UNITED STATES ENVIRON MEN TAL PR O TEC TI ON AGENCY

WASH IN GTON, D.C. 20460



### MEMORANDUM

DATE : February 20,201 4 O FFIC E OF
C HEMICAL S AFETY AND
POLL UTION PREVENT ION



### SUBJECT: Flutolanil

- Preliminary Human Health Risk Assessment for Registration Review

and Human Health Ri sk Assessment for Label Amendment s for 

### Brassica (Col e) Leafy Vegetables (Crop Group 5), Turnip Greens

, Ri ce, and Turf an d Addition of

Banded Applications for Peanuts.

PC Co d e: 128975 DP Barcodes: 0412198

, 0413582

, 0410729 Registration Nos.: 432-1223

, 71711-28 Decisio n Nos.: 478733

, 480092

, 477208

Petition Nos.: NA Regulatory Action: Registration Review and Section 3 Registration

Risk Assess ment Type: Single Chemica l / Aggregate

TXRNo .: NA Case No.: 7010

CAS No

. : 66332-96-5

40 CFR : § 180.484 MRID No.: NA



### FROM: Barry O'Keefe, Senior Biolo g i st 

## /3, 0

## ~ Nancy D odd,**Chemist~ ~**  Minerva Mercado, T oxicologi

- - ......, Risk Assessment Branch III (RAB III )

H eal th Effects Division (7509P)



### THROUGH: Christine Olinge r
, Bran c h Chief

R isk Assessment Branch III (RAB III)

Health Effects Division (7509P)

D onna Davis

, RARC Revie wer
P v Shah, RARC Reviewer



### TO: Erin Malone, Risk Manager Shaja Joyner, Product Manager 20 Cynthia G il es-Par ker

, Br a n ch Chief Fungicide Branch Registration Di visi on (7505P)

and

Jill Bl oom
, Chemical Revie w Manager

T om Myers, Team Leader

Kevin Costello, Branch Ch i ef

Risk Management and Implem entation Branch II

Pesticid e Re-evaluation D ivision (7508P)

Page 1 of 53This document provides the Health Effects Division (HED) preliminary human health exposure
and risk assessment for the Registration Review of the fungicide flutolanil. Additionally,

included i n this assessment are a pro p osed increase i n the max i mum seasonal application rate to
turf by Bayer CropScience that affects the estimated drinking water concentrat i ons (EDWC) and proposed change s by Nichino America, Inc. as follows : 1) adding a band e d application to the existing broadca st use for p ean uts on the so lubl e concentrate (SC) lab el; 2) adding the Bra ssica (co le ) leafy vegetables crop grou p and turnip greens to the SC label using residue data from the dry flowable (DF) formulation; and 3) slightly modifying the established SC u se rate on rice.

The toxicology reevaluation was performed by Minerva Mercado, the drinking water assessment

was conducted by Jose Melendez (EPA Environmental Fate and Effects Divi s ion (EFED)), the

review of the residue chemistry data and dietary exposure assessment were conducted by Nancy

Dodd

, and the human health risk assessment was conducted by Barry O ' Keefe.

Page 2 of 53Page 3 of 53 Table of Contents

1.0 Executive Summary

................................ ................................ ................................ ........... 5

2.0 HED Recommendations

................................ ................................ ................................ .... 7

2.1 Data Deficiencies

................................ ................................ ................................ ............ 7

2.2 Tolerance Considerations

................................ ................................ .............................. 8

2.2.1 Enforcement Analytical Method

................................ ................................ ............... 8

2.2.2 Recommended Tolerances

................................ ................................ ......................... 8

2.2.3 International Harmonization

................................ ................................ ..................... 9

3.0 Introduction

................................ ................................ ................................ ...................... 10

3.1 Chemical Identity

................................ ................................ ................................ ......... 10

3.2 Physical/Chemical Characteristics

................................ ................................ ............. 10

3.3 Pesticide Use Pattern

................................ ................................ ................................ .... 10

3.4 Anticipated Exposure Pathways

................................ ................................ ................. 13

3.5 Consideration of Environmental Justice

................................ ................................ .... 13

4.0 Hazard Characterization and Dose

- Response Assessment

................................ .......... 14

4.1 Toxicology Studies Available for Analysis

................................ ................................ . 14

4.2 Absorption, Distribution, Metabolism and Excretion (ADME)

.............................. 14

4.2.1 Dermal Absorption

................................ ................................ ................................ ... 15

4.3 Summary of Toxicological Effects

................................ ................................ .............. 15

4.4 Safety Factor for Infants and Children (FQPA Safety Factor)

............................... 16

4.4.1 Completeness of the Toxicology Database

................................ .............................. 16

4.4.2 Evidence of Neurotoxicity

................................ ................................ ........................ 16

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

........ 16

4.4.4 Residual Uncertainty in the Exposure Database

................................ ................... 16

4.5 Toxicity Endpoint and Point of Departure Selections

................................ .............. 17

4.5.1 Dose

- Response Assessment

................................ ................................ ...................... 17

4.5.2 Recommendation for Combining Routes of Exposure for Risk Assessment

...... 17

4.5.3 Cancer Classification and Risk Assessment Recommendation

............................ 18

4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk

Assessment

................................ ................................ ................................ ............................... 18

4.6 Endocrine Disruption

................................ ................................ ................................ ... 19

5.0 Dietary Exposure and Risk Assessment

................................ ................................ ......... 20

5.1 Residues of Concern Summary and Rationale

................................ .......................... 20

5.2 Food Residue Profile

................................ ................................ ................................ .... 21

5.3 Water Residue Profile

................................ ................................ ................................ .. 22

5.4 Dietary Risk Assessment

................................ ................................ .............................. 23

5.4. 1 Description of Residue Data Used in Dietary Assessment

................................ .... 23

5.4.2 Percent Crop Treated Used in Dietary Assessment

................................ .............. 23

5.4.3 Acute Dietary Risk Assessment

................................ ................................ ............... 23

5.4.4 Chronic Dietary Risk Assessments

................................ ................................ ......... 23

5.4.5 Cancer Dietary Risk Assessments

................................ ................................ ........... 23

5.4.6 Summary Table

................................ ................................ ................................ ......... 24

6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

............................. 24

7.0 Aggregate Exposure/Risk Characterization

................................ ................................ .. 24

8.0 Cumulative Exposure/Risk Characterization

................................ ............................... 25Page 4 of 53

9.0 Occupational Exposure/Risk Characterization

................................ ............................ 25

10.0 References

................................ ................................ ................................ ......................... 26 Appendix A. Tox icology Profile and Executive Summaries

................................ .................. 27

A.1 Toxicology Data Requirements

................................ ................................ ................... 27

A.2 Toxicity Profiles

................................ ................................ ................................ ............ 28

A.3 Hazard Identification and Endpoint Selection

................................ .......................... 31

A.4 Executive Summaries

................................ ................................ ................................ ... 33 Appendix B. Nomenclature and Physicochemical Properties of Flutolanil.

......................... 43 Appendix C. Incident Report

................................ ................................ ................................ .... 46 Appe ndix D. Food Residue Profile Details

................................ ................................ .............. 47 Appendix E. International Residue Limits Status Sheet

................................ ........................ 52Page 5 of 53

1.0 Executive Summary

Introduction Flutolanil, N

- [3

- (1

- methylethoxy)phenyl ]

- 2

- (trifluoromethyl)benzamide, is a systemic benzanilide fungicide with both preventative and curative actions against powdery scab, Spogospora subterranean

, Rhizoctonia solani (the causal agent of limb/pod rot in peanuts), sheath blight in rice, black sc urf in potato, wirestem in Brassica (Cole) leafy vegetables and turnip greens, and black scurf, Rhizoctonia solani, and crown rot in ginseng. Flutolanil is also effective in controlling white mold in peanuts and rust diseases in several crops.

