Document ID: EPA-HQ-OPP-2008-0885-0005
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2010-02-24T05:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, DC  20460

OFFICE OF

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

MEMORANDUM

Date:		1/07/10

Subject:	Flumioxazin.  Human Health Risk Assessment for the Proposed
Aquatic Use and Proposed Food Uses on Cucurbit Vegetables, Leaf
Petioles, and Hops.    

PC Code:  129034	DP Num:  D359142

Decision No.:  402046	Registration No.:  59639-161, 59639-99, 59639-119

Petition Nos.:  8F7438, 8E7462  	Regulatory Action:  Section 3
Registration

Risk Assess Type:  Single Chemical Aggregate	Case No.:  NA

TXR No.:  NA	CAS No.:  103361-09-7

MRID No.:   NA	40 CFR:  §180.568

From:		W. Cutchin, Acting Senior Branch Scientist   SEQ CHAPTER \h \r 1 

		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  	Christina Swartz, Chief

	Risk Assessment Branch II (RABII)

		Health Effects Division (HED; 7509P)

To:	L. Nolan / D. Rosenblatt

	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 flumioxazin. 

Valent has submitted a petition to establish a tolerance as a result of
the aquatic uses of flumioxazin, formulated as a 51% water-dispersible
granular (WDG) formulation, in freshwater fish.  The Interregional
Research Project No. 4 (IR-4) has also submitted petitions to establish
tolerances as a result of the uses of flumioxazin, formulated as two 51%
WDG formulations in/on cucurbit vegetables, leaf petioles, and hops.  In
this document, ARIA has conducted an assessment of the human exposure
and risks resulting from these proposed uses and all currently
registered uses.  The overall risk assessment, dietary risk assessment,
and residue chemistry assessment were provided by W. Cutchin, the water
exposure assessment by L. Liu (Environmental Fate and Effects Division
(EFED)) and the occupational exposure assessments by M. Dow (ARIA) and
S. Wang (HED, Risk Assessment Branch II (RABII)).  

TABLE OF CONTENTS

  TOC \o "1-4" \h \z \u    HYPERLINK \l "_Toc250621051"  1.0 EXECUTIVE
SUMMARY	  PAGEREF _Toc250621051 \h  5  

  HYPERLINK \l "_Toc250621052"  2.0	INGREDIENT PROFILE	  PAGEREF
_Toc250621052 \h  12  

  HYPERLINK \l "_Toc250621053"  2.1	Summary of Proposed Uses	  PAGEREF
_Toc250621053 \h  13  

  HYPERLINK \l "_Toc250621054"  2.2	Structure and Nomenclature	  PAGEREF
_Toc250621054 \h  14  

  HYPERLINK \l "_Toc250621055"  2.3	Physical and Chemical Properties:	 
PAGEREF _Toc250621055 \h  14  

  HYPERLINK \l "_Toc250621056"  3.0  HAZARD CHARACTERIZATION	  PAGEREF
_Toc250621056 \h  15  

  HYPERLINK \l "_Toc250621057"  3.1	Hazard and Dose-Response
Characterization	  PAGEREF _Toc250621057 \h  15  

  HYPERLINK \l "_Toc250621058"  3.1.1	Database Summary	  PAGEREF
_Toc250621058 \h  15  

  HYPERLINK \l "_Toc250621059"  3.1.1.1	Studies available and considered
  PAGEREF _Toc250621059 \h  15  

  HYPERLINK \l "_Toc250621060"  3.1.1.2	Mode of action, metabolism,
toxicokinetic data	  PAGEREF _Toc250621060 \h  15  

  HYPERLINK \l "_Toc250621061"  3.1.1.3	Sufficiency of studies/data	 
PAGEREF _Toc250621061 \h  15  

  HYPERLINK \l "_Toc250621062"  3.1.2	Toxicological Effects	  PAGEREF
_Toc250621062 \h  16  

  HYPERLINK \l "_Toc250621063"  3.1.3	Dose-response	  PAGEREF
_Toc250621063 \h  17  

  HYPERLINK \l "_Toc250621064"  3.1.4	FQPA	  PAGEREF _Toc250621064 \h 
18  

  HYPERLINK \l "_Toc250621065"  3.2	Absorption, Distribution,
Metabolism, Excretion (ADME)	  PAGEREF _Toc250621065 \h  18  

  HYPERLINK \l "_Toc250621066"  3.3	FQPA Considerations	  PAGEREF
_Toc250621066 \h  18  

  HYPERLINK \l "_Toc250621067"  3.3.1	Adequacy of the Toxicity Database	
 PAGEREF _Toc250621067 \h  18  

  HYPERLINK \l "_Toc250621068"  3.3.2	Evidence of Neurotoxicity	 
PAGEREF _Toc250621068 \h  18  

  HYPERLINK \l "_Toc250621069"  3.3.3	Developmental Toxicity Studies	 
PAGEREF _Toc250621069 \h  19  

  HYPERLINK \l "_Toc250621070"  3.3.4	Reproductive Toxicity Study	 
PAGEREF _Toc250621070 \h  19  

  HYPERLINK \l "_Toc250621071"  3.3.5	Additional Information from
Literature Sources	  PAGEREF _Toc250621071 \h  19  

  HYPERLINK \l "_Toc250621072"  3.3.6	Pre-and/or Post-natal Toxicity	 
PAGEREF _Toc250621072 \h  19  

  HYPERLINK \l "_Toc250621073"  3.3.6.1	Determination of Susceptibility	
 PAGEREF _Toc250621073 \h  19  

  HYPERLINK \l "_Toc250621074"  3.3.6.2	Degree of Concern Analysis and
Residual Uncertainties	  PAGEREF _Toc250621074 \h  20  

  HYPERLINK \l "_Toc250621075"  3.3.7	Recommendation for a Developmental
Neurotoxicity Study	  PAGEREF _Toc250621075 \h  20  

  HYPERLINK \l "_Toc250621076"  3.4	FQPA Safety Factor for Infants and
Children	  PAGEREF _Toc250621076 \h  20  

  HYPERLINK \l "_Toc250621077"  3.5	Hazard Identification and Toxicity
Endpoint Selection	  PAGEREF _Toc250621077 \h  21  

  HYPERLINK \l "_Toc250621078"  3.5.1    Acute Reference Dose (aRfD) -
Females age 13-49	  PAGEREF _Toc250621078 \h  21  

  HYPERLINK \l "_Toc250621079"  3.5.2	Acute Reference Dose (aRfD) -
General Population	  PAGEREF _Toc250621079 \h  22  

  HYPERLINK \l "_Toc250621080"  3.5.3	Chronic Reference Dose (cRfD)	 
PAGEREF _Toc250621080 \h  22  

  HYPERLINK \l "_Toc250621081"  3.5.4	Incidental Oral Exposure (Short-
and Intermediate-Term)	  PAGEREF _Toc250621081 \h  22  

  HYPERLINK \l "_Toc250621082"  3.5.5	Dermal Absorption	  PAGEREF
_Toc250621082 \h  23  

  HYPERLINK \l "_Toc250621083"  3.5.6(b)	Dermal Exposure (Short-,
Intermediate- and Long-Term) for Adults	  PAGEREF _Toc250621083 \h  23  

  HYPERLINK \l "_Toc250621084"  3.5.7	Inhalation Exposure (Short- and
Intermediate-Term)	  PAGEREF _Toc250621084 \h  24  

  HYPERLINK \l "_Toc250621085"  3.5.8	Inhalation Exposure (Long-Term)	 
PAGEREF _Toc250621085 \h  25  

  HYPERLINK \l "_Toc250621086"  3.5.9	Level of Concern for Margin of
Exposure	  PAGEREF _Toc250621086 \h  25  

  HYPERLINK \l "_Toc250621087"  3.5.10	Recommendation for Aggregate
Exposure Risk Assessments	  PAGEREF _Toc250621087 \h  26  

  HYPERLINK \l "_Toc250621088"  3.5.11	Classification of Carcinogenic
Potential	  PAGEREF _Toc250621088 \h  26  

  HYPERLINK \l "_Toc250621089"  3.6	Endocrine Disruption	  PAGEREF
_Toc250621089 \h  28  

  HYPERLINK \l "_Toc250621090"  4.0	PUBLIC HEALTH AND PESTICIDE
EPIDEMIOLOGY DATA	  PAGEREF _Toc250621090 \h  29  

  HYPERLINK \l "_Toc250621091"  5.0	DIETARY EXPOSURE/RISK
CHARACTERIZATION	  PAGEREF _Toc250621091 \h  29  

  HYPERLINK \l "_Toc250621092"  5.1	Pesticide Metabolism and
Environmental Degradation	  PAGEREF _Toc250621092 \h  29  

  HYPERLINK \l "_Toc250621093"  5.1.1	Metabolism in Primary Crops and
Livestock Commodities.	  PAGEREF _Toc250621093 \h  29  

  HYPERLINK \l "_Toc250621094"  5.1.2	Metabolism in Rotational Crops	 
PAGEREF _Toc250621094 \h  30  

  HYPERLINK \l "_Toc250621095"  5.1.3	Analytical Methodology	  PAGEREF
_Toc250621095 \h  30  

  HYPERLINK \l "_Toc250621096"  5.1.4	Multiresidue Methods	  PAGEREF
_Toc250621096 \h  31  

  HYPERLINK \l "_Toc250621097"  5.1.5	Storage Stability	  PAGEREF
_Toc250621097 \h  31  

  HYPERLINK \l "_Toc250621098"  5.1.6	Magnitude of the Residue	  PAGEREF
_Toc250621098 \h  32  

  HYPERLINK \l "_Toc250621099"  5.1.7	Magnitude of the Residue in Meat,
Milk, Poultry, and Eggs	  PAGEREF _Toc250621099 \h  33  

  HYPERLINK \l "_Toc250621100"  5.1.8	Confined and Field Rotational
Crops	  PAGEREF _Toc250621100 \h  33  

  HYPERLINK \l "_Toc250621101"  5.1.9	Pesticide Metabolites and
Degradates of Concern	  PAGEREF _Toc250621101 \h  33  

  HYPERLINK \l "_Toc250621102"  5.1.10	Drinking Water Residue Profile	 
PAGEREF _Toc250621102 \h  34  

  HYPERLINK \l "_Toc250621103"  5.2	Dietary Exposure and Risk	  PAGEREF
_Toc250621103 \h  34  

  HYPERLINK \l "_Toc250621104"  5.2.1	Acute Dietary Exposure/Risk	 
PAGEREF _Toc250621104 \h  34  

  HYPERLINK \l "_Toc250621105"  5.2.2	Chronic Dietary Exposure/Risk	 
PAGEREF _Toc250621105 \h  35  

  HYPERLINK \l "_Toc250621106"  5.2.3	Cancer Dietary Risk	  PAGEREF
_Toc250621106 \h  35  

  HYPERLINK \l "_Toc250621107"  6.0	RESIDENTIAL (NON-OCCUPATIONAL)
EXPOSURE/RISK CHARACTERIZATION	  PAGEREF _Toc250621107 \h  36  

  HYPERLINK \l "_Toc250621108"  6.1	Other (Spray Drift, etc.)	  PAGEREF
_Toc250621108 \h  39  

  HYPERLINK \l "_Toc250621109"  7.0	AGGREGATE RISK ASSESSMENTS AND RISK
CHARACTERIZATION	  PAGEREF _Toc250621109 \h  39  

  HYPERLINK \l "_Toc250621110"  7.1	Acute Aggregate Risk	  PAGEREF
_Toc250621110 \h  40  

  HYPERLINK \l "_Toc250621111"  7.2	Short- and Intermediate-Term
Aggregate Risk	  PAGEREF _Toc250621111 \h  40  

  HYPERLINK \l "_Toc250621112"  7.3	Chronic Aggregate Risk	  PAGEREF
_Toc250621112 \h  42  

  HYPERLINK \l "_Toc250621113"  7.4	Cancer Risk	  PAGEREF _Toc250621113
\h  42  

  HYPERLINK \l "_Toc250621114"  8.0	CUMULATIVE RISK
CHARACTERIZATION/ASSESSMENT	  PAGEREF _Toc250621114 \h  42  

  HYPERLINK \l "_Toc250621115"  9.0	OCCUPATIONAL EXPOSURE/RISK PATHWAY	 
PAGEREF _Toc250621115 \h  42  

  HYPERLINK \l "_Toc250621116"  9.1	Short-/Intermediate-/Long-Term
Handler Risk	  PAGEREF _Toc250621116 \h  43  

  HYPERLINK \l "_Toc250621117"  9.2	Short-/Intermediate-/Long-Term
Post-application Risk	  PAGEREF _Toc250621117 \h  52  

  HYPERLINK \l "_Toc250621118"  9.3	Restricted Entry Interval (REI)	 
PAGEREF _Toc250621118 \h  53  

  HYPERLINK \l "_Toc250621119"  10.0	TOLERANCE SUMMARY	  PAGEREF
_Toc250621119 \h  53  

  HYPERLINK \l "_Toc250621120"  11.0	DATA NEEDS AND LABEL
RECOMMENDATIONS	  PAGEREF _Toc250621120 \h  54  

  HYPERLINK \l "_Toc250621121"  11.1	Toxicology	  PAGEREF _Toc250621121
\h  54  

  HYPERLINK \l "_Toc250621122"  11.2	Residue Chemistry	  PAGEREF
_Toc250621122 \h  55  

  HYPERLINK \l "_Toc250621123"  11.3	Occupational and Residential
Exposure	  PAGEREF _Toc250621123 \h  55  

  HYPERLINK \l "_Toc250621124"  12.0	REFERENCES	  PAGEREF _Toc250621124
\h  55  

  HYPERLINK \l "_Toc250621125"  Appendix A:  Toxicology Assessment	 
PAGEREF _Toc250621125 \h  57  

  HYPERLINK \l "_Toc250621126"  A.1	Toxicology Data Requirements	 
PAGEREF _Toc250621126 \h  57  

  HYPERLINK \l "_Toc250621127"  A.2  Toxicity Profiles	  PAGEREF
_Toc250621127 \h  58  

  HYPERLINK \l "_Toc250621128"  A.3	Data Requirements	  PAGEREF
_Toc250621128 \h  62  

  HYPERLINK \l "_Toc250621129"  Appendix B:  Metabolism Assessment	 
PAGEREF _Toc250621129 \h  65  

  HYPERLINK \l "_Toc250621130"  Appendix C:  Review of Human Research	 
PAGEREF _Toc250621130 \h  65  

 

1.0 EXECUTIVE SUMMARY  TC \l1 "1.0 EXECUTIVE SUMMARY 

Background

This document is a human health risk assessment to support an aquatic
use (PP#: 8F7438) and Section 3 requests for crop uses (PP#: 8E7462) and
for the establishment of permanent flumioxazin tolerances in/on
freshwater fish, cucurbit vegetables, leaf petioles, and hops. 
Flumioxazin,
2-[7-fluoro-3,4-dihydro-3-oxo-4-(2-propynyl)-2H-1,4-benzoxazin-6-yl]-4,5
,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione, is an herbicide of the
N-phenylphthalimide class (Group 14) that is currently used for pre- and
post-emergence control of susceptible weeds in a variety of fruit,
vegetable and other field crops.  Its mode of action is as an inhibitor
of protoporphyrinogen oxidase (PPO); it is active against certain
grasses, broadleaf weeds, and sedges (including aquatic species).  

The most recent human health risk assessment for flumioxazin was
conducted in conjunction with a request for the establishment of
tolerances for residues on field corn (PP#: 7F7243, DP Num: D342248, B.
Hanson, 4/8/08). 

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

Proposed Uses

The registrant, Valent, proposes a use of Clipper( Herbicide (EPA Reg.
No 59639-161), a WDG formulation containing flumioxazin at 51%, for
management of aquatic weeds in bayous, canals, fresh water ponds, lakes,
marshes and reservoirs.  The proposed maximum rates are 0.3825 lb ai/A
for surface and aerial applications, and 8.62 lb ai/A for subsurface
application.

.  The end-use products (EPs) relevant to this registration request are
Valor™ Herbicide (EPA Reg. No. 59639-99) and Chateau™ Herbicide (EPA
Reg. No. 59639-119).  The products are WDG formulations containing 51%
flumioxazin.  Valor and Chateau are proposed for uses with ground
equipment for a pre-emergence or pre-transplant application and followed
by a second application to row middles at a total of 0.25 lb ai/A on
cucurbit vegetables; for a pre-transplant soil application at
0.094-0.188 lb ai/A on leaf petioles; and for 0.375 lb ai/A with a
30-day pre-harvest interval (PHI) on hops.

Toxicology and Dose-Response

The toxicology database for flumioxazin is not complete because several
studies newly required in accordance with the 12/2007 update of the Part
158 Guidelines for toxicology have not yet been submitted.  These
include rat acute and subchronic neurotoxicity studies, as well as an
immunotoxicity study.  Despite these missing studies, the toxicity
database is considered to be adequate for the purpose of dose and
endpoint selection for the current risk assessment, and for
characterizing toxic effects associated with flumioxazin.

Flumioxazin has mild or no acute toxicity (categories III or IV) when
administered orally, dermally, or by inhalation.  It has little or no
toxicity with respect to eye or skin irritation (categories III or IV). 
In addition, flumioxazin is not a dermal sensitizer.  Subchronic and
chronic toxicity studies demonstrated that toxicity associated with
flumioxazin include anemia, and effects on the liver and the
cardiovascular system.  Developmental effects were observed in
developmental rat studies but not in developmental rabbit studies. 
These effects were fetal cardiovascular anomalies, especially
ventricular septal defects.

Hematologic (hematopoietic) effects of anemia were noted in rats,
consisting of alterations in hemoglobin parameters.  Increased renal
toxicity in male rats was also reported following chronic exposure. 
Increased absolute and relative liver weights and/or increased alkaline
phosphatase values were observed in dogs.  Flumioxazin administered
orally and dermally to rats in developmental studies resulted in
cardiovascular anomalies, the most serious being ventricular septal
defects. The same effects occurred by both dermal and oral routes of
administration, with the oral being observed at 10 and the dermal at 100
mg/kg/day. A mechanistic oral developmental study in rats indicated that
a single dose of 400 mg/kg caused the ventricular septal defects when
administered on gestation day 12, but not when given on days 11 or 13 or
14 or 15.  In the 2-generation reproduction study, systemic effects
(clinical signs and mortality as well as a decrease in body weight/gain
and food consumption) were noted at approximately 19 and 23 mg/kg/day in
males and females, respectively; however, effects on the offspring
(decrease in the number of live born and decreased pup body weights,
decreased mating index, and testicular atrophy in F1 males) occurred at
lower doses (approximately 13 and 15 mg/kg/day).  Based on the lack of
evidence of carcinogenicity in mice and rats, flumioxazin is classified
as “not likely to be carcinogenic to humans.”

The endpoint selected for acute dietary risk assessment was based on the
cardiovascular effects, ventricular septal defects in fetuses, observed
in oral developmental and supplemental pre-natal studies in rats.  The
endpoint is only applicable to females of childbearing age (i.e.,
females 13-49).  No acute dietary endpoint (i.e., toxic effect resulting
from a single dose) applicable to the general population or any other
population subgroups was identified in the submitted studies.  The
endpoint selected for chronic dietary risk assessment for all population
subgroups was increased chronic nephropathy in males and decreased
hematological parameters in females observed in a 2-year
chronic/carcinogenicity study in rats.  This endpoint and dose are the
lowest of any long-term studies submitted for flumioxazin, and are also
protective of the offspring effects seen in the 2-generation
reproduction study.

A no observable adverse effects level (NOAEL) of 30.0 mg/kg/day was
selected from a rat dermal developmental toxicity study for short- and
intermediate-term dermal risk assessments for adults potentially exposed
to flumioxazin.  The NOAEL was based on a biologically significant
increase in cardiovascular abnormalities, particularly ventricular
septal defects observed at the lowest observed adverse effects level
(LOAEL) of 100 mg/kg/day.  Since the dermal endpoint and dose were
selected from a dermal study, an absorption factor was not used in the
dermal assessments.  However, for children potentially exposed to
flumioxazin via the dermal route, the offspring effects in the rat
reproduction study were chosen for risk assessment, and a dermal
absorption factor was used to account for route-to-route extrapolation.

