  SEQ CHAPTER \h \r 1

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

	OFFICE OF PREVENTION, PESTICIDE

	AND TOXIC SUBSTANCES

MEMORANDUM

Date:		01/22/10

Subject:	Flutolanil.  Human Health Risk Assessment. Requests for
Tolerances for Seed Treatment Use on Soybean, Cotton, and Sugar Beet

PC Code:	128975	DP Barcode:	363376

Decision No.:	407126	Registration No.:	71711-28

Petition No.:	9F7542	Regulatory Action:	Section 3 Registration

Risk Assessment Type:	Single Chemical /Aggregate	Case No.:	NA

TXR No.:	NA	CAS No.:	66332-96-5

MRID No.:	NA	40 CFR:	§180.484

From:	Stephen Funk, Risk Assessor

	Nancy Tsaur, Risk Assessor

	Risk Assessment Branch 3 (RAB3)

	Health Effects Division (HED) (7509P)

Through:	Paula Deschamp, Branch Chief

		Risk Assessment Branch 3 (RAB3)

		Health Effects Division (HED) (7509P)

To:		Lisa Jones/Mary Waller, PM Team 21

		Fungicides Branch

		Registration Division (7505P)

The Health Effects Division (HED) has conducted a human health risk
assessment for the fungicide flutolanil to estimate the risk to human
health that will result from proposed and registered uses of flutolanil.
 Nichino America, Inc. (formerly Nihon Nohyaku) has submitted a petition
 proposing the establishment of permanent tolerances for residues in/on
cotton and soybean commodities and an exemption from tolerance for sugar
beet commodities from the use of flutolanil (40 SC formulation) as a
seed treatment.

 HED has conducted a human health risk assessment for these proposed
uses.  This HED document provides a summary of the findings from the
data evaluation and subsequent assessment of human health risk resulting
from this submission.  The occupational and residential exposure data
review and assessment were conducted by Nancy Tsaur (D364463. The
residue chemistry data were reviewed and analyzed by Stephen Funk, who
also conducted the dietary exposure assessments and the human health
risk assessment (RAB3).  Additionally, the drinking water assessment was
conducted by Larry Liu of OPP’s Environmental Fate and Effects
Division (EFED).

Table of Contents

  TOC \f  1.0	Executive Summary	4

2.0	Ingredient Profile	8

2.1	Summary of Registered/Proposed Uses	8

2.2	Structure and Nomenclature	10

2.3	Physical and Chemical Properties	11

3.0	Hazard Characterization/Assessment	11

3.1	Hazard and Dose-Response Characterization	11

3.1.1     	Database Summary	11

3.1.2	Toxicological Effects	12

        3.1.3
Metabolism……………………………………………………
………………...12

        3.1.4
Dose-Response…………………………………………………
……………….12

    3.2                    FQPA Safety Factor
Considerations…………………………………………………
…   13

        3.2.1             Evidence of Neurotoxicity	13

        3.2.2             Evidence of Immunotoxicity	14

        3.2.3              Pre- and/or Postnatal Toxicology:
Deternmination of Susceptibility	14

3.3	Safety Factors for Infants and Children	14

3.4	Hazard Identification and Toxicity Endpoint Selection	15

    3.5		Endocrine
Disruption……………………………………………………
………………..15

4.0	Dietary Exposure/Risk Characterization	16

4.1                    Pesticide Metabolism and Environmental
Degradation	16

4.1.1	Metabolism in Primary Crops and Livestock	16

4.1.2	Metabolism in Rotational Crops	16

4.1.3	Analytical Methodology	17

4.1.4	Drinking Water Residue Profile	17

4.1.5	Food Residue Profile	19

4.1.6	Proposed Tolerances and Recommended Tolerances	20

4.1.7	International Residue Limits	22

4.2                    Dietary Exposure and Risk	22

5.0	Residential (Non-Occupational) Exposure/Risk Characterization	23

6.0	Aggregate Risk Assessments and Risk Characterization	23

7.0	Cumulative Risk Characterization/Assessment	24

8.0	Occupational Exposure/Risk Pathway	24

9.0	Data Needs and Label Recommendations	24

9.1	Toxicology	24

9.2	Residue Chemistry	24

         9.2.1	                Label	25

         9.2.2		Residue Enforcement Analytical
Method…………………………………….25

         9.2.3		  Proposed
Tolerances……………………………………………………
…….25

10.0	References									          27

Appendix A:  Chemical Structures	29

Appendix B: Toxicology	31

Appendix C:  Toxicology Study Requirements
Rationale……………………………………………...  35

  SEQ CHAPTER \h \r 1 1.0	EXECUTIVE SUMMARY

Flutolanil [N-[3-(1-methylethoxy)-phenyl]-2-(trifluoromethyl)-benzamide]
is a mildly systemic benzanilide fungicide.  Flutolanil has both
preventative and curative actions against economic pests such as
Rhizoctonia solani, which is the causal agent of limb/pod rot in
peanuts, sheath blight in rice, and black scurf in potatoes.  Flutolanil
is also effective in controlling white mold in peanuts and rust diseases
of several crops.

Flutolanil is currently registered for application to peanuts, potatoes,
and rice.   Tolerances have been established for these commodities as
well as tolerances for inadvertent residues for soybean and wheat
commodities as rotational crops and tolerances for ruminant commodities.
  Non-food uses of flutolanil include turf, and greenhouse, nursery, and
potted ornamentals.

Use Profile

The proposed uses on cotton seed, soybean seed, and sugar beet seed are
summarized in Table 2.1.2.  These proposed uses/tolerances result in new
dietary exposures and the proposed uses result in new occupational
exposures.

The flutolanil end-use product relevant to this registration action is
Convoy® Fungicide (Flutolanil 40SC), registration number 71711-28.
This aqueous suspension concentrate (SC)formulation  contains 3.8 pounds
of active ingredient (ai); per gallon. The petitioner wishes to amend
the product label for  Convoy® Fungicide to incorporate new uses on
sugar beet, cotton seed, and soybean.   Seeds may be treated with 0.06
– 0.12 lb ai per 100 lb of seed using a spray system, spray table, or
seed treatment equipment.

Proposed Tolerances

The proposed tolerances for soybean and cotton commodities are for
residues of the fungicide flutolanil and the metabolite desisopropyl
flutolanil a.k.a. M-4 in/on the following raw agricultural commodities
(RACs):

Cotton, undelinted seed	0.05 ppm

Soybean, seed	0.05 ppm

A tolerance is not proposed for sugar beets, as a radiolabeled
metabolism study clearly shows

that no residues are expected on sugar beet roots from the proposed seed
treatment use.

Hazard Profile

The toxicology data base is considered complete with the exception of
newly required studies for acute neurotoxicity (OPPTS Guideline
870.6200a), subchronic neurotoxicity (OPPTS Guideline 870.6200b), and
immunotoxicity (OPPTS Guideline 870.7800).  The toxicological  database
has been reviewed, considered for the overall hazard profile, endpoint
selection, and the susceptibility of infants and children as required by
FQPA.

In general, the toxicology studies conducted on flutolanil demonstrate
few or no biologically significant toxic effects at relatively low-dose
levels in animal studies and only mild or no toxic effects at high
doses.   The subchronic and chronic toxicity studies showed that the
primary effects of flutolanil are increases in liver weight combined
with decreases in body weight.   The toxicological database indicates
that technical grade flutolanil has relatively low acute toxicity
(Category III and IV).  Flutolanil is not a dermal sensitizer, primary
eye irritant, or primary skin irritant.  Flutolanil is also not
neurotoxic, carcinogenic, nor mutagenic.  Flutolanil is not a
developmental or reproductive toxicant.  There is no evidence of
increased susceptibility of rat or rabbit fetuses to in utero exposure
or rat pups to post-natal exposure to flutolanil.  No toxic effects were
observed in studies in which flutolanil was administered by the dermal
routes of exposure.

A chronic dietary endpoint was the only one identified for flutolanil.
HED selected a chronic reference dose (RfD) of 0.50 mg/kg/day (NOAEL =
50 mg/kg/day; Uncertainty Factor = 100).  This chronic RfD is based on
the chronic oral toxicity study in dogs in which increased incidences of
clinical signs (emesis, salivation, and soft stool) occurred following
65 weeks of exposure.

HED classified flutolanil as “not likely to be carcinogenic to
humans” based on the absence of significant tumor increased in two
adequate rodent carcinogenicity studies.

The potential for increased susceptibility of infants and children from
exposure to flutolanil was evaluated as required by the Food Quality
Protection Act (FQPA) of 1996.  The FQPA Safety Factor (SF) for
flutolanil was reduced to 1X because there was no increased sensitivity
to fetuses as compared to maternal animals in the developmental rat and
rabbit studies and no increased sensitivity to pups as compared to
adults in a multi-generation reproduction study in rats.

Dietary Exposure

A chronic aggregate dietary exposure and risk assessment was conducted
using the Dietary Exposure Evaluation Model (DEEM-FCID™), Version
2.03, which uses food consumption data from the U.S. Department of
Agriculture’s Continuing Surveys of Food Intakes by Individuals
(CSFII) from 1994-1996 and 1998.   An acute dietary risk assessment was
not conducted, as an acute dietary endpoint was not identified.

The chronic dietary analysis included tolerance level residues, 100% CT
estimates and processing factors (default).  The estimated drinking
water concentration (EDWC) was incorporated directly into the dietary
assessment (1 in 10 yr annual mean, 3.75 µg/L).

The chronic dietary assessment (food and drinking water) showed that for
all included commodities, the chronic risk estimates were below the
Agency’s level of concern (<100% chronic population adjusted dose
(cPAD)) for the general U.S. population (1% of the cPAD) and all
population subgroups (1 - 2% cPAD).

Since toxicological endpoints have only been identified for chronic oral
exposures, aggregate exposure and risk assessments include only chronic
dietary food and water sources of exposure.  As discussed above, the
aggregate chronic risk estimates were below the Agency’s level of
concern for all population subgroups.