Use Profi le Flutolanil is currently registered for application to Brassica (Cole) leafy vegetables, peanuts, potatoes, rice, and turnip greens, and as a seed treatment for soybean and cotton. Tolerances

have been established for these commodities as well as tolera nces for inadvertent residues for wheat commodities as rotational crops and tolerances for ruminant commodities. Non

- food uses of flutolanil include turf, and greenhouse, nursery, and potted ornamentals.

Bayer CropScience has proposed an increase in the maximum seasonal application rate to turf from 9 fl oz to 17.1 fl oz. Additionally, Nichino America, Inc. has proposed the following: 1) adding a banded application to the existing broadcast use for peanuts on the soluble concentrate ( SC ) label; 2) addin g the Brassica (cole) leafy vegetables crop group and turnip greens to the SC label using r esidue data from the DF formulation ; and 3) slightly modifying the lowest

established SC use rate on rice from 11.8 fl oz to 12 fl oz /A (0.35 to 0.36 lb ai/A)

.

Exposure Profile

The existing uses and the proposed changes to uses of fl utolanil would result in exposures from both food and drinking water. Non

- occupational/residential exposures via dermal, inhalation, and incidental oral routes are expected. Non

- occ upational/residential e xposures are expected to

o ccur for short

- term durations

. A gricultural uses w ill result in occupational dermal and

inhalation exposure s from handl er activities and dermal exposure from post

- application

activities. Occupational e xpos ures are expected to o ccur for short

- and intermediate

- term
durations

.

Hazard Assessment The existing flutolanil toxicity/hazard database is adequate for hazard characterization and endpoint selection. The toxicology studies conducted on flutolanil demonstrate few biologically significant effects, mainly in the liver and gastrointestinal (GI) system. Liver effects were

observed in several studies, but most of the changes were considered adaptive , especiall y in the

rat . The dog was the most sensitive species for liver effects, showing clinical chemistry and liver weight changes together with glycogen deposition in the subchronic study. The chronic dog study saw effects suggest ive of GI irritation, but no r elevant liver effects were reported.

Evaluation of the available data for flutolanil did not reveal any evidence to indicate that it is neurotoxic or that it targets the immune system , fetal development, or reproduction

.Page 6 of 53

There was no evidence for incre ased susceptibility of rat or rabbit fetuses to in utero exposure or

rat pups to post

- natal exposure to flutolanil.

No adverse effects were observed in studies in which flutolanil was administered by the dermal route of exposure. The s ubchronic inhalati on study has been waived base d on a weight of evidence approach (TXR 0056560) ; i.e. low vapor pressure, low acute inhalation toxicity, and low subchronic and chronic toxicity

. Further, there is no developmental or reproductive concern

at dose levels that do not exceed the limit dose. For these reasons, it is concluded that appropriate points of departure ( PODs ) are not established for any dermal or inhalation exposure

duration

. For chronic dietary exposure, the POD was based on increased incidence of GI effects

, decreased body weight and decreased food consumption observed in the c hronic dog study. For incidental oral exposure, no hazard was identified from appropriate oral toxicity studies

, including developmental toxicity studies in rats and rabbits.

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”.

Dietary Exposure The residue chemistry data are adequate to assess human dietary exposure

. The screening

- level assessments will not underestimate exposure or risk. As no acute dietary endpoint was identified, an acute exposure analysis was not performed. Tolerance

- level residues combined with 100% crop treated and default processing factors we re used to determine the chronic dietary exposure and risk estimates. Th e chronic dietary exposure estimates for food and drinking water are below HED’s level of concern for the general U.S. population ( 11 % of the chronic population adjusted dose (cPAD)). The most highly exposed population subgroup was all infants (<1 year old) at 29% of the cPAD. Estimated d rinking water c oncentrations (EDWCs) were incorporated directly into the chronic dietary assessment. The maximum screening level EDWC

for chronic e xposure is 2530 ppb, found in ground water associated with the use on turf using the ground water Tier I/II model PRZM

- GW

.

Residential Exposure

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 proh ibited through label directions, could be used in a residential/public site. A l though potential residential handler and post

- application exposures exist, quantitative assessments were not conducted because no dermal, oral (incidental), or inhalation toxicological endpoints attributable

to short

- or intermediate

- term exposures have be en identified, and the current use patterns do not indicate long

- term exposure (6 or more months of continuous exposure) potential

.

Aggregate Exposure Aggregate risk assessments were performed for chronic aggregate exposure (food and drinking water) on ly ; the resultant risk estimates are not of concern. Short

- term aggregate risk assessments were not performed because toxicological endpoints from dermal, inhalation, and incidental oral exposures were not identified. Also, t here is n o intermediate

- term residential

exposure , so, intermediate

- term aggregate risk assessments were not performed.

. Additionally, the Agency does not expect residential exposure durations that would result in long termPage 7 of 53

exposures. A cancer aggregate risk assessment was also not performed because flutolanil has been classified as not likely to be carcinogenic to humans

.

Occupational Exposure Workers may be exposed to flutolanil during mixing, loading, appl ying , and post

- application

activities

. Based on the existing registered uses and the proposed application rates and use scenarios, short

- and intermediate

- term dermal and inhalation occupational exposures may occur. However, since short

- and intermediate

- term endpoints have not been established, an occupati onal exposure assessment was not conduct ed. C hronic occupational exposure is not expected ; thus, c hronic occupational exposure risk assessments also were not conduct ed.

Environmental Justice Considerations Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income Populations," ( http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf

. Considerations made for the human

health risk assessment are discussed in more detail below.

2.0 HED Recommendations

Provided the registrant su bmits the analytical standards as described in Section 2.1 and amends the proposed labels as described in Section 2. 3 , HED has no objection to the proposed

amendments to the Brassica (cole) leafy vegetable, turnip greens, peanuts, and rice. These

amendmen ts are as follows: 1) add Brassica (cole) leafy vegetables and turnip greens to the Flutolanil 40 SC label; 2) add band application to peanuts to the Flutolanil 40 SC label; and 3) revise the lowest application rate on rice on the Flutolanil 40 SC label fr om 11.8 to 12.0 fl oz/A. Additionally, the proposal to increase the maximum seasonal application rate to turf from 9 fl oz to 17.1 fl oz is not a concern to HED; since this increase does not change any exposure and therefore a new assessment is not requir ed

.

For registration review, data recommendations are discussed in Section 2.1. The tolerances for

flutolanil will need to be updated in registration review as described in Section 2.2.

2.1 Data Deficiencies

Data recommended to be submitted under registration review and for any registration actions (i.e., the amendment to add the banded application on peanuts).

860.1650 Submittal of Analytical Reference Standards

Analytical ref

erence standards for flutolanil , the common moiety 2

- ( trifluoromethyl ) benzoic acid, M

- 2, M

- 3, M

- 4, and M

- 7 must be kept available at the EPA National Pesticide Standards Repository. The only flutolanil standards that are in stock are flutolanil and the common moiety

2

- (trifluoromethyl)benzoic acid (e

- mail from Theresa Cole , Analytical Chemistry Branch, 1/9/14)

. Analytical reference standards for M

- 2, M

- 3, M

- 4, and M

- 7 must be sent to the Reposito r y.Page 8 of 53

When new standards are submitted, they should be sent to the Analytical Chemistry Lab, which is located at Fort Meade, to th e attention of either of Theresa Cole or Thuy Nguyen at the following address:

USEPA National Pesticide Standards Repository/Analytical Chemistry Branch/OPP 701 Mapes Road Fort George G. Meade, MD 20755

- 5350

The full 9 digit zip code is mandatory or the mail will be returned to you.

2. 2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Adequate enforcement methods are available. A gas chromatography

- mass spectrometry (GC/MS) enforcement method (AU/95R/04) is available which analyzes the flutolanil residues

of concern in plants and livestock commodities for the tolerance expression and risk assessment.

