 

<EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE
PETITIONS PUBLISHED IN THE FEDERAL REGISTER  (7/1/2007)>

<EPA Registration Division contact: [insert name and telephone number
with area code]>

 

<INSTRUCTIONS:  Please utilize this outline in preparing the pesticide
petition.  In cases where the outline element does not apply, please
insert “NA-Remove” and maintain the outline. Please do not change
the margins, font, or format in your pesticide petition. Simply replace
the instructions that appear in green, i.e., “[insert company
name],” with the information specific to your action.>

<TEMPLATE:>

<[Dow AgroSciences, LLC]>

<[Insert petition number]>

<	EPA has received a pesticide petition ([insert petition number]) from
[Dow AgroSciences, LLC], [9330 Zionsville Road, Indianapolis, IN, 46268]
proposing, pursuant to section 408(d) of the Federal Food, Drug, and
Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180.576.>

<(Options (pick one)>

<	1. to reestablish and make permanent tolerances for residues of>

<	[the combined residues of cyhalofop (cyhalofop-butyl,
R-(+)-n-butyl-2-(4(4-cyano-2-fluorophenoxy)-phenoxy)propionate, plus
cyhalofop acid, R-(+)-2-(4(4-cyano-2-fluorophenoxy)-phenoxy)propionic
acid) and the di-acid metabolite,
(2R)-4-[4-(1-carboxyethoxy)phenoxy]-3-fluorobenzoic acid] in or on the
raw agricultural commodity [Rice, grain] at [0.35] parts per million
(ppm) and [Rice, wild grain] at [0.35] ppm.  EPA has determined that the
petition contains data or information regarding the elements set forth
in section 408 (d)(2) of  FDDCA; however, EPA has not fully evaluated
the sufficiency of the submitted data at this time or whether the data
supports granting of the petition. Additional data may be needed before
EPA rules on the petition.>

<A. Residue Chemistry>

<	1. Plant metabolism. [The metabolism of cyhalofop-butyl in plants
(rice) is adequately understood for the purposes of a tolerance in rice.
 Two separate foliar broadcast 14C NOR studies have been conducted. 
Results indicated cyhalofop-butyl was metabolized to cyhalofop (acid
form) and then subsequently to the free and conjugated forms of the
di-acid and the FHPBA.  Other minor metabolites were also identified. 
In addition, the rotational crop study showed no carryover of
significant cyhalofop-butyl related residues in representative crops.]>

<	2. Analytical method. [An adequate analytical method is available for
enforcement purposes; the method has been developed and validated to
determine the residues of cyhalofop-butyl, cyhalofop (acid form) and the
di-acid metabolite in rice grain, straw and processed products.  The
method was based on capillary gas chromatography with mass selective
detection.  Limits of detection were 0.005 or 0.006 ppm depending on the
analyte and matrix.]>

<	3. Magnitude of residues. [The existing MOR work in rice was conducted
as 18 field trials in 1998 in the major rice-growing regions of the US. 
Clincher* herbicide (formulation XRM-5151) was applied as a foliar
broadcast to established rice plants at proposed maximum label rates. 
Samples were analyzed for cyhalofop-butyl, cyhalofop-acid and the
di-acid metabolite via GC/MSD using method GRM 99.06 with a limit of
detection (LOD) of 0.005 ug/g.  No residues were detected in a majority
of the grain samples.  Residues in the grain ranged from ND to 0.02 ppm.
 Residues in the straw ranges from 0.02 to 6.14 ppm.  Within the
processing study conducted at ~ 5X the application rate, no detectable
residues were noted for grain, bran and polished rice.  

Six more residue trials were also conducted in 2009 in the major rice
growing areas of the country to provide updated residue data. Residues
of cyhalofop-butyl and metabolites in   DOCVARIABLE  Cr1lc  \*
MERGEFORMAT    DOCVARIABLE  Cr2lc  \* MERGEFORMAT  grain and rice straw
were determined by LC/MS/MS after two postemergent applications of
GF-2112 or NAF-541 at a total rate of 0.47 lb ai/A.  After treatments,
cyhalofop acid residues in rice grain and straw ranged from
non-detectable to 0.022 µg/g and from non-detectable to 0.788 µg/g,
respectively.  Cyhalofop diacid residues in rice grain and straw ranged
from non-detectable to 0.265 µg/g and from 0.564 to 3.33 µg/g,
respectively, after treatment with NAF-541.  

