Document ID: EPA-HQ-OPP-2008-0362-0004
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2009-04-01T04:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, DC  20460

OFFICE OF

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

MEMORANDUM

Date:		January 22, 2009

Subject:	Quinoxyfen.  Human Health Risk Assessment for the Proposed Food
Use of Quinoxyfen on Stone Fruits Crop Group 12 (excluding Cherry),
Artichoke, Winter Squash, (Pumpkin and Edible Gourds).  

PC Code:  	055459	DP Barcode:	351021

Decision No.:	390599	Registration No.:	62719-375

Petition No.:	8E7325	Regulatory Action:	Section 3

Assessment Type:	Single Chemical, Aggregate	Registration Case No.:	None

TXR No.:	None	CAS No.:	124495-18-7

MRID No.:	None	40 CFR:	§180.588

  SEQ CHAPTER \h \r 1 From:		  SEQ CHAPTER \h \r 1 Breann Hanson,
Biologist

			Alternative Risk Integration and Assessment (ARIA) Team

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

			Registration Division (RD; 7505P)

Through:		  SEQ CHAPTER \h \r 1 William Cutchin, Acting Senior Branch
Scientist

				ARIA

				RIMUERB/RD (7505P)

		

				AND

		

				Robert Mitkus, Ph.D., Chemist

				George Kramer, Ph.D., Chemist

				Dana Vogel, Branch Chief

			Risk Assessment Branch I (RABI)

			Health Effects Division (HED; 7509P)

To:	Susan Stanton/Dan Rosenblatt, RM Team 05 

			RIMUERB/RD (7505P)

	  SEQ CHAPTER \h \r 1 

ARIA/RIMUERB of RD of the Office of Pesticide Programs (OPP) is charged
with estimating the risk to human health from exposure to pesticides. 
RD of OPP has requested that ARIA 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 and currently registered uses of the active
ingredient quinoxyfen. 

In this document, ARIA has conducted an assessment of the human exposure
and health risks resulting from these proposed uses and all currently
registered uses.  The overall risk assessment was provided by Breann
Hanson (ARIA), the dietary assessment by Wesley Carr (California
Department of Pesticide Regulation), the residue chemistry assessment by
Donald Wilbur (HED), the water exposure assessment by Amy McKinnon
(Environmental Fate and Effects Division (EFED)) and the occupational
exposure assessment by Mark Dow (ARIA).  

This risk assessment incorporates all current, pending and proposed
tolerances for quinoxyfen as of January 22, 2009.

TABLE OF CONTENTS

  TOC \o "1-4" \h \z \u    HYPERLINK \l "_Toc220398770"  1.0 EXECUTIVE
SUMMARY	  PAGEREF _Toc220398770 \h  5  

  HYPERLINK \l "_Toc220398771"  2.0	INGREDIENT PROFILE	  PAGEREF
_Toc220398771 \h  10  

  HYPERLINK \l "_Toc220398772"  2.1	Summary of Proposed Uses	  PAGEREF
_Toc220398772 \h  10  

  HYPERLINK \l "_Toc220398776"  2.2	Structure and Nomenclature	  PAGEREF
_Toc220398776 \h  11  

  HYPERLINK \l "_Toc220398781"  2.3	Physical and Chemical Properties	 
PAGEREF _Toc220398781 \h  11  

  HYPERLINK \l "_Toc220398783"  3.0	HAZARD CHARACTERIZATION	  PAGEREF
_Toc220398783 \h  12  

  HYPERLINK \l "_Toc220398784"  3.1	Hazard and Dose-Response
Characterization	  PAGEREF _Toc220398784 \h  12  

  HYPERLINK \l "_Toc220398785"  3.1.1	Database Summary	  PAGEREF
_Toc220398785 \h  12  

  HYPERLINK \l "_Toc220398786"  3.1.1.1	Studies available and considered
(animal, human, general literature)	  PAGEREF _Toc220398786 \h  12  

  HYPERLINK \l "_Toc220398787"  3.1.1.2	Mode of action, metabolism,
toxicokinetic data	  PAGEREF _Toc220398787 \h  12  

  HYPERLINK \l "_Toc220398788"  3.1.1.3	Sufficiency of studies/data	 
PAGEREF _Toc220398788 \h  12  

  HYPERLINK \l "_Toc220398789"  3.1.2	Toxicological Effects	  PAGEREF
_Toc220398789 \h  13  

  HYPERLINK \l "_Toc220398790"  3.1.3	Dose-response	  PAGEREF
_Toc220398790 \h  14  

  HYPERLINK \l "_Toc220398791"  3.1.4	FQPA	  PAGEREF _Toc220398791 \h 
14  

  HYPERLINK \l "_Toc220398792"  3.2	Absorption, Distribution,
Metabolism, Excretion (ADME)	  PAGEREF _Toc220398792 \h  15  

  HYPERLINK \l "_Toc220398793"  3.3	FQPA Considerations	  PAGEREF
_Toc220398793 \h  15  

  HYPERLINK \l "_Toc220398794"  3.3.1	Adequacy of the Toxicity Database	
 PAGEREF _Toc220398794 \h  15  

  HYPERLINK \l "_Toc220398795"  3.3.2	Evidence of Neurotoxicity	 
PAGEREF _Toc220398795 \h  16  

  HYPERLINK \l "_Toc220398796"  3.3.3	Developmental Toxicity Studies	 
PAGEREF _Toc220398796 \h  17  

  HYPERLINK \l "_Toc220398797"  3.3.4	Reproductive Toxicity Study	 
PAGEREF _Toc220398797 \h  18  

  HYPERLINK \l "_Toc220398798"  3.3.5	Additional Information from
Literature Sources	  PAGEREF _Toc220398798 \h  19  

  HYPERLINK \l "_Toc220398799"  3.3.6	Pre-and/or Post-natal Toxicity	 
PAGEREF _Toc220398799 \h  19  

  HYPERLINK \l "_Toc220398800"  3.3.6.1	Determination of Susceptibility	
 PAGEREF _Toc220398800 \h  19  

  HYPERLINK \l "_Toc220398801"  3.3.6.2	Degree of Concern Analysis and
Residual Uncertainties	  PAGEREF _Toc220398801 \h  19  

  HYPERLINK \l "_Toc220398802"  3.3.7	Recommendation for a Developmental
Neurotoxicity (DNT) Study	  PAGEREF _Toc220398802 \h  19  

  HYPERLINK \l "_Toc220398803"  3.4	FQPA Safety Factor for Infants and
Children	  PAGEREF _Toc220398803 \h  20  

  HYPERLINK \l "_Toc220398804"  3.5	Hazard Identification and Toxicity
Endpoint Selection	  PAGEREF _Toc220398804 \h  20  

  HYPERLINK \l "_Toc220398805"  3.5.1    Acute Reference Dose (aRfD)	 
PAGEREF _Toc220398805 \h  20  

  HYPERLINK \l "_Toc220398806"  3.5.2	Chronic Reference Dose (cRfD)	 
PAGEREF _Toc220398806 \h  20  

  HYPERLINK \l "_Toc220398807"  3.5.3	Incidental Oral Exposure: Short-
and Intermediate-Term (1 day - 6 months)				  PAGEREF _Toc220398807 \h 
21  

  HYPERLINK \l "_Toc220398808"  3.5.4	Dermal Absorption	  PAGEREF
_Toc220398808 \h  22  

  HYPERLINK \l "_Toc220398809"  3.5.5	Dermal Exposure: Short- and
Intermediate-Term (1 day - 6 months)	  PAGEREF _Toc220398809 \h  23  

  HYPERLINK \l "_Toc220398810"  3.5.6	Dermal Exposure: Long-Term (> 6
Months)	  PAGEREF _Toc220398810 \h  23  

  HYPERLINK \l "_Toc220398811"  3.5.7	Inhalation Exposure: Short- and
Intermediate-Term (1 day - 6 months)	  PAGEREF _Toc220398811 \h  23  

  HYPERLINK \l "_Toc220398812"  3.5.8	Inhalation Exposure: Long-Term (>
6 Months)	  PAGEREF _Toc220398812 \h  24  

  HYPERLINK \l "_Toc220398813"  3.5.9	Level of Concern for Margin of
Exposure	  PAGEREF _Toc220398813 \h  24  

  HYPERLINK \l "_Toc220398814"  3.5.10	Recommendation for Aggregate
Exposure Risk Assessments	  PAGEREF _Toc220398814 \h  25  

  HYPERLINK \l "_Toc220398815"  3.5.11	Classification of Carcinogenic
Potential	  PAGEREF _Toc220398815 \h  25  

  HYPERLINK \l "_Toc220398816"  3.5.12	Summary of Toxicological Doses
and Endpoints for Quinoxyfen for Use in Human Risk Assessments	  PAGEREF
_Toc220398816 \h  25  

  HYPERLINK \l "_Toc220398817"  3.6	Endocrine Disruption	  PAGEREF
_Toc220398817 \h  26  

  HYPERLINK \l "_Toc220398818"  4.0	DIETARY EXPOSURE/RISK
CHARACTERIZATION	  PAGEREF _Toc220398818 \h  27  

  HYPERLINK \l "_Toc220398819"  4.1	Pesticide Metabolism and
Environmental Degradation	  PAGEREF _Toc220398819 \h  27  

  HYPERLINK \l "_Toc220398820"  4.1.1	Metabolism in Primary Crops and
Livestock Commodities.	  PAGEREF _Toc220398820 \h  27  

  HYPERLINK \l "_Toc220398821"  4.1.2	Analytical Methodology	  PAGEREF
_Toc220398821 \h  28  

  HYPERLINK \l "_Toc220398822"  4.1.3	Multiresidue Methods	  PAGEREF
_Toc220398822 \h  28  

  HYPERLINK \l "_Toc220398823"  4.1.4	Storage Stability	  PAGEREF
_Toc220398823 \h  28  

  HYPERLINK \l "_Toc220398824"  4.1.5	Magnitude of the Reside in Plants	
 PAGEREF _Toc220398824 \h  29  

  HYPERLINK \l "_Toc220398825"  4.1.6	Magnitude in Meat, Milk, Poultry,
and Eggs	  PAGEREF _Toc220398825 \h  32  

  HYPERLINK \l "_Toc220398826"  4.1.7	Confined and Field Accumulation in
Rotational Crops	  PAGEREF _Toc220398826 \h  32  

  HYPERLINK \l "_Toc220398827"  4.1.8	Environmental Degradation	 
PAGEREF _Toc220398827 \h  32  

  HYPERLINK \l "_Toc220398828"  4.1.9	Comparative Metabolic Profile	 
PAGEREF _Toc220398828 \h  32  

  HYPERLINK \l "_Toc220398829"  4.1.10	Toxicity Profile of Major
Metabolites and Degradates	  PAGEREF _Toc220398829 \h  33  

  HYPERLINK \l "_Toc220398830"  4.1.11	Pesticide Metabolites and
Degradates of Concern	  PAGEREF _Toc220398830 \h  34  

  HYPERLINK \l "_Toc220398831"  4.1.12	Drinking Water Residue Profile	 
PAGEREF _Toc220398831 \h  34  

  HYPERLINK \l "_Toc220398832"  4.1.13	Food Residue Profile	  PAGEREF
_Toc220398832 \h  35  

  HYPERLINK \l "_Toc220398833"  4.1.14	International Residue Limits	 
PAGEREF _Toc220398833 \h  36  

  HYPERLINK \l "_Toc220398834"  4.2	Dietary Exposure and Risk	  PAGEREF
_Toc220398834 \h  36  

  HYPERLINK \l "_Toc220398835"  4.2.1	Acute Dietary Exposure/Risk	 
PAGEREF _Toc220398835 \h  36  

  HYPERLINK \l "_Toc220398836"  4.2.2	Chronic Dietary Exposure/Risk	 
PAGEREF _Toc220398836 \h  36  

  HYPERLINK \l "_Toc220398837"  4.2.3	Cancer Dietary Risk	  PAGEREF
_Toc220398837 \h  37  

  HYPERLINK \l "_Toc220398838"  4.3	Anticipated Residue and Percent Crop
Treated (%CT) Information	  PAGEREF _Toc220398838 \h  37  

  HYPERLINK \l "_Toc220398839"  5.0	RESIDENTIAL (NON-OCCUPATIONAL)
EXPOSURE/RISK CHARACTERIZATION	  PAGEREF _Toc220398839 \h  37  

  HYPERLINK \l "_Toc220398840"  5.1	Other (Spray Drift, etc.)	  PAGEREF
_Toc220398840 \h  37  

  HYPERLINK \l "_Toc220398841"  6.0	AGGREGATE RISK ASSESSMENTS AND RISK
CHARACTERIZATION	  PAGEREF _Toc220398841 \h  38  

  HYPERLINK \l "_Toc220398842"  7.0	CUMULATIVE RISK
CHARACTERIZATION/ASSESSMENT	  PAGEREF _Toc220398842 \h  38  

  HYPERLINK \l "_Toc220398843"  8.0	OCCUPATIONAL EXPOSURE/RISK PATHWAY	 
PAGEREF _Toc220398843 \h  38  

  HYPERLINK \l "_Toc220398844"  8.1	Handler Exposure and Risk	  PAGEREF
_Toc220398844 \h  38  

  HYPERLINK \l "_Toc220398845"  8.2	Post-Application Exposure Risk	 
PAGEREF _Toc220398845 \h  40  

  HYPERLINK \l "_Toc220398846"  9.0	TOLERANCE SUMMARY	  PAGEREF
_Toc220398846 \h  42  

  HYPERLINK \l "_Toc220398848"  10.0	DATA NEEDS AND LABEL
RECOMMENDATIONS	  PAGEREF _Toc220398848 \h  42  

  HYPERLINK \l "_Toc220398849"  10.1	Toxicology	  PAGEREF _Toc220398849
\h  42  

  HYPERLINK \l "_Toc220398850"  10.2	Residue Chemistry	  PAGEREF
_Toc220398850 \h  43  

  HYPERLINK \l "_Toc220398851"  10.3	Occupational and Residential
Exposure	  PAGEREF _Toc220398851 \h  43  

  HYPERLINK \l "_Toc220398852"  11.0	REFERENCES	  PAGEREF _Toc220398852
\h  43  

  HYPERLINK \l "_Toc220398853"  Appendix A:  Toxicology Assessment	 
PAGEREF _Toc220398853 \h  45  

  HYPERLINK \l "_Toc220398854"  A.1	Toxicology Data Requirements	 
PAGEREF _Toc220398854 \h  45  

  HYPERLINK \l "_Toc220398855"  A.2      Toxicity Profiles	  PAGEREF
_Toc220398855 \h  48  

  HYPERLINK \l "_Toc220398856"  Appendix B:       Review of Human
Research	  PAGEREF _Toc220398856 \h  48  

  HYPERLINK \l "_Toc220398857"  Appendix C:	International Residue Limit
Status	  PAGEREF _Toc220398857 \h  49  

 	

1.0 EXECUTIVE SUMMARY tc  \l 1 "1.0 EXECUTIVE SUMMARY" 

Background

This document is a human health risk assessment to support a
Interregional Research Project No. 4 (IR-4) request for the
establishment of permanent tolerances for residues of quinoxyfen in/on
stone fruits crop group 12 (excluding cherry), artichoke, winter squash,
pumpkin and edible gourds (PP# 8E7325).  Quinoxyfen offers a new mode of
action to provide protection against powdery mildew diseases on a
variety of crops including grapes, cherries and hops.  This mode of
action, with attributes of a multi-site fungicide, differs from that of
either of the two primary classes of synthetic, single-site vine
fungicides (demethylation inhibitors and strobilurins).  Quinoxyfen has
a low overall risk for development of disease resistance and is safe to
non-target and beneficial organisms.  

Permanent tolerances have been established under 40 CFR §180.588(a) for
residues of quinoxyfen, 5,7-dichloro-4-(4-fluorophenoxy) quinoline, in
or on cherry (sweet and tart) at 0.30 ppm, dried hop cones at 3.0 ppm,
grape at 0.60 ppm, lettuce (head) at 7.0 ppm, lettuce (leaf) at 19.0
ppm, melon (subgroup 9A) at 0.08 ppm, pepper (bell) at 0.35 ppm, pepper
(non-bell) at 1.7 ppm and strawberry at 0.90 ppm.  There are currently
no active time-limited tolerances, FIFRA §18 emergency exemptions, for
residues of quinoxyfen.  The time-limited tolerances for melons
(subgroup 9A), pumpkin and winter squash expired on 12/31/2007.