The method is available in M RID 44526201, entitled Validation of an Analytical Method for Residues of Flutolanil in Milk, Peanuts, and Rice . The method has undergone a successful independent validation with peanut nutmeat and hay, rice grain, milk, egg s, beef muscle, and

beef fat. T he AU/95R/04 analytical method determines all metabolites converted to the common moiety 2

- trifluoromethyl benzoic acid (2

- TFBA), including flutolanil, M

- 2, M

- 3, M

- 4, and M

- 7. The limits of quantitation (LOQs) are 0.05 ppm for whole milk and livestock ti ssues and 0.2 ppm for rice and peanut matrices. Radiovalidation was conducted on peanut vines, hulls, and nutmeats using a similar GC/MS common moiety method (AU/01/94). A confirmatory method is required because the method AU/95R/04 is a common moiety me thod. Nichino America submitted a liquid chromatography

- mass spectrometry (LC/MS/MS) method (XAM

- 65), which is acceptable as a confirmatory method. Method XAM

- 65 separately determines residues of flutolanil and its major metabolite, M

- 4.

2.2. 2 Recommend ed Tolerances

Tolerances for flutolanil are established in 40 CFR §180.484. Tolerances are established for residues of flutolanil, N

- (3

- (1

- methylethoxy)phenyl)

- 2

- (trifluoromethyl)benzamide, including its metabolites and degradates, in or on commodities. Compliance with the tolerance levels specified is to be determined by measuring only flutolanil and its metabolites converted to 2

- (trifluoromethyl)benzoic acid, calculated as flutolanil

.

No tolerance revisions were proposed with the proposed amendments. The following tolerances should be modified as part of the registration review , except tolerances for peanut commodities which are modified due to the new request for the banded application to peanuts

.

Tolerances are established [ 40 CFR §180. 484 (a)] on rice straw and hulls. Tolerances on these commodities are no longer required ( Table 1 Feedstuffs , June 20 08) and should be removed.Page 9 of 53

Based on the OECD tolerance calculation procedures on peanut hay, including residues from both band and broadcast appli cations, the established tolerance of 15.0 ppm for peanut hay should be increased to 20.0 ppm.

The tolerance of 0.1 ppm on turnip greens and the Brassica (cole) leafy vegetable group 5 should be increased to 0.20 ppm; this is a reconsideration of the pr evious conclusion, since detectable residues of parent were found in one field trial on mustard greens.

Table 2.2.2 . Tolerance Summary for Flutolanil

.

Commodity Established Tolerance (ppm) HED

Recommended Tolerance (ppm) Comments ( correct commodity definition )

Peanut 0.5 0.5 Peanut, hay 15.0 20.0
Peanut, meal 1.0 1.0
Rice, bran 10.0 10.0 Rice, grain 7.0 7.0
Rice, hulls 25.0 Remove
Rice, straw 10.0 Remove Turnip, greens 0.1 0.20 Vegetable, brassica, leafy, group 5 0.1 0. 20

2.2. 3 International Harmonization

A n International Residue Limits (IRL) table is attached ( Appendix E ).

The US tolerance expression for plant and livestock commodities is flutolanil and its metabolites

converted to 2

- (trifluoromethyl) benzoic acid and calcula ted as flutolanil. The Codex tolerance expression is flutolanil for plants. For animal commodities, the Codex tolerance expression is flutolanil and its transformation products containing the 2

- ( trifluor o methyl ) benzoic acid moiety. Thus, the US toleran ce expression harmonizes with the Codex tolerance expression for livestock commodities but not for plants.

T here are no Codex, Canadian, or Mexican MRLs for p eanuts, turnip greens, or the Brassica (cole) leafy vegetables. Codex MRLs are established on rice grain, bran, and straw. Codex and

US tolerance levels are the same for rice bran and rice straw. Codex and US tolerance levels for rice grain are different, i.e., 7.0 ppm in the US versus 2 for husked rice grain and 1 f or polished rice grain in Codex. For livestock commodities, most Codex tolerance levels are the same as the

US tolerance levels . However, the tolerances for the livestock liver and kidney are higher than

the C odex MRLs and cannot be harmonized.

2.3 Lab el Recommendations

HED’s recommendations are predicated on the recommended label changes. T he rotational crop

restri ctions for the Flutolanil 40SC label (EPA Reg. No. 71711

- 28 ) should be amended to

include Brassica (cole) leafy vegetables and turnip gree ns under the 0

- day crop restriction

interval.Page 10 of 53

Since no tolerance is established for sugar beet, the 0

- day rotational crop restriction for sugar beet on the Artisan Fungicide label (EPA Reg. No. 71711

- 17) should be removed.

3.0 In troduction

Flutolanil, N

- [3

- (1

- methylethoxy)phenyl]

- 2

- (trifluoromethyl)benzamide, is a systemic benzanilide fungicide with both preventative and curative actions. Its mode of action is inhibition of mitochondrial respiration by inhibition of the enzyme succinate dehydrogenase.

3.1 Chemical Identity

The chemical structure and nomenclature of fl utolanil and its metabolites are presented in Appendix B , Table B

. 1

.

3.2 Physical/Chemical Characteristics

Fl utolanil has moderate water solubility of 6.53 mg/L @ 20

- 25 o C. It has a log octanol/water partition coefficient (log P

ow ) of 3 .74

. Fl utolanil is not very volatile, with a vapor pressure of

4.87 x 10 - 8 mm Hg at 2 5 o C and a Henry’s Law Constant of 2.12 x 10

- 9 atm

- m 3 /mol

.

The physicochemical properties of fl utolanil are summarized in Appendix B , Table B

. 2

.

3.3 Pesticide Use Pattern

Flutolanil is currently registered for application to Brassica ( c ole) leafy vegetables, peanuts, potatoes, rice, and turnip greens, and as a seed treatment for soybean and cotton. Toler ances have been established for these commodities as well as tolerances for inadvertent residues for wheat commodities as rotational crops and tolerances for ruminant commodities. Non

- food uses of flutolanil include turf, and greenhouse, nursery, and pott ed ornamentals.

Bayer CropScience has proposed an increase in the maximum seasonal application rate to turf from 9 fl oz to 17.1 fl oz. Additionally, Nichino America, Inc. has proposed the following: 1) adding a banded application to the existing broadc ast use for peanuts on the SC label; 2) adding

the Brassica (cole) leafy vegetables crop group and turnip greens to the SC label using r esidue

data from the DF formulation ; and 3) slightly modifying the lowest established SC use rate on

rice from 11.8 fl o z to 12 fl oz /A (0.35 to 0.36 lb ai/A)

.

Brassica (Cole) Leafy Vegetable Crop Group 5 and Turnip Greens : Brassica ( c ole) l eafy

v egetable c rop g roup 5 and t urnip g reens are registered by Gowan Company o n the Moncut® 70

- DF label ( EPA Reg. No. 10163

- 301 ) but not on the Nichino America Flutolanil 40SC Fungicide label (EPA Reg. No. 71711

- 28). The registered and proposed uses on Brassica (cole) leafy vegetables and turnip greens (as shown in Table 3.3 below) are for one ground application at planting or at transplanting as an in

- furrow or directed spray at the base of transplants at the rate of 0.77 lb ai/A. The proposed pre

- harvest interval ( PHI ) on the SC label is 45 days. No PHI is specified on the DF label, but the use is very early season on both labe ls.Page 11 of 53

Peanuts : Peanuts are already registered on the Flutolanil 40SC Fungicide label (EPA Reg. No

. 71711

- 28) for broadcast use at a maximum of 64.0 fl oz per acre (1.9 lb ai/A) per crop cycle with

a 40

- day PHI. The proposed label amendment is to add band application at a maximum rate of 64.0 fl oz per acre with a 90

- day PHI as described in Table 3.3 below. The peanut use will be added to the Convoy Fungicide label. (Convoy Fungicide has the same registration number and

is the same formulation as Flutolan il 40SC Fungicide.)