Occupational Exposure

Exposures can occur for occupational handlers loading or applying
flutolanil, as well as through postapplication exposure.  As regards the
new uses of the current petition, occupational handler exposure to
flutolanil is expected for individuals involved in commercial seed
treatment and potentially on-farm seed treatment (primary handlers) and
planting treated seeds (secondary handlers).  Additionally, workers may
be exposed to flutolanil following planting of treated seeds.  Workers
may also be exposed via non-food uses, application to turf, ornamentals,
 and greenhouses.  Based on the proposed application rates and use
scenarios, short- and intermediate-term occupational exposures may
occur.  However, assessments of exposures and risks were not conducted
because no dermal or inhalation toxicological points of departures
attributable to short- or intermediate-term exposures have been
identified, and the current use patterns do not indicate long-term
exposure potential.

Under the Worker Protection Standard (WPS) for Agricultural Pesticides,
active ingredients classified as acute toxicity categories III or IV for
these routes are assigned a 12-hour REI.  Therefore, the 12-hour REI
that appears on the proposed label is adequate.

Residential Exposure

No residential uses are being requested at this time.

There are existing non-occupational/residential uses associated with
flutolanil.  Registered products include several for use on turf grass
and potted ornamentals which, if not specifically prohibited through
label directions, could be used in a residential/public site.  However,
although such potential residential handler and post-application
exposures exist, assessments were not conducted because no dermal, oral
(incidental), or inhalation toxicological endpoints attributable to
short- or intermediate-term exposures have been identified, and the
current use patterns do not indicate long-term exposure (6 or more
months of continuous exposure) potential.  However, should HED identify
new regulatory endpoints for risk assessment purposes for flutolanil in
the future, then non-occupational/residential exposures may need to be
assessed.

 Conclusions

There are no residue chemistry, toxicology, and/or exposure issues that
would preclude granting permanent tolerances and registrations for the
requested use of  flutolanil as a seed treatment for sugar beets,
soybeans, and cotton.  However, registrations should be made conditional
pending adequate resolution of issues associated with the fulfillment of
new toxicology data requirements.

Recommended Tolerances Including Revisions to Petitioned for Tolerances

Pending the submission of a revised Section B (860.1200 Directions for
Use ) and a revised section F (860.1550 Proposed Tolerances), there are
no data gaps that would preclude granting a conditional registration for
the requested use of Flutolanil 40SC (Convoy®) as a seed treatment for
sugar beets, cotton, and soybeans.   The available data support the
establishment of a tolerance (40CFR§180.484(a)) for residues of
flutolanil, N-(3-(1-methylethoxy)phenyl)-2-(trifluoromethyl)benzamide,
including its metabolites and degradates, in or on the commodities in
the table below.  Compliance with the tolerance levels specified below
is to be determined by measuring only flutolanil and its metabolites
converted to 2-(trifluoromethyl) benzoic acid and calculated as
flutolanil, in or on the commodity.

Tolerances to be established under “(a) General”:

Soybean, seed	0.20 ppm

Soybean, forage	8.0 ppm

Soybean, hay	2.5 ppm

Cotton, undelinted seed	0.20 ppm

Cotton, gin byproducts	0.20 ppm

The recommended tolerances are greater than the proposed tolerance for
soybean seed and cotton seed because the enforcement analytical method
has not been validated at a level below 0.20 ppm, and the greater
tolerance value is needed to accommodate indirect residues from soybean
rotational crops. A tolerance is required for cotton gin byproducts, as
the radiolabeled seed treatment study revealed residues on cotton gin
trash.   A soybean hay tolerance is needed both to accommodate the seed
treatment use and the inadvertent residue from soybean as a rotational
crop.    Also, the tolerance definition proposed by the registrant is
not in agreement with the current residue definition.  The current
definition recognizes the common moiety determination of the current
enforcement method.

 Tolerances (inadvertent residue, rotational crop) have been established
previously for soybean forage and soybean hay, and these encompass the
use on soybean as a seed treatment.   The existing tolerances
established under “(d) Indirect or inadvertent residues” for
soybean, seed at 0.20 ppm; soybean, forage at 8.0 ppm, and soybean hay
at 2.5 ppm should be revoked upon establishment of the same tolerance
values under (a).

The seed treatment use for sugar beets at a maximum rate of 0.12 lb a
i/100 lbs seeds  is a non-food use and is exempt from the requirements
for a tolerance.  No residues are found on beet roots or beet tops
(<0.003 ppm total residue).

A permanent registration may be recommended following resolution of data
gaps summarized in Section 9 of this document.

Environmental Justice

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,” http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf.

As a part of every pesticide risk assessment, OPP considers a large
variety of consumer subgroups according to well-established procedures.
In line with OPP policy, HED estimates risks to population subgroups
from pesticide exposures that are based on patterns of that subgroup’s
food and water consumption, and activities in and around the home that
involve pesticide use in a residential setting.  Extensive data on food
consumption patterns are compiled by the USDA under the Continuing
Survey of Food Intake by Individuals (CSFII) and are used in pesticide
risk assessments for all registered food uses of a pesticide.  These
data are analyzed and categorized by subgroups based on age, season of
the year, ethnic group, and region of the country.  Additionally, OPP is
able to assess dietary exposure to smaller, specialized subgroups and
exposure assessments are performed when conditions or circumstances
warrant.  Whenever appropriate, 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.

EPA Review of Human Research

Occupational and residential exposure analyses were considered
unnecessary.  Therefore, this risk assessment does not rely on data from
Pesticide Handlers Exposure Database (PHED) and Outdoor Residential
Exposure Task Force (ORETF) studies in which adult human subjects were
intentionally exposed to a pesticide or other chemical.

2.0	INGREDIENT PROFILE

	2.1	Summary of Registered/Proposed Uses

Flutolanil is currently registered for use on peanut, potato, and rice.
Non-food uses include application to turf and to ornamentals grown in
containers, greenhouses, and nurseries, under registrations held by
Bayer Environmental Science.

Nichino America, Inc. (formerly Nihon Nohyaku) has submitted a petition
proposing seed treatment use on sugar beet, cotton,  and soybeans
(PP#9F7542).

The 40% suspension concentrate formulation (SC) is currently registered
for broadcast foliar and chemigation application  (0.95 lb a
i/acre/application and 1.9 lb a i/acre/season, 40 day PHI), and
in-furrow spray to the seed (0.74 lb a i/acre) for  peanuts and
seed-piece treatment either in-furrow (0.74 lb a i/acre)  or on a spray
table (0.015 lb a i/100 lb of seed pieces) for potatoes.  The petitioner
is proposing the addition of new uses, seed treatment for cotton,
soybean, and sugar beet at a maximum rate of 0.12 lb a i/100 lb seed.

The petitioner proposes feeding restrictions against the utilization of
soybean forage and hay from crops grown from flutolanil-treated seed.
The petitioner further proposes a twelve month grazing restriction for
cotton grown from flutolanil-treated seed

The proposed use directions for flutolanil as a seed treatment for sugar
beet, soybean, and cotton are presented in Table 2.1.1

Table 2.1.1	Summary of Directions for Proposed Use of Flutolanil

Applic. Timing, Type, and Equip. 	Formulation

[EPA Reg. No.]	Applic. Rate

(lb ai/A)1	Max. No. Applic. per Season	Max. Seasonal Applic. Rate

(lb ai/A)	PHI

(days)	Use Directions and Limitations

Cotton

Seed treatment	3.8 lb/gal

SC

[71711-28]	0.06 - 0.12 lb ai/ 100 lbs seed

[0.010-0.021 lb ai/ acre]	Not applicable	Do not graze for 12 months.2

Apply using a spray system, spray table, or seed treatment equipment for
this purpose.  If using a spray system, dilute 1 part product to three
parts water or less.  Maintain agitation of the spray solution during
application.

Soybean

Seed treatment	3.8 lb/gal

SC

[71711-28]	0.06-0.12 lb ai/ 100 lbs seed

[0.036-0.072 lb ai/ acre]	Not applicable	Do not feed forage and hay.2

Apply using a spray system, spray table, or seed treatment equipment for
this purpose.  If using a spray system, dilute 1 part product to three
parts water or less.  Maintain agitation of the spray solution during
application.

Sugar beet

Seed treatment	3.8 lb/gal

SC

[71711-28]	0.06-0.12 lb ai/ 100 lbs seed

[0.0048-0.0096 lb ai/ acre]	Not applicable	 Apply using a spray system,
spray table, or seed treatment equipment for this purpose.  If using a
spray system, dilute 1 part product to three parts water or less.
Maintain agitation of the spray solution during application.

1 The lb ai/A values have been calculated by HED and do not agree with
the calculations provided by Nichino America Inc (0.007 – 0.013 lb
ai/acre for cotton; 0.025 – 0.050 lb ai/acre soybean; 0.0008 –
0.0016 lb ai/acre sugar beet).

2Nichino America Inc incorrectly placed these limitations in Section F.

	2.2	Structure and Nomenclature

The nomenclature of flutolanil is summarized in Table 2.2.1, and the
physicochemical properties are summarized in Table 2.3.1.  The chemical
names and structures of flutolanil and its transformation products are
presented in Appendix B.

Table 2.2.1              Flutolanil Nomenclature.

Chemical structure

Common name	Flutolanil

Company experimental name	N/A

IUPAC name	α,α,α-trifluoro-3’-isopropoxy-o-toluanilide

CAS name	N-[3-(1-methylethoxy)phenyl]-2-(trifluoromethyl)benzamide

CAS registry number	66332-96-5

End-use product (EP)	Flutolanil 40 SC Fungicide (40%, 3.8 lbs flutolanil
per US gallon;  EPA Reg. No. 71711-28)

Chemical structure of common moiety determined by enforcement method

2-trifluoromethylbenzoic acid (2-TFBA)

	2.3	Physical and Chemical Properties  tc "2.3	Physical and Chemical
Properties " \l 2

Table 2.3.1	Physicochemical Properties of Flutolanil.