For both short- and intermediate-term incidental oral exposure and risk
assessments, the endpoint and dose were selected from the reproductive
toxicity study in rat, based on the offspring/reproductive effects,
including decreased live born pups and decreased pup body weights
observed at the LOAEL of 12.7 mg/kg/day.  The dose for risk assessment
was the NOAEL of 6.3 mg/kg/day.  The study was considered to be the most
appropriate for the route of exposure (oral), the duration, short- and
intermediate-term, and because the endpoint is relevant for the
potentially exposed population, children.

For short-term inhalation exposure, a NOAEL of 3.0 mg/kg/day was
selected from an oral developmental study in rats, based on a
biologically significant increase in cardiovascular abnormalities,
particularly ventricular septal defects, at the LOAEL of 10 mg/kg/day. 
For intermediate-term inhalation exposure, a NOAEL of 2.0 mg/kg/day was
selected from a 2-year chronic rat study, based on increased chronic
nephropathy in males, and decreased hematological parameters in females,
observed at the LOAEL of 18 mg/kg/day.  Since the doses and endpoints
for inhalation risk assessments were selected from oral studies, a 100%
inhalation absorption factor was used for risk assessment.

 

Both qualitative and quantitative susceptibility were observed in the
rat developmental toxicity studies, in which the effects on fetuses
occurred at doses which did not cause maternal toxicity.  In addition,
qualitative and quantitative susceptibility were observed in the rat
reproduction study, in which offspring effects were observed at lower
doses than those which caused parental/systemic toxicity, and in which
the offspring effects were considered to be more severe.  Although there
were both qualitative and quantitative susceptibility, HED concluded the
10X FQPA Safety Factor could be removed (reduced to1X).  This conclusion
was based on the low degree of concern for the observed susceptibility
because the observed effects were adequately characterized and the doses
and endpoints selected for risk assessment are sufficiently protective
of the fetal/offspring susceptibility.  In addition, there were no
concerns for neurotoxicity based on the submitted data, and a
developmental neurotoxicity study is not required.  Although there are
missing studies, including acute and subchronic neurotoxicity and
immunotoxicity studies, there is no evidence in the submitted data to
indicate flumioxazin directly impacts the nervous system or the immune
system.  Finally, the exposure assessment is conservative, and therefore
potential risks to infants and children have not been underestimated.

Since the FQPA factor was reduced to 1X, and there were no other
database uncertainty factors retained for missing data or the lack of a
NOAEL, the level of concern (LOC) for both residential and occupational
exposure and risk is margin of exposure (MOE) of 100, based on the
standard 10X uncertainty factors retained for interspecies extrapolation
and intraspecies variability.

Endocrine Disruptor Screening Program (EDSP)

Between October 2009 and February 2010, EPA is issuing test orders/data
call-ins for endocrine testing for the first group of 67 chemicals,
which contains 58 pesticide active ingredients and 9 inert ingredients. 
This list of chemicals was selected based on the potential for human
exposure through pathways such as food and water, residential activity,
and certain post-application agricultural scenarios, and should not be
construed as a list of known or likely endocrine disruptors. 
Flumioxazin is not among the group of 58 pesticide active ingredients on
the initial list to be screened under the EDSP.  Under FFDCA sec. 408(p)
the Agency must screen all pesticide chemicals.  Accordingly, EPA
anticipates issuing future EDSP test orders/data call-ins for all
pesticide active ingredients. 

For further information on the status of the EDSP, the policies and
procedures, the list of 67 chemicals, the test guidelines and the Tier 1
screening battery, please visit our website:  http://www.epa.gov/endo/.

Residue Chemistry

With the exception of the aquatic use and the need for a restriction on
the use of adjuvants, the proposed application labels are acceptable. 
Based on occupational exposure concerns associated with the aquatic use,
ARIA/HED recommends that the water depth for subsurface application
should not go beyond 7 feet (a 7 foot deep water column requires 7.55 lb
ai/A/application).  Updated labels are required.

The nature of flumioxazin residues in plants and animals is adequately
understood based on previously submitted studies.  In primary and
rotated crops, the residue of concern is the parent compound,
flumioxazin.  For ruminants, the residues of concern are parent,
3-OH-flumioxazin, 4-OH-flumioxazin, plus Metabolites B, C, and F.  For
poultry, the residues of concern are parent, 3-OH-flumioxazin,
4-OH-flumioxazin, and 4-OH-S-53482-SA.  For purposes of this petition,
ARIA has waived the requirement for a fish metabolism study and has
concluded that the residues of concern in fish include flumioxazin and
its major degradates in water, APF and 482-HA.

For tolerance enforcement in fish tissues, Valent has submitted a liquid
chromatography with tandem mass spectroscopy/mass spectroscopy detector
(LC-MS/MS) method (GPL-MTH-066) for determining residues of flumioxazin,
APF and 482-HA.  The validated limit of quantitation (LOQ) is 0.01 ppm
for each analyte in fish.  This method has undergone a successful
independent laboratory validation (ILV) trial and appears to be
acceptable for data collection and tolerance enforcement; however,
additional information/data are required before the method can be
recommended as an enforcement method (See Sec. 11, below).  In addition,
FDA multiresidue testing data are required for the metabolite/degradates
482-HA and APF, and reference standards must be provided for the EPA
National Pesticide Standards Repository.

An adequate gas chromatography/nitrogen-phosphorus detection (GC/NPD)
method, Valent Method RM-30-A-1, is available for enforcing tolerances
for residues of flumioxazin per se in/on plant commodities.  The
reported method LOQ and limits of detection (LOD) for flumioxazin in/on
plant commodities are 0.02 and 0.01 ppm, respectively.

 

Acceptable data collection methods were used in the submitted studies
based on acceptable concurrent method recoveries.

The submitted fish residue study is adequate and supports the proposed
aquatic use.  Residues of flumioxazin, APF and 482-HA were determined in
the water and edible fish tissues over a 28-day period of exposure to
residues at 2x the application rate.  Total flumioxazin residues were
highest at the earliest sampling interval (4 hours), ranging from
0.85-2.52 ppm.  Total residues declined rapidly by Day 3 and then
remained relatively steady up to Day 28 (0.063-0.204 ppm).  Total
flumioxazin residues did not bioaccumulate over the 28 day study.  When
extrapolated to reflect the 1x use rate, the estimated total residues
would support the proposed 1.5 ppm tolerance for residues in freshwater
fish.  Because applications to flowing water, intertidal or estuarine
areas and to water used for crawfish farming are prohibited, residue
data and tolerances are not required for shellfish or saltwater fishes.

The submitted residue data for cucumber and summer squash are adequate. 
In addition, residue field trial data on cantaloupe, the representative
crop for muskmelon subgroup 9A were submitted previously in support of
the tolerance using the same use pattern.  The data indicate that a
tolerance for residues on cucurbits should be established at 0.03 ppm. 
ARIA recommends for the proposed flumioxazin tolerance on cucurbit
vegetables, group 9, at 0.03 ppm. Concurrently, with the establishment
of the tolerance on cucurbit vegetables, the existing tolerance on
muskmelon subgroup 9A should be removed.

The submitted residue data for celery are adequate. Since celery is the
representative crop for leaf petioles, subgroup 4B, the data is adequate
to support the requested tolerance. ARIA recommends for the proposed
flumioxazin tolerance on leaf petioles, subgroup 4B, at 0.02 ppm.

The submitted residue data for hops are adequate.  Following Agency
policy, a tolerance of 0.05 ppm would be appropriate on hops.  ARIA
recommends for a tolerance of 0.05 ppm for the residues of flumioxazin
on hops.  A revised Section F is required. 

However, since adjuvants were not used in the submitted residue field
trials, the labels should prohibit such uses on cucurbit vegetables,
leaf petioles, and hops.

A previously submitted confined rotational crop study is adequate for
the proposed uses on the requested field corn commodities.  Based on the
results of the confined accumulation study, the existing rotational crop
plantback intervals (PBIs) are acceptable and rotational crop field
trials and tolerances are not necessary.

Dietary Risk (Food and Drinking Water)

The drinking water residues for flumioxazin (flumioxazin, 482-HA, and
APF) used in the dietary risk assessment were provided by EFED and
incorporated directly into the dietary assessments  The estimated
drinking water concentration (EDWC) for flumioxazin residues (used in
both the acute and chronic dietary analyses) was 0.048 ppm.

The acute dietary exposure analysis for flumioxazin is an unrefined
assessment, assuming 100% crop treated and tolerance level residues,
upper bound estimates of potential drinking water residues, and using
DEEM( default processing factors (Version 7.81) for processed
commodities (with the exception of tomato, which used the empirical
processing factor of 1x).  The acute dietary endpoint is applicable only
to the population subgroup females 13- 49 years old.  An acute dietary
endpoint for the general population, including infants and children was
not identified.  The estimated acute dietary exposure (food and drinking
water) for females 13-49 years old occupies 9% of the aPAD and does not
exceed ARIA’s level of concern.

Similarly, the chronic dietary exposure analysis for flumioxazin is an
unrefined assessment, with the same food residue and drinking water
assumptions as the acute analysis.  The chronic dietary endpoint applies
to all population subgroups, including infants and children.  The
estimated chronic dietary exposure (food and water) from flumioxazin
does not exceed ARIA’s level of concern for any population subgroup. 
Food and water exposure occupies 7% of the cPAD for the US population
and 19% of the cPAD for all infants (<1 year old), the subgroup with the
highest exposure. 

Non-Occupational and Residential Risk

Flumioxazin is not registered for use by homeowners for weed control in
residential areas.  However, HED recently reviewed a proposed use of
BroadStar™ Herbicide for use by commercial applicators for control of
weeds on walkways, parking lots and non-grassy areas in home landscapes.
 Although the product is not intended for use by homeowners, HED assumed
homeowners could buy the product if available in garden centers and
other retail outlets.  Therefore, residential handlers were assessed for
both dermal and inhalation exposure, and the risks were not of concern
(i.e., MOEs were significantly greater than the level of concern, and
MOE of 100).  No postapplication scenarios were assessed because
children and adults are not expected to come into contact with
flumioxazin following application to parking lots, walkways, and
non-grassy areas.

There is also the potential for non-occupational exposure associated
with swimming in treated water for recreational purposes.  ARIA used the
standard approach used for assessing exposure and risk for recreational
swimmers.  The exposure estimates are considered to be reasonable
high-end estimates based on observations from chemical-specific field
studies and professional judgment.  Swimmer assessments based on the
proposed use pattern indicated that all MOEs are above the level of
concern, with MOEs ranging from 2,300 to 84,000.  

Aggregate Risk

When aggregating exposures and risks from various sources, ARIA has
considered both the route and duration of exposure.  Potential
residential exposure scenarios include adult and child swimmers, and
adult handlers applying flumioxazin for weed control.  When these
short-term exposures were combined with background (chronic) dietary
exposure from food and drinking water, aggregate risks were not of
concern, with MOEs ranging from 900 to 1300.  The lowest MOE was
associated with children’s combined exposure from the diet (food and
water) and from swimming in water treated with flumioxazin.  ARIA notes
that both the adult and children’s short-term aggregate risk
assessments are conservative based on the use of the SWIMMODEL to
determine potential exposure from recreational swimming.  Acute and
chronic aggregate risks are the same as dietary risks which incorporated
exposure from both food and drinking water.  These risks were not of
concern.

Occupational Exposure and Risk

Based on the product use information, there is a potential for
occupational exposure from handling (mixing/loading/applying)
flumioxazin for the aquatic uses.  A MOE of 100 or more is sufficient to
protect occupational pesticide handlers.  Except for the short-term
total MOE for the subsurface application (MOE = 94), all short-term
total MOEs and intermediate-term dermal & inhalation MOEs for the
handlers performing the proposed uses on aquatic weeds are greater than
100 (110 ~ 43,000) and therefore, the risks do not exceed HED’s level
of concern.  The rate of 8.62 lb ai/A results a short-term total MOE of
94 when assessed using baseline protection plus gloves as required on
the label.  The short-term total MOE calculated for the next highest
application rate (7.55 lb ai/A) used in the subsurface application is
110.  Based on this result and given the serious nature of the
toxicological endpoint, ARIA/HED recommends that the water depth for
subsurface application shall not go beyond 7 feet; an updated label is
required.

Workers may also be exposed to flumioxazin during mixing, loading, and
application activities associated with agricultural crops.  Occupational
handler assessments indicate that all MOEs are above the levels of
concern at the baseline level (total MOEs = 210 to 4,400).  The
post-application MOEs for commodities were not determined because the
exposures to flumioxazin for workers performing post-application
activities on these commodities are expected to be negligible.  The
12-hour restricted entry interval (REI) appearing on the label is
appropriate for this chemical.

Environmental Justice

Potential areas of environmental justice concern, 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://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf" 
http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf ).

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 Intake 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.

Cumulative Exposure and Risk

Unlike other pesticides for which EPA has followed a cumulative risk
approach based on a common mechanism of toxicity, EPA has not made a
common mechanism of toxicity finding as to flumioxazin and any other
substances, and flumioxazin 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 flumioxazin has a
common mechanism of toxicity with other substances.

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 (listed in Appendix C) have been determined to
require a review of their ethical conduct, and have received that
review.

Additional Data Needs and Recommendations

Pending the resolution of the requirements listed in Section 11,   SEQ
CHAPTER \h \r 1 ARIA recommends in favor of establishing the tolerances
as listed in Table 10.0.

INGREDIENT PROFILE

Flumioxazin is an herbicide of the N-phenylphthalimide class (Group 14)
that is currently used for pre- and post-emergence control of
susceptible weeds in a variety of fruit, vegetable and other field
crops.  Its mode of action is as an inhibitor of protoporphyrinogen
oxidase (PPO); it is active against certain grasses, broadleaf weeds,
and sedges.  Tolerances are currently established for residues of
flumioxazin in/on various plant commodities, at levels ranging from 0.02
to 0.70 ppm (40 CFR §180.568[a]).  Temporary tolerances associated with
a Section 18 emergency exemption have also been established on alfalfa
forage and hay at 0.13 and 0.45 ppm, respectively (40 CFR 180.568[b]).

wish to amend the product labels for Valor™ Herbicide, Chateau™
Herbicide, and Clipper( Herbicide.  The products are WDG formulations
containing flumioxazin at 51% to incorporate new aquatic uses and uses
on cucurbit vegetable, leaf petioles, and hops.  The nomenclature and
physicochemical properties of flumioxazin are presented below in Tables
2.2 and 2.3.

2.1	Summary of Proposed Uses

Table 2.1.   Summary of Proposed Use Pattern of Flumioxazin. 

Applic. Timing, Type, and Equip.	Formulation

[EPA Reg. No.]	Applic. Rate 

(lb ai/A)	Max. No. Applic. per Season	Max. Seasonal Applic. Rate

(lb ai/A)	RTI 1 	PHI

(days)	Use Directions and Limitations

Aquatic Weeds and Algae

Surface application---broad spray using backpack or handgun sprayer,
airboat, or other equipment	Clipper™

51% WDG [59639-161]	0.3825	2	0.765	28	NA	Treat up to half of the water
body and wait 10 to 14 days before treating the remaining area. Do not
re-treat the same section of water within 28

days of application.

Aerial application---helicopter, airplane

0.3825	2	0.765	28	NA

	Subsurface application---hoses trailing behind a boat

8.62              (8 foot  deep water column)	2	17.24	28	NA

	Cucurbit Vegetables Group 9

Ground equipment	Valor™

51% WDG [59639-99]

Chateau™

51% WDG [59639-119]	0.125	2	0.250	21±2 after transplant

28±2 after emergence	NS2	Fist shielded application to row middles 14±2
before crop emergence or transplant. Apply at 10-40 gal/A.

Leaf Petioles Subgroup 4B

Ground equipment	Valor™

51% WDG [59639-99]

Chateau™

51% WDG [59639-119]	0.094-0.188	1	0.094-0.188	NA	NS	Apply to soil
surface before transplant. Apply at 20-40 gal/A.

Hops

Ground equipment	Valor™

51% WDG [59639-99]

Chateau™

51% WDG [59639-119]	0.375	2	0.750	30±3	30±3	Apply to lower 30in of
plant extending to 18in from row. Apply at 10-40 gal/A.

1  Retreatment Interval.  

2  NS = not specified.

Conclusion:  Based on occupational exposure and risk concerns, ARIA
recommends that the water depth for subsurface application shall not go
beyond 7 feet (a 7 foot deep water column requires 7.55 lb
ai/A/application to achieve the desired 400 ppb water concentration). 
An updated aquatic application label is required.  In addition, since
adjuvants were not used in the submitted residue field trials, the
labels should prohibit such uses on cucurbit vegetables, leaf petioles,
and hops; updated labels are required.

2.2	Structure and Nomenclature

Table 2.2.	Flumioxazin Nomenclature.

Compound	

Common name	Flumioxazin

Company experimental name	VC-1152

IUPAC name
N-(7-fluoro-3,4-dihydro-3-oxo-4-prop-2-ynyl-2H-1,4-benzoxazin-6-yl)cyclo
hex-1-ene-1,2-dicarboxamide

CAS name
2-[7-fluoro-3,4-dihydro-3-oxo-4-(2-propynyl)-2H-1,4-benzoxazin-6-yl]-4,5
,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione

CAS registry number	103361-09-7

End-use product (EP)	Valor™ Herbicide (EPA Reg. No 59639-99),
Chateau™ Herbicide (EPA Reg. No 59639-199), and Clipper( Herbicide
(EPA Reg. No 59639-161).  All products are WDG formulations containing
51% flumioxazin. 

2.3	Physical and Chemical Properties:

λ218,  ε = 14700 (pH(  1.9)

λ216,  ε = 43600 (pH(  6.8)

λ216ε = 51200 (pH 10.0)(,	MRID No. 44295004

3.0  HAZARD CHARACTERIZATION

3.1	Hazard and Dose-Response Characterization

3.1.1	Database Summary

  TC \l3 "3.1.1	Database Summary 

3.1.1.1	Studies available and considered

The following toxicity studies have been submitted in support of
registered and proposed uses of flumioxazin:

Acute- oral, dermal, inhalation, eye irritation, dermal irritation, skin
sensitization;

Subchronic- Dermal 21-day rat; Oral 28-day mouse, oral 90-day rat, oral
90-day dog;

Chronic- Oral dog and rat;

Carcinogenicity- Rat and mouse;

Reproductive/developmental- Oral Pre-natal developmental rat, oral
pre-natal developmental rabbit, dermal pre-natal developmental rat,
2-generation reproduction rat;

Other- Mutagenicity screens, metabolism and pharmacokinetic studies,
dermal penetration rat, and a Special Study: Rat Developmental: Critical
Time for Defects.

Mode of action, metabolism, toxicokinetic data

Flumioxazin is an herbicide of the N-phenylphthalimide class (Group 14)
that is currently used for pre- and post-emergence control of
susceptible weeds in a variety of fruit, vegetable and other field
crops.  Its mode of action is as an inhibitor of the enzyme PPO; it is
active against certain grasses, broadleaf weeds, and sedges.  In
mammals, the inhibition of the enzyme can interfere with porphyrin
component of heme.

Metabolism studies in rats indicated that there was extensive biliary
excretion following oral administration of flumioxazin.  It is noted
that 4-5 times more radioactivity is excreted in feces than in urine. 
Radioactivity excretion in urine was statistically significantly
elevated in females (38.8-42.8%, low dose; 22.9-23.4%, high dose) vs.
males (28.1-30.8%, low dose; 12.8-13.0%, high dose).  Highest levels of
residues were found in blood cells (35.9-48.8 ppb, low dose and
2823-3040 ppb, high dose), which were much higher than the plasma levels
(0.5-0.7 ppb, low dose and 53-37 ppb, high dose).  

