UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF

PREVENTION, PESTICIDES AND

TOXIC SUBSTANCES

[MEMORANDUM]{.underline}

Date: 07-August-2008

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

  ------------------------------ ----------------------------------------
  PC Code: 128975                DP Barcode: 349580

  MRID No.: None                 Registration No.: None

  Petition No.: None             Regulatory Action: Registration Review
                                 Scoping Document

  Assessment Type: None          Reregistration Case No.: None

  TXR No.: None                  
  ------------------------------ ----------------------------------------

FROM: Myron S. Ottley, Pharmacologist

Barry O'Keefe, Senior Biologist

Amelia Acierto, Chemist

Registration Action Branch 3

Health Effects Division (7509P)

Office of Pesticide Programs

THRU: Paula Deschamp, Branch Chief

Registration Action Branch 3

Health Effects Division (7509P)

Office of Pesticide Programs

TO: Tom Myers / Jill Bloom (RM-52

Reregistration Branch 2

Special Review and Reregistration Division (7508P)

Office of Pesticide Programs

**Executive Summary**

Flutolanil
\[N-\[3-(1-methylethoxy)-phenyl\]-2-(trifluoromethyl)-benzamide\] is a
systemic benzanilide fungicide which has preventative and curative
actions against *Rhizoctonia solani*, which causes limb/pod rot in
peanuts, sheath blight in rice, and black scurf in potatoes. Flutolanil
is also effective in controlling Southern stem rot (white mold)
*Sclerotium rolfsii* in peanuts and rust diseases of several crops.

Flutolanil is currently registered for food and non-food uses. Food uses
include application to wheat, soybean, peanut, potato, and rice.
Tolerances are also established for ruminant byproducts and other organ
meats. Non-food uses of flutolanil include turf, greenhouse, and potted
ornamentals.

The acute, subchronic and chronic toxicity of flutolanil is generally
low, producing low toxicity at moderate to high dose levels. An acute
dietary endpoint was not identified for flutolanil. A chronic dietary
endpoint was identified based on a chronic dog study, with the chronic
RfD set at 0.50 mg/kg/day based on an increased incidence of clinical
signs (NOAEL = 50 mg/kg/day) at the LOAEL of 250 mg/kg/day. Uncertainty
factors (including FQPA) totaled 100. Endpoints were not identified for
incidental oral, dermal or inhalation exposure. Flutolanil is considered
to be non-carcinogenic. The chronic dietary exposure estimates for food
and drinking water do not exceed the Agency's level of concern for the
general U.S. population (\<1% of the population adjusted dose (PAD) and
all population subgroups ([\<]{.underline} 1% PAD).

The HED Flutolanil Registration Review Team has evaluated the most
recent human health assessments and database for the fungicide
flutolanil, supporting several Section 3 registered products and Section
24C registrations by Nichino America, Inc. (formerly Nihon Nohyaku), to
determine the scope of work necessary to support the Registration Review
process. The most recent human health assessment (November 2007), which
addressed requests for inadvertent or indirect tolerances for use on
soybean, wheat, corn and cotton adequately reflects current
registrations and uses of flutolanil, current Food Quality Protection
Act (FQPA) policies, and adequately addresses susceptibility of infants
and children, and aggregate exposures**.** For a complete listing of the
registrations, please see the Attachments section.

**Introduction**

The HED Flutolanil Registration Review Team has evaluated the human
health assessments for the fungicide flutolanil to determine the scope
of work necessary to support the Registration Review. A comprehensive
listing of the documents considered is presented in the reference
section of this document. The purpose of this screen is to determine
whether sufficient data are available and whether a new human health
risk assessment is needed to support continued registration. The HED
Risk Assessment team is Myron Ottley, Barry O'Keefe, and Amelia M.
Acierto.

The HED registration review team contacted the Pesticide Management
Regulatory Agency (PMRA) of Canada, and the California Department of
Pesticide Regulation (CalDPR) to determine if they are actively working
on the active ingredient flutolanil, or are planning on doing so in the
near future. The team has learned that flutolanil has never been
registered in Canada and therefore not subject to re-evaluation.
Flutolanil has been placed in the low priority category for risk
assessment by CalDPR, and they do not expect to conduct any risk
assessment unless there are some significant changes in the established
use patterns. Additionally, the HED registration review team accessed
the OECD monograph document repository. An OECD Monograph was completed
for flutolanil in May 2006. Flutolanil is authorized for use on various
crops in Belgium, Finland, France, Great Britain, Netherlands, and Spain

No new data germane to risk assessment of flutolanil were available from
the open literature. The primary sources for the status update were the
risk assessments on the registered uses in peanut, potato and rice (F.
Fort, D334156, D335050, 11/26/07). The molecular structure, chemical
names, and other identifiers are found in the chemical identity table
attached to this document.

Flutolanil is currently registered for food and non-food uses. Food uses
include broadcast foliar applications and/or in-furrow applications to
soybean, wheat, peanuts, potatoes, and rice. Flutolanil is also used as
a tree bark dust application -- Non-food uses include turf, greenhouse,
and potted ornamentals. The currently registered uses of flutolanil will
result in exposures in food and drinking water. Residential uses of
flutolanil can result in dermal, inhalation, and incidental oral
exposures. Occupational uses will result in exposures via the dermal and
inhalation routes.

**Hazard Identification/Toxicology**

Overall, the quality of the toxicology data base for flutolanil is good
and confidence in the hazard and dose response assessments is high. At
the time of the last human health risk assessment (11/26/07), the
toxicology data base was deemed to be complete, adequate to support
existing and proposed registrations, and there were no data gaps. No new
data have been submitted since then; however, acute and subchronic
neurotoxicity studies and an immunotoxicity study are now required under
the revised 40 CFR §158.340. For more detailed information about the
toxicology of flutolanil, please refer to the Hazard Identification
Assessment Review Committee Report (HIARC report dated 11/2/99; TXR No.
013851).

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. Acute
toxicity data show 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.

Subchronic and chronic toxicity studies showed that the primary effects
of flutolanil are increases in liver weight combined with decreases in
body weight. The available data for flutolanil do not show neurotoxic,
carcinogenic, nor mutagenic effects. 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.

The FQPA Safety Factor 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.

Only a chronic dietary endpoint was identified for flutolanil (Table 4).
HED selected a chronic RfD/PAD of 0.50 mg/kg/day (NOAEL = 50 mg/kg/day;
Uncertainty Factor = 100). This chronic RfD/PAD is based on the chronic
oral toxicity study in dogs in which increased incidences of clinical
signs (emesis, salivation, and soft stool) occurred at LOAEL = 250
mg/kg/day following 65 weeks of exposure.