These studies are also supporting uses in wild rice varieties for the
minor use of cyhalofop in or on wild rice. Cultural practices and pest
problems are similar such that rice data can be used for bridging data
to wild rice.]

B. Toxicological Profile [The toxicological profile and endpoints for
cyhalofop-butyl which support this petition and tolerances were
previously published in the Federal Register of June 4, 2002 (67
FRL-7178-5).  The relevant information is summarized below.]>

<	1. Acute toxicity.  [No appropriate endpoint attributable to a single
dose was identified; the EPA has not established an acute RfD for
cyhalofop-butyl.]>

<	2. Genotoxicty. [No evidence of genetic toxicity was observed when
cyhalofop-butyl was tested in a battery of in vitro and in vivo tests.]>

<	3. Reproductive and developmental toxicity. [Cyhalofop-butyl did not
have any effects on reproductive parameters at dose levels that induced
treatment-related effects in parental rats.  In addition, no teratogenic
potential was demonstrated in either rats or rabbits at dose levels that
induced maternal toxicity.]>

<	4. Subchronic toxicity. [Sub-chronic studies on cyhalofop-butyl have
been conducted and reviewed.  No endpoint was established for dermal
exposure because no systemic effects were observed in the 21-day dermal
study in the rat at doses up to 1000 mg/kg/day.  A short-term incidental
NOAEL of 4.3 mg/kg/day was selected as endpoint based on subchronic
feeding study in mice; this endpoint was also designated as conservative
surrogate for inhalation exposures.  However, for the review of a
tolerance, no short-term oral, dermal or inhalation exposures are
considered.]>

<	5. Chronic toxicity. [A chronic reference dose (cRfD) of 0.01
mg/kg/day has been established based on the 18-month feeding study in
mice and the application of an uncertainty factor of 100 (10X for
interspecies extrapolation and 10X for intra-species variation).  A 1X
FQPA safety factor was applied to the chronic endpoint.  Thus in the
case of cyhalofop-butyl, the cPAD = cRfD = 0.01 mg/kg/day.

At the time of initial registration, the carcinogencity studies in rats
and mice showed no evidence of a tumorigenic response.  But the agency
also concluded the original studies did not reach a maximum tolerated
dose and deemed them inadequate to assess carcinogenic potential
(Federal Register of June 4, 2002 (67 FRL-7178-5).  The agency recently
reviewed additional information on peroxisome proliferation and the lack
of human relevance for liver tumors formed by this mode of action.  Per
HED Memorandum TXR: 0054798 dated December 20, 2007 and in accordance
with the EPA Final Guidelines for Carcinogen Risk Assessment (March 29,
2005) the EPA has now has classified cyhalofop-butyl as “Not Likely to
Be Carcinogenic to Humans”.

At the time of registration, the agency created a holding time for water
based on the original uncertainty for cancer classification coupled with
estimates of drinking water concentrations using a modified GENEEC
approach for rice paddies and SCI-GROW.  A 7-day holding time was
established to allow estimated concentrations of cyhalofop-butyl to fall
below 0.15 ppb.  Based on the recent cancer reclassification and Table 6
of the June 4, 2002 Final Rule for Cyhalofop-butyl; Time-Limited
Pesticide Tolerance, the 7-day holding time is not needed.]>

<	6. Animal metabolism. [Oral administration of cyhalofop-butyl, results
in rapid absorption, metabolism and excretion in the dog and rat.  The
butyl ester form is rapidly hydrolyzed to the acid form (cyhalofop) with
no significant quantities of unchanged parent in the plasma, tissues or
excreta.]>

