[Federal Register Volume 85, Number 98 (Wednesday, May 20, 2020)]
[Notices]
[Page 30691]
[FR Doc No: 2020-10847]

=======================================================================
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DEPARTMENT OF ENERGY

Federal Energy Regulatory Commission

Notice of Effectiveness of Exempt Wholesale Generator and Foreign
Utility Company Status

Blythe Solar III, LLC...................................     EG20-74-000
Blythe Solar VI, LLC....................................     EG20-75-000
ENGIE Long Draw Solar LLC...............................     EG20-76-000
FirstEnergy Nuclear Generation, LLC.....................     EG20-77-000
Cambria Wind, LLC.......................................     EG20-78-000
Thunderhead Wind Energy LLC.............................     EG20-79-000
Great Bay Solar II, LLC.................................     EG20-80-000
Pegasus Wind A, LLC.....................................     EG20-81-000
Cove Mountain Solar, LLC................................     EG20-82-000
Cove Mountain Solar 2, LLC..............................     EG20-83-000
SR Terrell, LLC.........................................     EG20-84-000
Diamond Leaf Energy, LLC................................     EG20-85-000
Tejas Power Generation, LLC.............................     EG20-86-000
Peetz Table Wind, LLC...................................     EG20-87-000
Blauracke GmbH..........................................      FC20-3-000
Energy Center Caguas LLC................................      FC20-4-000

    Take notice that during the month of April 2020, the status of the
above-captioned entities as Exempt Wholesale Generators or Foreign
Utility Companies became effective by operation of the Commission's
regulations. 18 CFR 366.7(a) (2019).

    Dated: May 14, 2020.
Nathaniel J. Davis, Sr.,
Deputy Secretary.
[FR Doc. 2020-10847 Filed 5-19-20; 8:45 am]
 BILLING CODE 6717-01-P


UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

	OFFICE OF PREVENTION, PESTICIDE

	AND TOXIC SUBSTANCES

  SEQ CHAPTER \h \r 1 MEMORANDUM

	Date:	01/08/2009

	SUBJECT:	  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: D351856; D354880;

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:	Zaida Figueroa, Industrial Hygienist

		Michael Doherty, Ph.D, Senior Chemist

		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

At the request of the Registration Division, the Health Effects Division
(HED) has conducted a human health risk assessment for the active
ingredient, cyhalofop-butyl, for the purposes of making a
tolerance/registration eligibility decision for the existing use on
rice, grain and the proposed use on wild rice, grain.  In addition,
requested changes in PPE and other label language are addressed.

Table of Contents

  TOC \f \h \z    HYPERLINK \l "_Toc219104682"  1.0  Executive Summary
PAGEREF _Toc219104682 \h  3

  HYPERLINK \l "_Toc219104683"  2.0 Physical/Chemical Properties
Characterization	  PAGEREF _Toc219104683 \h  7

  HYPERLINK \l "_Toc219104684"  3.0  Hazard Characterization/Assessment
 PAGEREF _Toc219104684 \h  8

  HYPERLINK \l "_Toc219104685"  3.1  Hazard and Dose-Response
Characterization	  PAGEREF _Toc219104685 \h  8

  HYPERLINK \l "_Toc219104686"  3.1.1  Database Summary	  PAGEREF
_Toc219104686 \h  8

  HYPERLINK \l "_Toc219104687"  3.5.10	Classification of Carcinogenic
Potential	  PAGEREF _Toc219104687 \h  16

  HYPERLINK \l "_Toc219104688"  4.0  Dietary Exposure/Risk
Characterization	  PAGEREF _Toc219104688 \h  17

  HYPERLINK \l "_Toc219104689"  4.1	Pesticide Metabolism and
Environmental Degradation	  PAGEREF _Toc219104689 \h  18

  HYPERLINK \l "_Toc219104690"  4.1.1	Metabolism in Primary Crops
PAGEREF _Toc219104690 \h  18

  HYPERLINK \l "_Toc219104691"  4.1.2	Metabolism in Livestock	  PAGEREF
_Toc219104691 \h  18

  HYPERLINK \l "_Toc219104692"  4.1.3	Analytical Methodology	  PAGEREF
_Toc219104692 \h  19

  HYPERLINK \l "_Toc219104693"  4.1.6	Comparative Metabolic Profile
PAGEREF _Toc219104693 \h  20

  HYPERLINK \l "_Toc219104694"  4.1.7	Toxicity Profile of Major
Metabolites and Degradates	  PAGEREF _Toc219104694 \h  20

  HYPERLINK \l "_Toc219104695"  4.1.8	Pesticide Metabolites and
Degradates of Concern	  PAGEREF _Toc219104695 \h  20

  HYPERLINK \l "_Toc219104696"  4.1.9	Drinking Water Residue Profile
PAGEREF _Toc219104696 \h  21

  HYPERLINK \l "_Toc219104697"  4.1.10	Food Residue Profile	  PAGEREF
_Toc219104697 \h  23

  HYPERLINK \l "_Toc219104698"  4.1.11	International Residue Limits
PAGEREF _Toc219104698 \h  24

  HYPERLINK \l "_Toc219104699"  4.2  Dietary Exposure/Risk Pathway
PAGEREF _Toc219104699 \h  24

  HYPERLINK \l "_Toc219104700"  4.2.1  Residue Profile	  PAGEREF
_Toc219104700 \h  24

  HYPERLINK \l "_Toc219104701"  4.2.2  Water Exposure/Risk Pathway
PAGEREF _Toc219104701 \h  24

  HYPERLINK \l "_Toc219104702"  4.2.3  Acute and Chronic Dietary
Exposure and Risk	  PAGEREF _Toc219104702 \h  25

  HYPERLINK \l "_Toc219104703"  5.0  Residential Exposure/Risk Pathway
PAGEREF _Toc219104703 \h  25

  HYPERLINK \l "_Toc219104704"  5.1  Other (Spray Drift, etc.)	  PAGEREF
_Toc219104704 \h  25

  HYPERLINK \l "_Toc219104705"  6.0  Aggregate Risk Assessments
PAGEREF _Toc219104705 \h  26

  HYPERLINK \l "_Toc219104706"  7.0  Cumulative Risk	  PAGEREF
_Toc219104706 \h  26

  HYPERLINK \l "_Toc219104707"  8.0  Occupational Exposure	  PAGEREF
_Toc219104707 \h  26

  HYPERLINK \l "_Toc219104708"  8.1 Handler Exposure	  PAGEREF
_Toc219104708 \h  27

  HYPERLINK \l "_Toc219104709"  8.2 Postapplication	  PAGEREF
_Toc219104709 \h  27

  HYPERLINK \l "_Toc219104710"  8.3 Label Amendment	  PAGEREF
_Toc219104710 \h  28

  HYPERLINK \l "_Toc219104711"  8.4 Restricted Reentry Interval
PAGEREF _Toc219104711 \h  28

  HYPERLINK \l "_Toc219104712"  9.0 Data Needs and Label Requirements
PAGEREF _Toc219104712 \h  28

  HYPERLINK \l "_Toc219104713"  9.1 Toxicology	  PAGEREF _Toc219104713
\h  28

  HYPERLINK \l "_Toc219104714"  9.2 Residue Chemistry	  PAGEREF
_Toc219104714 \h  28

  HYPERLINK \l "_Toc219104715"  9.3 Occupational and Residential
Exposure	  PAGEREF _Toc219104715 \h  28

  HYPERLINK \l "_Toc219104716"  A.1	Toxicology Data Requirements
PAGEREF _Toc219104716 \h  29

  HYPERLINK \l "_Toc219104717"  A.2	Toxicity Profile Tables for
Cyhalofop-butyl.	  PAGEREF _Toc219104717 \h  30

  HYPERLINK \l "_Toc219104718"  A.3	Rationale for Toxicology Data
Requirements	  PAGEREF _Toc219104718 \h  41

  HYPERLINK \l "_Toc219104719"  A.4	Recommended Tolerances for
Cyhalofop-butyl.	  PAGEREF _Toc219104719 \h  42

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.  There were no maternal or fetal effects observed in either the
rat or rabbit developmental studies up to the limit dose.  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.

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.   HED recommends
that submission of an adequate immunotoxicity study be made a condition
of registration for the uses on rice and wild rice.

  SEQ CHAPTER \h \r 1 2.0 Physical/Chemical Properties Characterization
TC "2.0 Physical/Chemical Properties Characterization" \f C \l "1"

The chemical structure and nomenclature of cyhalofop-butyl are provided
in Table 1, below.  The physicochemical properties of the technical
grade of cyhalofop-butyl are presented in Table 2.0.

Table 2.0   Cyhalofop-butyl Nomenclature.

Compound

Common name	Cyhalofop-butyl

IUPAC name	2-(4-(4-cyano-2-fluorophenoxy)phenoxy)propanoic acid, butyl
ester (R)

CAS name	R-(+)-n-butyl-2-(4-(4-cyano-2-fluorophenoxy)-phenoxy)propionate

CAS registry number	122008-85-9

End-use product (EPs) requested for registration	Clincher® CA Herbicide
(29.6% Emulsifiable Concentrate)

TABLE 2	Physicochemical Properties of Cyhalofop-butyl.

Parameter	Value	References

Melting point/range	45.5-49.5ºC	Memo, D277695, D. Davis, 4/10/2002

pH	9.0

	Relative Density (20ºC)	1.172 g/cm3

	Water solubility (20ºC)	0.44 mg/L at pH 7

	Solvent solubility (g/L)	n-heptane           6.06

n-octanol          16.0

methoanol     >250

acetone          >250

ethyl acetate  >250

acetonitrile    >250

	Vapor pressure (25ºC)	5.3 x 10-8 kPa (4.0 x 10-7 mmHg)

	Octanol/water partition coefficient, Log(KOW) (25ºC)	3.32

3.0	Hazard Characterization/Assessment  TC "3.0  Hazard
Characterization/Assessment" \f C \l "1"

3.1	Hazard and Dose-Response Characterization  TC "3.1  Hazard and
Dose-Response Characterization" \f C \l "2"

3.1.1	Database Summary  TC "3.1.1  Database Summary" \f C \l "3"

<IP_ADDRESS> Studies available and considered (animal, human, general
literature)

There are acceptable studies available for endpoint selection that
include: 1) subchronic oral toxicity studies in rats, mice and dogs; 2)
a chronic oral toxicity study in dogs, a chronic/carcinogenicity study
in rats and a carcinogenicity study in mice; 3) developmental studies in
rats and rabbits; 4) a reproduction study in rats;  5) acute as well as
subchronic neurotoxicity studies in rats; and 6) a dermal toxicity study
as well as a dermal penetration study in rats.  There is also a complete
mutagenicity battery and a metabolism studies in both the rat and dog.