**Dietary Exposure**

Sufficient residue data for flutolanil are available to assess
tolerances and conduct a dietary risk assessment. The most recent
chronic dietary food and drinking water 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 from 1994-1996 and
1998. An acute exposure assessment for flutolanil was not performed
since an appropriate endpoint attributable to a single oral dose was not
established.

The drinking water residues used in the dietary risk assessment were
provided by the Environmental Fate and Effects Division (EFED) in the
memorandum: "Flutolanil Tier II Estimated Environmental Concentration
for Use in the Human Health Drinking Water Risk Assessment" (D260066, S.
Abel, 12/13/99). The surface water and groundwater, estimated drinking
water concentrations (EDWCs) were generated from PRZM/EXAMS and from
Tier I SCI-GROW analysis, respectively. The inputs and assumptions used
to generate the EDWCs for flutolanil adequately cover the currently
registered use patterns. The water residues were incorporated directly
in the DEEM-FCID into the food categories "water, direct, all sources"
and "water, indirect, all sources."

The chronic dietary assessments for food and drinking water demonstrated
that exposures for the general population and all population subgroups
were less than 1% of the population adjusted dose. These assessments are
considered conservative as they were conducted assuming tolerance level
residues and 100% crop treated.

**Residential Exposure**

There are 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. Therefore, there is currently adequate
information to support non-occupational/residential uses of flutolanil.
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.

**Aggregate Risk Assessment**

Aggregate risk assessments for flutolanil 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, inhalation, and incidental oral
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) 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%). Therefore, the chronic aggregate risk associated with the
registered uses of flutolanil does not exceed HED's level of concern for
the general U.S. population or any population subgroups. Should HED
identify new regulatory endpoints for risk assessment purposes, revise
the current safety factors for flutolanil, or update the dietary
assessment, a new aggregate risk assessment may need to be conducted.

**Occupational Exposure**

Occupational handlers may be exposed to flutolanil during mixing,
loading, and application of products containing flutolanil.
Additionally, workers may be exposed to flutolanil residues during
postapplication activities. 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 endpoints attributable to
short- or intermediate-term exposures have been identified, and the
current use patterns do not indicate long-term exposure potential.
Therefore, there is currently adequate information to support
occupational uses of flutolanil. However, should HED identify new
regulatory endpoints for risk assessment purposes for flutolanil in the
future, then occupational exposures may needed to be assessed.

**Public Health and Pesticide Epidemiology Data**

A summary report listing incidents reported to EPA for flutolanil will
be provided for the docket. The reported incidents will be screened in
more detail during the development of the Final Work Plan for
flutolanil.

**Tolerance Assessment**

Tolerances have been established in 40 CFR§180.484 for residues of
flutolanil and its metabolites converted to 2-trifluoromethyl)benzoic
acid (calculated as flutolanil) in/on plant and livestock commodities.

**International Harmonization**

Codex Maximum Residue Limits (MRLs) for flutalonil and transformation
products containing the 2-trifluoromethyl-benzoic acid moiety, expressed
as flotolanil, are established in rice commodities at 1 to 10 ppm, and
in livestock commodities at 0.05 to 0.2 ppm.

The US tolerances for both plant and livestock commodities are expressed
as flutolanil, N-(3-(1-methylethoxy)phenyl)-2-(trifluoromethy)benzamide,
and its metabolites converted to 2-(trifluoromethyl) benzoic acid and
calculated as flutolanil. These US tolerance, for rice, peanuts and
potatoes, are listed under 40 CFR §180.484(a) at 0.2 -- 25.0 ppm, and
for soybean and wheat, are listed under 40 CFR §180.484(d) at 0.05 --
8.0 ppm. US tolerances for livestock commodities are also established
under §180.484(a) at levels ranging from 0.05 ppm for egg, milk, meat,
and meat byproducts to 2.0 ppm for liver.

The US and Codex residue definitions for livestock commodities both
include flutolanil and its metabolites converted to 2-(trifluoromethyl)
benzoic acid and calculated as flutolanil; however, there are
quantitative differences in the US tolerance levels and Codex MRLs. In
the case of plant commodities, the US and Codex residue definitions as
well as US tolerance levels and Codes MRLs are different. Future work is
needed to achieve harmonization in this area. For a complete listing of
US Tolerances and Codex MRLs, please refer to Table 5 in the Attachments
section.

No Canadian or Mexican MRLs have been established.

**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.epa.gov/compliance/resources/policies/ej/exec_order_12898.pdf>.
The Office of Pesticide Programs (OPP) typically considers the highest
potential exposures from the legal use of a pesticide when conducting
human health risk assessments, including, but not limited to, people who
obtain drinking water from sources near agricultural areas, the
variability of diets within the U.S., and people who may be exposed when
harvesting crops. Should these highest exposures indicate potential
risks of concern, OPP further refines the risk assessments to ensure
that the risk estimates are based on the best available information.

**Cumulative**

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
http://www.epa.gov/pesticides/cumulative/.

**Human Studies**

Flutolanil risk assessments rely in part on data from studies in which
adult human subjects were intentionally exposed to a pesticide or other
chemical. These studies have been determined to require a review of
their ethical conduct, and have received that review.

**Data Requirements**

**Toxicology**

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 studies are:

Acute neurotoxicity \[OPPTS Guideline 870.6200a\]

Subchronic neurotoxicity \[OPPTS Guideline 870.6200b\]

Immunotoxicity \[OPPTS Guideline 870.7800\]

For a more complete rationale on these data requirements, please see
Tables 6 and 7.

**Chemistry**

The availability of the analytical reference standards for flutolanil
and its metabolites has been verified and reported in 2007 to be either
"not in stock" or "have expired" (D335050, F. Fort, 11/26/2007). An
updated inventory from the National Pesticide Standard Repository
(e-mail, Dallas Wright, EPA, Analytical Chemistry Laboratory,
08/14/2008) showed that the analytical standards for flutolanil \[with
expiration date of 10/27/2011\] and flutolanil metabolite,
2-trifluoromethyl benzoic acid metabolites \[which expired 8/12/2008\]
are available. Standards for metabolites M-2 and M-4 are still not in
stock, and standards for metabolites M-3 and M-7 \[which expired on
1/1/04 and 4/1/02, respectively\] have not been replenished nor
recertified (updated Certificate of Analysis). Therefore, the
requirements for standards have not been satisfied.

The Agency previously concluded that the following additional data are
required to support the enforcement method AU/95R/04: (1) additional
radio validation data from all previously submitted metabolism studies;
and (2) additional recovery data for potato. In addition, because the
method is a common moiety method, a confirmatory method was required
that is able to confirm the identity and amount of all residues of
concern. These requirements do not appear to have been addressed, and
the results of the petition method validation were not available. In
addition, we note that the method must be rewritten to include
instructions for analysis of additional crops including potatoes and
rotational crops for which tolerances are to be established.