Rice : Rice is already registered on the Flutolanil 40SC Fungicide label (EPA Reg. No . 71711

- 28) . The proposal is to revise the application rates slightly (i.e., to revise the rates of 11.8

- 33.0 fl

oz/A and 11.8 to 16.5 fl oz/A on the established label to 12.0 to 33.0 fl oz/A and 12.0 to 16.5 fl oz/A, respectively, on the proposed label). The rice use will be added to the Convoy Fungicide

label. Convoy Fungicide has the same registration number and is the same formulation as

Flutolan il 40SC Fungicide.

Table 3.3 . Summary of Directions for Use of Flutolanil.

Applic. Timing, Type, and Equip. Formula

tion [EPA Reg. No.] Applic.

Rate (lb ai/A) Max. No.

Applic.

Per

Season Max.

Seasonal Applic.

Rate (lb ai/A) PHI

(days) Use Directions and

Limitations**

Brassica (Cole) Leafy Vegetables (Crop Group 5) and Turnip Greens (Proposed) (Broccoli; broccoli, Chinese (gai lon); broccoli raab (rapini); Brussels sprouts; cabbage; cabbage, Chinese (bok choy); cabbage, Chinese (napa); cabbage, Chinese mustard (gai choy); cauliflower; cavalo 11 roccoli; collards;

kale; kohlrabi; mizuna; mustard greens; mustard spinach; rape greens) At planting or transplanting;

In

- furrow or directed spray

at the base of transplants;

Ground equipment Flutolanil

40SC [71711

- 28]*

Convoy® Fungicide [71711

- 28]* 26.0 fl

oz/A (0.77 lb ai/A) 1

(implied) 26.0 fl oz/A

(0.77 lb ai/A) 45 Apply to the row at planting, as an in

- furrow or directed spray at the base of transplants. If transplanted, apply in a

narrow band directed at plant bases immediately after transplanting in 30

- 50 gals/A. Use a minimum of 3 gals. of spray volume per acre. If applied as a soil drench at planting, observe a 45

- day

PHI.

Brassica (Cole) Leafy Vegetables (Crop Group 5) and Turnip Gree ns (Registered) At planting or transplanting;

In

- furrow or directed spray

at the base of transplants;

Ground equipment Moncut ®

70

- DF [10163

- 301] 1.1 lb/A

(0.77 lb ai/A) 1

(implied) 1.1 lb/A

(0.77 lb ai/A) Not

Stated Make one application to the

row at planting, as an in

furrow or directed spray at the base of transplants. Apply in a minimum of 3 gallons of spray per acre.

Do not use oil as carrier or

add other additives to the finished spray. Use is prohibited in some areas of

Arkansas and NY state

. Peanuts (Proposed)Page 12 of 53

Table 3.3 . Summary of Directions for Use of Flutolanil.

Applic. Timing, Type, and Equip. Formula

tion [EPA Reg. No.] Applic.

Rate (lb ai/A) Max. No.

Applic.

Per

Season Max.

Seasonal Applic.

Rate (lb ai/A) PHI

(days) Use Directions and

Limitations**

Postemergence;

Band application;

Ground equipment Flutolanil

40SC
[ 71711

- 28 ] *

Convoy® Fungicide [71711

- 28]* 48.0

- 64.0

fl oz/A (1.4

- 1.9 lb ai/A)

broadcast equivalent not stated 64.0 fl oz/A (1.9 lb ai/A) 90 For ground application, apply in a minimum of 20 gals broadcast equivalent of

water per acre. Apply in a band over the

row within 40

- 60 days after planting but only after the entire crop has emerged.

Peanuts (Registered) Postemergence;

Broadcast application;

Ground or

aerial equipment Flutolanil

40SC
[ 71711

- 28 ] 20.0

- 32.0

fl oz/A (0.59

– 0.95 lb ai/A) or 10.0

- 16.0

fl oz/A (0.30

- 0.48 lb ai/A) 64.0 fl oz/A (1.9 lb ai/A) 40 Apply in a minimum of 10 gal water per acre by ground or 5 gals water per acre by air. Begin applications approximately 45

- 60 days after planting. Make sequential applications at 21

- 30 day intervals at the higher rate

or at 10

- 14 day intervals at

the lower rate.

Rice (Proposed) Postemergence; Broadcast;

Ground or

aerial equipment Flutolanil

40SC [71711

- 28]*

Convoy® Fungicide [71711

- 28]* 12.0

- 33.0

fl oz/A (0.36

- 0.98 lb ai/A) 1 33.0 fl oz/A (0.98 lb ai/A) 30 Apply in a minimum of 10 gal of water/A by ground or 5 gal/A by air. Apply 7

- 14 days after panicle differentiation. If applied at the lower rate,

follow with a second application 10

- 14 days after

the first. Do not apply within 30 days prior to harvest, or beyond 75% heading development stage, whichever occurs

first. Flooded fields may be used by aquaculture of crayfish only following rice harvest. 12.0

- 16.5

fl oz/A (0.36

- 0.49 lb ai/A) 2

Rice (Registered) Postemergence; Broadcast;

Ground or

aerial equipment Flutolanil

40SC [71711

- 28]* 11.8

- 33.0

fl oz/A (0.35

- 0.98 lb ai/A) 1 33.0 fl oz/A 0.98 lb ai/A) 30 Apply in a minimum of 10 gal of water/A by ground or 5 gal/A by air. Apply 7

- 14 days after panicle differentiation. If applied at the lower rate,Page 13 of 53 11.8

- 16.5

fl oz/A (0.35

- 0.49 lb ai/A) 2 follow with a second application 10

- 14 days after

the first. Do not apply within 30 days prior to harvest, or beyond

75 % heading development stage, whichever occurs

first. Flooded fields may be used by aquaculture of crayfish only following rice harvest.
*Formulations: Flutolanil 40SC Fungicide, also called Convoy® Fungicide, is a suspension concentrate which contains 3.8 lb ai/gal. Moncut® 70

- DF is a dry flowable containing 70.0% ai. ** Rotational Crops: Rotational crop restrictions on the established 40 SC label are not being changed. Plantback restrictions on the established SC label are 0 days for cotton, peanuts, potatoes, rice, and soybeans; 30 days for wheat; 150 days for leafy vegetables and small grain crops other than wheat; 240 days for corn and sorghum; and 365 days for all other crops. Rotational crop restrictions on the established 70

- DF label are 0 days for cotton, peanuts, potatoes, rice, soybeans, and turnip greens, and

Brassica (cole) leafy vegetables; 30 days for wheat; 150 days for leaf y vegetables and small grain crops other than wheat; 240 days for corn and sorghum; and 365 days for all other crops. The 70

- DF is not for use on peanuts and rice in CA.

3.4 Anticipated Exposure Pathways

Humans may be exposed to fl utolanil in food and d rinking water, since fl utolanil may be applied directly to growing crops and application may result in fl utolanil reaching surface and ground water drinking water sources . In occupational settings, mixers, loaders, and applicators may be exposed while han dling fl utolanil . There is also a potential for post

- application exposure for

workers re

- entering treated fields

. Additionally, t here is an existing residential uses on turf, so adults and children may be have post

- application exposure to flutolanil.

Risk assessments have been completed for proposed and existing uses of fl utolanil . This risk assessment considers all of the aforementioned exposure pathways based on the existing

flutolanil uses and the proposed changes to the fl utolanil use pattern , but also considers existing

uses of fl utolanil , particularly in the dietary exposure assessment.

3.5 Consideration of 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

p esticide 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 U.S. De partment of Agriculture’s National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA) 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 and ethnic group. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. WheneverPage 14 of 53

appropriate, non

- dietary exposures based on h ome use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas

post

- application are evaluated. Further considerations are currently in development as OPP has

committed res ources 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.

4.0 Hazard Characterization and Dose

- Response Assessment

The hazard characterization for flutolanil is discussed in detail in the original risk assessment (D268880, A. Lowit, 9/11/00)

. The conclusions from that assessment remain unchanged, with the exception that the chronic reference dose (RfD) whi ch was revisited in a 2007 risk assessment (D 334156 , F. Fort 11/27/07)

.

