Document ID: EPA-HQ-OPP-2008-0361-0005
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2009-04-08T04:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460      

	OFFICE OF PREVENTION, PESTICIDE

	AND TOXIC SUBSTANCES

	

  SEQ CHAPTER \h \r 1 MEMORANDUM

	Date:	03/03/2009

	SUBJECT:	  Revised Executive Summary for Cyhalofop-butyl:  Human Health
Risk Assessment for Proposed Uses on Wild Rice and A Proposed Amended
Labeling for Clincher® SF Herbicide.  

PC Code: 082583	DP Barcode: D362410 

MRID No.: None	EPA Reg. No.: 59639-357  

Petition Nos.: 8E7341	Reg. Action: Section 3

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

TXR No.: None	CAS No.:  122008-85-9

Decision Nos.:  394687: 391343	40 CFR 180.576

	FROM:	Margarita Collantes, Risk Assessor

		Alan Levy, Ph.D., Senior Toxicologist

		Douglas Dotson, Chemist

		Risk Assessment Branch II

		Health Effects Division (7509P)  SEQ CHAPTER \h \r 1 

	THROUGH:	Richard A. Loranger, Ph.D., Senior Scientist

		Christina Swartz, Branch Chief

		Risk Assessment Branch II

		Health Effects Division (7509P)

	TO:	Daniel Rosenblatt/Sidney Jackson/Barbara Madden, RIMUERB

		Joanne Miller, PM 23		

		Registration Division (7505P)  SEQ CHAPTER \h \r 1   SEQ CHAPTER \h \r
1 

ACTION REQUESTED:

The purpose for this amendment is to replace language in the executive
summary which characterizes the developmental and reproductive effects
observed in the toxicological studies for cyhalofop-butyl.  These
changes are provided in the 3rd paragraph on page 3 of this amendment.

1.0	Executive Summary  TC "1.0  Executive Summary" \f C \l "1"  

Cyhalofop-butyl
(R-(+)-n-butyl-2-(4-(4-cyano-2-fluorophenoxy)-phenoxy)propionate) is a
diphenyl ether (aka oxyphenoxy acid ester) herbicide for which a food
use on rice and wild rice has been proposed.  Other members of this
class of herbicides include fluazifop-butyl, fenoxaprop-ethyl,
haloxyfop-methyl, diclofop-methyl, quizalofop-ethyl, fomesafen sodium,
oxyfluorfen, acifluorfen sodium, nitrofen, and lactofen.  All these
esters form acid metabolites.  Cyhalofop-butyl inhibits acetyl coenzyme
A carboxylase, which catalyses an essential step in plant fatty acid
biosynthesis.

Cyhalofop-butyl is formulated as Clincher® EC, an emulsifiable
concentrate containing 29.6% cyhalofop-butyl as active ingredient
(equivalent to 2.38 lbs ai/gal of product).  Clincher® EC is a
postemergence herbicide for the selective control of emerged grass weeds
in drill-seeded and water-seeded rice.  According to the proposed
supplemental labeling, the maximum amount of active ingredient that can
be applied is no more than 2 applications or 0.46 lbs. ai or 25 fluid
ounces per acre during the growing season.  Product may be applied up to
60 days before harvest.  Applications of the herbicide may include a
crop oil concentrate or nonionic surfactant as specified in the label at
the rate of 0.25% (1 quart/100 gallons of spray solution).  This product
is applied aerially, and/or by groundboom equipment.

This memorandum presents the results of an assessment on the use of the
herbicide cyhalofop-butyl on rice and wild rice in response to a
tolerance petition submitted by Interregional Research Project Number 4
(IR-4).  Clincher® EC (EPA Reg. No. 62719-356) was previously approved
for use on rice with tolerances established on rice grain at 0.03 ppm
and rice straw at 8.0 ppm.  These tolerances were time-limited because
of deficiencies in the toxicology database (i.e., inadequate dosing in
carcinogenicity studies) and expired on 6/1/2007.  IR-4 has requested
that the rice field trial data be translated to wild rice, and that a
tolerance be established for residues of cyhalofop-butyl plus its acid
and diacid metabolites in rice, wild, grain, at 0.03 ppm.  Wild rice
straw is not a regulated commodity; therefore, a tolerance was not
proposed for this commodity.  

