Document ID: EPA-HQ-OPP-2008-0361-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2008-06-04T04:00Z

EPA Registration Division contact: Sidney Jackson, (703) 305-7610 

 

<Interregional Research Project #4>

<PP# 8E7341>

<	EPA has received a pesticide petition (PP) 8E7341 from Interregional
Research Project #4 (IR-4) Project Headquarters, 500 College Road East,
Suite 201 W, Princeton, NJ 08540 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.>

 by establishing a tolerance for 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)propionicacid) and the
di-acid metabolite, (2R)-4-[4-(1-carboxyethoxy)phenoxy]-3-fluorobenzoic
acid in or on the raw agricultural commodity Rice, wild, grain at 0.03
parts per million (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
diacid metabolite in rice grain, straw and processed products.  The
method was based on capillary gas chromatography with mass selective
detection.>

<	3. Magnitude of residues. This petition for wild rice builds on the
previous registration of cyhalofop-butyl for use in traditional rice. 
Both rice (Oryza sativa) and wild rice (Zizania palustris) are members
of the grass (Poaceae) subfamily (Bambusoideae) and tribe (Oryzeae). 
Cultural practices and pest problems are similar enough that rice data
can be used for bridging data to wild rice.  Production practices,
growth requirements and physical characteristics are very similar for
rice and wild rice in California.  Because the proposed use pattern is
similar to the representative rice crop and based on previous guidance
from EPA, IR-4 proposes that the tolerance on wild rice be established
based on bridging to the existing residue data for cyhalofop-butyl in
traditional rice.

>

<B. Toxicological Profile The toxicological profile and endpoints for
cyhalofop-butyl which support this petition to establish these
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, not
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 extension 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.

Cyhalofop-butyl has not been classified in relation to carcinogenicity. 
There was no evidence of carcinogenic potential under the conditions of
the mouse feeding study and there were no treatment-related increases in
tumors in the rat study.  However, the agency concluded the dosing was
too low to elicit frank toxicity in the original studies and deemed them
inadequate to assess carcinogenic potential (Federal Register of June 4,
2002 (67 FRL-7178-5).  In 2002, the EPA used a surrogate Q* value of
2.3x10-1 (mg/kg-day)-1 based on the structural analog diclofop-methyl to
assess cancer risk.  The agency stated use of this value was
conservative and protective for exposures to cyhalofop-butyl.  
Subsequently, Dow AgroSciences provided the agency with mechanistic
arguments for classification of cyhalofop-butyl as “Not Likely to Be
Carcinogenic to Humans”.  Dow AgroSciences believes no assessment
against the cancer endpoint is required.>

<	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
diacid as a major metabolite; the diacid 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 traditional and wild 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 III
dietary assessment was prepared using the average residue value from
field trials (0.0066 ppm) for rice, the 0.03 tolerance for wild rice and
a cPAD = cRfD = 0.01 mg/kg/day.  Marketing data for Clincher* herbicide
treated acres was used to confirm the percent crop treated (PCT) value
used in the DEEM file as the 2nd adjustment factor.  The average number
of planted rice acres over the last 3 year period is 3,214,000 acres. 
It is estimated that between % 1 and <5% of the treated fields utilize
the 2 applications of Clincher* herbicide allowed on the label.  The
average of the total treated acreage (Doune Agrotrak 2006) has been
conservatively adjusted by the lower 1% retreatment.  When the PCT is
calculated from the updated numbers there is excellent agreement with
the value originally projected for maturity of sales and used by the
EPA; the 2002 EPA projection was 17.6%, the revised number is 18.4%.  A
rounded value of 18% PCT has been used as the second adjustment factor
in the DEEM file.  Results indicate exposure to cyhalofop-butyl residues
is very low and represents less than 0.1 % of the cRfD for all
subpopulations.  Without the use of the PCT as the second adjustment
factor, all exposures are below 0.2% of the cPAD.>

<	ii. Drinking water. A 2001 surface water monitoring study in
California provided initial support for low levels of cyhalofop in
water.  The 2001 monitoring study was commenced just after initial
Section 18 Specific Exemption applications began in the area.  Although
fortified storage stability associated with the study indicated the
ester form was not stable under sampling and storage conditions of this
study (i. e. cyhalofop-butyl converted to cyhalofop (acid form)),
results indicated that no sample had a concentration of either
cyhalofop-butyl or cyhalofop above the limit of detection (LOD) of 0.5
ppb.

Prior to registration, preliminary estimates of drinking water
concentrations were made by the EPA using a modified GENEEC approach for
rice paddies and SCI-GROW.  Based on these results coupled with the 2002
surrogate Q* assessment, the label was modified to include a 7-day
holding pattern to allow time for concentrations of cyhalofop-butyl to
fall below 0.15 ppb.

Since that time, a second larger monitoring study of drinking water in
California has been concluded at a lower LOD.  Clincher* CA herbicide
was applied in California in 2002 under a Section 18 Specific Exemption.
 The 2002 monitoring study was conducted during the time of maximum use
of Clincher* herbicide in the Sacramento River Valley.  The study
monitored drinking water for cyhalofop-buyl and the 3 principal
metabolites (cyhalofop, cyhalofop-diacid and cyhalofop-amide).  Water
was sampled semiweekly from April 30 to July 18.  A total of 48 samples
were collected and analyzed.

Method GRM 99.07 (  NOTEREF _Ref184542359 \h  \* MERGEFORMAT  Error!
Bookmark not defined. ) was modified to achieve a limit of
quantitification of (LOQ) of 0.1 ug/L (ppb).  Neither cyhalofop-butyl
nor its metabolites were present in any of the drinking water samples
above the LOQ.  The limits of detections (LOD) were 0.04 ppb for
cyhalofop-butyl, 0.01 ppb for cyhalofop (acid), 0.01 ppb for
cyhalofop-amide and 0.04 ppb for cyhalofop-diacid.  Only one sample in
48 had a detection above the LOD and only cyhalofop-butyl (no
metabolites) was noted in that sample.  The lack of detections is
understood in light of the known rapid degradation of cyhalofop-butyl
and its metabolites in the environment.

Based on the drinking water monitoring information, 0.05 ppb (½ the
LOQ) has been incorporated as a single point estimate for both direct
and indirect water sources within DEEM.  This study is germane, because
the extension for wild rice was requested for use in California. 
Dietary and water exposure were chronically assessed against the cRfD of
0.01 mg/kg/day.

All subpopulations have exposure estimates of < 0.1% cPAD.  Comparison
of DEEM output with and without the water component demonstrates the
additional water exposure has minimal impact on the overall exposure
assessment for all sub populations.>

<	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 and proposed uses in wild rice plus drinking water will
utilize <0.1% 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” and “all infants (<1 year)”, but each are
exposed to estimated residues of <0.1 % 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 US
value of 0.03 ppm in rice is higher than values in Europe and Latin
America, but lower than values established in 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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