The most recent human health risk assessment for quinoxyfen was
conducted in conjunction with a request for the establishment of
tolerances for residues on peppers (bell and non-bell), eggplant, melon
subgroup 9A, strawberry, and lettuce (DP#s: 321331, 321333, 322261, G.
Kramer, 5/15/2006). 

This document includes dietary (food and drinking water), occupational
(handler and post-application), residue chemistry and aggregate
assessments. 

Proposed Uses

IR-4 has proposed new tolerances for residues of quinoxyfen in or on the
following commodities: artichoke; winter squash (includes pumpkin and
edible gourds); and stone fruits (crop group 12, peach and plum).  The
product requested for use is Quintec® Fungicide (EPA Reg. No.
62719-375).  Quintec® is formulated as a 2.08 lb active ingredient (ai)
per gallon liquid (22.58 % ai).  

Stone Fruit

Stone fruit (EPA Crop Group 12) includes apricot, cherry (sweet and
tart), nectarine, peach, plum, plum (Chickasaw, Damson, Japanese),
plumcot and prune.  The target pest is powdery mildew.  The rate of
application ranges from 7 – 8 fl oz formulation/A (0.11375 – 0.13 lb
ai/A).  There is a maximum of 32 fl oz formulation/A/season (0.52 lb
ai/A/season).  For ground applications quinoxyfen should be applied in
30 gallons of spray per acre (gpa).  It may also be applied aerially but
according to the IR4 submission, it is not recommended.  The retreatment
interval is 10 – 14 days under light disease pressure and 6 – 8 days
under severe disease pressure.  Not more than one application should be
made without alternating with another fungicide with a different mode of
action.  The preharvest interval (PHI) is 7 days.

Artichoke and Winter Squash

The use pattern for artichoke and winter squash is the same.  Winter
squash includes Cucurbita spp. such as acorn squash, hubbard squash,
pumpkin, calabaza, butternut squash, cushaw and other cultivars and/or
hybrids of these.  Powdery mildew is the target pest.  Applications may
be made by ground or by air although aerial applications are not
recommended.  Ground applications should be made in 30 gpa.  The rate of
application is 4 - 6 fl oz formulation/A (0.065 – 0.098 lb ai/A). 
Under severe disease conditions, the rate is 8 fl oz formulation/A (0.13
lb ai/A).   The maximum application is 32 fl oz formulation/A/season
(0.52 lb ai/A/season).  The reapplication interval is 10 – 14 days
under low disease conditions and 6 – 8 days under severe disease
conditions.  Not more than 1 application may be made without alternating
with another fungicide with a different mode of action.  The PHI is 3
days.  

Crops having quinoxyfen tolerances may be replanted at any time. 
Rotation to all other crops is prohibited.

Toxicology and Dose-Response

Quinoxyfen has low acute toxicity via the oral, dermal and inhalation
routes.  It is a mild eye irritant and dermal sensitizer, but it is not
a dermal irritant.  The primary target organs affected by quinoxyfen are
the liver and kidney.  Liver effects were seen in rat and mouse
subchronic and dog chronic studies.  Subchronic effects in rats and mice
included increased liver weights, hepatocellular hypertrophy and
individual cell hepatocellular necrosis.  Kidney effects were noted only
in the rat combined chronic/carcinogenicity study which resulted in an
increased severity of chronic progressive glomerulonephropathy in the
males.  

HED previously selected the endpoints for risk assessment and to
evaluate the potential for increased susceptibility of infants and
children from exposure to quinoxyfen according to the 2002 OPP 10X
guidance document.  Since there are no residual uncertainties in the
exposure database or for pre-/post-natal toxicity in the toxicology
database and since there was no evidence of potential immunotoxicity in
the animal studies, HED and the risk assessment team recommended that
the Food Quality Protection Act (FQPA) safety factor (SF) be reduced to
1X in assessing the potential risk posed by this chemical.  Also, an
additional safety factor is not needed for database uncertainties.  

Since there were no toxic effects attributable to a single dose, an
endpoint of concern was not identified to quantitate acute-dietary risk
to the general population or to the subpopulation females 13-50 years
old.  Therefore, there is no acute reference dose (aRfD) or acute
population-adjusted dose (aPAD) for the general population or females
13-50 years old.  The short-/intermediate-term dermal and inhalation
endpoints are based upon a minimal decrease in F1a pup weights.  The
chronic reference dose (cRfD) and long-term dermal and inhalation
endpoints are based upon increases in severity of chronic progressive
glomerulonephropathy in the males and minimal decreases in body weight
and body-weight gain in both sexes of rats in a combined
chronic/carcinogenicity study.  The cRfD is 0.20 mg/kg/day and the
chronic population-adjusted dose (cPAD) is 0.20 mg/kg/day.  Quinoxyfen
has been classified as "not likely to be carcinogenic to humans" by all
routes of exposure based upon lack of evidence of carcinogenicity in
rats and mice.  Therefore, a cancer risk assessment is not required. 
Since oral studies were selected for all durations of dermal and
inhalation exposure, and no dermal or inhalation absorption studies are
available, a 100% dermal-absorption factor and a 100% inhalation
absorption factor are assumed in the route-to-route extrapolation.

Residue Chemistry

Based on previously-submitted cucumber, grape, sugar beet, and tomato
metabolism studies, the nature of the residue in plants is adequately
understood for the purposes of this petition only. The residue of
concern is quinoxyfen per se. 

  SEQ CHAPTER \h \r 1 An adequate gas chromatography with mass-selective
detection (GC-MSD) method is available for enforcing the proposed
quinoxyfen tolerances (DowElanco Procedure ERC95.26).  The general
procedure of this method involves extraction of the sample with acidic
acetone, partitioning with hexane, purification of the extract by
amino-propyl solid-phase extraction (SPE) column chromatography, and
analysis of the extract by GC-MSD.  The lowest level of method
validation (LLMV) is 0.01 ppm. 

The field trials on artichoke, peach, plum, and winter squash are   SEQ
CHAPTER \h \r 1 adequate.  An adequate number of trials were conducted
reflecting the proposed use patterns in the appropriate geographic
regions, and the appropriate commodities were collected at the proposed
PHIs.  Samples were analyzed using adequate analytical methods, and the
sample storage intervals are supported by the available storage
stability data.  The available artichoke data will support a tolerance
for residues of 1.4 ppm on artichoke, globe; the peach and plum data
will support a tolerance for residues of 0.70 ppm on fruit, stone, group
12; and the winter squash data will support a tolerance for residues of
0.20 ppm on squash, winter, pumpkin, and gourd, edible.  The petitioner
did not submit any crop field trial data for pumpkin or edible gourd,
but based on the Reviewers Guide and Summary of HED ChemSAC Approvals
for Amending Commodity Definitions (B. Schneider, 6/14/2002) those
specific commodities are included in the definition for winter squash.

Adequate confined and field rotational crop studies are not available. 
Crops having quinoxyfen tolerances may be replanted at any time. 
Rotation to all other crops is prohibited.

Provided a revised Section B is submitted reflecting the rotational crop
restriction, ARIA and HED concludes there are no residue chemistry data
requirements that would preclude establishing unconditional
registrations and permanent tolerances for residues of quinoxyfen at 1.4
ppm on artichoke, globe; 0.70 on fruit, stone, group 12; and 0.20 on
squash, winter; pumpkin; and gourd, edible.

Dietary Risk (Food and Drinking Water)

Drinking Water

Estimated drinking water concentrations (EDWCs) for the proposed uses of
quinoxyfen were provided.  The highest chronic quinoxyfen concentration
was estimated for surface water using the FIRST model.  The chronic
(1-in-10 year annual mean) value of 0.66 ppb was incorporated directly
as a point estimate in the dietary analysis to assess exposure to
quinoxyfen from drinking water.

Food

Based on toxicological considerations from HED, acute and cancer
assessments were not required.  HED previously determined that there was
no appropriate endpoint for use in assessing acute dietary exposure and
classified quinoxyfen as a “not likely carcinogen.” 

The unrefined chronic dietary assessment assumed that quinoxyfen
residues were present in all commodities at tolerance levels and that
100% of all crops were treated.  DEEM™ Version 7.81 default processing
factors were used to estimate residues in dried fruit (apricot, peach,
prune and raisin) and fruit juices (cherry, grape and prune).  The
estimated chronic dietary exposure (food and water) from quinoxyfen does
not exceed ARIA’s level of concern for any population subgroup.  Food
and water exposure occupies 1% of the cPAD for the general US population
and 2% of the cPAD for children 1-2 years old, the subgroup with the
highest exposure. 

Non-Occupational and Residential Risk

There are no registered or proposed uses of quinoxyfen which result in
residential exposures.  

Aggregate Risk

An aggregate exposure risk assessment was conducted by incorporating the
drinking water directly into the dietary exposure assessment for the
following scenario:  chronic aggregate exposure (food + drinking water).
 Short, -intermediate- and long-term aggregate-risk assessments were not
performed because there are no registered or proposed uses of quinoxyfen
which result in residential exposures.  Acute and cancer aggregate-risk
assessments were not performed because no appropriate endpoint was
available to determine the aRfD for the general population or any
population subgroup and quinoxyfen is not carcinogenic.  

Chronic aggregate risk estimates do not exceed ARIA’s level of
concern.  Since the chronic aggregate risk exposures include only food
and water, and the chronic dietary analyses included both, no further
calculations are necessary.

Occupational Exposure and Risk

Workers may be exposed to quinoxyfen during mixing, loading, and
application activities associated with agricultural crops.  No
chemical-specific data were available with which to assess potential
exposure to pesticide handlers, so estimates of exposure to pesticide
handlers are based upon surrogate study data available in the Pesticide
Handler’s Exposure Database (PHED), Version 1.1 of August 1998.  

ARIA believes pesticide handlers will be exposed to short-term duration
(1 - 30 days) exposures but not to intermediate-term (1 - 6 months)
duration exposures.   Although multiple applications are possible, the
product label directs that they not be consecutive and that they be
separated by a minimum of 6 day retreatment intervals.   It is unlikely
that pesticide handlers would be exposed continuously for 30 days or
more.  

A margin of exposure (MOE) of 100 or more is sufficient to protect
occupational pesticide handlers.  Occupational handler assessments
indicate that all MOEs are above the levels of concern at the baseline
level (total MOEs = 640 - 5200), provided mixer/loaders wear protective
gloves.  Post-application MOEs are also above the levels of concern (MOE
= 172).  The 12-hour restricted entry interval (REI) appearing on the
label is appropriate for this chemical.  

Environmental Justice

Potential areas of environmental justice concerns, to the extent
possible, were considered in this human-health risk assessment, in
accordance with U.S. Executive Order 12898, "Federal Actions to Address
Environmental Justice in Minority Populations and Low-Income
Populations," ( HYPERLINK
"http://homer.ornl.gov/nuclearsafety/nsea/oepa/guidance/justice/eo12898.
pdf_"
http://homer.ornl.gov/nuclearsafety/nsea/oepa/guidance/justice/eo12898.p
df ).

As a part of every pesticide risk assessment, OPP considers a large
variety of consumer subgroups according to well-established procedures. 
In line with OPP policy, HED estimates risks to population subgroups
from pesticide exposures that are based on patterns of that subgroup’s
food and water consumption, and activities in and around the home that
involve pesticide use in a residential setting.  Extensive data on food
consumption patterns are compiled by the USDA under the Continuing
Survey of Food Intakes by Individuals (CSFII) and are used in pesticide
risk assessments for all registered food uses of a pesticide.  These
data are analyzed and categorized by subgroups based on age, season of
the year, ethnic group, and region of the country.  Additionally, OPP is
able to assess dietary exposure to smaller, specialized subgroups and
exposure assessments are performed when conditions or circumstances
warrant.  Whenever appropriate, non-dietary exposures based on home use
of pesticide products and associated risks for adult applicators and for
toddlers, youths, and adults entering or playing on treated areas
post-application are evaluated.  Further considerations are currently in
development as OPP has committed resources and expertise to the
development of specialized software and models that consider exposure to
bystanders and farm workers as well as lifestyle and traditional dietary
patterns among specific subgroups.

Review of Human Research

This risk assessment relies in part on data from studies in which adult
human subjects were intentionally exposed to a pesticide or other
chemical.  These studies (Appendix B) have been determined to require a
review of their ethical conduct, and have received that review.

Additional Data Needs and Recommendations

There is no evidence of immunotoxicity in the hazard database for
quinoxyfen. However, the Revised Part 158 requires immunoxicity studies
be submitted.  While the new Part 158 requirement for an immunotoxicity
study has not yet been fulfilled for quinoxyfen, the existing data are
sufficient for endpoint selection for exposure/risk assessment scenarios
and for evaluation of the requirements under the Food Quality Protection
Act (FQPA).  Note that data requirements pertaining to immunotoxicity
(see Section 10.1) must be fulfilled as a condition of registration.

 

Provided a revised Section B is submitted reflecting the rotational crop
restriction, ARIA and HED conclude that there are no toxicological,
residue chemistry or occupational data requirements that would preclude
establishing conditional registrations and permanent tolerances for
residues of quinoxyfen at 1.4 ppm on artichoke, globe; 0.70 ppm on
fruit, stone, group 12; and 0.20 ppm on squash, winter; pumpkin; and
gourd, edible.

2.0	INGREDIENT PROFILE

A summary of the proposed uses associated with these petitions is
presented in Table 2.1.  The nomenclature and physicochemical properties
of quinoxyfen are presented below in Tables 2.2 and 2.3.

2.1	Summary of Proposed Uses

There is currently one quinoxyfen end-use product (EP) registered to Dow
Agrosciences LLC for use on food/feed crops:  Quintec®, a 22.58% ai SC
(EPA Reg. No. 62719-375).  IR-4 is supporting the use of Quintec® on
winter squash (including pumpkins and edible gourds), artichoke, and
stone fruit (group 12).  Example labels were provided and the proposed
use directions are summarized below in Table 2.1.

Table 2.1.  Summary of Proposed Use Directions for Quinoxyfen.

Application Timing, Type and Equipment	

Formulation

[EPA reg. No.]	Single rate

(lb ai/A)	Max Number Applications per Season	Max. Seasonal Application
Rate (lb ai/A)	

PHI (Days)	Use Directions and Limitations 1

Artichoke

Directed foliar applications 

Ground equipment	Quintec®

[62719-375]	0.13	4	0.52	0	The minimum RTI is 6-7 days.

Winter Squash

Directed foliar applications 

Ground equipment	Quintec®

[62719-375]	0.13	4	0.52	3	The minimum RTI is 6-8 days.

Stone Fruit (group 12)

Directed foliar applications 

Ground equipment	Quintec®

[62719-375]	0.13	4	0.52	7	The minimum RTI is 6-8 days.

1   Crops having quinoxyfen tolerances may be replanted at any time. 
Rotation to all other crops is prohibited.

  SEQ CHAPTER \h \r 1 Conclusions.  The proposed use directions on
winter squash (including pumpkins and edible gourds), artichoke, and
stone fruit (group 12) are adequately supported by the available residue
data except that the rotational crop restrictions are not listed on the
labels.  A revised Section B should be submitted.

2.2	Structure and Nomenclature

 

2.3	Physical and Chemical Properties

Table 2.3.  Physicochemical Properties of the Technical Grade Test
Compound.

Parameter	Value1

Molecular Weight	308.13

Melting point/range	106.0ºC-107.5ºC

pH	7.97 (1% solution in water @ 22.7°C)

Density 	1.097 g/cm3 @ 20°C

Vapor pressure	1.2x 10-5 Pa @ 20°C

Log10 KOW (Log P)	4.66 @ 20°C

Solubility	0.116 mg/L @ 20°C in distilled water

0.128 mg/L @ 20°C in water (pH 5)

0.047 mg/L @ 20°C in water (pH 7)

0.036 mg/L @ 20°C in water (pH 5)

9.64 mg/L @ 20°C in n-hexane

21.5 mg/L @ 20°C in methanol

179 mg/L @ 20°C in ethyl acetate

272 mg/L @ 20°C in toluene

116 mg/L @ 20°C in acetone

589 mg/L @ 20°C in dichloromethane

Dissociation Constant	Ka = 2.77 x 10-4, pKa = 3.56

1Smith, Amy J., Group B: Physical and Chemical Properties of Quinoxyfen
(DE-795) and Supplemental Properties of 3-Hydroxy-XDE-795, Dow
AgroSciences, LLC, 20 December 2000.

