Document ID: EPA-HQ-OPP-2007-0309-0004
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-12-26T05:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF

PREVENTION, PESTICIDES, AND

TOXIC SUBSTANCES

MEMORANDUM

DATE:	 	14-NOV-2007

SUBJECT:	PP#: 6E7150.  REVISED:  Etoxazole in/on Cherries, Hops, and
Melon Subgroup 9A.  Health Effects Division (HED) Risk Assessment.  PC
Code: 107091.  DP#: 341209.  Decision#: 373129.

		DP#: 346198.  Decision#: 373129.

FROM:	Sarah J. Levy, Chemist

Registration Action Branch 1 (RAB1)/HED (7509P)

THRU:	Dana Vogel, Branch Chief

RAB1/HED (7509P)

TO:		Sidney Jackson/Daniel Rosenblatt, PM Team 05

Registration Division (RD, 7505P)

This memorandum supersedes the previous document (DP#: 341209). 

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 proposed uses of etoxazole
[2-(2,6-difluorophenyl)-4-[4-(1,1-dimethylethyl)-2-ethoxyphenyl]-4,5-dih
ydrooxazole] on cherries, hops, and melon subgroup 9A.

A summary of the findings and an assessment of human risk resulting from
the proposed uses of etoxazole is provided in this document.  The risk
assessment was provided by Jennifer Tyler and Sarah Levy (RAB1), the
residue chemistry review and dietary exposure assessment by Jennifer
Tyler (RAB1), the hazard characterization by P.V. Shah (RAB1), the
occupational/residential exposure assessment by Mark Dow (RD), and the
drinking water assessment by José Melendez of the Environmental Fate
and Effects Division (EFED).

NOTE:  A human-health risk assessment was completed on 3/30/05 in
conjunction with a request for the use of etoxazole on grapes and tree
nuts, including pistachios (Memo, J. Tyler, et al., D314515).  In this
memo, dietary, occupational and aggregate risks were re-evaluated based
on the addition of cherries, hops and melon subgroup 9A, to the
etoxazole use pattern.

Recommendation for Tolerances and Registration:  Provided a revised
Section F is submitted, the residue chemistry, toxicology and
occupational databases support the establishment of the following:

Unconditional registration and permanent tolerances for residues of
etoxazole per se in/on the following RACs:  cherry (1.0 ppm); and
vegetable, cucurbit subgroup 9A (0.20 ppm).  

Conditional registration and permanent tolerance for residues of
etoxazole per se in/on hop, dried, cones at 7.0 ppm.  The registration
should be made unconditional upon submission of additional residue data
on hops as follows:  1 trial each at 2 x 0.198 = 0.396 lb ai/A
(exaggerated application rate, PHI = 7 days) and one at 0.180 lb ai/A
(proposed application rate, PHI = 7 days), 4 samples per trial.  As R3
is a metabolite of concern in cotton gin byproducts, and a metabolism
data are not available for hops, R3 is a potential residue of concern
for this crop.  Therefore, the requested side-by-side hop field trials
should include data for R3, as well as the parent.  Subsequent to the
submission of these data, HED will make a determination as to whether or
not R3 is a residue of concern in hops.Table of Contents

  TOC \o "1-3" \u  1.0	EXECUTIVE SUMMARY	  PAGEREF _Toc182041410 \h  4 

2.0	PHYSICAL/CHEMICAL PROPERTIES CHARACTERIZATION	  PAGEREF
_Toc182041411 \h  7 

2.1	Structure and Nomenclature	  PAGEREF _Toc182041412 \h  7 

2.2.	Physical and Chemical Properties	  PAGEREF _Toc182041413 \h  7 

3.0	HAZARD CHARACTERIZATION	  PAGEREF _Toc182041414 \h  8 

3.1	Hazard Profile	  PAGEREF _Toc182041415 \h  8 

3.2	FQPA Considerations	  PAGEREF _Toc182041416 \h  11 

3.3	Dose-Response Assessment	  PAGEREF _Toc182041417 \h  12 

3.4	Endocrine Disruption	  PAGEREF _Toc182041418 \h  15 

4.0	EXPOSURE ASSESSMENT	  PAGEREF _Toc182041419 \h  16 

4.1	Summary of Registered and Proposed Uses	  PAGEREF _Toc182041420 \h 
16 

4.2	Dietary Exposure/Risk Pathway	  PAGEREF _Toc182041421 \h  17 

4.2.1	Residue Profile	  PAGEREF _Toc182041422 \h  17 

4.2.2	Chronic Dietary Exposure Analysis	  PAGEREF _Toc182041423 \h  20 

4.3	Water Exposure/Risk Pathway	  PAGEREF _Toc182041424 \h  21 

4.4	Residential Exposure/Risk Pathway	  PAGEREF _Toc182041425 \h  22 

4.4.1	Non-occupational Off-Target Exposure	  PAGEREF _Toc182041426 \h 
22 

5.0	AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION	  PAGEREF
_Toc182041427 \h  23 

6.0	CUMULATIVE RISK	  PAGEREF _Toc182041428 \h  23 

7.0	OCCUPATIONAL EXPOSURE	  PAGEREF _Toc182041429 \h  23 

7.1	Occupational Handler	  PAGEREF _Toc182041430 \h  24 

7.2	Occupational Post-application Exposure	  PAGEREF _Toc182041431 \h 
25 

7.3	Incidents	  PAGEREF _Toc182041432 \h  26 

8.0	DATA NEEDS/LABEL REQUIREMENTS	  PAGEREF _Toc182041433 \h  26 

8.1	Residue Chemistry	  PAGEREF _Toc182041434 \h  26 

8.2	Toxicology	  PAGEREF _Toc182041435 \h  26 

8.3	ORE	  PAGEREF _Toc182041436 \h  26 

9.0	ATTACHMENT	  PAGEREF _Toc182041437 \h  26 

 

1.0	EXECUTIVE SUMMARY tc \l1 "1.0	EXECUTIVE SUMMARY 

The Interregional Research Project Number 4 (IR-4) has submitted a
petition proposing uses for etoxazole, formulated as Zeal® Wettable
Powder (WP; EPA Reg. No. 59639-123) and Secure® WP (EPA Reg. No.
59639-138) on cherries, hops, and melon subgroup 9A.  The petitioner has
proposed the establishment of permanent tolerances for etoxazole
residues of 0.70 ppm in/on cherries; 7.0 ppm in/on hop, dried cones; and
1.5 ppm in/on melon, subgroup 9A.

Etoxazole is a contact acaricide/ovicide that is currently registered in
the United States (U.S.) for the control of mites on various raw
agricultural commodities (RACs).  Permanent tolerances have been
established for residues of etoxazole in/on various plant and livestock
commodities (40 CFR §180.593).  There are currently no registered or
proposed residential uses of etoxazole.

Hazard Assessment:  Etoxazole has low acute toxicity via the oral,
dermal, and inhalation routes. It is not an eye or dermal irritant or a
dermal sensitizer.  No systemic toxicity was seen at the limit dose in a
28-day dermal toxicity study in rats.  The liver is the main target
organ in mice, rats and dogs.   In a 90-day toxicity study in dogs,
increased liver weights and centrilobular hepatocellular swelling in the
liver were observed.  Similar effects were observed in a chronic
toxicity study in dogs at similar doses, indicating that the systemic
effects (mainly liver effects) occur at similar dose levels following
short-through long-term exposure without increasing in severity.  In a
90-day toxicity study in mice, hepatotoxicity, such as increased
relative liver weight, liver enlargement, and centrilobular
hepatocellular swelling, was observed at high doses (878 mg/kg/day). 
Similar effects were observed at the highest dose tested (HDT) in a
mouse carcinogenicity study.  No toxicity was observed at the 241
mg/kg/day dose level in a carcinogenicity study in mice.  Subchronic and
chronic toxicity studies in rats also produced similar effects
(increased liver weights, centrilobular hepatocellular swelling, etc.)
as seen in mice and dogs.  In addition, slight increases in thyroid
weights and elongated incisors were observed in the subchronic and
chronic toxicity study in rats at high doses and at terminal stages of
the study.

There is no evidence of neurotoxicity in any study.  No quantitative or
qualitative evidence of increased susceptibility was seen following in
utero exposure to rats or rabbits in developmental studies.  Offspring
toxicity was more severe (pup mortality) than maternal toxicity
(increased liver and adrenal weights) at the same dose in the rat
reproduction study.  The two mouse carcinogenicity studies showed no
evidence of carcinogenicity up through the HDT.  Two carcinogenicity
studies in rats are available.  Dosing was inadequate for
carcinogenicity testing in one study.  In an unacceptable study, benign
interstitial cell tumors (testis) at 104 weeks and pancreas benign islet
cell adenomas were observed in female rats at 104 weeks at the high
dose.  These effects were not seen in a repeat study at higher doses in
rats.  The Hazard Identification Assessment Review Committee (HIARC)
classified etoxazole as “not likely” to be carcinogenic. Etoxazole
is not mutagenic.  Etoxazole was rapidly absorbed from the
gastrointestinal (G.I.) tract of rats following oral dosing.  There were
no major sex-related difference in the pattern of excretion.  Fecal
excretion is the primary route of elimination and excretion was
essentially complete within 120 hours of dosing.  The major component in
the feces was the parent compound.