**References**

+---------+--------+----------+---------------------------------------+
| **A     | **Bar  | **Date** | **Title**                             |
| uthor** | code** |          |                                       |
+=========+========+==========+=======================================+
| M. Xue  | D      | 12       | PP# 6F4693 & PP#4F4380. Flutolanil    |
|         | 261391 | /10/1999 | in/on Potatoes and Rice. Memo to the  |
|         |        |          | Metabolism Assessment Review          |
|         |        |          | Committee (MARC)                      |
+---------+--------+----------+---------------------------------------+
| W.      | D      | 7        | PP6F4693/PP6H5749. Flutolanil in/on   |
| Wassell | 267571 | /21/2000 | Potatoes and Rice. Evaluation of      |
|         |        |          | Independent Laboratory Valiation      |
|         |        |          | Data.                                 |
+---------+--------+----------+---------------------------------------+
| M. Xue  | D      | 7        | Reevaluation of Chronic Dietary       |
|         | 265019 | /24/2000 | Exposure Analyses for Proposed        |
|         |        |          | Tolerances for Flutolanil in/on Rice, |
|         |        |          | Potatoes and Potato Processed         |
|         |        |          | Commodities. (PC Code 128975.         |
+---------+--------+----------+---------------------------------------+
| M. Xue  | D      | 8/2/2000 | PP# 6F4693 & PP#6H5749.. Flutolanil   |
|         | 267657 |          | in/on Potatoes and Rice. Review of    |
|         |        |          | Storage Stability and Magnitude of    |
|         |        |          | Residue Data for Rice.                |
+---------+--------+----------+---------------------------------------+
| A.      | D      | 9        | Residential uses of flutolanil        |
| Lowit,  | 268880 | /11/2000 | include turf, greenhouse, and potted  |
|         |        |          | ornamentals                           |
| J.      |        |          |                                       |
| Arthur  |        |          |                                       |
|         |        |          |                                       |
| M.      |        |          |                                       |
| Bonner  |        |          |                                       |
|         |        |          |                                       |
| M. Xue  |        |          |                                       |
+---------+--------+----------+---------------------------------------+
| M. Xue  | D2     | 1        | PP# 6F4693 & PP#6H5749.. Flutolanil   |
|         | 26667, | 2/1/2000 | in/on Potatoes, Potato Processed      |
|         | D22    |          | Commodities, Rice Grain and Rice      |
|         | 6670,D |          | Straw. Evaluation of Analytical       |
|         | 247229 |          | Methods and Residue Data.             |
+---------+--------+----------+---------------------------------------+
| M. Xue  | D      | 11       | ID#071711-00008, Flutolanil: Label    |
|         | 278457 | /28/2001 | Amendment for Rotational Crop         |
|         |        |          | Plantback Intervals for Corn,         |
|         |        |          | Soybeans, Cotton and Sorghum.         |
+---------+--------+----------+---------------------------------------+
| F. Fort | D      | 1        | Flutolanil Chronic Aggregate Dietary  |
|         | 346322 | 1/1/2007 | (Food and Drinking Water) Exposure    |
|         |        |          | and Risk Assessment for the Section 3 |
|         |        |          | Registration Action.                  |
+---------+--------+----------+---------------------------------------+
| F. Fort | D      | 11       | Flutolanil. Petitions for             |
|         | 335050 | /26/2007 | 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 PP6F7070 (Corn and     |
|         |        |          | Cotton).                              |
+---------+--------+----------+---------------------------------------+
| W.      | D      | 1        | WA010016; Special Local Needs         |
| Wassell | 277210 | 1/7/2001 | Registration (24c) for the use of     |
|         |        |          | Flutolanil on Potatoes. Review of     |
|         |        |          | residue Data for Potatoes.            |
+---------+--------+----------+---------------------------------------+

> **ATTACHMENTS**

+-------------------+--------------------------------------------------+
| **Table 1.        |                                                  |
| Flutolanil        |                                                  |
| Nomenclature**.   |                                                  |
+===================+==================================================+
| Chemical          | ![                                               |
| structure         | ](media/image3.wmf){width="2.5104166666666665in" |
|                   | height="1.6666666666666667in"}                   |
+-------------------+--------------------------------------------------+
| Common name       | Flutolanil                                       |
+-------------------+--------------------------------------------------+
| Company           | N/A                                              |
| experimental name |                                                  |
+-------------------+--------------------------------------------------+
| IUPAC name        | α,α,α-trifluoro-3'-isopropoxy-o-toluanilide      |
+-------------------+--------------------------------------------------+
| CAS name          | N-\[3-(1-me                                      |
|                   | thylethoxy)phenyl\]-2-(trifluoromethyl)benzamide |
+-------------------+--------------------------------------------------+
| CAS registry      | 66332-96-5                                       |
| number            |                                                  |
+-------------------+--------------------------------------------------+
| End-use product   | MonCoat MZ® (1.5% tree bark based dust           |
| (EP)              | formulation; EPA Reg. No. 71711-8; MAI           |
|                   | formulation containing mancozeb) and Moncut®     |
|                   | 70-DF (70% DF formulation; EPA Reg. No.          |
|                   | 71711-14)                                        |
+-------------------+--------------------------------------------------+
| Chemical          | ![](media/image4.wmf){width="1.21875in"          |
| structure of      | height="0.9375in"}                               |
| common moiety     |                                                  |
| determined by     | 2-trifluoromethylbenzoic acid (2-TFBA)           |
| enforcement       |                                                  |
| method            |                                                  |
+-------------------+--------------------------------------------------+

+--------------------+-------------------------+----------------------+
| **Table 2.         |                         |                      |
| 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]{.underline}  |                      |
|                    |                         |                      |
|                    | Methanol 232 g/L        |                      |
|                    |                         |                      |
|                    | n-Hexane 0.9 g/L        |                      |
+--------------------+-------------------------+----------------------+
| Vapor pressure     | 4.87 x 10^-8^ mm Hg at  |                      |
|                    | 25 °C                   |                      |
+--------------------+-------------------------+----------------------+
| Dissociation       | Not applicable          |                      |
| constant, pK~a~    |                         |                      |
+--------------------+-------------------------+----------------------+
| Octanol/water      | log P~OW~ = 3.74        |                      |
| partition          |                         |                      |
| coefficient,       |                         |                      |
| Log(K~OW~)         |                         |                      |
+--------------------+-------------------------+----------------------+
| UV/visible         | Not available           |                      |
| absorption         |                         |                      |
| spectrum           |                         |                      |
+--------------------+-------------------------+----------------------+