3.0	HAZARD CHARACTERIZATION

The existing toxicological database for quinoxyfen supports the
establishment of permanent tolerances for residues of quinoxyfen in/on
the RACs resulting from the proposed uses on winter squash (including
pumpkins and edible gourds), artichoke, and stone fruit (group 12).

3.1	Hazard and Dose-Response Characterization

3.1.1	Database Summary

 tc  \l 3 "3.1.1	Database Summary" 3.1.1.1	Studies available and
considered (animal, human, general literature)

Studies available and considered include acute oral, dermal, inhalation,
eye irritation, dermal irritation, and skin sensitization; subchronic;
chronic, carcinogenicity, reproductive/developmental, and neurotoxicity.

There is no evidence of immunotoxicity in the hazard database for
quinoxyfen. However, the Revised Part 158 requires immunoxicity studies
be submitted.  While the new Part 158 requirement for an immunotoxicity
study has not yet been fulfilled for quinoxyfen, the existing data are
sufficient for endpoint selection for exposure/risk assessment scenarios
and for evaluation of the requirements under FQPA.   

Note that data requirements pertaining to immunotoxicity (see Section
10.1) must be fulfilled as a condition of registration. 

Mode of action, metabolism, toxicokinetic data

Quinoxyfen is a systemic quinoline fungicide and was developed for the
control of powdery mildews on a variety of crops.  Its proposed mode of
action is the inhibition of GTP-binding proteins (G-proteins) in
intracellular signaling.  This mode of action, with attributes of a
multi-site fungicide, differs from that of either of the two primary
classes of synthetic, single-site vine fungicides (demethylation
inhibitors and strobilurins).  Quinoxyfen has a low overall risk for
development of disease resistance and is safe to non-target and
beneficial organisms.   

Sufficiency of studies/data

The available studies provide sufficient information to determine
whether, and to what extent, quinoxyfen poses a human health hazard (see
Appendix A for acute and repeated dose studies/findings).  Acute and
chronic reference doses for dietary risks as well as doses for
non-dietary risks are based on guideline acceptable studies with
well-characterized endpoints and NOAEL/LOAEL values.  The available
studies have been thoroughly evaluated for guideline acceptability by
individual reviewers and peer-review committees and the database is
considered sufficient to characterize and quantify risk.

3.1.2	Toxicological Effects

The toxicology database for quinoxyfen is basically complete.  HED did
request a 28-day inhalation study to characterize the direct effects of
quinoxyfen on the pulmonary system and any systemic effects via the
inhalation route; however, the active ingredient has low volatility, is
in acute inhalation Toxicity Category IV, and the extrapolated
inhalation MOE (based on an oral NOAEL) is approximately 10-fold higher
than the LOC, therefore a waiver can be granted for these use patterns..
 Quinoxyfen has low acute toxicity via the oral, dermal and inhalation
routes.  It is a mild eye irritant and dermal sensitizer, but is not a
dermal irritant.

The primary target organs affected by quinoxyfen are the liver and
kidney.  Liver effects were seen in rat and mouse subchronic and dog
chronic studies.  Subchronic effects in rats and mice included increased
liver weights, hepatocellular hypertrophy and individual cell
hepatocellular necrosis.  These effects were noted at high doses and
were not observed in the chronic rat and mouse studies since they were
performed at lower doses.  Chronic effects in the dog included increased
liver weights, increased alkaline phosphatase levels and increased
incidences of slight microscopic hepatic lesions (increased bile in
canaliculi and increased hepatocyte size).  Kidney effects were only
noted in the rat combined chronic/carcinogenicity study which resulted
in an increased severity of chronic progressive glomerulonephropathy in
the males.  Rabbits were much more susceptible to the effects of
quinoxyfen than any other species.  Systemic effects observed in the
rabbit developmental study included inanition, loss of body weight,
perineal soiling, blood in the cage pan associated with urine, and
abortions.  Body weight decrements were noted in the rat and/or mouse
subchronic, chronic and carcinogenicity studies and the rabbit
developmental and rat reproduction studies.  No effects were noted via
the dermal route.

Long-term dietary administration of quinoxyfen did not result in an
overall treatment-related increase in incidence of tumor formation in
rats or mice.  HED classified quinoxyfen as "not likely to be
carcinogenic to humans" by all routes of exposure based upon lack of
evidence of carcinogenicity in rats and mice.

Quinoxyfen did not show evidence of mutagenicity in in vitro or in vivo
studies.

Oral rat and rabbit developmental studies showed no increased
susceptibility of the fetus to quinoxyfen in utero.  No maternal or
developmental toxicity was observed in the rat developmental study up to
the limit dose of 1000 mg/kg/day.  In the developmental toxicity study
in the rabbit, maternal toxicity included inanition, decreased body
weight and weight gain, decreased fecal output, perineal soiling, blood
in the cage pan associated with urine, and abortions.  Developmental
toxicity was evidenced as increased abortions at the same dose.  There
was an increased quantitative susceptibility following pre/post natal
exposure to rats in the reproduction study.  No maternal effects were
observed up to the highest dose tested (100 mg/kg/day); however,
minimally reduced F1a pup weights were noted at 100 mg/kg/day.  However,
the concern is low since: 1) the effects in pups are well-characterized
with a clear NOAEL; 2) the pup effects are minimal at the LOAEL and only
noted in the first-generation offspring; and, 3) the doses and endpoints
selected for risk assessment are protective of the minimal pup effects
noted in the rat reproduction study.  For these reasons, and since there
are no residual uncertainties for pre-/post-natal toxicity and no
evidence of immuntoxicity in the database, the FQPA Safety Factor can be
reduced to 1X.

No evidence of neurotoxicity or neuropathology was seen in any of the
submitted studies, including the acute and subchronic neurotoxicity
studies (2003 HIARC report, TXR# 0051474).

3.1.3	Dose-response

Since there were no toxic effects attributable to a single dose, an
endpoint of concern was not identified to quantitate acute-dietary risk
to the general population or to the subpopulation females 13-50 years
old.  Therefore, there is no acute reference dose (aRfD) or acute
population-adjusted dose (aPAD) for the general population or females
13-50 years old.  The short-/intermediate-term dermal and inhalation
endpoints are based upon a minimal decrease in F1a pup weights.  The
chronic reference dose (cRfD) and long-term dermal and inhalation
endpoints are based upon increases in severity of chronic progressive
glomerulonephropathy in the males and minimal decreases in body weight
and body-weight gain in both sexes of rats in a combined
chronic/carcinogenicity study.  The cRfD is 0.20 mg/kg/day and the
chronic population-adjusted dose (cPAD) is 0.20 mg/kg/day.  Quinoxyfen
has been classified as "not likely to be carcinogenic to humans" by all
routes of exposure based upon lack of evidence of carcinogenicity in
rats and mice.  Therefore, a cancer risk assessment is not required. 
Since oral studies were selected for all durations of dermal and
inhalation exposure, and no dermal or inhalation absorption studies are
available, a 100% dermal-absorption factor and a 100% inhalation
absorption factor are assumed in the route-to-route extrapolation.

The dermal toxicological endpoint was identified from a multigeneration
reproduction study in the rat.  The toxic effect noted was a minimal
decrease in F1a pup weights.  The 

NOAEL is 20 mg ai/kg bw/day.  The LOC is for MOE < 100.   Although
intermediate-term exposures are not expected, the same endpoint, NOAEL
and LOC are applicable for intermediate-term exposures (1 – 6 months).
  The inhalation toxicological endpoint, NOAEL and LOC are the same as
were identified for dermal exposure.  The inhalation toxicological
endpoint was also identified from the multi-generation reproduction
study in the rat.  

3.1.4	FQPA

HED previously concluded that the hazard and exposure data for
quinoxyfen indicate there is no evidence of quantitative or qualitative
increased susceptibility, as compared to adults, of rat or rabbit
fetuses to in utero exposure to quinoxyfen in the developmental toxicity
studies.  There is quantitative evidence of increased susceptibility in
the rat multi-generation reproduction study, but the concern is low
since: 1) the effects in pups are well-characterized with a clear NOAEL;
2) the pup effects are minimal at the LOAEL and only noted in the first
generation offspring; and, 3) the doses and endpoints selected for
regulatory purposes would address the concerns of the pup effects noted
in the rat reproduction study.  

The FQPA SF can be removed [1x] since there are no residual
uncertainties for pre-/post-natal toxicity and there is no evidence of
immunotoxicity in the database.

3.2	Absorption, Distribution, Metabolism, Excretion (ADME)

Quinoline-labeled and phenyl-labeled quinoxyfen were rapidly absorbed
with approximately 68-85% of the administered dose being eliminated
within 24 hours.  Overall recovery of the dosed radioactivity ranged
from 83.5-96.2%.  Sex, dose, and multiple dosing had little or no effect
on the excretion profile at 48 hours post-dosing.  Changing the position
of the 14C-label altered the pattern of excretion.  The major route of
elimination was through the urine in the phenyl-labeled test substance
(44.9-48.7% of dose in urine and 38.2-39.8% of dose in feces) and
through the feces in the quinoline-labeled test substance (65.8-78.3% of
dose in feces and 13.4-19.7% of dose in urine).  Biliary excretion
increased its contribution to fecal radioactivity as the dose increased.
 Concentrations of radioactivity in the tissues were generally slightly
lower in the males than females and in the low-dose compared to the
high-dose group.  The highest concentrations of radioactivity were found
in the kidney, liver, ovaries, perirenal fat, GI tract and carcass. 
Maximum plasma concentration occurred between 0.5 and 1.5 hours, and
elimination half-lives were </= 1 hour and 15-19 hours (10 mg/kg group)
and 2-3 hours and 18-22 hours (500 mg/kg group).

The presence of several radioactive components was determined in the
unhydrolyzed urine (up to 12), fecal extracts (up to 8), and bile (up to
6).  No differences in the metabolite profile were observed that were
related to sex or multiple dosing.  Increasing amounts of the parent
compound were found in the feces with increasing dose.  No other
dose-related differences were observed.  Identified metabolites
accounted for 41.0-42.8% dose in the [Phenyl-U-14C] XDE-795 treated
group, and only 17.0-31.7% dose in the other treated groups.  The
[Phenyl-U-14C] XDE-795 treated group had no urinary metabolites in
common with the [2-Quinoline-14C] XDE-795 treated groups suggesting
cleavage of the parent molecule.  An acid-labile conjugate of
4-fluorophenol was found in the urine of the [Phenyl-U-14C] XDE-795
treated group (28.7-32.8% dose).  5,7-Dichloro-4-hydroxyquinoline was
observed in the urine of the [2-Quinoline-14C] XDE-795 treated groups in
small quantities (0.7-1.7% dose).  Thus, the identified metabolites in
the urine followed diaryl-ether cleavage of the parent compound. 
Fluorophenyl-ring-OH-XDE-795 (two isomers) were found in the feces of
all treated groups (5.4-10.6% dose).  In the bile of the treated groups,
two major metabolites were identified, a glucuronide and/or sulfate
conjugate(s) of the two isomers of fluorophenyl ring-hydroxy-XDE-795
(9-19% dose) and an unidentified metabolite (13-21% dose).

3.3	FQPA Considerations

3.3.1	Adequacy of the Toxicity Database

HED concluded that the toxicology database for quinoxyfen is complete
and is adequate for an FQPA evaluation.  The following studies are
available:

Two developmental toxicity studies - Rat and Rabbit

Two-generation reproduction toxicity study - Rat

Acute neurotoxicity study - Rat

Subchronic neurotoxicity study - Rat

Evidence of Neurotoxicity

HED concluded that there is no evidence of neurotoxicity as a result of
exposure to quinoxyfen. 

Acute Neurotoxicity

In an acute neurotoxicity study (MRID 45360515) quinoxyfen (XR-795;
97.4% ai, Batch/Lot # DECO-97-152-1) was administered to 10 Fischer 344
rats/sex/group at dose levels of 0, 200, 632, or 2000 mg/kg (limit
dose), once via gavage, in 0.5% methylcellulose, in a dosing volume of
10 mL/kg bw.  The time of peak effect was determined in a previous study
to be five hours post-dosing, based on lacrimation.  Neurobehavioral
assessment (functional observational battery and motor activity testing)
was performed on all animals pretest and on days 1 (five hours
post-dosing), 8, and 15.  At study termination, 5 animals/sex/group were
sacrificed by perfusion fixation.  Perfused animals in the control and
2000 mg/kg groups were subjected to histopathological evaluation of
central and peripheral nervous system tissues.  Three studies were
submitted to generate positive control data and validate the procedures
of the performing lab in performing the functional observational battery
(FOB) and in assessing motor activity and neuropathology.  All studies
were performed by The Dow Chemical Company (Midland, MI); and were
published in a 1995 report.

No mortalities occurred.  Clinical signs, ophthalmology, body weights,
body weight gain, FOB, motor activity, gross pathology, and
neuropathology were unaffected by the test substance.  Motor activity
subsession data indicated that habituation was normal.  There was no
evidence of neurotoxicity at any dose tested.  The LOAEL for this study
was not observed.  The NOAEL for this study is 2000 mg/kg (limit dose).

Subchronic Neurotoxicity

In a one-year neurotoxicity toxicity study (MRID 45360518), quinoxyfen
(XDE-795; Lot/batch # TSN100097, 97.4% ai) was administered to Fischer
344 rats (15/sex/dose) in the diet at dose levels of 0, 5, 20, or 80
mg/kg/day for 12 months, along with a concurrent chronic carcinogenicity
study of quinoxyfen at the same dose levels.  10 Fischer 344
rats/sex/dose were assigned to the neurotoxicity study.  The
neurotoxicity subset of rats were evaluated pre-exposure, and at months
3, 6, 9 and 12 by a FOB, forelimb and hindlimb grip performance, landing
footsplay, and an automated test of motor activity.  After completion of
12 months of exposure, neuropathologic examination of perfusion fixed
central and peripheral nervous tissues was conducted on 5 rats/sex from
the control and 80 mg/kg/day groups.  Three studies were submitted that
generated positive control data and validated the procedures of the
performing lab in performing the FOB and in assessing motor activity and
neuropathology.  All studies were performed by The Dow Chemical Company
(Midland, MI); study dates were not provided.

Mortality, body weights, body weight gain, FOB parameters, motor
activity, gross pathology, and neuropathology were unaffected by the
test substance.  Motor activity subset data indicated that habituation
was normal.  Brain weights were not reported.  No treatment-related
findings were noted at any dose tested.  No evidence of neurotoxicity
was observed at any dose tested.  The LOAEL for this study was not
observed.  The NOAEL for this study is 80 mg/kg/day.

No evidence of neurotoxicity was noted in any other oral toxicity
studies submitted.

Developmental Toxicity Studies

Rat

In a developmental toxicity study (MRID 45360520), XDE-795 (quinoxyfen;
Lot/batch # TSN 100097; 97.4% ai) was administered in 1% methylcellulose
orally via gavage, in a dosing volume of 10 mL/kg, to 30 female
Sprague-Dawley Crl: CD®(SD) BR VAF/Plus rats/group, at dose levels of
0, 100, 300, or 1000 (limit dose) mg/kg/day, on gestation days (GDs) 6
through 15.  All surviving dams were sacrificed on GD 20 and their
fetuses were removed by cesarean and examined.

No treatment-related changes were observed in maternal survival, body
weight, body weight gain, food consumption, gross pathology, or liver
weights.  The mean numbers of live fetuses, numbers of early and late
embryonic deaths (resorptions and fetal deaths), sex ratios, and
post-implantation losses were comparable among treated groups and
controls.  There were no abortions.  The maternal LOAEL was not
observed.  The maternal NOAEL is 1000 mg/kg/day (limit dose).