Dose-Response Assessment and Food Quality Protection Act (FQPA)
Decision:  The HED HIARC met on 2/4/03 to select endpoints for risk
assessment and to evaluate the potential for increased susceptibility of
infants and children from exposure to etoxazole according to the
February 2002 OPP 10X guidance document.  The FQPA Safety Factor (SF)
was reduced to 1x based on toxicological considerations by HIARC (Memo,
PV Shah, 3/19/03; TXR No. 0051659), the conservative residue assumptions
used in the dietary exposure and risk assessment, the completeness of
the residue chemistry and environmental fate databases and the lack of
the potential for residential exposures (evaluated by the risk
assessment team).

Risk assessments were conducted for the specific exposure scenarios
listed below.  The chronic reference dose (cRfD) was calculated by
dividing the no-observable-adverse-effect-level (NOAEL) by the
uncertainty factors totaling 100 (10X for interspecies extrapolation and
10X for intraspecies variation).  Since the FQPA SF has been reduced to
1X, the chronic population- adjusted dose (cPAD) is equal to the cRfD. 
Since an oral study was selected for all durations of inhalation
exposure, a 100% inhalation-absorption factor was used in the
route-to-route extrapolation.  The level of concern for occupational
inhalation exposures is for margins of exposure (MOEs) <100.  The RAB1
risk assessment team re-evaluated the decisions made by the Committees
and deemed that all previous conclusions remain appropriate.

Exposure Scenario	

Dose	

Endpoint	

Study/Effect

Chronic Dietary	

NOAEL = 4.62 mg/kg/day	

cRfD and cPAD = 0.046 mg/kg/day	

Chronic Oral Toxicity Study - Dog/Increased alkaline phosphatase
activity, increased liver weights, liver enlargement (females), and
incidences of centrilobular hepatocellular swelling in the liver at a
lowest-observable-adverse-effect-level (LOAEL) of 23.5 mg/kg/day.

Inhalation

(All Durations)	

NOAEL = 4.62 mg/kg/day	

Target MOE = 100 (occupational)	

Chronic Oral Toxicity Study - Dog/Increased alkaline phosphatase
activity, increased liver weights, liver enlargement (females), and
incidences of centrilobular hepatocellular swelling in the liver at a
LOAEL of 23.5 mg/kg/day.

Dietary Exposure Estimates:  An unrefined, chronic dietary exposure
assessment [using HED-calculated residues of concern (parent and
metabolites of concern) for livestock commodities and HED-recommended
tolerance-level residues for all other commodities; 100% crop treated
(CT) information for all commodities; modified processing factors for
apple juice, grape juice and raisins and default factors for all other
processed commodities] was conducted for the general U.S. population and
various population subgroups using the Dietary Exposure Evaluation Model
software with the Food Commodity Intake Database (DEEM-FCID(, Version
2.03).  Drinking water was incorporated directly in the dietary
assessment using the chronic concentration for surface water generated
by the FQPA Index Reservoir Screening Tool (FIRST) model.  The chronic
dietary exposure estimates are not of concern to HED (<100% cPAD) for
the general U.S. population (1.6% cPAD) and all population subgroups
(the most highly exposed population subgroup is children 1-2 years old
at 8.3% cPAD).

Aggregate Exposure Scenarios and Risk Conclusions:  A chronic aggregate
(food + drinking water) risk assessment was conducted.  An acute
aggregate risk assessment was not performed because an endpoint of
concern attributable to a single oral dose was not selected for any
population subgroup (including infants and children).  Short- and
intermediate-term aggregate risk assessments were not performed because
there are no registered or proposed residential non-food uses.  A cancer
aggregate risk assessment was not performed because etoxazole is not
carcinogenic.  The chronic aggregate exposure and risk estimates do not
exceed HED's level of concern.

Occupational Exposure Estimates:  HED assessed occupational handler and
post-application risks for etoxazole.  Based on the proposed use
patterns, short- and intermediate-term inhalation exposures are expected
for commercial and private applicators.  The most highly exposed
occupational workers are expected to be mixer/loaders using wettable
powders, and applicators using groundboom and airblast equipment. 

No chemical-specific data are available with which to assess potential
exposure to pesticide handlers; therefore, estimates of exposure are
based on data available in the Pesticide Handler Exposure Database
Version 1.1 (PHED Surrogate Exposure Guide, 8/98).  Exposure/risks for
short- and intermediate-term inhalation handler mixer/loader exposures
were presented at baseline (workers wearing a single layer of work
clothing consisting of a long-sleeved shirt, long pants, shoes plus
socks and no protective gloves).  All occupational handler MOEs are >100
with baseline personal protective equipment (PPE) and, therefore, are
not of concern to HED (i.e., MOE >100).

There is typically concern for post-application exposures of
agricultural workers to dislodgeable pesticide residues.  In the case of
etoxazole, the HIARC did not identify dermal toxicological endpoints of
concern.  Therefore, dermal post-application risks were not assessed. 
There is a 12 hour restricted entry interval (REI) for etoxazole.  The
vapor pressure of etoxazole is 7.0 x 10-6 Pascals @ 25(C.  Based upon
the REI and the low vapor pressure, HED believes post-application
exposure to agricultural workers via the inhalation route is negligible
and was not assessed.  Therefore, an assessment of post-application
exposure is not necessary.

Etoxazole is classified in Acute Toxicity Category III for acute dermal
and inhalation and Category IV for primary eye irritation and primary
skin irritation.  It is not a dermal sensitizer.  Therefore, the interim
worker protection standard (WPS) REI of 12 hours is adequate to protect
agricultural workers.  The SecureTM and ZealTM labels list a 12-hour
REI.  

Recommendation for Tolerances and Registration:  Provided a revised
Section F is submitted, the residue chemistry, toxicology and
occupational databases support the establishment of the following:

Unconditional registration and permanent tolerances for residues of
etoxazole per se in/on the following RACs:  cherry (1.0 ppm); and
vegetable, cucurbit subgroup 9A (0.20 ppm).

Conditional registration and permanent tolerance for residues of
etoxazole per se in/on hop, dried, cones at 7.0 ppm.  The registration
should be made unconditional upon submission of additional residue data
on hops as follows:  1 trial each at 2 x 0.198 = 0.396 lb ai/A
(exaggerated application rate, PHI = 7 days) and one at 0.180 lb ai/A
(proposed application rate, PHI = 7 days), 4 samples per trial.  As R3
is a metabolite of concern in cotton gin byproducts, and a metabolism
data are not available for hops, R3 is a potential residue of concern
for this crop.  Therefore, the requested side-by-side hop field trials
should include data for R3, as well as the parent.  Subsequent to the
submission of these data, HED will make a determination as to whether or
not R3 is a residue of concern in hops.

2.0	PHYSICAL/CHEMICAL PROPERTIES CHARACTERIZATION tc \l1 "2.0
PHYSICAL/CHEMICAL PROPERTIES CHARACTERIZATION 

2.1	Structure and Nomenclature tc \l2 "2.1	Structure and Nomenclature  

 

Common name	Etoxazole

Company experimental names	S-1283, V-1283, YI-5301

IUPAC name
(RS)-5-tert-butyl-2-[2-(2,6-difluorophenyl)-4,5-dihydro-1,3-oxazol-4-yl]
phenetole

CAS name
2-(2,6-difluorophenyl)-4-[4-(1,1-dimethylethyl)-2-ethoxyphenyl]-4,5-dihy
drooxazole

CAS #	153233-91-1

End-use products/EP	72% WDG (Zeal® WP Miticide and Secure™ Miticide)

2.2.	Physical and Chemical Properties tc \l2 "2.2	Physical and Chemical
Properties  

Table 2.2. 	Physicochemical Properties of Etoxazole (Technical Gracde
Active Ingredient (TGAI)).

Parameter	Value	References

Melting range	101.5-102.5(C	46018505.der.wpd

pH	6.2

	Density	1.2389 g/cm3

	Water solubility 	3.99 x 10-5 at 10(C

7.04 x 10-5 at 20(C

6.69 x 10-5 at 30(C

	Solvent solubility (g/L at 20(C)	acetone: 309		1,2-dichloroethane: 402

ethyl acetate: 249		n-heptane: 18.7

methanol: 104		xylene: 252

	Vapor pressure at 25(C	7.0 x 10-6 pascals

	Dissociation constant (pKa)	no measurable pKa

	Octanol/water partition coefficient Log(KOW)	5.52 ± 0.58 at 20(C

	UV/visible absorption	Not available.