HED has re-evaluated the database for cyhalofop-butyl and found it to be
adequate for purposes of evaluating the requested use expansion. 
However, due to revisions in 40 CFR Part 158, there is now a requirement
for an immunotoxicity study (OPPTS Guideline 870-7800).  Although the
lack of this study now represents a data gap, HED does not believe that
a database uncertainty factor is warranted at this time.

Cyhalofop-butyl has low or minimal acute toxicity via the oral (category
IV), dermal (category IV) and inhalation routes of exposure (category
IV).  It is minimally irritating to the eye (category IV),
non-irritating to the skin (category IV); and is not a dermal
sensitizer.  

Kidney effects were observed after subchronic and chronic dosing of the
rat and mouse as well as in the rabbit developmental and rat
reproduction studies.  In the 90-day rat study, lipofuscin pigment
deposition in proximal tubule kidney cells was noted in both sexes in
addition to hepatocyte eosinophilic granules (males only); and in the
90-day mouse study (females only), there was an increase in absolute and
relative kidney weights as well as swelling of the proximal tubule
cells.  In the rabbit developmental study, 1/18 dams in the mid-dose
group and 9/18 dams in the high-dose group died or were sacrificed in
extremis after exhibiting hematuria (gross pathological examinations
revealed cloudy or dark colored kidneys).  Slight kidney tubular cell
swelling was observed only in adult males in the rat reproductive
toxicity study.  In the 18-month mouse carcinogenicity study, kidney
findings included tubular dilatation, chronic glomurulonephritis and
hyaline casts in females (not males).  In both sexes in the
chronic/carcinogenicity rat study increased deposition of kidney changes
(early and increased deposition of the pigments lipofuscin and
hemosiderin in the renal proximal tubular cells) was observed.  In
addition, in females only, renal mineralization was observed.

In the 18-month mouse carcinogenicity study, hyperplasia of the stomach
mucosal epithelium was reported in males only.  Brown and/or atrophied
thymuses as well as decreased thymus weight was observed in the 90-day
dog study. 

No reproduction and/or endocrine effects were noted in any of the
studies.  In the rat developmental toxicity study, there were no
maternal or fetal effects observed up to the limit dose.  In the rabbit
developmental toxicity study, no fetal effects were observed up to the
limit dose; whereas, kidney effects (deaths related to hematuria and the
occurrence of cloudy or dark colored kidneys on gross pathological
examination) were seen in maternal animals.  There was no evidence of
teratogenicity or indications of increased neonatal sensitivity in the
developmental and reproduction toxicity studies.

There were no systemic or neurotoxicity effects noted at the limit dose
in the gavage acute neurotoxicity study.  In addition, in the 90-day
feeding neurotoxicity study (males up to 75 mg/kg/day and females up to
250 mg/kg/day, limited by doses in other studies), there were no
systemic or neurotoxicity findings.

nce the PPARά rodent liver mode of action is not likely to occur in
humans and because cyhalofop-butyl is a weak rodent liver PPARά
agonist.  There were no positive effects in the battery of mutagenic
studies.

No observed toxic effects appeared to be associated with a single dose
of cyhalofop-butyl in the submitted studies.  Therefore, no appropriate
endpoints were identified for establishing an acute reference dose for
any population subgroup, including females age 13-49 years of age.  For
chronic dietary exposure, the carcinogenicity study in mice was used to
calculate the chronic reference dose (cRfD) of 0.01 mg/kg/day.  The
NOAEL of 1.0 mg/kg/day was selected based upon the LOAEL of 10.3
mg/kg/day at which there were increased incidences of kidney tubular
dilatation, hyaline casts and chronic glomerulonephritis in females. 
For the incidental oral short- and intermediate-exposure, the NOAEL of
4.3 mg/kg/day was based on the LOAEL of 14.1 mg/kg/day from a 90-day
study in mice where there were enlarged kidneys in females with swelling
of proximal tubular cells in 4/12 mice.  No endpoints were selected for
the short- or intermediate-term dermal exposure because no toxicity was
noted at the limit dose in the 21-day dermal study.  For short- and
intermediate-term inhalation, the NOAEL of 4.3 mg/kg/day was chosen from
the 90-day mouse study (incidental short- and intermediate-term noted
above). 