No treatment-related external, visceral, or skeletal malformations,
variations, or anomalies were noted.  Fetal weights were comparable
among treated groups and controls.  The developmental toxicity LOAEL was
not observed.  The developmental toxicity NOAEL is 1000 mg/kg/day (limit
dose).

Rabbit

In a developmental toxicity study (MRIDs 45360521 & 45360519), XDE-795
(quinoxyfen; Lot/batch # TSN 100097; 96.2% ai) was administered in 0.5%
methylcellulose orally via gavage, in a dosing volume of 4 mL/kg, to 18
female New Zealand White rabbits/group, at dose levels of 0, 20, 80, or
200 mg/kg/day, on gestation days (GDs) 7 through 19.  All surviving does
were sacrificed on GD 28 and their fetuses were removed by cesarean and
examined.

When compared to concurrent controls, no treatment-related changes were
observed in maternal survival, liver weights, or kidney weights.  The
mean number of live fetuses, number of resorptions, sex ratios, and
post-implantation losses were comparable among treated groups and
controls.  At 200 mg/kg, 5 does aborted during GDs 20-25; marked
inanition, decreased fecal output, and body weight loss were observed in
all 5 of these does prior to aborting.  Other clinical observations
related to abortion were seen at 200 mg/kg/day, including perineal
soiling, blood in the pan, and blood associated with urine in the pan. 
Gross examination revealed slight liver necrosis with fibrous adhesions,
pale liver foci, and non-specific lesions secondary to inanition (gas
and watery cecal contents, decreased ingesta, and gastric hairball)in 1
out of 5 animals per observation.

Additionally at 200 mg/kg, maternal body weights were decreased ((9%;
p(0.05) on GD 20; body weight gains were decreased during GDs 16-20
((268%; p(0.05) and for the overall (GDs 7-20) treatment interval ((76%;
not significant).  Maternal food consumption was decreased during GDs
7-24 ((5-55%; statistics not performed), recovering at the end of the
post-treatment interval (GDs 24-28).  Decreased feces (11/18 treated vs
0/18 controls) and soft feces (4/18 treated vs 0/18 controls) were
observed in these does.  Not including the animals that aborted, gross
pathological findings at 200 mg/kg included perineal soiling and pale
liver (1/12 each observation vs 0/18 controls). The maternal LOAEL is
200 mg/kg/day based on inanition, clinical signs, decreased body
weights, body weight gains, and food consumption, and on increased
incidences of abortion.  The maternal NOAEL is 80 mg/kg/day.

There were no treatment-related differences in the number of
resorptions.  No fetal deaths were reported.  Mean fetal weights of the
treated groups were comparable to controls.  No treatment-related
external, visceral, or skeletal malformations or variations were noted. 
The developmental toxicity LOAEL is 200 mg/kg/day based on increased
incidences of abortion.  The developmental toxicity NOAEL is 80
mg/kg/day.

Reproductive Toxicity Study

In a two-generation reproduction toxicity study (MRID 45360522),
quinoxyfen (97.4% ai; Lot/batch # TSN 100097) was administered
continuously in the diet to Sprague-Dawley rats (30/sex/dose) at nominal
dose levels of 0, 5, 20, or 100 mg/kg/day.  The P animals were fed test
article diet formulations approximately 10 weeks prior to mating to
produce the F1a litters.  After weaning, 30 male and 30 female F1a
animals were selected (one/sex/litter whenever possible) to become F1
parents of the F2 generation and treated with the same concentration
test formulation as their dam from post-natal day (PND ) 21 until
sacrifice following weaning of the F2 generation.  F1 animals were fed
the test formulation for approximately 12 weeks prior to mating to
produce the F2 litters.  The F1b animals were weaned at 21 days and
10/sex/dose were selected for necropsy.

Mortality, clinical signs, body weights, body weight gains, food
consumption, reproductive performance (mating index, fertility index,
and gestation length), and gross pathology were unaffected by treatment.
 In the 100 mg/kg P and F1 males, very slight to slight hepatocellular
hypertrophy was observed (P: 24/30 treated vs. 1/28 controls; F1: 28/30
treated vs. 0/30 controls).  This effect, due to the minimal hepatic
response and the absence of any other liver histopathology or clinical
chemistry data, is considered not adverse.  No other treatment-related
findings were noted at any dose tested.  The NOAEL for parental toxicity
is 100 mg/kg/day.  The LOAEL for parental toxicity was not determined.

At 100 mg/kg, body weights were decreased (p(0.05) in the F1a males and
females on PND 21 ((9-11%).  In addition, body weights were slightly
decreased (p(0.05) in the F1a males on PND 7 ((6%).  Decreased (p(0.05)
body weights in the 100 ppm F1b males on PNDs 4-7 ((11-12%) correlated
with increased mean litter size and were considered to be of equivocal
toxicological importance.  No other treatment-related findings were
noted at any dose tested.  The LOAEL for offspring toxicity is 100
mg/kg/day based upon a minimal decreased in F1a pup weights.  The NOAEL
for offspring toxicity is 20 mg/kg/day.

The NOAEL for reproductive toxicity is 100 mg/kg/day.  The LOAEL was not
determined.

3.3.5	Additional Information from Literature Sources

	

No additional information is available from the published literature.

3.3.6	Pre-and/or Post-natal Toxicity

The HIARC concluded that there is no concern for pre- and/or postnatal
toxicity resulting from exposure to quinoxyfen.

3.3.6.1	Determination of Susceptibility

There is no quantitative or qualitative evidence of increased
susceptibility of rat and rabbit fetuses to in utero exposure in
developmental studies.

There is quantitative evidence of increased susceptibility of rat
offspring in the multi-generation reproduction study.  No maternal
effects were observed up to the highest dose tested (100 mg/kg/day);
however, minimally reduced F1a pup weights were noted at 100 mg/kg/day.

3.3.6.2	Degree of Concern Analysis and Residual Uncertainties

Since there is no evidence of increased susceptibility of rat and rabbit
fetuses to in utero exposure, there is no concern and no residual
uncertainties for pre-natal toxicity.

There is quantitative evidence of increased susceptibility in the rat
multi-generation reproduction study, but the concern is low since: 1)
the effects in pups are well-characterized with a clear NOAEL; 2) the
pup effects are minimal at the LOAEL and only noted in the first
generation offspring; and, 3) the doses and endpoints selected for
regulatory purposes would address the concerns of the pup effects noted
in the rat reproduction study.  Therefore, there are no residual
uncertainties for pre-/post-natal toxicity in this study.

3.3.7	Recommendation for a Developmental Neurotoxicity (DNT) Study

HED determined that a DNT study was not required.

Evidence that suggests requiring a DNT study:

None.

Evidence that does not support a need for a DNT study:

-	No evidence of neurotoxicity in the acute or subchronic neurotoxicity
studies or any other submitted study.

-	No neuropathology noted in any study.

FQPA Safety Factor for Infants and Children

The FQPA SF can be removed [1x] since there are no residual
uncertainties for pre-/post-natal toxicity.

HED recommended the FQPA SF assuming that the exposure databases
(dietary food, drinking water, and residential) are complete and that
the risk assessment for each potential exposure scenario includes all
metabolites and/or degradates of concern and does not underestimate the
potential risk for infants and children.

Hazard Identification and Toxicity Endpoint Selection

3.5.1    Acute Reference Dose (aRfD)  

 tc  \l 3 "3.5.1    Acute Reference Dose (aRfD) - Females age 13-49" 

Study Selected:   None 

MRID No.:   None

Executive Summary:   None

Dose and Endpoint for Establishing aRfD:   Not applicable

Uncertainty Factor (UF):  Not applicable 

Comments about Study/Endpoint/Uncertainty Factor:  No appropriate
endpoint was available to quantitate risk to the general population from
a single-dose administration of quinoxyfen.  The abortions that were
noted in the rabbit developmental study were not considered to occur
after a single dose since they were observed late in pregnancy in the
presence of substantial maternal toxicity.  Therefore, no endpoint was
chosen to quantitate risk to females 13-50 from a single-dose
administration of quinoxyfen.

3.5.2	Chronic Reference Dose (cRfD) 

 tc  \l 3 "3.5.3	Chronic Reference Dose (cRfD)" 

Study Selected: Combined Chronic Toxicity/Carcinogenicity - Rat    OPPTS
870.4300

MRID No.: 45360523

Executive Summary:  In a combined chronic/oncogenicity study (MRID
45360523), XDE-795 (quinoxyfen, 96.2-97.4% ai, Lot Batch No. TSN100097)
was administered daily in the diet to 50 Fischer 344 rats/sex/dose at
dose levels of 0, 5, 20 or 80 mg/kg/day for 24 months.  At 12 months, 10
rats/sex/group were terminated.  

No treatment-related effect was observed on mortality.  Clinical signs,
food consumption, food efficiency, hematology, clinical chemistry,
urinalysis and ophthalmological parameters were also unaffected by
treatment.  No treatment-related effects were noted at 5 or 20 mg/kg. 

At 80 mg/kg, minimal reductions (p<=0.05) in body weights (dec. 2-9%)
and cumulative body weight gain (dec. 4-14%) were observed in both
sexes; overall (study days -3 to 730) body weight gain was also reduced
(p<=0.05) by 9-10%.  In addition at the final sacrifice, decreased
(p<=0.05) terminal body weights were observed in this group (dec. 6-7%).
 Increased (inc. 8-11%; p<=0.05) absolute and relative to body kidney
weights were observed in the 80 mg/kg males at the interim sacrifice and
increased (inc. 3-7%; p<=0.05) relative to body kidney weights were
observed at the final sacrifice in both sexes, with no increase in
absolute kidney weights.  Microscopic and gross pathology may not be
causative of the minor differences in kidney weights observed in the 80
mg/kg males.  At the interim sacrifice, very slight to slight bilateral
chronic progressive glomerulonephropathy (CPN) was observed in 90-100%
of the males.  Grossly at the final sacrifice (n=50), the incidence of
roughened surface of the kidney was dose-dependently increased in the
males (38, 40, 50, 64%, in the control, 5, 20, and 80 mg/kg groups,
respectively).  At the final sacrifice (including decedents), an
increased incidence of moderate (p<=0.05) to severe (not statistically
significant) CPN was observed in the 80 mg/kg males (70 % treated vs 34%
controls). 

Dosing was considered adequate based on the treatment-related changes
observed in the kidneys of the 80 mg/kg males and on the minimal
decreases in body weight and body weight gain observed in the 80 mg/kg
males and females.

The LOAEL is 80 mg/kg/day based on increases in severity of CPN in the
males and minimal decreases in body weight and body weight gain in the
males and females.  The NOAEL for this study is 20 mg/kg/day. 

Under the conditions of this study, the carcinogenic potential of
XDE-795 is considered negative.

This study is acceptable/guideline and does satisfy the guideline
requirement for a chronic/ carcinogenicity study (OPPTS 870.4300; OECD
453) in rats.

Dose and Endpoint for Risk Assessment: 20 mg/kg/day (NOAEL), based upon
increases in severity of CPN in the males and minimal decreases in body
weight and body weight gain in both sexes at the LOAEL of 80 mg/kg/day.

Uncertainty Factor(s): 100 

Comments about Study/Endpoint/Uncertainty Factor:  This study and
endpoint are appropriate for the route and duration of exposure.  The
NOAEL is the lowest in the database for chronic effects and is
protective of all populations.

Chronic RfD   =       20 mg/kg/day (NOAEL)    =	0.20 mg/kg/day

				100 (UF)

3.5.3	Incidental Oral Exposure: Short- and Intermediate-Term (1 day - 6
months) 

 tc  \l 3 "3.5.4	Incidental Oral Exposure (Short- and
Intermediate-Term)" 

Study Selected:  Multi-generation Reproduction Study - Rat	OPPTS
870.3800

MRID No.: 45360522

Executive Summary: In a two-generation reproduction toxicity study (MRID
45360522), quinoxyfen (97.4% ai; Lot/batch # TSN 100097) was
administered continuously in the diet to Sprague-Dawley rats
(30/sex/dose) at nominal dose levels of 0, 5, 20, or 100 mg/kg/day.  The
P animals were fed test article diet formulations approximately 10 weeks
prior to mating to produce the F1a litters.  After weaning, 30 male and
30 female F1a animals were selected (one/sex/litter whenever possible)
to become F1 parents of the F2 generation and treated with the same
concentration test formulation as their dam from post-natal day (PND) 21
until sacrifice following weaning of the F2 generation.  F1 animals were
fed the test formulation for approximately 12 weeks prior to mating to
produce the F2 litters.  The F1b animals were weaned at 21 days and
10/sex/dose were selected for necropsy.

Mortality, clinical signs, body weights, body weight gains, food
consumption, reproductive performance (mating index, fertility index,
and gestation length), and gross pathology were unaffected by treatment.
 In the 100 mg/kg P and F1 males, very slight to slight hepatocellular
hypertrophy was observed (P: 24/30 treated vs. 1/28 controls; F1: 28/30
treated vs. 0/30 controls).  This effect, due to the minimal hepatic
response and the absence of any other liver histopathology or clinical
chemistry data, is considered not adverse.  No other treatment-related
findings were noted at any dose tested.  No other treatment-related
findings were noted at any dose tested.  The NOAEL for parental toxicity
is 100 mg/kg/day.  The LOAEL for parental toxicity was not determined.

At 100 mg/kg, body weights were decreased (p(0.05) in the F1a males and
females on PND 21 ((9-11%).  In addition, body weights were slightly
decreased (p(0.05) in the F1a males on PND 7 ((6%).  Decreased (p(0.05)
body weights in the 100 ppm F1b males on PNDs 4-7 ((11-12%) correlated
with increased mean litter size and were considered to be of equivocal
toxicological importance.  No other treatment-related findings were
noted at any dose tested.  The LOAEL for offspring toxicity is 100
mg/kg/day based upon a minimal decrease in F1a pup weights.  The NOAEL
for offspring toxicity is 20 mg/kg/day.

The reproductive study in the rat is acceptable/guideline and satisfies
the guideline requirements for a two-generation reproduction study in
the rat (OPPTS 870.3800; OECD 416).  

Dose and Endpoint for Risk Assessment:  20 mg/kg/day (Offspring NOAEL),
based upon a minimal decrease in F1a pup weights at the LOAEL of 100
mg/kg/day.

Comments about Study/Endpoint:  The endpoint of concern is appropriate
for the population of concern (infants and children) and the duration of
exposure.  The chosen endpoint would address the concerns for the
effects in offspring noted in this study during the lactation period.

3.5.4	Dermal Absorption

Dermal Absorption Factor:  No dermal absorption study was submitted.
There were no effects seen in the rat dermal or rat developmental
studies up to the limit dose of 1000 mg/kg/day.  Since there is no
information on dermal penetration of quinoxyfen, a default absorption
factor of 100% (oral equivalent) will be assumed.

3.5.5	Dermal Exposure: Short- and Intermediate-Term (1 day - 6 months)

 tc  \l 3 "3.5.6	Dermal Exposure (Short-, Intermediate- and Long-Term)" 

Study Selected:  Multi-generation Reproduction Study - Rat	OPPTS
870.3800

MRID No.: 45360522

Executive Summary:  See 3.5.4, Incidental Oral Exposure: Short- and
Intermediate-Term (above)

Dose and Endpoint for Risk Assessment:  20 mg/kg/day (Offspring NOAEL),
based upon a minimal decrease in F1a pup weights at the LOAEL of 100
mg/kg/day.

Comments about Study/Endpoint: A 21-day dermal study was submitted with
no systemic effects noted up to 1000 mg/kg/day; however, the dermal
study did not evaluate systemic effects in lactational offspring. 
Therefore, it is appropriate to choose an oral endpoint for this risk
assessment and do route-to-route extrapolation to adequately protect
infants during the lactation period of female workers and children via
post-application dermal exposure.  The chosen endpoint is from a study
of the appropriate duration of exposure.  A dermal absorption factor of
100% should be applied.

3.5.6	Dermal Exposure: Long-Term (> 6 Months)

Study Selected:  Combined Chronic Toxicity/Carcinogenicity - Rat   
OPPTS 870.4300 

MRID No.: 45360523

Executive Summary: See 3.5.2 Chronic Reference Dose (cRfD) (above)

Dose and Endpoint for Risk Assessment: 20 mg/kg/day (NOAEL), based upon
increases in severity of CPN in the males and minimal decreases in body
weight and body weight gain in both sexes at the LOAEL of 80 mg/kg/day.