+-----------------+-----------------------+----------------------------+
| **Table 3.      |                       |                            |
| Chemical Names  |                       |                            |
| and Structures  |                       |                            |
| of Flutolanil   |                       |                            |
| and             |                       |                            |
| Metabolites.**  |                       |                            |
+=================+=======================+============================+
| Common name;    | Chemical name         | Chemical structure         |
|                 |                       |                            |
| Company code    |                       |                            |
+-----------------+-----------------------+----------------------------+
| Flutolanil; M1  | N-\[3\'-(1-methylet   | ![](media                  |
|                 | hoxy)phenyl\]-2-(trif | /image5.wmf){width="2.5in" |
|                 | luoromethyl)benzamide | heig                       |
|                 |                       | ht="1.6666666666666667in"} |
+-----------------+-----------------------+----------------------------+
| M-2             | N                     | ![](media                  |
|                 | -\[4\'-hydroxy-3\'-(1 | /image6.wmf){width="2.5in" |
|                 | -methylethoxy)phenyl\ | height="1.65625in"}        |
|                 | ]-2-(trifluoromethyl) |                            |
|                 | benzamide             |                            |
+-----------------+-----------------------+----------------------------+
| M-3             | N-\[3\'-(2-hy         | ![](media/image7.wmf){wi   |
|                 | droxy-1-methylethoxy) | dth="2.5861111111111112in" |
|                 | phenyl\]-2-(trif      | heig                       |
|                 | luoromethyl)benzamide | ht="1.5729166666666667in"} |
+-----------------+-----------------------+----------------------------+
| M-4             | N-(3\'-h              | ![](media/image8.wmf){wi   |
|                 | ydroxyphenyl)-2-(trif | dth="2.0416666666666665in" |
|                 | luoromethyl)benzamide | heig                       |
|                 |                       | ht="1.4166666666666667in"} |
+-----------------+-----------------------+----------------------------+
| M-5             | N-\[3\',4\'-(         | ![](media/image9.wmf){wi   |
|                 | dihydroxy)phenyl\]-2- | dth="2.3229166666666665in" |
|                 | (trifluoromethyl)     | heig                       |
|                 | benzamide             | ht="1.4270833333333333in"} |
+-----------------+-----------------------+----------------------------+
| M-6             | N-(3\'-methoxy)phenyl | ![](media/image10.wmf){wi  |
|                 | -2-(trif              | dth="2.3645833333333335in" |
|                 | luoromethyl)benzamide | heig                       |
|                 |                       | ht="1.4270833333333333in"} |
+-----------------+-----------------------+----------------------------+
| M-7             | N-(4\'-hydro          | ![](media/image11.wmf){wi  |
|                 | xy-3\'-methoxy)phenyl | dth="2.3645833333333335in" |
|                 | -2-(trif              | heig                       |
|                 | luoromethyl)benzamide | ht="1.4270833333333333in"} |
+-----------------+-----------------------+----------------------------+
| M-11            | 2                     | ![](media/image12.wmf){w   |
|                 | -\[\[3-\[2-(trifluoro | idth="2.584722222222222in" |
|                 | methyl)benzoyl\]-amin | heig                       |
|                 | o\]phenoxy\]propanoic | ht="1.6180555555555556in"} |
|                 | acid                  |                            |
+-----------------+-----------------------+----------------------------+
| 2-TFBA:         | 2-trifluoromethyl     | ![](media/imag             |
|                 | benzoate              | e13.wmf){width="1.21875in" |
|                 |                       | height="0.9375in"}         |
+-----------------+-----------------------+----------------------------+