<IP_ADDRESS>	Mode of action

Cyhalofop-butyl is a diphenyl ether (aka oxyphenoxy acid esters)
herbicide for which there is a registered food use on rice.  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 of these esters form acid metabolites.  Cyhalofop-butyl
inhibits acetyl coenzyme A carboxylase which catalyses an essential step
in plant fatty acid biosynthesis.

<IP_ADDRESS>	Sufficiency of studies/data

Based on the proposed use pattern, the toxicology database for
cyhalofop-butyl is adequate for risk assessment.  A developmental
neurotoxicity study is not required at this time.  However, as part of
the new 40 CFR158 requirments, an immunotoxicity study in rats and/or
mice is required (see appendix II).  In a 90-day feeding study in dogs,
brown and/or atrophied thymuses and decreased thymus weights were
reported.  However, these effects were not observed in the 1-year dog
study or in other species (rats, mice or rabbits) and were not seen in
any tested species as a result of chronic exposure.  The doses and
endpoints selected for risk assessment (along with traditional
uncertainty factors) are considered protective of potential
immunotoxicity.  Therefore, an additional 10x database uncertainty
factor (UFDB) is not warranted pending receipt of the required study.

3.1.2.	Toxicological Effects

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) and
non-irritating to the skin (category IV); it is not a dermal sensitizer.

The target organs are the kidney in rats, mice and rabbits, the stomach
in mice and the thymus in dogs.  The mechanism of toxicity in test
animals is not known.  A common finding in many studies is
hepatocellular hypertrophy with a corresponding increase in liver
weights.  In the absence of adverse clinical chemistry and/or
histopathologic findings, this was not considered to be of toxicological
significance.

Kidney effects were observed after subchronic and chronic dosing 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 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 effects were observed in the chronic dog study at the
doses tested).

No reproduction and/or endocrine effects were noted in any of the
studies.  There were no maternal or fetal effects observed in either the
rat or rabbit developmental studies up to the limit dose.  There was no
evidence of teratogenicity or indications of increased neonatal
sensitivity in the developmental and reproduction toxicity studies.

In a 21-day dermal toxicity study in rats, other than suggested liver
adaptation, there were no systemic or dermal effects noted up to the
limit dose.  An acceptable/non-guideline dermal penetration study was
performed (only one exposure duration instead of six).

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.

HED previously determined that the doses administered in the 104-week
chronic/carcinogenicity rat and 78-week carcinogenicity mouse studies
were not adequate to characterize carcinogenicity in either study.  In
the absence of data, HED used the Q1* value of 2.3 x 10-1 for the
structural analog, diclofop-methyl for risk assessment purposes.  For
purposes of fulfilling this data gap requirement, the Registrant and HED
agreed that, instead of repeating the two long-term rodent studies,
specific mechanistic studies were to be conducted in the mouse.  Upon
review of the data, HED concluded that the results indicated that
cyhalofop-butyl is not a liver toxicant or carcinogen for humans based
on mechanistic information and that the doses in the original long-term
studies were approaching a maximum tolerated dose (a repeat of the
long-term studies would not provide useful information to the risk
assessment and, therefore, would not be required).  Accordingly, the
quantification of cancer risk and the derivation of an RfD should not be
based on liver effects since 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 (Evaluation of Mode of Action Data and
Classification of Carcinogenicity of Cyhalofop-butyl, J. Kidwell,
December 2007, TXR No. 0054798).

There were no positive effects in the following battery of mutagenic
studies: bacterial reverse gene mutation (Salmonella strains and E.
coli), mouse lymphoma, In vitro chromosomal aberration Chinese hamster
lung (polyploidy induced when CHL [V79] cells treated for 48 hours in
absence of S9, no clastogenic effect on DNA), In vivo micronucleus in
mouse bone marrow cells and unscheduled DNA in rat hepatocytes.

3.1.3	Dose-response

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 short- and intermediate-term oral exposure
assessment, 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
appropriate endpoints were identified for an acute reference dose for
the general population or for females age 13-49 years of age.  No
observed toxic effects appeared to be associated with a single dose of
cyhalofop-butyl in the submitted studies.  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 (see incidental short- and intermediate-term oral
exposure noted above).  The endpoint for the long-term dermal and
inhalation exposure was the same as for the chronic RfD (NOAEL = 1.0
mg/kg/day, LOAEL =10.3 mg/kg/day).

3.2	Absorption, Distribution, Metabolism, Excretion (ADME)

ministered dose in males and females, respectively, in the low-dose
[ά-14C]XRD-537 BE group, and 17.0% (males) and 11.6% (females) of the
administered dose in the [β-14C]XRD-537 BE low-dose group.  The
greatest radioactivity levels were found in liver, kidneys, plasma,
whole blood, heart, lung, and stomach, with the highest tissue levels
being found in the liver and kidney at 2 hours.  Most tissue levels
accounted <1% of the administered dose.  Due to rapid excretion, levels
in tissue/organ levels declined to near detection limits by 24 hours in
all dose groups.  There was a biphasic pattern for both labels with no
substantial differences in pharmacokinetic indices (Cmsc, tcmax, t1/2,
AUC).  Time-to-maximum plasma concentration (tcmax of 0.5 to 4 hrs) and
elimination half-times (t 1/2 of 1.4 to 7.9 hrs) reflected the
relatively rapid absorption.  Females had somewhat shorter tcmax and
lower Cmax values suggestive of saturated absorption processes.  The
acid metabolite (R-(+)-2-[4-(4-cyano-2-fluoro-phenoxy)phenoxy]propanoic
acid) was the most prominent plasma fraction (~90-94% of the plasma
activity for males and ~75-81% for females regardless of dose).  No
parent compound or other metabolites were detected.  The acid metabolite
was the most common product in urine and feces – 71-87% (urine) and
46-75% (feces) of the activity in those matrices.

In a dog metabolism study, no treatment related adverse effects were
reported.  Approximately 50% of a single gavage dose was absorbed over
several hours.  Blood and plasma radioactivity peaked after 1-2 hours.
Clearance from plasma and blood was not especially rapid but nearly
complete at 48 hours.  Over 168 hours, excretion was 42.5-43.9% in the
urine, and 48.6-50.6% in feces.  Tissue distribution was not measured.
The test article appears to be metabolized primarily by hydrolysis to
R-(+)-2-[4-cyano-2-fluorophenoxy)phenoxy]propanoic acid which was found
in both the urine and feces.  Several other metabolites were also
formed, each representing <5% of the administered dose.  No parent
compound was found in the urine, and only minimal amounts were detected
in the feces.  Level tested: Two male beagles were gavaged with 14C
XRD-537 BE and nonlabeled XRD-537 at a dose of 1 mg/kg.

3.3	FQPA Considerations

3.3.1	Adequacy of the Toxicity Database

The database is adequate to characterize potential pre- and/or
post-natal risk for infants and children.  Acceptable/guideline
developmental toxicity studies in rats and rabbits and a reproduction
study in rats were available for FQPA assessment.

3.3.2	Evidence of Neurotoxicity

There was no evidence of neurotoxicity observed in the submitted
toxicology database which included acute and subchronic neurotoxicity
studies.

3.3.3	Developmental Toxicity Studies

There were no treatment-related effects observed in dams or fetuses in
the developmental toxicity study in rats up to the limit dose of 1000
mg/kg/day.  In the rabbit developmental study (doses of 0, 40, 200 and
1000 mg/kg/day), 1/18 dams in the mid-dose group and 9/18 dams in the
high-dose group either died or were sacrificed in extremis after
exhibiting hematuria.  Gross pathological examinations revealed the
occurrence of cloudy or dark colored kidneys.  No developmental toxicity
was observed up to the limit dose of 1000 mg/kg/day.

 3.3.4	Reproductive Toxicity Study

In the rat 2-generation reproduction study in rats (one
litter/generation), there was slight kidney tubular cell swelling in
males of both generations at the 86 mg/kg/day dose (HDT).  There were no
treatment-related effects seen in females or offspring up to 101
mg/kg/day.

3.3.5	Additional Information from Literature Sources

A literature search did not reveal information that would impact the
risk assessment.

3.3.6	Pre-and/or Postnatal Toxicity

<IP_ADDRESS>	Determination of Susceptibility

There is no concern for increased quantitative and/or qualitative
susceptibility after in utero or postnatal exposure to cyhalofop-butyl
in rat and rabbit developmental toxicity studies or in a reproduction
study in rats.

<IP_ADDRESS>	Degree of Concern Analysis and Residual Uncertainties for Pre-
and/or Postnatal Susceptibility

The purposes of the Degree of Concern analysis are: (1) to determine the
level of concern for the effects observed when considered in the context
of all available toxicity data; and 2) to identify any residual
uncertainties after establishing toxicity endpoints and traditional
uncertainty factors to be used in the risk assessment.  If residual
uncertainties are identified, then HED determines whether these residual
uncertainties can be addressed by a FQPA safety factor and, if so, the
size of the factor needed.

There is no evidence (quantitative or qualitative) of increased
susceptibility and no residual uncertainties with regard to prenatal
toxicity following in utero exposure to rats or rabbits (developmental
studies) and pre and/or post-natal exposures to rats (reproduction
study).

3.3.7	Recommendation for a Developmental Neurotoxicity Study

There was no evidence of neurotoxicity observed in adults following
acute, subchronic or chronic exposure (including an acute and subchronic
neurotoxicity studies) to cyhalofop-butyl or in offspring following
prenatal or postnatal exposure.  Additionally, there was no indication
of increased susceptibility in either of the developmental studies or
the reproduction study.  Therefore, a DNT study is not required at this
time.