Comments about Study/Endpoint:  No long-term dermal study was submitted.
 The chosen endpoint is from a study of the appropriate duration of
exposure.  It is protective of all populations, including infants and
children.  A dermal absorption factor of 100% should be applied.

3.5.7	Inhalation Exposure: Short- and Intermediate-Term (1 day - 6
months)

 tc  \l 3 "3.5.7	Inhalation Exposure (Short-, Intermediate- and
Long-Term)" 

Study Selected:  Multi-generation Reproduction Study - Rat	OPPTS
870.3800

MRID No.: 45360522

Executive Summary:  See 3.5.4, Incidental Oral Exposure: Short- and
Intermediate-Term (above) 

Dose and Endpoint for Risk Assessment:  20 mg/kg/day (Offspring NOAEL),
based upon a minimal decrease in F1a pup weights at the LOAEL of 100
mg/kg/day.

Comments about Study/Endpoint:  No inhalation study was submitted. 
Therefore, it is appropriate to choose an oral endpoint for this risk
assessment and do route-to-route extrapolation to adequately protect
infants during the lactation period of female workers and children via
post-application inhalation exposure.  The chosen endpoint is from a
study of the appropriate duration of exposure.  Absorption via
inhalation (100%) is presumed to be equivalent to oral absorption.

3.5.8	Inhalation Exposure: Long-Term (> 6 Months)

Study Selected:  Combined Chronic Toxicity/Carcinogenicity - Rat   
OPPTS 870.4300 

MRID No.: 45360523

Executive Summary: See 3.5.2 Chronic Reference Dose (cRfD) (above).

Dose and Endpoint for Risk Assessment: 20 mg/kg/day (NOAEL), based upon
increases in severity of chronic progressive glomerulonephropathy in the
males and minimal decreases in body weight and body weight gain in both
sexes at the LOAEL of 80 mg/kg/day.

Comments about Study/Endpoint:  No inhalation study was submitted.  The
chosen endpoint is from a study of the appropriate duration of exposure.
 It is protective of all populations, including infants and children. 
Absorption via inhalation (100%) is presumed to be equivalent to oral
absorption.

3.5.9	Level of Concern for Margin of Exposure

The target MOEs for risk assessments are noted below, in Table 3.5.9.

Table 3.5.9. Summary of Levels of Concern for Risk Assessment.

Route                         	Short-Term

(1-30 Days)	Intermediate-Term

(1 - 6 Months)	 Long-Term

(> 6 Months)

Occupational (Worker) Exposure

Dermal	100	100	100

Inhalation	100	100	100

Residential (Non-Dietary) Exposure

Oral	100	100	100

Dermal	100	100	100

Inhalation	100	100	100

The MOEs for dermal and inhalation exposures may be combined for
occupational exposure risk assessment because oral equivalent doses were
used for these routes of exposure.

3.5.10	Recommendation for Aggregate Exposure Risk Assessments

As per FQPA, 1996, when there are potential residential exposures to the
pesticide, aggregate risk assessment must consider exposures from three
major sources: oral, dermal and inhalation exposures.  The toxicity
endpoints selected for these routes of exposure may be aggregated as
follows:

For short- and intermediate-exposure, oral and dermal and inhalation
endpoints can be aggregated because of the use of oral equivalents and a
common endpoint (decreased body weights).

For long-term exposure, oral and dermal and inhalation endpoints can be
aggregated because of the use of oral equivalents and common endpoints
(kidney toxicity and body weight decrements).

 tc  \l 3 "3.5.9	Recommendation for Aggregate Exposure Risk Assessments"

There are no registered or proposed uses of quinoxyfen which result in
residential exposures; therefore, aggregate risk includes only food and
water exposures.   

3.5.11	Classification of Carcinogenic Potential

HED classified quinoxyfen as "not likely to be carcinogenic to humans"
by all routes of exposure based upon lack of evidence of carcinogenicity
in rats and mice.

  

3.5.12	Summary of Toxicological Doses and Endpoints for Quinoxyfen for
Use in Human Risk Assessments

Table 3.5.12. Summary of Toxicological Doses and Endpoints for
Quinoxyfen Human Health Risk Assessments.

Exposure

Scenario	Point of Departure,

Uncertainty/ FQPA SFs	RfD, PAD, Level of Concern for Risk Assessment
Study and Toxicological Effects

Acute Dietary

all populations

	Not applicable	Not applicable	Since there were no adverse effects
attributable to a single dose, an endpoint of concern was not identified
to quantitate acute dietary risk to the general population or to the
subpopulation females 13-50 years old.

Chronic Dietary

all populations	NOAEL= 20 mg/kg/day

UF = 100

	FQPA SF = 1X

cPAD = cRfD

             FQPA SF

= 0.20 mg/kg/day	Combined chronic tox/carcinogenicity - rat

LOAEL = 80 mg/kg/day, based upon increases in severity of chronic
progressive glomerulonephropathy in the males and minimal decreases in
body weight and body weight gain in both sexes.

Short-/ Intermediate-Term Incidental Oral (1 day - 6 months)	oral

NOAEL= 20 mg/kg/day	LOC for MOE = 100 (Residential, includes the FQPA
SF)	Multigeneration reproduction - rat

Offspring LOAEL = 100 mg/kg/day, based upon a minimal decrease in F1a
pup weights.

Short-/ Intermediate-Term Dermal (1 day - 6 months)

	oral

NOAEL= 20 mg/kg/day

(dermal absorption rate = 100%)	LOC for MOE = 100 (Occupational)

LOC for MOE = 100 (Residential, includes the FQPA SF)	Multigeneration
reproduction - rat

Offspring LOAEL = 100 mg/kg/day, based upon a minimal decrease in F1a
pup weights.

Long-Term Dermal (> 6 months)

	oral

NOAEL= 20 mg/kg/day

(dermal absorption rate = 100%)	LOC for MOE = 100 (Occupational)

LOC for MOE = 100 (Residential, includes the FQPA SF)	Combined chronic
tox/carcinogenicity - rat

LOAEL = 80 mg/kg/day, based upon increases in severity of chronic
progressive glomerulonephropathy in the males and minimal decreases in
body weight and body weight gain in both sexes.

Short-/ Intermediate-Term Inhalation (1 day - 6 months)

	oral

NOAEL= 20 mg/kg/day

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

LOC for MOE = 100 (Residential, includes the FQPA SF)	Multigeneration
reproduction - rat

Offspring LOAEL = 100 mg/kg/day, based upon a minimal decrease in F1a
pup weights.

Long-Term Inhalation (> 6 months)

	oral

NOAEL= 20 mg/kg/day

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

LOC for MOE = 100 (Residential, includes the FQPA SF)	Combined chronic
tox/carcinogenicity - rat

LOAEL = 80 mg/kg/day, based upon increases in severity of chronic
progressive glomerulonephropathy in the males and minimal decreases in
body weight and body weight gain in both sexes.

Cancer (oral, dermal, inhalation)	Classified as “Not likely to be
carcinogenic to humans” based on the absence of carcinogenicity in
rats or mice

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

3.6	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 were scientific
bases 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).

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

4.0	DIETARY EXPOSURE/RISK CHARACTERIZATION

4.1	Pesticide Metabolism and Environmental Degradation

4.1.1	Metabolism in Primary Crops and Livestock Commodities.

Plants

Based on acceptable cucumber, grape, sugar beet, and tomato metabolism
studies, the nature of the residue in plants is adequately understood
for the purposes of this petition only.  Quinoxyfen was the primary
residue component in all reviewed plant metabolism studies except in
wheat grain and straw where Metabolite A was the predominant residue. 
Metabolite A was determined not to be associated with the parent
quinoxyfen, or related compounds, but was characterized to be highly
polar and multi-component in nature.

In cucumber and tomato, unchanged quinoxyfen remained largely on the
surface of treated plants.  The presence of multiple unidentified polar
residues suggests that metabolism of quinoxyfen does occur to some
extent to form more polar soluble components with the incorporation into
insoluble material.  Degradates and conjugates may be incorporated into
natural constituents such as lignin and cellulose.  Minor differences in
the characterized residues (unknowns) from phenyl- and quinoline-labeled
crop commodities indicate that cleavage of the parent molecule between
the rings may occur at a minor level.  However, levels of unidentified
components were too low for the petitioner to conclusively define the
route of metabolism. 

Quinoxyfen appears to be metabolized in sugar beets to some extent and
may then be incorporated with natural plant constituents such as lignin.
 The initial breakdown of quinoxyfen on leaves may result from surface
photolysis and resulting photo-degradates may be further metabolized to
polar residues.  In addition, the ether bond of the quinoxyfen compound
may be broken during metabolism yielding the 4-fluorophenol and DCHQ
(5,7-dichloro-4-hydroxyquinoline) metabolites.

The results of the plant metabolism studies were forwarded to HED to
determine the residues of concern in plants.  HED concluded that based
on the currently-available data, parent only is the residue of concern
for purposes of the tolerance expression and risk assessment (DP#:
227383, G. Kramer, 3/26/2003).

Livestock

There are no livestock feed items associated with on winter squash
(including pumpkins and edible gourds), artichoke, and stone fruit
(group 12)  Therefore, no livestock metabolism studies are required to
support these petitions.

4.1.2	Analytical Methodology

Plants  

  SEQ CHAPTER \h \r 1 An adequate GC-MSD method is available for
enforcing quinoxyfen tolerances (DowElanco Procedure ERC95.26); a
successful petition method validation (PMV) has been completed (DP#:
285350, E. Kolbe, 5/11/06).  The general procedure of this method
involves extraction of the sample with acidic acetone, partitioning with
hexane, purification of the extract by amino-propyl SPE column
chromatography, and analysis of the extract by GC-MSD.  The LLMV was
0.01 ppm. 

Residues of quinoxyfen in samples from the current crop field trials
were determined using modifications of DowElanco Procedure ERC95.26. 
Each of the above methods was validated in conjunction with the field
trials.  For artichokes fortified at 0.01, 0.10, and 1.0 ppm, average
recoveries were 95 ± 4%; for winter squash fortified at 0.01, 0.10, and
1.0 ppm, average recoveries were 92 ± 3%; for plum fortified at 0.01,
0.10, and 1.0 ppm, average recoveries were 95 ± 3%; and for peach
fortified at 0.01, 0.10, and 1.0 ppm, the average recovery was 91 ± 3%.

Livestock

  SEQ CHAPTER \h \r 1 There are no livestock feed items associated with
this petition; therefore, data-collection and tolerance-enforcement
methods for livestock commodities are not required.

4.1.3	Multiresidue Methods

A study which investigated the behavior of quinoxyfen through MRMs
outlined in the Food and Drug Administration (FDA) Pesticide Analytical
Manual (PAM), Volume I, Appendix II was submitted previously.  The study
summary reported that, depending on spike levels, certain MRM Protocols
(D, E, and F) yielded partial (incomplete) to complete recoveries of
quinoxyfen in grapes (non-fatty matrix) and ground beef (fatty matrix). 
HED has forwarded this study to FDA for a complete evaluation (DP#:
285352, G. Kramer, 9/20/2002).

4.1.4	Storage Stability

Adequate data are available indicating that quinoxyfen is stable during
frozen storage for 83 days in artichoke; 158 days in plums (pitted
fruit); 92 days in plums (dried pitted fruit); 183 days in peaches; and
109 days in winter squash.

 

To validate sample storage conditions and intervals, the petitioners
conducted concurrent storage stability studies.  The results of these
studies are reported in the respective magnitude of the residue DERs for
winter squash (47340603.DER.doc), peach (47340602.DER.doc), artichoke
(47340604.DER.doc) and plum (47340601.DER.doc).  The concurrent storage
stability studies are adequate to support the storage conditions and
intervals of collected samples.

4.1.5	Magnitude of the Reside in Plants

IR-4 submitted crop field trials supporting the use of quinoxyfen on
winter squash (including pumpkins and edible gourds), artichoke, and
stone fruit (group 12).  These studies have been reviewed, and the
conclusions of field trial DERs are reproduced (DP#: 354559, D. Wilbur,
11/6/2008).  The appropriate tolerance levels were calculated using the
Agency’s Guidelines for Setting Pesticide Tolerances Based on Field
Trial Data, and the methodology formulated by the NAFTA MRL/Tolerance
Harmonization Workgroup for calculating statistically-based pesticide
tolerances for plant commodities based on field trial residue data.

Artichoke

Three supervised field trials were conducted during the 2004 growing
season with artichoke in CA (Region 10). In these trials, four foliar
applications of Quintec EF 1295 (22.58% quinoxyfen) were made at a
nominal rate of 0.13 lb ai/A (0.146 kg ai/ha) per application, for a
total of approximately 0.52 lb ai/A (0.58 kg ai/ha) per season.
Applications were made 6-7 days apart and mature flower heads were
harvested on the day of final application. No adjuvants or additives
were added to the spray mixture for any of the above applications. The
number and locations of field trials are in accordance with OPPTS
Guideline 860.1500.  

Residues of quinoxyfen were quantified using a method based on Dow
Elanco Europe (Letcombe Laboratory) Method ERC95.26, Determination of
DE-795 Residues in Grape Wine, Must and Pomace, with minor
modifications.  Artichoke samples were extracted with 20/80 of 0.12M
HCL/acetone, partitioned into hexane, and evaporated to dryness in a
40ºC water bath. After solid phase extraction (SPE) cleanup, the
extract was evaporated and reconstituted with 0.1% corn oil in
isooctane.  Quantitation was achieved by GC-MSD.  For method validation,
control samples of artichoke were fortified at levels of 0.01, 0.10 and
1.0 ppm. During sample analysis, untreated artichoke was fortified at
0.10 ppm and 2.0 ppm for concurrent recovery spikes. The LLMV was
reported as 0.01 ppm. Based on recoveries of fresh artichoke samples
fortified at the LLMV, the limit of detection (LOD) and the limit of
quantitation (LOQ) calculated as 0.0033 ppm and 0.0099 ppm,
respectively.  Concurrent recoveries of quinoxyfen on/in artichoke
ranged from 85-93% and method validation recoveries ranged from 86-108%.
The method is adequate for data collection.

In all trials, artichoke was harvested on the day of the final
application and analyzed within 83 days.  Analytical results show that
quinoxyfen residues ranged from 0.063 ppm to a maximum of 1.09 ppm on/in
zero-day PHI artichoke samples. No residue decline data were collected. 

Winter Squash

Four supervised field trials were conducted in 2003 with winter squash
in CA (Region 10), NJ (Region 2), MD (Region 2), and OH (Region 5). One
additional supervised field trial was conducted in FL (Region 3) in
2004. In all trials, four foliar applications of Quintec EF 1295 (22.58%
quinoxyfen) were made at a rate of 0.13 lb ai/A (0.146 kg ai/ha) per
application, for a total of approximately 0.52 lb ai/A (0.58 kg ai/ha).
Applications were made 6-9 days apart and mature fruit was harvested
with a PHI of 3-4 days. No adjuvants or additives were added to the
spray mixture for any of the above applications. The number and
locations of field trials are in accordance with OPPTS Guideline
860.1500.  

Residues of quinoxyfen were quantified using a method based on Dow
Elanco Europe (Letcombe Laboratory) Method ERC95.26, Determination of
DE-795 Residues in Grape Wine, Must and Pomace, with minor
modifications.  Squash samples were extracted with 20/80 of 0.12M
HCL/acetone, partitioned into hexane, and evaporated to dryness in a
40ºC water bath. After solid phase extraction (SPE) cleanup, the
extract was evaporated and reconstituted with 0.1% corn oil in
isooctane.  Quantitation was achieved by GC-MSD.  For method validation,
control samples of squash were fortified at levels of 0.01, 0.10 and 1.0
ppm. During sample analysis, untreated squash was fortified at 0.10 ppm
for concurrent recovery spikes. The LLMV was reported as 0.01 ppm. Based
on recoveries of fresh squash samples fortified at the LLMV, the LOD and
the LOQ calculated as 0.0014 ppm and 0.0041 ppm, respectively. 
Concurrent recoveries of quinoxyfen on/in winter squash ranged from
88-93% and method validation recoveries ranged from 89-101%. The method
is adequate for data collection.