Sufficiency of studies/data

The toxicology database for flumioxazin is not complete because several
studies newly required in accordance with the 12/2007 update of the Part
158 Guidelines for toxicology have not yet been submitted.  These
include acute and subchronic neurotoxicity studies, as well as an
immunotoxicity study.  Despite these missing studies, the toxicity
database is considered to be adequate for the purpose of assessment of
susceptibility, dose and endpoint selection for the current risk
assessment, and for characterizing toxic effects associated with
flumioxazin.

3.1.2	Toxicological Effects

The toxicity profile of flumioxazin may be found in Appendix A.  In
general, the subchronic and chronic toxicity studies demonstrated that
toxic effects associated with flumioxazin include anemia, and effects on
the liver and the cardiovascular system.  Developmental effects were
observed in developmental rat studies but not in developmental rabbit
studies.  Hematologic (hematopoietic) effects of anemia were noted in
rats, consisting of alterations in hemoglobin parameters.  Increased
renal toxicity in male rats was also reported following chronic
exposure.

Acute Toxicity:  Flumioxazin has mild or no acute toxicity (categories
III or IV) when administered orally, dermally, or by inhalation.  It is
also classified as Toxicity Category III or IV for primary eye and skin
irritation.  Flumioxazin is not a dermal sensitizer.

Reproductive and Developmental Toxicity:  The pre- and post-natal
toxicity database for flumioxazin includes the rat and rabbit
developmental toxicity studies and the two-generation reproduction
toxicity study in rats.  There is quantitative evidence of increased
susceptibility of rat fetuses to in-utero exposure to flumioxazin in the
oral and dermal developmental studies.  In both studies, there was an
increased incidence in fetal cardiovascular anomalies (especially
ventricular septal defects).  In the oral study, no maternal effects
were seen at the highest dose tested (30 mg/kg/day); however, the
effects in the fetuses were observed at 10 mg/kg/day.  In the dermal
study, no maternal effects were noted at the highest dose tested (300
mg/kg/day) but the effects in fetuses were observed at 100 mg/kg/day. 
In the 2-generation rat reproduction study, parental effects (red
substance in vagina and increased mortality in females as well as
decreases in male and female body weights, body weight gains and food
consumption) were noted at 18.9 mg/kg/day in males at the highest dose
tested (HDT) and 22.7 mg/kg/day in females (HDT).  The observed
reproduction/offspring effects were a decrease in the number of
liveborn, a decrease in pup body weights, and a decrease in mating index
at 12.7 mg/kg/day for males and 15.1 mg/kg/day for females.  In
addition, testicular atrophy was observed in the F1 males at 12.7
mg/kg/day.

The effects observed in the fetuses and offspring in the developmental
and reproductive toxicity studies occurred at lower doses than those
which caused maternal and/or parental effects, which is considered to be
evidence of an increase in quantitative susceptibility.  An additional
rat developmental study was submitted in which a single dose of 400
mg/kg/day was administered to pregnant rats on gestation days (GDs) 11,
12, 13 or 14.  The results of the study indicated that a single dose on
gestation day 12 was the cause of the ventricular septal defect observed
in the rat developmental toxicity studies.

A number of mechanistic studies were submitted by the Registrant to
further describe the hematopoietic and fetal effects, and to determine
the relationship between these effects.  The registrant postulated that
the anemia observed in rats leads to fetal anemia and subsequent fetal
hypoxia, followed by suppressed liver function and a decrease in protein
synthesis.  The decreased protein synthesis was proposed to result in
wavy ribs and changes in osmotic forces leading to edema observed in the
fetus.  Concurrently, the fetus would compensate for the anemia by
pumping a greater volume of blood leading to the observed enlargement of
the heart.  The registrant further postulated that the ventricular
septal defect was produced by mechanical distortion of the heart.  The
two other signs of developmental toxicity reported, growth retardation
and fetal death were also considered to be related to the hypoxia
produced by the anemic condition in the fetus.

After evaluating the data, the Agency concluded the mechanistic studies
were not sufficiently robust to support the registrant’s proposed
mechanism of toxicity.  However, since doses and endpoints for risk
assessment were chosen to be protective of the cardiovascular (acute
dose and endpoint) and hematopoietic (chronic dose and endpoint)
effects, the lack of a conclusion regarding the mechanism of toxicity
does not result in the need for additional uncertainty factors.

There was no evidence (quantitative or qualitative) of susceptibility
following in-utero oral exposure in rabbits.  No developmental toxicity
was seen at the HDT (3x the limit-dose).  The absence of effects in
rabbits was supported by literature studies indicating rabbits are less
susceptible to the effects of PPO inhibitors.

Neurotoxicity:  HED concluded there is no concern for neurotoxicity
resulting from exposure to flumioxazin.  None of the acute, subchronic,
chronic, developmental or reproduction studies indicated an effect on
the nervous systems.  Based on the lack of concern for neurotoxicity,
HED concluded a developmental toxicity study (DNT) was not required. 
Nonetheless, the acute and chronic neurotoxicity studies are now
required for all pesticide active ingredients, in accordance with 40
CFR, Part 158 (Updated, 12/2007).

Carcinogenicity:  In accordance with the 1999 Proposed Guidelines for
Carcinogen Risk Assessment, HED determined that flumioxazin was “not
likely to be a human carcinogen.”  Flumioxazin did not induce
significant increases in any tumor type in either rats or mice under the
conditions of the studies and it did not induce any mutagenic activity
in the required battery of mutgenicity studies.  

3.1.3	Dose-response

Ventricular septal defects in the rat oral and dermal developmental
toxicity studies were seen in the absence of maternal toxicity. 
Therefore to be protective of potential developmental effects from
exposure to pregnant females, the adults’ dermal and inhalation risk
assessments were based on these effects.  In addition, since the
developmental effect was demonstrated to occur on gestation day 12, it
was considered to be a single-dose effect and served as the basis for
the acute dietary risk assessment for females 13-49.  In addition,
offspring effects observed in the rat reproductive toxicity study
(decreased number of females with liveborn and mean number of
pups/litter on lactation day 1, decreased pup body weight, testicular
atrophy in F1 males and decreased mating index) served as the basis for
assessing potential risks to children from dermal and incidental oral
exposure.  No acute dietary endpoint was identified in the database for
children or the general population.

Based on the submitted studies, the rat appeared to be the most
sensitive species, and the risk assessments (all durations and routes of
exposure) were based on effects observed in rats.  Long-term dosing in
the chronic/carcinogenicity study did not yield evidence of
carcinogenicity.  However, after long-term dosing, effects on blood
parameters and the kidney were observed and these effects were used for
risk assessment purposes.  The dose of 2 mg/kg/day selected from the
chronic rat study for chronic dietary risk assessment was the lowest
dose observed in the toxicity database.

3.1.4	FQPA

HED evaluated the toxicology data base of flumioxazin and determined
that it was adequate to characterize the potential for pre-natal or
post-natal risks to infants and children, despite the previously
mentioned data gaps (i.e., acute and subchronic neurotoxicity,
immunotoxicity).  The scientific quality of the flumioxazin database is
relatively high, and the toxicity profile can be characterized for most
effects, including potential carcinogenic, mutagenic and
developmental/reproductive.

3.2	Absorption, Distribution, Metabolism, Excretion (ADME)

The absorption, distribution, metabolism and excretion (ADME) of
flumioxazin was investigated in rats following single oral doses of
radiolabeled flumioxazin.  Metabolism studies in rats indicated that
there was extensive biliary excretion following oral administration of
flumioxazin.  G.I. tract absorption of flumioxazin may amount to over
90% of the dose.  Total recovery of radioactivity in feces and urine, 7
days after dosing, accounted for 96.5-100.7% of the dose in all test
groups.  It was noted that 4-5 times more radioactivity is excreted in
feces than in urine.  Radioactivity excretion in urine was statistically
significantly elevated in females (38.8-42.8%, low dose; 22.9-23.4%,
high dose) vs. males (28.1-30.8%, low dose; 12.8-13.0%, high dose). 
Highest levels of residues were found in blood cells (35.9-48.8 ppb, low
dose and 2823-3040 ppb, high dose), which were much higher than the
plasma levels (0.5-0.7 ppb, low dose and 53-37 ppb, high dose).  Thin
layer chromatography analysis of feces and urine revealed up to 35
putative metabolites.  In addition to untransformed parent compound, 7
metabolites were identified in urine and feces.  Identified compounds
amounted to 37.5-46.1% of the dose at the low dose treatments and to
70.7-71.5% of the dose at the high dose.

3.3	FQPA Considerations

3.3.1	Adequacy of the Toxicity Database

The submitted toxicology studies are considered adequate to support a
determination of the need for additional uncertainty factors to account
for potential pre- and postnatal susceptibility.

Evidence of Neurotoxicity

No neurotoxicity studies are available for flumioxazin.  However, none
of the acute, subchronic, chronic, developmental or reproduction studies
indicated an effect on the nervous system.  HED concluded that there is
no concern for neurotoxicity resulting from exposure to flumioxazin.  In
accordance with the updated Part 158 Toxicology Data Requirements,
12/2007, acute and subchronic neurotoxicity studies must be submitted.

Developmental Toxicity Studies

Acceptable gavage developmental toxicity studies are available in both
the rat and rabbit, and in addition a dermal developmental toxicity
study in the rat was submitted.  In the rat developmental studies,
developmental effects, including cardiovascular abnormalities, were
observed in fetuses at doses which did not cause maternal toxicity.  In
the oral study, maternal doses of 30 mg/kg did not result in maternal
toxicity, whereas the developmental LOAEL was 10 mg/kg/day, with a NOAEL
of 3 mg/kg/day.  In the dermal study, no maternal effects were observed
at dermal doses of up to 300 mg/kg/day, whereas the developmental LOAEL
was 100 mg/kg/day, with a NOAEL of 30 mg/kg/day.  A special study was
conducted which demonstrated that the developmental effects were most
prominent when dosing with flumioxazin occurred on gestation day 12.  In
the rabbit developmental study, maternal effects were limited to
decreased body weight and food consumption at the high dose of 3000
mg/kg/day, with no developmental/fetal effects (i.e., developmental
LOAEL not determined).

Reproductive Toxicity Study

In the rat reproductive toxicity study, reproductive effects in the
offspring were observed at lower doses than those which caused effects
in the parental animals.  The systemic/parental LOAEL was 18.9/22.7
mg/kg/day (males/females) based on increased clinical signs, increased
mortality and liver effects, and decreased food consumption during
lactation in females; and decreased body weight/weight gain in males and
females.  The systemic/parental NOAEL for these effects was 12.7/15.1
mg/kg/day (males/females).  Reproductive parameters were affected in
both generations of offspring.  These effects were more pronounced at
the 18.9/22.7 mg/kg/day dose level, and were observed to a lesser extent
at the next lowest dose, the LOAEL of 12.7/15.1 mg/kg/day
(males/females).  Reproductive/offspring effects were decreased number
of females with liveborn and mean number of pups/litter on lactation day
1, decreased pup body weight, testicular atrophy in F1 males and
decreased mating index.  The reproductive/offspring NOAEL was 6.3/7.6
mg/kg/day (males/females).

3.3.5	Additional Information from Literature Sources

No additional literature sources were consulted in conjunction with
evaluating the currently proposed agricultural and aquatic uses.  

3.3.6	Pre-and/or Post-natal Toxicity

3.3.6.1	Determination of Susceptibility

Based upon the oral as well as the dermal developmental rat studies, due
to cardiovascular anomalies (ventricular septal defect) which occurred
at doses which did not cause maternal toxicity, there is evidence of
increased qualitative and quantitative susceptibility of fetuses.  The
rat reproduction study demonstrated evidence of qualitative and
quantitative post-natal susceptibility because reproductive effects in
offspring were observed at doses lower than those which cause
parental/systemic toxicity, and were also considered to be more severe
than the parental/systemic effects.

3.3.6.2	Degree of Concern Analysis and Residual Uncertainties

Since there is evidence of increased qualitative and quantitative
susceptibility of the young following exposure to flumioxazin in the
oral and dermal developmental toxicity studies in the rat and in the rat
reproduction study, a degree of concern analysis was performed to: 1)
determine the level of concern for the effects observed when considered
in the context of all available toxicity data; and 2) identify any
residual concerns after establishing toxicity endpoints and traditional
uncertainty factors to be used in the risk assessment.  If residual
concerns are identified, HED examines whether these residual concerns
can be addressed by a special FQPA safety factor and, if so, the size of
the factor needed.

While the toxicity database is not complete, due to the lack of
neurotoxicity and immunotoxicity studies, the database is adequate for
the purpose of evaluating susceptibility.  There was no evidence in any
of the submitted studies that flumioxazin affects the nervous system or
directly targets the immune system.  HED’s degree of concern for the
susceptibility observed in the rat developmental and reproductive
studies is low, because the regulatory endpoints for flumioxazin are
based on clear NOAELs for developmental and offspring effects that are
protective of the increased susceptibility seen in the developmental and
reproduction studies, and there are no residual concerns for these
effects.

3.3.7	Recommendation for a Developmental Neurotoxicity Study

There was no evidence of neurotoxicity in any of the submitted studies,
including chronic (rat, mouse or dog), 90 day (rat, mouse or dog), 4
week (mouse), 21-day rat dermal, 2-generation rat reproduction and
developmental (oral rat, dermal rat or oral rabbit).  In addition, the
developmental effects observed in the rat, cardiovascular anomalies, are
not related to developmental effects of the central or peripheral
nervous systems.  Therefore, a DNT study is not required. 

FQPA Safety Factor for Infants and Children

HED recommends the 10X FQPA Safety Factor (as required by the Food
Quality Protection Act) be reduced to 1X (i.e., removed) for all
population subgroups for all exposure durations in assessing the risk
posed by flumioxazin.  Although increased prenatal and postnatal
qualitative and quantitative susceptibility were seen in rats, there is
low concern for this susceptibility and no residual uncertainties for
pre- and/or post-natal toxicity because:

1) The only missing toxicity data for flumioxazin are the newly required
neurotoxicity and immunotoxicity studies; however, no additional
uncertainty factor is needed in the absence of these studies because
there is no evidence in the available studies indicating that
flumioxazin targets the nervous system or the immune system.  Further,
HED has concluded a developmental neurotoxicity study is not required.

2)  Although increased prenatal and postnatal qualitative and
quantitative susceptibility was seen in rats, HED concluded that there
is a low concern and no residual uncertainties for pre- and/or postnatal
toxicity because the developmental toxicity NOAELs/LOAELs are well
characterized after oral and dermal exposure; the offspring toxicity
NOAEL and LOAEL are well characterized; and the doses and endpoints have
been selected from the developmental and reproductive toxicity studies
for risk assessment for the relevant exposed populations, i.e., pregnant
females and children, with the exception of the chronic dietary
endpoint, for which a chronic study was chosen for endpoint selection.

3) The exposure assessment is conservative, based on tolerance-level
residues in food and drinking water and upper-bound estimates of
potential residential/aggregate exposure; therefore, the potential risk
for infants and children will not be underestimated.

Hazard Identification and Toxicity Endpoint Selection

The available toxicity database was evaluated for endpoint selection for
acute and chronic dietary risk assessments; residential exposures
including dermal and incidental oral exposure for children and dermal
and inhalation exposure for adults; and for occupational exposures via
the dermal and inhalation routes.  HED notes that although long-term
dermal and inhalation doses and endpoints were considered and selected,
there are no long-term exposures expected for these routes based on the
existing and proposed use patterns.

3.5.1    Acute Reference Dose (aRfD) - Females age 13-49

  TC \l3 "3.5.1    Acute Reference Dose (aRfD) - Females age 13-49 

Study Selected: Pre-natal Developmental Toxicity Study - Rat 

MRID Nos.: 42684930 (pilot study); 42684925 (main study); 42884006;
42694931 and 42684932 

(studies demonstrating critical time to effects).

Dose and Endpoint for Risk Assessment: NOAEL = 3 mg/kg/day, Endpoint =
cardiovascular effects, specifically ventricular septal defects in
fetuses, seen at the LOAEL of 10 mg/kg/day

Comments about Study/Endpoint/Uncertainty Factors:   The endpoint
selected is appropriate because the critical effect, cardiovascular
abnormalities observed in fetuses, has been demonstrated to be the
result of a single dose, with dosing on gestation day 12 being the most
critical time period for the effect.  The application of the endpoint
and dose to the population of potentially pregnant females is protective
of fetal effects.  A clear NOAEL and LOAEL were identified for the fetal
abnormalities; therefore no additional uncertainty factors (other than
the standard 10X for interspecies extrapolation and 10X for intraspecies
variability) are needed.  Furthermore, the FQPA factor has been reduced
to 1X.  Therefore, the acute reference dose and acute population
adjusted dose are calculated as follows:

Acute RfD = Acute PAD = 3 mg/kg/day (NOAEL) = 0.03 mg/kg/day

                                            	 100 (UF)

3.5.2	Acute Reference Dose (aRfD) - General Population

  TC \l3 "3.5.2	Acute Reference Dose (aRfD) - General Population 

No appropriate endpoints were selected because there were no toxic
effects relevant to the general population (including infants and
children) identified in the database which could result from a single
dose.

3.5.3	Chronic Reference Dose (cRfD) 

  TC \l3 "3.5.3	Chronic Reference Dose (cRfD) 

Study Selected: Combined chronic carcinogenicity - rat 

MRID No.: 44295028 

Dose and Endpoint for Risk Assessment: NOAEL = 2.0 mg/kg/day, Endpoint =
increased chronic nephropathy in males and decreased hematological
parameters in females (Hgb, MCV, MCH, and MCHC) seen at the LOAEL of 18
mg/kg/day.

Comments about Study/Endpoint/Uncertainty Factors:   The duration and
route of exposure, in the rat study are applicable to the chronic
dietary route (oral) and duration (long term to lifetime) of exposure. 
In addition, the rat is the most sensitive species; in the one-year dog
study, liver effects were observed at the LOAEL of 1000 mg/kg/day, with
a NOAEL of 100 mg/kg/day.  In the carcinogenicity study in the mouse, no
systemic effects were seen at the highest dose tested.  Finally, the
NOAEL selected from the rat study is the lowest observed in the
submitted studies, and is protective of all other effects, including the
offspring effects in the reproductive toxicity study.  Since the FQPA
factor has been reduced to 1X, and there are no other uncertainty
factors needed, the standard 100X (10X for interspecies extrapolation
and 10X for intraspecies variability) UF has been applied to attain the
chronic reference dose and population adjusted dose, which are
equivalent.

Chronic RfD = Chronic PAD = 2 mg/kg/day (NOAEL) = 0.02 mg/kg/day

                             		                     		100 (UF)   

3.5.4	Incidental Oral Exposure (Short- and Intermediate-Term) 

  TC \l3 "3.5.4	Incidental Oral Exposure (Short- and Intermediate-Term) 

Study Selected: Reproduction and fertility effects - rat

MRID No.:  42684934 and 42684936 (pilot studies); 42684935 (main study)

Dose and Endpoint for Risk Assessment: NOAEL = 6.3 mg/kg/day, Endpoint =
decreased live born pups and decreased pup body weight, and testicular
atrophy in F1 males seen at the LOAEL of 12.7 mg/kg/day. 

Comments about Study/Endpoint/Uncertainty Factors:  The endpoint and
dose have been selected from an oral study, which is appropriate for
assessing the incidental oral pathway of exposure.  In addition the
endpoint, offspring effects in a reproductive study, is relevant for the
exposed population (infants and children) and therefore the risk
assessment will be protective for the qualitative and quantitative
susceptibility observed in the reproductive study.  Since the FQPA
factor has been reduced to 1X, and a clear NOAEL and LOAEL were
identified in the study, the standard UFs of 100X (10X for interspecies
extrapolation and 10X for intraspecies variability) define the LOC for
risk assessment as an MOE of 100 for residential exposure and risk
assessments.