3.4	FQPA Safety Factor for Infants and Children

After evaluating the toxicological and exposure data, the
cyhalofop-butyl risk assessment team

recommends that the FQPA SF be reduced to 1x based on the following:

The toxicological database for cyhalofop-butyl is complete for the
intended uses (with the exception of an immunotoxicity study which is
currently required by the latest 40 CFR Part 158).

The toxicity data showed no increase in qualitative or quantitative
susceptibility in fetuses and pups with in utero and post-natal
exposure.

The aggregate exposure assessment is based on HED-recommended
tolerance-level residues and modeled drinking water estimates and will
not underestimate exposure.

Currently there are no registered or proposed residential uses of
cyhalofop-butyl.

There is no evidence of neurotoxicity in the reviewed database
(including the acute and subchronic neurotoxicity studies).

3.5	Hazard Identification and Toxicity Endpoint Selection

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

No appropriate endpoint was identified for this population.  There was
no toxic effect attributable to a single dose in the cyhalofop-butyl
toxicity database.

3.5.2	Acute Reference Dose (aRfD) – General Population

No appropriate endpoint was identified for this population.  There was
no toxic effect attributable to a single dose in the cyhalofop-butyl
toxicity database.

Comments about Study/Endpoint/Uncertainty Factors:

3.5.3	Chronic Reference Dose (cRfD)

	Study Selected:  Carcinogenicity study – mice

	MRID No.: 45000418

	Dose and Endpoint for Risk Assessment: NOAEL = 1.0 mg/kg/day

Uncertainty Factor: 100x (10x interspecies extrapolation, 10x
intraspecies variability)

Chronic RfD = 1.0 mg/kg/day = 0.01 mg/kg/day

100 (UF)

Comments about Study/Endpoint/Uncertainty Factors:

A carcinogenicity study in mice was used to select the dose and endpoint
for establishing the cRfD of 0.01 mg/kg/day.  The NOAEL of 1.0 mg/kg/day
and LOAEL of 10.1 mg/kg/day were based on kidney effects including
tubular dilatation, chronic glomerulonephritis and hyaline casts in
females as well as hyperplasia of the stomach mucosal epithelium in
males. The 2-year rat chronic/carcinogenicity feeding study with a NOAEL
of 0.82/2.5 (M/F) mg/kg/day and a LOAEL of 3.4/25.0 (M/F) mg/kg/day,
showed kidney effects as follows: early and increased deposition of the
pigments lipofuscin and hemosiderin in the renal proximal tubular cells
of both sexes, and renal mineralization in females.  The rat study
NOAELs were not chosen for endpoint dose for the following reasons: the
NOAEL in the mouse study (1.0 mg/kg/day M/F) was similar to the male
NOAEL in the rat study but was lower (2.5 mg/kg/day) than in the
females; the finding of glomerulonephritis in the mouse study was
considered to be a more toxic effect than the deposition of pigments in
the rat study; and the dose-spacing was different in the two studies
(mice = 0.0, 0.3,1.0 and 10.0 mg/kg/day M/F; rats = 0.0, 0.1, 0.2, 0.8
and 3.4 mg/kg/day for males and 0.0, 0.2, 2.5 and 25.0 mg/kg/day for
females.

Uncertainty factors (100x) include: 10x interspecies extrapolation, 10x
intraspecies variability.  The duration and route of the study are
appropriate for chronic assessment; and, the NOAEL/LOAEL are protective
of effects seen in other long-term studies (i.e., dogs, rats).

3.5.4	Dermal Absorption

Dermal absorption was ~ 25-34% for the spray formulation and ~ 11-16%
for the EF-1218 formulation following a 24-hour dermal dosing.  Within
48 hours, excretion was >85% in the urine and <1% in the feces, which is
consistent with metabolism to water soluble metabolites and subsequent
urinary excretion. [Only a 24-hour duration exposure instead of six
exposure durations: acceptable/non-guideline.]

3.5.5	Dermal Exposure (Short- and Intermediate-Term)

Study Selected: 21-Day Dermal study - rat

MRID No.: 45000415

Dose and Endpoint for Risk Assessment: No endpoint selected

Comments about Study/Endpoint/Uncertainty Factors

In a 21-day dermal toxicity study conducted in rats (plus a recovery
group) increased liver weights and clinical chemistry changes suggestive
of liver adaptation were observed with reversibility occurring in the
recovery group.  The reversibility of the effects demonstrates these
changes are biological markers of exposure, not toxicity. No systemic or
dermal effects were observed at the limit dose of 1000 mg/kg/day.
Therefore, no endpoint was selected for short- or intermediate-term
dermal risk assessment.

3.5.6	Inhalation Exposure (Short- and Intermediate-Term)

Study Selected: 90-Day study – mice

MRID No.: 45000418

Dose and Endpoint for Risk Assessment:  NOAEL = 4.3 mg/kg/day

Uncertainty Factor: 100x (10x interspecies extrapolation, 10x
intraspecies variability)

Comments about Study/Endpoint/Uncertainty Factors:

No inhalation toxicity study was submitted. A 90-day feeding study in
mice was used to select the dose and endpoint.  The NOAEL of 4.3
mg/kg/day and LOAEL of 14.1 mg/kg/day were based on enlarged kidneys
accompanied by swelling of the proximal tubule cells in 4/12 females.
Uncertainty factors (100x) include: 10x interspecies extrapolation, 10x
intraspecies variability.  While route specific inhalation data are not
available, this oral study has appropriate duration of exposure for this
assessment.  By default, HED is assuming 100% absorption (relative to
oral absorption) when assessing inhalation exposure to cyhalofop-butyl.

3.5.7	Level of Concern for Margin of Exposure

Table 3.5.7.  Summary of Levels of Concern for Risk Assessment

Route	Short-Term

(1-30 Days)	Intermediate-Term

(1-6 Months)	Long-Term

(> 6 Months)

Occupational (Worker) Exposure

Dermal	N/A	N/A	N/A

Inhalation	100	100	N/A

Residential Exposure

There are no proposed or registered residential uses for
cyhalofop-butyl.

3.5.8	Classification of Carcinogenic Potential

ce 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
(Evaluation of Mode of Action Data and Classification of Carcinogenicity
of Cyhalofop-butyl, J. Kidwell, December 2007, TXR No. 0054798).

Therefore, the classification is: “Not Likely to be Carcinogenic to
Humans.”

3.5.9	Summary of Toxicological Doses and Endpoints for Cyhalofop-butyl
for Use in Human Risk Assessments

Table 3.5.9a  Toxicological Doses and Endpoints for Cyhalofop-butyl for
Use in Dietary and Non-Occupational Human Health Risk Assessments

Exposure/

Scenario	Point of Departure	Uncertainty/

FQPA Safety Factors	RfD, PAD, Level of Concern for Risk Assessment	Study
and Toxicological Effects

Acute Dietary (General Population, including Infants and Children)	N/A

	N/A

	N/A

	No appropriate endpoint identified.

Acute Dietary

(Females 13-49 years of age)	N/A

	N/A

	N/A

	No appropriate endpoint identified.

Chronic Dietary (All Populations)	NOAEL = 1.0 mg/kg/day	UFA = 10X

UFH = 10X

FQPA SF = 1X	Chronic RfD = 0.01 mg/kg/day

cPAD = 0.01 mg/kg/day	Carcinogenicity – mice

LOAEL = 10.0 mg/kg/day, based on effects on the kidney including tubular
dilatation, chronic glomerulonephritis and hyaline casts in females as
well as hyperplasia of the stomach mucosal epithelium in males.

Cancer (oral, dermal, inhalation)	Because of the mechanistic studies
submitted by the Registrant and a review by HED, it has been determined
that the cancer classification be:”Not Likely to be Carcinogenic to
Humans.”

  TC \l3 "3.5.10	Classification of Carcinogenic Potential NOAEL = no
observed adverse effect level.  LOAEL = lowest observed adverse effect
level.  UF = uncertainty factor.  UFA = extrapolation from animal to
human (interspecies).  UFH = potential variation in sensitivity among
members of the human population (intraspecies).  FQPA SF = Food Quality
Protection Act Safety Factor.  PAD = population adjusted dose (a =
acute, c = chronic).  RfD = reference dose.  N/A = not applicable.

Table 3.5.9b  Summary of Toxicological Doses and Endpoints for
Cyhalofop-butyl  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 (1-30 days) and Intermediate-term (1-6 months)	N/A

	N/A	N/A 	21-Day Dermal - rats

No systemic or dermal effects at the LIMIT dose (1000 mg/kg/day)

Inhalation Short-(1-30 days) and Intermediate-term (1-6 months)	NOAEL =
4.3 mg/kg/day

IAF=100%	UFA = 10X

UFH = 10X

FQPA SF = 1X	Occupational LOC for MOE = 100	90-Day Oral - mice

LOAEL = 14.1 mg/kg/day (M/F),

based on enlarged kidneys in females with swelling of proximal tubular
cells in 4/12 mice.

Cancer (oral, dermal, inhalation)	Because of the mechanistic studies
submitted by the Registrant and a review by HED, it has been determined
that the cancer classification be: ”Not Likely to be Carcinogenic to
Humans.”

NOAEL = no observed adverse effect level.  LOAEL = lowest observed
adverse effect level.  UF = uncertainty factor.  UFA = extrapolation
from animal to human (interspecies).  UFH = potential variation in
sensitivity among members of the human population (intraspecies).  MOE =
margin of exposure.  LOC = level of concern.  N/A = not applicable.
IAF=inhalation absorption factor, FQPA SF = Food Quality Protection Act
Safety Factor.

3.6	Endocrine Disruption

EPA is required under the FFDCA, as amended by FQPA, to develop a
screening program to determine whether certain substances (including all
pesticide active and other ingredients) “may have an effect in humans
that is similar to an effect produced by a naturally occurring estrogen,
or other such endocrine effects as the Administrator may designate.”
Following recommendations of its Endocrine Disruptor Screening and
Testing Advisory Committee (EDSTAC), EPA determined that there was a
scientific basis for including, as part of the program, the androgen and
thyroid hormone systems, in addition to the estrogen hormone system.
EPA also adopted EDSTAC’s recommendation that the Program include
evaluations of potential effects in wildlife.  For pesticide chemicals,
EPA will use FIFRA and, to the extent that effects in wildlife may help
determine whether a substance may have an effect in humans, FFDCA
authority to require the wildlife evaluations.  As the science develops
and resources allow, screening of additional hormone systems may be
added to the Endocrine Disruptor Screening Program (EDSP).