Parameter	Value	Reference

Melting range	100.4-103.8 °C	DP#s 190584 and 190586, 3/24/94, J.
Garbus; MRID 42606601

Ph	5.69

	Density	1.325 @ 20-25

	Water solubility	6.53 mg/L at 20 °C

	Solvent solubility			at 20 °C

Methanol	232 g/L

n-Hexane	  0.9 g/L

	Vapor pressure	4.87 x 10-8 mm Hg at 25 °C

	Dissociation constant, pKa	Not applicable

	Octanol/water partition coefficient, Log(KOW)	log POW = 3.74

	UV/visible absorption spectrum	Not available

3.0	Hazard Characterization/Assessment  TC \l1 "3.0	Hazard
Characterization/Assessment

3.1	Hazard and Dose-Response Characterization  TC \l2 "3.1	Hazard and
Dose-Response Characterization

3.1.1	Database Summary  TC \l3 "3.1.1	Database Summary

A summary of the hazard assessment of flutolanil is provided below.
Additional details may be found in the 2000 Human Health Risk Assessment
(DP Barcode 268880) and the 2007 Human Health Risk Assessment (DP
Barcode 335050). The acute toxicity of flutolanil technical is
summarized in Appendix B: Table B.1 and the toxicity profile of
flutolanil is shown in Appendix B: Table B.2.   The following study
types were considered.

Subchronic: 21-day dermal toxicity (rat), 90-day oral toxicity (rat,
dog)

Developmental:  rat and rabbit developmental toxicity studies

Reproduction: two-generation reproduction study (rat)

Chronic:  oral chronic toxicity (dog), combined chronic
toxicity/carcinogenicity (rat), carcinogenicity (mouse)

Other:  mutagenicity battery, metabolism

As there is no new toxicity data associated with this current action,
the hazard characterization and endpoint selection from the previous
risk assessment are applied directly to this action.

The existing database is considered adequate for hazard
characterization, endpoint selection, and assessment.  However, the
toxicology database is incomplete.  The revised Toxicology Data
Requirements for Conventional Pesticides [40 CFR §158.340] now include
studies which are better able to detect toxicities that are outside the
scope of standard subchronic and chronic assays.  These new study
requirements are:

   Acute neurotoxicity  [OPPTS Guideline 870.6200a]

   Subchronic neurotoxicity  [OPPTS Guideline 870.6200b]

   Immunotoxicity  [OPPTS Guideline 870.7800]

3.1.2	Toxicological Effects  TC \l3 "3.1.2	Toxicological Effects

The toxicology studies conducted on flutolanil demonstrate few or no
biologically significant toxic effects. Liver effects in rats included
increases in absolute and relative liver weight in the absence of
clinical chemistry and/or histopathology findings. In dogs, there was an
elevation in alkaline phosphatase and cholesterol levels together with
dose-related increases in absolute and relative liver weights, slightly
enlarged livers, and an increase in severity of glycogen deposition. The
increased liver weights are considered to be an adaptive response to
flutolanil treatment and not an adverse effect. Based on the lack of
evidence of carcinogenicity and the lack of evidence of mutagenicity,
flutolanil is classified as “not likely to be carcinogenic to
humans.”

Evaluation of the available data for flutolanil did not reveal any
clinical signs, clinical chemistry changes, and/or histopathology to
indicate that it is neurotoxic or that it targets the immune system.  It
 is not a developmental or reproductive toxicant.  No maternal,
reproductive, or developmental toxicity was observed at the limit dose.
There was no evidence for increased susceptibility of rat or rabbit
fetuses to in utero exposure or rat pups to post-natal exposure to
flutolanil.  No toxic effects were observed in studies in which
flutolanil was administered by the dermal route of exposure at the limit
dose.

3.1.3  Metabolism

A rat metabolism study (20 mg/kg for 14 days) showed 70% of the
administered dose in urine and 10% in feces.  At a 1000 mg/kg dosing
level, 10% of the administered dose was found in urine and about 70% was
found in feces.  M-4 (Appendix A) was identified in urine.  The main
constituent in feces was parent flutolanil, along with some M-4.

Dose-Response  TC \l3 "3.1.3	Dose-Response

Previously HED concluded that no appropriate toxicological endpoint
attributable to a single oral dose (exposure) was identified in the
available data on flutolanil. Therefore, no acute reference dose (RfD)
was selected and an acute dietary risk assessment was not required.
Originally  a chronic RfD of 0.87 mg/kg/day was selected for use in
chronic dietary risk assessment, based on the 2-year combined chronic
toxicity/carcinogenicity study in rats in which decreases in body
weight/gain and increases in absolute and relative liver weights were
observed at the lowest-observable-effect level (LOAEL) of 460 mg/kg/day.
The HED Food Quality Protection Act (FQPA) Safety Factor Committee
(November 9, 1999) concluded that the 10X FQPA safety factor should be
reduced to 1X.

Subsequently the HED flutolanil risk assessment team reevaluated the
database and reaffirmed  the lack of an appropriate endpoint for the
acute RfD and reduction of the FQPA safety factor to 1X. However, the
team identified an endpoint from the 2-year chronic dog study as
providing a more appropriate endpoint for the chronic RfD. This is based
on the conclusion that the liver effects, in the absence of clinical
chemistry or histopathological findings, in the chronic rat study used
previously, are considered to be an adaptive response and not adverse.
In the chronic dog study, the increased incidence of clinical signs
(emesis, salivation, and soft stool) at 250 mg/kg/day (LOAEL) occurred
following 65 weeks of exposure.  The flutolanil risk assessment team
selected a chronic RfD of 0.5 mg/kg/day (NOAEL of 50 mg/kg/day; 10X
interspecies factor; 10X intraspecies factor; 1X FQPA SF).

No adverse effects were identified from oral or dermal exposure for
dosing up to 90 days. In a 90 day oral dosing of rats study, no
treatment-related changes in ophthalmoscopic, hematological, clinical
chemistry, gross pathology, or histopathology parameters were observed.
A 21-day rat dermal study showed a systemic LOAEL of 1000 mg/kg/day
(limit dose).  There is no appropriate endpoint for either short-term or
intermediate-term incidental oral assessment based on the lack of
adverse effects following these exposure durations.

  FQPA Safety Factor Considerations

The database for flutolanil is adequate for FQPA consideration.

3.2.1   Evidence of Neurotoxicity

A thorough evaluation of the available toxicology database on flutolanil
(including open literature) reveals no clinical signs, clinical
chemistry changes, organ weights, and histopathology  indicating
possible neurotoxicity.  Included were studies conducted at high doses
between 500 mg/kg/day and a 1000 mg/kg/day dose (limit dose), where
signs of neurotoxicity were not detected.  Based on this analysis, a
database uncertainty factor is not needed to account for the missing
neurotoxicity studies on flutolanil at this time.

Evidence of Immunotoxicity

None of the available submitted or open-literature studies suggest that
flutolanil produces hematological or thymus/spleen effects indicative of
immunotoxicity.  A database uncertainty factor is not needed to account
for the missing immunotoxicity study at this time.

3.2.3	Pre-and/or Postnatal Toxicity:  TC \l3 "3.2.6	Pre-and/or Postnatal
Toxicity   Determination of Susceptibility  TC \l4 "<IP_ADDRESS>
Determination of Susceptibility

There is no evidence of increased susceptibility.  There was no
increased sensitivity to fetuses as compared to maternal animals in the
developmental rat and rabbit studies and no increased sensitivity to
pups as compared to adults in a multi-generation reproduction study in
rats.

Safety Factor for Infants and Children

  TC \l2 "3.3	Safety Factor for Infants and Children

HED has determined that reliable data show that it would be safe for
infants and children to reduce the FQPA SF to 1X for all potential
exposure scenarios.  The FQPA Safety Factor (SF) for flutolanil was
reduced to 1X based on the following findings:

1) The toxicity database for flutolanil is complete except for acute and
subchronic neurotoxicity and immunotoxicity studies. Recent changes to
40 CFR 180.158 make acute and subchronic neurotoxicity testing (OPPTS
Guideline 870.6200), and immunotoxicity testing (OPPTS Guideline
870.7800) required for pesticide registration. However, the available
data for flutolanil do not suggest that the compound produces
hematological or thymus/spleen organ effects indicative of
immunotoxicity. Further, there is no evidence of neurotoxicity in any
study in the toxicity database for flutolanil. Therefore, EPA does not
believe that conducting neurotoxicity and immunotoxicity studies will
result in a NOAEL lower than the NOAEL of 50 mg/kg/day already
established for flutolanil. Consequently, an additional database
uncertainty factor does not need to be applied.

2) There is no indication that flutolanil is a neurotoxic chemical and
there is no need for a developmental neurotoxicity study or additional
Uncertainty Factors (UFs) to account for neurotoxicity.

3) There is no evidence of increased susceptibility.  There was no
evidence of increased susceptibility of rat or rabbit fetuses to in
utero exposure or rat pups to post-natal exposure to flutolanil at dose
levels as high as 1000 mg/kg/day.

4) There are no residual uncertainties in the exposure data base.  The
calculations were extremely conservative.  Percent crop treated was
assumed to be 100%, tolerance level values were used for food residue
concentrations, and high end modeling was used for water.  Moreover no
relevant endpoint was identified for dermal or incidental oral or
inhalation exposure related to residential use.

3.4	Hazard Identification and Toxicity Endpoint Selection  TC \l2 "3.5
Hazard Identification and Toxicity Endpoint Selection

The toxicity endpoints and doses for risk assessment were selected based
upon the available toxicity data and the use exposure information on
flutolanil.  The toxicological doses and endpoints selected for various
exposure scenarios are summarized in Table 3.4.1.