3.5.5	Dermal Absorption

  TC \l3 "3.5.5	Dermal Absorption 	

Study Selected: Dermal penetration - rat

MRID No.: 42684944

Dermal absorption following application of 200 and 800 mg/kg was 3.9%
and 8.0%, respectively, by 48 hours after initiation of treatment for 6
hours.  Blood levels at 6-24 hours after dermal dosing with 200 mg/kg
were similar to those obtained at 2-6 hours after oral dosing with 1
mg/kg.  Blood levels at 6-24 hours after dermal dosing with 800 mg/kg
were similar to those obtained at 2-6 hours after oral dosing with 30
mg/kg.  For the purpose of risk assessment, an upper-bound estimate of
8% dermal absorption should be used.

3.5.6(a)	Dermal Exposure (Short, Intermediate-Term) for Children

Study Selected: Reproduction and fertility effects - rat

MRID No.:  42684934 and 42684936 (pilot studies); 42684935 (main study)

Dose and Endpoint for Risk Assessment: NOAEL = 6.3 mg/kg/day, Endpoint =
decreased live born pups and decreased pup body weight, and testicular
atrophy in F1 males seen at the LOAEL of 12.7 mg/kg/day. 

Comments about Study/Endpoint/Uncertainty Factors:  The endpoint and
dose have been selected from the oral reproductive toxicity study in the
rat; the route-specific dermal study was not appropriate because
reproductive parameters were not measured in the dermal study in rats. 
In addition the endpoint, offspring effects in a reproductive study, is
relevant for the exposed population (infants and children) and therefore
the risk assessment will be protective for the qualitative and
quantitative susceptibility observed in the reproductive study.  Since
the FQPA factor has been reduced to 1X, and a clear NOAEL and LOAEL were
identified in the study, the standard UFs of 100X (10X for interspecies
extrapolation and 10X for intraspecies variability) define the LOC for
risk assessment as an MOE of 100 for residential exposure and risk
assessments.

3.5.6(b)	Dermal Exposure (Short-, Intermediate- and Long-Term) for
Adults

  TC \l3 "3.5.6	Dermal Exposure (Short-, Intermediate- and Long-Term) 

Study Selected: Dermal Developmental Study (Rat)

MRID No.: 42684929 (pilot); 42684926 (main study)

Dose and Endpoint for Risk Assessment: Dermal NOAEL = 30 mg/kg/day,
Endpoint = cardiovascular effects, specifically ventricular septal
defects, in fetuses observed at the LOAEL of 100 mg/kg/day.

Comments about Study/Endpoint/Uncertainty Factors:   The study is
appropriate for dermal risk assessment because the most critical toxic
effect, ventricular septal defect in fetuses, was evaluated following
exposure via the dermal route.  This study is appropriate for all
durations because of the developmental toxicity concerns.  The oral
NOAEL selected for chronic dietary risk assessment is typically used to
assess long-term dermal risk.  However, for flumioxazin, the
developmental NOAEL was selected for all dermal exposures, including
long-term, since the use of the oral NOAEL of 2.0 mg/kg/day (chronic
RfD) with an 8% dermal absorption factor yielded a dermal equivalent
dose of 25 mg/kg/day (2.0/0.08 = 25), which is essentially comparable to
the selected dermal NOAEL of 30 mg/kg/day.

Since the FQPA factor has been reduced to 1X, and a clear NOAEL and
LOAEL were identified in the study, the standard UFs of 100X (10X for
interspecies extrapolation and 10X for intraspecies variability) define
the LOC for risk assessment as an MOE of 100 for both residential and
occupational exposure and risk assessments.

3.5.7	Inhalation Exposure (Short- and Intermediate-Term) 

  TC \l3 "3.5.7	Inhalation Exposure (Short-, Intermediate- and
Long-Term) 

Study Selected: Oral Developmental Study (Rat)

MRID No.: 42684930 (pilot study); 42684925 (main study); 42884006

Dose and Endpoint for Risk Assessment: NOAEL = 3 mg/kg/day, Endpoint =
cardiovascular effects, specifically ventricular septal defects, in
fetuses seen at the LOAEL of 10 mg/kg/day. 

Comments about Study/Endpoint/Uncertainty Factors:   In the absence of
an inhalation study with flumioxazin, HED selected the endpoint from an
oral study.  The developmental study was considered to be the most
appropriate because the duration is relevant for short-term exposure,
and because selection of the endpoint from the study ensures the risk
assessment is protective of potential developmental effects. 
Furthermore, although the selection of the dose and endpoint are
considered to be conservative for short- and intermediate-term exposure
durations, the selection of the developmental effects allows for
aggregation of dermal and inhalation exposure for both residential and
occupational scenarios.  Since an oral study was selected for the
inhalation route, an inhalation absorption factor of 100% should be
applied during risk assessment.

Because the FQPA factor has been reduced to 1X, and a clear NOAEL and
LOAEL were identified in the study, the standard UFs of 100X (10X for
interspecies extrapolation and 10X for intraspecies variability) define
the LOC for risk assessment as an MOE of 100 for both residential and
occupational exposure and risk assessments.

Inhalation Exposure (Long-Term)

Study Selected: 2-Year Chronic/Carcinogenicity Study (Rat)

MRID No.:  44295028

Dose and Endpoint for Risk Assessment: NOAEL = 2 mg/kg/day, Endpoint =
increased chronic nephropathy in males and decreased hematological
parameters in females (Hgb, MCV, MCH, and MCHC) seen at the LOAEL of 18
mg/kg/day.

Comments about Study/Endpoint/Uncertainty Factors:  In the absence of an
inhalation study for flumioxazin, HED selected an oral study.  The
duration of exposure in the chronic rat study is applicable long-term
durations of exposure.  In addition, the rat is the most sensitive
species; in the one-year dog study, liver effects were observed at the
LOAEL of 1000 mg/kg/day, with a NOAEL of 100 mg/kg/day.  In the
carcinogenicity study in the mouse, no systemic effects were seen at the
highest dose tested.  Furthermore, the selected NOAEL is the lowest
observed in the submitted studies, and is protective of all other
effects, including the offspring effects in the reproductive toxicity
study.  Since a route-specific inhalation study is not available, an
inhalation absorption factor of 100% should be used for risk assessment
purposes.  Finally, because the FQPA factor has been reduced to 1X, and
a clear NOAEL and LOAEL were identified in the study, the standard UFs
of 100X (10X for interspecies extrapolation and 10X for intraspecies
variability) define the LOC for risk assessment as an MOE of 100 for
both residential and occupational exposure and risk assessments.

3.5.9	Level of Concern for Margin of Exposure  TC \l3 "3.5.8	Level of
Concern for Margin of Exposure 

Table 3.5.9 Summary of Levels of Concern for Risk Assessment.

                 Duration 

Route	Short-Term	Intermediate-Term	Long-Term

Occupational (Worker) Exposure

Dermal	100	100	N/A

Inhalation	100	100	N/A

Residential (Non-Dietary) Exposure

Oral	100	100	N/A

Dermal	100	100	N/A

Inhalation	100	100	N/A

For Occupational Exposure: A MOE of 100 is required. This is based on
the

conventional uncertainty factor of 100X (10X for intraspecies
extrapolation and 10X for

interspecies variation).

For Residential Exposure: A MOE of 100 is required. This is based on the
conventional

uncertainty factor of 100X (10X for intraspecies extrapolation and 10X
for interspecies

variation).

3.5.10	Recommendation for Aggregate Exposure Risk Assessments  TC \l3
"3.5.9	Recommendation for Aggregate Exposure Risk Assessments 

As per FQPA, 1996, when there are potential residential exposures to a
pesticide, aggregate risk assessment must consider exposures from three
major sources: food, drinking water and residential (oral, dermal and
inhalation) exposure pathways.  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 has considered both the route and duration of exposure. 
For the purpose of occupational exposures, the dermal and inhalation
exposures can be aggregated because the same endpoint, fetal effects,
was selected for risk assessment.  Likewise, children’s dermal and
oral exposures associated with swimming in treated water can be
aggregated due to the same offspring effects being used to assess dermal
and oral risks.  Residential handlers’ dermal and inhalation risks can
also be aggregated, as can adults’ post-application exposure from
swimming.  These combined occupational and residential exposures should
be combined with background exposure from food and water determined in
the chronic dietary exposure assessment.

3.5.11	Classification of Carcinogenic Potential

HED classified flumioxazin as “not likely to be a carcinogen to
humans;” therefore, there is no cancer risk associated with the
existing or proposed uses of flumioxazin. 

3.5.12	Summary of Toxicological Doses and Endpoints for Flumioxazin for
Use in Human Risk Assessments  TC \l3 "3.5.11	Summary of Toxicological
Doses and Endpoints for [Chemical] for Use in Human Risk Assessments 

Table 3.5.12a  Summary of Toxicological Doses and Endpoints for
Flumioxazin for Use in Dietary and Non-Occupational Human Health Risk
Assessments

Exposure/

Scenario	Point of Departure (POD) 	Uncertainty/FQPA Safety Factors	RfD,
PAD, Level of Concern for Risk Assessment	Study and Toxicological
Effects

Acute Dietary

Females 13-49 only	NOAEL = 3

mg/kg/day

 	UFA=10x

UFH=10x

FQPA SF=1x 	Acute RfD = Acute PAD

= 0.03 mg/kg/day

	Oral Developmental and Supplemental Pre-natal Studies (Rat)

LOAEL = 10 mg/kg/day, based on cardiovascular effects in fetuses.  

Acute Dietary

General Population including infants and children	There were no
appropriate toxicological effects attributable to a single exposure
(dose) observed in oral toxicity studies including maternal effects in
developmental studies in rats and rabbits.  Therefore, a dose and
endpoint were not identified for this risk assessment.  

Chronic Dietary

all populations	NOAEL= 2.0 mg/kg/day

	UFA=10x

UFH=10x

FQPA SF=1x	Chronic RfD = Chronic PAD

= 0.02 mg/kg/day

	2-Year Chronic/Carcinogenicity Study (Rat)

LOAEL = 18 mg/kg/day, based on increased chronic nephropathy in males
and decreased hematological parameters in females.  

Incidental Oral - Short- (1-30 days) and Intermediate-Term (1- 6 months)
NOAEL= 6.3 mg/kg/day	UFA=10x

UFH=10x

FQPA SF = 1X	LOC for MOE = 100 	2-Generation Reproduction Study (Rat)

LOAEL = 12.7 mg/kg/day, based on decreased pup body weight and
testicular atrophy in F1 males.  

Dermal – Children

Short- (1-30 days) and Intermediate-Term (1-6 months) 	NOAEL = 6.3
mg/kg/day

DAF = 8%	UFA=10x

UFH=10x

FQPA SF = 1X	LOC for MOE = 100	2-Generation Reproduction Study (Rat)
LOAEL = 12.7 mg/kg/day, based on decreased pup body weight and
testicular atrophy in F1 males.  

Dermal  - Adults

(All durations)	NOAEL= 30 mg/kg/day

	UFA=10x

UFH=10x

FQPA SF = 1X 	LOC for MOE = 100 	Dermal Developmental Study (Rat)

LOAEL = 100 mg/kg/day, based on cardiovascular effects in fetuses.

Inhalation

Short- (1-30 days) and Intermediate-Term (1 - 6 months)	NOAEL = 3
mg/kg/day

(inhalation absorption rate = 100%)	UFA=10x

UFH=10x

FQPA SF = 1X	LOC for MOE = 100 

	Oral Developmental Study (Rat)

LOAEL = 10 mg/kg/day, based on cardiovascular effects in fetuses.

Inhalation 

Long-Term (> 6 months) Inhalation	NOAEL= 2 mg/kg/day

(inhalation absorption rate = 100%)	UFA=10x

UFH=10x

FQPA SF = 1X 	LOC for MOE = 100 

	2-Year Chronic/Carcinogenicity Study (Rat)

LOAEL = 18 mg/kg/day, based on increased chronic nephropathy in males
and decreased hematological parameters in females.

Cancer

(oral, dermal, inhalation)	“Not likely to be a carcinogen for
humans,” based on the lack of carcinogenicity in a 2-year rat study,
an 18-month mouse study, and a battery of mutagenic studies.  

Point of Departure (POD) = A data point or an estimated point that is
derived from observed dose-response data and  used to mark the beginning
of extrapolation to determine risk associated with lower environmentally
relevant human exposures.  NOAEL = no observed adverse effect level. 
LOAEL = lowest observed adverse effect level.  UF = uncertainty factor. 
UFA = extrapolation from animal to human (intraspecies).  UFH =
potential variation in sensitivity among members of the human population
(interspecies).  UFL = use of a LOAEL to extrapolate a NOAEL.  UFS = use
of a short-term study for long-term risk assessment.  UFDB = to account
for the absence of key data (i.e., lack of a critical study).  FQPA SF =
FQPA Safety Factor.  PAD = population adjusted dose (a = acute, c =
chronic).  RfD = reference dose.  MOE = margin of exposure.  LOC = level
of concern.  NA = not applicable.

Table 3.5.12b  Summary of Toxicological Doses and Endpoints for
Flumioxazin for Use in Occupational Human Health Risk Assessments

Exposure/

Scenario	Point of Departure	Uncertainty Factors	Level of Concern for
Risk Assessment	Study and Toxicological Effects

Dermal  - All Durations	NOAEL= 

30 mg/kg/day

	UFA = 10X

UFH = 10X	LOC for MOE = 100	Dermal Developmental Study in Rats

LOAEL = 100 mg/kg/day based on cardiovascular  effects in fetuses.

Inhalation Short- and Intermediate-Term (1- day up to 6 months) 	NOAEL=
3.0 mg/kg/day

(inhalation absorption rate = 100%)	UFA = 10X

UFH = 10X 	LOC for MOE = 100	Oral Developmental Study in Rats

LOAEL = 10 mg/kg/day based on cardiovascular effects in fetuses.

Inhalation Long-Term Inhalation (>6 months)	NOAEL = 2.0 mg/kg/day

(inhalation absorption rate = 100%)	UFA = 10X

UFH = 10X 	LOC for MOE = 100	2-Year Chronic/Carcinogenicity Study (Rat)

LOAEL = 18 mg/kg/day, based on increased chronic nephropathy in males
and decreased hematological parameters in females 

Cancer (oral, dermal, inhalation)	“Not likely to be a carcinogen for
humans,” based on the lack of carcinogenicity in a 2-year rat study,
an 18-month mouse study, and a battery of mutagenic studies.  

Point of Departure (POD) = A data point or an estimated point that is
derived from observed dose-response data and  used to mark the beginning
of extrapolation to determine risk associated with lower environmentally
relevant human exposures.  NOAEL = no observed adverse effect level. 
LOAEL = lowest observed adverse effect level.  UF = uncertainty factor. 
UFA = extrapolation from animal to human (intraspecies).  UFH =
potential variation in sensitivity among members of the human population
(interspecies).  UFL = use of a LOAEL to extrapolate a NOAEL.  UFS = use
of a short-term study for long-term risk assessment.  UFDB = to account
for the absence of key data (i.e., lack of a critical study).  MOE =
margin of exposure.  LOC = level of concern.  NA = not applicable.

 

3.6	Endocrine Disruption

As required under FFDCA section 408(p), EPA has developed the Endocrine
Disruptor Screening Program (EDSP) to determine whether certain
substances (including pesticide active and other ingredients) may have
an effect in humans or wildlife similar to an effect produced by a
“naturally occurring estrogen, or other such endocrine effects as the
Administrator may designate.”  The EDSP employs a two-tiered approach
to making the statutorily required determinations.  Tier 1 consists of a
battery of 11 screening assays to identify the potential of a chemical
substance to interact with the estrogen, androgen, or thyroid (E, A, or
T) hormonal systems.  Chemicals that go through Tier 1 screening and are
found to have the potential to interact with E, A, or T hormonal systems
will proceed to the next stage of the EDSP where EPA will determine
which, if any, of the Tier 2 tests are necessary based on the available
data.  Tier 2 testing is designed to identify any adverse endocrine
related effects caused by the substance, and establish a dose-response
relationship between the dose and the E, A, or T effect.

Between October 2009 and February 2010, EPA is issuing test orders/data
call-ins for the first group of 67 chemicals, which contains 58
pesticide active ingredients and 9 inert ingredients.  This list of
chemicals was selected based on the potential for human exposure through
pathways such as food and water, residential activity, and certain
post-application agricultural scenarios.  This list should not be
construed as a list of known or likely endocrine disruptors.

Flumioxazin is not among the group of 58 pesticide active ingredients on
the initial list to be screened under the EDSP.  Under FFDCA sec. 408(p)
the Agency must screen all pesticide chemicals.  Accordingly, EPA
anticipates issuing future EDSP test orders/data call-ins for all
pesticide active ingredients. 

For further information on the status of the EDSP, the policies and
procedures, the list of 67 chemicals, the test guidelines and the Tier 1
screening battery, please visit our website:  http://www.epa.gov/endo/.

4.0	PUBLIC HEALTH AND PESTICIDE EPIDEMIOLOGY DATA

  SEQ CHAPTER \h \r 1 There are no new public health data or pesticide
epidemiology data to report at this time.

5.0	DIETARY EXPOSURE/RISK CHARACTERIZATION

5.1	Pesticide Metabolism and Environmental Degradation

Metabolism in Primary Crops and Livestock Commodities.

  SEQ CHAPTER \h \r 1 The nature of the residue has been adequately
delineated for both plant and animal commodities.  In plants, the major
metabolic pathway is hydrolysis of the imide moiety to produce the
metabolites THPA and APF.  The THPA is then hydrated to produce
1-OH-HPA.  The residue of concern in plants, for both tolerance
expression and risk assessment purposes, is the parent compound only.

The results of the ruminant and poultry metabolism studies with both
phenyl- and THP-labeled flumioxazin show that the major metabolic
pathways are hydrolysis of the imide moiety, hydroxylation of the
cyclohexene ring, and the equivalent of addition of sulfonic acid to the
alkene function.  The residues of concern in ruminants for risk
assessments are the parent, 3-OH-flumioxazin, 4-OH-flumioxazin, and
metabolites B, C, and F.  In poultry, the residues of concern are
parent, 3-OH-flumioxazin, 4-OH-flumioxazin, and 4-OH-S-53482-SA (PP#:
1F06296, DP Num: D284045, W. Drew, 5/24/04).  For purposes of this
petition, ARIA/HED has waived the requirement for a fish metabolism
study and has concluded that the residues of concern in fish include
flumioxazin and its major degradates in water, APF and 482-HA.

Metabolism in Rotational Crops

 ≤0.015 ppm.  Low levels of flumioxazin (≤0.003 ppm) were detected
in carrot tops and wheat chaff and straw, along with trace amounts
(<0.001 ppm) of the metabolites 482-HA, IMOXA, and 482-CA.

HED has concluded that the residue of concern in rotational crops is the
parent compound only.  Based on the results of the confined accumulation
study, HED concluded that the existing rotational crop PBIs are
acceptable, and that field trials and tolerances in rotated crops are
not necessary.

Analytical Methodology

An adequate GC/NPD method is available for enforcing tolerances of
flumioxazin in plant commodities (MRID No. 43935509, Valent Residue
Method #RM-30A-1, Determination of Flumioxazin Residues in Crops, J.
Garbus, 1/8/96).  This method has undergone a successful ILV trial and a
successful PMV trial by the Agency.  The reported method LOQ and LOD for
flumioxazin are 0.020 and 0.010 ppm, respectively.

For tolerance enforcement in fish tissues, Valent has submitted a
LC-MS/MS method (GPL-MTH-066) for determining residues of flumioxazin,
APF and 482-HA.  For this method, residues are extracted with
acetonitrile (ACN) and aqueous ACN, each containing either 1% formic
acid for extraction of parent and APF or 1% ammonium hydroxide for
extraction of 482-HA.  Extracted residues are diluted with water and
analyzed directly by LC-MS/MS using external standards for quantitation.
 The validated LOQ is 0.01 ppm for each analyte in fish.  This method
has undergone a successful ILV trial and appears to be acceptable for
enforcing tolerances; however, additional information/data are required
before the method can be recommended as an enforcement method (See Sec.
11, below).