In all trials, squash was harvested 3-4 days after the final application
and analyzed within 98 days.  Analytical results show that quinoxyfen
residues ranged from 0.027 ppm to a maximum of 0.106 ppm on/in 3-4 day
PHI squash samples. No residue decline data were collected.  

Stone Fruit (Group 12)

Peach

Eleven supervised field trials were conducted with peach in CA (Region
10, four trials), NJ (Region 2, two trials), NC (Region 2, two trials),
MI (Region 5), NY (Region 1), and TX (Region 6). In all trials, four
foliar applications of Quintec EF 1295 (22.58% quinoxyfen) were made at
a rate of 0.13 lb ai/A (0.146 kg ai/ha) per application, for a total of
approximately 0.52 lb ai/A (0.58 kg ai/ha). Applications were made 6-8
days apart and mature fruit was harvested with a PHI of 7 ± 1 days. One
additional application was made at the TX trial (for a total of five
applications) to allow the fruit to become mature. No adjuvants or
additives were added to the spray mixture for any of the above
applications. The number and locations of field trials are in accordance
with OPPTS Guideline 860.1500.  

Residues of quinoxyfen were quantified using a method based on Dow
Elanco Europe (Letcombe Laboratory) Method ERC95.26, Determination of
DE-795 Residues in Grape Wine, Must and Pomace, with minor
modifications.  Peach samples were extracted with 20/80 of 0.12M
HCL/acetone, partitioned into hexane, and evaporated to dryness in a
40ºC water bath. After solid phase extraction (SPE) cleanup, the
extract was evaporated and reconstituted with 0.1% corn oil in
isooctane.  Quantitation was achieved by GC-MSD.  For method validation,
control samples of peach fruit were fortified at levels of 0.01, 0.10
and 1.0 ppm. During sample analysis, untreated peach fruit were
fortified at 0.10 ppm and 0.50 ppm for concurrent recovery spikes. The
LLMV was reported as 0.01 ppm. Based on recoveries of fresh peach
samples fortified at the LLMV, the LOD and the LOQ calculated as 0.0012
ppm and 0.0037 ppm, respectively.  Concurrent recoveries of quinoxyfen
on/in peach ranged from 86-94% and method validation recoveries ranged
from 87-97%. The method is adequate for data collection.

In all trials, peach was harvested 6-8 days after the final application
and analyzed within 134 days.  Analytical results show that quinoxyfen
residues ranged from 0.057 ppm to a maximum of 0.55 ppm on/in 7±1 day
PHI peach samples. No residue decline data were collected.  

Plum

Four supervised plum field trials were conducted in CA (Region 10), one
trial was conducted in MI (Region 5) and one trial was conducted in OR
(Region 12). In all trials, four foliar applications of Quintec EF 1295
(22.58% quinoxyfen) were made at a rate of 0.13 lb ai/A (0.146 kg ai/ha)
per application, for a total of approximately 0.52 lb ai/A (0.58 kg
ai/ha). No adjuvants or additives were added to the spray mixture for
any of the above applications. The number and locations of field trials
are in accordance with OPPTS Guideline 860.1500.  

Residues of quinoxyfen were quantified using a method based on Dow
Elanco Europe (Letcombe Laboratory) Method ERC95.26, Determination of
DE-795 Residues in Grape Wine, Must and Pomace.  Plum samples were
extracted with 20/80 of 0.12M HCL/acetone, partitioned into hexane, and
evaporated to dryness in a 40ºC water bath. After solid phase
extraction (SPE) cleanup, the extract was evaporated and reconstituted
with 0.1% corn oil in isooctane. Quantitation was achieved by GC-MSD.  

For method validation, control samples of dried pitted plum fruit and
pitted plum fruit were fortified at levels of 0.01, 0.10 and 1.0 ppm.
During sample analysis, untreated plum fruit were fortified at 0.10 ppm
for concurrent recovery spikes. The LLMV was reported as 0.01 ppm for
both dried pitted plum fruit and pitted plum fruit. Based on recoveries
of fresh plum samples fortified at the LLMV, the LOD and the LOQ
calculated as 0.002 ppm and 0.005 ppm, respectively.  Concurrent
recoveries of quinoxyfen on/in pitted plum and dried pitted plum ranged
from 89-92% and 88-95%, respectively.  Method validation recoveries
ranged from 90-101% for quinoxyfen on/in pitted plum and from 99-110%
for quinoxyfen on/in dried pitted plum. The method is adequate for data
collection.

In all trials, plum was harvested 7-days after the final application and
analyzed within 89 (dried pitted fruit) to 147 (pitted fruit) days. 
Analytical results show that quinoxyfen residues ranged from below the
LLMV (<0.01 ppm) to 0.095 ppm on/in 7-day PHI pitted plum samples.  The
maximum reside found on dried pitted plum was 0.03 ppm. No residue
decline data were collected.  

An estimated concentration factor of 3.5x was calculated for quinoxyfen
in dried pitted plum.

Conclusions.  The field trials on artichoke, peach, plum, and winter
squash are   SEQ CHAPTER \h \r 1 adequate.  An adequate number of trials
were conducted reflecting the proposed use patterns in the appropriate
geographic regions, and the appropriate commodities were collected at
the proposed PHIs.  Samples were analyzed using adequate analytical
methods, and the sample storage intervals are supported by the available
storage stability data.  The available artichoke data will support a
tolerance for residues of 1.4 ppm on artichoke, globe; the peach and
plum data will support a tolerance for residues of 0.70 ppm on fruit,
stone, group 12; and the winter squash data will support a tolerance for
residues of 0.20 ppm on squash, winter, pumpkin, and gourd, edible.  The
petitioner did not submit any crop field trial data for pumpkin or
edible gourd, but based on the Reviewers Guide and Summary of HED
ChemSAC Approvals for Amending Commodity Definitions (B. Schneider,
6/14/2002) those specific commodities are included in the definition for
winter squash.

4.1.6	Magnitude in Meat, Milk, Poultry, and Eggs

There are no livestock feed items associated with the proposed new uses
of quinoxyfen.  Data on residues of quinoxyfen in livestock tissues,
milk and eggs are not required to support these petitions.

4.1.7	Confined and Field Accumulation in Rotational Crops

Adequate confined and field rotational crop studies are not available
(DP#: 276835, G. Kramer, 3/26/2003).  Crops having quinoxyfen tolerances
may be replanted at any time.  Rotation to all other crop tolerances
should be prohibited.

4.1.8	Environmental Degradation

Environmental fate data suggest that the parent is persistent in the
environment susceptible to hydrolysis under acidic conditions (pH 4) but
is stable to hydrolysis at pH 7 and 9.  The three major metabolites are:
 DCHQ (86% applied dose in hydrolysis at pH 4 in 4 days, 3% at pH 7 in
21 days), CFBPQ (2-chloro-10-fluoro(1)benzopyrano(2,3,4-de)quinoline;
91% in aqueous photolysis), and 3-OH-quinoxyfen (62% applied dose in
aerobic soil metabolism).  Under typical environmental pH ranges, DCHQ
is not likely to be found in drinking water sources in substantial
quantities; therefore, it can be excluded as a residue of concern. 
CFBPQ degraded rapidly as the aqueous photolysis study continued, with
an estimated half-life of 7 hours, and can also be excluded as a residue
of concern.  3-OH-quinoxyfen is stable in soil and there is a
possibility of accumulation with multiple applications.  Due to the lack
of definitive soil partitioning data on this metabolite, there is
uncertainty concerning its mobility.  Because hydroxylation (the
addition of the 3-OH) could increase its mobility relative to
quinoxyfen, this metabolite has the potential to reach drinking water
sources in significant quantities.  Based on the structure similarity,
this metabolite might have similar toxicity as the parent.  

4.1.9	Comparative Metabolic Profile

Quinoxyfen is readily absorbed through the rat gastro-intestinal tract
and is primarily excreted in the urine, with most of a dose being
excreted in 24 hours. Sex, dose, and multiple dosing had little or no
effect on the excretion profile at 48 hours post-dosing.  The major
route of elimination was through the urine in the phenyl-labeled test
substance (44.9-48.7% of dose in urine and 38.2-39.8% of dose in feces)
and through the feces in the quinoline-labeled test substance
(65.8-78.3% of dose in feces and 13.4-19.7% of dose in urine).  Biliary
excretion increased its contribution to fecal radioactivity as the dose
increased.  Concentrations of radioactivity in the tissues were
generally slightly lower in the males than females and in the low-dose
compared to the high-dose group.  The highest concentrations of
radioactivity were found in the kidney, liver, ovaries, perirenal fat,
GI tract and carcass.  No differences in the metabolite profile were
observed that were related to sex or multiple dosing.  Increasing
amounts of the parent compound were found in the feces with increasing
dose.  

In cucumber and tomato, unchanged quinoxyfen remained largely on the
surface of treated plants.  The presence of multiple unidentified polar
residues suggests that metabolism of quinoxyfen does occur to some
extent to form more polar soluble components with the incorporation into
insoluble material.  Degradates and conjugates may be incorporated into
natural constituents such as lignin and cellulose.  Minor differences in
the characterized residues (unknowns) from phenyl- and quinoline-labeled
crop commodities indicate that cleavage of the parent molecule between
the rings may occur at a minor level.  However, levels of unidentified
components were too low for the petitioner to conclusively define the
route of metabolism. 

Quinoxyfen appears to be metabolized in sugar beets to some extent and
may then be incorporated with natural plant constituents such as lignin.
 The initial breakdown of quinoxyfen on leaves may result from surface
photolysis and resulting photo-degradates may be further metabolized to
polar residues.  In addition, the ether bond of the quinoxyfen compound
may be broken during metabolism yielding the 4-fluorophenol and DCHQ
(5,7-dichloro-4-hydroxyquinoline) metabolites.

Based on the metabolism studies, the nature of the residue in plants is
adequately understood for the purposes of this petition only. The
residue of concern is quinoxyfen per se.   Quinoxyfen was the primary
residue component in all reviewed plant metabolism studies except in
wheat grain and straw where Metabolite A was the predominant residue. 
Metabolite A was determined not to be associated with the parent
quinoxyfen, or related compounds, but was characterized to be highly
polar and multi-component in nature.

4.1.10	Toxicity Profile of Major Metabolites and Degradates tc  \l 3
"5.1.7	Toxicity Profile of Major Metabolites and Degradates" 

Photodegradation of quinoxyfen in clear, shallow surface water is rapid
(<1 day) and results in the formation of a degradate which is also
rapidly degraded. However, direct photolytic degradation of either the
parent or the degradate in turbid and/or deeper waters may be limited by
the attenuation of sunlight due to unfavorable conditions with regard to
light penetration.  Also, adsorption of the compound to suspended
particles in the water column will decrease the amount of compound
available for photolytic degradation.  In aerobic soil and in aerobic
and anaerobic aquatic systems the primary degradation pathway is
biodegradation, with more rapid degradation in the aquatic environments,
particularly where anaerobic conditions exist.  Quinoxyfen only slowly
biodegrades in aerobic soil, but is moderately rapidly degraded in the
sediment phase of aquatic environments.  While the photodegradation on
soil half-life (74 days) is shorter than the aerobic soil metabolism
half-lives (102-577 days), the former was determined under ideal
laboratory conditions where the compound remained on the soil surface
and was irradiated consistently; this is not likely to occur in the
natural environment.  Additionally, the soil photodegradation half-life
was extrapolated beyond the scope of the data and, thus, is of
questionable value in terms of representing an actual degradation rate
expected in the environment.  For these reasons, photodegradation on
soil is not likely to be as significant a fate process in the
environment as biodegradation will be.  Although quinoxyfen is degraded
in the environment, its major degradate in most soil and aquatic systems
is the transformation product 3-OH quinoxyfen, which is structurally
similar to the parent compound, the only difference being the addition
of an hydroxyl group on the quinoline ring of the degradate.  Based on
the submitted laboratory data, 3-OH quinoxyfen is essentially stable to
biodegradation in both aerobic and anaerobic aquatic systems. 
Quinoxyfen is hydrolytically stable at most environmentally relevant pHs
and temperatures, but hydrolyzes slowly at more acidic pHs.  Quinoxyfen
is stable to photodegradation on soil.

Degradates of quinoxyfen include 5,7-dichloroquinoline-4-ol (DCHQ);
5,7-dichloro-4-(4-fluorophenoxy)quinolin-3-ol (3-OH quinoxyfen);
2-chloro-10-fluoro[1]benzopyrano[2,3,4-de]quinoline (CFBPQ); and
5,7-dichloro-4-methoxyquinoline (DCMQ; methylated DCHQ).   

4.1.11	Pesticide Metabolites and Degradates of Concern

Table 4.1.11.  Summary of Metabolites and Degradates to be included in
the Risk Assessment and Tolerance Expression

Matrix	Residues included in Risk Assessment	Residues included in
Tolerance Expression

Plants

	Primary Crop*	Quinoxyfen	Quinoxyfen

	Rotational Crop	Not Determined	Not Determined

Livestock

	Ruminant	N/A	N/A

	Swine	N/A	N/A

	Poultry	N/A	N/A

Drinking Water

	Quinoxyfen + 3-OH Quinoxyfen	Quinoxyfen + 3-OH Quinoxyfen

* Registered and proposed crops

4.1.12	Drinking Water Residue Profile

The drinking water residues used in this assessment were provided by the
Environmental Fate and Effects Division (EFED) in a memoranda “Tier 1
Drinking Water Exposure Assessment in Support of New Uses of Quinoxyfen
on Stone Fruits (Excluding Cherry), Artichokes, Winter Squash, Pumpkin
and Edible Gourds” (DP#: 351023; Amy McKinnon; 10/20/2008) and
incorporated directly into the dietary assessment.  Additional
information was also referenced from an earlier EFED memorandum: 
“EFED Drinking Water Assessment for the IR-4 Tolerance Petition for
Use of Quinoxyfen on Lettuce, Strawberries, Melons, Peppers (Bell and
Non-bell), and Eggplants” (DP Num: 314492; Cheryl Sutton; 03/23/2006).
 Water residues were included in the DEEM-FCID file into the food
categories “water, direct, all sources” and “water, indirect, all
sources.” 

Estimates reflect drinking water exposure to residues of concern for
quinoxyfen, which include the parent compound and the degradate of
concern, 3-OH quinoxyfen.  The first drinking water assessment (DP#s:
278515, 285770, 286376) was completed in March 2006.  Uses included in
the assessment were grapes, hops and cherries.  EDWCs for use in the
human health risk assessment were determined using a maximum annual
application rate for cherries of 0.55 lb ai/A.  Because the maximum
application rates for the proposed uses on lettuce, strawberries, melons
and peppers did not exceed the application rate for cherries, the EDWCs
previously generated in the August 2003 EFED memo were considered
applicable and used in the April 2006 quinoxyfen assessment. 

However, the drinking water EDWCs for quinoxyfen were reexamined due to
several proposed new 2008 uses.  Uses included in the recent assessment
were in addition to the previous maximum application rate for cherries
listed in the March 2006 EFED memo.  

EDWCs for use in the human health risk assessment were determined using
both the maximum annual aerial application of 0.52 lb a.i./A (0.13 lb
a.i./A x4 apps/yr) for the proposed 2008 new uses and the maximum
orchard air blast annual rate of 0.57 lb a.i./A (0.114 lb a.i./A x5
apps/yr) for cherries.  The 2 screening programs used in the 2008 EFED
quinoxyfen evaluation for drinking water are the Tier I FIRST aquatic
model (FQPA Index Reservoir Screening Tool, v1.1.1) and the SCI-GROW
ground water model (Screening Concentration in Ground Water, v2.3). 
Since the maximum application rates for the proposed uses on stone
fruits group 12, artichoke, winter squash, pumpkin and edible gourds do
not exceed the maximum annual application rate for cherries, both the
cherry EDWCs previously generated from the August 2003 EFED memo and the
proposed 2008 new uses were modeled and the results were included in the
October 2008 EFED memo.    

