythiazox is currently registered for
application to several crops with tolerances for the combined residues
of hexythiazox and metabolites containing the (4-chlorophenyl)
-4-methyl-2-oxo-3-

thiazolidine moiety (expressed as parent) ranging from 0.10-10 ppm (40
CFR 180.448).  Tolerances have also been established for these same
compounds in/on milk (0.02 ppm), ruminant fat (0.02 ppm), and ruminant
meat byproducts (0.02 ppm) as a result of secondary residues. 
Hexythiazox is also registered for application by professional
applicators to the following:  (1) ornamental plants and nonbearing
trees and vines growing in nurseries, greenhouses, shade houses; (2)
Christmas tree plantations; and (3) to established ornamental landscape
plantings in interiorscapes, residences, public areas, commercial areas,
rights of way and other easements, and recreational sites.  

The petitioner is currently proposing a Section 3 registration for
application of Onager® Miticide (1 lb ai/gallon;
emulsifiable-concentrate (EC); EPA Reg. No. 10163-277) to field corn
grown in Texas (west of Rt. 283 and northwest of Rt. 377); Oklahoma
(west of Rt. 281/183); and Kansas, Nebraska, South Dakota, and North
Dakota (west of Rt. 281 in all these states).  These restrictions result
in application to field corn grown in zones 7 and 8 of the specified
states.  The petitioner is requesting a single application to field corn
at 0.176 lb ai/acre with a preharvest interval (PHI) of 45 days.  The
petitioner is also proposing the establishment of the following
permanent tolerances for the combined residues of hexythiazox and
metabolites containing the (4-chlorophenyl) -4-methyl
-2-oxo-3-thiazolidine moiety (expressed as parent):  (1) corn, field,
grain - 0.05 ppm; (2) corn, field, forage - 2.0 ppm; and (3) corn,
field, stover - 2.0 ppm.



Hazard Characterization:  Hexythiazox has a low order of acute toxicity
and is classified as Toxicity Category IV for the oral, dermal and
inhalation routes of exposure.  It produces mild eye irritation
(reddened conjunctiva; Toxicity Category III), is not a dermal irritant
(Toxicity Category IV), and is negative for dermal sensitization.  The
target organs of hexythiazox are the liver and adrenal glands, with the
dog being the most sensitive species.  In a subchronic toxicity study in
rats, increased liver and adrenal weights as well as adrenal
histopathology (fatty degeneration of the adrenal zone fasciculata) were
seen.  In a 4-week range-finding study in dogs, effects included
increased liver and adrenal weights (reported in the chronic dog study).
 Chronic studies in dogs, rats, and mice support the liver and adrenal
effects seen in the subchronic studies.  In the chronic dog study,
increased liver and adrenal weights were observed, along with associated
histopathology of the liver (hypertrophy) and adrenal glands (adrenal
cortex hypertrophy).  In the chronic feeding/carcinogenicity studies in
rats and mice, effects included decreased body weight gain and increased
liver weights.  The effects of hexythiazox on the adrenal glands could
be an indication of endocrine disruption.  The data provided no
indication of increased susceptibility in rats or rabbits from in utero
and post-natal exposure to hexythiazox.  There was no evidence of
carcinogenicity in male and female rats; however, there were increased
incidences of malignant and combined benign/malignant liver tumors in
female B6C3FT mice.  Hexythiazox was not mutagenic in bacteria or
Chinese hamster ovary (CHO) cells.  It was negative for chromosomal
aberrations in CHO and did not cause unscheduled DNA synthesis (UDS) in
primary rat hepatocytes.  In an acceptable micronucleus assay, there was
no statistically significant increase in the frequency of micronucleated
polychromatic erythrocytes in bone marrow of treated mice after any dose
or treatment time. Hexythiazox has been found classified as
nonmutagenic.

Dose Response, Endpoint Selection, and Food Quality Protection Act
Safety Factor (FQPA SF) Decision:  The Cancer Peer Review Committee
classified hexythiazox as a Category C chemical (possible human
carcinogen) requiring a quantitative risk assessment (Memo, E. Rinde,
16-Mar-1988).    SEQ CHAPTER \h \r 1 The HED Hazard Identification and
Assessment Review Committee (HIARC; TXR No. 014022, 1-Mar-2000) met on
16-December-1999 and selected points of departure (PODs; e.g.
no-observable-adverse-effect-level (NOAELs)) for risk assessment and
addressed the potential enhanced sensitivity of infants and children
from exposure to hexythiazox as required by the FQPA of 1996.  In
addition, the HED FQPA SF Assessment Review Committee evaluated the
hexythiazox toxicological database and determined that there is no
evidence of increased susceptibility or residual uncertainties regarding
pre- or post-natal toxicity (developmental neurotoxicity (DNT) study is
not required; HED Doc. No. 012614, 6-May-1998).  Based on the
conclusions of these committees, the completeness of the residue
chemistry and environmental fate databases, and the assumptions
incorporated into the dietary exposure analyses, all FQPA SFs were
reduced to 1x.  Table 1 summarizes the endpoints chosen for the exposure
scenarios assessed as part of the current document.  

Table 1:  Summary of the Endpoints Chosen for the Exposure Scenarios
Assessed as part of the Current Document. 

Risk Assessment Scenario	Dose Used in Risk Assessment	Level of Concern
(LOC) for Risk Assessment	Study and Endpoint

Acute Dietary:  females 13-50 yrs old	aPAD1=

2.4 mg/kg/day	(100% of aPAD	Developmental Toxicity Study - Rat: 
developmental LOAEL = 720 mg/kg/day based on delayed ossification.

Acute Dietary: General Population	A dose and endpoint attributable to a
single exposure were not identified from the available oral toxicity
studies, including maternal toxicity in the developmental toxicity
studies.

Chronic Dietary:  general population	cPAD=

0.025 mg/kg/day	(100% of cPAD	One-Year Toxicity Feeding Study - Dog: 
LOAEL = 12.5 mg/kg/day based on increased absolute and relative adrenal
weights and associated adrenal histopathology

Cancer (oral, dermal, inhalation)	Increases in incidence of malignant
and combined benign/malignant liver tumors in mice; Category C (possible
human carcinogen).  HED's LOC is for residential cancer risks >3 x 10-6
and occupational cancer risks >1 x 10-4.  Q1*= 2.22x10-2 mg/kg/day-1.  

Short-term Dermal	oral maternal NOAEL=240 mg/kg/day

(dermal absorption 

rate = 2%)	MOEs2≤100	Developmental Toxicity Study - Rat:  maternal
LOAEL = 720 mg/kg/day based on decreased maternal body weight gain
during gestation days 7-17 and decreased food consumption on gestation
days 9-12.

Short-term Inhalation	oral maternal NOAEL=240 mg/kg/day

(inhal. absorption 

rate = 100%)	MOEs≤100

	1  PAD (population adjusted dose) = NOAEL ÷ (FQPA SF x
interspecies(10x)/intraspecies(10x) variation).

2  MOE = margin-of-exposure = NOAEL ÷ exposure.

Dietary Risk Assessments:  The acute, chronic, and cancer dietary
exposure and risk assessments were conducted using the Dietary Exposure
Evaluation Model - Food Consumption Intake Database (DEEM-FCID(, ver.
2.03).  DEEM-FCID( incorporates food consumption data from the United
States Department of Agriculture (USDA) Continuing Surveys of Food
Intakes by Individuals (CSFII; 1994-1996 and 1998).  The current
assessment is being conducted in support of a Section 3 registration for
application of hexythiazox to field corn.  

The acute analysis assumed modeled drinking water estimates,
tolerance-level residues, 100% crop treated, and DEEM-FCID( (ver 7.81)
default processing factors for all plant and livestock residues.  The
resulting DEEM-FCID( exposure estimates for females 13-49 years old were
<1% the aPAD (95th percentile); therefore, acute exposure to hexythiazox
is not of concern to HED.  An acute endpoint for the remaining
population subgroups was not identified.

 were ≤1% of the cPAD and resulted in a cancer risk of 2 x 10-6;
therefore, chronic (both cancer and noncancer) exposure to hexythiazox
is not of concern to HED.  Based on a critical commodity analysis, the
major contributors to the cancer risk were water (38% of total
exposure), strawberry (20% of total exposure), and field corn syrup (16%
of total exposure).

Aggregate Risk Estimates:  The uses proposed as part of the current
petition and the currently registered uses are not expected to result in
residential exposure.  Therefore, the acute and chronic risk assessments
provided in the Dietary Exposure Section represent aggregate risk. 