Residues of flumioxazin in/on cucumber, summer squash, and celery were
quantified by GC/NPD.  The harvested RAC samples were analyzed by
Cornell Analytical Laboratory using the Method, Residue Analysis of
Flumioxazin on Cucumber by GC/NPD Detection, Version #6, adapted and
modified from Determination of Flumioxazin Residues in Crops; Residue
Method RM-30A-1.  Valent USA Corporation (Revised January 1996).  
Residues were extracted with acetone:water (4:1, v:v).  The residues
were partitioned into dichloromethane (DCM), concentrated to dryness,
and further purified by partitioning in hexane/ACN.  The residues in the
ACN phase were evaporated to dryness, re-dissolved in hexane:ethyl
acetate (2:1, v:v), and cleaned up on a Florisil column eluted with
hexane:ethyl acetate (2:1, v:v).  The residues were evaporated to
dryness, re-constituted in acetone, and analyzed by GC/NPD.  The LLMV
for residues of flumioxazin in/on cucumbers, summer squash celery was
0.02 ppm.  The analytical method was adequate for data collection
purposes

Residues of flumioxazin in/on hops RAC samples (dried cones) were
quantified by GC/MSD using Valent method RM-30A-3, Determination of
Flumioxazin Residues in Crops, modified by the analytical laboratory,
IR-4 Western Region Leader Laboratory, University of California,
Department of Environmental Toxicology, Davis, CA.  The residues were
partitioned into DCM, concentrated to dryness, re-dissolved in
hexane:ethyl acetate (2:1, v:v), and cleaned up on a Florisil column
eluted with hexane:ethyl acetate (2:1, v:v).  The residues were
evaporated to dryness, re-dissolved in hexane:ethyl acetate (1:1, v:v)
and further purified on a tandem NH2 carbon SPE column eluted with
hexane:ethyl acetate (1:1, v:v).  The residues in the eluate were
evaporated to dryness, re-constituted in acetone, and analyzed by GC/MSD
in the selective ion monitoring (SIM) mode.  The LLMV for residues of
flumioxazin on hops samples was 0.02 ppm. The analytical method was
adequate for data collection purposes

Residues of flumioxazin and its two hydroxy metabolites
(3-OH-flumioxazin and 4-OH-flumioxazin) were determined in milk and
tissues using two related liquid chromatography with tandem mass
spectroscopy/mass spectroscopy (LC/MS/MS) methods, Valent Methods
RM-30MK for milk and RM-30T for tissues.  Recoveries from milk, cream
and skim milk averaged 84-92% (± 1-9%) for flumioxazin, 89-95% (±
8-11%) for 3-OH-flumioxazin, and 84-93% (± 6-10%) for 4-OH-flumioxazin.
 Recoveries from tissues averaged 77-88% (± 3-12%) for flumioxazin,
85-102% (± 12-25%) for 3-OH-flumioxazin, and 96-102% (± 17-20%) for
4-OH-flumioxazin.  For both methods, the validated LOQ is 0.02 ppm for
each analyte, and the reported LOD is 0.01 ppm.  

5.1.4	Multiresidue Methods

  SEQ CHAPTER \h \r 1 Data depicting the analysis of flumioxazin through
FDA Multiresidue Protocols were submitted and will be forwarded to FDA
for review.  The multiresidue method testing data indicate that
flumioxazin is not recovered through Sections 304 and 402 of PAM, Vol. I
(DP Num: D259493, D. Dotson, 3/12/01).  However, analytical reference
standards and multiresidue method testing data are not available for APF
and 482-HA.

5.1.5	Storage Stability

During the fish magnitude of residue study, tissue samples were stored
frozen for 8-14 days prior to extraction for analysis.  As samples were
stored frozen for <30 days prior to extraction and analysis, storage
stability data is not required to support the fish residue study.  The
available storage stability data are adequate and support the sample
storage durations incurred in the cucumber, summer squash, celery, and
hop field trials. 

Magnitude of the Residue

Fish

The submitted fish residue study is adequate and supports the proposed
aquatic use.  Juvenile bluegill sunfishes (Lepomis macrochirus) and
channel catfish (Ictalurus punctatus) were treated under static water
conditions with flumioxazin at an initial concentration of 800 ppb (2x
maximum proposed rate), and residues of flumioxazin, APF and 482-HA were
determined in the water and edible fish tissues over a 28-day period of
exposure.  In edible fish tissues, the distribution and decline of
residues were similar for both test species, although residue levels
were generally higher in catfish than in bluegills.  Total flumioxazin
residues were highest at the earliest sampling interval (4 hours) in
both catfish (2.52 ppm) and bluegills (0.85 ppm).  Total residues
declined rapidly by Day 3 and then remained relatively steady up to Day
28 in both bluegills (0.063-0.075 ppm) and catfish (0.098-0.204 ppm). 
At the earliest sampling interval, total residues in both species were
comprised primarily of parent (55-65%) and 482-HA (34-45%), with trace
amounts of APF (<1%), but by Day 28, total residues were distributed
equally between parent (38-39%), 482-HA (26-27%) and APF (34-39%). 
Total flumioxazin residues did not bioaccumulate in either test species
over the 28 day study.  When extrapolated to reflect the 1x use rate,
the estimated total residues in bluegills (0.43 ppm) and catfish (1.26
ppm) would support the proposed 1.5 ppm tolerances for freshwater fish. 
Because applications are prohibited to flowing water, intertidal or
estuarine areas and to water used for crawfish farming, residue data and
tolerances are not required for shellfish or saltwater fishes.

Plants

The submitted residue data for cucumber and summer squash are adequate. 
In addition, residue field trial data on cantaloupe, the representative
crop for muskmelon subgroup 9A were submitted previously in support of
the tolerance using the same use pattern.  The only cucurbit vegetable
residue data set containing quantifiable residues is cucumber.  The data
indicate that a tolerance for residues on cucurbits should be
established at 0.03 ppm.  ARIA recommends for the proposed flumioxazin
tolerance on cucurbit vegetables, group 9 at 0.03 ppm. Concurrently,
with the establishment of the tolerance on cucurbit vegetables, the
existing tolerance on muskmelon subgroup 9A should be removed.

The submitted residue data for celery are adequate.  No residues of
flumioxazin above the LOQ of 0.02 ppm were found on celery.  Since
celery is the representative crop for leaf petioles, subgroup 4B, the
data is adequate to support the requested tolerance. ARIA recommends for
the proposed flumioxazin tolerance on leaf petioles, subgroup 4B, at
0.02 ppm.

The submitted residue data for hops are adequate.  The submitted data is
adequate to support a tolerance on hops.  However, the proposed
tolerance was calculated with the MRL spreadsheet using half the LLMV
value.  Following Agency policy, using the LLMV value in place of the
residue result lower than LOQ, the MRL spreadsheet indicates a tolerance
of 0.05 ppm would be appropriate.  ARIA recommends for a tolerance of
0.05 ppm for the residues of flumioxazin on hops.  A revised Section F
is required. 

Since adjuvants were not used in the submitted residue field trials, the
labels should prohibit such uses on cucurbit vegetables, leaf petioles,
and hops.

There are no processed food or feed items of regulable interest
associated with the raw agricultural commodities in the current
petitions.

Magnitude of the Residue in Meat, Milk, Poultry, and Eggs

None of the commodities in this petition, fish, cucurbit vegetables,
leaf petioles, and hops are associated with livestock feed items of
regulable interest.  ARIA concludes that tolerances for meat, milk,
poultry, and eggs are not required for the purpose of this petition.

Confined and Field Rotational Crops

Current label directions for both 51% WDG formulations of flumioxazin
specify the following general rotational crop restriction:  Do not plant
any crop except cotton, peanut, soybean and sugarcane earlier than 30
days after application of flumioxazin.  In addition, the labels also
specify a variety of PBIs for different field crops depending on the
application rate.  For the highest use rate on any rotated crop (0.38 lb
ai/A), the specified PBIs are 9 months for cotton, field corn, peanut,
rice, sorghum, soybean, sunflower, tobacco and wheat, and 18 months for
all other field crops. 

Pesticide Metabolites and Degradates of Concern

Table 5.1.9.  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	Flumioxazin	Flumioxazin

	Rotational Crop	Flumioxazin	Flumioxazin

Livestock

	Ruminant	Flumioxazin; 3-OH-flumioxazin, 4-OH-flumioxazin, and
metabolites B, C, and F.	Not Applicable*

	Swine	Flumioxazin; 3-OH-flumioxazin, 4-OH-flumioxazin, and metabolites
B, C, and F.	Not Applicable*

	Poultry	Flumioxazin and 3-OH-flumioxazin, 4-OH-flumioxazin, and
4-OH-S-53482-SA.  	Not Applicable*

Drinking Water

	Flumioxazin, 482-HA and APF	Not Applicable

* Tolerances have not been required for livestock commodities to date.

Drinking Water Residue Profile

The EDWC for flumioxazin residues (flumioxazin, 482-HA, and APF) used in
this dietary risk assessment was obtained from EFED’s environmental
risk assessment for flumioxazin, Drinking Water Assessment for: (1) IR-4
Registration for Flumioxazin to be used on Asparagus, Dry Bean,
Bushberry Subgroup 13B, Fruiting Vegetable Subgroup 8, Melon Subgroup
9A, Okra and Tree Nut Subgroup 14; and (2) Section 3 Registration for
Use on Field Corn and Alfalfa; DP Num: D336195, D342249, and D331732; L.
Liu; 9/25/07.  The hydrolysis study for flumioxazin indicates that
flumioxazin forms the metabolite 482-HA, which can further hydrolyze to
the metabolites APF and THPA.  The rates of the two hydrolytic reactions
are very pH dependent, but flumioxazin (parent compound) is not very
stable at any likely environmental pH.  Data also indicates that THPA
and APF are likely to be very mobile.  Although THPA can comprise a
major portion of the total residue in water, it does not possess the
phenyl ring and is thus considered significantly less toxic than parent,
APF, and 482-HA.  Thus, THPA has not been included in the residue of
concern for drinking water. Therefore, parent flumioxazin and the
metabolites 482-HA and APF are the residues of concern in drinking
water.  The EDWC for flumioxazin residues (used in both the acute and
chronic dietary analyses) was 0.048 ppm, the concentration in
groundwater as estimated by the SCI-GROW model.  SCI-GROW is an
empirical model for predicting pesticide levels in groundwater; the
value from SCI-GROW is considered an upper bound concentration estimate,
and thus conservative.  In order to be conservative with the estimates,
the groundwater EDWC (0.048 ppm), which is greater than the surface
water EDWC (0.034 ppm), was used in both dietary analyses.  Table 5.1.10
summarizes the drinking water concentrations provided by EFED.  The
model and its description are available at the EPA internet site:  
HYPERLINK "http://www.epa.gov/oppefed1/models/water/" 
http://www.epa.gov/oppefed1/models/water/ .

Table 5.1.10.  EDWCs for Flumioxazin and its Degradates in Surface Water
and Groundwater at pH 7. 1

Compound	Average 56-Day Conc. in  Surface Water	Peak Conc. in Surface
Water	Conc. in Groundwater

Flumioxazin	negligible	1.03 ppb	negligible

482-HA	4.84 ppb	6.87 ppb	45.27 ppb

APF	12.85 ppb	26.46 ppb	2.66 ppb

THPA	19.50 ppb	27.67 ppb	182.28 ppb

	1 Total EDWC = Flumioxazin + 482-HA + APF

5.2	Dietary Exposure and Risk

5.2.1	Acute Dietary Exposure/Risk

The analysis summarized in Table 5.2.2 (below) is based on
tolerance-level residues in all RACs (modified by DEEM( processing
factors, Version 7.81, for processed commodities), and 100% CT
assumptions.  Dietary exposure via drinking water was also included in
this assessment.  Even with the conservative assumptions utilized, the
risk estimate is well below ARIA’s level of concern.  The only
population subgroup analyzed is females 13-49 (only subgroup with an
identified acute dietary endpoint), which has an exposure estimate of
0.002734 mg/kg/day at the 95th percentile, and utilizes 9% of the aPAD.

Chronic Dietary Exposure/Risk

The analysis summarized in Table 5.2.2 (below) are based on
tolerance-level residues in all RACs (modified by DEEM( processing
factors, Version 7.81, for processed commodities), and 100% CT
assumptions.  Dietary exposure via drinking water was also included in
these assessments.  Even with the conservative assumptions utilized, the
risk estimates are well below ARIA’s level of concern.  The most
highly exposed population subgroup is all infants <1, which has an
exposure estimate of 0.003761 mg/kg/day, and utilizes 19% of the cPAD.

  

TABLE 5.2.2.  Summary of Dietary Exposure and Risk for Flumioxazin.  

Population Subgroup1	

DEEM Acute Dietary Analysis,

95th Percentile	

DEEM Chronic Dietary Analysis

	

aPAD (mg/kg)	

Exposure (mg/kg/day)	

% aPAD	

cPAD (mg/kg/day)	

Exposure (mg/kg/day)	

% cPAD

General U.S. Population	

NA 2	0.02	0.001307	7

All Infants (< 1 year old)

0.02	0.003761	19

Children 1-2 years old

0.02	0.002289	11

Children 3-5 years old

0.02	0.002120	11

Children 6-12 years old

0.02	0.001433	7

Youth 13-19 years old

0.02	0.000980	5

Adults 20-49 years old

0.02	0.001165	6

Adults 50+ years old

0.02	0.001225	6

Females 13-49 years old	0.03	0.002734	9	0.02	0.001165	6

1 Values for the population with the highest risk for each type of risk
assessment are bolded.  

2 NA = Not Applicable; no acute dietary endpoint was identified for
these population subgroups

5.2.3	Cancer Dietary Risk

HED classified flumioxazin as “not likely to be a human carcinogen.”
 Therefore, quantification of human cancer risk was not necessary. 

RESIDENTIAL (NON-OCCUPATIONAL) EXPOSURE/RISK CHARACTERIZATION

HED has reviewed two proposed use patterns that could potentially result
in residential (non-occupational) exposure.  First, a new use site, to
include walkways, parking lots and non-grassy areas around residential
dwellings was assessed for residential handlers.  Although the product
is not intended for use by homeowners, the label does not specifically
prohibit use by residential handlers.  However, based on the use sites,
no postapplication exposure for adults or children was expected or
assessed.  Residential handler risks were not of concern (refer to the
8/11/09 S. Oonnithan memo for details (DP Num: D362611).  The results of
the handler exposure and risk assessment are presented below, in Table
6.1.

Table 6.1  Short-term Risk to Homeowners From the Use of BroadStar
Granules on Non-crop Areas Within Residential Settings 1

Exposure            Scenario         	Appl. rate,  lb AI/A              
                      	Dermal           unit exp.              (mg AI
/lb) 	Inhal.        unit exp.               (mg AI/lb) 	Dermal         
dose               (mg/kg/day) 2/

Dermal MOE	Inhal. dose               (mg/kg/      day) 2/

Inhal. MOE	Total                    MOE 3

Applying granules with push-type  spreader 4 	0.375	0.67	0.00088
0.00209/

14,000	2.75E-06/

1 x 106	14,000 

Applying granules with a hand        shaker 5	0.375	3.5	0.045	0.01094/

2700	1.41E-04/

21,000	2,400

1. Inputs used for the exposure and MOE calculations are : (1) area
treated per day = 0.5 Acres (from HED's ExpoSAC Policy No. 12, (2) body
wt. of handlers, (3) Inhalation absorp., (4) short-term dermal NOAEL,
(5) short-term inhalation NOAEL. 

2. Dermal dose (mg/kg/day) =  (appl. rate * area treated/day * dermal
unit exp.) / body wt.  Inhalation exposure (mg/kg/day) = (appl. rate *
area treated/day * inhalation unit exp. * inhalation absorption rate) /
body wt.

3. Total MOE = 1 / [(1/dermal MOE) + (1/inhal. MOE)].  Dermal MOE =
dermal NOAEL / dermal exposure. Inhalation MOE = inhalation NOAEL/
inhalation exposure.  The short-term dermal and inhalation MOEs were
combined because of the common endpoints (i.e., developmental effects)
for both exposure routes.   

4. The unit exposures (geometric means) represent homeowners applying
granules with push-type drop/rotary spreader while wearing T-shirt and
shorts (ORETF Study No. OMA 003, 2003). 

5. The unit exposures are for homeowners applying granules with a shaker
can (S. Recore, D296625, 5/6/04).  The area treated/day with a
shaker-can was taken as 0.5 Acres, which is on the higher side. 

In conjunction with the proposed use for control of aquatic weeds, there
is a potential for non-occupational/residential post-application
exposure to treated water for recreational purposes (i.e., swimming)
because there is no post-application holding restriction against such
use.  

HED used the SWIMODEL to assess short-term post-application
exposures/risks for children and adults exposed to flumioxazin-treated
water.  The SWIMODEL uses well-accepted screening exposure assessment
equations to calculate the total worst-case exposure for swimmers
expressed as a mass-based intake value (mg/event).  

The formula the model uses to calculate the dermal dose of the swimmer
is as follows:

ADR = CW * SA * ET * Kp * CF1

Where:

ADR = Absorbed Dose Rate (mg/day)

CW = Concentration of ai in pool water (mg/L)

SA = Surface Area exposed (cm2)

ET = Exposure Time (hours/day)

Kp = permeability coefficient (cm/hr)

CF1 = volume unit Conversion Factor (L/1,000 cm3)

Dermally absorbed dose rate, normalized to body weight, is calculated
as:

ADRnorm = ADR / BW

Where:

ADRnorm = Absorbed Dose Rate, normalized to body weight (mg/kg/day)

BW = Body Weight (kg)

The formula used to calculate incidental oral dose is as follows:

PDR = CW * IgR * ET

Where:

PDR = Potential Dose Rate (mg/day)

CW = Concentration of ai in pool water (mg/L)

IgR = Ingestion Rate of pool water (L/hour)

ET = Exposure Time (hours/day)

Potential dose rates, normalized to body weight, are calculated as:

PDRnorm = PDR / BW

Where:

PDRnorm = Potential Dose Rate, normalized to body weight (mg/kg/day)

BW = Body Weight (kg)

The assumptions and factors used in the risk calculations are consistent
with current EPA policy for completing residential exposure assessments
(SOPs for Residential Exposure Assessment).  The SWIMODEL was applied
incorporating the assumptions and factors of the SOPs for Residential
Exposure Assessments.  The values used in the assessment include:

It is assumed that 100% of the application concentration is available in
the water for dermal contact.  This is believed to be a reasonable
assumption because biocides are typically maintained in water at
specified levels.

For subsequent days after application, it may be assumed that the
pesticide will not dissipate because it is usually desirable to maintain
a specified level of biocide in the water.

The skin surface area of adults is assumed to be 21,000 cm2 cited in the
Residential SOPs.  This is the 95th percentile value for females (EPA
Exposure Factors Handbook, 1997).

The body weight for children is assumed to be 22 kg as cited in the
Residential SOPs.  This is a mean value for 6 year old children.

The skin surface area for children is assumed to be 9,000 cm2 as cited
in the Residential SOPs.  This is the 90th percentile value for male and
female children.

The exposure time is assumed to be 3 hours per day.  This is the 90th
percentile value for time spent swimming in a freshwater pool.  (EPA
Child Specific Exposure Factors Handbook, 2002).

The body weight for adult short-term exposures is assumed to be 60 kg
(due to the use of a developmental endpoint in the risk assessment).

Post-application risks are based on maximum application rates specific
on the label.  The maximum concentration of 0.4 mg/liter (400 ppb) was
used to assess exposures.

Post-application inhalation exposure was not required as the active
ingredient flumioxazin has a vapor pressure less than 10-6 mm Hg and is
non-volatile, thus exposure is negligible and was not calculated.

The permeability coefficient of flumioxazin (Kp) is 0.00085 cm/hr.

The assumed mean inhalation rates are 1.7 m3/hour for adults and 1.2
m3/hour for children, based on a moderate activity level (U.S. EPA,
1996).  These rates were not needed in the present assessment due to the
low vapor pressure noted above.

The assumed mean ingestion rate for adult and children swimmers is 0.05
L/hour (U.S EPA, 1989; Dang 1996) and as cited in the Residential SOP.