+------------+---------+--------+--------+---------------------------+
| **Table 4  |         |        |        |                           |
| Summary of |         |        |        |                           |
| Tox        |         |        |        |                           |
| icological |         |        |        |                           |
| Doses and  |         |        |        |                           |
| Endpoints  |         |        |        |                           |
| for        |         |        |        |                           |
| Flutolanil |         |        |        |                           |
| for Use in |         |        |        |                           |
| Dietary    |         |        |        |                           |
| and        |         |        |        |                           |
| Non-Oc     |         |        |        |                           |
| cupational |         |        |        |                           |
| Human Risk |         |        |        |                           |
| Ass        |         |        |        |                           |
| essments** |         |        |        |                           |
+============+=========+========+========+===========================+
| []{.mark}  | **Point | **Unc  | **RfD, | **Study and Toxicological |
|            | of      | er-tai | PAD,   | Effects**                 |
| **         | Depa    | nty/** | Level  |                           |
| Exposure** | rture** |        | of     |                           |
|            |         | **FQPA | C      |                           |
| **         |         | Fac    | oncern |                           |
| Scenario** |         | tors** | for    |                           |
|            |         |        | Risk   |                           |
|            |         |        | A      |                           |
|            |         |        | ssess- |                           |
|            |         |        | ment** |                           |
+------------+---------+--------+--------+---------------------------+
| Acute      | No      |        |        |                           |
| Dietary    | appr    |        |        |                           |
|            | opriate |        |        |                           |
| (All       | toxico  |        |        |                           |
| po         | logical |        |        |                           |
| pulations) | e       |        |        |                           |
|            | ndpoint |        |        |                           |
|            | attri   |        |        |                           |
|            | butable |        |        |                           |
|            | to a    |        |        |                           |
|            | single  |        |        |                           |
|            | e       |        |        |                           |
|            | xposure |        |        |                           |
|            | (dose)  |        |        |                           |
|            | was     |        |        |                           |
|            | ide     |        |        |                           |
|            | ntified |        |        |                           |
|            | from    |        |        |                           |
|            | the     |        |        |                           |
|            | oral    |        |        |                           |
|            | t       |        |        |                           |
|            | oxicity |        |        |                           |
|            | studies |        |        |                           |
|            | in      |        |        |                           |
|            | cluding |        |        |                           |
|            | develo  |        |        |                           |
|            | pmental |        |        |                           |
|            | t       |        |        |                           |
|            | oxicity |        |        |                           |
|            | studies |        |        |                           |
|            | in rats |        |        |                           |
|            | and     |        |        |                           |
|            | r       |        |        |                           |
|            | abbits. |        |        |                           |
|            | This    |        |        |                           |
|            | risk    |        |        |                           |
|            | ass     |        |        |                           |
|            | essment |        |        |                           |
|            | is      |        |        |                           |
|            | [no     |        |        |                           |
|            | t]{.und |        |        |                           |
|            | erline} |        |        |                           |
|            | re      |        |        |                           |
|            | quired. |        |        |                           |
+------------+---------+--------+--------+---------------------------+
| []{.mark}  | []      | UF~    | cRfD = | 2-year Chronic study in   |
|            | {.mark} | A~=10X |        | dogs.                     |
| Chronic    |         |        | 0.5    |                           |
| Dietary    | NOAEL=  | UF~    | mg/    | MRID no. 40342922         |
|            | 50      | H~=10X | kg/day |                           |
| (All       | mg      |        |        | LOAEL = 250 mg/kg/day     |
| po         | /kg/day | FQPA   | cPAD = | based on increased        |
| pulations) |         | SF =   |        | incidence of clinical     |
|            | []      | 1X     | 0.5    | toxic signs (emesis,      |
|            | {.mark} |        | mg/    | salivation, and soft      |
|            |         |        | kg/day | stool)                    |
|            | []      |        |        |                           |
|            | {.mark} |        |        |                           |
+------------+---------+--------+--------+---------------------------+
| []{.mark}  | No      |        |        |                           |
|            | appr    |        |        |                           |
| Incidental | opriate |        |        |                           |
| Oral       | e       |        |        |                           |
| Short- and | ndpoint |        |        |                           |
| intermed   | was     |        |        |                           |
| iate-Terms | ide     |        |        |                           |
| []{.mark}  | ntified |        |        |                           |
|            | in the  |        |        |                           |
|            | d       |        |        |                           |
|            | atabase |        |        |                           |
|            | for     |        |        |                           |
|            | these   |        |        |                           |
|            | du      |        |        |                           |
|            | rations |        |        |                           |
|            | of      |        |        |                           |
|            | ex      |        |        |                           |
|            | posure. |        |        |                           |
+------------+---------+--------+--------+---------------------------+
| Dermal     | No      |        |        |                           |
|            | appr    |        |        |                           |
| (all       | opriate |        |        |                           |
| durations) | e       |        |        |                           |
|            | ndpoint |        |        |                           |
|            | was     |        |        |                           |
|            | ide     |        |        |                           |
|            | ntified |        |        |                           |
|            | in the  |        |        |                           |
|            | d       |        |        |                           |
|            | atabase |        |        |                           |
|            | for     |        |        |                           |
|            | this    |        |        |                           |
|            | route   |        |        |                           |
|            | of      |        |        |                           |
|            | ex      |        |        |                           |
|            | posure. |        |        |                           |
+------------+---------+--------+--------+---------------------------+
| []{.mark}  | No      |        |        |                           |
|            | appr    |        |        |                           |
| Inhalation | opriate |        |        |                           |
|            | e       |        |        |                           |
| Short- and | ndpoint |        |        |                           |
| Intermed   | was     |        |        |                           |
| iate-Terms | ide     |        |        |                           |
|            | ntified |        |        |                           |
|            | in the  |        |        |                           |
|            | d       |        |        |                           |
|            | atabase |        |        |                           |
|            | for     |        |        |                           |
|            | these   |        |        |                           |
|            | du      |        |        |                           |
|            | rations |        |        |                           |
|            | of      |        |        |                           |
|            | ex      |        |        |                           |
|            | posure. |        |        |                           |
+------------+---------+--------+--------+---------------------------+
| Long-term  | The     |        |        |                           |
| inhalation | current |        |        |                           |
|            | use     |        |        |                           |
|            | pattern |        |        |                           |
|            | does    |        |        |                           |
|            | not     |        |        |                           |
|            | i       |        |        |                           |
|            | ndicate |        |        |                           |
|            | lo      |        |        |                           |
|            | ng-term |        |        |                           |
|            | inh     |        |        |                           |
|            | alation |        |        |                           |
|            | e       |        |        |                           |
|            | xposure |        |        |                           |
|            | pot     |        |        |                           |
|            | ential. |        |        |                           |
+------------+---------+--------+--------+---------------------------+
| []{.mark}  | C       |        |        |                           |
|            | lassifi |        |        |                           |
| Cancer     | cation: |        |        |                           |
| (oral,     | "Not    |        |        |                           |
| dermal,    | likely  |        |        |                           |
| i          | to be   |        |        |                           |
| nhalation) | Carci   |        |        |                           |
|            | nogenic |        |        |                           |
|            | to      |        |        |                           |
|            | Humans" |        |        |                           |
|            | based   |        |        |                           |
|            | on the  |        |        |                           |
|            | absence |        |        |                           |
|            | of      |        |        |                           |
|            | sign    |        |        |                           |
|            | ificant |        |        |                           |
|            | tumor   |        |        |                           |
|            | in      |        |        |                           |
|            | creases |        |        |                           |
|            | in two  |        |        |                           |
|            | a       |        |        |                           |
|            | dequate |        |        |                           |
|            | rodent  |        |        |                           |
|            | c       |        |        |                           |
|            | arcinog |        |        |                           |
|            | enicity |        |        |                           |
|            | s       |        |        |                           |
|            | tudies. |        |        |                           |
+------------+---------+--------+--------+---------------------------+

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.
UF~A~ = extrapolation from animal to human (interspecies). UF~H~ =
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