There was the no indication in the available data that the endocrine
system may have been affected by cyhalofop-butyl.

4  SEQ CHAPTER \h \r 1 .0  Dietary Exposure Risk Characterization  TC
"4.0  Dietary Exposure/Risk Characterization" \f C \l "1"

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 0.46 lbs. (25 fluid ounces of product) per acre during the
growing season.  The product may be applied twice with the last
application being 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).  The use directions for wild rice are outlined in Table
4.0.

Table 4.0.	Summary of Directions for Use of Cyhalofop-butyl on Wild
Rice.

Method of Application	Formulation	Applic. Rate

(lb ai/A)

	Max. No. Applic. per Season

Max. Seasonal Applic. Rate

(lb ai/A)

	PHI

(days)	Use Directions and Limitations

Rice and Wild Rice

Broadcast foliar

Ground or aerial	29.6% Emulsifiable Concentrate

EPA Reg # 59639-357

	0.24-0.28

(2.38 lb ai/gallon)	2

0.46

	60

Applications are to be made with crop oil concentrate at a rate of 2.5%
v/v.  A spray volume of 10-15 gallons per acre should be used.
Sequential applications must be made at least 10 days apart.  Do not
apply through any type of irrigation system.  Do not allow discharge of
paddy water from treated areas for a minimum of 7 days after the most
recent application.  12-hour resticted entry interval (REI)

4.1	Pesticide Metabolism and Environmental Degradation  TC \l2 "4.1
Pesticide Metabolism and Environmental Degradation

4.1.1	Metabolism in Primary Crops  TC \l3 "4.1.1	Metabolism in Primary
Crops

Residue Chemistry Memo D267558, 11/13/01, M. Nelson, (PP# 0F6089)

HED MARC Decision Memo Y. Donovan, DP# 277192, 11/13/2001

  SEQ CHAPTER \h \r 1 The nature of cyhalofop-butyl residues in rice is
adequately understood based upon acceptable 14C metabolism studies
conducted on rice.  Much of the administrated material was incorporated
into natural plant components (starch, lignin,etc.).  The principal
residues in rice are the parent compound and the diacid metabolite.  The
acid metabolite occurred to a lesser degree.  HED assumes that the
metabolism in wild rice is the same as that in rice.

4.1.2	Metabolism in Livestock  TC \l3 "4.1.2	Metabolism in Livestock

Residue Chemistry Memo D267558, 11/13/01, M. Nelson, (PP# 0F6089)

The proposed use on wild rice does not result in an increase in residues
that are expected to occur in animal commodities.  As a result, there is
still no reasonable expectation of finite cyhalofop-butyl residues of
concern in egg, milk and edible livestock tissues [Category 3, 40 CFR
§180.6(a)].  Therefore, the requirements for tolerances, analytical
methods, and data depicting magnitude of the residue in eggs, milk and
edible livestock tissues are not required.  The Category 3 situation may
not remain applicable if additional livestock feed items are proposed
for tolerances in the future.

4.1.3	Analytical Methodology  TC \l3 "4.1.3	Analytical Methodology

Residue Chemistry Memo D267558, 11/13/01, M. Nelson, (PP# 0F6089)

GC/MS Method GRM 99.06 is the enforcement method for determining
cyhalofop-butyl residues of concern in/on rice commodities.  Method GRM
99.06 quantitates residues of cyhalofop-butyl and cyhalofop-acid as the
acid equivalent, and residues of cyhalofop-diacid and cyhalofop-amide as
the diacid equivalent.  The validated method LOQ for cyhalofop-acid and
cyhalofop-diacid is 0.01 ppm each in all rice matrices, except in straw,
where the LOQ for cyhalofop-diacid is 0.05 ppm.

Method GRM 99.06 has had a successful laboratory validation (ILV).  It
has also undergone a successful petition method validation by ACB/BEAD
(Memo, D272679, E. Kolbe, 3/18/2002).  A copy of the method can be
obtained from ACB/BEAD.  Method GRM 99.06 was also the residue
analytical method used in the analysis of rice commodities collected
from the field trial, processing, and storage stability studies.  The
concurrent method recoveries indicate that the method is adequate for
data collection.

4.1.4	Multiresidue Methods

Residue Chemistry Memo D278385, 8/15/03, M. Nelson, (PP# 1F06313)

Complete recovery of cyhalofop-butyl was achieved through Protocol D
(without Florisil cleanup and using NPD detection), and through Protocol
E.  The acid and diacid metabolites do not appear to be recovered by any
of the FDA MRMs.

Environmental Degradation

(Drinking Water Assessment for the Proposed Section 3 Registration of
Cyhalofop-butyl for New Uses on Wild Rice Grown in California; K. White;
October 2008)

Review of the environmental fate data of cyhalofop-butyl indicate that
the parent is degraded to cyhalofop-acid, cyhalofop-amide,
cyhalofop-diacid, 3-fluoro-4-(4-hydroxyphenoxy)benzoic acid (FHPBA), and
3-fluoro-4-(4-hydroxyphenoxy)benzonitrile (DP).

Hydrolysis and photolysis are much slower (half-lives ranged from 25
days to stable at pH 5 and 7) compared to biological degradation at
neutral to acidic pH.  Abiotic hydrolysis is more rapid at pH 9
(half-life = 2 days).

The major degradates of Cyhalofop-butyl (acid, amide, diacid) are
generally water-soluble and acidic.  The pKa of Cyhalofop-acid is 3.80,
which makes it an anion at pH 7, and its solubility is 251 mg/L.
Reliable sorption data on cyhalofop-butyl is not available.  Sorption of
cyhalofop-acid in the aquatic environment was not well predicted by
organic carbon and Kd values ranged from 0.46 – 6.2 L/kg.  The Kd
values for cyhalofop-amide ranged from 0.3 – 0.47 L/kg and the Kd for
cyhalofop-diacid ranged from 5.7 – 10.4 L/kg.  Not enough data was
available to evaluate the relationship of sorption to percent OC for the
diacid and amide.

These properties indicate that the degradates will have little tendency
to volatilize, or to sorb to soil.  The degradates will be quite mobile
due to the low Koc values.  Cyhalofop-butyl residues will likely degrade
in the water column, and be substantially mineralized to carbon dioxide.
  Residues in paddy water from California and Arkansas field studies
dissipated to below detectable levels after 28 days.

Cyhalofop-butyl and cyhalofop-acid may exist as an R or S enantiomer.
The active ingredient registered is in the R form; however, conversion
to the S enantiomer may occur in the natural environment.

4.1.6	Comparative Metabolic Profile TC \l3 "4.1.6	Comparative Metabolic
Profile

Metabolism and environmental fate studies indicate that cyhalofop-butyl
is generally biologically available.  The parent compound along with the
acid, diacid, and amide metabolites were the primary residues in rice
and environmental fate studies.  In rats and dogs, the most common
metabolite was the acid metabolite and very little of the administered
material remained in the form of the parent compound.  Most of the
absorbed material was eliminated fairly rapidly in the rat (24 hours)
and dog (48 hours) studies.  The available data indicate that
cyhalofop-butyl undergoes significant metabolism in plants, animals, and
the environment, and that the acid metabolite can be found in a variety
of systems.

4.1.7	Toxicity Profile of Major Metabolites and Degradates TC \l3 "4.1.7
Toxicity Profile of Major Metabolites and Degradates

The metabolism, or degradation of cyhalofop-butyl, has been studied in
the rat, dog, plants, and in the environment.  The available
environmental fate data indicates that the route of metabolism
(hydrolysis) in drinking water was similar to that observed in plant and
animals.  No additional metabolites of any significance were observed.
The diacid was the major residue in crop field trials, but was not
observed as a rat metabolite.  Based on structure-activity relationship
(SAR) considerations, HED concluded that this metabolite is likely to be
of comparable toxicity to the parent.  Separate toxicology studies on
the diacid were not required.

4.1.8	Pesticide Metabolites and Degradates of Concern TC \l3 "4.1.8
Pesticide Metabolites and Degradates of Concern

Table 4.1.8 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	Cyhalofop-butyl, Cyhalofop-acid, Cyhalofop-amide,
Cyhalofop-diacid	Cyhalofop-butyl, Cyhalofop-acid, and Cyhalofop-diacid

	Rotational Crop	N/A	N/A

Livestock

	Ruminant	N/A	N/A

	Poultry	N/A	N/A

Drinking Water

	Cyhalofop-butyl, Cyhalofop-acid, Cyhalofop-amide, Cyhalofop-diacid	N/A

4.1.9	Drinking Water Residue Profile TC \l3 "4.1.9	Drinking Water
Residue Profile

(Drinking Water Assessment for the Proposed Section 3 Registration of
Cyhalofop-butyl for New Uses on Wild Rice Grown in California; K. White;
October 2008)

An updated drinking water assessment was conducted for the proposed uses
on the wild rice (K. White; D; 10/17/2008).  To account for exposure to
potential residues in water under the most conservative scenario, the
value of 21 ppb was used in the chronic dietary exposure assessment.
Water-borne residues were incorporated in the DEEM-FCID assessment into
the food categories “water, direct, all sources” and “water,
indirect, all sources.”

SCI-GROW was used to derive the Expected Environmental Concentrations
(EEC) for ground water. The input parameters used in the SCI-GROW model
resulted in an estimated groundwater concentration of 0.16 ug/L
(parts-per-billion).

Since the last drinking water assessment was completed in 2001, a
standard model was developed to estimate surface water concentrations
from use of pesticides on rice, the Tier I Rice Model.  The model was
modified to account for possible aerobic aquatic degradation and aquatic
dissipation over time and used to estimate surface water concentrations
in water released from the rice paddy (tail water). Peak surface water
EECs for the tail water ranged from 12 – 279 µg/L for total residues.
 The annual average concentrations ranged from 0.13 – 21 µg/L.