Occupational Risk Assessment:  Based on the proposed use patterns,
pesticide handlers are anticipated to have short-term dermal and
inhalation exposure and agricultural workers are anticipated to have
short-term post-application dermal exposure.  Since hexythiazox has been
classified as a possible human carcinogen (Q1*), a cancer risk
assessment is also necessary.  No chemical-specific data are available
to assess potential exposures to pesticide handlers or to estimate
post-application exposure to agricultural workers.  Therefore, for
handlers, the exposure assessment was conducted using data available in
the Pesticide Handlers Exposure Database (PHED; ver. 1.1; 1998) and the
post-application exposure assessment was conducted using the Standard
Operating Procedure (SOP) Regarding Agricultural Transfer Coefficients
(SOP 003.1; 7-Aug-2000; as amended by the HED Science Advisory Council
for Exposure (ExpoSAC; 13-Sep-2001)).   The transfer coefficients (TCs)
used in this assessment are taken from the interim TC policy developed
by ExpoSAC using propriety data from the Agricultural Re-entry Task
Force (ARTF) database.  

Since short-term dermal and inhalation PODs are identical, aggregate
dermal and inhalation risk assessments were conducted by adding the
exposures and comparing to the NOAEL.  The resulting aggregate MOEs were
≥1200 and are therefore not of concern to HED.  The occupational
cancer risks were all <5 x 10-5 and are therefore not of concern to HED
except for mixer-loaders (open-pour; no gloves) which resulted in a
cancer risk of 2 x 10-4.  HED notes that the proposed label directs
handlers to wear gloves and that the cancer analysis assumed 10 (private
growers) or 30 (commercial) days of exposure per year which are
conservative in that only a single application of hexythiazox is
permitted per year to field corn and the petitioner proposed regional
restrictions will result in ≤3% of the total U.S. field corn
production being treated. Based on the interim Worker Protection
Standard (WPS) and the acute toxicity data, the proposed 12-hour
restricted-entry interval (REI) is acceptable. 

Recommendations:  Provided the petitioner submits revised Sections B and
F, HED concludes that the toxicological, residue chemistry, and
occupational/residential databases are sufficient to support an
unconditional registration for application of hexythiazox to field corn
and establishment of the following permanent tolerances for the combined
residues of hexythiazox and metabolites containing the
(4-chlorophenyl)-4- methyl-2-oxo-3-thiazolidine moiety (expressed as
parent):

corn, field, grain	0.02 ppm

corn, field, stover	2.5 ppm

corn, field, forage	6.0 ppm

HED notes that these tolerance should be established in 40 CFR
180.448(c).  

Summary of Data Deficiencies:

Revised Section B which indicates the following:  (1) application after
the V15 crop stage is prohibited (45-day PHI for forage, stover, and
grain should be retained) and (2) labeled crops may be planted at any
time after application and all other crops may be planted 120 days after
application.  

Revised Section F.

2.0  PHYSICAL/CHEMICAL PROPERTIES CHARACTERIZATION

Tables 2 and 3 summarize the nomenclature and physiochemical properties
for hexythiazox.

Table 2:  Nomenclature of Hexythiazox.

Structure	

 

Common name	

Hexythiazox

Company experimental names	

DPX-Y5893, NA-73

IUPAC name	

(4RS,5RS)-5-(4-chlorophenyl)-N-cyclohexyl-4-methyl-2-oxo-1,3-thiazolidin
e-3-carboxamide

CAS name	

trans-5-(4-chlorophenyl)-N-cyclohexyl-4-methyl-2-oxo-3-thiazolidinecarbo
xamide

CAS #	

78587-05-0

End-use products/EP	

1 lb gal/EC (EPA Reg. No. 10163-277; Onager® Miticide)

2 lb gal/EC (EPA Reg. No. 10163-253; Onager® 2E Ovicide/Miticide)

50% WP (EPA Reg. No. 10163-208;  Savey® Ovicide/Miticide)

Table 3:  Physicochemical Properties.

Melting range	108-108.5ºC 	Hexythiazox: Pesticide Fact Sheet

The Pesticide Manual: Twelfth Edition (2000)

pH	not applicable

	Bulk Density	0.5-0.7 g/ml

	Water solubility	0.5 ppm

	Solvent solubility (g/100 ml)	chloroform - 137.9; acetone - 16.0;
n-hexane - 0.39; methanol – 2.06; xylene - 36.2; acetonitrile - 2.86

	Vapor pressure	2.54 x 10-8 mmHg

	Dissociation constant, pKa	not reported

	Octanol/water partition coefficient, Log(KOW)	2.53

	UV/visible absorption spectrum	not reported

	

  SEQ CHAPTER \h \r 1 3.0  HAZARD CHARACTERIZATION

The Cancer Peer Review Committee classified hexythiazox as a Category C
chemical (possible human carcinogen) requiring a quantitative risk
assessment (Memo, E. Rinde, 16-Mar-1988).    SEQ CHAPTER \h \r 1 The
HIARC (TXR No. 014022, 1-Mar-2000) met on 16-December-1999 and selected
endpoints for risk assessment and addressed the potential enhanced
sensitivity of infants and children from exposure to  hexythiazox as
required by the FQPA of 1996.  In addition, the HED FQPA SF Assessment
Review Committee evaluated the hexythiazox toxicological database as it
relates to pre- and post-natal toxicity (HED Doc. No. 012614,
6-May-1998).  

A detailed summary of these meetings and of the hazard characterization
for hexythiazox is presented in a previous HED risk assessment (D269766,
G. Kramer et al., 22-Feb-2001).  Note that since this risk assessment, a
micronucleus assay (MRID No. 45480101) has been submitted and reviewed. 
The study was classified as Acceptable/Guideline.  With the submission
of this study, the 1991 mutagenicity guideline requirements have been
satisfied and hexythiazox has been found classified as nonmutagenic.  A
summary of the Toxicological Profile can be found in Attachment 2 and
brief summary of the hexythiazox toxicological data can be found in the
Executive Summary.    

3.1  FQPA Considerations

On December 16, 1999, the HIARC addressed the potential enhanced
sensitivity of infants and children from exposure to hexythiazox as
required by the FQPA of 1996 (TXR No. 014022, 1-Mar-2000). The HIARC
concluded the following:

●The pre- and post-natal toxicology database for hexythiazox is
complete with respect to

FQPA considerations. The results of these studies indicated no increased
susceptibility of

rats or rabbits to in utero and/or postnatal exposure to hexythiazox. 
In the developmental toxicity study in rabbits, no developmental effects
were seen at doses up to the limit dose.  In the developmental toxicity
study in rats, the developmental effects (delayed ossification) occurred
at the same dose level (720 mg/kg/day) as the maternal effects
(decreased maternal body weight gain and decreased food consumption). 
In the two-generation reproduction study, the effects in the offspring
(decreased pup body weight during lactation and delayed hair growth
and/or eye opening) were observed
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楫湤祥‬湡⁤摡敲慮⁬敷杩瑨⥳മ

●A DNT study is not required at this time.  However, HIARC requested
an evaluation to determine the relationship between the adrenal effects
(increased adrenal weights and/or adrenal pathology) seen in four
studies (90-day feeding study in rats, chronic/carcinogenicity rat,
chronic dog, and 2-generation reproduction study in rats) and the need
for a DNT.  It appears that the effects are more endocrine-related (not
developmental) and will be addressed once the endocrine policy is in
place.  The possibility of the effects being endocrine related is also
supported by reports of ovarian weight increases in several studies in
rats.  In addition, the results of the developmental toxicity studies in
rats and rabbits and the 2-generation reproduction study do not support
a DNT.  No neuropathology or central nervous system (CNS) malformations
were seen in the developmental toxicity studies.  In the 2-generation
reproduction study in rats, there were no findings in pups that were
suggestive of changes in neurological development, although no
functional assessment was performed.  Additionally, there was no
evidence of neurotoxicity in other studies.

Table 4 is a summary of all FQPA SFs (dietary exposures) and uncertainty
factors (UF; occupational) for hexythiazox and the rationale for these
factors.  

Table 4:  Summary of UFs for Hexythiazxo.

Safety Factors	Factor	Rationale for the Factor	Endpoints the Factor 

is Applied

LOAEL to NOAEL 

(FQPA UFL and UFL)	1x	all PODs are based on a NOAEL	all

Subchronic to Chronic 

(FQPA UFs and UFs)	1x	subchronic studies not used for chronic exposure
assessments	all

Incomplete Database 

(FQPA UFDB and UFDB)	1x	the hexythiazox database has been determined to
be complete	all

Uncertainties related to exposure and residual uncertainties regarding
pre- or post-natal toxicity (SFFQPA)	1x	based on the res. chem. and
environmental fate databases, assumptions incorporated into the dietary
exposure analyses, no evidence of increased susceptibility, and no
residual uncertainties regarding pre- or post-natal toxicity	all

Inter-/Intra-species variation (UFA/H)	100x	default (10x/10x
intra-/inter-species variation)	all

3.2  Dose-Response Assessment

A summary of the hexythiazox PODs for occupational assessments are
provided in Table 5.  A summary of hexythiazox PODs for dietary and
residential assessments are provided in Table 6.  