+---------------------+---+----+-------+-------+-------------------------+
| **Table 5. Summary  |   |    |       |       |                         |
| of US and           |   |    |       |       |                         |
| International       |   |    |       |       |                         |
| Tolerances and      |   |    |       |       |                         |
| Maximum Residue     |   |    |       |       |                         |
| Limits**            |   |    |       |       |                         |
+=====================+===+====+=======+=======+=========================+
| **US**              |   |    | **Can | **Mex | **Codex**               |
|                     |   |    | ada** | ico** |                         |
+---------------------+---+----+-------+-------+-------------------------+
| **Residue           |   |    |       |       |                         |
| Definition:**       |   |    |       |       |                         |
+---------------------+---+----+-------+-------+-------------------------+
| 40CFR180.484 (a)    |   |    | None  | None  | For plant commodities,  |
|                     |   |    |       |       | flutolanil.             |
| flutolanil, *N*     |   |    |       |       |                         |
| -(3-(1-methylethoxy |   |    |       |       | For animal commodities, |
| )phenyl)-2-(trifluo |   |    |       |       | flutolanil and          |
| romethyl)benzamide, |   |    |       |       | transformation products |
| and its metabolites |   |    |       |       | containing the          |
| converted to        |   |    |       |       | 2-                      |
| 2-(trifluoromethyl) |   |    |       |       | trifluoromethyl-benzoic |
| benzoic acid and    |   |    |       |       | acid moiety, expressed  |
| calculated as       |   |    |       |       | as flutolanil.          |
| flutolanil .        |   |    |       |       |                         |
+---------------------+---+----+-------+-------+-------------------------+
| Commodity Tolerance |   |    |       |       |                         |
| (ppm) /Maximum      |   |    |       |       |                         |
| Residue Limit       |   |    |       |       |                         |
| (mg/kg)             |   |    |       |       |                         |
+---------------------+---+----+-------+-------+-------------------------+
| Commodity           | U |    | C     | M     | Codex                   |
|                     | S |    | anada | exico |                         |
+---------------------+---+----+-------+-------+-------------------------+
| Cattle, fat         | 0 |    | None  | None  |                         |
|                     | . |    |       |       |                         |
|                     | 1 |    |       |       |                         |
|                     | 0 |    |       |       |                         |
+---------------------+---+----+-------+-------+-------------------------+
| Cattle, kidney      | 1 |    |       |       | 0.1                     |
|                     | . |    |       |       |                         |
|                     | 0 |    |       |       |                         |
|                     | 0 |    |       |       |                         |
+---------------------+---+----+-------+-------+-------------------------+
| Cattle, liver       | 2 |    |       |       | 0.2                     |
|                     | . |    |       |       |                         |
|                     | 0 |    |       |       |                         |
|                     | 0 |    |       |       |                         |
+---------------------+---+----+-------+-------+-------------------------+
| Cattle, meat        | 0 |    |       |       |                         |
| byproducts          | . |    |       |       |                         |
|                     | 0 |    |       |       |                         |
|                     | 5 |    |       |       |                         |
+---------------------+---+----+-------+-------+-------------------------+
| Cattle, meat        | 0 |    |       |       | 0.05 (\*)               |
|                     | . |    |       |       |                         |
|                     | 0 |    |       |       |                         |
|                     | 5 |    |       |       |                         |
+---------------------+---+----+-------+-------+-------------------------+
| Egg                 | 0 |    |       |       | 0.05 (\*)               |
|                     | . |    |       |       |                         |
|                     | 0 |    |       |       |                         |
|                     | 5 |    |       |       |                         |
+---------------------+---+----+-------+-------+-------------------------+
| Goat, fat           | 0 |    |       |       |                         |
|                     | . |    |       |       |                         |
|                     | 1 |    |       |       |                         |
|                     | 0 |    |       |       |                         |
+---------------------+---+----+-------+-------+-------------------------+
| Goat, kidney        | 1 |    |       |       | 0.1                     |
|                     | . |    |       |       |                         |
|                     | 0 |    |       |       |                         |
|                     | 0 |    |       |       |                         |
+---------------------+---+----+-------+-------+-------------------------+
| Goat, liver         | 2 |    |       |       | 0.2                     |
|                     | . |    |       |       |                         |
|                     | 0 |    |       |       |                         |
|                     | 0 |    |       |       |                         |
+---------------------+---+----+-------+-------+-------------------------+
| Goat, meat          | 0 |    |       |       |                         |
| byproducts          | . |    |       |       |                         |
|                     | 0 |    |       |       |                         |
|                     | 5 |    |       |       |                         |
+---------------------+---+----+-------+-------+-------------------------+
| Goat, meat          | 0 |    |       |       | 0.05 (\*)               |
|                     | . |    |       |       |                         |
|                     | 0 |    |       |       |                         |
|                     | 5 |    |       |       |                         |
+---------------------+---+----+-------+-------+-------------------------+
| Hog, fat            | 0 |    |       |       |                         |
|                     | . |    |       |       |                         |
|                     | 1 |    |       |       |                         |
|                     | 0 |    |       |       |                         |
+---------------------+---+----+-------+-------+-------------------------+
| Hog, kidney         | 1 |    |       |       | 0.1                     |
|                     | . |    |       |       |                         |
|                     | 0 |    |       |       |                         |
|                     | 0 |    |       |       |                         |
+---------------------+---+----+-------+-------+-------------------------+
| Hog, liver          | 2 |    |       |       | 0.2                     |
|                     | . |    |       |       |                         |
|                     | 0 |    |       |       |                         |
|                     | 0 |    |       |       |                         |
+---------------------+---+----+-------+-------+-------------------------+
| Hog, meat           | 0 |    |       |       |                         |
| byproducts          | . |    |       |       |                         |
|                     | 0 |    |       |       |                         |
|                     | 5 |    |       |       |                         |
+---------------------+---+----+-------+-------+-------------------------+
| Hog, meat           | 0 |    |       |       | 0.05 (\*)               |
|                     | . |    |       |       |                         |
|                     | 0 |    |       |       |                         |
|                     | 5 |    |       |       |                         |
+---------------------+---+----+-------+-------+-------------------------+
| Horse, fat          | 0 |    |       |       |                         |
|                     | . |    |       |       |                         |
|                     | 1 |    |       |       |                         |
|                     | 0 |    |       |       |                         |
+---------------------+---+----+-------+-------+-------------------------+
| Horse, kidney       | 1 |    |       |       |                         |
|                     | . |    |       |       |                         |
|                     | 0 |    |       |       |                         |
|                     | 0 |    |       |       |                         |
+---------------------+---+----+-------+-------+-------------------------+
| Horse, liver        | 2 |    |       |       |                         |
|                     | . |    |       |       |                         |
|                     | 0 |    |       |       |                         |
|                     | 0 |    |       |       |                         |
+---------------------+---+----+-------+-------+-------------------------+
| Horse, meat         | 0 |    |       |       |                         |
| byproducts          | . |    |       |       |                         |
|                     | 0 |    |       |       |                         |
|                     | 5 |    |       |       |                         |
+---------------------+---+----+-------+-------+-------------------------+
| Horse, meat         | 0 |    |       |       | 0.05 (\*)               |