Modeling results are presented in Table 4.1.9.

Table 4.1.9.	Summary of Estimated Surface Water and Groundwater
Concentrations for Cyhalofop-butyl , cyhalofop-acid and cyhalofop-diacid

	Surface Tail Water Conc., ppb a	Surface Tail Water Conc., ppb b
Groundwater Conc., ppb c

Acute or Peak	279	12	0.152

Chronic (non-cancer)	21	0.13	0.152

a From the Tier 1 Rice Model with Aerobic Aquatic Degradation only
Considered

b From the Tier 1 Rice Model with Aquatic Dissipation Considered

c From the SCI-GROW model (Version 2.3) assuming a maximum seasonal use
rate of 0.23 lb ai/A.

Monitoring Data

Cyhalofop-butyl and its degradates were not detected in surface water
and drinking water monitoring studies conducted in California where rice
is grown.

Surface Water Monitoring Study

Dow AgroSciences submitted a study entitled, “Surface water monitoring
of cyhalofop-butyl in a California rice growing region in 2001,” MRID
45573201.  Surface water monitoring was conducted weekly on Thursdays
from May 24 to August 9, 2001.  Application began on May 4, about three
weeks before the monitoring began.  Samples were collected from the
Cross Canal where it enters the Feather River at State Highway 99.  Dow
states that this sampling site integrates drainage from the five-county
area where application of cyhalofop-butyl was allowed under the Section
18 registration (155,000 acres in Hydrologic Catalog Unit number
180201109).  According to California Pesticide Use Reports, 788 lbs of
cyhalofop-butyl was applied to 2,688 acres of rice in the monitored
watershed (Sacramento River) in 2001.

It is difficult to interpret the results of the study.  While it is
encouraging that no parent or metabolites were detected at 0.5 ppb, the
chronic drinking water level of comparison was lower, estimated to be
0.015 ppb in 2002 (HED Aggregate Assessment, 4/10/2002).  Additionally,
1) we do not know when paddy water was released in relation to when
surface water samples were collected, 2) the one week sampling interval
was a long period and could easily miss residues in water, and 3) the
environmental chemistry method did not have an independent laboratory
validation as required.  Control samples were collected from an area
where cyhalofop-butyl was not used and fortified with cyhalofop-butyl in
the lab.  The data tables in the study report are difficult to read but
recoveries appear to range from 8-96%, with stored samples yielding
lower recoveries.  This indicates that a large percentage of residues in
the water samples may have been lost due to the analytical method or
during storage.  The analytical method report indicates a much higher
recovery rate with average recoveries ranging from 88 – 107% for the
different compounds.  Finally, monitoring should begin closer in time to
the start of chemical application, rather than the 20-day lag in the
study.

Drinking Water Monitoring Study

A drinking water monitoring study was also submitted (MRID 47380601) and
is still being reviewed by the Agency.  According to the report,
approximately 4,250 kg of cyhalofop-butyl was applied in California
(Sutter, Yuba, Placer, Glenn, Colusa, Sacramento, and Butte counties)
between May 5, 2002 and July 21, 2002 under a Section 18 Specific
Exemption.  Water samples were collected on a semi-weekly basis from the
drinking water facility intakes of Sacramento and West Sacramento
facilities from April 30 to July 18, 2002.  Cyhalofop-butyl,
cyhalofop-acid, cyhalofop-amide, and cyhalofop-diacid residues were not
found at the limit of quantitation (0.1 µg/L) in any drinking water
samples.  Cyhalofop-butyl was detected in one sample near the limit of
detection of 0.04 µg/L at the West Sacramento facility.

While it is encouraging that no parent or metabolites were detected at
0.1 ppb, it is difficult to interpret the results of the study because
the environmental chemistry method did not have an independent
laboratory validation as required.  Control samples included matrix
spikes (deionized water spiked with cyhalofop-butyl) with recoveries of
cyhalofop-butyl ranging from 78-102%.  Assuming the method was a valid
method and significant loss did not occur with storage and transport,
this study indicates that when approximately 4,250 kg of cyhalofop-butyl
is applied in the Sacramento Valley area on rice, drinking water
exposure to Sacramento residents getting water from the two facilities
monitored will be less than 0.1 µg/L.  It does not provide any
information about drinking water intakes upstream of the Sacramento and
West Sacramento areas or for when applications exceed 4,250 kg in a
season.

OPP has no information on the effect of drinking water treatment on
cyhalofop-butyl and its degradates.  The softening of drinking water
will generally result in an increase in pH and could result in
hydrolysis of the butyl ester to the acid.

4.1.10		Food Residue Profile  TC \l3 "4.1.10	Food Residue Profile

<IP_ADDRESS>	Crop Field Trials

(M. Nelson, D267558, 11/13/2001)

Rice grain field trial residues ranged from below the combined LOQ of
0.01 ppm to a maximum of 0.0253 ppm.  Of the 42 field trial samples
analyzed, 35 of them had residue levels that were below the combined LOQ
(0.01 ppm).

The results of storage stability testing for cyhalofop-butyl,
cyhalofop-acid, and cyhalofop-diacid   SEQ CHAPTER \h \r 1  can be found
in the residue chemistry summary document prepared for rice.  The
storage stability data are adequate to support the submitted field trial
and metabolism studies for cyhalofop-butyl.

<IP_ADDRESS>	Confined and Field Accumulation in Rotational Crops

(M. Nelson, D267558, 11/13/2001)

The same cultural practices are followed for rice and wild rice.  For
this reason, the rotational crops would be the same for the two
commodities.  The confined rotational crop study using spring wheat,
leaf lettuce, and radishes was deemed adequate for the purposes of
characterizing the nature of the cyhalofop-butyl residues in rotational
crops.  HED concluded that the proposed 3-month plantback interval for
crops other than rice was adequate.  HED further concluded that field
rotational crop studies were not required.  The proposed label for wild
rice specifies a plantback interval of 3 months for crops other than
rice.  HED’s conclusions concerning the rotational crop studies and
the plantback interval apply to the current petition for wild rice.

<IP_ADDRESS> 	Meat, Milk, Poultry, and Eggs

For the purpose of this petition only, the data requirements for
magnitude of cyhalofop-butyl residues of concern in eggs, milk, and
edible tissues of animals are waived based on low levels of radioactive
residues observed from the animal metabolism studies.  In the event that
tolerances are proposed on additional livestock feed items in the
future, the Agency will recalculate the maximum dietary burdens and
reassess the need for animal feeding studies and tolerances.

<IP_ADDRESS>	Processed Food and Feed

Residues of cyhalofop (cyhalofop-butyl and cyhalofop-acid, determined as
the acid equivalent) and cyhalofop-diacid were each less than the method
LOQ (<0.010 ppm) in/on rice grain treated with Clincher( (2.38 lb/gal EC
formulation) at 1.40 lb ai/A (5x the maximum proposed single application
rate and 3x the maximum proposed seasonal rate).  Following processing
of treated rice grain according to simulated commercial practices,
residues did not concentrate in bran and polished rice; residues
concentrated marginally (1.1-1.2x) in hulls.  Based on the results of
the current processing study, tolerances for cyhalofop-butyl residues of
concern in the processed commodities of rice are not required.

4.1.11	International Residue Limits TC \l3 "4.1.11	International Residue
Limits

No international harmonization issues are associated with this petition,
as there are no established or proposed Canadian, Mexican or Codex MRLs
for residues of cyhalofop-butyl on the proposed crops rice and wild
rice.

4.2	Dietary Exposure/Risk Pathway  TC "4.2  Dietary Exposure/Risk
Pathway" \f C \l "2"

4.2.1	Acute Dietary Exposure/Risk  TC "4.2.1  Residue Profile" \f C \l
"3"

No toxicological endpoint attributable to a single dose of
cyhalofop-butyl was identified by the Cyhalofop-butyl Risk Assessment
Team; therefore, an acute dietary risk is not a concern.

4.2.2	Chronic Dietary Exposure/Risk  TC "4.2.2  Water Exposure/Risk
Pathway" \f C \l "3"

(Chronic Dietary (Food and Drinking Water) Exposure Analysis for the
Section 3 Registration Action, D. Dotson, D358391, 01/07/09)

A chronic dietary risk assessment was conducted using the Dietary
Exposure Evaluation Model (DEEM-FCID(, Version 2.03), which uses food
consumption data from the USDA’s Continuing Surveys of Food Intakes by
Individuals (CSFII) from 1994-1996 and 1998.  The analysis was performed
to support the Section 3 requests for existing use on rice and the
proposed use on wild rice.

A chronic dietary (food and drinking water) exposure and risk assessment
was conducted for cyhalofop-butyl using tolerance-level residues, a
conservative estimate of residues in drinking water, and 100% crop
treated assumptions.  Cyhalofop-butyl exposure from the existing use on
rice and the proposed use on wild rice results in an estimated risk
equivalent to 4.5% of the chronic population adjusted dose (cPAD) for
the U.S. population.  The most highly exposed population subgroup is all
infants (<1 year old), whose estimated risk is 15% of the cPAD.

            Table 4.2.2.  Summary of Dietary Exposure and Risk for
Cyhalofop-butyl

(Food and Drinking Water)

Population Subgroup	Acute Dietary	Chronic Dietary	Cancer

	Dietary Exposure (mg/kg/day)	% aPAD*	Dietary Exposure

(mg/kg/day)	% cPAD*	Dietary Exposure

(mg/kg/day)	Risk

General U.S. Population	N/A	0.000451	4.5	N/A

All Infants (< 1 year old)

0.001473	15

	Children 1-2 years old

0.000675	6.7

	Children 3-5 years old

0.000630	6.3

	Children 6-12 years old

0.000435	4.4

	Youth 13-19 years old

0.000328	3.3

	Adults 20-49 years old

0.000422	4.2

	Adults 50+ years old

0.000440	4.4

	Females 13-49 years old

0.000419	4.2

4.2.3  Cancer Dietary Exposure and Risk  TC "4.2.3  Acute and Chronic
Dietary Exposure and Risk" \f C \l "3"

Cyhalofop-butyl is classified as a “Not likely to be Carcinogenic to
Humans.”  Therefore there is no cancer concern for this compound.