3.3  Endocrine Disruption  tc "3.1  Endocrine Disruption " \l 2 

	

EPA is required under the FFDCA, as amended by FQPA, to develop a
screening program to determine whether certain substances (including all
pesticide active and other ingredients) “may have an effect in humans
that is similar to an effect produced by a naturally occurring estrogen,
or other such endocrine effects as the Administrator may designate.” 
Following recommendations of its Endocrine Disruptor and Testing
Advisory Committee (EDSTAC), EPA determined that there was a scientific
basis for including, as part of the program, the androgen and thyroid
hormone systems, in addition to the estrogen hormone system.  EPA also
adopted EDSTAC’s recommendation that the Program include evaluations
of potential effects in wildlife.  For pesticide chemicals, EPA will use
FIFRA and, to the extent that effects in wildlife may help determine
whether a substance may have an effect in humans, FFDCA authority to
require the wildlife evaluations.  As the science develops and resources
allow, screening of additional hormone systems may be added to the
Endocrine Disruptor Screening Program (EDSP).



Table 5:  Summary of Toxicological Dose and Endpoints for Occupational
Hexythiazox Exposure Assessments.

Exposure

Scenario	POD	UFs and LOC for Risk Assessment	Study and Toxicological
Effects

Short-Term Dermal

(1-30 days)	  SEQ CHAPTER \h \r 1 Oral maternal NOAEL = 

240 mg/kg/day

(dermal absorption rate = 2%)	UF1 = 1x; UFA/H2= 100x

LOC MOEs ≤ 100	  SEQ CHAPTER \h \r 1 Developmental Toxicity Study -
Rat

LOAEL = 720 mg/kg/day based on decreased maternal body weight gain
during gestation days 7-17 and decreased food consumption on gestation
days 9-12.

Intermediate-Term Dermal 

(1-6 Months)	  SEQ CHAPTER \h \r 1 Oral NOAEL= 5.4 mg/kg/day

(dermal absorption rate = 2%)	UF1 = 1x; UFA/H2= 100x

LOC MOEs ≤ 100	  SEQ CHAPTER \h \r 1 13-Week Feeding Study - Rat

LOAEL = 38.1 mg/kg/day based on increased absolute and relative liver
weights in both sexes, increased relative ovarian and kidney weights,
and fatty degeneration of the adrenal zone fasciculata.

Long-Term Dermal 

(>6 Months)	At the time the HIARC reviewed the hexythiazox toxicological
database, long-term dermal endpoints were not selected.  Based on the
proposed application scenarios, long-term dermal exposures are not
anticipated.

Short-Term Inhalation 

(1-30 days)	  SEQ CHAPTER \h \r 1 Oral maternal NOAEL = 

240 mg/kg/day

(inhalation absorption rate = 100%)	UF1=1x; UFA/H2= 100x

LOC MOEs ≤ 100	  SEQ CHAPTER \h \r 1 Developmental Toxicity Study -
Rat

LOAEL = 720 mg/kg/day based on decreased maternal body weight gain
during gestation days 7-17 and decreased food consumption on gestation
days 9-12.

Intermediate-Term Inhalation  

(1-6 Months)	  SEQ CHAPTER \h \r 1 Oral NOAEL= 5.4 mg/kg/day

(inhalation absorption rate = 100%)	UF1=1x; UFA/H2= 100x

LOC MOEs ≤ 100	  SEQ CHAPTER \h \r 1 13-Week Feeding Study - Rat

LOAEL = 38.1 mg/kg/day based on increased absolute and relative liver
weights in both sexes, increased relative ovarian and kidney weights,
and fatty degeneration of the adrenal zone fasciculata.

Long-Term Inhalation 

(>6 Months)	At the time the HIARC reviewed the hexythiazox toxicological
database, long-term inhalation endpoints were not selected.  Based on
the proposed application scenarios, long-term inhalation exposures are
not anticipated.

Cancer (oral, dermal, inhalation)	Increases in incidence of malignant
and combined benign/malignant liver tumors in mice; Category C (possible
human carcinogen).  Q1*= 2.22x10-2 mg/kg/day-1.  

1  UF = UFL x UFs x UFDB (see Table 4).

2  UFA/H = intraspecies and interspecies variation (see Table 4).



Table 6:  Summary of Toxicological Dose and Endpoints for Residential
and Dietary Exposure Assessments.

Exposure

Scenario	POD	FQPA SFs and LOC for Risk Assessment	Study and
Toxicological Effects

  SEQ CHAPTER \h \r 1 Acute Dietary:

females 13-50 years of age	NOAEL = 240 mg/kg/day

	FQPA SF1=1x; UFA/H2=100x

aPAD = NOAEL÷( UFA/H x FQPA SF) = 2.4 mg/kg/day	Developmental Toxicity
Study – Rat

Developmental LOAEL = 720 mg/kg/day based on delayed ossification.

  SEQ CHAPTER \h \r 1 Acute Dietary:  

general population including infants and children	A dose and endpoint
attributable to a single exposure were not identified from the available
oral toxicity studies, including maternal toxicity in the developmental
toxicity studies.

  SEQ CHAPTER \h \r 1 Chronic Dietary:  

all populations	NOAEL=2.5 mg/kg/day	FQPA SF1=1x; UFA/H2=100x

aPAD = NOAEL÷(UFA/H x FQPA SF) = 0.025 mg/kg/day	One-Year Toxicity
Feeding Study - Dog

LOAEL = 12.5 mg/kg/day based on increased absolute and relative adrenal
weights and associated adrenal histopathology.

Short- Intermediate-Term Incidental Oral	At the time the HIARC reviewed
the hexythiazox toxicological database, incidental oral endpoints were
not selected.  Based on the uses requested as part of the current
petition and the currently registered uses, incidental oral exposures
are not anticipated.

Short-Term Dermal

(1-30 days)	  SEQ CHAPTER \h \r 1 Oral maternal NOAEL = 

240 mg/kg/day

(dermal absorption rate = 2%)	FQPA SF1=1x; UFA/H2=100x

LOC MOEs ≤ 100	  SEQ CHAPTER \h \r 1 Developmental Toxicity Study -
Rat

LOAEL = 720 mg/kg/day based on decreased maternal body weight gain
during gestation days 7-17 and decreased food consumption on gestation
days 9-12.

Intermediate-Term Dermal 

(1-6 Months)	  SEQ CHAPTER \h \r 1 Oral NOAEL= 5.4 mg/kg/day

(dermal absorption rate = 2%)	FQPA SF1=1x; UFA/H2=100x

LOC MOEs ≤ 100	  SEQ CHAPTER \h \r 1 13-Week Feeding Study - Rat

LOAEL = 38.1 mg/kg/day based on increased absolute and relative liver
weights in both sexes, increased relative ovarian and kidney weights,
and fatty degeneration of the adrenal zone fasciculata.

Long-Term Dermal 

(>6 Months)	At the time the HIARC reviewed the hexythiazox toxicological
database, long-term dermal endpoints were not selected.  Based on the
uses requested as part of the current petition and the currently
registered uses, long-term dermal exposures are not anticipated.

Short-Term Inhalation 

(1-30 days)	  SEQ CHAPTER \h \r 1 Oral maternal NOAEL = 

240 mg/kg/day

(inhalation absorption rate = 100%)	FQPA SF1=1x; UFA/H2=100x

LOC MOEs ≤ 100	  SEQ CHAPTER \h \r 1 Developmental Toxicity Study -
Rat

LOAEL = 720 mg/kg/day based on decreased maternal body weight gain
during gestation days 7-17 and decreased food consumption on gestation
days 9-12.

Intermediate-Term Inhalation  

(1-6 Months)	  SEQ CHAPTER \h \r 1 Oral NOAEL= 5.4 mg/kg/day

(inhalation absorption rate = 100%)	FQPA SF1=1x; UFA/H2=100x

LOC MOEs ≤ 100	  SEQ CHAPTER \h \r 1 13-Week Feeding Study - Rat

LOAEL = 38.1 mg/kg/day based on increased absolute and relative liver
weights in both sexes, increased relative ovarian and kidney weights,
and fatty degeneration of the adrenal zone fasciculata.

Long-Term Inhalation 

(>6 Months)	At the time the HIARC reviewed the hexythiazox toxicological
database, long-term inhalation endpoints were not selected.  Based on
the uses requested as part of the current petition and the currently
registered uses, long-term inhalation exposures are not anticipated.

Cancer (oral, dermal, inhalation)	Increases in incidence of malignant
and combined benign/malignant liver tumors in mice; Category C (possible
human carcinogen).  Q1*= 2.22x10-2 mg/kg/day-1.  

1  FQPA SF = FQPA UFL x FQPA UFs x FQPA UFDB  x SFFQPA (see Table 4);
for dermal and inhalation exposures a SFFQPA of 1x is assumed (this will
need to be reevaluated when and if residential dermal and inhalation
exposures occur).  