All short-term post-application MOEs are greater than 100 and therefore
are not of concern.  HED notes that the children’s exposures were
assessed using the NOAEL and endpoint from the reproductive toxicity
study, in which offspring effects were observed.  For adults, however,
HED used the oral and developmental NOAELs and endpoints for risk
assessment, in order to be protective of potential fetal effects.  In
addition, the use of the developmental effects observed via the dermal
and oral routes allowed for combining exposure and risk from both routes
of exposure.  HED notes that the SWIMODEL provides an upper-bound
assessment for exposure associated with aquatic weed control, since it
is representative of potential exposure to competitive swimmers in
pools.  A summary of the MOEs is presented in Table 6.2.

Table 6.2.  Flumioxazin Recreational Swimmer Exposures and Risks.

Exposed Person	Route of Exposure	Water Concentration (mg/L)	Dose
(mg/kg/day)	NOAEL (mg/kg/day)	       MOE

Child- 22 kg

	Oral	0.4	0.002727	6.3	2,300

	Dermal	0.4	0.000417	6.3	15,000

Adult- 60 kg	Oral	0.4	0.001	3	3,000

	Dermal	0.4	0.000357	30	84,000

For children’s exposures, the NOAEL and endpoint were selected from
the reproductive study in rats.  No additional corrections were made for
dermal absorption, based on the use of the permeability coefficient.  
MOE = NOAEL/Dose

For adult exposure, the NOAELs were selected from route-specific
studies, the dermal and oral developmental toxicity studies in rats. 
MOE = NOAEL/Dose.  

The exposures calculated using the SWIMODEL are based on some central
tendency (i.e., ingestion rate, body weight) and some upper-percentile
assumptions (i.e., exposure duration, application rate, surface area),
and are assumed to be representative of high-end exposure.  The
uncertainties associated with this assessment stem from the assumptions
regarding dissipation of chemical residue in the water, and the use of
an assumed permeability coefficient.  The dose estimates are considered
to be reasonable high-end estimates based on observations from
chemical-specific field studies and professional judgment.   A MOE of
100 or more is sufficient to protect swimmers.  Swimmer assessments
indicate that all MOEs are above the levels of concern, with MOEs
ranging from 3,000 to 84,000.  

6.1	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 flumioxazin.
 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, HED must consider and aggregate flumioxazin
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 considers both the route and duration of exposure, and also
determines which scenarios are likely to co-occur.  Flumioxazin
exposures can occur through food and drinking water (all populations),
swimming in treated waters (adults and children), and, potentially,
applying (handler only) a granular formulation around residences (adults
only).  In the current risk assessment, HED considered both the handler
and postapplication (swimmer) assessments to be very conservative; in
addition, HED concluded that co-occurrence of these exposure scenarios
is unlikely.  Therefore, short-term aggregate assessments were conducted
for food and water plus handlers, and food and water plus swimmers (see
below).

7.1	Acute Aggregate Risk

There were no appropriate toxicological effects attributable to a single
exposure (dose) for the general population; therefore, a dose and
endpoint were not identified for this risk assessment.  The aPAD for
females 13-49 years was 0.03 mg/kg/day.  The aggregate acute risk is
equivalent to the dietary (food and water) risk shown in Section 5.2.1;
acute aggregate risk is below the level of concern.

Short- and Intermediate-Term Aggregate Risk

Intermediate-term aggregate risks were not calculated, since endpoints
for short- and intermediate-term risk assessments were the same, and
since residential exposure durations are expected to be short-term in
nature.  For calculating short-term aggregate risks for adults
(residential handler and swimming), the 1/MOE approach was used because
a route-specific study was used to select the endpoint for dermal risk
assessment (developmental dermal toxicity study, fetal cardiovascular
abnormalities).  For children’s risks from swimming, both the dermal
and oral routes were assessed based on an endpoint selected from an oral
study (offspring effects in the reproductive toxicity), so the exposures
were simply combined, along with the contribution from food and water.
The specific equations and calculations used are described below:

Residential Handlers Aggregate Exposure and Risk

Aggregate MOE =	________________1_______________                        

    1/MOEDermal + 1/MOEInhalation + Dietary

Where the dermal MOE was presented in Table 6.1, and the MOE for
Inhalation + dietary exposure was calculated as follows:

MOEInhalation + Dietary =	___________Oral NOAEL________

						    Inhalation Exp. + Dietary Exposure

Chronic dietary exposure for the general US population was used, since
it was higher than the other adult subpopulations (Table 5.2.2, 0.001307
mg/kg/day)

		MOEInhalation + Dietary = 	______     3          ___ = 2070

						0.000141 + 0.001307

	Aggregate MOE =	______1______

				1/2700 + 1/2070

			   =	1170 (1200 after rounding)

Adult Swimmers Aggregate Exposure and Risk

Aggregate MOE =	________________1_______________                        

    1/MOEDermal + 1/MOE Oral + Dietary

Where the dermal MOE was presented in Table 6.2 and the MOE for oral +
dietary exposure was calculated as follows:

MOE Oral + Dietary =	___________Oral NOAEL________

					    Oral Exposure + Dietary Exposure

Chronic dietary exposure for the general US population was used, since
it was higher than the other adult subpopulations (Table 5.2.2, 0.001307
mg/kg/day)

		MOE Oral + Dietary = 	______     3          ___ = 1300

					    0.001 + 0.001307

Aggregate MOE =	______1________

				1/84,000 + 1/1300

			   =	1280 (1300 after rounding)

Children Swimmers Aggregate Exposure and Risk

Aggregate Exposure	=	Oral Dose + Dermal Dose + Chronic Dietary Exposure

			=	0. 002727 +0.000417 + 0.003761

			=	0.006905 mg/kg/day

Where Oral and Dermal Doses were taken from Table 6.2, and the chronic
dietary exposure for all infants, the highest exposed subpopulation, was
taken from Table 5.2.2.

Aggregate MOE = 	____NOAEL______

			Aggregate Exposure

Aggregate MOE =	____6.3_mg/kg/day__	= 912 (900 after rounding)

			  0.006905 mg/kg/day

 

Both adults’ and children’s short-term aggregate exposure and risk
are below HED’s level of concern, since combined exposure through
dietary (food + water) and residential (handlers and postapplication
swimmers) resulted in MOEs greater than 100, ranging from a minimum of
900 for children swimmers to 1300 for adult swimmers.  The residential
aggregate exposure assessment is conservative and health protective,
since upper-bound estimates of both residential and dietary exposure
were used to calculate aggregate exposure and risk.

Chronic Aggregate Risk

Because there are no long-term (chronic) exposures associated with the
residential pathway, the chronic aggregate risk is equivalent to chronic
dietary (food plus water) risk.  Refer to section 5.2.2 for the chronic
aggregate risk estimates, which are not of concern.

Cancer Risk

HED classified flumioxazin as "not likely” to be a human carcinogen. 
Therefore, there is no cancer risk associated with flumioxazin exposure.

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 flumioxazin and any other
substances and flumioxazin 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 flumioxazin 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/. 

9.0	OCCUPATIONAL EXPOSURE/RISK PATHWAY

Based on the product use information, there is a potential for
occupational exposure from handling (mixing/loading/applying)
flumioxazin for the aquatic uses:

Mixing/Loading Dry Flowable for Aerial Applications (Scenario 1)

Applying Sprays with Helicopter or Fix-Wing Airplane (Scenario 2)

Flagging during Aerial Applications (Scenario 3)

Mixing/Loading Dry Flowable for Boom Mounted Airboat Application
(Scenario 4)

Applying Sprays with Boom Mounted Airboat (Scenario 5)

Mixing/Loading/Applying for Sprays with Boom Mounted Airboat (Scenario
6)

Mixing/Loading/Applying for Sprays with Low Pressure Handwand Sprayer
(Scenario 7)

Mixing/Loading/Applying for Sprays with Backpack Sprayer (Scenario 8)

Mixing/Loading/Applying for Sprays with Right of Way Sprayer (Scenario
9)

Mixing/Loading/Applying for Sub-Surface Application---hoses trailing
behind a boat (Scenario 10)

Based upon the proposed new use patterns for cucurbit vegetables, leaf
petiole vegetables, and hops, the methods of application are by
ground-boom sprayer which includes hooded or directed sprays.  The most
highly exposed occupational pesticide handlers for these uses are:

Mixing/Loaders using open pour loading of granules

Applicators using open-cab, ground-boom sprayers.  

It should be noted that HED and RD do not have study data regarding the
loading of water dispersible granules, per se.  However, the data for
loaders using open-pour loading of dry flowable (DF) formulation are
considered appropriate surrogates.  

9.1	Short-/Intermediate-/Long-Term Handler Risk

Aquatic Uses

Equations/Calculations

The following equations were used to calculate handler exposure and
risk:

Dermal Dose (mg/kg/day) 	=	Rate (lb ai/A) x UE (mg/lb ai) x  Acres
Treated (A/day)

BW (kg)

Inhalation Dose (mg/kg/day)	=	 Rate (lb ai/acre) x UE (mg/lb ai) x Acres
Treated (A/day)

        BW (kg)

Where:

Rate (Application Rate)	=	Maximum application rate on product label (lb
ai/acre)

UE (Unit Exposure)		=	Exposure value derived from August 1998 PHED
Surrogate Exposure Table (mg/lb ai handled)

Acres Treated			=	Maximum number of acres treated per day (acres/day)

               BW				=	Body weight (kg)

Dermal MOE       	                             =	NOAEL (30 mg/kg/day)   
           

(Short- & Intermediate-Term)                        Dermal Dose
(mg/kg/day)

Short-Term Inhalation MOE                    =	NOAEL (3 mg/kg/day)      
        

                                                                        
  Inhalation Dose (mg/kg/day)

Intermediate-Term Inhalation MOE          =	NOAEL (2 mg/kg/day)         
     

                                                                        
             Inhalation Dose (mg/kg/day)

Short-Term Total MOE                               =         
________________1________________ 

                                                                        
           (1/ Dermal MOE) + (1/ Inhalation MOE)

  

Application Rate

The maximum application rates given in the label were used for all
exposure assessments. The maximum rates are 0.3825 lb ai/A for surface &
aerial applications, and 8.62 lb ai/A (note: an 8 foot deep water column
requires this rate to achieve a desired 400 ppb water concentration, and
a 7 foot deep water column requires 7.55 lb ai/A to achieve a desired
400 ppb water concentration) for subsurface application.

Area or the Amount Treated

Based on HED’s Exposure Science Advisory Council Policy Number 9.1,
and the values used in a previous assessment (DP Num: D316596, T. Dole,
2005), the following acres per day treated were assumed:

350 acres/day for aerial applications;

10 acres/day for surface applications (DP Num: D316596, T. Dole, 2005);
and

30 acres/day for subsurface application (DP Num: D316596, T. Dole,
2005).

Body Weight									

The female body weight (60 kg) was used for all assessments because: (1)
NOAELs are identified from a developmental study with fetal effects, or
(2) it produces a more conservative exposure estimate which can be
protective to all workers (both females and males).

Exposure Frequency

No data on the number of exposure days per year was provided.  For this
risk assessment, HED assumes that most handlers would be exposed for
less than 30 days per year (short-term exposure).  However, commercial
pesticide handlers could be exposed for more than 30 days but less than
6 months (intermediate-term exposure).  Long-term exposure is not
expected.

Unit Exposures

Based on the PHED Version 1.1 as presented in the August 1998 PHED
Surrogate Exposure Guide, the unit exposures used in the handlers’
exposure/risk assessment are:   

Dermal unit exposure for mixing/loading dry flowables = 0.066 mg/lb ai

Inhalation unit exposure for mixing/loading dry flowables = 0.77 µg/lb
ai

Dermal unit exposure for applying with helicopter or airplane = 0.0050
mg/lb ai

Inhalation unit exposure for applying with helicopter or airplane =
0.068 µg/lb ai

Dermal unit exposure for flagging = 0.011 mg/lb ai

Inhalation unit exposure for flagging = 0.35 µg/lb ai

Dermal unit exposure for applying with airboat-boom = 0.014 mg/lb ai

Inhalation unit exposure for applying with airboat-boom = 0.74 µg/lb ai

Dermal unit exposure for mixing/loading/applying with airboat-boom =
0.37 mg/lb ai

Inhalation unit exposure for mixing/loading/applying with airboat-boom =
1.3 µg/lb ai

Dermal unit exposure for mixing/loading/applying with low-pressure
handwand sprayer = 0.43 mg/lb ai (gloves) 

Inhalation unit exposure for mixing/loading/applying with low-pressure
handwand sprayer = 30 µg/lb ai

Dermal unit exposure for mixing/loading/applying with backpack sprayer =
2.5 mg/lb ai (gloves)

Inhalation unit exposure for mixing/loading/applying with backpack
sprayer = 30 µg/lb ai

Dermal unit exposure for mixing/loading/applying with right-of-way
sprayer = 1.3 mg/lb ai

Inhalation unit exposure for mixing/loading/applying with right-of-way
sprayer = 3.9 µg/lb ai

Dermal unit exposure for mixing/loading/applying for subsurface
application = 0.066 mg/lb ai

Inhalation unit exposure for mixing/loading/applying for subsurface
application = 0.77 µg/lb ai

PHED was designed by a task force of representatives from the U.S. EPA,
Health Canada, the California Department of Pesticide Regulation, and
member companies of the American Crop Protection Association.  PHED is a
software system consisting of two parts–a database of measured
exposure values for workers involved in the handling of pesticides under
actual field conditions and a set of computer algorithms used to subset
and statistically summarize the selected data.  Currently, the database
contains values for over 1,700 monitored individuals (i.e., replicates).

Users select criteria to subset the PHED database to reflect the
exposure scenario being evaluated.  The subsetting algorithms in PHED
are based on the central assumption that the magnitude of handler
exposures to pesticides is primarily a function of activity (e.g.,
mixing/loading, applying), formulation type (e.g., wettable powders,
granulars), application method (e.g., aerial, ground-boom), and clothing
scenarios (e.g., gloves, double layer clothing).

Once the data for a given exposure scenario have been selected, the data
are normalized (i.e., divided by) by the amount of pesticide handled
resulting in standard unit exposures (milligrams of exposure per pound
of active ingredient handled).  Following normalization, the data are
statistically summarized.  The distribution of exposure values for each
body part (e.g., chest, upper arm) is categorized as normal, lognormal,
or “other” (i.e., neither normal nor lognormal).  A central tendency
value is then selected from the distribution of the exposure values for
each body part.  These values are the arithmetic mean for normal
distributions, the geometric mean for lognormal distributions, and the
median for all “other” distributions.  Once selected, the central
tendency values for each body part are composited into a “best fit”
exposure” value representing the entire body.

There are three basic risk mitigation approaches considered appropriate
for controlling occupational exposures.  These include administrative
controls, the use of personal protective equipment or PPE, and the use
of engineering controls.  Occupational handler exposure assessments are
often completed by HED using baseline, PPE, and engineering controls.
[Note: Administrative controls available generally involve altering
application rates for handler exposure scenarios.  These are typically
not utilized for completing handler exposure assessments.] The baseline
clothing level scenario for occupational exposure scenarios is generally
an individual wearing long pants, a long-sleeved shirt, no chemical
resistant gloves, and no respirator.  The first level of mitigation
generally applied is PPE.  PPE may involve the use of an additional
layer of clothing, chemical-resistant gloves, and a respirator.  The
next level of mitigation considered in the risk assessment process is
the use of appropriate engineering controls which, by design, attempt to
eliminate the possibility of human exposure.  Examples of commonly used
engineering controls include enclosed tractor cabs and cockpits, closed
mixing/loading/transfer systems, and water-soluble packets.

Except for scenarios 7, 8, & 10, the handler exposure/risk were
evaluated at baseline level (handlers wearing long pants, a long-sleeved
shirt, no gloves, and no respirator).  For all scenarios except
sub-surface use, mitigation controls (i.e. PPE and engineering controls)
were not needed for the MOE to be greater than or equal to the level of
concern (MOE = 100).

Handlers’ Exposure and Risk

Except for the short-term total MOE for the subsurface application (MOE
= 94), all short-term total MOEs and intermediate-term dermal &
inhalation MOEs for the handlers performing the proposed uses on aquatic
weeds are greater than 100 (110 ~ 43,000) and therefore, the risks do
not exceed HED’s level of concern.  The short-term total MOE
calculated for the next highest application rate (7.55 lb ai/A) used in
the subsurface application is 110.  Based on this result and given the
serious nature of the toxicological endpoint, HED recommends that the
water depth for subsurface application shall not go beyond 7 feet (a 7
foot deep water column requires 7.55 lb ai/A to achieve desired 400 ppb
water concentration, while an 8 foot deep water column requires 8.62 lb
ai/A to achieve desired 400 ppb water concentration).  The rate of 8.62
lb ai/A results a short-term total MOE of 94 when assessed using
baseline protection plus gloves as required on the label.    				 

Summaries of the exposures/risks for flumioxazin occupational handlers
are presented in Tables 9.1.a and 9.1.b.  

The handler exposure estimates in this assessment are based on a central
tendency estimate of unit exposure and an upper-percentile assumption
for the application rate, and are assumed to be representative of
high-end exposures.  The uncertainties associated with this assessment
stem from the use of surrogate exposure data (e.g., differences in use
scenario and data confidence), and assumptions regarding that amount of
chemical handled.  The estimated exposures are believed to be reasonable
high-end estimates based on observations from field studies and
professional judgment.

Table 9.1.a.  Non-Cancer Short-Term Risk for Flumioxazin Handlers for
Aquatic Uses.

Exposure Scenario (Scenario #)	

Mitigation Levela	

Dermal Unit Exposureb (mg/lb ai)	

Inhalation Unit Exposurec   (µg/lb ai)	

Crop	

Application Rate

(lb ai/A)	

Amount Treatedd

(A/day)	

Daily

Dermal

Dosee (mg/kg/day)	

Daily

Inhalation

Dosef (mg/kg/day)	

Dermal MOEg 	

Inhalation    MOEh	

Total

MOEi  

Mixer/Loader

Dry Flowables for Aerial Application (1)	

Baseline	

0.066	

0.77	Aquatic Weeds	0.3825	350	0.1473	0.00172	204	1,744	180

Dry Flowables for Airboat Application (4)	

Baseline	

0.066	

0.77	Aquatic Weeds	0.3825	10	<0.1473	<0.00172	>204	>1,744	>180

Applicator

Sprays with Helicopter/  Fix-Wing Airplane (2)	

En. Control	0.0050	0.068	Aquatic Weeds	0.3825	350	0.0112	0.00015	2,679
20,000	2,400

Sprays with Boom Mounted Airboat (5)	Baseline	0.014	0.74	Aquatic Weeds
0.3825	10	0.00089	0.000047	33,708	63,830	22,000

Mixer/Loader/Applicator

Sprays with Boom Mounted Airboat (6)	Baseline	0.37	1.3	Aquatic Weeds
0.3825	10	0.0236	0.000083	1,271	36,145	1,200

Sprays with Low-Press Handwand (7)	Baseline + gloves	0.43	30	Aquatic
Weeds	0.3825	10	<0.1594	0.0019	>188	>1,579	>170

Sprays with Back Pack

Sprayer (8)	Baseline + gloves	

2.5	

30	Aquatic Weeds	0.3825	10	0.1594	0.0019	188	1,579	170

Sprays with Right-of-Way (9)	Baseline	1.3	3.9	Aquatic Weeds	0.3825	10
<0.1594	<0.0019	>188	>1,579	>170

Sub-Surface Application (10)	Baseline + gloves	0.066	0.77	Aquatic Weeds
8.62

7.55	30	0.2845

0.2492	0.0033

0.0029	105

120	909

1034	94

110

Flagger

Flagging during 

Aerial Application (3)	Baseline	0.011	0.35	Aquatic Weeds	0.3825	350
0.0245	0.00078	1,224	3,846	930

a	Baseline consists of long-sleeve shirt, long pants, shoes, and socks
and no respirator.  PPE consists of long-sleeve shirt, long pants,
shoes, socks, chemical-resistant gloves, and no respirator.

b	Baseline Dermal Unit Exposure represents long pants, long sleeved
shirt, no gloves, open mixing/loading, and open cab tractors, as
appropriate.  

c	Baseline Inhalation Exposure represents no respiratory protection,
open mixing/loading, and open cab tractors, as appropriate.  

d	Daily acres treated values are from EPA estimates of acreage that
could be treated or volume handled in a single day for each exposure
scenario of concern, based on the application method and
formulation/packaging type; and also based on values used in D 316596
(T. Dole 2005).

e	Daily dermal dose (mg/kg/d) =  unit dermal exposure (mg/lb ai) *
application rate (lb ai/acre) * daily acres treated /  body weight (60
kg).

f	Daily inhalation dose (mg/kg/d) = unit exposure (µg/lb ai) *
(1mg/1000 µg) conversion * application rate (lb ai/acre) * daily acres
treated / body weight (60 kg).

g	Dermal MOE = NOAEL (30 mg/kg/d) / daily dermal dose.  UF = 100.  

h	Inhalation MOE = NOAEL (3 mg/kg/d) / daily inhalation dose.  UF = 100.

i	Total MOE = 1 / 1 / Dermal MOE + 1/ Inhalation MOE.  UF = 100.