5.0	Residential Exposure/Risk Pathway  TC "5.0  Residential
Exposure/Risk Pathway" \f C \l "1"

There are no cyhalofop-butyl containing products registered for use in
residential areas and no new use is being proposed at this time.
Therefore, a residential exposure assessment is not applicable.

5.1	Other (Spray Drift, etc.)  TC "5.1  Other (Spray Drift, etc.)" \f C
\l "2"

Spray drift is always a potential source of exposure to residents living
in close proximity to spraying operations.  This situation is
particularly the case with aerial application.  However, to a lesser
extent, spray drift resulting from the ground application of
cyhalofop-butyl could also be a potential source of exposure.  The
Agency has been working with the Spray Drift Task Force (a membership of
U.S. pesticide registrants), EPA Regional Offices, State Lead Agencies
for pesticide regulation, and other parties to develop the best spray
drift management practices.  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, and is developing
a policy on how to apply appropriately 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 risks associated with pesticide
application.

6.0	Aggregate Risk Assessments  TC "6.0  Aggregate Risk Assessments" \f
C \l "1"

In accordance with the FQPA, when there are potential residential
exposures to a pesticide, aggregate risk assessment must consider
exposures from three major routes: oral, dermal, and inhalation.  There
are three sources for these types of exposures:  food, drinking water,
and residential uses.  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.

As noted previously, acute risk is not a concern for cyhalofop-butyl.
There are also no residential uses; therefore, the chronic aggregate
exposure and risk are equivalent to dietary (food and water) exposure
and risk, and these are below HED’s level of concern.  Since there are
no residential uses, short- and intermediate-term aggregate risks do not
exist.  In addition, cancer risks are not a concern due to
cyhalofop-buyl being classified as not likely to be carcinogenic to
humans.

7.0	Cumulative Risk  TC "7.0  Cumulative Risk" \f C \l "1"

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 for cyhalofop-butyl and any other
substances, and cyhalofop-butyl does not appear to produce a toxic
metabolite produced by other substances.  For the purposes of this
tolerance action, therefore, EPA assumed that cyhalofop-butyl does not
have 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 OPP
concerning common mechanism determinations and procedures for cumulating
effects from substances found to have a common mechanism on EPA’s
website at http://www.epa.gov/pesticides/cumulative/.

8.0	 Occupational Exposure  TC "8.0  Occupational Exposure" \f C \l "1"

(Cyhalofop-Butyl: Occupational Exposure and Risk Assessment for Proposed
Use on Wild Rice and Proposed Amended Labeling for Clincher ® SF
Herbicide; M. Collantes; D354880; December 2008)

The herbicide, cyhalofop-butyl is a diphenyl ether (aka oxyphenoxy acid
esters) herbicide for which a food use on rice has been proposed.
Clincher® EC is a postemergence herbicide for the selective control of
emerged grass weeds in drill-seeded and water-seeded rice.
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).

The proposed use pattern calls for 1-2 postemergence foliar applications
of Clincher® EC at 0.24-0.28 lb ai/A per application with a minimum
10-day retreatment interval, and a maximum seasonal rate of 0.46 lb
ai/A.   Application can be made when rice plants are at the 1-2 leaf
growth stage and up to 60 days prior to harvest.  This product is
applied aerially, and by groundboom equipment.  Based on the number of
seasonal applications indicated on these product labels, exposures are
expected to be short- and intermediate-term in duration.

8.1	Handler Exposure  TC "8.1 Handler Exposure" \f C \l "2"

Occupational exposure and risk resulting in MOEs greater than or equal
to 100 are not of concern to HED.  All handler scenarios resulted in
MOEs greater than the level of concern (MOEs ≥ 100) at baseline attire
(i.e., long-sleeve shirt, long pants, shoes, and socks, no respirator),
while aerial applicator risks were assessed for enclosed cockpits
(engineering controls).  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.  Summaries of the short- and
intermediate-term inhalation MOEs are provided in Table 8.1.

Table 8.1: Short- and Intermediate-term Handler Exposure and Risk for
Cyhalofop-butyl

Exposure Scenario (Scenario #)

Mitigation Level

Inhalation Unit Exposure

 (mg/lb ai)

Crop

Application Rate

(lb ai/acre)

Amount Treated

(acres/day)

Inhalation Dose a (mg/kg/day)

Total MOEb

Mixer/loader

Clincher® EC Groundboom	Baseline 	0.0012

	Wild rice

0.28	80	0.00038	11,000

	Rice

200	0.00096	4,500

Clincher® EC

Aerial

	Wild Rice

350 	0.0017	2,600

	Rice

1200	0.0058	750

Applicator

Clincher® EC Groundboom	Baseline	0.00074	Wild Rice

0.28

80	0.00024	18,000

	Rice

200	0.00059	7,300

Clincher® EC Aerial	Engineer Controls	0.000068	Wild Rice

350 	0.000095	45,000

	Rice

1200	0.00033	13,000

Flagger

Clincher® EC	Baseline	0.00035	Rice	0.28	350	0.00049	8,800

a. Short- and Intermediate-term Inhalation Dose (mg/kg/day) = [ Rate (lb
ai/A) x IAF (100%) x  UE (mg /lb ai ) x  Acres Treated

A/day)] / BW (70 kg)

b. Inhalation MOE = NOAEL (4.3 mg/kg/day)/ Total Dose (mg/kg/day)

8.2	Postapplication  TC "8.2 Postapplication" \f C \l "2"

Postapplication inhalation exposure potential is anticipated to be
negligible as all agricultural activities are conducted outdoors and the
vapor pressure for cyhalofop-butyl is 4.0 x 10-7 mmHg.

No major postapplication activities that result in significant exposure
to cyhalofop-butyl are expected prior to harvesting.  Harvesting will
likely be done with mechanized equipment.  In addition, as no short- or
intermediate-term dermal endpoints of concern were selected for
cyhalofop-butyl, a quantitative risk assessment for postapplication
activities was not required.

8.3	Label Amendment  TC "8.3 Label Amendment" \f C \l "2"

Based on 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.

8.4	Restricted Reentry Interval  TC "8.4 Restricted Reentry Interval" \f
C \l "2"

The Toxicity Category for the technical is IV for oral, dermal, and
inhalation toxicity, as well as for eye and skin irritation.
Cyhalofop-butyl is not a dermal sensitizer. Under the Worker Protection
Standard for Agricultural Pesticides, active ingredients classified as
acute toxicity categories IV are assigned a 12-hour REI.  Based on the
acute toxicity of cyhalofop-butyl, the 12 hour restricted-entry interval
appearing on the proposed label is in compliance with the Worker
Protection Standard (WPS).

9.0	Data Needs and Label Requirements  TC "9.0 Data Needs and Label
Requirements" \f C \l "1"

9.1	Toxicology  TC "9.1 Toxicology" \f C \l "2"

As part of the revised 40 CFR Part 158, an immunotoxicity study (OPPTS
870.7800) is required for registration of a pesticide.

9.2	Residue Chemistry    None  TC "9.2 Residue Chemistry" \f C \l "2"

9.3	Occupational and Residential Exposure      TC "9.3 Occupational and
Residential Exposure" \f C \l "2"  None.

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

The requirements (40 CFR 158.340) for food uses for cyhalofop-butyl are
in the table below. Use of the new guideline numbers does not imply that
the new 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	Yes

Yes

Yes

Yes

Yes

870.5100    Mutagenicity—Gene Mutation - bacterial

870.5300    Mutagenicity—Gene Mutation - mammalian

870.5385    Mutagenicity—Mammalian Bone Marrow

                                          Chromosome Aberration
Aberrations

870.5550    Mutagenicity—Unscheduled DNA Synthesis		Yes

Yes

Yes

No	Yes

Yes

Yes

No

870.6200a  Acute Neurotoxicity Screening Battery (rat)

870.6200b  90-Day Neurotoxicity Screening Battery (rat)

870.6300    Developmental Neurotoxicity		Yes

Yes

No	Yes

Yes

No

870.7485    General Metabolism

870.7600    Dermal Penetration

870.7800    Immunotoxicity		Yes

No

Yes	Yes

No

No

Special Studies for Ocular Effects

Acute Oral (rat)

Subchronic Oral (rat)

Six-month Oral (dog)

No

No

No

No

No

No

A.2	Toxicity Profile Tables for Cyhalofop-butyl.  TC "A.2	Toxicity
Profile Tables for Cyhalofop-butyl." \f C \l "1"

Table A.2.1	Acute Toxicity Profile - Test Substance

Guideline

No.	Study Type	MRID(s)	Results	Toxicity Category

870.1100

	Acute Oral - Rat

	45000237	LD50 >5000 mg/kg (limit test)

	Toxicity Category IV

870.1100

	Acute Oral - Mice

	45000238	LD50 >5000 mg/kg (limit test)

	Toxicity Category IV

870.1200

	Acute Dermal - Rat

	45000240	LD50 >2000 mg/kg (limit test)

	Toxicity Category III

870.1200

	Acute Dermal - Rat	45381901

45000241	LD50 >5000 mg/kg (2.5 x the limit dose)	Toxicity Category IV

870.1300

	Acute Inhalation - Rat	45000401	LC50 >5.63 mg/L (2.8 x the limit
concentration)	Toxicity Category IV

870.2400

	Primary Eye Irritation - Rabbit

	45000403	Minimally irritating	Toxicity Category IV

870.2500

	Primary Skin Irritation - Rabbit

	45000405	Essentially nonirritating

	Toxicity Category IV

870.2600

	Dermal Sensitization - Guinea Pig	45000407	Not a dermal 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

 	Subchronic (4 and 13 Week) Feeding - Rat

	45000413

(1991)

Acceptable/Guideline

Main - 0, 3 (males), 10 (females), 25 (males), Satellite - 0, 25, 400
(males), 800 (females), or 1600 mg/kg/day in the feed for 4 weeks.

	NOAEL (male) (400 mg/kg/day (HDT)

NOAEL (female) 400 mg/kg/day

LOAEL (female) = 800 mg/kg/day (HDT) based on perineal soiling and
reduced body weights and body weight gain.

The only short-term effect was perineal staining. Onset was late except
in 60% of the 800 mg/kg/day females which had involvement as early as
day 16.