	

Note that all property values are given at 20(C unless noted otherwise. 
Etoxazole is a solid at room temperature with a low vapor pressure;
thus, any losses due to volatilization/sublimation are expected to be
minimal.

3.0	HAZARD CHARACTERIZATION tc \l1 "3.0	HAZARD CHARACTERIZATION 

The existing toxicological database for etoxazole supports the
establishment of permanent tolerances for residues of etoxazole in/on
the raw agricultural and livestock commodities resulting from the
proposed uses.  On 2/4/03, the HED HIARC reviewed the recommendations of
the toxicology reviewer for etoxazole with regard to the acute and
chronic RfDs and the toxicological endpoint selection for use as
appropriate in occupational/residential exposure risk assessments.  The
potential for increased susceptibility of infants and children from
exposure to etoxazole was also evaluated as required by the FQPA of 1996
(Memo, PV Shah, 3/19/03; TXR No. 0051659).  

3.1	Hazard Profile tc \l2 "3.1	Hazard Profile 

Etoxazole has low acute toxicity via the oral, dermal, and inhalation
routes.  It is not an eye or dermal irritant or a dermal sensitizer.  No
toxicity was seen at the limit dose in a 28-day dermal toxicity study in
rats.  The liver is the main target organ in mice, rats and dogs.  In a
90-day toxicity study in dogs, increased liver weights and centrilobular
hepatocellular swelling in the liver were observed.  Similar effects
were observed in a chronic toxicity study in dogs at similar doses,
indicating that the systemic effects (mainly liver effects) occur at
similar dose levels following short-through long-term exposure without
increasing in severity.  In a 90-day toxicity study in mice,
hepatotoxicity, such as increased relative liver weight, liver
enlargement, and centrilobular hepatocellular swelling, were observed at
high doses (878 mg/kg/day).  Similar effects were observed at the HDT in
a mouse carcinogenicity study.  No toxicity was observed at 241
mg/kg/day dose level in a carcinogenicity study in mice.  Subchronic and
chronic toxicity studies in rats also produced similar effects
(increased liver weights, centrilobular hepatocellular swelling, etc.)
as seen in mice and dogs.  In addition, slight increases in thyroid
weights and elongated incisors were observed in subchronic and chronic
toxicity study in rats at high doses and at terminal stages of the
study.

There is no evidence of neurotoxicity in any study.  No quantitative or
qualitative evidence of increased susceptibility was seen following in
utero exposure to rats or rabbits in developmental studies.  Offspring
toxicity was more severe (pup mortality) than maternal toxicity
(increased liver and adrenal weights) at the same dose in the rat
reproduction study.  The two mouse carcinogenicity studies showed no
evidence of carcinogenicity up through the HDT.  Two carcinogenicity
studies in rats are available.  Dosing was inadequate for
carcinogenicity testing in one study.  In an unacceptable study, benign
interstitial cell tumors (testis) at 104 weeks and pancreas benign islet
cell adenomas were observed in female rats at 104 weeks at the high
dose.  These effects were not seen in a repeat study at higher doses in
rats.  HIARC classified etoxazole as “not likely” to be
carcinogenic.  This decision was based on weight of evidence such as the
lack of carcinogenicity in two studies in mice, lack of carcinogenicity
in one study in rats, and the lack of hormonal and reproductive effects
in special studies.  Etoxazole is not mutagenic.

Etoxazole was rapidly absorbed from the G.I. tract of rats following
oral dosing.  There were no major sex-related differences in the pattern
of excretion.  Fecal excretion is the primary route of elimination and
excretion was essentially complete within 120 hours of dosing.  The
major component in the feces is the parent compound.

Table 3.1.	Acute Toxicity Profile of Etoxazole TGAI.

Guideline No.	Study Type	MRID	Results	Toxicity Category

81-1	Acute Oral (rat)	45089919	LD50 > 5000 mg/kg	IV

81-2	Acute Dermal	45089921	LD50 > 2000 mg/kg	III

81-3	Acute Inhalation	45089923	LC50 > 1.09 m/L	III

81-4	Primary Eye Irritation	45089925	Not an eye irritant	IV

81-5 	Primary Skin Irritation	45089927	Not a dermal irritant	IV

81-6	Dermal Sensitization	45089929	Not a dermal sensitizer	N/A

Table 3.2.	Toxicity Profile of Etoxazole TGAI.

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

870.3100

90-Day oral toxicity rodents (rat)	45089935, 45089934 (1995)

Acceptable/guideline

0, 100, 300, 1000 or 3000 ppm

M: 0, 6.12, 18.28, 61.8 or 183.7 mg/kg/day 

F: 0, 6.74, 20.50, 69.0 or 204.8 mg/kg/day	NOAEL = 61.8/69.0 mg/kg/day
(M/F)

LOAEL = 183.7/204.8 mg/kg/day (M/F), based upon increases in hepatic
enzyme levels, increased liver weights and centrilobular hepatocellular
swelling in both sexes and liver enlargement in females only.

870.3100

90-Day oral toxicity rodents (rat)	45089931 (1998)

Acceptable/guideline

0, 5000 or 10000 ppm

M: 0, 300.4 or 610 mg/kg/day 

F: 0, 336.6 or 692 mg/kg/day	NOAEL = not determined

LOAEL = 300.4/336.6 mg/kg/day (M/F), based upon clinical signs, clinical
chemistry, increased liver weights, and histopathology.

870.3100

90-Day oral toxicity rodents (mouse)	45089936 (1994), 45089938 (1992)

Acceptable/guideline

0, 100, 400, 1600 or 6400 ppm

M: 0, 13.42, 55.13, 213.6 or 878.4 mg/kg/day 

F: 0, 15.15, 62.00, 250.5 or 994.5 mg/kg/day	NOAEL = 213.6/250.5
mg/kg/day (M/F)

LOAEL = 878.4/994.5 mg/kg/day (M/F), based upon periportal
hepatocellular necrosis, increased alkaline phosphatase levels,
accompanied by increased relative liver weight, liver enlargement, and
centrilobular hepatocellular swelling.

870.3150

90-Day oral toxicity in nonrodents (dog)	45089933 (1995), 45089932
(1992)

Acceptable/guideline

 0, 200, 2000 or 10000 ppm

M: 0, 5.33, 53.7 or 268 mg/kg/day

F: 0, 5.42, 55.9 or 277  mg/kg/day	NOAEL = 5.33/5.42 mg/kg/day (M/F)

LOAEL = 53.7/55.9 mg/kg/day (M/F), based upon clinical signs (vomiting
foamy fluid and mucous stool), clinical chemistry, increased liver
weights, and centrilobular swelling in the liver and acinar cell atrophy
in the prostate.

870.3200

21/28-Day dermal toxicity (rabbit)	45089941 (1999)

Acceptable/guideline

M & F: 0 or 1000 mg/kg/day	NOAEL = 1000 mg/kg/day (M/F)

LOAEL = not determined

No systemic effects noted

870.3250

90-Day dermal toxicity	NA	NA

870.3465

90-Day inhalation toxicity	NA	NA

870.3700a

Prenatal developmental toxicity in rodents (rat)	45090005 (1994),
45090004 (1993)

Acceptable/guideline

F: 0, 40, 200 or 1000 mg/kg/day	Maternal NOAEL = 1000 mg/kg/day

LOAEL = not determined

Developmental NOAEL = 1000 mg/kg/day

LOAEL = not determined

870.3700b

Prenatal developmental toxicity  in nonrodents (rabbit)	45090003,
45090002 (1994) Acceptable/guideline

F: 0, 40, 200 or 1000 mg/kg/day	Maternal NOAEL = 200 mg/kg/day

LOAEL = 1000 mg/kg/day based upon liver enlargement and decreased body
weight gains and food consumption.

Developmental NOAEL = 200 mg/kg/day

LOAEL = 1000 mg/kg/day based upon increased incidences of 27 presacral
vertebrae and 27 presacral vertebrae with 13th ribs in the fetuses

870.3800

Reproduction and fertility effects (rat)	45090007 (1996), 45090006
(1993)

Acceptable/guideline

0, 80, 400 or 2000 ppm

M & F: 0, 4, 20 or 100 mg/kg/day	Parental/Systemic NOAEL = 20 mg/kg/day

LOAEL = 100 mg/kg/day (M/F), based upon increased liver weights in the P
and  F1 males and increased adrenal weights in the P females

Offspring/Systemic NOAEL = 20 mg/kg/day

LOAEL = 100 mg/kg/day (M/F), based upon pup mortality

Reproductive NOAEL = 100 mg/kg/day

LOAEL = not determined

870.4300

Combined chronic toxicity/ carcinogenicity rodents (rat)	45250903,
45089937 (1996)

Unacceptable/guideline

0, 4, 16 or 64 mg/kg/day nominal M: 0, 4.01, 16.1 or 64.4 mg/kg/day

F: 0, 4.03, 16.1 or 64.5 mg/kg/day	NOAEL = 64 mg/kg/day (M/F)

LOAEL = not determined

Equivocal evidence of carcinogenicity

870.4300

2-Year feed/carcinogenic (rat)	45571802 (2001)

Acceptable/guideline

0, 50, 5000, 10000 ppm

M/F: 0/0, 1.83/2.07, 187/216, 386/445 mg/kg/day	NOAEL = 1.83/2.07
mg/kg/day (M/F)

LOAEL =  187/216 (M/F), based upon effects on the incisors including
abnormal amelogenesis.