2  UFA/H = intraspecies and interspecies variation (see Table 4). 

4.0  EXPOSURE ASSESSMENT

- residue chemistry reviews:  D319090, T. Bloem, 3-July-2006; D332304,
T. Bloem 7-Mar-2007; D340179, T. Bloem, 7-Mar-2007; D347948, T. Bloem,
14-Feb-2008

-dietary exposure review:  D348775, T. Bloem, 14-Feb-2008

-EFED drinking water assessment:  D313192, D315434, and D317141; M.
Corbin, 7-Jun-2005

4.1  Summary of Registered Uses

Hexythiazox is currently registered for application to tree nuts, pome
fruit, caneberry, citrus (CA, AZ, and TX only), dates, stone fruits,
grape, hop, mint, strawberry, and cotton (CA only) with tolerances for
the combined residues of hexythiazox and metabolites containing the
(4-chlorophenyl)-4-methyl -2-oxo-3-thiazolidine moiety (expressed as
parent) ranging from 0.10-10 ppm (40 CFR 180.448).  Tolerances have also
been established for these same compounds in/on milk (0.02 ppm),
ruminant fat (0.02 ppm), and ruminant meat byproducts (0.02 ppm) as a
result of secondary residues.

Hexythiazox is also registered for application by professional
applicators to the following (Hexygon (EPA Reg. No. 10163-240) and
Hexygon DF (dry flowable; EPA Reg. No. 10163-251):  (1) ornamental
plants and nonbearing trees and vines growing in nurseries, greenhouses,
shade houses; (2) Christmas tree plantations; and (3) to established
ornamental landscape plantings in interiorscapes, residences, public
areas, commercial areas, rights of way and other easements, and
recreational sites.  HED also notes that the petitioner has previously
proposed professional/homeowner application to turf, caneberries, pome
fruit, stone fruit, and tree nuts.  HED conducted residential exposure
assessment for these uses (D321219, M. Dow, 3-Jan-1999); however, due to
issues raised by EFED, these uses were never registered and are not
considered in the current risk assessment.    

4.2  Summary of Proposed Uses

 The petitioner provided proposed directions for application of Onager®
Miticide (1 lb ai/gallon; emulsifiable-concentrate (EC); EPA Reg. No.
10163-277) to field corn grown in Texas (west of Rt. 283 and northwest
of Rt. 377); Oklahoma (west of Rt. 281/183); and Kansas, Nebraska, South
Dakota, and North Dakota (west of Rt. 281 in all these states).  These
restrictions result in application to field corn grown in zones 7 and 8
of the specified states.  Table 7 is a summary of the proposed field
corn application scenario.  The label specifies a 12-hour REI and
indicates the following personnel protective equipment (PPE): 
long-sleeved shirt and long pants, waterproof gloves, and shoes plus
socks.  HED requests a revised Section B with the following changes: 

●	Based on the currently-available field trial data, the label should
indicate that application after the V15 crop growth stage is prohibited
(45-day PHI for forage, stover, and grain should be retained).

●	Based on the currently-available data, the label should indicate
120-day plant-back interval (PBI) for all crops not currently on the
label (labeled crops may be planted anytime after application).    

Table 7:  Proposed Application Scenarios

Formulation	

Crop	

Application Rate (lb ai/acre)	

PHI1 (days)	

Comments

Onager® Miticide (0.94 lb ai/gal)	

field corn	

1 x 0.04-0.176	

45	

apply with ground (15-20 gallons per acre (GPA)) or aerial (5 GPA)
equipment

do not apply more than 0.176 lb ai/acre/growing season

do not make more than one application per growing season

do not apply though irrigation equipment 

do not apply within 45 days of harvest

do not harvest corn forage for 45 days after application

1	PHI = preharvest interval

4.3  Dietary Exposure/Risk Pathway

4.3.1  Food Residue Profile

Nature of the Residue:  Table 8 summarizes HED conclusions concerning
the nature of the residue in grape, apple, pear, citrus, field corn,
livestock, and rotational crops.  The following text is a summary of the
rationale for these decisions.  

Plants:  Grape, apple, pear, and citrus metabolism studies have been
previously submitted and reviewed.  Based on these data, HED concluded
that the residues of concern in/on these crops, for tolerance expression
and risk assessment purposes, are hexythiazox and metabolites containing
the (4-chlorophenyl)-4-methyl-2-oxo-3-thiazolidine moiety (PP#7G3469, F.
Suhre, 12-Feb-1987; PP#3F3254 and FAP#5H5469, E. Haeberer, 13-Jan-1986).
 Since the nature of the residue in a cereal grain was not demonstrated,
HED requested a cereal grain metabolism study.  The petitioner argued
that the analytical method employed in the field corn field trial study
quantifies hexythiazox and all compounds hydrolyzed to PT-1-3 and that
based on the fruit crop metabolism data (fruit and leaves), there is no
reasonable expectation that field corn or soils will produce any
metabolite of interest that cannot be converted to PT-1-3.  HED noted
that the confined rotational crop study resulted in unknowns in wheat
straw which were not hydrolyzed to PT-1-3 (only wheat straw was
analyzed; combined concentration for these compounds of 21% total
radioactive residue (TRR); D247631, G. Kramer, 20-Mar-2000); therefore,
these data demonstrate that the metabolism and/or degradation of
hexythiazox may result in the formation of compounds which are not
hydrolyzed to PT-1-3; the magnitude of these compounds in a primary crop
other than fruit is unknown.   

In response, the petitioner submitted and HED reviewed a tea metabolism
study (see 47236301.der.wpd).  HED notes that all of the compounds
identified in the tea metabolism study are likely to by hydrolyzed to
PT-1-3 and would, therefore, be quantified using the method employed in
the field corn field trial and processing studies.  Therefore,
hexythaizox plant metabolism data on tea and fruit crops have been
submitted and these data demonstrate a similar metabolic pathway. 
Normally, HED requires metabolism data either on the proposed/similar
crop or metabolism data on three dissimilar crops which demonstrate a
similar metabolic route (generally root vegetable, leafy vegetable,
fruit, pulses, cereal grain, and/or oilseed).  However, for the reasons
listed below, HED concludes that the currently-available metabolism data
are sufficient and the residues of concern in field corn are hexythiazox
and metabolites containing the (4-chlorophenyl)-4-methyl-2-oxo-3-
thiazolidine moiety (expressed as parent).  HED notes that if the
petitioner proposes a field corn registration in an area which
represents a significant percentage of the national field corn
production, then a cereal grain metabolism would be requested.  

●  Based on Table 6 of OPPTS 860.1500 and the proposed regional
restrictions concerning application, ≤3% of the total U.S. field corn
production will be treated.     

●  The previous dietary exposure analysis included field corn residues
resulting from a Section 18 registration and resulted in acute and
chronic exposures of <1% the acute/chronic PAD and a cancer risk of 2.3
x 10-6 (D317359, T. Bloem, 29-Jun-2005).  Since field corn grain is a
blended commodity and/or based on the low production in the proposed
areas, HED does not anticipated significant chronic exposure to treated
field corn grain or meat, milk, poultry, or egg derived from livestock
which consumed treated field corn feed commodities.  

Livestock:  A lactating goat metabolism study has been previously
submitted and reviewed.  Based on these data, HED concluded that the
residues of concern in/on ruminants, for tolerance expression and risk
assessment purposes, are hexythiazox and metabolites containing the
(4-chlorophenyl)-4-methyl-2-oxo-3-thiazolidine moiety (PP#5F3254,
17-Jun-1988).  The petitioner has also submitted a poultry metabolism
study; however, this study was deemed inadequate due to incomplete
characterization of 14C-residues in liver, fat, and eggs.  Based on the
TRRs in the various poultry commodities and the current dietary burden,
HED concludes that residue in poultry are likely to be insignificant and
a new poultry metabolism study is unnecessary (180.6(a)(3); see below). 

HED notes, that if the petitioner requests a field corn registration in
an area which represents a significant percentage of the total U.S.
field corn production, then a poultry metabolism study may be necessary.
 The need for a poultry metabolism study will be contingent on the
residues of concern identified in the required cereal grain metabolism
study and, if necessary, additional field corn field trial and
processing studies.  Depending on these data and the poultry dietary
burden, a poultry feeding study may be requested. 

day PBI radish top (≤0.047 ppm) and sorghum stover (≤0.014 ppm). 
Based on the TRRs from the confined rotational crop study, the
concentration of the identified/unidentified residues in wheat straw
from the confined rotational crops study (based on TRRs, only wheat
straw was analyzed), and the concentration of residues in the field
rotational crop study and since the field/confined rotational crop
studies employed bare soil application, HED concludes that a 120-day PBI
for all crops following application to field corn is acceptable.  A
revised Section B is requested.  HED notes that recommended rotational
crop restrictions are consistent with previously recommended rotational
crop restrictions for cotton (1 x 0.16 lb ai/acre; D247631, G. Kramer,
20-Mar-2000).  

  SEQ CHAPTER \h \r 1 Table 8:  Residues for Tolerance Expression and
Risk Assessment.