 Table 9.1.b.  Non-Cancer Intermediate-Term Risk for Flumioxazin
Handlers for Aquatic Uses.

Exposure Scenario (Scenario #)	

Mitigation Levela	

Dermal Unit Exposureb (mg/lb ai)	

Inhalation Unit Exposurec   (µg/lb ai)	

Crop	

Application Rate

(lb ai/A)	

Amount Treatedd

(A/day)	

Daily

Dermal

Dosee (mg/kg/day)	

Daily

Inhalation

Dosef (mg/kg/day)	

Dermal MOEg 	

Inhalation    MOEh	

Total

MOEi  

Mixer/Loader

Dry Flowables for Aerial Application (1)	

Baseline	

0.066	

0.77	Aquatic Weeds	0.3825	350	0.1473	0.00172	200	1,200	NA

Dry Flowables for Airboat Application (4)	

Baseline	

0.066	

0.77	Aquatic Weeds	0.3825	10	<0.1473	<0.00172	>200	>1,200	NA

Applicator

Sprays with Helicopter/  Fix-Wing Airplane (2)	

En. Control	0.0050	0.068	Aquatic Weeds	0.3825	350	0.0112	0.00015	2,700
13,000	NA

Sprays with Boom Mounted Airboat (5)	Baseline	0.014	0.74	Aquatic Weeds
0.3825	10	0.00089	0.000047	34,000	43,000	NA

Mixer/Loader/Applicator

Sprays with Boom Mounted Airboat (6)	Baseline	0.37	1.3	Aquatic Weeds
0.3825	10	0.0236	0.000083	1,300	24,000	NA

Sprays with Low-Press Handwand (7)	Baseline + gloves	0.43	30	Aquatic
Weeds	0.3825	10	<0.1594	0.0019	>190	>1,100	NA

Sprays with Back Pack

Sprayer (8)	Baseline + gloves	

2.5	

30	Aquatic Weeds	0.3825	10	0.1594	0.0019	190	1,100	NA

Sprays with Right-of-Way (9)	Baseline	1.3	3.9	Aquatic Weeds	0.3825	10
<0.1594	<0.0019	>190	>1,100	NA

Sprays for Sub-Surface Application (10)	Baseline	0.066	0.77	Aquatic
Weeds	8.62

7.55	30	0.2845

0.2492	0.0033

0.0029	110

120	610

690	NA

Flagger

Flagging during 

Aerial Application (3)	Baseline	0.011	0.35	Aquatic Weeds	0.3825	350
0.0245	0.00078	1,200	2,600	NA

a	Baseline consists of long-sleeve shirt, long pants, shoes, and socks
and no respirator.  PPE consists of long-sleeve shirt, long pants,
shoes, socks, chemical-resistant gloves, and no respirator.

b	Baseline Dermal Unit Exposure represents long pants, long sleeved
shirt, no gloves, open mixing/loading, and open cab tractors, as
appropriate.  

c	Baseline Inhalation Exposure represents no respiratory protection,
open mixing/loading, and open cab tractors, as appropriate.  

d	Daily acres treated values are from EPA estimates of acreage that
could be treated or volume handled in a single day for each exposure
scenario of concern, based on the application method and
formulation/packaging type; and also based on values used in D 316596
(T. Dole 2005).

e	Daily dermal dose (mg/kg/d) =  unit dermal exposure (mg/lb ai) *
application rate (lb ai/acre) * daily acres treated/body weight (60 kg).

f	Daily inhalation dose (mg/kg/d) = unit exposure (µg/lb ai) *
(1mg/1000 µg) conversion * application rate (lb ai/acre) * daily acres
treated / body weight (60 kg).

g	Dermal MOE = NOAEL (30 mg/kg/d) / daily dermal dose.  UF = 100.  

h	Inhalation MOE = NOAEL (2 mg/kg/d) / daily inhalation dose.  UF = 100.

i	Total MOE is not applicable since the intermediate-term dermal and
inhalation NOAELs are based on different toxicological endpoints.



Cucumber Vegetables, Leaf Petioles, and Hops

ARIA/RD believes handlers will be exposed to short-term duration
exposures (1-30 days).  Depending on crop, there are one or two
applications per year as described in the proposed supplemental product
labels and the IR-4 submission. ARIA/RD expects that ground applications
will be conducted by private, (i.e., grower) applicators.  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.  PPE for the two products was discussed earlier. 

The toxicological endpoints used herein for risk assessment are listed
in Table 3.5.12b, above.

A short-term duration (1 - 30 days) dermal toxicological endpoint was
identified from a dermal developmental study in the rat. The NOAEL is
30.0 mg ai/kg bw/day and the effects seen were cardiovascular effects,
especially ventricular septal defects in fetuses.  The level of concern
for occupational exposures is for MOE < 100.  Since the toxicological
endpoint was identified from a dermal study, dermal exposure is not
corrected for dermal absorption.  Also, since the effects were
identified from a developmental study with fetal toxicological effects,
a 60 kg body weight is used to calculate average daily exposure.  

The short-term inhalation toxicological NOAEL is 3.0 mg ai/kg bw/day. 
The endpoint was identified from an oral developmental study in the rat.
 The effects seen were the same as those noted in the dermal study
(i.e., cardiovascular effects, especially ventricular septal defects in
fetuses).  Since the toxic effects were identified from a developmental
study with fetal effects, a 60 kg bw is used to calculate exposure.  HED
and RD assume 100 % absorption via the inhalation route of exposure. 
MOEs are calculated separately and as “combined” MOEs.  The dermal
and inhalation NOAELs are different, therefore, the combined MOE is
calculated as 1/(1/MOEdermal + 1/MOEinhalation).

Flumioxazin is classified as "not likely" to be a human carcinogen based
on the lack of carcinogenicity in a 2-year rat study, an 18-month mouse
study, and a battery of mutagenic studies.  Therefore there is no cancer
risk for flumioxazin.  

Table 9.1.c.   Summary of Exposure & Risk for Occupational Handlers
Applying Flumioxazin 

Unit Exposure1

mg ai/lb handled	Applic. Rate2

lb ai/unit	Units Treated3	Avg. Daily Exposure4

mg ai/kg bw/day	MOE5	Combined

MOE6

Mixer/Loader Using Open Pour Loading of Dry Flowable  (Hops)

Dermal:

SLNoGlove     0.066

SLWithGlove  0.066

Inhal.               0.00077	

0.375 

lb ai/A	

40 

A/day	Dermal:

SLNoGlove     0.0165

SLWithGlove  0.0165

Inhal.             0.00019	

1,818

1,818

15,789	

1,630

1,630

Mixer/Loader Using Open Pour Loading of Dry Flowable  (Leaf  Petiole)

Dermal:

SLNoGlove     0.066

SLWithGlove  0.066

Inhal.               0.00077	

0.188 

lb ai/A	

200

A/day	Dermal:

SLNoGlove     0.0414

SLWithGlove  0.0414

Inhal.             0.000483	

725

725

6,211	

649

649

Applicator Using Open-cab Ground-boom Sprayer

Dermal:

SLNoGlove     0.014  

SLWithGlove  0.014

Inhal.               0.00074	

0.375 

lb ai/A	

40

A/day	Dermal:

SLNoGlove     0.0035

SLWithGlove  0.0035

Inhal.             0.00019	

8,571

8,571

15,789	

5,555

5,555

Applicator Using Open-cab Ground-boom Sprayer

Dermal:

SLNoGlove     0.014  

SLWithGlove  0.014

Inhal.               0.00074	

0.188 

lb ai/A	

200

A/day	Dermal:

SLNoGlove      0.0088

SLWithGlove   0.0088

Inhal.            0.000464       	

3,409

3,409

6,465	

2,233

2,233

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

2.  Applic. Rate. = Taken from the proposed draft labels

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

4.  Average Daily Dose (ADD) = Unit Exposure * Applic. Rate * Units
Treated ( Body Weight (60 kg since NOAELs are identified from a
developmental study with fetal effects).

5.  MOE = Margin of Exposure = No Observed Adverse Effect Level (NOAEL) 
( ADD.  NOAEL = 30.0 mg ai/kg bw/day for short-term dermal; 3.0 mg ai/kg
bw/day for short-term inhalation).

6.  Combined MOE = 1 ÷ (1 ÷ MOEDermal + 1 ÷ MOEInhalation)

Conclusion: A MOE of 100 is adequate to protect occupational pesticide
handlers from exposures to flumioxazin.  Except for the short-term total
MOE for the subsurface application (MOE = 94; application rate for 8
foot deep water column = 8.62 lb ai/A), all short-term total MOEs and
intermediate-term dermal & inhalation MOEs for handlers performing the
proposed uses on aquatic weeds and terrestrial crops are greater than
100 and therefore, the risks do not exceed ARIA/HED’s level of
concern.  The short-term total MOE calculated for the next highest
aquatic application rate of 7.55 lb ai/A (the application rate for 7
foot deep water column in the subsurface application) is 110.  Based on
this result and given the serious nature of the toxicological endpoint,
HED recommends that the water depth for subsurface application shall not
go beyond 7 feet.  Pending the receipt of an updated aquatic application
label, the proposed new uses do not exceed ARIA/HEDs level of concern.  

Short-/Intermediate-/Long-Term Post-application Risk

Occupational post-application exposures are not expected for the
proposed aquatic uses.

It is possible for agricultural workers to have post-application
exposures to pesticide residues during the course of typical terrestrial
agricultural activities.  HED in conjunction with the Agricultural
Re-entry Task Force (ARTF) has identified a number of post-application
agricultural activities that may occur and which may result in
post-application exposures to pesticide residues.  HED has also
identified Transfer Coefficients (TC) (cm²/hr) relative to the various
activities which express the amount of foliar contact over time, during
each of the activities identified.  For the proposed new crop use sites,
the highest appropriate TC is 1,500 cm²/hr which results from
"scouting" (i.e., crop advisors) in peanut, leaf petiole vegetables and
cucurbit vegetables.  The TC for scouting hops in the earlier parts of
the season is 1,300 cm2/hr.  One might typically expect high exposures
in late season hops, however, the directions for application to hops
indicates application to the hop yard floor for sucker control and are
made earlier in the season.  Therefore, as a “screening” level
assessment, RD herein uses a TC of 1,500 cm²/hr.

The TCs used in this assessment are from an interim TC Standard
Operating Procedure (SOP) developed by HED’s ExpoSAC using proprietary
data from the ARTF database (SOP # 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 transfer coefficients.  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.

Lacking compound specific dislodgeable foliar residue (DFR) data, HED
assumes 20 % of the application rate is available as DFR on day zero
after application.  This is adapted from the ExpoSAC SOP No. 003 (7 May
1998 - Revised 7 August 2000).  

The following convention may be used to estimate post-application
exposure.  

Average Daily Dose (ADD) (mg ai/kg bw/day) = DFR µg/cm2 * TC cm2/hr *
hr/day * 0.001 mg/µg * 1/60 kg bw 

 and where:

Surrogate Dislodgeable Foliar Residue (DFR) = application rate * 20%
available as dislodgeable residue * (1-D)t * 4.54 x 108 µg/lb * 2.47 x
10-8 A/cm2 .  

0.188 lb ai/A * 0.20 * (1-0)0 * 4.54 x 108 µg/lb * 2.47 x10-8 A/cm² =
0.42 µg/cm2 , therefore,

0.42 µg/cm2 * 1,500 cm2/hr * 8 hr/day * 0.001 mg/µg  ( 60 kg bw =
0.084 mg/kg bw/day.

MOE = NOAEL ( ADD then 30 mg/kg bw/day ( 0.084 mg/kg bw/day = 357.

0.375 lb ai/A * 0.20 * (1-0)0 * 4.54 x 108 µg/lb * 2.47 x10-8 A/cm² =
0.84 µg/cm2 , therefore,

0.84 µg/cm2 * 1,500 cm2/hr * 8 hr/day * 0.001 mg/µg  ( 60 kg bw =
0.168 mg/kg bw/day.

MOE = NOAEL ( ADD then 30 mg/kg bw/day ( 0.168 mg/kg bw/day = 178.

Conclusion: A MOE of 100 is adequate to protect agricultural workers
from post-application exposures.  Since the estimated MOEs are > 100,
the proposed uses do not exceed ARIA’s level of concern.

 

Restricted Entry Interval (REI)

Flumioxazin is classified in Acute Toxicity Category III for acute
dermal toxicity and for eye irritation.  It is classified in Acute
Toxicity Category IV for acute inhalation toxicity and for dermal
irritation.  It is not a dermal sensitizer.

The interim worker protection standard (WPS) REI of 12 hours is adequate
to protect agricultural workers from postapplication exposures to
flumioxazin.  The product labels both list 12 hour REIs.  

 

10.0	TOLERANCE SUMMARY

Flumioxazin tolerances are established under 40 CFR §180.568. 
Tolerances for residues in/on plant commodities are listed in 40 CFR
§180.568[a] and are expressed in terms of flumioxazin per se. 
Tolerances ranging from 0.02 to 0.70 ppm have been established in/on the
commodities of almonds, cotton, pome fruits (group 11), stone fruits
(group 12), garlic, grape, onion, peanut, peppermint, pistachio,
shallot, soybean, spearmint, strawberry, sugarcane, and tuberous/corm
vegetables (subgroup 1C).  Time-limited tolerances in/on alfalfa forage
and hay, with a 12/31/09 expiration date, are also listed in 40 CFR
§180.568[b].  No tolerances have been established in meat, milk,
poultry, or eggs.

HED/ARIA notes that the residue definition for the tolerance expression
for CFR § 180.568 (a) General should be as follows: “Tolerances are
established for residues of flumioxazin, including its metabolites and
degradates, in or on the commodities in the table below. Compliance with
the tolerance levels specified below is to be determined by measuring
only flumioxazin,
2-[7-fluoro-3,4-dihydro-3-oxo-4-(2-propynyl)-2H-1,4-benzoxazin-6-yl]-4,5
,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione.”

HED/ARIA notes that once the analytical method deficiencies have been
resolved for fish, the residue definition for the tolerance expression
for fish should be as follows: “Tolerances are established for
residues of flumioxazin, including its metabolites and degradates, in or
on the commodities in the table below.  Compliance with the tolerance
levels specified below is to be determined by measuring only the sum of
flumioxazin,
2-[7-fluoro-3,4-dihydro-3-oxo-4-(2-propynyl)-2H-1,4-benzoxazin-6-yl]-4,5
,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione, and its metabolites APF
(3-oxo-4-prop-2ynyl-6-amino-7-fluoro-3,4-dihydro-1,4-benzoxazin) and
482-HA
(N-(7-fluoro-3,4-dihdyro-3-oxo-4-prop-2-ynyl-2H-1,4-benzoxazin-6-yl)cycl
ohex-1-ene-1-carboxamide-2-carboxylic acid), calculated as the
stoichiometric equivalent of flumioxazin, in or on the commodity.”

There are no Codex, Canadian or Mexican MRLs for flumioxazin; therefore,
there are no issues of international harmonization raised by this
action.

Table 10.0.   Tolerance Summary for Flumioxazin.

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

Correct Commodity Definition

Fish, freshwater	1.5	1.5

	Cucurbit vegetables, group 9	0.03	0.03

	Leaf petioles, subgroup 4B	0.02	0.02

	Hops, dried cones	0.07	0.05

	Melon subgroup 9A	0.02	remove	With the establishment of the tolerance
on cucurbit vegetables, the existing tolerance on muskmelon subgroup 9A
should be removed.

	

11.0	DATA NEEDS AND LABEL RECOMMENDATIONS

11.1	Toxicology

The following toxicology studies should be submitted as a condition of
registration – 

870.7800 Immunotoxicity – in accordance with the 12/2007 updated Part
158 Toxicology Data Requirements, an immunotoxicity study is required.

870.6200 Neurotoxicity – in accordance with the 12/2007 updated Part
158 Toxicology Data Requirements, acute and subchronic neurotoxicity
studies are required.  

11.2	Residue Chemistry

The following residue chemistry deficiencies must be resolved prior to
establishment of the tolerance for residues in fish:

 

An updated aquatic application label is required (see Section 11.3
below).

The labels should prohibit the use of adjuvants on cucurbit vegetables,
leaf petioles, and hops. Updated labels are required.

A confirmatory method is required for the proposed enforcement method
for fish (GPL-MTH-066).

FDA multiresidue method testing data are required for 482-HA and APF.

 

Reference standards for 482-HA and APF must be submitted to the EPA
National Pesticide Standards Repository.

The following should be submitted to support the recommended tolerance
for residues in hops:

A revised Section F is required for a tolerance of 0.05 ppm for the
residues of flumioxazin on hops.

11.3	Occupational and Residential Exposure

ARIA/HED recommends that the water depth for subsurface application
should not go beyond 7 feet (a 7 foot deep water column requires 7.55 lb
ai/A/application to achieve desired 400 ppb water concentration).  An
updated aquatic application label is required.

12.0	REFERENCES

Dietary Exposure Memorandum

Flumioxazin.  Acute and Chronic Dietary (Food and Water) Exposure
Assessments for the Petition Proposing Tolerances for Residues of
Flumioxazin on Fish, Cucurbit Vegetables, Leaf Petioles, and Hops. DP
Num: D367978, W. Cutchin, 8/11/09.

Drinking Water Memorandum

Section 3 Registration for Use on Field Corn and Alfalfa. DP Num:
D336195, D342249, D331732; L. Liu; 9/25/07.

Product Chemistry Memorandum

EPA Fact Sheet for Flumioxazin.

Residue Chemistry Data Reviews

Flumioxazin.  Petition for the Establishment of Permanent Tolerances on
Cucurbit Vegetables, Leaf Petioles, and Hops.  Summary of Analytical
Chemistry and Residue Data.  PP#8E7462, DP Num: D359142, W. Cutchin,
12/14/09

Occupational and Residential Exposure Memorandum

Flumioxazin - Occupational Exposure/Risk Assessment for the Proposed
Uses of Flumioxazin on Cucurbit Vegetables (Crop Group 9), Leaf Petiole
Vegetables (Crop Group 4B), Hops, and Peanut. DP Num: D359690, M. Dow,
1/5/09.

Flumioxazin: Occupational and Residential Exposure/Risk Assessment of
Flumioxazin for Section 3 Registration of a New Use on Aquatic Weeds. DP
Num: D358360, S. Wang, 4/20/09.

Flumioxazin: Occupational and Residential Exposure Assessment for the
Registration of New Uses for BroadStar Herbicide. DP Num: D362611, S.
Oonnithan, 8/11/09.

Flumioxazin:  Addendum to the Residential Exposure Assessment of
Flumioxazin for Seciotn 3 Registration of a New Use on Aquatic Weeds. DP
Num: D372257, C. Swartz, 12/14/09.

Appendix A:  Toxicology Assessment  TC \l1 "Appendix A:  Toxicology
Assessment 

A.1	Toxicology Data Requirements TC \l2 "A.1  Toxicology Data
Requirements  

The requirements (40 CFR 158.340) for food use for flumioxazin are in
Table A.1. Use of the new guideline numbers does not imply that the new
(1998) guideline protocols were used.