No evidence of carcinogenicity

870.4100b

Chronic toxicity nonrodents (dog)	45089942 (1996)

Acceptable/guideline

0, 200, 1000 or 5000 ppm

M: 0, 4.62, 23.5 or 116 mg/kg/day

F: 0, 4.79, 23.8 or 117 mg/kg/day	NOAEL = 4.62/4.79 mg/kg/day (M/F)

LOAEL = 23.5/23.8 mg/kg/day (M/F), based upon increased alkaline
phosphatase activity, increased liver weights, liver enlargement
(females), and incidences of centrilobular hepatocellular swelling in
the liver.

78-Week Carcinogenic Mouse	45571801  (2001)

Acceptable/guideline

0, 2250, 4500 ppm

M/F: 0/0, 242/243, 484/482 mg/kg/day	NOAEL = 242/243 (M/F)

LOAEL = 484/482 (M/F), based on a slight increase in the incidence of a
fatty change in the centrilobular hepatocytes in males.

870.4200b

Carcinogenicity mouse	45090001 (1996)

Unacceptable/guideline

0, 15, 60 or 240 ppm 

M: 0, 15.1, 60.1 or 241 mg/kg/day

F: 0, 15.1, 60.5 or 243 mg/kg/day	NOAEL = 241/243 mg/kg/day (M/F)

LOAEL = not determined

No evidence of carcinogenicity

Non-guideline

13-week study: Effect on proliferative activity of testicular
interstitial cells in rat	45089939 (1996)

Acceptable/non-guideline

0 or 3000 ppm

Test performed in conjunction with subchronic oral toxicity test in rats
(MRID 45089935)	A toxic level of the test substance did not affect the
proliferative activity of testicular interstitial cells.

Gene Mutation

870.5100

reverse gene mutation assay in bacteria	45250905 (1992)

Acceptable/guideline	When tested up to cytotoxic levels, there was no
evidence of induced mutant colonies over background.

Gene Mutation

Non-guideline

reverse gene mutation assay in bacteria	45090015 (1999)

Acceptable/non-guideline	When tested up to cytotoxic levels, there was
no evidence of induced mutant colonies over background.

Gene Mutation 

870.5300

in vitro forward gene mutation assay in mouse lymphoma cells	45090013
(1996)

Acceptable	When tested up to cytotoxic levels, mutagenic in the presence
of S9 activation and equivocal for mutagenicity in the absence of S9
activation.

Cytogenetics 

870.5375

in vitro mammalian cytogenetics assay 	45250904 (1994)

Acceptable/guideline	When tested up to cytotoxic levels, not clastogenic
in the presence or absence of S9 activation.

870.5395

bone marrow micronucleus assay 	45090010 (1996)

Acceptable	There was no significant increase in the frequency of
micronucleated polychromatic erythrocytes in bone marrow after any
treatment time.

870.5550

unscheduled DNA synthesis in primary rat hepatocytes/ mammalian cell
cultures	45090014 (1997)

Acceptable

	When tested up to cytotoxic levels, there was no evidence that
unscheduled DNA synthesis was induced by the test substance.

870.7600

Dermal penetration	NA	NA

3.2	FQPA Considerations tc \l2 "3.2	FQPA Considerations 

On 2/4/03, HIARC evaluated the potential for increased susceptibility of
infants and children from exposure to etoxazole according to the
February 2002 OPP 10X guidance document (Memo, PV Shah, 3/19/03; TXR No.
0051659).  Since there is qualitative evidence of increased
susceptibility following exposure to etoxazole in the rat reproduction
study, HIARC performed a Degree-of-Concern Analysis to:  1) determine
the level of concern for the effects observed when considered in the
context of all available toxicity data; and 2) identify any residual
uncertainties after establishing toxicity endpoints and traditional
uncertainty factors to be used in the risk assessment of this chemical. 
If residual uncertainties were identified, HIARC examined whether these
residual uncertainties can be addressed by a FQPA safety factor and, if
so, the size of the factor needed.

There is evidence of increased qualitative susceptibility in the rat
reproduction study, but the concern is low since: 1) the effects in pups
are well-characterized with a clear NOAEL; 2) the pup effects occur at
the same dose as maternal toxicity; and, 3) the doses selected for
various risk assessment scenarios are lower than the doses that caused
off spring toxicity.  Therefore, there are no residual uncertainties for
pre-/post-natal toxicity in this study.

Based on the hazard data, HIARC recommended the FQPA SF be reduced to
1X.  The etoxazole risk assessment team evaluated the quality of the
exposure data; and, based on these data, recommended that the FQPA SF be
reduced to 1X.  The recommendation is based on the following:

The toxicological database is complete for FQPA assessment.

The chronic dietary food exposure assessment utilizes HED-calculated
residues of concern (parent and metabolites for livestock commodities;
tolerance-level residues for pome fruit, cottonseed, strawberries and
tangerines; and 100% CT information for all proposed uses.  By using
these screening-level assumptions, actual exposures/risks will not be
underestimated.

The dietary drinking water assessment utilized modeling results which
included conservative assumptions for the parent and all degradates of
concern.  Since conservative assumptions were used in the water models
where environmental fate data are lacking, the water exposure assessment
will not underestimate the potential risks for infant and children.

There are no registered or proposed residential uses for etoxazole.

3.3	Dose-Response Assessment tc \l2 "3.3	Dose-Response Assessment 

Acute Dietary Endpoint:  An endpoint of concern attributable to a single
oral dose was not selected for either the general U.S. population
(including infants and children) or the females 13-50 years old
population subgroup for etoxazole; therefore, an acute dietary exposure
analysis was not performed.  The HIARC evaluated the suitability of the
developmental toxicity study in rabbits in which the developmental NOAEL
of 200 mg/kg/day is based upon increased incidences of 27 presacral
vertebrae and 27 presacral vertebrae with 13th ribs (skeletal
variations) in the fetuses at the LOAEL of 1000 mg/kg/day (limit dose). 
Although these developmental effects may be attributed to a single dose,
the HIARC concluded that these effects are minor in magnitude and were
observed only at the limit dose (1000 mg/kg/day).  Therefore,
quantitation of the acute risk is not required.

Chronic Dietary Endpoint:  The chronic oral toxicity study in dogs was
used to select the dose and endpoint for establishing the cRfD of 0.046
mg/kg/day for the general U.S. population and all population subgroups. 
The NOAEL of 4.62 mg/kg/day was based upon increased alkaline
phosphatase activity, increased liver weights, liver enlargement
(females), and incidences of centrilobular hepatocellular swelling in
the liver at the LOAEL of 23.5 mg/kg/day.  A 100-fold uncertainty factor
(10X for interspecies extrapolation and 10X for intraspecies variation)
was incorporated into the cRfD.  The dog is the most appropriate species
for chronic dietary exposure to etoxazole.  The rat is a better model
for incisor evaluation compared to dog.  The two combined chronic
toxicity/carcinogenicity rat studies together (MRIDs 45571802 and
45250903) show that the NOAEL for chronic exposure to etoxazole in adult
rats is at least 64 mg/kg/day, and the NOAEL in the rat reproduction
study for all effects (systemic, reproductive and off spring toxicity)
is 20 mg/kg/day.  In a separate combined chronic
toxicity/carcinogenicity study in rats (MRID 45250903), no elongated
incisors were seen at 64 mg/kg/day, the HDT.  In a rat chronic toxicity
study (MRID 45571802), elongated incisors were observed at a dose level
of 216 mg/kg/day and above (LOAEL) with a NOAEL of 2.07 mg/kg/day. 
Although the NOAEL in the chronic rat study is lower, it was not
selected because the lower NOAEL is an artifact of the study dose
selection; there is a 100-fold difference between the NOAEL (2.07
mg/kg/day) and the LOAEL (216 mg/kg/day).  When there is such a wide
gap, the true NOAEL could substantially be higher than the study NOAEL. 
Therefore, the chosen study in dogs with a NOAEL of 4.62 mg/kg/day would
be protective of incisors and other effects seen in rats and provide the
most conservative dose for the cRfD.  This study provides the lowest
NOAEL in the database.  The study duration and the endpoint are
appropriate for this exposure duration and route.  The FQPA SF of 1X is
applicable for the chronic dietary risk assessment.  Thus, the cPAD is
0.046 mg/kg/day. The standard 100 UF was applied to account for
interspecies extrapolation and intraspecies variation.  The FQPA SFC
determined that a FQPA SF of 1x is applicable for chronic dietary risk
assessment.  Thus, the cPAD is equivalent to the cRfD of 0.046 mg/kg.