Table 3.4.1	Summary of Toxicological Doses and Endpoints for Flutolanil
for Use in Dietary and Non-Occupational Human Risk Assessments

Exposure

Scenario

Point of Departure

Uncertainty/

FPQA Factors

RfD, PAD, Level of Concern for Risk Assessment

Study and Toxicological Effects

 Acute Dietary

(All populations)	No appropriate toxicological endpoint attributable to
a single exposure (dose) was identified from the oral toxicity studies
including developmental toxicity studies in rats and rabbits.  This risk
assessment is not required.

Chronic Dietary

(All populations)

NOAEL= 50 mg/kg/day

 	UFA=10X

UFH=10X

FQPA SF = 1X

	cRfD =

0.5 mg/kg/day

cPAD =

0.5 mg/kg/day	2-year Chronic study in dogs.

MRID no. 40342922

LOAEL = 250 mg/kg/day based on increased incidence  of clinical toxic
signs (emesis, salivation, and soft stool)

Incidental Oral Short- and Intermediate-Terms 	No appropriate endpoint
was identified in the database for these durations of exposure.

Dermal

 (all durations)	No appropriate endpoint was identified in the database
for this route of exposure.

Inhalation

 Short- and Intermediate-Terms	No appropriate endpoint was identified in
the database for these durations of exposure.

Inhalation

Long-term	The current use pattern does not indicate long-term inhalation
exposure potential.

Cancer (oral, dermal, inhalation)

Classification:  “Not likely to be Carcinogenic to Humans” based on
the absence of significant tumor increases in two adequate rodent
carcinogenicity studies.

Point of Departure (POD) = A data point or an estimated point that is
derived from observed dose-response data and used to mark the beginning
of extrapolation to determine risk associated with lower environmentally
relevant human exposures.  NOAEL = no observed adverse effect level.
LOAEL = lowest observed adverse effect level.  UF = uncertainty factor.
UFA = extrapolation from animal to human (interspecies).  UFH =
potential variation in sensitivity among members of the human population
(intraspecies).  RfD = reference dose.  MOE = margin of exposure.  LOC =
level of concern.  PAD = Population adjusted dose

3.5	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 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).

When additional appropriate screening and/or testing protocols being
considered under the Agency’s EDSP have been developed, flutolanil may
be subjected to further screening and/or testing to better characterize
effects related to endocrine disruption.

4.0	DIETARY EXPOSURE/RISK CHARACTERIZATION tc "5.0	Dietary Exposure/Risk
Characterization"

4.1	Pesticide Metabolism and Environmental Degradation  tc "5.1
Pesticide Metabolism and Environmental Degradation " \l 2

4.1.1	Metabolism in Primary Crops and Livestock tc "5.1.1	Metabolism in
Primary Crops " \l 3

The subject petition included a nature of the residue study for seed
treatment of sugar beet, cotton, and soybean.  The study was conducted
with radiolabeled material at the proposed 1X application rate.  Low
residue concentrations precluded characterization of the metabolites.
It has been previously concluded that the nature of the residue in
plants is adequately understood based on acceptable metabolism studies
in rice, cucumber leaves, and peanuts.  Flutolanil and its metabolite
M-4 ( N-(3'-hydroxyphenyl)-2-(trifluoromethyl)benzamide) were the major
residue components in plants.  The residues of concern for the
tolerance expression and dietary risk assessment for primary crops are
flutolanil and metabolites containing the common moiety,
2-trifluoromethyl benzanilide.

No livestock metabolism data were submitted with the subject petition.
The nature of the residue in livestock is adequately understood based on
acceptable metabolism studies in goats and poultry.  HED previously
concluded that the residues of concern for tolerance expression and
dietary risk assessment in livestock commodities are flutolanil and
metabolites M-2
(N-[4'-hydroxy-3'-(1-methylethoxy)phenyl]-2-(trifluoromethyl)
benzamide), M-4, and M-7 (N-(4'-hydroxy-3'-methoxy)phenyl
-2-(trifluoromethyl)benzamide) in livestock tissues, and the
glucuronide/sulfate conjugates of M-4 in milk.  As the petitioner
proposed an enforcement analytical method that determines residues of
flutolanil and metabolites converted to 2-trifluoromethyl benzoic acid,
tolerances are  established in terms of parent plus metabolites
converted to the common moiety.

what is the common moiety name?- note that this same language was in the
November 27, 2007 rotational crop RA.

See Appendix A for chemical structures of flutolanil and metabolites.

4.1.2	Metabolism in Rotational Crops

The nature of the residue in rotational crop commodities is adequately
understood based on an acceptable confined rotational crops study with
lettuce, radish, and oat/sorghum conducted with
[U-14C-aminophenoxy]flutolanil.  The major residue components were
flutolanil and metabolites M-4 and M-5 (N-[3',4'-(dihydroxy)phenyl]-2-
(trifluoromethyl)benzamide).  The residues of concern for tolerance
expression and dietary risk assessment for rotational crops are
flutolanil and metabolites containing the common moiety,
2-trifluoromethyl benzanilide.

4.1.3	Analytical Methodology  tc "5.1.4	Analytical Methodology " \l 3

The enforcement analytical method (Method AU/95R/04) is a common moiety
GC/MS method which determines residues of flutolanil and metabolites as
2-trifluoromethyl benzoic acid (2-TFBA).  The method has undergone a
successful independent laboratory validation and has been successfully
validated by EPA (A. Krynitsky, D. Swineford, Analytical Chemistry
Branch, BEAD, 06/25/2001).  However, recovery of M7 from liver was low.
  Generally, the limit of quantitation is 0.2 ppm for plant commodities
and 0.05 ppm for livestock commodities.

Because the method is a common moiety method, a confirmatory method is
necessary. LC/MS/MS Method XAM-65 is  adequate for confirmatory
purposes. This method potentially  does not determine all components of
the residues of concern in plant commodities, flutolanil and metabolites
containing the common moiety, 2-trifluoromethyl benzanilide.   However,
it is acceptable as a confirmatory method, in that it determines
flutolanil and major specific metabolites.  In addition, HED notes that
the primary  method must be rewritten to include instructions for
analysis of additional crops including potatoes, cotton seed, cotton gin
byproducts, soybean seed, soybean forage, soybean hay, wheat grain,
wheat hay, wheat straw, wheat forage, and wheat bran.

Samples from the radiolabeled seed treatment study for cotton, sugar
beet, and soybean were not analyzed by either the enforcement Method
AU/95R/04 or Method XAM-65.  Methanol/water extracts of commodities were
analyzed first for total radioactive residue (TRR).  Extracts were
further analyzed by HPLC with uv/vis detection and liquid scintillation
counting.   TRR levels  were considered too low (<0.003 ppm – 0.075
ppm) to permit utilization of either Method AU/95R/04 or Method XAM-65.

Adequate multiresidue method testing data for flutolanil and metabolite
M-4 were submitted in conjunction with petitions for an experimental use
permit on rice (PP#3G4184/PP#3H5658).  Both analytes were tested through
Protocol I (corresponding to current Protocols C, E, and F) and Protocol
III (corresponding to Protocol D).  Because neither flutolanil nor M-4
was recovered through the Florisil column, no further testing was
conducted under Protocol I.  Under Protocol III (a.k.a. D), recoveries
of flutolanil were 90.2% and 90.9% at fortifications of 0.05 and 0.5
ppm, and recoveries of M-4 were 68.4% and 88.2% for M-4 at the same
fortification levels; neither analyte was recovered from spiked rice
samples at 0.05 ppm.  The multiresidue test results were forwarded to
FDA.

4.1.4	Drinking Water Residue Profile  tc "5.1.8	Drinking Water Residue
Profile " \l 3

There is no established Maximum Contaminant Level for residues of
flutolanil in drinking water.  No health advisory levels for flutolanil
in drinking water have been established.

EFED does not have monitoring data available to perform a quantitative
drinking water risk assessment for flutolanil at this time.  Therefore,
the Agency is presently relying on computer-generated estimated drinking
water concentrations (EDWCs).  For any given pesticide, the SCI-GROW
model generates a single EDWC value of pesticide concentration in ground
water.  SCI-GROW is an empirical model based upon actual monitoring data
collected for a number of pesticides that serve as benchmarks.  SCI-GROW
is used to predict EDWCs in  ground water. Ground and surface water
exposure estimates for use of flutolanil on rice were provided by EFED
(Memo from S. Abel, 12/13/1999; Memo from L.Liu, 11/24/09).    The first
approximation model generates a single mean concentration in surface
water for rice paddy water for an acute assessment and pond water for
the chronic assessment.  These models take into account the use patterns
and the environmental profile of a pesticide, but do not consider
processing of raw water for distribution as drinking water.  The primary
use of these models by the Agency at this stage is to provide a coarse
screen for assessing whether a pesticide is likely to be present in
drinking water at concentrations which would exceed human health levels
of concern.

For this risk assessment, the first approximation rice model was used to
estimate EDWCs in surface water.  The first approximation model is an
interim pesticide fate and transport model to account for the direct
application of pesticides to rice paddy water.  Fundamental
transformation processes (e.g., hydrolysis, metabolism, and photolysis)
are not incorporated into the model.  However, the partitioning between
the water and sediment/organic material fractions are accounted for
using a set of mathematical algorithms both in the paddy water for an
acute assessment and pond water for the chronic assessment.  Paddy water
depth is assumed to be 4 inches with a field size of 1 hectare and the
sediment-water interaction zone of 5 cm. Equilibrium is assumed to be
instantaneous between the water-sediment faction.  The release of the
paddy water is to the standard farm pond ( 1 hectare, 2 meters deep)
with subsequent partitioning between the water-sediment fractions.