4.1 Toxicolog y Studies Available for Analysis

The existing flutolanil database is adequate for hazard characterization and endpoint selection. Toxicology studies available for risk assessment are summarized in Appendix A.2 and include (1) subchroni c oral toxicity studies in rats and dogs; (2) 21/28 day dermal toxicity study in rats; (3) developmental toxicity studies in rats and rabbits; (4) 2

- generation reproduction study in ra ts; ( 5) chronic toxicity study in dogs; (6) carcinogenicity study in mice and combined chronic/carcinogenicity study in rats; (7) a battery of the required genotoxicity studies; (8) a

metabolism stud ies in rats; (9) acute and subchronic neurotoxicity battery st udies, and (10)

immunotoxi city study in mice. The routes of administration for the toxicity studies are consistent with the potential exposure scenarios.

4. 2 Absorption, Distribution, Metabolism and Excretion (ADME)

While absorption was not directly measured, urinary excretion data suggests that up to 45% of an oral dose of flutolanil may be absorbed. Absorption seems to increase with repeated dosing

b ased on the radioactivity fraction eliminated in urine vs. feces ; however, the increased urinary

exc retion may also be due to enzyme induction since an increased amount of water

- soluble conjugates was detected in urine from rats dosed repeatedly. There was no appreciable concentration remaining in any tissue 7 days post dose, regardless of the dose leve l

. According to the observed metabolites, flutolanil may be conjugated directly or hydroxylated at the

i sopropoxybenzene ring before conjugation. At the single low oral dose (20 mg/kg), excretion in urine and feces was equivalent (40% via each) route. Re peated low oral dosing resulted in increased urine (about 70%) with a corresponding decreased fecal excretion. At the single high dose (1000 mg/kg), most of the excret ion was via the feces

. The parent chemical accounted for the majority of the radioactivi ty eliminated in urine and feces. The major metabolite is N

- (3'

- hydroxyphenyl)

- 2

- (trifluoromethyl)benzamide, also known as de

- isopropylflutolanil (3.5

- 36% in

urine and 0.6

- 4.4% in feces)

. Males and females showed similar overall ADME profiles, except

a h igher percentage of the major metabolite was detected in urine of females with repeated dosing. Bioaccumulation was not demonstrated.Page 15 of 53

4.2.1 Dermal Absorption

No dermal penetration study is available. However, n o dermal or systemic toxicity was observe d

in rats in the 21/28 day dermal toxicity up to the limit dose ( 1000 mg/kg/day )

.

4.3 Summary of Toxicological Effects

Flutolanil is a systemic benzanilide fungicide with both preventative and curative actions against a variety of plant diseases caused by fungi of the phylum Basidomycota , including Rhizoctnia

solani and Sclerotium rolfsii (AKA Athelia rolfsii ). Flutolanil strongly inhibits the succinate dehydrogenase complex (Complex II) in mitochondria of Basidomycot a fungi but has minimal

effect on mitochondria of other fungi and mammalian liver (Motoba et. al. 1988). The mode of action (MOE) of flutolanil in mammals has not been elucidated.

The toxicology studies conducted on flutolanil demonstrate few biologically significant effects, mainly in the liver and gastrointestinal (GI) system. Liver effects were observed in several studies, but most of the changes were considered adaptive. Rat subc hronic and chronic studies showed increases in liver weight but no supporting clinical chemistry and/or histopathology findings. The dog was the most sensitive species for liver effects, showing elevated alkaline phosphatase and cholesterol levels togethe r with dose

- related increases in absolute and relative liver weights and an increase in severity of glycogen deposition in the subchronic study. The chronic dog study saw an increase in emesis, salivation and soft stool as well as decreased body weight ga ins and food consumption that suggest GI irritation, but no relevant liver effects were reported.

Evaluation of the available data for flutolanil did not reveal any evidence to indicate that it is neurotoxic or that it targets the immune system. Guidelin e acute and subchronic neurotoxicity studies did not show any neurological effects at the limit dose (2000 mg/kg and 1024 mg/kg/day, respectively). A guideline immunotoxicity study showed no effect at the limit dose (1004.2 mg/kg/day).

Flutolanil is not a developmental or reproductive toxicant. No maternal, reproductive, or developmental toxicity was observed at the limit dose (1000 mg/kg/day). There was no evidence for increased susceptibility of rat or rabbit fetuses to in utero exposure or rat pups t o post

- natal exposure to flutolanil.

No adverse effects were observed in studies in which flutolanil was administered by the dermal route of exposure. The acute dermal LD50 is >2000 mg/kg (acute Toxicity Category III) and

acute inhalation LD50 is betwee n 0.51 and 2.04 mg/L (Toxicity Category III). The s ubchronic inhalation study has been waived base d on a weight of evidence approach (TXR 0056560 ) ; i.e. low vapor pressure (4.87 x 10 - 8 mm Hg at 25 o C), low acute inhalation toxicity (Toxicity category IV), and low subchronic toxicity with rat, rabbit and dog studies all showing no toxicity evident up to the limit dose, and low chronic toxicity, in which the principal adverse effects up to the limit dose are liver and body weight changes

. Further, there is n o developmental or reproductive concern at dose levels that do not exceed the limit dose. For these reasons, it is concluded that appropriate PODs are not available for any dermal or inhalation exposure length.Page 16 of 53

Based on the lack of evidence of carcinogen icity and the lack of evidence of mutagenicity, flutolanil is classified as “not likely to be carcinogenic to humans”.

4.4 Safety Factor for Infants and Children (FQPA Safety Factor)

On October 25, 1999 the FQPA Safety Factor Committee recommended an FQPA safety factor

of 1X (TXR 0013828 ). The risk assessment team reevaluated the flutolanil database and

reaffirmed that the FQPA Safety Factor be reduced to 1X based on the reasons outlined below

.

4. 4

. 1 Completeness of the Toxicology Database

The fluto lanil database is complete . Based on a weight of evidence approach , a subchronic inhalation study was waived (TXR 0056560 ). Guideline acute and subchronic neurotoxicity studies and the immunotoxicity study submitted by the registrant since the last risk assessment showed no relevant effects up to the limit dose (discussed in Section 4.3 )

.

4.4.2 Evidence of Neurotoxicity

The flutolanil toxicology database revealed no evidence of neurological effects. Included in the

evaluation were recently submitted acute and subchronic neurotoxicity studies tested up to the limit dose (2000 mg/kg acute, 1000 mg/kg subchronic), as well as all other repeated dose studies in the database, some conducted at limit doses (between 500 mg/kg/day and 1000 mg/kg/day )

.

4. 4 .3 Evidence o f Sensitivity/Su sceptibility in the Developing o r Young Animal

The flutolanil toxicology database revealed no evidence of increased susceptibility in the developing or young animal

. There was no increased sensitivity to fetuses as compared to

m aternal 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.

4. 4 .4 Residual Uncertainty in the Exposure Datab ase

There are no residual uncertainti es in the fl utolanil exposure database. An unrefined

, conservative chronic dietary exposure assessment for food and drinking water was conducted, assuming tolerance

- level residues for all existing and proposed commodities and that 100% of registered and p roposed crops treated. The drinking water assessment utilized water concentration values generated by models and associated modeling parameters which are designed to produce conservative, health protective, high

- end estimates of water concentrations

which are not likely to be exceeded. The dietary (food and drinking water) exposure assessment does not underestimate the potential exposure for infants, children, or women of child bearing

age. Additionally, although residential dermal and incidental oral, p ost

- application exposure may occur a quantitative assessment was not needed, since there was no hazard.Page 17 of 53

4.5 Toxicity Endpoint and Point of Departure Selections

4.5.1 Dose

- Response Assessment

D etailed description of the toxicity studies used for selecting toxicity endpoints and PODs for the various exposure scenarios are presented in appendix Table A.2.2 and the Toxicology Disciplinary Chapter for Registration Support Document (M. Bonner 2000; D 262989 ). A 2007 reassessment of toxicological endpoints can be found in the Human Health RAD for Inadvertent or Indirect Tolerances for Use on Soybean, Wh e at, Corn and Cotton (F. Fort 2007 ; D334156). The 2007 reassessment concurs with earlier endpoint sel ection except for the NOAEL used as

chronic oral POD. Immunotoxicology, acute neurotoxicity screening battery, and subchronic neurotoxicity screening battery studies have been received since the last risk assessment

. The

new studies did not alter the end points or PODs listed in the last risk assessment. A review of the current toxicology literature revealed no additional information rele vant to this risk

assessment.