Matrix	Residues Included in Risk Assessment	Residues Included in
Tolerance Expression

grape, apple, pear, citrus,

field corn1, and ruminant	  SEQ CHAPTER \h \r 1 hexythiazox and
metabolites containing the
(4-chlorophenyl)-4-methyl-2-oxo-3-thiazolidine moiety	  SEQ CHAPTER \h
\r 1 hexythiazox and metabolites containing the
(4-chlorophenyl)-4-methyl-2-oxo-3-thiazolidine moiety

poultry	  SEQ CHAPTER \h \r 1 not determined

A poultry metabolism study has been submitted and reviewed and was
deemed inadequate due to incomplete characterization of 14C-residues in
liver, fat and eggs (PP#5F3254/5H5469, E. Haeberer, 1-Aug-1986); based
on the TRRs in the various poultry commodities from the metabolism study
and the current dietary burden, HED concludes that residue in poultry
are likely to be insignificant and a new poultry metabolism study is
unnecessary (40 CFR 180.6(a)(3); D).

rotational crops	  SEQ CHAPTER \h \r 1 not determined

A confined rotational crop has been submitted and deemed inadequate due
to incomplete characterization of 14C-residues (D247631, G. Kramer,
20-Mar-2000); however, based on the results of this study, a field
rotational crop study, the proposed application rates, and the proposed
120-day plant-back interval, HED concluded that no additional data were
required and tolerances in/on rotational crops were unnecessary.

water	  SEQ CHAPTER \h \r 1 hexythiazox, PT-1-2, PT-1-3, PT-1-4, PT-1-5,
PT-1-8, and PT-1-92	not relevant

1  Based on Table 6 of OPPTS 860.1500 and the proposed regional
restrictions concerning application, ≤3% of the total US field corn
production will be treated; if the petitioner requests registration for
application to field corn in regions which represent a significant
proportion of the US field corn production, these conclusions may not be
appropriate (see residue chemistry review for further information;
D347948, T. Bloem, 14-Feb-2008).

2  See attachment 10 for structures.  

Magnitude of the Residue - Field Corn:  The petitioner has submitted and
HED has reviewed acceptable field corn field trial and processing study
(46567001.der.wpd).  Provided a revised Section B is submitted, the
field corn field trial study (n=3) is adequate to support the limited
proposed geographical areas.  The study resulted in combined residues of
hexythiazox and metabolites containing the (4-chlorophenyl)-4-methyl-2-
oxo-3-thiazolidine moiety (expressed as parent) in/on field corn grain,
forage, and stover of <0.02 ppm, 0.051-1.72 ppm, and 0.067-0.830 ppm,
respectively (see Table 9 for a summary).  The field corn processing
study (5x) resulted in combined residues of hexythiazox and metabolites
containing the (4-chlorophenyl)-4-methyl-2-oxo- 3-thiazolidine moiety
(expressed as parent) in/on field corn grain of <0.02 ppm.  Based on
these data and the maximum residue limit (MRL) tolerance calculator, HED
concludes that the following tolerances for combined residues of 
hexythiazox and metabolites containing the
(4-chlorophenyl)-4-methyl-2-oxo-3-thiazolidine moiety (expressed as
parent) are appropriate (MRL calculator was not used for grain as
residues were <LOQ):  corn, field, grain - 0.02 ppm; corn, field, stover
- 2.5 ppm;  and corn, field, forage - 6.0 ppm.  A revised Section F is
requested.    



Table 9:  Summary of Residue Data.

Commodity	App. Rate

(lb ai/acre)	PHI (days)	Residues (ppm)2

	n	Min.	Max.	HAFT1	Median	Mean	Std. Dev.

Field corn forage	1 x 0.190-0.197	44-60	10	0.051	1.72	1.13	0.640	0.735
0.543

Field corn grain	1 x 0.190-0.197	89-110	12	<0.02	<0.02	<0.02	<0.02	<0.02
--

Field corn stover	1 x 0.190-0.197	89-110	12	0.067	0.830	0.728	0.512
0.489	0.271

1  HAFT = Highest Average Field Trial.

2  Residues expressed in hexythiazox equivalents.

h resulted in TRRs in egg, liver, fat, kidney, and muscle at ≤0.50 ppm
following dosing at 5 ppm and ≤2.1 ppm following dosing at 50 ppm, HED
concludes that residues in poultry commodities are likely to be
insignificant and tolerances are unnecessary (40 CFR 180.6(a)(3)). 
Based on the beef/dairy cattle and hog dietary burdens and a previously
reviewed 28-day dairy cow feeding study conducted at dietary burdens of
5 ppm, 15 ppm, and 50 ppm (PP#5F3254, E. Haeberer, 1-Aug-1986), HED
concludes that the currently established milk, hog, and ruminant
tolerances are sufficient.  

Magnitude of the Residue - Rotational Crops:  As indicated in the nature
of the residue section, provided a revised Section B is submitted which
specifies a 120-day PBI, residues in rotational crops are expected to be
insignificant. 

Analytical Enforcement Method - Plants/Livestock:  Method AMR-985-87 has
been deemed an acceptable method (D219922, W. Cutchin, 19-Oct-1995) for
enforcement of the currently-established plant and livestock tolerances.
 The method has been validated for use on various crop commodities and
has been forwarded to the Food and Drug Administration (FDA) for
inclusion in the Pesticide Analytical Manual (PAM) II.  The method used
in the field trial study was adequately validated and is similar to the
current enforcement method.  Since adequate method validation and
concurrent recoveries were attained in the field trial study, HED
concludes that the current enforcement method is appropriate for
enforcement of the tolerances associated with this petition.  

Multiresidue Method:  The petitioner has submitted data (MRID 43878201)
describing the testing of hexythiazox through FDA Multiresidue protocols
C through E.  This information has been forwarded to the FDA (G. Kramer,
22-Feb-1996).  In addition, hexythiazox and its metabolites have been
tested according to the FDA Multiresidue protocols C through E in
conjunction with a petition for use on hops (PP#4E04411).  The
information pertaining to the testing of hexythiazox per se, which
indicated that hexythiazox was not recovered from fortified hops
samples, has been forwarded to the FDA (G. Kramer, 5-Sep-1996).  The
information pertaining the testing of hexythiazox metabolites, which
indicated that the hexythiazox metabolites were not recovered through
protocols C through E, has also been forwarded to the FDA for review
(D249358, G. Kramer, 10-Mar-2000).

Proposed and Recommended Tolerances:  Table 10 is a summary of the
HED-recommended tolerances for residues of hexythiazox and metabolites
containing the (4-chlorophenyl)-4-methyl-2-oxo-3-thiazolidine moiety. 
There are currently no established Codex, Canadian, or Mexican MRLs for
residues of hexythiazox in/on the proposed commodities.  Therefore,
harmonization is not an issue.  A revised Section F is requested. 

Table 10:  HED-recommended Tolerances.

Petitioner Proposed	HED-Recommended	Comments 

(requested Section F revisions)

Commodity	Tolerance (ppm)	Commodity	Tolerance (ppm)

	corn, field, grain (EPA Region 8)	0.05	corn, field, grain	0.02	Revise
commodity definition and tolerance value.

corn, field, stover (EPA Region 8)	2.0	corn, field, stover	2.5

	corn, field, forage (EPA Region 8)	2.0	corn, field, forage	6.5

	 

4.3.2  Water Residue Profile Exposure/Risk Pathway

Based on an evaluation of the environmental fate data, HED and EFED
determined that the following compounds are of concern in drinking
water:  hexythiazox, PT-1-2, PT-1-3, PT-1-4, PT-1-5, PT-1-8, and PT-1-9
(see attachment 1 for structures).

Drinking Water Fate Assessment:  Based on the available environmental
fate data, degradation of hexythiazox would be expected to occur
primarily through microbial-mediated metabolism under aerobic conditions
and by photolysis in water and on soils.  Hexythiazox was stable to
hydrolysis at pH 5, 7, and 9.  Aerobic soil metabolism half-life values
were 29.2 and 34.8 days @ 15°C and 16.8 and 20.5 days @ 25°C for a
sandy loam and clay loam, respectively.  The reported aqueous photolysis
half-life was about 17 days and the soil photolysis half-life value 116
days.  Hexythiazox Koc values of 2589, 3234, 5747 and 13,621 in clay
loam, sandy loam, silt loam, and sand, respectively, are reported.  In
summary, in aerobic environments, parent hexythiazox is a relatively
immobile compound with a moderately short degradation half life. 