Metabolism studies in water showed that flutolanil is resistant to all
modes of abiotic and biotic degradation. The residues in water are the
parent compound and M4; and the parent is the major residue.  HED
concluded that only the parent needs to be included in the drinking
water exposure assessment for flutolanil.   EFED conducted its Tier I
screening-level assessments using the simulation models SCI-GROW and
first approximation rice model to generate EDWCs for ground and surface
water, respectively.  The modeling was conducted based on the
environmental profile and the maximum seasonal application rate proposed
for flutolanil (0.5 lb ai/A x 2 applications/A/year on rice).  The first
approximation rice model was used to account for the direct application
of pesticides to rice paddy water.  The EWDCs are shown in Table
<IP_ADDRESS>.

	Table <IP_ADDRESS>:  EFED Estimated Drinking Water Concentrations (EDWCs)
from Rice Use

	SCI-GROW1   (µg/L)2

Ground Water

First Approximation Model 3   (µg/L) 2

Surface Water

	0.34   (acute & chronic)

3.75 (Mean, Chronic)

11.6 (Peak, Acute)

1	SCI-GROW (Screening Concentration in Ground Water) is an empirical
model for predicting pesticide levels in ground water.  The value from
SCI-GROW is considered an upper bound concentration estimate.

2	µg/L  = parts per billion.

3	First approximation model is an interim pesticide fate and transport
model to account for the direct application of pesticides to rice pond
water (surface water).

The previous drinking water assessment completed in 1999 also included
the use of flutolanil on potato seed piece treatment and can be
considered  in place of a new assessment for the currently proposed uses
on cotton, soybean, and sugar beet seed treatment (L Liu, DP Barcode
D363302, 12/07/09).  This is because the application rate used in
PRZM/EXAM and SCI-GROW modeling in the 1999 Drinking Water Assessment
for Use of Flutolanil on Potato Seed Piece was 0.65 lb ai/A which is
much higher than the rates (ranging from 0.01-0.07 lb ai/A) proposed for
cotton sees, soybean seed,  and sugar beet seed treatment.

For fluotolanil, the surface water acute (peak) value is 0.46 ppb and
the chronic value is 0.09 ppb based on the application on potato seed
pieces.  The ground water screening concentration is 0.34 ppb for
flutolanil.  The greater value obtained from consideration of the rice
scenario (3.75 ppb compared to 0.09 ppb) was used in the chronic dietary
intake calculation.

4.1.5	Food Residue Profile

Nature of the Residue/Field Trial

The nature of the residue studies with soybeans, cotton seed, and sugar
beet are adequate to determine the quantity of residue to be found from
the proposed seed treatment use. A nature of the residue study was
submitted for seeds of cotton, soybean, and sugar beet treated with
flutolanil radiolabeled with 14C on the isopropoxy phenyl ring and grown
to maturity in the field.  The seed treatment rates were 92% - 130% of
the proposed label rate.  Total radioactive residues were
non-quantifiable on sugar beet roots and tops (<0.003 ppm).  Total
radioactive residues were non-quantifiable on cotton seed but 0.013 ppm
on cotton gin byproducts.  Total radioactive residues ranged from 0.006
ppm on soybean seeds to 0.075 ppm on soybean forage.  No compounds were
identified for any matrix.  Residue levels associated with cotton and
soybean commodities as rotational crops are at least an order of
magnitude greater than residues resulting from seed treatment use.

Storage Stability

The nature of the residue/field trial study was completed within 7 –
48 days of sample harvest.  Samples were stored frozen.  Therefore,
demonstration of storage stability is not considered necessary.

Meat, Milk, Poultry, and Eggs

In addition to the feedstuffs associated with the registered uses of
flutolanil on potatoes, peanuts, rice, soybean, and wheat there are
livestock feedstuffs associated with the proposed amended uses as seed
treatment on soybeans and cotton.  The seed treatment use on soybeans is
covered by use on rotated soybeans.  The seed treatment use on sugar
beets is considered a non-food use. The dietary burdens of flutolanil to
livestock, based on maximum reasonably balanced diets, have been
recalculated.  The total dietary burden for beef cattle is 5.03 ppm; for
dairy cattle, 8.99 ppm; for poultry, 1.61 ppm; and for swine, 1.65 ppm.
Based on the available feeding studies, the proposed amended uses on
cotton and soybean will not result in residues exceeding the established
tolerances for livestock commodities.

Processed Food and Feed

No new processing studies or data were submitted with the subject
petition.

Nichino America, Inc. has previously submitted a processing study with
rotated cotton which indicated that residues of flutolanil and M-4 were
each below the method LOQ (<0.05 ppm) in  cotton seed (RAC) and
processed cotton seed commodities cotton hulls, meal, crude oil, and
refined oil.  Because residues were below the LOQ in both the RAC and
processed commodities, processing factors could not be calculated.

The previously submitted processing study for rotated cotton was
unacceptable because no storage stability data are available which
demonstrate that residues of flutolanil and M-4 are stable in cotton
seed and its processed commodities stored frozen for up to 7.5 years.
In addition, samples were not analyzed for the residues of concern in
rotated crops:  flutolanil and metabolites containing the common moiety,
2-trifluoromethyl benzanilide.  HED previously concluded that given the
extended storage durations, a new processing study will be required for
rotated cotton if residues are detectable in the RACs in the required
limited rotational crop trials .  Use of an exaggerated rate application
is recommended if residues are near or below the analytical method LOQ
in the rotated RACs  (F. Fort, DP Barcode 335050, 11/26/07).

The previously submitted  processing study for soybean was acceptable
and indicated that residues of flutolanil and metabolites do not
concentrate in soybean hulls, meal, and oil.

4.1.6		Proposed Tolerances and Recommended Tolerances

The Agency has determined that the residue of concern in primary and
rotated crops is flutolanil and its metabolites converted to
2-(trifluoromethyl) benzoic acid and calculated as flutolanil.
Permanent tolerances are established in/on peanut, potato, and rice
commodities (40 CFR §180.484(a))  Indirect or inadvertent residue
tolerances are established for soybean and wheat commodities (40 CFR
§180.484(d)) .

The tolerance expression proposed by Nichino America for soybean and
cotton tolerances is not acceptable.  The proposed expression is for
flutolanil and the metabolite desisopropyl flutolanil (M-4).

The Agency has determined that the residue of concern in ruminant and
poultry commodities is flutolanil and its metabolites converted to
2-(trifluoromethyl) benzoic acid and calculated as flutolanil (40 CFR
§180.484(a)). Tolerances have been established for ruminant and poultry
commodities ranging from 0.05 ppm in milk and eggs to 2.00 ppm in
ruminant liver.  These tolerances do not need to be reassessed because
the residue levels on regulated livestock feed commodities associated
with the proposed use (seed treatment) are significantly lower than
residue levels from established uses.

The tolerance expression for established and proposed tolerances should
be corrected in

40 CFR §180.484(a) and (d) to conform to HED policy (S. Knizner,
5/27/09):

“Tolerances are established for residues of flutolanil,
N-(3-(1-methylethoxy)phenyl)-2-(trifluoromethyl)benzamide, including its
metabolites and degradates, in or on the commodities in the table below.
 Compliance with the tolerance levels specified below is to be
determined by measuring only flutolanil and its metabolites converted to
2-(trifluoromethyl) benzoic acid and calculated as flutolanil, in or on
the commodity.”

The radiolabeled seed treatment studies with sugar beet, cotton seed,
and soybean showed no residues for sugar beet commodities and residue
levels significantly below those associated with soybean and cotton seed
commodities as rotational crops.  Therefore, sugar beet use may be
regarded as nonfood, and no tolerance is necessary.  The tolerances for
soybean commodities established under 40 CFR §180.484(d) should be
deleted and replaced by the same entries under

40 CFR §180.484(a).  Tolerances at the limit of quantitation of the
enforcement analytical method (0.20 ppm) should be established for
cotton seed and cotton gin trash under 40 CFR  §180.484(a).

Tolerances are not necessary for processed commodities of soybeans, as
concentration has been shown not to occur from the raw agricultural
commodity to any of the processed fractions.  The processing study for
cotton seed (as a rotational crop) was found unacceptable as storage
stability was not demonstrated.  Nonetheless, for purposes of the seed
treatment use only, any concentration from the raw agricultural
commodities to the processed commodities is unlikely to exceed the
recommended raw agricultural commodity tolerance of 0.20 ppm, where
residues in the raw agricultural commodity are about 0.01 ppm.

Table  <IP_ADDRESS>. 	Tolerance Summary for Flutolanil

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

40 CFR §180.484(a)

Tolerances are established for residues of flutolanil,
N-(3-(1-methylethoxy)phenyl)-2-(trifluoromethyl)benzamide, including its
metabolites and degradates, in or on the commodities in the table below.
 Compliance with the tolerance levels specified below is to be
determined by measuring only flutolanil and its metabolites converted to
2-(trifluoromethyl) benzoic acid and calculated as flutolanil, in or on
the commodity.

(Note that the registrant proposal is not acceptable:  Flutolanil and
the metabolite desisopropyl flutolanil a.k.a. M-4.  This definition does
not include all components of the existing definition and is not
supported by a validated enforcement analytical method.)

Cotton, seed	0.05	0.20	Cotton, undelinted seed

Cotton,   gin byproducts	-	0.20

	Soybean, seed	0.05	0.20	Withdraw corresponding tolerance under 40 CFR
§180.484(d)

Soybean, forage	-	8.0	Withdraw corresponding tolerance under 40 CFR
§180.484(d)

Soybean, hay	-	2.5	Withdraw corresponding tolerance under 40 CFR
§180.484(d)

4.1.7	International Residue Limits  tc "5.2.10	International Residue
Limits " \l 3

Codex maximum residue limits (MRLs) are established for residues of
flutolanil in rice commodities at 1-10 ppm, and in livestock commodities
at 0.05-0.2 ppm.  No Canadian or Mexican MRLs have been established.  No
Codex MRLs are established for soybean, cotton seed, or sugar beet
commodities.