Based on hazard and exposure data, HED recommends the special FQPA
Safety Factor be reduced to1x because there are low concerns, no
evidence of increased susceptibility, no residual uncertainties with
regard to pre- and/or postnatal toxicity, no evidence of neurotoxicity
(a DNT study is not required), and high confidence that exposure
estimates have not been underestimated.

Product chemistry data, residue chemistry data relevant to food use, and
environmental fate data relevant to drinking water are adequate to
assess human dietary exposure to cyhalofop-butyl and to its metabolites
or degradates. 

HED has conducted a new dietary exposure assessment.  As per current
policy, the new assessment incorporated exposure via residues in
drinking water directly into the dietary exposure model.  The resulting
dietary cPAD risk estimates for the general U.S. population (4.5% cPAD)
and the highest exposed population subgroups (all infants < 1 year old,
15% cPAD) are well below HED’s level of concern ( typically 100% of
the PAD).  The risk estimates are based on tolerance-level residues and
an assumption of 100% crop treatment for the food uses, and “Tier 1”
estimates for the drinking water contamination that may be associated
with the crop use.  

There are no residential uses proposed for cyhalofop-butyl; therefore, a
residential exposure assessment is not required.   

Based on the use patterns for cyhalofop-butyl and the information in the
toxicological database, only the chronic exposure requires a
quantitative aggregate assessment.  The only source of exposure to
cyhalofop-butyl that is appropriate for assessing aggregate risk is
dietary (food and water) exposure.  The chronic aggregate risk is based
on tolerance-level residues and an assumption of 100% crop treatment for
the food uses, and on “Tier 1” estimates for the drinking water
contamination that may be associated with crop use.  A determination of
safety can be made for aggregate 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 cyhalofop-butyl and any other
substances.  Also, cyhalofop-butyl 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 cyhalofop-butyl
has a common mechanism of toxicity with other substances.

HED has completed occupational exposure assessments to evaluate the
requested uses.   Occupational risk estimates associated with
application as well as post-application activities are below HED’s
level of concern.  The level of concern for margins of exposure of
safety for occupational risk assessments is 100.

Furthermore, upon review of newly submitted Mode of Action studies on
the liver, HED has determined that cyhalofop-butyl is not likely to be
carcinogenic to humans.  Therefore, the requirement for a closed system
while mixing and loading for aerial application and the restriction of
limiting  aerial treatment  to 800 acres on the current label, as a
result of the previous cancer classification and Q* value, are no longer
required.

Environmental Justice Considerations

Potential areas of environmental justice concerns, to the extent
possible, were considered in this human health risk assessment, in
accordance with U.S. Executive Order 12898, "Federal Actions to Address
Environmental Justice in Minority Populations and Low-Income
Populations,"   HYPERLINK
"http://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 Intakes by Individuals (CSFII) and are used in pesticide
risk assessments for all registered food uses of a pesticide.  These
data are analyzed and categorized by subgroups based on age, season of
the year, ethnic group, and region of the country.  Whenever
appropriate, nondietary 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 postapplication
are evaluated.  Further considerations are currently in development as
OPP has committed resources and expertise to the development of
specialized software and models that consider exposure to bystanders and
farm workers as well as lifestyle and traditional dietary patterns among
specific subgroups.

Review of Human Research

This risk assessment relies in part on data from studies in which adult
human subjects were intentionally exposed to a pesticide or other
chemical.  These studies, which comprise the Pesticide Handlers Exposure
Database (PHED), have been determined to require a review of their
ethical conduct, and have received that review.  The studies in PHED
were considered appropriate (ethically conducted) for use in risk
assessments.  

CONCLUSIONS/RECOMMENDATIONS

Based on highly conservative, health-protective assumptions, there are
no human health considerations that would preclude granting the
requested uses of cyhalofop-butyl on rice and wild rice.  The database
for cyhalofop-butyl is complete except for the immunotoxicity study.

HED recommends for establishing permanent tolerances for residues of
cyhalofop-butyl, cyhalofop-acid and cyhalofop-diacid at 0.03 ppm in/on
rice, grain, and rice, wild, grain.  

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6is study now represents a data gap, HED does not believe that a
database uncertainty factor is warranted at this time.   HED recommends
that submission of an adequate immunotoxicity study be made a condition
of registration for the uses on rice and wild rice. 

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