The highest chronic quinoxyfen concentration was estimated for surface
water using the FIRST model.  The chronic (1-in-10 year annual mean)
value of 0.66 ppb was incorporated directly as a point estimate in the
DEEM analysis to assess exposure to quinoxyfen from drinking water.

Table 4.1.12.  Quinoxyfen drinking water assessment EDWCs based on stone
fruit (excluding cherries), artichoke, winter squash, pumpkin and edible
gourds uses.

Surface water drinking water sources1	acute: 9.3 ug/L (ppb)

1-in-10-years (chronic): 0.66 ug/L (ppb) 30-year average: 5.95 ug/L
(ppb)

Groundwater drinking water sources1	0.0031 ug/L (ppb) or 3.1 ng/L (parts
per trillion)

1EDWC values were generated using the FIRST and SCI-GROW models. 
Cherries used an orchard airblast  application scenario.  This
represents the highest annual application rate among the registered and
proposed new uses.  The cherry results were: surface water, 9.9 ppb
(acute) and 0.62 ppb (chronic); the groundwater result was 0.0034 ug/L
(ppb). For the proposed new uses, an aerial application scenario was
used.  The new application results were: surface water, 93 ppb (acute)
and 0.66 ppb (chronic); the groundwater result was 0.0031 ug/L (ppb).  

4.1.13	Food Residue Profile

Based on the previously-submitted cucumber, grape, sugar beet, and
tomato metabolism studies, the nature of the residue in plants is
adequately understood for the purposes of this petition only. The
residue of concern is quinoxyfen per se. 

  SEQ CHAPTER \h \r 1 An adequate GC-MSD method is available for
enforcing the proposed quinoxyfen tolerances (DowElanco Procedure
ERC95.26).  The general procedure of this method involves extraction of
the sample with acidic acetone, partitioning with hexane, purification
of the extract by amino-propyl SPE column chromatography, and analysis
of the extract by GC-MSD.  The LLMV is 0.01 ppm. 

The field trials on artichoke, peach, plum, and winter squash are   SEQ
CHAPTER \h \r 1 adequate.  An adequate number of trials were conducted
reflecting the proposed use patterns in the appropriate geographic
regions, and the appropriate commodities were collected at the proposed
PHIs.  Samples were analyzed using adequate analytical methods, and the
sample storage intervals are supported by the available storage
stability data.  The available artichoke data will support a tolerance
for residues of 1.4 ppm on artichoke, globe; the peach and plum data
will support a tolerance for residues of 0.70 ppm on fruit, stone, group
12; and the winter squash data will support a tolerance for residues of
0.20 ppm on squash, winter, pumpkin, and gourd, edible.  The petitioner
did not submit any crop field trial data for pumpkin or edible gourd,
but based on the Reviewers Guide and Summary of HED ChemSAC Approvals
for Amending Commodity Definitions (B. Schneider, 6/14/2002) those
specific commodities are included in the definition for winter squash.

4.1.14	International Residue Limits tc  \l 3 "5.1.11	International
Residue Limits" 

CODEX MRLs exist for quinoxyfen on cherry, tart and cherry, sweet at 0.4
ppm; and Canadian MRLs exist for cherry, sweet and cherry, tart at 0.3
ppm.  While these differ from the fruit, stone, group 12 tolerance
proposed herein, residues above both the CODEX and Canadian MRLs were
observed in the submitted field trial data. No Mexican MRLs have been
established for quinoxyfen.  An International Residue Limits Status
(IRLS) sheet is attached (Appendix C).

4.2	Dietary Exposure and Risk

A dietary (food + drinking water) exposure analysis for quinoxyfen was
conducted by the California Department of Pesticide Regulation (PP#:
8E7325, DP#: 354561, W. Carr, 12/2/2008) and reviewed/approved by ARIA
and Dietary Exposure SAC scientists (W. Cutchin and D. Rate, 12/2/2008).
 

4.2.1	Acute Dietary Exposure/Risk

No toxic effects attributable to a single (i.e., acute) exposure to
quinoxyfen have been identified; therefore, an acute Reference Dose
(aRfD) has not been established for quinoxyfen and an acute dietary
exposure assessment was not
conducted.†഍⸴⸲ल桃潲楮⁣楄瑥牡⁹硅潰畳敲刯獩൫

The unrefined chronic assessment assumed that quinoxyfen residues are
present in all commodities at established or, for the new crops,
recommended tolerance levels and that 100% of all crops are treated. 
DEEM™ Version 7.81 default processing factors were used to estimate
residues in dried fruit (apricot, peach, prune and raisin) and fruit
juices (cherry, grape and prune).  Drinking water was incorporated
directly into the dietary assessment using the EDWC generated by the
FIRST surface water and SCI-GROW ground water models.

Dietary exposure is estimated at 0.002566 mg/kg/day for the general U.S.
population (1% of the cPAD) and 0.004169 mg/kg/day (2% of the cPAD) for
children 1 to 2 years old, the population subgroup with the highest
estimated chronic dietary exposure to quinoxyfen.

TABLE 4.2.2.  Summary of Dietary (Food and Drinking Water) Exposure and
Risk for Famoxadone.  

Population Subgroup1	DEEM Acute Dietary Analysis,

95th Percentile	DEEM Chronic Dietary Analysis

	Exposure (mg/kg/day)	% aPAD	Exposure (mg/kg/day)	% cPAD

General U.S. Population	

Not calculated: No acute dietary exposure endpoint identified 	0.002566
1

All Infants (< 1 year old)

0.001685	< 1

Children 1-2 years old

0.004169	2

Children 3-5 years old

0.003583	2

Children 6-12 years old

0.002566	1

Youth 13-19 years old

0.002135	1

Adults 20-49 years old

0.002569	1

Adults 50+ years old

0.002394	1

Females 13-49 years old

0.002668	1

1The population subgroup with the highest estimated chronic dietary
(food + drinking water) exposure and risk is indicated by bold text. 
The % cPAD is reported to 1 significant figure.

4.2.3	Cancer Dietary Risk

HED classified quinoxyfen as “not likely to be carcinogenic to
humans.”  Therefore, quantification of human cancer risk was not
necessary. 

4.3	Anticipated Residue and Percent Crop Treated (%CT) Information

The unrefined chronic assessment assumed that quinoxyfen residues are
present in all commodities at established or, for the new crops,
recommended tolerance levels and that 100% of all crops are treated.  

5.0	RESIDENTIAL (NON-OCCUPATIONAL) EXPOSURE/RISK CHARACTERIZATION

There are no registered or proposed uses of quinoxyfen which result in
residential exposures.  Therefore, residential exposure is not expected,
and no residential risk assessment was performed.  

5.1	Other (Spray Drift, etc.)

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 the ground application method employed for quinoxyfen. 
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.  On
a chemical by chemical basis, 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 with specific products with significant risks
associated with drift.

AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION

In accordance with the FQPA, ARIA and HED must consider and aggregate
quinoxyfen pesticide exposures and risks from three major sources: food,
drinking water, and residential exposures.  In an aggregate assessment,
exposures from relevant sources are added together and compared to
quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks
themselves can be aggregated.  When aggregating exposures and risks from
various sources, HED and ARIA have considered both the route and
duration of exposure. 

Aggregate exposure risk assessments were assessed by incorporating the
drinking water directly into the dietary exposure assessment for the
following scenario:  chronic aggregate exposure (food + drinking water).
 Short, -intermediate- and long-term aggregate-risk assessments were not
performed because there are no registered or proposed uses of quinoxyfen
which result in residential exposures.  Acute and cancer aggregate-risk
assessments were not performed because no appropriate endpoint was
available to determine the aRfD for the general population or any
population subgroup and quinoxyfen is not carcinogenic.  Refer to
section 4.2.2 for the long-term aggregate risk (chronic dietary and
drinking water) estimates.  Chronic aggregate risk does not exceed
ARIA’s level of concern.

7.0	CUMULATIVE RISK CHARACTERIZATION/ASSESSMENT

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 quinoxyfen and any other
substances and quinoxyfen 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 quinoxyfen 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 
HYPERLINK "http://www.epa.gov/pesticides/cumulative/."
http://www.epa.gov/pesticides/cumulative/. 

8.0	OCCUPATIONAL EXPOSURE/RISK PATHWAY

8.1	Handler Exposure and Risk

Based upon the proposed use patterns, ARIA believes the most likely
methods of application will be by ground-boom spray machinery and
airblast sprayers.  While it is doubtful that aerial application would
be used to any appreciable extent, it is considered in the exposure
assessment herein.  ARIA further believes that for the proposed new
uses, the most highly exposed occupational pesticide handlers will be
mixer/loaders using open-pour loading of liquid formulations;
applicators using open-cab, ground-boom sprayers; applicators using
airblast sprayers; and aerial applicators.  

ARIA believes pesticide handlers will be exposed to short-term duration
(1 - 30 days) exposures but not to intermediate-term (1 - 6 months)
duration exposures.  Although multiple applications are possible, the
product label directs that they not be consecutive and that they be
separated by a minimum of 6 day retreatment intervals.  It is unlikely
that pesticide handlers would be exposed continuously for 30 days or
more.  

Particularly for ground applications, private (i.e., grower) applicators
may perform all functions, that is, mix, load and apply the material. 
Standard HED procedure directs that although the same individual may
perform all those tasks, they shall be assessed separately.  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 Pesticide
Handler Exposure Database (PHED) Surrogate Exposure Guide (August 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 personal protective equipment (PPE) for each aspect of the job
without requiring an applicator to wear unnecessary PPE that might be
required for a mixer/loader (e.g., chemical resistant gloves may only be
necessary during the pouring of a liquid formulation).  

No chemical specific data were available with which to assess potential
exposure to pesticide handlers.  The estimates of exposure to pesticide
handlers are based upon surrogate study data available in the PHED (v.
1.1, 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.  As discussed earlier, the product label directs
applicators and other handlers to wear personal protective equipment
(PPE) which consists of a long-sleeved shirt, long pants, shoes plus
socks and chemical resistant gloves.

The toxicological parameters used herein are taken from:  Memo, DP#
321331, G. Kramer et al., 5/15/2006, “Quinoxyfen on Peppers (Bell and
Non-Bell) (PP#3E6755), Eggplant (PP#3E6755), Melon Subgroup 9A
(PP#5E6970), Strawberry (PP#5E6970), and Lettuce (Head and Leaf)
(PP#5E6970).  Health Effects Division Risk Assessment.”  See Table 8.1
for a summary of exposures and risks to occupational pesticide handlers.

Table 8.1. Summary of Exposure & Risk for Occupational Handlers Applying
Quinoxyfen to Stone Fruit, Winter Squash and Artichoke.

Unit Exposure1

mg ai/lb handled	Applic. Rate2

lb ai/unit	Units Treated3	Avg. Daily Exposure4

mg ai/kg bw/day	MOE5

Mixer/Loader Open Pour Loading Liquid

Dermal:

SLNoGlove     2.9

SLWithGlove  0.023

Inhal.               0.0012	

0.13 lb ai/A	

350 A/day	Dermal:

SLNoGlove 2.2

SLWGlove  0.017

Inhal.           0.00091	SLNoGlove

9.1

SLWithGlove

1,116

Applicator Groundboom Open-cab

Dermal:

SLNoGlove     0.014

SLWithGlove  0.014

Inhal.               0.00074	

0.13 lb ai/A	

200 A/day	Dermal:

SLNoGlove 0.0061

SLWGlove  0.0061

Inhal.           0.00032	SLNoGlove

3115

SlWithGlove

3115

Applicator Airblast Open-cab

Dermal:

SLNoGlove     0.36

SLWithGlove  0.24

Inhal.               0.0045	

0.13 lb ai/A	

40 A/day	Dermal:

SLNoGlove 0.031

SLWGlove  0.021

Inhal.           0.00039	SLNoGlove

637

SlWithGlove

935

Aerial Applicator (gloves not required for pilots) 

Dermal:

SLNoGlove    0.005

Inhal.              0.000068	

0.13 lb ai/A	

350 A/day	Dermal:

SLNoGlove 0.0038

Inhal.           0.000052	SLNoGlove

5192

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.  SLNG = Dermal Single Layer Work
Clothing No Gloves; SLWG = Dermal Single Layer Work Clothing With
Gloves; Inhal. = Inhalation.  Units = mg a.i./pound of active ingredient
handled.  

2.  Applic. Rate = Taken from Section B of IR-4 submission for each crop

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

4.  Average Daily Dose = Unit Exposure * Applic. Rate * Units Treated ÷
Body Weight (60 kg).  

5.  MOE = Margin of Exposure = No Observable Adverse Effect Level
(NOAEL) ÷ ADD.  Short-term and intermediate-term dermal and inhalation
NOAEL = 20.0 mg a.i./kg bw/day.   ADD = dermal + inhalation (since the
dermal and inhalation toxicological effects are the same and are
identified from the same study).

A MOE of 100 is adequate to protect occupational pesticide handlers from
occupational exposures to quinoxyfen.  Provided mixer/loaders wear
protective gloves as directed on the label, all MOEs are > 100. 
Therefore these exposures do not exceed ARIA/RDs level of concern.

8.2	Post-Application Exposure Risk

Typically there is the possibility for agricultural workers to
experience post-application exposures to dislodgeable foliar pesticide
(DFR) residues.  There were no chemical-specific data with which to
estimate post-application exposure of agricultural workers to
dislodgeable foliar residues of quinoxyfen.  Therefore, theoretical
estimates of exposure, based on surrogate studies, have been conducted. 
The ExpoSAC (SOP 003.1, Rev. 7 Aug. 2000, Regarding Agricultural
Transfer Coefficients; Amended ExpoSAC Meeting notes - 13 Sept 01) lists
a number of possible post-application agricultural activities relative
to the subject crops that might result in pesticide exposure to
agricultural workers.  Transfer coefficients (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 (i.e., most conservative) TCs relative to the subject crops
are for hand harvesting:  3,000 cm2/hr for stone fruit; 2,500 cm2/hr for
melons and 1,000 cm2/hr for artichoke.  For risk assessment purposes
here, a TC of 3,000 cm2/hr is used in conjunction with the maximum rate
of application which is 0.13 lb ai/A.  

The TCs used in this assessment are from an interim transfer coefficient
SOP developed by HED’s ExpoSAC using proprietary data from the
Agricultural Re-Entry Task Force (ARTF) database (policy # 3.1).  It is
the intention of HED’s ExpoSAC that this SOP 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 does not expect post-application
exposures to exceed short term exposure.  However, the HED ExpoSAC
directs that there may be intermediate-term exposures (1-6 months) to
agricultural workers.  The following convention is used to estimate
post-application exposures to agricultural workers. 

PDRt  =  DFRt * CF1 * Tc * ET where:

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

DFRt  = dislodgeable foliar residue on day “t” (µg/cm2)

CF1   =   weight unit conversion factor to convert µg units in DFR
value to mg for the daily dose     (0.001 mg/µg)

Tc     =  transfer coefficient (cm2/hr) (In this case 3,000 cm2/hr;
ExpoSAC SOP 003.1 Rev. 7 Aug. 2000; amended 13 Sept 01 ExpoSAC meeting
Notes). 

ET     = Exposure Time (hrs) (8)

And

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

AR  = Application rate (lb a.i./A) (0.13 lb a.i./A)

F     = fraction of a.i. on foliage available as dislodgeable residue
(unitless) (20.0 %)

D     = fraction of residue that dissipates daily (unitless) (10.0 %)

t      = postapplication day on which exposure is being assessed

CF2 = weight unit conversion factor to convert the lbs a.i. in the
application rate to µg for the DFR value (4.54E8 µg/lb)

CF3 = Area unit conversion factor to convert the surface area units
(ft2) in the application rate to cm2 for the DFR value (1.08E-3 ft2/cm2
or 2.47E-8 acre/cm2 if the application rate is per acre).

( DFR = 0.13 lb a.i./A * 0.20 * (1-0)0 * 4.54E8 µg a.i./lb *
2.47E-8A/cm2 = 0.29 µg/cm2

PDR = 0.29 µg/cm2 * 0.001 mg/µg * 3,000 cm2/hr * 8 hr/day = 6.96 mg
a.i./day ( ÷ 60 kg bw = 0.116 mg a.i./kg bw/day

MOE = NOAEL ÷ PDR 

( 20 mg a.i./kg bw/day ( 0.116 mg a.i./kg bw/day = 172 

These estimates are considered to be screening-level estimates; i.e.,
conservative (protective).  The level of concern for dermal exposure is
for MOEs <100.  In this case, the MOEs are greater than 100; therefore,
post-application dermal exposure is not of concern for agricultural
workers.  Post-application inhalation exposure is expected to be
negligible.