Modeled Drinking Water Estimates:  The proposed field corn application
rate is less than the rates previously modeled and EFED indicates that a
previous analysis (D313192, D315434, and D317141; M. Corbin, 7-Jun-2005)
is applicable for the current assessment (Email from A Vaughan to D.
Vogel, 7-Feb-2008).  Currently, the Agency does not have monitoring data
available to perform a quantitative drinking water risk assessment for
hexythiazox.  Therefore, the potential for hexythiazox residues in
drinking water were evaluated through modeling.  Surface water
concentrations were estimated using the Tier II model Pesticide Root
Zone Model 3 (PRZM3; ver. 3.12.2; 2-May-2005)/Exposure Analysis Modeling
System (EXAMS; ver. 2.98.04.06; 25-Apr-2005) and ground water
concentrations were estimated using the Tier I model Screening
Concentration in Ground Water (SCIGROW).  Since no environmental fate
data has been submitted for any of the degradates of concern, EFED
conducted a total residue exposure assessment.  The SCIGROW model was
run assuming the highest registered/proposed application rate (1 x
0.1875 lb ai/acre) while all registered/proposed application scenarios
were evaluated in PRZM/EXAMS.  The PRZM/EXAMS evaluation considered
potential spatial variation by using model scenarios which represent a
combination of specific agronomic, soil, and climatological parameters
which are geographically specific.  Table 11 is a summary of the SCIGROW
and highest PRZM/EXAMS model estimates.

  SEQ CHAPTER \h \r 1 Table 11:  Drinking Water Estimates.

	SCIGROW (μg/L; ground water)	PRZM/EXAMS (μg/L; surface water)

acute	0.005031	4.232

chronic	0.005031	2.263

cancer	0.005031	1.724

1  Assumed 1 application at 0.1875 lbs ai/acre.

2  1-in-10-year annual peak concentration; based on the TX alfalfa
application scenario (1 x 0.1875 lb ai/acre; 67% of the basin cropped
(BC) and 100% of the cropped area treated (CAT)).

3  1-in-10-year annual mean; based on the NY grape application scenario
(1 x 0.1875 lb ai/acre; 77% BC and 100% CAT).

4  30-year annual mean; based on the NY grape application scenario (1 x
0.1875 lb ai/acre; 77% BC and 100% CAT).

4.4  Dietary Exposure Analyses

The acute, chronic, and cancer exposure and risk estimates are
summarized in Table 12, 13, and 14, respectively.  HED's level of
concern is for acute and chronic exposures >100% the acute and chronic
PAD.  Cancer risks presented in this assessment are expressed to one
significant figure. However, it should be noted that, in general, the
precision which can be assumed for cancer risk estimates is best
described by rounding to the nearest integral order of magnitude on the
log scale (3.16 x 10-7 to 3.16 x 10-6 expressed as 10-6).  Risks are
generally reported to one significant figure in HED risk assessments to
allow better characterization of changes in risk which might result from
potential risk mitigation. This rounding procedure indicates that risks
should generally not be assumed to exceed the benchmark level of concern
of 10-6 until the calculated risks exceed approximately 3 x 10-6. 

The acute analysis assumed modeled drinking water estimates,
tolerance-level residues, 100% crop treated, and DEEM-FCID( (ver 7.81)
default processing factors for all plant and livestock residues.  The
resulting DEEM-FCID( exposure estimates for females 13-49 years old were
<1% (95th percentile) the aPAD and are therefore not of concern to HED. 
An acute endpoint for the remaining population subgroups was not
identified.

The chronic/cancer dietary analyses assumed modeled drinking water
estimates, average/projected percent crop treated estimates, average
field trial residues, experimentally determined processing factors when
available, and anticipated livestock residues (dietary burden calculated
using average field trial).  The resulting DEEM-FCID( exposure estimates
were ≤1% of the cPAD and resulted in a cancer risk of 2 x 10-6;
therefore, chronic (both cancer and noncancer) exposure to hexythiazox
is not of concern to HED.  

  

Table 12:  Summary of Acute Dietary Exposure and Risk for Hexythiazox.

Population Subgroup	aPAD (mg/kg/day)	Acute (95th Percentile)

Exposure (mg/kg/day)	%aPAD

Females 13-49 years old	2.4	0.010176	<1



Table 13:  Summary of Chronic Dietary Exposure and Risk for Hexythiazox.

Population Subgroup	cPAD (mg/kg/day)	Exposure (mg/kg/day)	%cPAD

General U.S. Population	0.025	0.000108	<1

All Infants (< 1 year old)

0.000222	<1

Children 1-2 years old

0.000250	1

Children 3-5 years old

0.000225	<1

Children 6-12 years old

0.000143	<1

Youth 13-19 years old

0.000091	<1

Adults 20-49 years old

0.000090	<1

<

Adults 50+ years old

0.000086	<1

Females 13-49 years old

0.000088	<1

  SEQ CHAPTER \h \r 1 

Table 14:  Summary of Cancer Dietary Exposure and Risk for Hexythiazox.

Population	Q1*	Exposure (mg/kg/day)	risk

General U.S. Population	0.0222	0.000096	2 x 10-6

4.5  Residential Exposure/Risk Pathway

HED notes that the petitioner has previously proposed
professional/homeowner application to turf and residential caneberries,
pome fruit, stone fruit, and tree nuts and that a residential exposure
assessment for these uses was conducted (D321219, M. Dow, 3-Jan-1999);
however, due to issues raised by EFED, these uses were never registered
and are not considered in the current risk assessment.    

HED does not anticipate residential exposure from the remaining
proposed/registered uses.  Spray drift is always a potential source of
exposure to residents nearby to spraying operations.  This is
particularly the case with aerial application, but, to a lesser extent,
could also be a potential source of exposure from groundboom application
methods.  The Agency has been working with the Spray Drift Task Force,
EPA Regional Offices and State Lead Agencies for pesticide regulation
and other parties to develop the best spray drift management practices. 
The Agency is now requiring interim mitigation measures for aerial
applications that must be placed on product labels/labeling.  The Agency
has completed its evaluation of the new data base submitted by the Spray
Drift Task Force, a membership of U.S. pesticide registrants, and is
developing a policy on how to appropriately apply the data and the
AgDRIFT® computer model to its risk assessments for pesticides applied
by air, orchard airblast and ground hydraulic methods.  After the policy
is in place, the Agency may impose further refinements in spray drift
management practices to reduce off-target drift and risks associated
with aerial as well as other application types where appropriate. 

5.0  AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION

In accordance with the FQPA, exposures from relevant sources (oral,
dermal, and inhalation) are combined when appropriate and compared to
quantitative estimates of hazard.  When aggregating exposures and risks
from various sources, HED considers both the route and duration of
exposure.  The uses proposed as part of the current petition and the
currently registered uses are not expected to result in residential
exposure (incidental oral, dermal, or inhalation).  Therefore, the acute
and chronic risk assessments provided in the Dietary Exposure Section
represent aggregate risk. 

6.0  CUMULATIVE RISK

Unlike other pesticides for which EPA has followed a cumulative risk
approach based on a common mechanism of toxicity, EPA has not made a
common mechanism of toxicity finding as to hexythiazox and any other
substance and hexythiazox does not appear to produce a toxic metabolite
produced by other substances.  For the purposes of this tolerance
action, therefore, EPA has assumed that hexythiazox does not have a
common mechanism of toxicity with other substances.  For information
regarding EPA’s efforts to determine which chemicals have a common
mechanism of toxicity and to evaluate the cumulative effects of such
chemicals, see the policy statements released by EPA’s Office of
Pesticide Programs concerning common mechanism determinations and
procedures for cumulating effects from substances found to have a common
mechanism on EPA’s website at   HYPERLINK
http://www.epa.gov/pesticides/cumulative/.
http://www.epa.gov/pesticides/cumulative/. 

7.0  OCCUPATIONAL EXPOSURE

The techniques used to assess occupational risk have been developed and
refined by the HED ExpoSAC and reflect HED SOPs.  A summary of the
proposed application scenario can be found in Section 4.2.  

7.1  Occupational Handler Exposure and Risk

Based upon the proposed use pattern, HED believes the most highly
exposed occupational pesticide handlers (mixers/loaders/applicators)
will be:  (1) mixer/loaders using open-pour of liquid formulations and
(2) applicators using open-cab, ground-boom equipment.  

HED believes pesticide handlers (mixers/ loaders/applicators) will be
exposed over the short-term (1-30 days) duration.  Exposures of
intermediate-term (1-6 months) are not expected since applications must
occur at the first evidence of mite presence, only one application per
year is permitted, and private applicators are expected to make the
great majority of the applications.  

Chemical-specific data were not available with which to assess pesticide
handler exposure.   Therefore, surrogate data from studies in PHED (Ver.
1.1; Aug-1998) were used to estimate mixer/loader and applicator
exposure.  HED is aware that some private (i.e., grower/applicators)
pesticide handlers may conduct all functions, that is, mix/load and
apply the material.  The available exposure data for combined
mixer/loader/applicator scenarios are limited in comparison to the
monitoring of these two activities separately.  These exposure scenarios
are outlined in the PHED (Aug-1998).   HED has adopted a methodology to
present the exposure and risk estimates separately for the job functions
in some scenarios and to present them as combined in other cases.  Most
exposure scenarios for hand-held equipment (such as hand wands, backpack
sprayers, and push-type granular spreaders) are assessed as a combined
job function.  With these types of hand-held operations, all handling
activities are assumed to be conducted by the same individual.  The
available monitoring data support this and HED presents them in this
way.  Conversely, for equipment types such as fixed-wing aircraft,
groundboom tractors, or air-blast sprayers, the applicator exposures are
assessed and presented separately from those of the mixers and loaders. 
By separating the two job functions, HED determines the most appropriate
levels of PPE for each aspect of the job without requiring an 
applicator to wear unnecessary PPE that may be required for a
mixer/loader (e.g., chemical-resistant gloves may only be necessary
during the pouring of a liquid formulation).