The only functional observation battery (FOB) finding was perineal
soiling at the high-dose in 1/10 males and 6/10 females.

In addition to the 13 week study, which included a FOB, a 4 week
satellite was used to determine organ weight and microscopic changes in
potential target tissues.

870.3100

	Subchronic Feeding - Rat

	45014705

(1993)

Acceptable/Guideline Levels tested:  0, 30, 300, 1000, or 3000 ppm in
the feed (0, 1.719, 17.43, 60.5, or 189.5 mg/ kg/day in males; 0,
1.958, 19.64, 65.3, or 199.6 mg/kg/day in females) in Fischer strain.

	NOAEL = 60.5 / 65.3 mg/kg/day, M/F

LOAEL = 189.5 / 199.6 mg/kg/day, M/F (HDT) based on kidney toxicity
(lipofuscin pigment deposition in proximal tubule cells) in both sexes,
and possible liver toxicity (hepatocyte eosinophilic granules) in males.

No short-term effects were observed which could be used for a short-term
endpoint.

870.3100

 	Subchronic Feeding - Mice

	45000412

(1991)

Acceptable/Guideline Levels tested (main):  0, 1 (males), 3, 10, 30, or
100 (females) mg/kg/day in the feed.

Levels tested (pilot):  0, 10 (males), 30, 100, or 350 (females)
mg/kg/day in the feed.

	NOAEL (male) (30 mg/kg/day (HDT)

NOAEL (female) (100 mg/kg/day (HDT)

870.3100

	Subchronic Feeding - Mice

	45014706

(1993)

Acceptable/Guideline Levels tested:  0, 3, 30, 100, or 300 ppm in the
diet (0, 0.4, 3.6, 12.4, or 37.5 mg/kg/day in males; 0, 0.4, 4.3, 14.1,
or 41.4 mg/kg/day in females)

	NOAEL (male) (37.5 mg/kg/day (HDT)

NOAEL (female) = 4.3 mg/kg/day

LOAEL (female) = 14.1 mg/kg/day based on enlarged kidneys (20% absolute
and relative) accompanied by swelling of the proximal tubule cells (4/12
mice).

Kidney weights and pathology were normal in males.

Compared to controls, absolute and (relative) kidney weight increases in
females were 1, 14, 20, and 23% (-1, 12, 20, and 18%); and proximal
tubular cell swelling incidences were 0/12, 0/12, 0/12, 4/12, and 6/12
at doses of 0, 3, 30, 100, and 300 ppm, respectively.

870.3150

	Subchronic Feeding - Dog

	45014707

(main)

45000410

(pilot, palatab.)

(1994 Acceptable/Guideline

Levels tested: 0, 100, 500, or 2500 ppm (0, 2.91, 14.7, or 75.2
mg/kg/day in males; 0, 3.17, 15.6, or 79.4 mg/kg/day in females)	NOAEL =
14.7 / 15.6 mg/kg/day, M/F

LOAEL = 75.2 / 79.4 mg/kg/day, M/F (HDT) based on brown and/or atrophied
thymuses, and decreased thymus weight.

MRID 45000410 was a combination 4-week pilot toxicity and a 2 week
palatability study.  Doses in the palatability study were 250, 500, or
1000 mg/kg/day.  At 1000 mg/kg/day, food consumption was dramatically
reduced, suggesting decreased palatability of the treated diet.

870.3200

	21-Day Dermal - Rat

	45000415

(1999)

Acceptable/Guideline Levels tested:  0, 10, 100, 1000 mg/kg/day in
aqueous 0.5% methylcellulose, 6 hours/day, 5 days/week for 4 weeks.  A
recovery group was held for a 2 week period.	Systemic NOAEL  (1000
mg/kg/day (limit dose)

Dermal NOAEL (1000 mg/kg/day (limit dose)

Increased liver weights and clinical chemistry changes suggestive of
liver adaptation were observed during the dosing interval.  The
reversibility of the clinical chemistry and liver weight effects in the
recovery group demonstrates these changes are biological markers of
exposure, not toxicity.

870.3700

	Gavage Developmental Toxicity - Rat

	45014709

(1992)

Acceptable/Guideline Levels tested: 0, 25, 250, or 1000 mg/kg/day by
gavage on gestation days 6-15.

	Maternal NOAEL =1000 mg/kg/day (limit dose)

Developmental NOAEL (1000 mg/kg/day (limit dose)

870.3700

	Gavage Developmental Toxicity - Rabbit

	45014710

(1994)

Acceptable/Guideline Levels tested: 0, 40, 200, or 1000 mg/kg/day by
gavage on gestation days 6-18	Maternal NOAEL = 40 mg/kg/day

Maternal LOAEL = 200 mg/kg/day based on maternal death (1/18 dams at 200
and 9/18 at 1000 mg/kg/day exhibited hematuria and died or were
sacrificed in extremis with gross pathology showing cloudy or dark
colored kidneys)

Developmental NOAEL (1000 mg/kg/day (limit dose)

.

870.3800

	Feeding Reproductive Toxicity - Rat	45000419

(1994)

Acceptable/Guideline Levels tested:  Dietary levels of 0, 10, 100, or
1000 ppm (F0 males - 0, 0.495-1.049, 4.88-10.68, or 50.0-102.9
mg/kg/day; F1 males - 0, 0.499-1.361, 4.85-13.75, or 51.1-138.7
mg/kg/day; F0 females - 0, 0.695-1.113, 6.75-11.13, or 69.2-113.1
mg/kg/day; F1 females -  0, 0.750-1.430, 7.42-13.96, or 74.8-147.7
mg/kg/day) in Crj:CD (SD) strain.

	Systemic NOAEL (males) = 100 ppm (4.85-13.75 mg/kg/day)

Systemic LOAEL (males) = 1000 ppm (50.0-138.7 mg/kg/day) based on kidney
lesions (slight tubular cell swelling) in F0 and F1 male rats.

Systemic NOAEL (females) (1000 ppm (69.2-147.7 mg/kg/day, HDT)

Reproductive NOAEL (1000 ppm (50.1-138.7 mg/kg/day for males; 69.2-147.7
mg/kg/day for females)

Offspring NOAEL (1000 ppm (50-147.7 mg/kg/day)

No short-term effects were observed which could be used for a short-term
endpoint.

Acceptable/Guideline

870.4100

	Chronic Feeding Toxicity - Dog

	45014708

(1994)

Acceptable/Guideline

Levels tested:  0, 50, 300, or 1800 ppm in the feed (males- 0, 1.22,
7.59, and 46.7 mg/kg/day; females - 0, 1.29, 7.63, and 45.9 mg/kg/day.
NOAEL (46.7 / 45.9 mg/kg/day; M/F (HDT)

No short-term effects were observed which could be used for a short-term
endpoint.

870.4200

	Carcinogenicity Feeding - Mouse (18 months)

	45000418

(1994)

Unacceptable/Guideline

Levels tested:  0, 3, 10, or 100 ppm (0, 0.31, 1.0, and 10.06 mg/kg/day
in males; 0, 0.29, 1.0, or 10.28 mg/kg/day in females) in CD-1 strain.
Satellite groups were sacrificed at 26 and 52 weeks

	NOAEL = 1.0 mg/kg/day

LOAEL = 10.06 / 10.28 mg/kg/day, M/F (HDT) based on effects on the
kidney including tubular dilatation, chronic glomerulonephritis, and
hyaline casts in females, and hyperplasia of the stomach mucosal
epithelium in males.

There was no evidence of carcinogenic potential under the conditions of
this study.

Dosing was too low to elicit frank toxicity and inadequate to assess
carcinogenic potential.

The high dose of approximately 10 mg/kg/day was based on the endpoint of
liver hypertrophy which is an adaptive response.

No short-term effects were observed which could be used for a short-term
endpoint.

.

870.4300

	Chronic Feeding Toxicity/Carcinogenicity-Rat

	45000417

(1994)

Acceptable/Guideline (chronic toxicity)

Unacceptable/Guideline (carcinogenicity Levels tested:  0, 3, 6, 24, or
100 ppm (0, 0.1020, 0.2047, 0.823, or 3.44 mg/kg/day) in males; 0, 6,
60, or 600 ppm (0, 0.2451, 2.475, or 24.97 mg/kg/day) in females for 104
weeks in Fischer strain.  Satellite groups were sacrificed at 13, 26,
52, and 78 weeks.

	NOAEL = 0.823 mg/kg/day in males and 2.475 mg/kg/day in females

LOAEL = 3.44 mg/kg/day (HDT in males), 24.97 mg/kg/day (HDT in females)
based on the early and increased deposition of the pigments lipofuscin
and hemosiderin in the renal proximal tubular cells of both sexes, and
renal mineralization in female rats.

There were no treatment-related increases in tumor incidence, compared
to controls.

Dosing was too low to elicit frank toxicity and inadequate to assess
carcinogenic potential.

No short-term effects were observed which could be used for a short-term
endpoint.

870.5100

	Bacterial Reverse Gene Mutation Test (Ames Assay)	45000421

(1991)

Acceptable/Guideline	Negative in Salmonella TA strains and E. coli WP2
uvrA.

870.5300

	Gene Mutation in Mouse Lymphoma L5178Y TK Cells	45014711

(1996)

Acceptable/Guideline	Negative

870.5375

	In Vitro Chromosomal Aberration in Chinese Hamster Lung	45000423

(1991)

Acceptable/Guideline	Polyploidy was induced when CHL (V79) cells were
treated for 48 hours in the absence of S9, but there was no clastogenic
effect on DNA.

870.5395

	In Vivo Mammalian Cytogenetics - Micronucleus Assay in Mouse Bone
Marrow Cells	45000422

(1991)

Acceptable/Guideline	Negative

870.5550

	Unscheduled DNA Synthesis in Rat Hepatocytes	45000420

(1991)

Acceptable/Guideline	Negative

870.6200

	Gavage Acute  Neurotoxicity - Rats

	45000409

(1998)

Acceptable/Guideline

Doses: 0, 200, 600 or 2000 by gavage	NOAEL (2000 mg/kg (limit dose)
based on the absence of clinical signs, a lack of effects on FOB
parameters and motor activity, and the absence of neuropathologic
lesions.