Given the lack of observable effects in most toxicology studies for flutolanil, an appro priate endpoint could be identified only for chronic dietary exposure scenarios (all populations)

. HED’s Hazard Identification Assessment Review Committee (HIARC 10/14/ 199 9 ) selected the combined chronic/oncogenicity rat study NOAEL (87 mg/kg/day based on decreased body weight and increased liver weight) as the chronic dietary POD for flutolanil . However, a 2007 reassessment of toxicological endpoints (F. Fort 11/27/2007; D334156, page 8) identified the

c hronic dog study NOAEL (50 mg/kg/day base on increased incidence of GI effects , decreased body weight and decreased food consumption) as a more appropriate chronic dietary POD

. This

is based on the conclusion that liver weight changes like those observed in the chronic/oncogenicity rat study a re con sidered an adaptive response in the absence of supporting clinical chemistry or histopath ological findings

. Taking into consideration 3 new studies submitted since the last reassessment of toxicological endpoints (acute and subchronic neurotoxicity and im munotoxicity)

, which showed no effects up to the limit dose, the current

flutolanil risk assessment team reaffirms the chronic dog study NOAEL (50 mg/kg/day ) as the chronic dietary POD for all populations

.

Based on the available toxicological data, no obs erved toxic effects could be attributed to a single, short

- or intermediate

- term oral exposure. Likewise, no observed toxic effects could be attributed to dermal exposures of any duration.

4.5.2 Recommendation for Combining Routes of Exposure for Risk As sessment

Under FQPA, when there are potential residential exposures t o the pesticide, aggregate risk assessment must consider exposures from three major sourc es: oral, dermal and inhalation

exposures. These combined residential exposures must then be a ggregated with dietary exposure (food and drinking water) to determine aggregate risk. In the case of flutolanil, no risk is expected from inhalation or dermal short

- and intermediate term exposure scenarios since no hazard was identified from appropriate toxicology studies. Furthermore

, the current use pattern does not indicate long

- term dermal or inhalation exposure potential. Therefore, combiningPage 18 of 53

routes of exposure is not necessary

.

4.5.3 Cancer Classification and Risk Assessment Recommendation

Flutolanil is “not likely” to be a human carcinogen based on the lack of treatment

- related tumors in the combined chronic/oncogenicity rat study (MRID 40342921) or in the carcinogenicity mouse study (MRID 41850803), and the lack of genotoxicity in an accep table battery of mutagenicity studies.

4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk

Assessment

The toxicological doses and endpoints selected for various exposure scenarios are summarized in

Table 4.5.4.1

.

Table 4 .5. 4. 1 Summary of Toxicol ogical Doses and Endpoints for Flutolanil for Use in Dietary

, Non

Occupational and Occupational Human Health Risk Assessments

Exposure/

Scenario Point of

Departure Uncertainty/

FQPA Safety

Factors RfD, PAD,

Level of

Concern for

Risk

Assessment Study and Toxicological Effects

Acute Dietary (General Population, including Infants

and Children and

Females 13

- 49 years of age) No hazard was identified from appropriate oral toxicity studies

.

Chronic Dietary (All Populations) NOAEL= 50

mg/kg/day UF A = 10X

UF H = 10X FQPA SF= 1X Chronic RfD =

0.5 mg/kg/day

cPAD = 0.5 mg/kg/day 2

- year Chronic study in dogs.

MRID 40342922 LOAEL = 250 mg/kg/day based on increased incidence of GI toxicity (emesis, salivation, soft stool , decrease

food consumption and decreased body weight )

Incidental Oral

Short

- (1

- 30 days)

and Intermediate

Term (1

- 6 months) No hazard was identified from appropriate oral toxicity studies

.

Dermal and

Inhalation Short

and Intermediate

Term No hazard was identified from appropriate oral, dermal or inhalation toxicity studies

including developmental toxicity studies in rats and rabbits.

Long

- term
inhalation 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 ob served adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation inPage 19 of 53

sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

4.6 Endocrine Disruption

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental, reproductive, and general or systemic toxicity. These studies include endpoints which may be susceptible to endocrine influence, including effects on endocrine target organ histopathology, organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, repro ductive loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess growth, developmental and reproductive effects in different taxonomic groups. As part of its reregistration decision for flutolanil, EPA reviewed these data and selected the most sensitive endpoints for relevant risk assessment scenarios from the existing hazard database. However, as required by FFDCA section 408(p), flutolanil is subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP).

EPA has developed the EDSP to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP employs a two

- tiered approach to making the statutorily required determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine

- related effects caused by the substance, and

establish a dose

- response re lationship between the dose and the E, A, or T effect.

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between October 2009 and February 2010, EPA issued test orders/data call

- ins for the first group of 67 chemicals,

which cont ains 58 pesticide active ingredients and 9 inert ingredients. A second list of chemicals identified for EDSP screening was published on June 14, 2013 1 and includes some pesticides scheduled for registration review and chemicals found in water. Neither of t hese lists should be construed as a list of known or likely endocrine disruptors.

Flutolanil is on List 1 for which EPA has received all the required Tier 1 assay data. The Agency is currently reviewing all of the assay data received for the appropriate L ist 1 chemicals and planning to make the conclusions of those reviews available in early 2015. For further information on the status of the EDSP, the policies and procedures, the lists of chemicals, future lists, the test guidelines and the Tier 1 screenin g battery, please visit our website. 2

1 See http://www.regulations.gov/#!documentDetail;D=EPA

- HQ

- OPPT

- 2009

- 0477

- 0074 for the final second list of

chemicals.

2 http://www.epa.gov/endo/Page 20 of 53

5.0 Dietary Exposure and Risk A ssessment

5.1 Residues of Concern Summary and Rationale

The residues of concern for the risk assessment and the tolerance expression are summarized in

Table 5.1.

Plants : The nature of the residue in plants is adequately understood based on acceptable metabolism studies on rice, cucumber leaves, and peanuts

. When flutolanil is metabolized, t he amide linkage between the two aromatic rings remains intact ; metabolism occurs at the more highly activated aminophenyl ring. Flutolanil is metaboliz ed via O

- deisopropylation, hydroxylation, and methylation to yield N

- (3'

- hydroxyphenyl)

- 2

- (trifluoromethyl)benzamide (M

4), and N

- (4'

- hydroxy

- 3'

- methoxy)phenyl

- 2

- (trifluoromethyl)benzamide (M

- 7). Most of the metabolites are found bound or conjugated. The major identified components in plants were parent and metabolite M

- 4. T he parent compound and metabolites containing the common moiety, 2

- ( trifluoromethyl ) benzanilide, are the residues of concern which need to be included in the tolerance expression and dietary risk assessment

. The enforcement method converts parent and metabolites containing the common moiety 2

- ( trifluoromethyl ) benzanilide to 2

- ( trifluoromethyl ) benzoic acid.

Livestock : The nature of the residue in livestock is adequately understood ba sed on acceptable metabolism studies in goats and poultry. As with plants, t he amide linkage between the two aromatic rings remains intact ; metabolism occurs at the more highly activated aminophenyl ring. The specific metabolites identified as residues o f concern are M

- 2 ( N

- [4'

- hydroxy

- 3'

- (1

- methyleth oxy)phenyl]

- 2

- (trifluoromethyl) benzamide), M

- 4, and M

- 7 in livestock tissues, and the glucuronide/sulfate conjugates of M

- 4 in milk.