|                     | . |    |       |       |                         |
|                     | 0 |    |       |       |                         |
|                     | 5 |    |       |       |                         |
+---------------------+---+----+-------+-------+-------------------------+
| Milk                | 0 |    |       |       | 0.05 (\*)               |
|                     | . |    |       |       |                         |
|                     | 0 |    |       |       |                         |
|                     | 5 |    |       |       |                         |
+---------------------+---+----+-------+-------+-------------------------+
| Peanut              | 0 |    |       |       |                         |
|                     | . |    |       |       |                         |
|                     | 5 |    |       |       |                         |
+---------------------+---+----+-------+-------+-------------------------+
| Peanut, hay         | 1 |    |       |       |                         |
|                     | 5 |    |       |       |                         |
|                     | . |    |       |       |                         |
|                     | 0 |    |       |       |                         |
+---------------------+---+----+-------+-------+-------------------------+
| Peanut, meal        | 1 |    |       |       |                         |
|                     | . |    |       |       |                         |
|                     | 0 |    |       |       |                         |
+---------------------+---+----+-------+-------+-------------------------+
| Potato              | 0 |    |       |       |                         |
|                     | . |    |       |       |                         |
|                     | 2 |    |       |       |                         |
|                     | 0 |    |       |       |                         |
+---------------------+---+----+-------+-------+-------------------------+
| Potato, wet peel    | 0 |    |       |       |                         |
|                     | . |    |       |       |                         |
|                     | 3 |    |       |       |                         |
|                     | 0 |    |       |       |                         |
+---------------------+---+----+-------+-------+-------------------------+
| Poultry, fat        | 0 |    |       |       |                         |
|                     | . |    |       |       |                         |
|                     | 0 |    |       |       |                         |
|                     | 5 |    |       |       |                         |
+---------------------+---+----+-------+-------+-------------------------+
| Poultry, meat       | 0 |    |       |       | 0.05 (\*)               |
|                     | . |    |       |       |                         |
|                     | 0 |    |       |       |                         |
|                     | 5 |    |       |       |                         |
+---------------------+---+----+-------+-------+-------------------------+
| Poultry, meat       | 0 |    |       |       | 0.05 (\*)               |
| byproducts          | . |    |       |       |                         |
|                     | 0 |    |       |       |                         |
|                     | 5 |    |       |       |                         |
+---------------------+---+----+-------+-------+-------------------------+
| Rice, bran          | 1 |    |       |       | 10 (unprocessed)        |
|                     | 0 |    |       |       |                         |
|                     | . |    |       |       |                         |
|                     | 0 |    |       |       |                         |
+---------------------+---+----+-------+-------+-------------------------+
| Rice, grain         | 7 |    |       |       | 2 husked                |
|                     | . |    |       |       |                         |
|                     | 0 |    |       |       | 1 polished              |
+---------------------+---+----+-------+-------+-------------------------+
| Rice, hulls         | 2 |    |       |       |                         |
|                     | 5 |    |       |       |                         |
|                     | . |    |       |       |                         |
|                     | 0 |    |       |       |                         |
+---------------------+---+----+-------+-------+-------------------------+
| Rice, straw         | 1 |    |       |       | 10                      |
|                     | 0 |    |       |       |                         |
|                     | . |    |       |       |                         |
|                     | 0 |    |       |       |                         |
+---------------------+---+----+-------+-------+-------------------------+
| Sheep, fat          | 0 |    |       |       |                         |
|                     | . |    |       |       |                         |
|                     | 1 |    |       |       |                         |
|                     | 0 |    |       |       |                         |
+---------------------+---+----+-------+-------+-------------------------+
| Sheep, kidney       | 1 |    |       |       | 0.1                     |
|                     | . |    |       |       |                         |
|                     | 0 |    |       |       |                         |
|                     | 0 |    |       |       |                         |
+---------------------+---+----+-------+-------+-------------------------+
| Sheep, liver        | 2 |    |       |       | 0.2                     |
|                     | . |    |       |       |                         |
|                     | 0 |    |       |       |                         |
|                     | 0 |    |       |       |                         |
+---------------------+---+----+-------+-------+-------------------------+
| Sheep, meat         | 0 |    |       |       | 0.05 (\*)               |
|                     | . |    |       |       |                         |
|                     | 0 |    |       |       |                         |
|                     | 5 |    |       |       |                         |
+---------------------+---+----+-------+-------+-------------------------+
| Sheep, meat         | 0 |    |       |       |                         |
| byproducts          | . |    |       |       |                         |
|                     | 0 |    |       |       |                         |
|                     | 5 |    |       |       |                         |
+---------------------+---+----+-------+-------+-------------------------+
| **Residue           |   |    |       |       |                         |
| Definition:**       |   |    |       |       |                         |
+---------------------+---+----+-------+-------+-------------------------+
| 40CFR180.484 (d)    |   |    | None  | None  | None                    |
|                     |   |    |       |       |                         |
| indirect or         |   |    |       |       |                         |
| inadvertent         |   |    |       |       |                         |
| residues of the     |   |    |       |       |                         |
| fungicide           |   |    |       |       |                         |
| flutolanil, *N*     |   |    |       |       |                         |
| -(3-(1-methylethoxy |   |    |       |       |                         |
| )phenyl)-2-(trifluo |   |    |       |       |                         |
| romethyl)benzamide, |   |    |       |       |                         |
| and its metabolites |   |    |       |       |                         |
| converted to        |   |    |       |       |                         |
| 2-(trifluoromethyl) |   |    |       |       |                         |
| benzoic acid and    |   |    |       |       |                         |
| calculated as       |   |    |       |       |                         |
| flutolanil          |   |    |       |       |                         |
+---------------------+---+----+-------+-------+-------------------------+
| Soybean, forage     |   | 8  |       |       |                         |
|                     |   | .0 |       |       |                         |
+---------------------+---+----+-------+-------+-------------------------+
| Soybean, hay        |   | 2  |       |       |                         |
|                     |   | .5 |       |       |                         |
+---------------------+---+----+-------+-------+-------------------------+
| Soybean, seed       |   | 0. |       |       |                         |
|                     |   | 20 |       |       |                         |
+---------------------+---+----+-------+-------+-------------------------+
| Wheat, bran         |   | 0. |       |       |                         |
|                     |   | 20 |       |       |                         |
+---------------------+---+----+-------+-------+-------------------------+
| Wheat, forage       |   | 2  |       |       |                         |
|                     |   | .5 |       |       |                         |
+---------------------+---+----+-------+-------+-------------------------+
| Wheat, grain        |   | 0. |       |       |                         |
|                     |   | 05 |       |       |                         |
+---------------------+---+----+-------+-------+-------------------------+
| Wheat, hay          |   | 1  |       |       |                         |
|                     |   | .2 |       |       |                         |
+---------------------+---+----+-------+-------+-------------------------+
| Wheat, straw        |   | 0. |       |       |                         |
|                     |   | 20 |       |       |                         |
+---------------------+---+----+-------+-------+-------------------------+