<	7. Metabolite toxicology. [In all matrices (animal, plant,
environmental), cyhalofop-butyl is rapidly metabolized to the acid form,
cyhalofop.  Hence mammalian toxicity studies inherently include the acid
metabolite as part of the study.  Plant studies have identified the
di-acid as a major metabolite; the di-acid is more polar, and less lipid
soluble and is expected to be less toxic than the parent.]>

<	8. Endocrine disruption. [No evidence from any of the studies
indicates cyhalofop-butyl is an endocrine disrupter.]>

<C. Aggregate Exposure>

<	1. Dietary exposure. [Chronic exposure resulting from agricultural use
of cyhalofop-butyl on rice has been assessed for the US population and
sub-populations.  The dietary assessment model DEEM-FCID version 2.16
was employed.  It estimates US consumption patterns based on the
Continuing Survey of Food Intake by Individuals (CSFII) and EPA/USDA
translation recipes from August 2002.  An estimate of the residue level
in each food (e.g., water or rice) is multiplied by the average daily
consumption estimate for that food.  The resulting residue consumption
estimate for each food is summed to determine the total estimated
exposure.  Exposure estimates are expressed in mg/kg body weight/day and
compared to the cPAD.]

>

<	i. Food. [For cyhalofop-butyl, a DEEM residue file for a Tier I
dietary assessment was prepared using the 0.35 ppm proposed tolerance
for “Rice, grain”, “Rice, wild, grain”, for rice.  The exposure
was assessed against a cPAD = cRfD = 0.01 mg/kg/day.  The assessment
assumes that all commodities with cyhalofop-butyl tolerances (i.e., rice
and wild rice) contain residues of cyhalofop-butyl at the tolerance
level.

Results indicate exposure to cyhalofop-butyl residues is very low and
represents less than 2.9 % of the cRfD for all subpopulations.]>

<	ii. Drinking water. [The estimated drinking water concentrations
(EDWCs) used in the dietary risk assessment were provided by the
Environmental Fate and Effects Division (EFED). The EDWC was
incorporated directly into this dietary assessment into the food
categories “water, direct, all sources” and “water, indirect, all
sources.”

Dietary and water exposure were chronically assessed against the cRfD of
0.01 mg/kg/day.  All subpopulations have exposure estimates of < 20.9%
cPAD.]>

<	2. Non-dietary exposure. [There are no residential uses for this
compound.]>

<D. Cumulative Effects>

<	[For purposes of this tolerance petition, no assumption of a common
mechanism of toxicity for cyhalofop-butyl with other substances has been
made.]>

<E. Safety Determination []. >

<	1. U.S. population. [Based on the dietary and water exposure
assessments, chronic dietary exposure to cyhalofop-butyl from registered
uses in rice plus drinking water will utilize <20.9% of the cRfD for the
U. S. population.  Exposures below 100% of the cRfD are typically below
the EPA’s level of concern because the chronic RfD represents the
level at or below which daily dietary exposures over a lifetime will not
pose appreciable risks to human health.]>

<	2. Infants and children. [Per Federal Register of June 4, 2002 (67
FRL-7178-5), EPA has previously determined that an FQPA safety factor of
1X is applicable to all population subgroups for cyhalofop-butyl.  The
major identifiable subgroup with the highest chronic dietary exposure is
“non-nursing infants” with exposure to estimated residues of <21 %
of the cPAD.  Dow AgroSciences concludes with reasonable certainty that
no harm will result to infants and children from the aggregate exposure
to cyhalofop-butyl residues from registered and proposed uses.]>

<F. International Tolerances>

<	[A review of national websites and the Homologa MRL database indicates
several values have been set for cyhalofop in rice globally.  The
proposed US value of 0.35 ppm in rice is higher than values in Europe
and Latin America, and most of the Pacific.  No MRLs were noted by
Codex.

Argentina, Brazil, Australia, Turkey	Rice	0.01	PPM

EU and various individual member states	Rice	0.02	PPM

Japan, South Korea and Taiwan	Rice	0.1	PPM

]>

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