870.6200

	Feeding Subchronic  Neurotoxicity - Rats

	45000509

(1999)

Acceptable/Guideline

Levels tested:  0, 2, 20, or 75 (males) / 250 (females) mg/kg/day for 13
weeks.

	NOAEL (75/ (250 mg/kg/day M/F (HDT) based on the absence of clinical
signs, lack of effects on FOB parameters and motor activity, and absence
of neuropathologic lesions.

NOTE:  The doses tested were based on mild systemic effects (perineal
soiling, reduced body weights, and lipofuscin pigment deposition in
proximal tubule cells) at similar doses in two subchronic feeding
studies in rats, and were too low to elicit toxicity in this study.

870.xxxx

[special study]

	Pharmacology - Mice and Rabbits - Special Study

	45000424

(1992)

Acceptable/Non-Guideline

Levels tested in mice: 0, 4.88, 19.5, 78.1, 313, 1250, or 5000 mg/kg as
a single I.P. dose.

Levels tested in rabbits: 0, 313, 1250, 2500 or 5000 mg/kg as single
gavage dose

	Mice:  A single I.P. dose of 1250 or 5000 mg/kg was lethal to all male
and female mice within 24 hours.  Death occurred as early as three hours
at 5000 mg/kg and was preceded by behavioral and motor function
abnormalities (e.g., alterations in alertness, visual placing,
spontaneous activity, motor incoordination, decreased muscle tone, and
compromised autonomic reflexes), some of which appeared as early as 30
minutes postdosing.  Male and female mice responded similarly.

NOAEL = 78.1 mg/kg

LOAEL = 313 mg/kg (based on minimal effects including decreased
spontaneous activity, minor alterations in muscle tone, and minor
changes in autonomic functions such as slight hyperthermia, and slightly
decreased respiratory rate).

LD (1250 mg/kg

Rabbits: One of three rabbits gavaged at 5000 mg/kg showed decreased
spontaneous activity, prostration, decreased muscle tone, compromised
autonomic reflexes, and decreased respiratory and heart rate at one day
after dosing, and died on Day 4.  There were no clinically significant
findings in the remaining rabbits of the 5000 mg/kg dose group or any
lower dose groups, and no significant effects on EKGs or blood pressure
in any dosed rabbits.

NOAEL = 2500 mg/kg

LOAEL = 5000 mg/kg (based on the response of one of three test subjects
including decreased spontaneous activity, prostration, decreased muscle
tone, compromised autonomic reflexes, decreased respiratory and heart
rate at one day after dosing, and death on day 4).

870.7485

	Absorption, Metabolism, and Excretion - Dog

	45000425

(1995 Acceptable/Non-Guideline (Two dogs were used instead of four; and
tissue distribution was not measured.) Level tested:  Two male beagles
were gavaged with [(-14C]XRD-537 BE and nonlabeled XRD-537 at a dose of
1 mg/kg.

	No treatment-related adverse effects were reported.  Approximately 50%
of a single gavage dose was absorbed over several hours.  Blood and
plasma radioactivity peaked after 1-2 hours.  Clearance from plasma and
blood was not especially rapid but nearly complete at 48 hours.  Over
168 hours, excretion was 42.5-43.9% in the urine, and 48.6-50.6% in the
feces.  Tissue distribution was not measured.  The test article appears
to be metabolized primarily by hydrolysis to
R-(+)-2-[4-cyano-2-fluorophenoxy)phenoxy]propanoic acid which was found
in both the urine and feces.  Several other metabolites were also
formed, each representing <5% of the administered dose.  No parent
compound was found in the urine, and only minimal amounts were detected
in the feces.

870.7485

	Metabolism and Pharmacokinetics - Rat

	45000427

(main)

45000426 (prelim.)

45000528

(stability, homog.)

(1995)

Acceptable/Guideline	Absorption of gavaged test article was 93-100%, and
urinary excretion was the major route of elimination regardless of dose,
label position, or gender.  Over 168-hours, 84-100% of the radioactivity
was eliminated in urine, with 86-90% eliminated within 24 hours.  Fecal
excretion was <5%.  There was no elimination via expired air.

 and 20.1% of the administered dose in males and females, respectively,
in the low-dose [α-14C]XRD-537 BE group, and 17.0% (males) and 11.6%
(females) of the administered dose in the [β-14C]XRD-537 BE low-dose
group.

The greatest radioactivity levels were found in liver, kidneys, plasma,
whole blood, heart, lung, and stomach, with the highest tissue levels
being found in the liver and kidney at 2 hours.  Most tissue levels
accounted for <1% of the administered dose.   Due to rapid excretion,
tissue/organ levels declined to near detection limits by 24 hours in all
dose groups.

There was a biphasic pattern for both labels with no substantial
differences in pharmacokinetic indices (Cmax, tcmax, t1/2, AUC).
Time-to-maximum plasma concentration (tcmax of 0.5 to 4 hrs) and
elimination half-times (t1/2 of 1.4 to 7.9 hrs) reflected the relatively
rapid absorption.  Females had somewhat shorter tcmax and lower Cmax
values suggestive of saturated absorption processes.  The acid
metabolite (R-(+)-2-[4-(4-cyano-2-fluorophenoxy)phenoxy]propanoic acid)
was the most prominent plasma fraction (~90-94% of the plasma activity
for males and ~75-81% for females regardless of dose).   No parent
compound or other metabolites were detected.  The acid metabolite was
the most common product in urine and feces–71-87% (urine) and 46-75%
(feces) of the activity in those matrices.

E, and [α-14C] XRD-537 BE or [β-14C]

XRD-537 BE by gavage.

870.7600

	Dermal Penetration - Rat

	45000505

(1998)

Acceptable/Non-Guideline (Only one exposure duration (24 hours) was used
instead of six.

Levels tested:  Four Fischer 344 rats were dermally dosed for 24 hours
with 14C-labeled DE-537 n-butyl ester and nonlabeled DE-537 n-butyl
ester in two formulations–200 mg/mL test article in EF1218 (Clincher
EDC with which DE-537 n-butyl ester is normally formulated) and a spray
solution–at 0.005, 1.0, or 1.8 mg/cm2.	Dermal absorption was ~25-34%
for the spray formulation and ~11-16% for the EF-1218 formulation
following a 24 hour dermal dosing.  Within 48 hours, excretion was >85%
in the urine and <1% in the feces, which is consistent with metabolism
to water soluble metabolites and subsequent urinary excretion.

870.xxxx [special study]

	Hepatocellular Proliferation in Rats

	45000414

(1991)

Acceptable/Non-Guideline

	In a subchronic oral toxicity study in rats (MRID 45000413), satellite
rats dosed for 4 weeks had hepatocellular hypertrophy and focal necrosis
at all dose levels.  Although multiple necrotic foci accompanied by
inflammatory cells were graded very slight, and were not considered
dose-related, this study was performed to explore these findings.

  An initial dramatic increase in DNA synthesis during the first week of
treatment was followed by hepatocellular hypertrophy at subsequent
observations.  This was the reason for enlarged livers observed in
XRD-537nBu-treated rats.

h sacrifices at 1, 2, 4, and 13 weeks.  One week prior to sacrifice, 10
μL BrdU/hour was administered via an ALZET osmotic pump implanted
subcutaneously.  BrdU is a DNA stain used to quantify hepatocellular
proliferation.

870.xxxx

[special study]	28-Day Mechanistic Study for Evaluation of Peroxisome
Proliferation

(Mouse)	46471101

(2004)

Acceptable/Non-Guideline

Doses: 0, 0.5, 5, 50 &150 mg/kg/day	Increased liver weight and
hepatocellular hypertrophy at ≥5 mg/kg/day (M&F); ecrosis at ≥50 (M)
& 150 (F) mg/kg/day.

Increased peroxisomal acyl-CoA oxidase activity ≥5 mg/kg/day (M) and
≥50 mg/kg/day (F).  Increases are reversible.

Peroxisome volume density in hepatocytes increased ≥0.5 mg/kg/day (M)
and ≥5 mg/kg/day (F).  Increases are reversible.

870.xxxx

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pecial study]	Evaluation of Activity in a Peroxisome Proliferator
Receptor-Alpha Reporter Assay (Mouse)	46471102

(2004)

Acceptable/Non-Guideline

PPAR-γ specific activator (Ciglitazone); non-activator (TPA)
Cyhalofop-butyl binds to the PPAR-ά receptor and activates a downstream
reporter gene.  Considered a weak PPAR-ά agonist.

870.xxxx

[special study]	Discussion of Mechanistic data in the mouse.	46471103

(2005)

Acceptable/Non-Guideline	Discussion of mechanistic data in the mouse in
support of a waiver for repeating chronic studies.

A.3 – Rationale for Toxicology Data Requirements.  TC "A.3	Rationale
for Toxicology Data Requirements" \f C \l "1"

Guideline Number:  870.7800

Study Title:  Immunotoxicity

Rationale for Requiring the Data

The immunotoxicity study 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 not specifically conducted to assess immunotoxic
endpoints are inadequate to characterize a pesticide’s potential
immunotoxicity.  While data from hematology, lymphoid organ weights, and
histopathology in routine chronic or subchronic toxicity studies may
offer useful information on potential immunotoxic effects, these
endpoints alone are insufficient to predict immunotoxicity.

Practical Utility of the Data

How will the data be used?

Immunotoxicity studies provide critical scientific information needed to
characterize potential hazard to the human population on the immune
system from pesticide exposure. Since epidemiologic data on the effects
of chemical exposures on immune parameters are limited and are
inadequate to characterize a pesticide’s potential immunotoxicity in
humans, animal studies are used as the most sensitive endpoint for risk
assessment.  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 these data, a 10X database uncertainty
factor may be applied for conducting a risk assessment from the
available studies.

>

Tolerance Summary for Cyhalofop-butyl." \f C \l "1"

Appendix IV. 	Recommended Tolerance Summary for Cyhalofop-Butyl.

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

Rice, grain	0.03	0.03	Adequate data are available on the representative
crop of rice and wild rice.

Rice, wild, grain	0.03

Page   PAGE  42  of   NUMPAGES  42