T he parent compound and metabolites containing the common moiety, 2

- ( trifluoromethyl ) benzanilide, are the residues of concern which need to be included in the tolerance expression and dietary risk assessment

. The enforcement method converts parent and metabolites containing the common moiety 2

- ( trifluoromethyl ) benzanilide to 2

- ( trifluoromethyl ) benzoic acid.

Rotational Crops : The nature of the residue in rotational crop commodities is adequately understood based on an acceptable confined rotational crop study with lettuce, radish, and oat/sorghum conducted with [U

14 C

- amin ophenoxy]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 the tolerance expression and dietary risk assessment for rotational crop s are flutolanil and metabolites containing the common moiety , 2

- ( trifluoromethyl ) benzanilide, which is converted by the enforcement method to 2

- ( trifluoromethyl ) benzoic acid.

Water : Parent is the major residue in water; no major (>10%) degradation produ cts were
identified in environmental fate studies. O nly the parent needs to be included in the drinkingPage 21 of 53

water exposure assessment for flutolanil ( Metabolism Assessment Review Committee (MARC)

determined on 12/16/1999 ; M . Xue, 1/6/00, no DP#)

.

A summary of the metabolites and degradates of fl utolanil for human health risk assessment is

summarized in Table 5.1.

Table 5.1. Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expression

.

Matrix Residues included in Risk

Assessment Residues included in Tolerance Expression

Plants Primary Crop flutolanil and metabolites

converted to

2

- ( trifluoromethyl ) benzoic

acid flutolanil and metabolites

converted to

2

- ( trifluoromethyl ) benzoic

acid Rotational Crop

Livestock Ruminant flutolanil and metabolites

converted to

2

- ( trifluoromethyl ) benzoic

acid flutolanil and metabolites

converted to

2

- ( trifluoromethyl ) benzoic

acid Poultry

Drinking Water flutolanil (parent) Not Applicable

5 .2 Food Residue Profile

Crop field trials : Flutolanil is a systemic fungicide. It forms a protective barrier on the plant, enters the plant, and moves upward in the xylem. Flutolanil is currently registered under 40 CFR §180.484(a) on cotton, peanuts, potatoes, rice, soybeans, turnip gree ns, the Brassica leafy vegetable group 5, and livestock commodities, including milk, eggs, and the meat, fat and meat byproducts of cattle, goats, hogs, horses, poultry, and sheep. Plant commodity tolerance levels range from 0.1 ppm in turnip greens and t he Brassica leafy vegetable group 5 to 25 ppm in rice hulls. Livestock tolerance levels range from 0.05 ppm to 2.00 ppm. Flutolanil is also registered under 40 CFR §180.484(d) for indirect or inadvertent residues on wheat commodities at levels ranging fr om 0.05 ppm to 2.5 ppm. No Section 18 emergency exemptions or tolerances with regional registrations are established. Adequate field trials are available to support the established/recommended tolerances. Because of amendments (D413582, N. Dodd , 12/12/1 3)

, the Agency reconsidered a prior conclusion and now recommends increasing the 0.1 ppm

established tolerances on turnip greens and the Brassica leafy vegetables crop group 5 to 0.20

ppm , since detectable residues were found in one mustard green sample. The Agency also recommends increasing the 15.0 ppm established tolerance on peanut hay to 20.0 ppm , based on the Organization for Economic Cooperation and Development’s (OECD’s) tolerance calculation procedures, including residues from both band and broadc ast applications. Also, the t olerances

e stablished on rice straw and hulls [ 40 CFR §180. 484 (a)] are no longer required ( Table 1 Feedstuffs , June 2008) and should be removed.

Processing S tudies : Of the registered crops , processed commodities are associat ed with cotton, peanut, potato, rice, soybean, and wheat. Adequate processing data are available as discussed in Appendix D

.Page 22 of 53

Storage Stability : Adequate storage stability data are available to support the field trials of the primary (treated) crops for existing uses and the rotational crop wheat as discussed and shown in Appendix D

.

Meat, Milk, Poultry, and Eggs : Acceptable feeding studies with dairy cattle and poultry were previously reviewed. Tolerances are established for residues of flutolanil and its metabolites

converted to 2

- TFBA in ruminant (cattle, goat, horse, and sheep) commodities at 0.05 ppm for milk, 0.10 ppm for fat, 1.00 ppm for kidney, 2.00 ppm for liver, and 0.05 ppm for meat and meat byproducts, and in poultry commodities at 0.05 ppm for egg, fat, meat, and meat byproducts. Feeding studies are available on lactating cows and laying hens. Based on the feeding studies and the maximum reasonably balanced diets for livestock, t he established livestock tolerances are adequate.

Rotational C

rops : Rotational crop restrictions and inadvertent residue tolerances have been

established on the Flutolanil 40SC label ( EPA Reg. No. 71711

- 28 ) based on the available

confined and field accumulation studies

.

Since Brassica (cole ) leafy vegetables and turnip greens are being registered on the 40SC label, the rotational crop restrictions for the Flutolanil 40SC label ( EPA Reg. No. 71711

- 28 ) should be

amended to include Brassica (cole) leafy vegetables and turnip greens under the 0

- day rotational crop restriction interval.

Since no tolerance is established for sugar beet, the 0

- day rotational crop restriction for sugar beet on the Artisan Fungicide label (EPA Reg. No. 71711

- 17 ) should be removed.

5.3 Water Residue Profile

T here ar e no established Maximum Contaminant Level s for residues of f lutolanil in drinking water. No health advisory levels for f lutolanil in drinking water have been established.

The drinking water residues used in the dietary assessment were provided by the Environmental Fate and Effects Division (EFED) and were incorporated directly into this dietary assessment. Water residues were incorporated in the DEEM Food Commodity Intake Database (FCI D) into the food categories “water, direct, all sources” and “water, indirect, all sources.”

The Tier I/II Estimated Drinking Water Concentrations (EDWCs) were calculated using the Tier I Rice Model v.1.0 (surface waters), the Tier II PRZM/EXAMS models (surface waters), the Tier

I/II model PRZM

- GW (in the Tier I mode), and the Tier I ground water model SCI

- GROW for

use in the human health risk assessment.

Results obtained from the models that yielded the highest EDWCs for flutolanil are summarized

in Ta ble 5.3

. The maximum screening EDWC for chronic exposure is 2530 ppb, found in groundwater associated with the use on turf. Residues in surface water are lower. T he

maximum chronic E DWC in surface water is ≤531 ppb, which is associated with the use on r ice

.Page 23 of 53

Table 5.3. Maximum EDWCs based on Ground Application of Flutolanil on Turf and Ground/Aerial

Application on Rice. Drinking

Water Source Model Scenario/Use 1 Acute (ppb) Chronic (ppb) Cancer/Chronic (ppb)

Surface water Tier 1 Rice

Model Rice 531 < 531

Ground water PRZM

- GW WI Sand Turf 2730 2530 1 For rice, the application rate is 0.980 lb a.i./A/season; for turf, the application rate is 17.1 lb a.i./A/year.

5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

Tolerance level residues were used in the assessment. No acute dietary assessment was conducted. The EDWCs are residues in groundwater using the WI sand turf scenario.

5.4.2 Percent Crop Treated Used in Dietary Assessment

Percent crop treated refinements were not used for this assessment.

5.4.3 Acute Dietary Risk Assessment

No appropriate endpoint attributable to a single dose was identified. As no acute dietary endpoint was identified, an acute exposure analysis was not performed.

5.4.4 Ch ronic Dietary Risk Assessment s

Tolerance

- level residues combined with 100% crop treated and default processing factors were used to determine the chronic dietary exposure and risk estimates. As shown in Table 5.4.6, t he chronic dietary exposure estimates for food and drinking water are below HED’s level of concern for the general U.S. population (11% of the chronic population adjusted dose (cPAD)). The most highly exposed population subgroup was all infants (<1 year old) at 29% of the cPAD.

EDWCs were i ncorporated directly into the dietary assessment

.