8.3	Restricted Entry Interval (REI)

Quinoxyfen is classified in acute Toxicity Category III for acute dermal
toxicity and for primary eye irritation.  It is classified in Category
IV for acute inhalation and primary skin irritation.  It is not a dermal
sensitizer.  Therefore the Worker Protection Standard (WPS) interim
restricted entry interval of 12 hours is adequate to protect
agricultural workers.  The product label lists an REI of 12 hours.

9.0	TOLERANCE SUMMARY

Based on the previously-submitted cucumber, grape, sugar beet, and
tomato metabolism studies, the nature of the residue in plants is
adequately understood for the purposes of this petition only. The
residue of concern is quinoxyfen per se.   Tolerances for quinoxyfen
residues can be found at 40 CFR §180.588.  

The available artichoke data will support a tolerance for residues of
1.4 ppm on artichoke, globe; the peach and plum data will support a
tolerance for residues of 0.70 ppm on fruit, stone, group 12; and the
winter squash data will support a tolerance for residues of 0.20 ppm on
squash, winter, pumpkin, and gourd, edible.

Table 9.0.  Tolerance Summary for Quinoxyfen.

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

  SEQ CHAPTER \h \r 1 (correct commodity definition)

Fruit, stone, group 12	0.70	0.70

	Squash, winter	0.20	0.20

	Pumpkin	0.20	0.20

	Gourd, edible	0.20	0.20

	Artichoke, globe	1.4	1.4

	Cherry, sweet	Revoke	Revoke	Included in Fruit, stone, group 12

Cherry, tart	Revoke	Revoke	Included in Fruit, stone, group 12

10.0	DATA NEEDS AND LABEL RECOMMENDATIONS

The scientific quality and completeness of the available toxicology data
base are considered adequate to support the registration and proposed
tolerances for quinoxyfen.   

10.1	Toxicology

	1)  28-day inhalation study - Rat

HED requested this study based on the concern for repeated exposure
based on the use pattern; however, since the active ingredient is in
Toxicity Category IV, a waiver can be granted for this study provided
that an extrapolated inhalation MOE (based on an oral NOAEL) is
approximately 10-fold higher than the LOC.

	2) Guideline immunotoxicity study (OPPTS 870.7800)

10.2	Residue Chemistry

A revised Section B is requested that reflects the correct rotational
crop restrictions.  The proposed use directions on winter squash
(including pumpkins and edible gourds), artichoke, and stone fruit
(group 12) are adequately supported by the available residue data except
that the rotational crop restrictions are not listed on the labels.  

10.3	Occupational and Residential Exposure

No additional data is required. 

11.0	REFERENCES

Endpoint Selection Document

Quinoxyfen - Report of the Hazard Identification Assessment Review
Committee, D. Nixon, TXR No. 0051474, 1/28/2003.

Dietary Exposure Memorandum

Quinoxyfen: Chronic Aggregate Dietary (Food and Drinking Water) Exposure
and Risk Assessment for the Proposed Section 3 Registration on Proposed
New Uses of Quinoxyfen on Stone Fruits crop group 12 (excluding cherry),
Artichoke, Winter Squash, Pumpkin and Edible Gourds (PP#8E7325); DP#:
354561, W. Carr, 12/2/2008.

Drinking Water Memorandum

Tier 1 Drinking Water Exposure Assessment in Support of New Uses of
Quinoxyfen on Stone Fruits (Excluding Cherry), Artichokes, Winter
Squash, Pumpkin and Edible Gourds; DP#: 351023; A. McKinnon; 10/20/2008.

EFED Drinking Water Assessment for the IR-4 Tolerance Petition for Use
of Quinoxyfen on Lettuce, Strawberries, Melons, Peppers (Bell and
Non-bell), and Eggplants; DP#: 314492; C. Sutton; 3/23/2006.

Residue Chemistry Data Reviews

Quinoxyfen.  Petition for Tolerances and Uses on Winter Squash
(including Pumpkin and Edible Gourd), Artichoke, and Stone Fruit (Group
12) (PP#8E7325).  Summary of Analytical Chemistry and Residue Data. 
PP#8E7325, DP#: 354559, D. Wilbur, 11/6/2008.

Occupational and Residential Exposure Memorandum

QUINOXYFEN – Occupational Exposure/Risk Assessment for the Proposed
Use of Quinoxyfen on Stone Fruit, Winter Squash and Artichoke; DP#
351766; M. Dow; 4/21/2008.	

Appendix A:  Toxicology Assessment tc  \l 1 "Appendix A:  Toxicology
Assessment" 

A.1	Toxicology Data Requirements tc  \l 2 "A.1  Toxicology Data
Requirements"  

Guideline No./ Study Type	

MRID No. (year)/ Classification /Doses	

Results

870.3100

90-Day oral toxicity rodents (rat)	

45406705, 45406702 (1992)

Acceptable/guideline

0, 10, 100 or 250 mg/kg/day	

NOAEL = 10 mg/kg/day

LOAEL = 100 mg/kg/day based on decreased body weight gain in females,
increased liver weights in males and slight hepatocellular hypertrophy
(centrilobular and midzonal; both sexes).

870.3100

90-Day oral toxicity rodents (mouse)	

45406701 (1992)

Acceptable/guideline

0, 10, 50, 100 or 500 mg/kg/day	

NOAEL = 100 mg/kg/day

LOAEL = 500 mg/kg/day based on increased liver weights, individual cell
hepatocellular necrosis and hepatocellular hypertrophy in both sexes.

870.3150

90-Day oral toxicity in Non-rodent (dog)	

45406706 (1992)

0, 10, 50 or 100 mg/kg/day

Range finding studies:

45406703 (1992)

0, 100, 500 or 1000 mg/kg/day

45406704 (1993)

0 or 250 mg/kg/day 

Acceptable/guideline when combined with range finding studies	

NOAEL = 100 mg/kg/day

LOAEL = Not identified.

870.3200

28-Day dermal toxicity

(rat)	

45360516 (2000)

Acceptable/guideline

0, 10, 100 or 1000 mg/kg/day 

6 hr/day, 5 d/week	

NOAEL = 1000 mg/kg/day

LOAEL = Not identified.

870.3250

90-Day dermal toxicity	

NA	

NA

870.3465

90-Day inhalation toxicity	

NA	

NA

870.3700a

Prenatal developmental in rodents (rat)	

45360520 (1994)

Acceptable/guideline 

F: 0, 100, 300, or 1000 mg/kg/day	

Maternal NOAEL = 1000 mg/kg/day

LOAEL = Not identified.

Developmental NOAEL = 1000 mg/kg/day

LOAEL = Not identified.

870.3700b

Prenatal developmental in non-rodent (rabbit)	

45360521 (1994)

Acceptable/guideline

F: 0, 20, 80, or 200 mg/kg/day

Range finding: 45360519 (1993)

F: 0, 100, 300, 600 or 1000 mg/kg/day	

Maternal NOAEL = 80 mg/kg/day

LOAEL = 200 mg/kg/day based on inanition, clinical signs, decreased body
weights, body weight gains, and food consumption and on increased
incidences of abortion.

Developmental NOAEL = 80 mg/kg/day

LOAEL = 200 mg/kg/day based on increased incidences of abortion.

870.3800

Reproduction and fertility effects (rat)	

45360522 (1995)

Acceptable/guideline

0, 5, 20 or 100 mg/kg/day

	

Parental/Systemic NOAEL = 100 mg/kg/day

LOAEL = Not identified.

Reproductive NOAEL = 100 mg/kg/day

LOAEL = Not identified.

Offspring NOAEL = 20 mg/kg/day

LOAEL = 100 mg/kg/day based on a minimal decrease in F1a pup weights.

870.4100a

Chronic toxicity rodents	

NA; see 870.4300	

NA

870.4100b

Chronic toxicity (dog)	

45360517 (1995)

Acceptable/guideline

0, 5, 20 or 200 mg/kg/day	

NOAEL = 20 mg/kg/day

LOAEL = 200 mg/kg/day based on increased alkaline phosphatase, increased
absolute and relative (to body) liver weights, and an increased
incidence of very slight to slight microscopic hepatic lesions.

870.4200a

Carcinogenicity (rat)	

NA; see 870.4300	

NA

870.4200b

Carcinogenicity (mouse)	

45406707 (1995)

Acceptable/guideline

0, 20, 80 or 250 mg/kg/day	

NOAEL = 80 mg/kg/day

LOAEL = 250 mg/kg/day based on decreased body weight gain in both sexes.

No evidence of carcinogenicity

870.4300

Combined Chronic/carcinogenicity (rat)	

45360523 (1995) 45724201 (2001)

Acceptable/guideline

0, 5, 20 or 80 mg/kg/day	

NOAEL = 20 mg/kg/day

LOAEL = 80 mg/kg/day based on increases in severity of chronic
progressive glomerulonephropathy in the males and minimal decreases in
body weight and body weight gain in the males and females.

No evidence of carcinogenicity.

870.5100

Bacterial reverse mutation	

 45360601 (1993)

Acceptable/guideline	

Negative for inducing reverse mutation in bacteria exposed to doses up
to 5000 ug/plate (-S9) and 1000ug/plate (+S9).

870.5300

In vitro mammalian cell gene mutation	

45360602 (1994)

Acceptable/guideline	

Negative for inducing forward mutation in CHO (mammalian) cells treated
up to 20 ug/ml (-S9) and 80 ug/ml (+S9).

870.5375

In vitro mammalian chromosome aberration (RL)	

45360604 (1994)

Acceptable/guideline	

Negative up to 100 ug/ml (- S9 and +S9)

870.5395

Mammalian micronucleus (mouse)	

45360603 (1994)

45724203 (2001)

Acceptable/guideline

0, 1250, 2500 or 5000 mg/kg	

Negative up to 5000 mg/kg.

870.6200a

Acute neurotoxicity screening battery

(rat)	

45360515 (1999)

Acceptable/guideline

0, 200, 632 or 2000 mg/kg	

NOAEL = 2000 mg/kg

LOAEL = Not identified.

870.6200b

Subchronic neurotoxicity screening battery (rat)	

45360518 (1995)

Acceptable/guideline

0, 5, 20 or 80 mg/kg/day	

NOAEL = 80 mg/kg/day

LOAEL = Not identified.

870.6300

Developmental neurotoxicity (rat)	

NA	

NA

870.7485

Metabolism and pharmacokinetics

(rat)	

45360605 (1995)

45360606 (2001)

M&F: 10 or 500 mg/kg (labeled) as single oral dose or

10 mg/kg (labeled) as single oral dose followed by 10 mg/kg/day
(unlabeled) orally for 14 days.

M: 10 or 500 mg/kg (labeled) single oral dose or 500 mg/kg/day oral
gavage dose for 3 days.

Unacceptable/upgradable	

Quinoline-labeled and phenyl-labeled quinoxyfen were rapidly absorbed
with approximately 68-85% of the administered dose being eliminated
within 24 hours.  Overall recovery of the dosed radioactivity ranged
from 83.5-96.2%.  Sex, dose, and multiple dosing had little or no effect
on the excretion profile at 48 hours post-dosing.  Changing the position
of the 14C-label altered the pattern of excretion.  The major route of
elimination was through the urine in the phenyl-labeled test substance
(44.9-48.7% of dose in urine and 38.2-39.8% of dose in feces) and
through the feces in the quinoline-labeled test substance (65.8-78.3% of
dose in feces and 13.4-19.7% of dose in urine).  Biliary excretion
increased its contribution to fecal radioactivity as the dose increased.
 Concentrations of radioactivity in the tissues were generally slightly
lower in the males than females and in the low-dose compared to the
high-dose group.  The highest concentrations of radioactivity were found
in the kidney, liver, ovaries, perirenal fat, GI tract and carcass. 
Maximum plasma concentration occurred between 0.5 and 1.5 hours, and
elimination half-lives were </= 1 hour and 15-19 hours (10 mg/kg group)
and 2-3 hours and 18-22 hours (500 mg/kg group).

The presence of several radioactive components was determined in the
unhydrolyzed urine (up to 12), fecal extracts ( up to 8), and bile (up
to 6).  No differences in the metabolite profile were observed that were
related to sex or multiple dosing.  Increasing amounts of the parent
compound were found in the feces with increasing dose.  No other
dose-related differences were observed.  Identified metabolites
accounted for 41.0-42.8% dose in the [Phenyl-U-14C] XDE-795 treated
group, and only 17.0-31.7% dose in the other treated groups.  The
[Phenyl-U-14C] XDE-795 treated group had no urinary metabolites in
common with the [2-Quinoline-14C] XDE-795 treated groups suggesting
cleavage of the parent molecule.  An acid-labile conjugate of
4-fluorophenol was found in the urine of the [Phenyl-U-14C] XDE-795
treated group (28.7-32.8% dose).  5,7-Dichloro-4-hydroxyquinoline was
observed in the urine of the [2-Quinoline-14C] XDE-795 treated groups in
small quantities (0.7-1.7% dose).  Thus, the identified metabolites in
the urine followed diaryl-ether cleavage of the parent compound. 
Fluorophenyl-ring-OH-XDE-795 (two isomers) were found in the feces of
all treated groups (5.4-10.6% dose).  In the bile of the treated groups,
two major metabolites were identified, a glucuronide and/or sulfate
conjugate(s) of the two isomers of fluorophenyl ring-hydroxy-XDE-795
(9-19% dose) and an unidentified metabolite (13-21% dose).

870.7600

Dermal penetration	

NA	

NA

A.2   Toxicity Profiles

Table A.2.  Acute Toxicity Profile for Quinoxyfen

Guideline

 No.	Study Type	MRID #(s)	Results	Toxicity Category

81-1	Acute Oral	45360428	LD50 > 5000 mg/kg	IV

81-2	Acute Dermal	45360501	LD50 > 2000 mg/kg	III

81-3	Acute Inhalation	45360504	LC50 > 3.38 mg/L	IV

81-4	Primary Eye Irritation	45360505	Mild eye irritant	III

81-5 	Primary Skin Irritation	45360508	Not a dermal irritant	IV

81-6	Dermal Sensitization	45360511

Buehler method

45360514

Magnusson-Klingman	

Not a dermal sensitizer

A dermal sensitizer	N/A

 tc  \l 2 "A.2  Toxicity Profiles" 

Appendix B:  Review of Human Research

No MRID - PHED Surrogate Exposure Guide

Appendix C:	International Residue Limit Status

INTERNATIONAL RESIDUE LIMIT STATUS

Chemical Name:

5,7-dichloro-4-(4-

fluorophenoxy)quinoline	

Common Name:

Quinoxyfen	

X Proposed tolerance

   Reevaluated tolerance

   Other	

Date:

10/30/2008

Codex Status (Maximum Residue Limits)	

U. S. Tolerances

X  No Codex proposal step 6 or above

     No Codex proposal step 6 or above for the crops requested	

Petition Number:  PP#8E7325

DP#s:  354559

Other Identifier:

Residue definition: N/A	

Reviewer/Branch:  DB Wilbur

	

Residue definition:  parent only

Crop (s)	

MRL (mg/kg)	

Crop(s)	

Tolerance (ppm)

	

	

Artichoke	1.4

	

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Squash, winter	0.20

	

	Pumpkin	0.20

	

	Gourd, edible	0.20

Cherry, sweet	0.4	Fruit, stone, group 12	0.70

Chery, tart	0.4

	

Limits for Canada	

Limits for Mexico

 No Limits

 No Limits for the crops requested	

X No Limits

 No Limits for the crops requested

Residue definition: 5,7-dichloro-4-(4-

fluorophenoxy)quinoline

	

Residue definition: N/A

Crop(s)	

MRL (mg/kg)	

Crop(s)	

MRL (mg/kg)

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Cherry, tart	0.3

	

	

Notes/Special Instructions:  

Steve Funk, 10/20/2008

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