It is HED policy to assess handler exposure and risk using
“baseline” (PPE) which is comprised of long-sleeved shirt, long
pants, and shoes plus socks and if necessary to assess “baseline”
plus the use of protective gloves or other PPE as might be necessary or
appropriate.   The proposed label directs pesticide handlers to wear a
long-sleeved shirt, long pants, water-proof gloves, and shoes plus
socks.  

HED has concluded that a MOE of >100 is adequate to protect occupational
pesticide handlers from dermal and inhalation exposure.  All dermal and
inhalation MOEs are ≥1200 and are therefore not of concern to HED. 
Since short-term dermal and inhalation exposure assessment are based on
the same study, the exposures were combined and a MOE calculated.  All
combined dermal and inhalation MOEs are ≥1200 and are therefore not of
concern to HED.  Table 15 is a summary of occupational handler exposures
and risks.   



Table 15:  Estimated Handler Exposure and Risk from the Use of
Hexythiazox on Field Corn.

Unit Exposure1

(mg ai/lb handled)	

Applic. Rate2

(lb ai/acre)	

Units Treated3

Per Day (acres)	

Average Daily Dose4

(mg ai/kg/day)	

MOE5	Combined MOE

Mixer/Loader - Liquid Open-pour

Dermal:

SLNG6	2.9 LC

SLWG6	0.023 MC

Inhal.:	0.0012 HC	

0.176	

1200	Dermal:

SLNG	0.204

SLWG	0.0016

Inhal.:	0.0042	Dermal:

SLNG	1200 

SLWG	1.5 x 105

Inhal.:	57000		19,000,000	

SLNG	1200

SLWG	4.1 x 104

Applicator - Ground-boom - Open Cab

Dermal:

SLNG	0.014 HC

SLWG	0.014  MC

Inhal.:	0.00074  HC	

0.176	

200	Dermal:

SLNG	0.00016

SLWG	0.00016

Inhal.:	0.00043	Dermal:

SLNG	1.5 x 106

SLWG	1.5 x 106

Inhal.:	5.5 x 105		32,000,000	

SLNG	4.0 x 105

SLWG	4.0 x 105

Aerial Applicator

Dermal:

SLNG	0.0050

Inhal.:	0.000068	0.176	1200	Dermal:

SLNG	0.00035

Inhal.:	0.00024	Dermal:

SLNG	6.8 x 105	4,800,000

Inhal.: 	1.0 x 106	SLNG	4.1 x 105 

1  Unit Exposures are taken from PHED (Ver. 1.1, Aug-1998); dermal SLNG
= long-sleeved short, long pants, socks, and shoes (no gloves); dermal
SLWG = long-sleeved short, long pants, socks,  shoes, and water-proof
gloves; Inhal. = Inhalation; data Confidence: LC = Low Confidence, MC =
Medium Confidence, HC = High Confidence.

2  Application Rate. = see section 4.2.

3  Units Treated are taken from “Standard Values for Daily Acres
Treated in Agriculture” (ExpoSAC SOP  No. 9.1.,  Revised 5-
July-2000). 

4  Average Daily Dose = Unit Exposure x Applic. Rate x Units Treated x
absorption factor (2.0 % dermal; 100 % inhalation)  ( Body Weight (60
kg; maternal NOAEL).  

5  MOE = NOAEL (240 mg/kg/day)  ( ADD; since short-term dermal and
inhalation PODs are identical (based on the same study), the exposures
were combined and a MOE calculated.    

7.2  Post-application Exposure and Risk

There is a potential for agricultural workers to have post-application
exposure to pesticides during the course of typical agricultural
activities.  There were no chemical-specific data with which to estimate
post-application exposures of agricultural workers to dislodgeable
hexythiazox residues.  Therefore, exposure estimates are based on the
ExpoSAC SOP 003.1 (7-Aug-2000;  Regarding Agricultural Transfer
Coefficients; as amended by ExpoSAC 13-Sept-2001) which lists a number
of possible post-application agricultural activities relative to field
corn that result in pesticide exposure to agricultural workers. TCs,
expressed as cm²/hr, are identified for each of the post-application
agricultural activities.  The TCs are derived from data in surrogate
exposure studies conducted during the various activities listed.  The
highest (most conservative) TC relative to field corn is for activities
related to scouting and irrigation (1,000 cm²/hr).

    

The TCs used in this assessment are from an interim policy developed by
ExpoSAC using proprietary data from the ARTF database.  It is the
intention of ExpoSAC that this procedure will be periodically updated to
incorporate additional information about agricultural practices in crops
and new data on TCs.  Much of this information will originate from
exposure studies currently being conducted by the ARTF, from further
analysis of studies already submitted to the Agency, and from studies in
the published scientific literature.

Post-application worker exposure is estimated using HED procedure that
assumes 20% of the application rate is available as dislodgeable foliar
residue on the day of treatment.  HED expects post-application
agricultural exposures to scouts (i.e., crop advisors) or workers
involved in irrigation would typically be short-term.  The total number
of acres treated per day is comparatively small and treatment is not
expected to be necessary at the same time for all acres on a given farm,
therefore scouting after treatment will occur in short-term periods of
time.



PDRt	= DFRt x CF1 x TC x ET:

PDRt	= potential dose rate on day “t” (mg/day)

DFRt	= dislodgeable foliar residue on day “t” (ug/cm2; see below for
equation)

CF1	= weighted unit conversion factor changing µg to mg (0.001 mg/µg)

TC  	=  (cm2/hr) (1,000 cm²/hr)

ET	= Exposure Time (8 hr/day)

	DFRt	= (AR x F) x (1 - D)t x CF2 x CF3:

	AR	= application rate (lb ai/ft2 or lb ai/acre) (0.176 lb ai/acre)

	F	= fraction of ai retained on foliage (unitless =  20%)

	D	= fraction of residue that dissipates daily (unitless) (0%)

	t	= post-application day on which exposure is being assessed

	CF2	= conversion factor lb a.i. to µg for DFR (4.54 x 108 µg/lb)

	CF3	= conversion factor to convert surface area units (ft2) in
application rate to cm2 for DFR value =

		(1.08 x 10-3 ft2/cm2 or 2.47 x 10-8 acre/cm2 if rate is per acre).

The PDRt is then normalized to the body weight of a worker.  The result
is expressed as mg/kg/day.  The body weight used is determined by the
toxicological endpoint identified for use in the assessment.  For this
assessment, the toxicological endpoints are based on a maternal NOAEL;
therefore, 60-kg body weight is used to calculate the MOE.  

DFR = 0.176 lb ai/acre x 0.20 x (1-0)0 x 4.54 x 108 µg ai/lb x 2.47 x
10-8A/cm2 = 0.3947 µg/cm2

PDR = 0.3947 µg/cm2 x 0.001 mg/µg x 1,000 cm2/hr x 8 hr/day = 3.1576
mg/day x 2.0 % dermal absorption ( 60 kg = 0.001053 mg/kg/day; MOE = 240
mg/kg/day ( 0.001053 mg/kg/day = 230,000.

HED has concluded that MOEs >100 are adequate to protect agricultural
workers from dermal exposure to hexythiazox.   The calculated
post-application dermal MOE on day zero is 230,000 and is therefore not
of concern to HED.  

7.3 Cancer Assessment

≤3% of the total U.S. field corn production being treated.  Table 16
is a summary of the occupational cancer risks.  	

Table 16:  Occupational Cancer Risk.

Average Daily Dose1	LADD2 (mg/kg/day)	Cancer Risk

dermal	inhalation	total

Mixer Loader - Liquid Open-pour

SLNG 0.20	0.0042	0.21	0.0029	2 x 10-4

SLWG  0.0016	0.0042	0.0058	8.0 x 10-5	5 x 10-6

Applicator - Ground-boom - Open Cab

SLNG 0.00016	0.00043	0.00059	8.1 x 10-6	5 x 10-7

SLWG  0.00016	0.00043	0.00059	8.1 x 10-6	5 x 10-7

Aerial Applicator

0.00035	0.00024	0.00059	8.1 x 10-6	5 x 10-7

Post Application

0.0011	--	0.0011	1.4 x 10-5	1 x 10-6

1  The average daily dose are take from Table 15.

2  LADD = (ADDDermal + Avg. Daily DoseInhalation) x (30 day/yr x 35 yr)
÷ (70 yr x 365 day/yr).

7.4 Restricted Entry Interval

Hexythiazox is classified in Acute Toxicity Category IV for acute
dermal, inhalation and primary skin irritation.  It is classified in
Category III for primary eye irritation.  It is not a skin sensitizer. 
Therefore, the interim
WP⁓敲瑳楲瑣摥攠瑮祲椠瑮牥慶⁬景ㄠ′潨牵⁳愨⁳楬
瑳摥漠⁮桴⁥慬敢獬 獩愠敤畱瑡⁥潴瀠潲整瑣愠牧捩
汵畴慲⁬潷歲牥⁳牦浯瀠獯⵴灡汰捩瑡潩⁮硥潰畳敲⁳
潴栠硥瑹楨穡硯‮഍⸸‰䐠呁⁁䕎䑅⽓䅌䕂⁌䕒啑剉䵅
久協഍⸸‱吠硯捩汯杯൹

●None

 

8.2  Residue Chemistry

●Revised Sections B and F.