\* = absent at the limit of quantitation.

> **[Data Call-In Tables]{.underline}**

+-----------------------------------------------------------------------+
| **Table 6.**                                                          |
|                                                                       |
| **Guideline Number: 870.7800**                                        |
|                                                                       |
| **Study Title**: **Immunotoxicity**                                   |
+-----------------------------------------------------------------------+
| **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 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 flutolanil poses either a      |
| greater or a diminished risk than that given in the interim           |
| decision's conclusion, the risk assessments 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 for conducting a risk assessment from the       |
| available studies.                                                    |
+-----------------------------------------------------------------------+

+-----------------------------------------------------------------------+
| **Table 7.**                                                          |
|                                                                       |
| **Guideline Number: 870.6200**                                        |
|                                                                       |
| **Study Title: Neurotoxicity Screening Battery**                      |
+-----------------------------------------------------------------------+
| **Rationale for Requiring the Data**                                  |
+-----------------------------------------------------------------------+
| Acute and subchronic neurotoxicity studies with flutolanil were not   |
| conducted, flutolanil showed no indication of neurotoxicity in the    |
| provided studies and there was no evidence of neurotoxicity in open   |
| literature searches, however, the submitted studies did not examine   |
| neurotoxicity endpoints. These data are now required under the        |
| revised CFR 158.340.                                                  |
+-----------------------------------------------------------------------+
| **Practical Utility of the Data**                                     |
+-----------------------------------------------------------------------+
| **How did the Agency make its re-registration decision without this   |
| data?**                                                               |
|                                                                       |
| []{.mark}                                                             |
|                                                                       |
| For many chemicals, the amount of toxicity data that is available for |
| flutolanil would be considered to be a complete toxicity database. In |
| fact, the Agency was able to select doses and endpoints for           |
| conducting a risk assessment from the available studies. However,the  |
| existing toxicity database for flutolanil does not include any        |
| neurotoxicity studies. None of the submitted studies measured         |
| neurotoxicity endpoints. In the absence of any such data, there is    |
| uncertainty about the neurotoxicity potential of flutolanil**.**      |
|                                                                       |
| **How will the data be used?**                                        |
|                                                                       |
| After the review and evaluation of the acute and subchronic           |
| neurotoxicity studies, it is possible that the Agency could choose a  |
| dose and endpoint from either the acute or subchronic neurotoxicity   |
| study that is appropriate for the deriving the acute RfD.             |
|                                                                       |
| **How could the data impact the Agency's future decision-making?**    |
|                                                                       |
| If a dose can be selected for the acute RfD from the new data, then a |
| flutolanil acute dietary risk assessment would need to be conducted.  |
| At present there were no effects observed in oral toxicity studies    |
| including developmental toxicity studies in rats or rabbits that      |
| could be attributable to a single dose (exposure). The risk would     |
| then be identified for the acute RfD.                                 |
+-----------------------------------------------------------------------+

**Existing Registrationsfor Flutolanil**

**[Section 3]{.underline}** :

EPA Reg Nos.:

Bayer Environmental Science

> 432-1222 Prostar 50WP. Contains 50.3% flutolanil. Labeled for the
> control of brown patch, fairy ring, red thread/pink patch,
> yellow/patch/Southern blight, gray snow mold, and large brown patch on
> turf.
>
> 432-1223 Prostar 70 WP. Contains70% flutolanil. Labeled for control of
> brown patch, fairy ring, red thread/pink patch, yellow/patch/Southern
> blight, gray snow mold, and large brown patch on turf, various fungal
> diseases of greenhouse, container, and nursery grown ornamentals.
>
> 432-1403 Prostar 1.5G. Contains 1.5% flutolanil, with fertilizer.
> Labeled for control of brown patch on turf.
>
> 432-1440 Sysstar WDG. Contains 51.42% flutolanil and 28.6%
> thiophanate-methyl. Labeled for control of multiple fungal diseases of
> turf and ornamentals.
>
> 432-1477 Prostar 70 WDG Fungicide. Contains 70% flutolanil. Labeled
> for control of multiple fungal diseases of turf and ornamentals.

Gowan Company

> 10163-247 Flutolanil Technical. Contains 98.3% flutolanil. For
> formulation only.
>
> Nichino America, Inc.
>
> 71711-1 Moncut® 70 WP (70% ai) registered for control of Southern stem
> rot (white mold) caused by *Sclerotium rolfsii* and limb/pod rot
> complex caused by *Rhizoctonia solani* in peanuts, and for control of
> sheath blight caused by *Rhizoctonia solani* in rice. The existing
> label for rotational crops states that corn, soybean, or cotton may be
> planted 240 days or more following the last application of Moncut 70WP
> to peanuts; soybean or grain sorghum may be planted 240 days or more
> following last application to rice.

71711-2 Moncut CL Flowable fungicide. Contains 38.6% chlorothalonil and
10.3% flutolanil. Designed for use on peanuts, under conditions which
favor the development of diseases caused by fungi which attack both the
crop canopy and structures beneath the soil surface (roots, pegs, and
pods).

> 71711-3 Moncut® 50WP (50% ai) registered for use on peanuts and rice.
> The same use as EPA Reg. No. 71711-1. For control of Southern stem rot
> (white mold) caused by *Sclerotium rolfsii* and limb/pod rot complex
> caused by *Rhizoctonia solani* in peanuts; for control of sheath
> blight caused by *Rhizoctonia solani* in rice; and for control of
> clack scurf caused by *Rhizoctonia solani* in peanuts.
>
> 71711-5 Flutolanil Technical. Contains 98.3% flutolanil. For
> formulation only.

71711-8 Moncoat® MZ---a coformulation containing 1.5% flutolanil and 6%
mancozeb in a tree bark based formulation. MonCoat MZ is to be used as
an integral part of a potato disease management strategy for the
suppression of Black scurf and Rhizoctonia stem canker (*Rhizoctonia
solani*), Fusarium dry rot (*Fusarium sambucinum, F. coeruleum)*, and
Silver scarf (*Helminthosporium solani*) on potato seed pieces. Use for
potato seed treatment @ 0.75 -- 1.0 lb product/100 lb seed. (\<0.25 lb
ai/A).

> 71711-14 Moncut®70-DF (70% DF formulation) used for on peanut, rice
> and potato ( Not for use on peanuts and rice in California). as
> broadcast foliar 2 lb ai/A in forrow application. For control of
> Southern stem rot (white mold) caused by *Sclerotium rolfsii* and
> limb/pod rot complex caused by *Rhizoctonia solani* in peanuts; for
> control of sheath blight caused by *Rhizoctonia solani* in rice; and
> for control of clack scurf caused by *Rhizoctonia solani* in potatoes.
>
> 71711-17 Artisan™ Fungicide, 32%, containing 3 lb flutolanil and 0.6
> lb propiconazole per gallon. For use on peanuts.
>
> 71711-24 NAI-301, 4SE fungicide (Alternate name fro Artisan Trifecrs)
> containing 17.2% flutolanil, 1.8% propiconazole and 21.65%
> chlorothalonil. Used for the control of early and late leaf spot
> disease as well as control of whit mold (Southern blight) caused by
> *Sclerotium rolfsii* and limb rot caused by *Rizoctonia solani*.
>
> 71711-28 Flutolanil 40SC Fungicide. Contains 40% flutolanil.
> Registered 5/2/08; labeled for control of fungal diseases of peanut
> and potato (in-furrow and seed-piece treatments).

**[Section 24(c)]{.underline}**

ID040008

ID080003

NV020006

WA010016

WA040032