4.2	Dietary Exposure and Risk  tc "5.2  Dietary Exposure and Risk " \l 2

A chronic dietary exposure assessment (using tolerance-level residues
and assuming all crops are treated (100 %CT) and using default
concentration factors for processed commodities) was conducted for the
general U.S. population and various population subgroups.  Exposure to
drinking water was incorporated directly into the dietary assessment
using the chronic (annual average) concentration for surface water
generated by the first approximation rice model.  This assessment
concludes that the chronic dietary exposure estimates are below HED’s
level of concern (<100% cPAD) for the general U.S. population and all
population subgroups.  The chronic dietary exposure is estimated for the
U.S. population at 1% of the cPAD and for the most highly exposed
population subgroup, children 1 - 2 years old, at 2% of the cPAD.

Table 4.2.1:            Results of the Chronic Dietary Risk Analysis

Population Subgroup	Chronic Dietary

	Dietary Exposure

(mg/kg/day)	% cPAD

General U.S. Population	0.002998	1

All Infants (< 1 year old)	0.006662	1

Children 1-2 years old	0.007335	2

Children 3-5 years old	0.006159	1

Children 6-12 years old	0.004135	1

Youth 13-19 years old	0.002760	1

Adults 20-49 years old	0.002699	<1

Adults 50+ years old	0.001830	<1

Females 13-49 years old	0.002301	<1

5.0	RESIDENTIAL (NON-OCCUPATIONAL) EXPOSURE AND RISK

There are non-occupational uses associated with flutolanil.
Non-occupational handlers may mix, load and apply flutolanil products to
turf grass.  Although residential (non-occupational) exposure exists, an
assessment was not conducted since no toxicological endpoint
attributable to short- or intermediate-term route of exposure have been
identified and the current use pattern does not indicate long-term
exposure (6 or more months of continuous exposure) potential.

6  SEQ CHAPTER \h \r 1 .0	Aggregate Risk Assessments and Risk
Characterization

In accordance with the FQPA, the Agency must consider aggregate
pesticide exposures and risks from three major sources: food, drinking
water, and residential exposures.  In an aggregate assessment, exposures
from relevant sources are added together and compared to quantitative
estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can
be aggregated.  When aggregating exposures and risks from various
sources, the Agency considers both the route and duration of exposure.
In the case of flutolanil, aggregate risk assessments were performed for
chronic aggregate exposure (food + drinking water) only.  Short-, and
intermediate-term aggregate risk assessments were not performed because
toxicological endpoints  from dermal and inhalation exposures were not
identified.  Additionally, the Agency does not expect residential
exposure durations that would result in long term exposures.  A cancer
aggregate risk assessment was also not performed because flutolanil is
not carcinogenic.

The chronic aggregate risk assessment takes into account average
exposure estimates from dietary consumption of flutolanil (food and
drinking water) and residential uses.  However, due to the use patterns,
no chronic residential exposure is expected.  Therefore, the chronic
aggregate risk assessment will consider exposure from food and drinking
water only.  The chronic dietary exposure estimates for food and
drinking water are below HED’s level of concern (<100% cPAD) for the
general U.S. population (1% of the cPAD) and all population subgroups (1
-  2% cPAD).  Therefore, the chronic aggregate risk associated with the
proposed and registered uses of flutolanil does not exceed HED’s level
of concern for the general U.S. population or any population subgroups.

7  SEQ CHAPTER \h \r 1 .0	Cumulative Risk Characterization/Assessment

Unlike other pesticides for which EPA has followed a cumulative risk
approach based on a common mechanism of toxicity, EPA has not made a
common mechanism of toxicity finding as to flutolanil and any other
substances and flutolanil 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 flutolanil has a common mechanism of
toxicity with other substances. For information regarding EPA’s
efforts to determine which chemicals have a common mechanism of toxicity
and to evaluate the cumulative effects of such chemicals, see the policy
statements released by EPA’s Office of Pesticide Programs concerning
common mechanism determinations and procedures for cumulating effects
from substances found to have a common mechanism on EPA’s website at
HYPERLINK "http://www.epa.gov/pesticides/cumulative/._"
http://www.epa.gov/pesticides/cumulative/.

8.0	Occupational Exposure/Risk Pathway

Workers may be exposed to flutolanil during mixing, loading, applying,
and postapplication activities.   Based on the proposed application
rates and use scenarios, short-  and intermediate-term occupational
exposures may occur.  However, since short-and intermediate-term
endpoints have not been established, an occupational exposure assessment
is not required.

Chronic occupational exposure is not expected; thus, chronic
occupational exposure risk assessments are also not required.

9.0	DATA NEEDS/LABEL REQUIREMENTS

9.1  Toxicology

The revised Toxicology Data Requirements for Conventional Pesticides [40
CFR §158.340] now includes studies which are better able to detect
toxicities that are outside the scope of standard subchronic and chronic
assays.  These new study requirements are:

   Acute neurotoxicity  [OPPTS Guideline 870.6200a];

   Subchronic neurotoxicity  [OPPTS Guideline 870.6200b];

   Immunotoxicity  [OPPTS Guideline 870.7800]

See Appendix C.

9.2 Residue Chemistry

9.2.1 Label

The feeding restrictions proposed for the flutolanil 40 SC label
(71711-28) against the utilization of soybean forage and hay must be
removed.  This language is not in the proposed label, but is included in
the petitioner’s Section F.

The grazing restriction of 12 months (relative to use as a seed
treatment) for cotton proposed for the flutolanil 40 SC label (71711-28)
must be removed.  Cotton forage is not considered a livestock feed item;
therefore, the restriction is unnecessary.   Feeding restrictions also
cannot be placed on cotton gin byproducts (“trash”), as this item is
not under grower control.  This language is not in the proposed label,
but is included in the petitioner’s Section F.

The seeding rate information provided (lbs seed/per acre) is not in
agreement with standard information used by HED.  This section must be
revised (See Table 2.1.1).

9.2.2 Residue Enforcement Analytical Methods

The enforcement method AU/95R/04 is acceptable, and method XAM-65 is
acceptable as a confirmatory method. HED  notes that the enforcement
method must be rewritten to include instructions for analysis of
additional crops including soybean commodities and cotton seed and
cotton gin byproducts for which tolerances are to be established.

9.2.3 Proposed Tolerances

In the proposed tolerance expression, the  residue definition for cotton
seed and soybean seed is not in agreement with the established tolerance
residue definition expression.  The expression must be revised, as
indicated in Table <IP_ADDRESS>

The proposed tolerances for soybean and cotton commodities should be
revised to reflect the recommended tolerance levels as specified in
Table <IP_ADDRESS>.

A tolerance must be proposed for cotton gin byproducts.  See Table
<IP_ADDRESS>.

In the proposed tolerance expression, the  commodity definition for
cotton seed is not in agreement with the established commodity
definition and should be revised as indicated in Table <IP_ADDRESS>.

The tolerance expressions of 40CFR§180.484(a) and (d) should be changed
to comply with HED policy (S. Knizner, 5/27/09), as indicated in Table
<IP_ADDRESS>  The revised expression for 40CFR§180.484(a) is:

“Tolerances are established for residues of  flutolanil,
N-(3-(1-methylethoxy)phenyl)-2-(trifluoromethyl)benzamide, including its
metabolites and degradates, in or on the commodities in the table below.
 Compliance with the tolerance levels specified below is to be
determined by measuring only flutolanil and its metabolites converted to
2-(trifluoromethyl) benzoic acid and calculated as flutolanil, in or on
the commodity.”

The revised expression for 40CFR§180.484(d) is:

“Tolerances are established for the indirect or inadvertent residues
of  flutolanil,
N-(3-(1-methylethoxy)phenyl)-2-(trifluoromethyl)benzamide, including its
metabolites and degradates, in or on the commodities in the table below.
 Compliance with the tolerance levels specified below is to be
determined by measuring only flutolanil and its metabolites converted to
2-(trifluoromethyl) benzoic acid and calculated as flutolanil, in or on
the commodity.”

10.0 	REFERENCES

DP#:	None

Subject:	Flutolanil.  HED Metabolism Assessment Review Committee (MARC)
Meeting Held on 12-16-99.  PC Code 128975

From:	M. Xue

To:	G. Kramer

Date:	1/6/00

MRIDs:			None

DP#:	267571

Subject:	PP#6F04693/PP#6H05749, Flutolanil in/on Potatoes and Rice.
Evaluation of Independent Laboratory Validation Data.

From:	W. Wassell

To:	M. Waller

Date:	7/21/00

MRIDs:			44537601

DP#:	349580

Subject:	Flutolanil.  Human Health Assessment Scoping Document in
Support of Registration Review

From:	M Ottley

To:	T. Myers and J. Bloom

Date:	08/07/2008

MRIDs:	None

DP#:	364462

Subject:	Flutolanil.  Petition for Exemption from the Requirement for a
Tolerance for Seed Treatment Use for Sugar Beet Commodities and for the
Establishment of Tolerances for Seed Treatment Use for Cotton and
Soybean Commodities.    Summary of Analytical Chemistry and Residue Data

From:	S. Funk

To:	L. Jones and M. Waller

Date:	11/30/2009

MRIDs:	47699701

DP#:	364586

Subject:	 Flutolanil Chronic Aggregate Dietary (Food and Drinking Water)
Exposure and Risk Assessment for the Section 3 Registration Action
(Soybean, Cotton)

From:	S. Funk

To:	M Waller

Date:	11/11/2009

MRIDs:			None

DP#:	363302

Subject:	Estimated  Environmental Concentrations of Flutolanil for Use
on Cotton, Soybean, and Sugar beet Seed Treatment in Human Health Risk
Assessment

From:	L. Liu

To:	S. Funk and L. Jones

Date:	12/07/2009

MRIDs:			None

DP#:	335050

Subject:	Flutolanil.  Petitions for Establishment of Tolerances for
Indirect or Inadvertent Residues in/on Corn, Cotton, Soybean, and Wheat
Commodities.  Summary of Analytical Chemistry and Residue Data.  PRIA
R17.  PP#0F6159 (Soybean and Wheat) and PP#6F7070 (Corn and Cotton).