Carcinogenicity:  The HIARC classified etoxazole as “not likely to be
carcinogenic to humans” according to EPA Proposed Guidelines for
Carcinogen Risk Assessment (April 10, 1996).

Short- and Intermediate-Term Incidental Oral Endpoints:  Short- and
intermediate-term incidental oral endpoints were selected from the
chronic oral toxicity study in dogs.  The NOAEL of 4.62 mg/kg/day was
chosen based upon increased alkaline phosphatase activity, increased
liver weights, liver enlargement (females), and incidences of
centrilobular hepatocellular swelling in the liver at the LOAEL of 23.5
mg/kg/day.  The weight-of-the-evidence from the 28-day, 90-day, 52-week
interim chronic toxicity/carcinogenicity and the 2-year chronic
toxicity/carcinogenicity rat studies shows that the systemic effects
(mainly in the liver) occur around the same dose levels from short-
through long-term exposure without increasing in severity.  Since the
dog is the most sensitive species tested and the subchronic and chronic
dog studies appear to have the same effects at similar doses, it is
expected that a subchronic dog study would have the same effects at
similar doses also.  This study and endpoints are appropriate for the
population of concern (infants and children) and the route and durations
of exposure (1-30 days and 1-6 months).

Dermal Penetration:

Dermal-Absorption Factor:  No dermal absorption study was submitted.

Short-, Intermediate- and Long-Term Dermal Endpoints:  No hazard
quantitation is required for any duration.  No systemic effects were
noted up to 1000 mg/kg/day in the 28-day dermal rat study.  There are no
developmental or reproductive concerns.  The weight-of-the-evidence from
the 28-day, 90-day, 52-week interim chronic toxicity/carcinogenicity and
the 2-year chronic toxicity/carcinogenicity rat studies shows that the
systemic effects (mainly in the liver) occur around the same dose levels
from short- through long-term exposure without increasing in severity. 
Therefore, results of the 28-day dermal toxicity study can be applicable
to long-term exposure.

Short-, Intermediate, and Long-Term Inhalation Endpoints:  Short-,
intermediate-, and long-term inhalation endpoints were chosen from the
chronic oral toxicity study in dogs.  The NOAEL of 4.26 mg/kg/day was
chosen based upon increased alkaline phosphatase activity, increased
liver weights, liver enlargement (females), and incidences of
centrilobular hepatocellular swelling in the liver at the LOAEL of 23.5
mg/kg/day.  In the absence of an inhalation toxicity study, an oral
NOAEL was selected.  Absorption via the inhalation route is assumed to
be equivalent to oral absorption for the purpose of this risk
assessment.  The weight-of-the-evidence from the 28-day, 90-day, 52-week
interim chronic toxicity/carcinogenicity and the 2-year chronic
toxicity/ carcinogenicity rat studies shows that the systemic effects
(mainly in the liver) occur around the same dose levels from short-
through long-term exposure without increasing in severity.  Since the
dog is the most sensitive species tested and the subchronic and chronic
dog studies appear to have the same effects at similar doses, it is
expected that a short-term dog study would have the same effects at
similar doses also.  This study/endpoint is appropriate for the
population of concern (general population, including infants and
children) and the durations of exposure (1-30 days, 1-6 months, and >6
months).

MOE for Occupational/Residential Risk Assessments:  An MOE of 100 is
required for short-, intermediate-, and long-term occupational risk
assessment for the inhalation route of exposure.  This MOE is based on
the conventional uncertainty factor of 100X (10X for interspecies
extrapolation and 10X for intraspecies variation).

The doses and toxicological endpoints selected for various exposure
scenarios are summarized in Table 3.3.

Table 3.3.	Summary of Toxicological Dose and Endpoints for Etoxazole for
Use in Human Health Risk Assessment1

Exposure

Scenario	Dose Used in Risk Assessment, UF 	Special FQPA SF* and Level of
Concern for Risk Assessment	Study and Toxicological Effects

Acute Dietary

(Females 13-50 years of age)	NOAEL = None mg/kg/day

UF = N/A

Acute RfD = None	FQPA SF = 1x

aPAD = acute RfD

              FQPA SF

= None	A dose and endpoint attributable to a single dose were not
identified in the database including the developmental toxicity studies.

Acute Dietary

(General population including infants and children)	NOAEL = None
mg/kg/day

UF = N/A

Acute RfD = None	FQPA SF = 1x

aPAD = acute RfD

              FQPA SF

= None	A dose and endpoint attributable to a single dose were not
identified in the database including the developmental toxicity studies.

Chronic Dietary

(All populations)	NOAEL= 4.62 mg/kg/day

UF =100

Chronic RfD = 

0.046 mg/kg/day	FQPA SF = 1x

cPAD = 

chronic RfD

 FQPA SF

= 0.046 mg/kg/day	Chronic Oral Toxicity Study- Dog

LOAEL = 23.5 mg/kg/day based upon increased alkaline phosphatase
activity, increased liver weights, liver enlargement (females), and
incidences of centrilobular hepatocellular swelling in the liver.

Short-Term 

Incidental Oral (1-30 days)	NOAEL= 4.62 mg/kg/day	Residential LOC for
MOE = 100

Occupational = NA	Chronic Oral Toxicity Study- Dog

LOAEL = 23.5 mg/kg/day based upon increased alkaline phosphatase
activity, increased liver weights, liver enlargement (females), and
incidences of centrilobular hepatocellular swelling in the liver.

Intermediate-Term 

Incidental Oral (1- 6 months)

	NOAEL= 4.62 mg/kg/day	Residential LOC for MOE = 100

Occupational = NA	Chronic Oral Toxicity Study- Dog

LOAEL = 23.5 mg/kg/day based upon increased alkaline phosphatase
activity, increased liver weights, liver enlargement (females), and
incidences of centrilobular hepatocellular swelling in the liver.

Short-Term Dermal (1 to 30 days)	Dermal (or oral) study NOAEL= None
Residential LOC for MOE = N/A

Occupational LOC for MOE = N/A	No hazard quantitation required for any
duration.  No systemic effects noted up to 1000 mg/kg/day in the 28-day
dermal rat study.  There are no developmental or reproductive concerns.

Intermediate-Term

Dermal (1 to 6 months)	Dermal (or oral) study NOAEL =  None	Residential
LOC for MOE = N/A

Occupational LOC for MOE = N/A 	No hazard quantitation required for any
duration.  No systemic effects noted up to 1000 mg/kg/day in the 28-day
dermal rat study.  There are no developmental or reproductive concerns. 

Long-Term Dermal (>6 months)	Dermal (or oral) study NOAEL= None
Residential LOC for MOE = N/A

Occupational LOC for MOE = N/A	No hazard quantitation required for any
duration.  No systemic effects noted up to 1000 mg/kg/day in the 28-day
dermal rat study.  The weight-of-the-evidence from the 28-day, 90-day,
52-week interim chronic toxicity/carcinogenicity and the 2-year chronic
toxicity/carcinogenicity rat studies shows that the systemic effects
(mainly in the liver) occur around the same dose levels from short-
through long-term exposure without increasing in severity.  Therefore,
results of the 28-day dermal toxicity study can be applicable to
long-term exposure.

Short-Term Inhalation (1 to 30 days)	Oral study NOAEL= 4.62 mg/kg/day

(inhalation absorption rate = 100%)	Residential LOC for MOE = 100

Occupational LOC for MOE = 100 	Chronic Oral Toxicity Study- Dog

LOAEL = 23.5 mg/kg/day based upon increased alkaline phosphatase
activity, increased liver weights, liver enlargement (females), and
incidences of centrilobular hepatocellular swelling in the liver.

Intermediate-Term Inhalation (1 to 6 months)	Oral study NOAEL= 4.62
mg/kg/day

(inhalation absorption rate = 100%)	Residential LOC for MOE = 100

Occupational LOC for MOE = 100 	Chronic Oral Toxicity Study- Dog

LOAEL = 23.5 mg/kg/day based upon increased alkaline phosphatase
activity, increased liver weights, liver enlargement (females), and
incidences of centrilobular hepatocellular swelling in the liver.

Long-Term Inhalation (>6 months)	Oral study NOAEL= 4.62 mg/kg/day

(inhalation absorption rate = 100%)	Residential LOC for MOE = 100

Occupational LOC for MOE = 100 	Chronic Oral Toxicity Study- Dog

LOAEL = 23.5 mg/kg/day based upon increased alkaline phosphatase
activity, increased liver weights, liver enlargement (females), and
incidences of centrilobular hepatocellular swelling in the liver.