Test 

	Technical

	Required	Satisfied

870.1100    Acute Oral Toxicity	

870.1200    Acute Dermal Toxicity	

870.1300    Acute Inhalation Toxicity	

870.2400    Primary Eye Irritation	

870.2500    Primary Dermal Irritation	

870.2600    Dermal Sensitization		yes

yes

yes

yes

yes

yes	yes

yes

yes

yes

yes

yes

870.3100    Oral Subchronic (rodent)	

870.3150    Oral Subchronic (nonrodent)	

870.3200    21-Day Dermal	

870.3250    90-Day Dermal	

870.3465    90-Day Inhalation		yes

yes

yes

no

no	yes

yes

yes

no

no

870.3700a  Developmental Toxicity (rodent)	

870.3700b  Developmental Toxicity (nonrodent)	

870.3800    Reproduction		yes

yes

yes	yes

yes

yes

870.4100a  Chronic Toxicity (rodent)	

870.4100b  Chronic Toxicity (nonrodent)	

870.4200a  Oncogenicity (rat)	

870.4200b  Oncogenicity (mouse)	

870.4300    Chronic/Oncogenicity		yes

yes

yes

yes

yes	yes1

yes

yes1

yes

yes

870.5100    Mutagenicity—Gene Mutation - bacterial	

870.5375    Mutagenicity—Gene Mutation – CHO cells	

870.5395    Mutagenicity— In vivo rat bone marrow	

870.5550    Mutagenicity—Other Genotoxic Effects- UDS assay		yes

yes

yes

yes	yes

yes

yes

yes

870.6100a  Acute Delayed Neurotox. (hen)	

870.6100b  90-Day Neurotoxicity (hen)	

870.6200a  Acute Neurotox. Screening Battery (rat)	

870.6200b  90-Day Neuro. Screening Battery (rat)	

870.6300    Develop. Neuro		no

no

yes

yes

no	-

-

no

no

-

870.7485    General Metabolism	

870.7600    Dermal Penetration	

870.7800    Immunotoxicity		yes

yes

yes	yes

yes

no

Special Studies for Ocular Effects

Acute Oral (rat)	

Subchronic Oral (rat)	

Six-month Oral (dog)		no	-

1 Requirements for 870.4100a and 870.4200a are satisfied by the receipt
of an acceptable/guideline combined chronic/carcinogenicity study in
rats (870.4300.)

A.2  Toxicity Profiles TC \l2 "A.2  Toxicity Profiles 

Table A.2.1	Acute Toxicity Profile for Flumioxazin

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

870.1100	Acute oral [rat]	42684911 	LD50>5000 mg/kg M & F	IV

870.1200	Acute dermal [rat]	42684913	LD50>2000 mg/kg	III

870.1300	Acute inhalation [rat]	42684915	LC50 =3.93 mg/L	IV

870.2400	Acute eye irritation [rabbit]	42684917	Not an ocular irritant
III

870.2500	Acute dermal irritation [rabbit]	42684917	Non-irritating	IV

870.2600	Skin sensitization [guinea pig]	42684921	Non-sensitizer	N/A

Table A.2.2	Subchronic, Chronic and Other Toxicity Profile

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

870.3100

	90-Day oral toxicity - rat	 42684923

dose levels: 0, 2.3, 20.7, 69.7, and 243.5 mg/kg/day (M)

and 0, 2.2, 21.7, 71.5, and 229.6 mg/kg/day (F)	NOAEL = 69.7 (M), 71.5
(F)  mg/kg/day

LOAEL = 243.5 (M), 229.6 (F) mg/kg/day based on a decrease in MCV both
sexes; increase in platelets F only.

870.3100

	90-Day oral toxicity - rat	42683922

dose levels: 0, 1.9, 19.3, 65.0, and 196.7 mg/kg/day (M) and 0, 2.2,
22.4, 72.9, and

218.4 mg/kg/day (F)	NOAEL = 65.0 (M), 72.9 (F)  mg/kg/day    LOAEL =
196.7 (M), 218.4 (F) mg/kg/day based on hematology changes.

870.3100

	90-Day oral toxicity - mouse	MRID unknown (referred to in 79-week
study, MRID 44295018)

dose levels:  0, 143, 429, or 1429 (M & F) mg/kg/day	NOAEL = 429 
mg/kg/day

LOAEL = 1429 mg/kg/day based on increased liver weight in males.

870.3100

	4-Week oral toxicity - mouse	44307301 (see MRID 44295018 DER#2)

dose levels: 0, 151.5, 419.9 or 1366.5 (M) and 0, 164.5, 481.6 or 1698.3
(F) mg/kg/day 	NOAEL = 151.5 (M), 164.5 (F) mg/kg/day

LOAEL = 419.9 (M), 481.6 (F)  mg/kg/day based on increased absolute &/or
relative liver weights in M & F.

870.3150

	90-Day capsule - dog	42684924

dose levels of  0, 10, 100, or 1000 mg/kg/day	NOAEL = 10 mg/kg/day

LOAEL = 100 mg/kg/day based on dose dependent increase in total
cholesterol, phospholipid & alkaline phosphatase activity.

870.3200

	21-Day dermal toxicity - rat	44295016

dose levels:  1, 100, 300,  or 1000 mg/kg/day	NOAEL = mg/kg/day: 1000
(LIMIT DOSE)

LOAEL = mg/kg/day: >1000 based on no effects.

870.3250

	90-Day dermal toxicity (species)

Study Not Submitted

870.3465

	90-Day inhalation toxicity (species)

Study Not Submitted 

870.3700a

	Pre-natal developmental - rat (oral)

	(1)42684930 (pilot study); 42684925 (main study); (2) 42884006

dose levels: 0, 1, 3, 10 and 30 mg/kg/day	Maternal NOAEL = 30 mg/kg/day
(HDT)

LOAEL = >30 mg/kg/day (HDT)

Developmental NOAEL = 3 mg/kg/day

LOAEL = 10 mg/kg/day based on cardiovascular effects (especially
ventricular septal defects).

870.3700a	Pre-natal developmental - rat

(dermal)	42684929 (pilot); 42684926 (main study)

dose levels: 0, 30, 100, and 300 mg/kg/day	

Maternal NOAEL = 300 mg/kg/day (HDT)

LOAEL = >300 mg/kg/day (HDT)

Developmental NOAEL = 30 mg/kg/day

LOAEL = 100 mg/kg/day based on cardiovascular effects (especially
ventricular septal defects).

870.3700b

	Pre-natal developmental - rabbit (oral)	42684927 (range-finding);
42684928 (main study)

dose levels:  0, 300, 1000, or 3000 mg/kg/day	Maternal NOAEL = 1000
mg/kg/day

LOAEL = 3000 mg/kg/day (HDT) based on decrease in body weight and food
consumption during dosing

Developmental NOAEL = 3000 mg/kg/day (HDT) LOAEL = >3000 mg/kg/day

870.3800

	Reproduction and fertility effects - rat)	42684934 and 42684936 (pilot
studies); 42684935 (main study)

dose levels:  0, 3.2, 6.3, 12.7, and 18.9 mg/kg/day (M) and 0, 3.8, 7.6,
15. 1, and 22.7 mg/kg/day (F)	Parental/Systemic NOAEL = 12.7 (M), 15.1
(F) mg/kg/day;  LOAEL = 18.9 (M), 22.7 (F) mg/kg/day based on increase
in clinical signs (red substance in vagina) and increased female
mortality as well as decreased body weight, body weight gain and food
consumption.

Reproductive NOAEL = 18.9 (HDT) (M), 22.7 (HDT) (F) mg/kg/day;  LOAEL =
>18.9 (HDT) (M), >22.7 (HDT) (F) mg/kg/day

Offspring NOAEL = 6.3 (M), 7.6 (F) mg/kg/day; LOAEL = 12.7 (M), 15.1 (F)
mg/kg/day based on a decrease in the number of liveborn, a decrease in
pup body weight, a decrease in the mating index, and testicular atrophy
of F1 males.

870.4100b

	12-Month capsule - dog	44295017

dose levels:  0, 10, 100 or 1000 mg/kg/day	NOAEL = 100 mg/kg/day (M & F)

LOAEL = 1000 mg/kg/day (M &F), (LIMIT DOSE) based on the following for
males and females: increased absolute and relative liver weights; 300%
increase in alkaline phosphatase values

870.4100a

	Chronic toxicity (species)	[ ]	NOAEL = [ ] mg/kg/day

LOAEL = [ ] mg/kg/day based on [ ].

870.4200b

	Carcinogenicity - mouse	44295018

dose levels: 0, 31.1, 314.9 or 754.1 mg/kg/day in males and 0, 36.6,
346.4, or 859.1 mg/kg/day in females 	NOAEL = 754.1 (M), 859.1 (F)
mg/kg/day (LIMIT DOSE); LOAEL = no systemic effects at LIMIT DOSE in
males or females

No evidence of carcinogenicity

870.4300

	Combined chronic carcinogenicity - rat	44295028

dose levels: 0, 1.8, 18.0, and 36.5 mg/kg/day in male rats and 0, 2.2,
21.8, and 43.6 mg/kg/day in female rats	NOAEL = 1.8 (M), 2.2 (F)
mg/kg/day

LOAEL = 18.0 (M), 21.8 (F) mg/kg/day based on increased chronic
nephropathy in males and decreased hematological parameters in females
(Hgb, MCV, MCH and MCHC).

No evidence of carcinogenicity

Gene Mutation

870.5100	Gene mutation in S. typhimurium and E. coli	42684938

 μg/plate	Neither cytotoxic nor mutagenic up to 2000 µg/plate.  There
were reproducible increases in revertant colonies of S. typhimurium
strains TA1538 and TA98 in S9 activated phases of the preliminary
cytotoxicity and both mutation assays. [Results are considered to be
equivocal.]

Gene Mutation

870.5375	Gene mutation in chinese hamster ovary cells	42684939

nonactivated levels, 30, 100, 200, and 500 μM (11, 35, 70, and 177
μg/mL, respectively)	Precipitation at (200 µM.  Cytotoxicity at 500
µM.  Positive +S9 (100 µM and negative at 30-500 µM -S9.  Aberrations
were chromatid breaks and exchanges.

870.5395	

In vivo rat bone marrow	42684940

dose levels: 1250, 2500, or 5000 mg/kg	

Negative in male (up to 5000 mg/kg) and female rats (up to 4400 mg/kg)
when tested orally.

870.5550	UDS assay	42684941

dose levels: by oral gavage to 5000 mg/kg or 12 hours post exposure to
1250 or 2500 mg/kg	

Negative up to 5000 mg/kg.

870.6200a

	Acute neurotoxicity screening battery

Data Gap

870.6200b

	Subchronic neurotoxicity screening battery

Data Gap

870.6300

	Developmental neurotoxicity

Not required.

870.7485

	Metabolism and pharmacokinetics - rat (oral)	42684943

single oral dose of 1 mg/kg or 100 mg/kg,	Gastrointestinal tract
absorption >90% at 1 mg/kg and up to 50% at 100 mg/kg.  At least 97%
recovery in feces and urine 7 days after dosing.  Highest levels of
residues (36-49 ppb) in blood cells at low dose and 2800-3000 ppm at
high dose (RBC levels > plasma).  In addition to untransformed parent, 7
metabolites identified in urine and feces (38-46% for low dose and about
71% at high dose).   

870.7600	Dermal penetration - rat	42684944

dose levels:  200 or 800 mg/kg bw  

	Females dosed with 200 or 800 mg/kg b.w.  Dermal absorption for 200 and
800 mg/kg was 3.9% and 8.0%, respectively, by 48 hours after initiation
of treatment for 6 hours.  Blood levels at 6-24 hours after dermal
dosing with 200 mg/kg were similar to those obtained at 2-6 hours after
oral dosing with 1 mg/kg.  Blood levels at 6-24 hours after dermal
dosing with 800 mg/kg were similar to those obtained at 2-6 hours after
oral dosing with 30 mg/kg.

870.7800	Immunotoxicity

Data Gap

Non-guideline 	Special Study -

Rat Developmental: Critical Time for Defects	42694931, 42684932

single dose:400 mg/kg bw	Pregnant females were administered 400 mg/kg by
gavage on gestation day 11 or 12 or 13 or 14 or 15.  Day 12
administration showed: largest incidence of embryonic death, lowest
fetal body weights and greatest incidence of ventricular septal defects.

A.3	Data Requirements

Guideline Number: 870.6200

Study Title:  Neurotoxicity Battery (Acute and Subchronic Studies)

Rationale for Requiring the Data

This is a new data requirement under 40 CFR Part 158 as a part of the
data requirements for registration of a pesticide (food and non-food
uses). 

The Neurotoxicity Screening Battery (OPPTS 870.6200) is designed to
evaluate the potential adverse effects on the nervous system from
exposure to pesticide chemicals.  The Agency believes that the guideline
studies are inadequate in their assessment of behavioral effects and do
not use optimal methods to evaluate the potential toxicity to the
nervous tissue structure and function. To detect and characterize these
potential effects more fully, a battery of more sensitive testing is
required. The objective of this neurotoxicity battery testing is to
evaluate the incidence and severity of the functional and/or behavioral
effects, the level of motor activity, and the histopathology of the
nervous system. The acute neurotoxicity study is required to detect
possible effects resulting from a single exposure. The subchronic
neurotoxicity study is intended to detect possible effects resulting
from repeated or long-term exposures.

T

X

Z

`

a

c

i

k

l

€

ƒ

„

„

š

›

œ

¶

º

¼

½

Ü

Þ

å

ç

è

é

ê

ò

b

›

¾

å

æ

ì

í

蘁ਤ

옍

§

«

ì

í

h

h

j´

j7

j¨

j+

j

j

␱䀀&摧碧ù

hç

hç

hç

hç

  h

h+

h+

愀Ĥ摧᷎ê

kd

É	M

É	M

É	M

É	M

愀Ĥ摧᷎ê

É	M

愀Ĥ摧᷎ê

É	M

愀Ĥ摧᷎ê

É	M

  h

将

\

\

\

h+

\

\

\

\

\

\

  h0

& h0

  h0

  h0

h+

  h0

  h0

B

  h0

ጀ咤᐀⾤㄀$摧⩲ÓༀB

  h0

 

)

9

q

  h0

  h0

  h0

  h0

ༀᄈᢄㇷ$葞ࣨ葠摧秌Ý

  h0

  h0

  h0

瑹ⓠB

摧ⓠB

摧ៈ_

摧ⓠB

摧໺U

摧滩

hF4

hF4

摧呧V

&

摧呧V

Ȁ摧桓æ

㄀$摧ࡧ

਀Ȧ䘋

h¾w

将

@

\

@

\

@

\

@

\

@

\

@

\

@

\

摧᪀m

਀&䘋

਀&䘋

㄀$摧ђe

㄀$摧㮎e

㄀$摧瞾

㄀$摧瞾

㄀$摧瞾

h¾w

฀튄ㇾ$葝ﻒ摧ᵄF

摧ђe

␱䀀Ħ摧瞾

☊ଁن㄀$␷㠁Ĥ♀䠁Ĥ摧瞾

# h

h

h

 h

  h

# h

@

  h

@

®

Ñ

Ù

Û

ç

è

é

ê

 

&

4

6

H

O

_

b

d

n

|

ê

-

b

«

ì

í

摧ᛛᘀ|

}

š

ª

«

¬

²

¹

ß

ë

ì

í

î

ï

ð

õ

û

h

h

# h

h

h

h

hY

h

 h

h

  h

h

h

 h

h

@

&

@

gdY

gd=

;

h; 

h=

h=

摧ᢕ 	㜀Ĥ␸䠁Ĥ摧※

옍)

  h; 

h; 

 h; 

h; 

 h; 

h; 

 h; 

h; 

  h; 

h; 

옍)

옍)

옍)

  h; 

h; 

h; 

态ú摧※

☊଀၆㜀Ĥ␸䠁Ĥ摧※

	㜀Ĥ␸䠁Ĥ摧※

☊଀ፆ㜀Ĥ␸䠁Ĥ摧※

摧䛣©

옍)

옍)

  h

 h

h

옍)

h

  h

h

h

  h

h

h

 h

h

h

옍)

옍)

옍)

@

$

@

$

@

$

@

$

@

@

$

@

$

@

$

@

$

@

$

@

@

$

@

$

@

@

$

@

@

š

摧᷂:

摧᷂:

摧Ⓡ§

摧⦕&

摧᷂:

摧Ⓡ§

摧Ⓡ§

摧ูI

摧憴§

摧᷂:

摧嶲§

摧⦕&

摧嶲§

옍)

瑹噽»਀a wide range of functional tests for evaluating neurotoxicity
including sensory effects, neuromuscular effects, learning and memory
and histopathology of the nervous system  For example, animal studies
with organophosphorous chemicals  have shown neurotoxicity to be the
primary toxic endpoints (e.g., cholinesterase inhibition) of concerns in
rodents and non-rodents.    These animal studies can be used to select
endpoints and doses for use in risk assessment of all exposure scenarios
and are considered a primary data source for reliable reference dose
calculation. The Agency has established an oral reference dose (RfD) for
assessing dietary risks for a number of chemicals (e.g.,
organophosphates and carbamates) where neurotoxicity was the most
sensitive endpoint of concern.

How could the data impact the Agency's future decision-making? 

If the acute or subchronic neurotoxicity studies show that flumioxazin
poses either a greater or a diminished risk than that given in the
interim decision’s conclusion, the risk assessments for flumioxazin
may need to be revised to reflect the magnitude of potential risk
derived from the new data.

 

If the Agency does not have this data, a 10X database uncertainty factor
may be applied when conducting a risk assessment using the currently
available studies.

 TC \l2 "A.3  Immunotox Data Requirements  

Guideline Number: 870.7800

Study Title:  Immunotoxicity

Rationale for Requiring the Data

This is a new data requirement under 40 CFR Part 158 as a part of the
data requirements for registration of a pesticide (food and non-food
uses). 

The Immunotoxicity Test Guideline (OPPTS 870.7800) prescribes functional
immunotoxicity testing and is designed to evaluate the potential of a
repeated chemical exposure to produce adverse effects (i.e.,
suppression) on the immune system. Immunosuppression is a deficit in the
ability of the immune system to respond to a challenge of bacterial or
viral infections such as tuberculosis (TB), Severe Acquired Respiratory
Syndrome (SARS), or neoplasia.  Because the immune system is highly
complex, studies assessing functional immunotoxic endpoints are helpful
in fully characterizing a pesticide’s potential immunotoxicity.  These
data will be used in combination with data from hematology, lymphoid
organ weights, and histopathology in routine chronic or subchronic
toxicity studies to characterize potential immunotoxic effects.  

Practical Utility of the Data

How will the data be used?

These animal studies can be used to select endpoints and doses for use
in risk assessment of all exposure scenarios and are considered a
primary data source for reliable reference dose calculation. For
example, animal studies have demonstrated that immunotoxicity in rodents
is one of the more sensitive manifestations of TCDD
(2,3,7,8-tetrachlorodibenzo-p-dioxin) among developmental, reproductive,
and endocrinologic toxicities.  Additionally, the EPA has established an
oral reference dose (RfD) for tributyltin oxide (TBTO) based on observed
immunotoxicity in animal studies (IRIS, 1997).

How could the data impact the Agency's future decision-making? 

If the immunotoxicity study shows that the test material poses either a
greater or a diminished risk than that given in the interim decision’s
conclusion, the risk assessments for the test material may need to be
revised to reflect the magnitude of potential risk derived from the new
data.

 

If the Agency does not have this data, a 10X database uncertainty factor
may be applied for conducting a risk assessment from the available
studies.

 



Appendix B:  Metabolism Assessment

  TC \l1 "Appendix B:  Metabolism Assessment 

Not included.

Appendix C:  Review of Human Research

No MRID - PHED Surrogate Exposure Guide

Page   PAGE  2  of   NUMPAGES  64 

Page   PAGE  54  of   NUMPAGES  63