From:	F. Fort

To:	L. Jones and M. Waller

Date:	11/26/07

MRIDs:			45104001, 46790801 - 46790803

Date:	11/19/07

MRIDs:	46790801-4670803

DP#:	268880

Subject:	PP#6F4693 and PP#4F04380  Flutolanil on Rice and Potato: Human
Health Risk Assessment

From:	A. Lowit, et al

To:	L. Jones

Date:	09/11/00

MRIDs:			None

DP#:	D264638

Subject:	PP#6F4693/6H5749 – Flutolanil ion/on Potatoes and Rice.
MRID# 445262-01.  DP Barcode D264638 [B00-73-78]

From:	A. Krynitsky, D. Swineford

To:	S. Swintzel

Date:	06/25/01

MRIDs:			None

DP#:	D364463

Subject:	Flutolanil. Occupational and Residential Exposure Assessment
for proposed seed treatment uses of flutolanil on soybeans, sugar beets,
and cotton.

From:	N. Tsaur

To:	S. Funk

Date:	11/25/2009

MRIDs:			None

Appendix A:  Chemical Structures

APPENDIX  A.	Chemical Names and Structures of Flutolanil and
Metabolites.

Common name;

Appendix B:   Toxicology

Table B.1.  Acute Toxicity of Flutolanil Technical1

GDLN

Study Type

MRID nos.

Results

Tox Category

§81-1

Acute Oral

40342905

LD50 > 10,000 mg/kg

IV

§81-2

Acute Dermal

40342906

LD50 > 2,000 mg/kg

III

§81-3

Acute Inhalation

40342910

LC50 > 5.98 mg/L (4 hours)

IV

§81-4

Primary Eye  Irritation

40342912

Minimal irritation

IV

§81-5

Primary Skin Irritation

40342915

Not a dermal irritant

IV

§81-6

Dermal Sensitization

40342917

Not a dermal sensitizer

N/A

	1  All studies were conducted on technical grade flutolanil, 98%
purity.

Table B.2. Toxicity Profile of Flutolanil Technical

Guideline No./ Study Type

MRID No. (year)/ Classification /Doses

Results

870.3100 (82-1)

90-day Oral Toxicity Rat - diet

40342919 (1986)/

Acceptable-Guideline/

0, 500, 4000, 20000 ppm (M: 0, 37, 299, 1512 mg/kg/d; F: 0, 44, 339,
1743 mg/kg/d)

NOAEL = 1512 mg/kg/day (HDT),

LOAEL =  not established

At 1512  mg/kg/day (HDT): increased absolute liver weights (males),
increased relative liver weights (males and females), slight decrease in
body weights (males) and slight increases in absolute and relative
thyroid/parathyroid weights were observed.  No treatment-related changes
in ophthalmoscopic, hematological, clinical chemistry, gross pathology,
or histopathology parameters were observed.  Therefore, the increased
liver weights are considered to be an adaptive response to flutolanil
treatment.

870.3150 (82-1)

90-day Oral Toxicity In Nonrodents (Dog) - gelatin capsule

40342920 (1986)/ Acceptable-Guideline/ 0, 80, 400, 2000 mg/kg/d

NOAEL = 80 mg/kg/day,

LOAEL = 400 mg/kg/day based on enlarged livers and increased severity of
hepatic glycogen deposition in both males and females.

At 2000 mg/kg/day (HDT), an elevation in alkaline phosphatase and
cholesterol levels and slight increases in absolute and relative
thyroid/parathyroid weights were observed

870.3200 (82-2)

21-day Dermal Toxicity - Rat

41841205 (1991)/ Acceptable-Guideline/ 0, 1000 mg/kg/d

Systemic NOAEL=  1000 mg/kg/day (limit dose),

Systemic LOAEL > 1000 mg/kg/day.

Dermal irritation NOAEL=  1000 mg/kg/day (limit dose),

Dermal irritation > 1000 mg/kg/day.

870.3250

90-day Dermal Toxicity

Not available

Not available

870.3465

90-day Inhalation Toxicity

Not available

Not available

870.3700a(83-3a)

Prenatal Developmental In Rat - oral gavage

41850804(1987)/ Acceptable-Guideline/0, 40, 200, 1000 mg/kg/d

Maternal NOAEL = 1000 mg/kg/day,

LOAEL > 1000 mg/kg/day,

Developmental NOAEL= 1000 mg/kg/day,

LOAEL > 1000 mg/kg/day.

870.3700b(83-3b)

Prenatal Developmental In Rabbit - oral gavage

40342924(1987)/ Acceptable-Guideline/ 0,40,200,1000 mg/kg/d

Maternal NOAEL= 1000 mg/kg/day,

LOAEL > 1000 mg/kg/day,

Developmental NOAEL = 1000 mg/kg/day,

LOAEL > 1000 mg/kg/day.

870.3800(83-4)

Reproduction And Fertility Effects In Rat - 2 Generation - diet

41850805(1992)/ Acceptable-Guideline/ 0,200,2000,20000 ppm

(M: 0,16,159,1625 mg/kg/d;

F: 0,19,190,1936 mg/kg/d)

Parental/Systemic NOAEL = 1000 mg/kg/day,

LOAEL > 1000 mg/kg/day,

Reproductive NOAEL = 1000 mg/kg/day,

LOAEL > 1000 mg/kg/day.

Offspring NOAEL = 1000 mg/kg/day,

LOAEL > 1000 mg/kg/day.

870.3800(83-4)

Reproduction And Fertility Effects In Rat - 3 Generation - diet

40342923(1982)/ Unacceptable/ 0, 1000, 10000 ppm (M: 0, 63, 661 mg/kg/d;
F: 0, 86, 880 mg/kg/d)

Parental/Systemic NOAEL = 661 mg/kg/day,

LOAEL > 661 mg/kg/day,

Reproductive NOAEL = 661 mg/kg/day,

LOAEL > 661 mg/kg/day.

870.4100a

Chronic Toxicity Rodents

See combined chronic / carcinogenicity study available (see below)

870.4100b (83-1)

Chronic Toxicity Dogs- gelatin capsule

40342922(1982)/ Acceptable-Guideline/ 0, 50, 250, 1250 mg/kg/d

NOAEL = 50 mg/kg/day,

LOAEL = 250 mg/kg/day based on increased incidence of clinical toxic
signs (emesis, salivation, and soft stool) observed from the 65th week.

At 1250 mg/kg/day (HDT), increased incidence of clinical toxic signs
(from the 65th week), decreased body weight gains (from 82nd week in
males and from 81st week in females) and decreased food consumption
(from 79th week in males and from 74th week in females) were observed.

No treatment-related changes in ophthalmoscopic, hematological, clinical
chemistry, organ weights, gross pathology, or histopathology parameters
were observed.

870.4100a & 870.4200

 (83-1 & 83-5)

Chronic/ Oncogenicity Rats - diet

40342921 (1982)/ Acceptable-Guideline/

0, 40, 200, 2000, 10000 ppm

(M: 0, 2, 9, 87, 460 mg/kg/d F: 0, 2, 10, 103, 536 mg/kg/d)

NOAEL = 460 mg/kg/day,

LOAEL = not established

At 460 mg/kg/day (HDT), increased absolute and relative liver weights
(males and females) were observed in the absence of clinical chemistry
or histopathology findings.  Therefore, the increased liver weights are
considered to be an adaptive response to flutolanil treatment.

870.4300(83-2)

Carcinogenicity Mice - diet

41850803(1990)/ Acceptable-Guideline/ 0, 300, 1500, 7000, 30000 ppm (M:
0,32,162,735,3333 mg/kg/d; F: 0, 34, 168, 839, 3676 mg/kg/d)

NOAEL = 735 (M) and 168 (F) mg/kg/day,

LOAEL = 3333 (M) and 839 (F) mg/kg/day based on decreased body weight
gains.

Gene Mutation

870.5375 (84-2), In vitro Chromosomal Aberration Assay in Cultured
Mammalian Cell

40342925(1986)/ Acceptable-Guideline/0, 37, 75, 150 uM/plate

Positive finding, flutolanil induced chromosomal aberrations in cultured
Chinese hamster lung cells in the presence of metabolic activation (S9).

Gene Mutation  870.5100 (84-2), Reverse Mutation Assay

40342926(1981)/  Acceptable-Guideline/0, 10, 50, 100, 500, 1000, 5000,
10000, 25000 ug/plate.

Negative (with and without S-9 metabolic activator) at doses up to 25
mg/plate in the increase in revertant colonies using Salmonella strains
TA98, TA10, TA1535, TA1537, and TA1538 and in the E. Coli WP2 uvrA
strain.

Gene Mutation  870.5375 (84-2), Gene Mutation in Cultured Mammalian
Cells (Mouse Lymphoma Cells)

41841207(1989)/ Acceptable-Guideline/0,  6, 15, 30, 60, 80, 100 ug/mL.

Negative (either in the presence or absence of S9 activation) for the
induction of forward mutations at the TK+/- locus in L5178Y mouse
lymphoma cells.

Cytogenetics

870.5395 (84-2), Mouse Micronucleus

40342927(1983)/ Acceptable-Guideline/0, 6400, 8000, 10000 mg/kg either
in a single dose or 10 gm/kg/day over 4 days by gastric intubation to
BDF1 mice (6/sex/group).

Negative up to a dose of 10000 mg/kg in the induction of micronuclei in
the bone marrow erythrocytes of male and female mice.

Cytogenetics  870.5385 (84-2), Mammalian Cells in Culture Cytogenetics
Assay in Human Lymphocytes

42606628(1990)/ Acceptable-Guideline/0, 120, 250, 500, 1000 ug/mL.

Negative in the structural chromosome assay.  There was no significant
increase in the frequency of aberrations with any treatment levels,
either with or without activation.

Other Genotoxicity Effects  84-2,  In Vitro Unscheduled DNA Synthesis
Assays in Primary Rat Hepatocytes

41841206(1989)/ Acceptable- Nonguideline/0,  2.67, 27, 53, 80 ug/mL.