Cancer (oral, dermal, inhalation)

	The HIARC classified etoxazole as “not likely to be carcinogenic to
humans” according to EPA Proposed Guidelines for Carcinogen Risk
Assessment (April 10, 1996).

1 UF = uncertainty factor, FQPA SF = FQPA safety factor, NOAEL = no
observed adverse effect level, LOAEL = lowest observed adverse effect
level, PAD = population adjusted dose (a = acute, c = chronic) RfD =
reference dose, MOE = margin of exposure, LOC = level of concern, NA =
Not Applicable

3.4	Endocrine Disruption tc \l2 "3.4	Endocrine Disruption 

EPA is required under the Federal Food Drug and Cosmetic Act (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 the
recommendations of its Endocrine Disruptor Screening 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 has 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).

When the appropriate screening and/or testing protocols being considered
under the Agency’s EDSP have been developed, etoxazole may be
subjected to additional screening and/or testing to better characterize
effects related to endocrine disruption.

4.0	EXPOSURE ASSESSMENT tc \l1 "4.0	EXPOSURE ASSESSMENT 

4.1	Summary of Registered and Proposed Uses tc \l2 "4.1	Summary of
Registered and Proposed Uses 

Registered Uses:  Etoxazole [5% wettable granule (WG); EPA Reg. No.
59639-108], is currently registered to Valent U.S.A Corporation only for
use on greenhouse ornamentals.  Etoxazole, formulated as Secure(
Miticide (72% etoxazole; EPA Reg. No. 59639-107), is registered for use
in the U.S. on cotton, pome fruits, and strawberries.  The Borneo®
formulation (0.92 lb/gal; No EPA Reg. No.) is registered for use on
mandarin oranges in Japan, Korea, South Africa, France and Spain.

Proposed Uses:  Etoxazole is proposed for use on cherries, hops, and
melon, subgroup 9A.  IR-4 provided copies of the Zeal® WP (EPA Reg. No.
59639-123) and Secure® WP (EPA Reg. No. 59639-138) product labels. 
Etoxazole can be applied by ground equipment to the proposed crops.  The
proposed application rates, number of applications, application
interval, and pre-harvest interval vary by crop (see Table 4.1).

Table 4.1.  Summary of Proposed Directions for Use of Etoxazole.

Application, Timing, Type, and Equipment	Formulation

(EPA Reg. No.)	Application Rate

(lb ai/A)	Maximum Number Applications/Season	RTI (days)1	PHI

™ Miticide (59639-123)	0.09-0.135	0.135	1	-	7	A minimum application
volume of 50 gallon/A is recommended.

	Zeal® WP Miticide (59639-138)	0.09-0.135	0.135	1	-	7	A minimum
application volume of 50 gallon/A is recommended.

Hops

Broadcast foliar application; ground equipment.	Secure™ Miticide
(59639-123)	0.135-0.18	0.18	1	-	7	A minimum application volume of 50
gallon/A is recommended.

	Zeal® WP Miticide (59639-138)	0.135-0.18	0.18	1	-	7	A minimum
application volume of 50 gallon/A is recommended.

Melon Subgroup 9A

Broadcast foliar application; ground equipment.	Secure™ Miticide
(59639-123)	0.09-0.135	0.135	1	-	7	A minimum application volume of 50
gallon/A is recommended.

	Zeal® WP Miticide (59639-138)	0.09-0.135	0.135	1	-	7	A minimum
application volume of 50 gallon/A is recommended.

1.  RTI = minimum retreatment interval; PHI = minimum preharvest
interval.

2.  The proposed label does not include any rotational crop
restrictions.

HED Conclusions:  Although the submitted cherry, cantaloupe, and hop
crop field trials were conducted at exaggerated rates (~2x), HED
concludes that the data are adequate to support the proposed uses. 
However, the registration on hops should be conditional until additional
crop field trial data are submitted.

4.2	Dietary Exposure/Risk Pathway tc \l2 "4.2	Dietary Exposure/Risk
Pathway 

The residue chemistry data submitted in support of proposed petitions
were evaluated by HED on 11/14/07 (Memo, S. Levy, D346199).  The
drinking water assessment was completed by EFED on 4/24/07 (Memo, J.
Melendez, D335338).  The chronic dietary exposure assessment was
completed in a HED memorandum dated 06-NOV-2007 (Memo, S. Levy,
D346200).

4.2.1	Residue Profile tc \l3 "4.2.1	Residue Profile 

The qualitative nature of etoxazole residues in plants is understood
based upon the plant metabolism studies on cotton, eggplant, apple and
orange.  In each of the studies, the major 14C-residue in/on various
matrices was identified as parent compound.  Based on the metabolite
profiles observed in these studies, etoxazole may undergo
photo-oxidation to yield Metabolite R-13.  Parent and Metabolite R-13
then undergo opening of the oxazole ring to form a variety of
metabolites (R-4, R-7, R-14, and R-3), and subsequent cleavage of the
opened ring forms Metabolites DFB, R-8, R-10, R-11, R-12, and R-15.

Based on the above studies, the MARC (Memo, J. Tyler, 6/17/03; D289666)
concluded that parent is the only residue of concern in plant
commodities for purposes of the tolerance expression and risk
assessment.  However, for cotton gin byproducts, the risk assessment
should also include Metabolite R-3 (16.0-18.1% TRR).  In addition, based
on the results of the crop field trial on almonds, HED has determined
that Metabolite R-3 should also be included in the risk assessment for
almond hulls (Memo, J. Tyler, 3/30/05; D303628).  As etoxazole is
applied foliarly to both cotton and hops, and metabolism data are not
available for hops (or any other similar crop), HED is assuming that R3
is a potential residue of concern for this crop.  Therefore, the
requested side-by-side hop field trials should include data for R3, as
well as the parent.  Subsequent to the submission of these data, HED
will make a determination as to whether or not R3 is a residue of
concern in hops.

In the crop field trials submitted with the current petition, residues
of etoxazole were determined using modifications of previously submitted
gas chromatography (GC) with nitrogen-phosphorus detector (NPD) or
mass-selective detector (MSD) methods (Methods RM-37, or RM-37HM). 
These methods have been reviewed by HED and deemed adequate for data
collection.  The methods and any modifications were also adequately
validated in conjunction with the sample analyses.  In addition, the
current tolerance enforcement methods are adequate for enforcing the
proposed tolerances on the proposed tolerances.  The aforementioned
methods were forwarded to the Analytical Chemistry Laboratory (ACL) for
Agency PMVs (Memos, J. Tyler, 6/17/03; D290912 and D290914).  These
methods were deemed adequate by ACL for tolerance enforcement (personal
communication, C. Stafford to D. Vogel, 11/5/07).

Food and Drug Administration (FDA) multiresidue methods (MRMs) may be
used to determine residues of etoxazole in fatty and non-fatty matrices
and to determine residues of Metabolite R-3 in nonfatty matrices. 
Etoxazole was completely recovered from fortified samples of apple using
Methods 302, E1 with GC/NPD or Method 303, C1 or C2 with GC/NPD. 
Etoxazole was partially recovered from cottonseeds (fatty matrix) using
Method 304, E5, C1 or C2 with GC/NPD.  Metabolite R-3 could be
completely recovered from cotton gin byproducts using Method 302, E4
using GC/NPD.  However, matrix interferences enhanced the recoveries of
R-3 from gin byproducts.  The results of the MRM testing were forwarded
to the FDA for inclusion in the Pesticide Analytical Method (PAM) Vol. I
(Memo, J. Tyler, 6/17/03; D290919).

Adequate storage stability data are available to support the current
magnitude of the residue and processing studies.  The available hop
storage stability data are adequate to support crop field trial data. 
For cherries and cantaloupe, adequate storage stability data are
available; however, residue values were corrected in order to correct
for storage dissipation (64% and 67% for cherries and cantaloupe,
respectively).

The submitted cherry field trial data reflect a total of 2 foliar
applications of etoxazole (Zeal® 72 WDG) on tart and sweet cherries at
a rate of 0.135 pounds (lb) active ingredient (ai)/acre (A)/application
for a total application rate of ~0.27 lb ai/A [2x the maximum proposed
seasonal application rate; preharvest interval (PHI)=7 days].  The
results show that corrected residues of etoxazole (corrected for storage
dissipation) in tart and sweet pitted cherries were 0.31-1.2 ppm and
0.13-0.28 ppm, respectively.

The submitted cantaloupe field trial data reflect a total of 2 foliar
applications of etoxazole (Zeal® 72 WDG) on cantaloupes at a rate of
0.135 lb ai/A/application for a total application rate of ~0.27 lb ai/A
(2x the maximum proposed seasonal application rate; PHI=5-8 days).  The
results show that residues of etoxazole (corrected for storage
dissipation) in cantaloupe were 0.016-0.12 ppm.