8.3  Occupational/Residential

●None

Attachment 1:  Chemical Structures

Attachment 2:  Toxicological Profile

RDI: RAB1 review (13-Feb-2008)

T. Bloem:S10945:PY1:(703)-605-0217(7509P)

Attachment 1:  Chemical Structures

Compound	Structure

hexythiazox

PT-1-2

 

PT-1-3

PT-1-4

PT-1-5

PT-1-8

PT-1-9

Attachment 2:  Toxicological Profile

Guideline No./ 

Study Type	MRID No. (year)/ Classification /Doses	Results

870.3100

90-Day oral toxicity rat	45067101 (1983)

Acceptable/guideline

0, 10, 70, 500, or 3500 ppm 

M: 0, 1.2, 8.1, 58.6, or 397.5 mg/kg/day 

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males

LOAEL = 58.6/38.1 mg/kg/day, males/females, based on increased absolute
and relative liver weights in both sexes, increased relative ovarian and
kidney weights, and fatty degeneration of the adrenal zona fasciculata. 

870.3700a

Prenatal developmental toxicity rat	44955711 (1984) 

Acceptable/guideline

0, 240, 720, or 2160 mg/kg/day	Maternal NOAEL = 240 mg/kg/day; LOAEL =
720 mg/kg/day based on decreased maternal body weight gain, and
decreased food consumption.

Developmental NOAEL = 240 mg/kg/day; LOAEL = 720 mg/kg/day based on
delayed ossification.

870.3700b

Prenatal developmental toxicity rabbit	00146555 (1984)

Acceptable/guideline

0, 120, 360, or 1080 mg/kg/day	Maternal NOAEL ≥1080 mg/kg/day; LOAEL
>1080 mg/kg/day 

Developmental NOAEL ≥1080 mg/kg/day; 

LOAEL >1080 mg/kg/day

870.3800

Two-Generation reproduction and fertility effects rat	00147578 (1985)

Acceptable/guideline

0, 60, 400, or 2400 ppm 

Average doses across generations: 

M:  0, 4.45, 29.73, or 180.67 mg/kg/day

 F:  0, 5.27, 34.77, or 207.67 mg/kg/day	Parental/Systemic NOAEL =
29.73/34.77 mg/kg/day, males/females; LOAEL = 180.67/207.67 mg/kg/day,
males/females, based on decreased body weight gain and increased
absolute and relative liver, kidney, and adrenal weights.

OAEL ≥180.67/207.67 mg/kg/day, males/females; LOAEL >180.67/207.67
mg/kg/day, males/females

Offspring NOAEL = 29.73/34.77 mg/kg/day, males/females; LOAEL =
180.67/207.67 mg/kg/day, males/females, based on decreased pup body
weight during lactation, and delayed hair growth and/or eye opening.

870.4100b

Chronic toxicity dog	00151359, 00146556, 00156895 (1984)

Acceptable

0, 100, 500, or 5000 ppm (0, 2.5, 12.5, or 125 mg/kg/day)

M: 0, 2.87, 13.1, or 153 mg/kg/day

F:  0, 3.17, 13.9, or 148 mg/kg/day	NOAEL = 2.5 mg/kg/day; LOAEL = 12.5
mg/kg/day based on increased absolute and relative adrenal weights and
associated adrenal histopathology.

870.4300

Chronic Toxicity/

Carcinogenicity rat	00146559 (1984)

Acceptable/guideline

0, 60, 430, or 3,000 ppm

M: 0, 3, 23, or 163 mg/kg/day

F: 0, 4, 29, or 207 mg/kg/day	NOAEL = 23/29 mg/kg/day, males/females;
LOAEL =163/207 mg/kg/day, males/females based on decreased body weight
and body weight gain and increased absolute and relative liver weights
in both sexes.  No evidence of carcinogenicity.

870.4300

Carcinogenicity mice	00147577, 00156896  (1985)

Acceptable/guideline

0, 40, 250, or 1500 ppm 

M: 0, 6.72, 41.6, or 267 mg/kg/day

F:  0, 8.38, 51.2, or 318 mg/kg/day	NOAEL = 41.6/51.2 mg/kg/day,
males/females; LOAEL = 267/318 mg/kg/day, males/females) based on
decreased male body weight and body weight gain, and increased absolute
and relative liver weights in both sexes.  Evidence of carcinogenicity
(causes liver tumors in females). 

Gene Mutation

870.5100

(Salmonella typhimurium and Escherichia coli reverse gene mutation
assay)	44955710 (1983)

Acceptable

	The test was negative up to the highest dose tested (6400 µg/plate
+/-S9.

Gene Mutation

870.5300

(In vitro mammalian cell forward gene mutation assay in CHO cells)
00155154 (1985)

Acceptable

	Independently performed trials were negative up to precipitating doses
(≥60 µg/mL) and severely cytotoxic concentrations (200 µg/mL -S9;
400 µg/mL +S9).

Cytogenetics

870.5375

In vitro mammalian cell cytogenetic assay in CHO cells	00156894 (1986)

Acceptable	The test was negative up to precipitating doses accompanied
by severe cytotoxicity (≥167 µg/mL +/-S9).

Cytogenetics

870.5395

In vivo mouse micronucleus assay	44955708

Unacceptable	The results were inconclusive because a positive response,
which was within the wide range of historical background data, was
recorded for female mice at the mid-and high-doses (500 and 1000 mg/kg).
 The assay should be repeated to confirm or refute the equivocal
results. 

Cytogenetics

870.5395

In vivo mammalian micronucleus assay in mouse bone marrow cells

	45480101

Acceptable/Guideline	Hexythiazox technical was tested to a limit value
of 2000 mg/kg.  The test material did not increase the incidence of
micronucleated PCEs in the bone marrow of male or female mice treated at
concentrations up to 2000 mg/kg.

Other Effects 

870.5550

In vitro UDS assay in primary rat hepatocytes	00156893 (1985)

Acceptable	The test was negative up to a lethal dose (250 µg/mL).

870.7485

Metabolism and pharmacokinetics	00146558 (1985)

Acceptable/guideline

Single oral dose at 10 mg/kg (Group B); 14 daily oral doses (10 mg/kg)
of unlabeled material followed by one dose (10 mg/kg) of [14C] test
material (Group C); and a single oral dose of 880 mg/kg (Group D).
Absorption and distribution of dosed radioactivity were rapid.  The
radioactive material was rapidly eliminated in the urine and feces; the
majority of the radioactivity was eliminated within 24 hours.  There
were no observable differences in the total elimination of NA-73 between
male and female rats.  The major route of elimination in both the male
and female rats was by fecal excretion.  The major metabolite found,
PT-1-8 (cis), accounted for 8-12% of the administered radioactivity in
the low dose groups.  Approximately 11-20% and 65-69% of the dosed
radioactivity was identified as unchanged NA-73 in the low-dose and
high-dose groups, respectively.  All other metabolites were present at
low concentrations (<2%).  There was no apparent sex difference in
metabolite formation.  Significant levels of NA-73 equivalent
[14C]-residues were detected in the fat, liver, and adrenals.  A
sex-related difference in the residue levels of all tissues was
observed, with residues in female tissues being two-fold higher than
those found in male tissues.

870.7485

Metabolism and pharmacokinetics	0146557 (1983)

Acceptable/non-guideline

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摧⨙Ñ܀cis) accounting for 10% of the dosed radioactivity.  The
others were all minor metabolites accounting for less than 1.4%.  About
20% of the dose was excreted as unchanged NA-73 (97% of which was in the
feces).  No significant sex difference was apparent with respect to
metabolite formation.

870.7600

Dermal penetration	40608402, 40787901 (1985)

Unacceptable	The total percent of dose absorbed averaged 2%, 1%, and
1.1% for cannulated rats (10-hour sacrifice) and 0.8%, 0.2%, and 0.2%
for non-cannulated rats (1-hour sacrifice) at the low, medium, and high
dose levels, respectively.  The amount of radioactivity in the blood,
carcass, urine and other organs totaled <2% of the applied dose.  The
results of this study (2% dermal absorption) can be used for risk
assessment purposes.

Hexythiazox (128849)	Human-Health Risk Assessment	D345087

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