Negative in the induction of unscheduled DNA synthesis in primary rat
hepatocytes.

870.6200a

Acute Neurotoxicity Screening Battery

Not available

Not available.  Required.

870.6200b

Subchronic Neurotoxicity Screening Battery

Not available

Not available. Required.

870.6300

Developmental Neurotoxicity

Not available

Not available. Conditionally required.

870.7485

Metabolism And Pharmacokinetics -Rat

42606602(1992)/ Acceptable-Guideline/ single oral dose of 20 and 1000
mg/kg and

repeated oral doses of 20 mg/kg for 14 days

No appreciable tissue levels of flutolanil at study termination (168
hours post-dose).

20 mg/kg: urine (40%) and feces (40% of dose).

Repeated dose of 20 mg/kg: urine (70%) and feces (10%)

1000 mg/kg: urine (10%) and feces (66-78%)

Urinary metabolite by TLC:   M-4
[N-(3'-hydroxyphenyl)-2-(trifluoromethyl)   benzamide]

Fecal metabolite by TLC:  Mainly parent chemical with limited conversion
to M-4.

870.7600

Dermal penetration - Rat

Not available

Not available. Required.

  870.7800

Immunotoxicity	Not available.	Immunotoxicity  Required.

Special Studies

Not available

Not available

Appendix C:  Toxicology Study Requirements Rationale

Guideline Number: 870.6200

Study Title:  Neurotoxicity Battery (Acute and Subchronic Studies)

Test Substance: Flutolanil

Rationale for Requiring the Data

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

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

Practical Utility of the Data

How will the data be used?

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

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

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

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

OPPTS Guideline Number:  870.7800

Study Title:  Immunotoxicity

Test Substance: Flutolanil

Rationale for Requiring the Data

	The immunotoxicity study is a new data requirement under 40CFR §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
(such as 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.

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	  PAGE  24  of   NUMPAGES  35


[Federal Register Volume 86, Number 56 (Thursday, March 25, 2021)]
[Notices]
[Pages 15948-15950]
[FR Doc No: 2021-06202]

-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2007-D-0369]

Product-Specific Guidances; Draft and Revised Draft Guidances for
Industry; Availability

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of availability.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA or Agency) is announcing
the availability of additional draft and revised draft product-specific
guidances. The guidances provide product-specific recommendations on,
among other things, the design of bioequivalence (BE) studies to
support abbreviated new drug applications (ANDAs). In the Federal
Register of June 11, 2010, FDA announced the availability of a guidance
for industry entitled ``Bioequivalence Recommendations for Specific
Products'' that explained the process that would be used to make
product-specific guidances available to the public on FDA's website.
The guidances identified in this notice were developed using the
process described in that guidance.

DATES: Submit either electronic or written comments on the draft
guidances by May 24, 2021 to ensure that the Agency considers your
comment on these draft guidances before it begins work on the final
versions of the guidances.

ADDRESSES: You may submit comments on any guidance at any time as
follows:

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: https://www.regulations.gov.
Follow the instructions for submitting comments. Comments submitted
electronically, including attachments, to https://www.regulations.gov
will be posted to the docket unchanged. Because your comment will be
made public, you are solely responsible for ensuring that your comment
does not include any confidential information that you or a third party
may not wish to be posted, such as medical information, your or anyone
else's Social Security number, or confidential business information,
such as a manufacturing process. Please note that if you include your
name, contact information, or other information that identifies you in
the body of your comments, that information will be posted on https://www.regulations.gov.

     If you want to submit a comment with confidential
information that you do not wish to be made available to the public,
submit the comment as a written/paper submission and in the manner
detailed (see ``Written/Paper Submissions'' and ``Instructions'').

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand Delivery/Courier (for written/paper
submissions): Dockets Management Staff (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Dockets
Management Staff, FDA will post your comment, as well as any
attachments, except for information submitted, marked and identified,
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No.
FDA-2007-D-0369 for ``Product-Specific Guidances; Draft and Revised
Draft Guidances for Industry.'' Received comments will be placed in the
docket and, except for those submitted as ``Confidential Submissions,''
publicly viewable at https://www.regulations.gov or at the Dockets
Management Staff between 9 a.m. and 4 p.m., Monday through Friday, 240-
402-7500.
     Confidential Submissions--To submit a comment with
confidential information that you do not wish to be made publicly
available, submit your comments only as a written/paper submission. You
should submit two copies total. One copy will include the information
you claim to be confidential with a heading or cover note that states
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will
review this copy, including the claimed confidential information, in
its consideration of comments. The second copy, which will have the
claimed confidential information redacted/blacked out, will be
available for public viewing and posted on https://www.regulations.gov.
Submit both copies to the Dockets Management Staff. If you do not wish
your name and contact information to be made publicly available, you
can provide this information on the cover sheet and not in the body of
your comments and you must identify this information as
``confidential.'' Any information marked as ``confidential'' will not
be disclosed except in accordance with 21 CFR 10.20 and other
applicable disclosure law. For more information about FDA's posting of
comments to public dockets, see 80 FR 56469, September 18, 2015, or
access the information at: https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: For access to the docket to read background documents or
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in
the heading of this document, into the ``Search'' box and follow the
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane,
Rm. 1061, Rockville, MD 20852,<PHONE_NUMBER>.
    You may submit comments on any guidance at any time (see 21 CFR
10.115(g)(5)).
    Submit written requests for single copies of the draft guidances to
the Division of Drug Information, Center for Drug Evaluation and
Research, Food and Drug Administration, 10001 New Hampshire Ave.,
Hillandale Building, 4th Floor, Silver Spring, MD 20993-0002. Send one
self-addressed adhesive label to assist that office in processing your
requests. See the SUPPLEMENTARY INFORMATION section for electronic
access to the draft guidance documents.

FOR FURTHER INFORMATION CONTACT: Kris Andre, Center for Drug Evaluation
and Research, Food and Drug Administration, 10903 New Hampshire Ave.,
Bldg. 75, Rm. 4728, Silver Spring, MD 20993-0002,<PHONE_NUMBER>.

SUPPLEMENTARY INFORMATION:

I. Background

    In the Federal Register of June 11, 2010 (75 FR 33311), FDA
announced the availability of a guidance for industry entitled
``Bioequivalence Recommendations for Specific Products'' that explained
the process that would be used to make product-specific guidances
available to the public on FDA's website at https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.
    As described in that guidance, FDA adopted this process as a means
to develop and disseminate product-specific guidances and provide a
meaningful opportunity for the public to consider and comment on those
guidances. Under that process, draft guidances are posted on FDA's
website and announced periodically in the Federal Register. The public
is encouraged to submit comments on those recommendations within 60
days of their announcement in the Federal Register. FDA considers any
comments received and either publishes final guidances or publishes
revised draft guidances for comment. Guidances were last announced in
the Federal Register on November 19, 2020. This notice announces draft
product-specific guidances, either new or revised, that are posted on
FDA's website.

II. Drug Products for Which New Draft Product-Specific Guidances Are
Available

    FDA is announcing the availability of new draft product-specific
guidances for industry for drug products containing the following
active ingredients:

     Table 1--New Draft Product-Specific Guidances for Drug Products
------------------------------------------------------------------------
                          Active ingredient(s)
-------------------------------------------------------------------------
Bremelanotide acetate.
Calcifediol.
Cysteamine bitartrate.
Degarelix acetate.
Elexacaftor, Ivacaftor, Tezacaftor; Ivacaftor.
Entrectinib.
Ethinyl estradiol; levonorgestrel (multiple referenced listed drugs).
Fedratinib hydrochloride.
Ferric maltol.
Guanfacine hydrochloride.
Istradefylline.
Ledipasvir; Sofosbuvir.
Monomethyl fumarate.
Octreotide acetate (multiple referenced listed drugs).
Penicillin G benzathine.
Selinexor.
Siponimod fumaric acid.
Sofosbuvir.
Solriamfetol hydrochloride.
Testosterone undecanoate.
------------------------------------------------------------------------

III. Drug Products For Which Revised Draft Product-Specific Guidances
Are Available

    FDA is announcing the availability of revised draft product-
specific guidances for industry for drug products containing the
following active ingredients:

   Table 2--Revised Draft Product-Specific Guidances for Drug Products
------------------------------------------------------------------------
                          Active ingredient(s)
-------------------------------------------------------------------------
Cannabidiol.
Ciclesonide.
Doxycycline hyclate.
Fenoprofen calcium.
Ipratropium bromide.
Ivacaftor; Ivacaftor, Tezacaftor.
Labetalol hydrochloride.
Nitazoxanide (multiple referenced listed drugs).
Pazopanib hydrochloride.
Regorafenib.
Rucaparib camsylate.
Ursodiol (multiple referenced listed drugs).
------------------------------------------------------------------------

    For a complete history of previously published Federal Register
notices related to product-specific guidances, go to https://www.regulations.gov and enter Docket No. FDA-2007-D-0369.
    These draft guidances are being issued consistent with FDA's good
guidance practices regulation (21 CFR 10.115). These draft guidances,
when finalized, will represent the current thinking of FDA on, among
other things, the product-specific design of BE studies to support
ANDAs. They do not establish any rights for any person and are not
binding on FDA or the public. You can use an alternative approach if it
satisfies the requirements of the applicable statutes and regulations.

IV. Paperwork Reduction Act of 1995

    FDA tentatively concludes that these draft guidances contain no
collection of information. Therefore, clearance by the Office of
Management and Budget under the Paperwork Reduction Act of 1995 is not
required.

V. Electronic Access

    Persons with access to the internet may obtain the draft guidances
at either https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs or https://www.regulations.gov.

    Dated: March 22, 2021.
Lauren K. Roth,
Acting Principal Associate Commissioner for Policy.
[FR Doc. 2021-06202 Filed 3-24-21; 8:45 am]
BILLING CODE 4164-01-P