The submitted hop field trial data reflect a total of 2 foliar
applications of etoxazole (Zeal® 72 WDG) on hops at a rate of 0.198 lb
ai/A, for at total application rate of approximately 0.396 lb ai/A (~2x
the maximum proposed seasonal application rate; PH I = 6-7 days).  The
results show that residues of etoxazole in dried hop cones were
1.98-4.18 ppm.  HED is requesting side-by-side data as follows:  1 trial
each at 2 x 0.198 = 0.396 lb ai/A (exaggerated application rate, PHI = 7
days) and one at 0.180 lb ai/A (proposed application rate, PHI = 7
days), 4 samples per trial.  As R3 is a metabolite of concern in cotton
gin byproducts, and metabolism data are not available for hops, R3 is a
potential residue of concern for this crop.  Therefore, the requested
side-by-side hop field trials should include data for R3, as well as the
parent.  Subsequent to the submission of these data, HED will make a
determination as to whether or not R3 is a residue of concern in hops.

The application rates used in the cherry (2 applications at 0.135 lb
ai/A/application for a total application rate of ~0.27 lb ai/A),
cantaloupe (2 applications at 0.135 lb ai/A/application for a total
application rate of ~0.27 lb ai/A), and hop field trials (2 applications
at 0.198 lb ai/A/application for a total application rate of 0.396 lb
ai/A) do not match the proposed application rates (1 application at
0.135 lb ai/A for cherry and melon; 1 application at 0.180 lb ai/A for
hops).  However, as the residue decline data show that residues decrease
in cherries and cantaloupe with increasing PHIs, the majority of the
residues seen the field trials would most likely be due to the second
application.  Therefore, potential residues of etoxazole in/on cherries
and cantaloupe will not be underestimated.  As the unrefined dietary
risk (using tolerance level residues & 100% crop treated (CT) data for
all crops) is not of concern to HED (Memo, S. Levy, 11/6/07; D346200),
cherry and cantaloupe field trial data reflecting a 1x application rate
will not be requested at this time.  For hops, the additional residue
data will be used to adjust the existing data for the exaggerated
application rate.    

The recommended tolerance levels for all crops were determined using
Agency Guidance (Guidance for Setting Pesticide Tolerances Based on
Field Trial Data SOP).  HED concludes that 0.20 ppm is the appropriate
tolerance level for etoxazole on vegetable, cucurbit subgroup 9A
following 2 foliar applications at a rate of ~0.135 lb ai/A for a total
application rate of ~0.27 lb ai/A.  HED concludes that 1.0 ppm is the
appropriate tolerance level for etoxazole on cherry following 2 foliar
applications at a rate of ~0.135 lb ai/A for a total application rate of
~0.27 lb ai/A.  HED concludes that 7.0 ppm is the appropriate tolerance
level for etoxazole on hop, dried cones following 2 foliar applications
at a rate of ~0.362 for a total application rate of ~0.396 lb ai/A.

There are no rotational crop restrictions on the proposed labels.  HED
concluded that, based on the available confined rotational crop data, no
rotational crop restrictions would be required for rotational crops
following applications at rates of 0.135 lb ai/A/season, which is the
maximum proposed application rate for cantaloupe (the only proposed use
that is considered to be a rotated crop).  Therefore, the available
rotational crop data are adequate to support the proposed uses.

There are no established or proposed Codex, Canadian or Mexican maximum
residue limits (MRLs) for etoxazole; therefore, harmonization is not an
issue for this action.

4.2.2	Chronic Dietary Exposure Analysis tc \l3 "4.2.2	Chronic Dietary
Exposure Analysis 

The etoxazole chronic dietary exposure assessment was conducted using
DEEM-FCID(, Version 2.03), which incorporates consumption data from
United States Department of Agriculture’s (USDA’s) Continuing
Surveys of Food Intakes by Individuals (CSFII), 1994-1996 and 1998.  The
1994-96, 98 data are based on the reported consumption of more than
20,000 individuals over two non-consecutive survey days.  Foods “as
consumed” (e.g., apple pie) are linked to EPA-defined food commodities
(e.g. apples, peeled fruit - cooked; fresh or N/S; baked; or wheat flour
- cooked; fresh or N/S, baked) using publicly available recipe
translation files developed jointly by USDA/ARS and EPA.  Consumption
data are averaged for the entire U.S. population and within population
subgroups for chronic exposure assessment.

For chronic exposure and risk assessment, an estimate of the residue
level in each food or food-form (e.g., orange or orange juice) on the
food commodity residue list is multiplied by the average daily
consumption estimate for that food/food form.  The resulting residue
consumption estimate for each food/food-form is summed with the residue
consumption estimates for all other food/food-forms on the commodity
residue list to arrive at the total average estimated exposure. 
Exposure is expressed in mg/kg body weight/day and as a percent of the
cPAD.  This procedure is performed for each population subgroup.

The results of the chronic assessment are listed in Table 4.2.2. 
DEEM-FCID( (Version 2.03) estimates the dietary exposure for the U.S.
population and various population subgroups.  Based on an analysis of
1994-96, 98 CSFII consumption data which took into account dietary
patterns and number of survey respondents, HED determined that the
following population groupings were appropriate for regulatory purposes
(only the exposure estimates for these populations are reported in this
document):  U.S. population, all infants (<1 year old), children 1-2
years old, children 3-5 years old, children 6-12 years old, youth 13-19
years old, females 13-49 years old, adults 20-49 years old, and/or
adults 50+ years old.

An unrefined, chronic dietary exposure assessment (see Table 4.2.2) was
conducted for the general U.S. population and various population
subgroups using HED-calculated residues of concern (parent and
metabolites) for livestock commodities and tolerance-level residues for
all other commodities.  For all registered and proposed uses, 100% CT
information was used, as well as DEEM 7.81 default processing factors
(apple and grape residue data showed that there was no concentration in
processed commodities; therefore; these default values were set to 1). 
Drinking water was incorporated directly in the dietary assessment using
the acute concentration for surface water generated by the FIRST model. 
This assessment concludes that the chronic dietary exposure estimates
are not of concern to HED (<100% cPAD) for the general U.S. population
(1.6% cPAD) and all population subgroups.  The most highly exposed
population subgroup is children 1-2 years old at 8.3% cPAD.



Table 4.2.2.     Summary of Dietary (Food and Drinking Water) Exposure
and Risk for Etoxazole.

Population

Subgroup	Acute Dietary1	Chronic Dietary2

	Dietary Exposure

(mg/kg/day)	% aPAD	Dietary Exposure

(mg/kg/day)	% cPAD

U.S. Population (total)	Not applicable.	0.000735	1.6

All Infants (< 1 year old)

0.002089	4.5

Children 1-2 years old

0.003805	8.3

Children 3-5 years old

0.002464	5.4

Children 6-12 years old

0.000997	2.2

Youth 13-19 years old

0.000402	0.9

Adults 20-49 years old

0.000451	1.0

Adults 50+ years old

0.000484	1.1

Females 13-49 years old

0.000434	0.9

1 No acute dietary endpoint was chosen for the general U.S. population
or any population subgroup, including infants and children.

2 Chronic dietary endpoint of 0.046 mg/kg/day applies to the general
U.S. population and all population subgroups.

4.3	Water Exposure/Risk Pathway tc \l2 "4.3	Water Exposure/Risk Pathway 

EFED (Memo, J. Meléndez, 4/24/07; D335338) provided Tier 1 estimated
drinking water concentrations (EDWCs) for etoxazole and the metabolites
of concern R-8 and R-13 (Memo, J. Tyler, et al., 8/7/03; DP#: 292548). 
FIRST and SCI-GROW models were used to calculate the chronic surface
water and groundwater EDWCs (parent and metabolites), respectively, as
listed in Table 4.3.1.  This assessment was based on a maximum
application rate of 0.18 lb. ai/A.

Table 4.3.  Tier I EDWCs.*

Chemical	Acute (peak) Surface Water Concentration (ppb)1	Annual Average
Surface Water Concentration (ppb)2	Ground Water Concentration (ppb)

Etoxazole	3.49	0.332	0.00173

R-8	2.80	0.913	0.316

R-13	0.802	0.0285	0.000322

Total	7.09	1.27	0.318

* Results presented in ppb of the chemical, as opposed to ppb of parent
equivalent.

1.  FIRST

2.  SCI-GROW

4.4	Residential Exposure/Risk Pathway tc \l2 "4.4	Residential
Exposure/Risk Pathway 

There are no proposed or registered products containing etoxazole that
would result in residential exposure.  Therefore, a residential exposure
assessment was not performed.

4.4.1	Non-occupational Off-Target Exposure tc \l3 "4.4.1
Non-occupational Off-Target Exposure 

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 database 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 tc \l1 "5.0
AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION 

An acute aggregate risk assessment was not performed because an endpoint
of concern attributable to a single oral dose was not selected for any
population subgroup (including infants and children).  Short- and
intermediate-term aggregate risk assessments were not performed because
there are no registered or proposed residential non-food uses.  A cancer
aggregate risk assessment was not performed because etoxazole is not
carcinogenic.  

A chronic aggregate exposure risk assessment was conducted, which
included food and drinking water only, as there are no residential uses.
 Therefore, the chronic aggregate exposure and risk estimates are
equivalent to the chronic dietary exposure estimates (as seen in Section
4.2.2) and, therefore, are not of concern to HED.

6.0	CUMULATIVE RISK tc \l1 "6.0	CUMULATIVE RISK 

Section 408(b)(2)(D)(v) of the FFDCA requires that, when considering
whether to establish, modify, or revoke a tolerance, the Agency consider
"available information” concerning the cumulative effects of a
particular pesticide's residues and "other substances that have a common
mechanism of toxicity.” 

EPA does not have, at this time, available data to determine whether
etoxazole has a common mechanism of toxicity with other substances. 
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 etoxazole and any other
substances and etoxazole does not appear to produce a toxic metabolite
produced by other substances.  For the purposes of this tolerance
action, therefore, EPA has not assumed that etoxazole has 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 http://www.epa.gov/pesticides/cumulative/.

7.0	OCCUPATIONAL EXPOSURE tc \l1 "7.0	OCCUPATIONAL EXPOSURE 

An occupational exposure assessment for etoxazole was prepared in an HED
memorandum (M. Dow, 02-JUL-2007; DP#: 341212).  Based on the proposed
use patterns, occupational handler and post-application exposure to
etoxazole is expected.  Both short- and intermediate-term exposures are
anticipated and were assessed.

Use Pattern

The use pattern summary is taken from Sections B of the IR-4 submission
and from draft labeling from Valent.  It is proposed that two currently
registered products be amended to include the new uses.  The first
product is SecureTM Miticide (Reg. No. 59639-123), a WP formulation that
contains 72.0 % by weight etoxazole.  According to information in the
draft label, it may be available packaged in water-soluble packages. 
However, the label is not limited to such packaging.  Therefore, HED
assumes the WP is packaged in non-water soluble packages. The label
directs applicators and other handlers to wear PPE consisting of: 
long-sleeved shirt, long pants, shoes plus socks and chemical-resistant
gloves made of any waterproof material such as polyethylene or polyvinyl
chloride.  

The second product is ZealTM WP Miticide (Reg. No. 59639-138) which is
also a 

72.0 % by weight ai WP formulation.  The ZealTM label requires the same
PPE as SecureTM (see above).

Labels for both products list the same application parameters for use on
the proposed crops.

Cherry (Sweet and Tart)

The range of application rate is 2.0 - 3.0 oz formulation/A (0.09 -
0.135 lb ai/A).  Etoxazole should be applied in a minimum of 50 gallons
of spray per acre (GPA) in ground equipment only.  There is a 7-day PHI.
 There is a maximum of one application per season and a maximum of 3.0
oz/A/season (0.135 lb ai/A/season).  The target pests are Two-spotted
spider mite, European red mite, and the Pacific spider mite. 

Melon (Crop SubGroup 9A; includes cantaloupe, citron melon, muskmelon,
and watermelon).  

The application factors are the same as described for cherry.  The
target pest is the Two-spotted spider mite.

Hops

The range of application rates is 3.0 - 4.0 oz/A (0.135 - 0.18 lb ai/A).
 It may only be applied in ground equipment in a minimum of 50 GPA. 
There is a 7-day PHI and a maximum of 4.0 oz/A/season (0.18 lb
ai/A/season).  The target pest is Two-spotted spider mite.

7.1	Occupational Handler tc \l2 "7.1	Occupational Handler 

The proposed use patterns indicate that the most highly-exposed
occupational pesticide handlers are likely to be mixer/loaders using
wettable powders, and applicators using groundboom and airblast
equipment.  

As no chemical-specific data were available with which to assess
potential exposure of etoxazole to pesticide handlers, the estimates of
exposure to pesticide handlers are based upon surrogate study data
available in the PHED Surrogate Exposure Guide (August 1998).  For
pesticide handlers, it is HED standard practice to present estimates of
dermal exposure for “baseline”; that is, for workers wearing a
single layer of work clothing consisting of a long-sleeved shirt, long
pants, shoes plus socks and no protective gloves, as well as for
baseline and the use of protective gloves or other PPE as might be
necessary.  The proposed product labels involved in this assessment
direct applicators and other handlers to wear a long-sleeved shirt, long
pants, shoes plus socks and chemical-resistant gloves made of any
waterproof material such as polyethylene or polyvinyl chloride.  

Table 7.1 presents the exposure/risks for short and intermediate-term
inhalation exposures at baseline.  A MOE of 100 is adequate to protect
occupational pesticide handlers.  All MOEs are greater than 100 with
baseline PPE; and, therefore, are not of concern to HED.

Table 7.1.    Estimated Short- and Intermediate-term Handler Exposure
and Risk from the Use of Etoxazole on  Cherry, Melon and Hops

Unit Exposure1

mg ai/lb handled	Applic. Rate2

lb ai/A	Units Treated3

Acres Per Day	Average Daily

Dose4

mg ai/kg bw/day	NOAEL5	MOE6

Mixer/Loader - Wettable Powder -  Open Pour

Inhal         0.0434 HC	

0.135	

80	

Inhalation  0.0067	

4.62	

700

Applicator - Air-blast – Open Cab

Inhal         0.0045 HC	

0.180	

40	

Inhalation   0.00046	

4.62	

10,000

Applicator - Ground-boom - Open Cab

Inhal         0.00074 HC	

0.135	

80	

Inhalation   0.00011	

4.62	

40,000

1.  Unit Exposures are taken from “PHED SURROGATE EXPOSURE GUIDE”,
Estimates of Worker Exposure from The Pesticide Handler Exposure
Database Version 1.1, August 1998.  Inhal. = Inhalation.  Units = mg
ai/pound of active ingredient handled. HC = High confidence data.

2.  Application Rate. = Taken from IR-4 Sections B and from supplemental
labeling for Zeal and Secure Miticides.

3.  Units Treated are taken from “Standard Values for Daily Acres
Treated in Agriculture”;  SOP No. 9.1.   Science Advisory Council for
Exposure;  Revised 5 July 2000.

4.  Average Daily Dose (ADD) = Unit Exposure * Applic. Rate * Acres
Treated  ( Body Weight (70 kg).  

5.  No Observable Adverse Effect Level (NOAEL) 4.62 mg ai/kg bw/day. HED
assumes 100% inhalation absorption.

6.  MOE = Margin of Exposure = NOAEL ( ADD.

7.2	Occupational Post-application Exposure tc \l2 "7.2	Occupational
Post-application Exposure 

There is typically concern for post-application exposures of
agricultural workers to dislodgeable pesticide residues.  In the case of
etoxazole, the HIARC did not identify dermal toxicological endpoints of
concern.  

There is a 12-hour REI for etoxazole.  The vapor pressure of etoxazole
is 7.0 x 10-6 Pascals @ 25(C.  Based upon the REI and the low vapor
pressure, HED believes post-application exposure to agricultural workers
via the inhalation route is negligible.  Therefore, an assessment of
post-application exposure is not necessary.

Etoxazole is classified in Acute Toxicity Category III for acute dermal
and inhalation and Category IV for primary eye irritation and primary
skin irritation.  It is not a dermal sensitizer.  Therefore, the interim
WPS REI of 12 hours is adequate to protect agricultural workers.  The
SecureTM and ZealTM labels list a 12 hour REI.

 

7.3	Incidents tc \l2 "7.3	Incidents 

There are no incidents reported.

8.0	DATA NEEDS/LABEL REQUIREMENTS tc \l1 "8.0	DATA NEEDS/LABEL
REQUIREMENTS 

8.1	Residue Chemistry tc \l2 "8.1	Residue Chemistry 

Revised Section F.

Additional residue data on hops.

8.2	Toxicology tc \l2 "8.2	Toxicology 

None.

8.3	ORE tc \l2 "8.3	ORE 

None.

9.0	ATTACHMENT tc \l1 "9.0	ATTACHMENT 

Attachment 1.	 Summary of Proposed and HED-Recommended Tolerances.

Attachment 2.	 Chemical Structures and Nomeclature.

cc:  S. Levy (RAB1)

RDI:  RAB1 Branch (8/01/07), RAB1 Chemists (8/1/07)

S. Levy:S10953:PY1:(703)305-0783:7509P:RAB1

ATTACHMENT 1.  Summary of Proposed and HED-Recommended Tolerances.

Commodity	Proposed Tolerance (ppm)	Recommended Tolerance (ppm)	Comments

(Correct commodity definition)

Cherry	0.70	1.0

	Hop, dried cones	7.0	7.0	Hop, dried, cones

Melon subgroup 9A	0.15	0.20	Vegetable, cucurbit subgroup 9A



ATTACHMENT 2.  Chemical Structures and Nomenclature.

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structure

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