5.4. 5 C ancer Dietary Risk Assessment s

Flutolanil is classified as “not likely to be carcinogenic to humans,” so a quantitative cancer dietary assessment was not conducted.Page 24 of 53

5.4. 6 Summary Table

Table 5.4.6. Summary of Dietary Food and Drinking Water Exposure and Risk for Flutolanil

Population Subgroup Chronic Dietary

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

General U.S. Population 0.055661 11

All Infants (< 1 year old) * 0.144721 29

Children 1

- 2 years old 0.084103 17

Children 3

- 5 years old 0.070104 14

Children 6

- 12 years old 0.049893 10

Youth 13

- 19 years old 0.040594 8.1

Adults 20

- 49 years old 0.055422 11

Adults 50

- 99 years old 0.053959 11

Females 13

- 49 years old 0.054666 11

* The values for the highest exposed population are bolded.

6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

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 proh ibited through label directions, could be used in a residential/public site. Ad ditionally, spray drift, i.e. off

- target movement of pesticides can occur via many types of pathways and it is governed by a variety of factors. Sprays that are released and do not deposit in the application area end up off

- target and can lead to exposure s to those it may directly contact. They can also deposit on surfaces where contact with residues can eventually lead to exposures ( e.g. children playing on lawns where residues have deposited next to treated fields). A lthough potential

residential handl er and post

- application exposures exist, and spray drift exposures could potentially exist, assessments were not conducted because no dermal, oral (incidental), or inhalation toxicological endpoints attributable to short

- or intermediate

- term exposures hav e been identified, and the current use patterns do not indicate long

- term exposure (6 or more months of continuous exposure) potential

. Also, because a turf use exists, a separate assessment from spray drift exposures is not needed.

7.0 Aggregate Exposure/Ri sk Characterization

In accordance with FQPA, HED must consider and aggregate (add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. In an aggregate assessment, exposures from relevant sources are ad ded together and compared to quantitativePage 25 of 53

estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure.

For fluto lanil, only potential chronic exposures from food and drinking water were aggregated. There were no observed effects attributable to a single dose and an acute dietary endpoint was

not established. 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 aggr egate risk assessment was also not performed because flutolanil is not carcinogenic. Because drinking water estimates have been combined with dietary exposures, the dietary assessment described earlier (see Section 5. 4 ) serves as the

aggregate exposure an d risk assessment for fl utolanil . Because aggregated food and drinking water exposures from this conservative assessment for the most highly exposed population subgroup ( all infants <1 year old) only amount to 29 % of the cPAD, exposure to fl utolanil from all registered/proposed uses do not exceed HED’s level of concern.

8.0 Cumulative Exposure/Risk Characterization

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 fl utolanil and any other substances and fl u tolanil 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 fl utolanil 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/.

9.0 Occupational Exposure/Risk Characterization

Workers may be exposed to flutolanil during mixing, loading, appl ying , and post

- application

activities

. Based on the proposed application rates and use scenarios, short

- and intermediate

term occupational exposures may occur. However, since short

- and intermediate

- term toxicity endpoints have not been established, an occupational exposure assessment is not required.

C hronic occupational exposure is not expected ; thus, c hronic occupational exposure risk assessments are also not required

.

Restricted Entry Interval: For all activities and crops, the REI of 12 hours on existing labels is adequate to protect workers. In addition to systemic hazard, the WPS for Agricultural Pesticides sets a REI based on the acute toxicity of chemicals. Technical fl utolanil is classified as toxicity category I II for acute dermal toxicity and toxicity category IV for primary eye irritation and skin irritation. Under the WPS, active ingredients classified as acute toxicity categories III or IV for

these ro utes are assigned a 12

- hour REI. Therefore, the REI of 12

- hours is adequate to protect agricultural workers from post

- application exposures to fl utolanil

.Page 26 of 53

10.0 References

Tier I/II Estimated Drinking Waters Concentrations of Flutolanil for the New Uses on Peanuts (Banded Applications), Brassica Leafy Vegetables (Crop Group 5) Plus Turnip Greens, Turf and Ornamentals for the Product Convoy® Fungicide, and for Increased Annual Rate on Turf for the Product ProStar® 70WP Fungicide. DP414000, J. Meléndez, 12 / 12 /13

.

Flutolanil Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessment for the Section 3 Registration Actions on Brassica Leafy Vegetables (Crop Group 5), Turnip Greens, Peanuts, and Rice, and for Registration Review. DP416620 , N. Dodd,

12/ 12 /13

.

Flutolanil. Petition for Amendments to Section 3 Uses of Flutolanil on Brassica (Cole) Leafy Vegetables (Crop Group 5), Turnip Greens, Peanuts, and Rice. Summary of Analytical Chemistry and Residue Data. DP413582, N. Dodd, 12/ 12 /13

.Page 27 of 53

A ppendix A

. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.340) for food use for f lutolanil are in Table A. 1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Table A.1. Toxicology Data Requirements.

Study Technical

Required Satisfied

870.1100 Acute Oral Toxicity

................................ ....................... 870.1200 Acute Dermal Toxicity

................................ .................. 870.1300 Acute Inhalation Toxicity

................................ .............. 870.2400 Primary Eye Irritation

................................ .................... 870.2500 Primary Dermal Irritation

................................ .............. 870.2600 Dermal Sensitization

................................ ...................... yes

yes

yes

yes

yes

yes yes

yes

yes

yes

yes

yes

870.3100 Oral Subchronic (rodent)

................................ ............... 870.3150 Oral Subchronic (nonrodent)

................................ ......... 870.3200 21

- Day Dermal

................................ .............................. 870.3250 90

- Day Dermal

................................ .............................. 870.3465 90

- Day Inhalation

................................ .......................... yes

yes

no

no

no yes

yes

yes

- waived 1

870.3700a Developmental Toxicity (rodent)

................................ ... 870.3700b Developmental Toxicity (nonrodent)

............................. 870.3800 Reproduction

................................ ................................ . yes

yes

yes yes

yes

yes

870.4100a Chronic Toxicity (rodent)

................................ .............. 870.4100b Chronic Toxicity (nonrodent)

................................ ........ 870.4200a Oncogenicity (rat)

................................ .......................... 870.4200b Oncogenicity (mouse)

................................ .................... 870.4300 Chronic/Oncogenicity

................................ .................... yes

yes

yes

yes

no 2

yes

2

yes

yes

870.5100 Mutagenicity

— Gene Mutation

- bacterial

..................... 870.5300 Mutagenicity

— Gene Mutation

- mammalian

................ 870.5xxx Mutagenicity

— Structural Chromosomal Aberrations

... 870.5xxx Mutagenicity

— Other Genotoxic Effects

....................... yes

yes

yes

yes yes

yes

yes

yes

870.6100a Acute Delayed Neurotoxicity (hen)

............................... 870.6100b 90

- Day Neurotoxicity (hen)

................................ ........... 870.6200a Acute Neurotoxicity Screening Battery (rat)

................. 870.6200b 90

- Day Neurotoxicity Screening Battery (rat)

............... 870.6300 Develop. Neurotoxicity

................................ ................. no

no

yes

yes

no -

- yes

yes

-

870.7485 General Metabolism

................................ ...................... 870.7600 Dermal Penetration

................................ ........................ 870.7800 Immunotoxicity

................................ ............................. yes

no

yes yes

- yes

Special Studies for Ocular Effects no

- 1 = Based on a weight of evidence approach a subchronic inhalation toxicity study is not required for the current uses (TXR 0056560).

2 = A chronic/onco genicity study is available for the rat, thus separate chronic and oncogenicity studies are not

necessary.Page 28 of 53

A.2 Toxicity Profile s

Table A.2.1 Acute Toxicity Profile

– Flutolanil Technical 1

Guideline No. Study Type MRID(s) Results Toxicity Category

870.1100 Acute oral mouse 40342905 LD 50 > 10,000 mg/kg IV

870.1200 Acute dermal rat 40342906 LD 50 > 5 ,000 mg/kg III

870.1300 Acute inhalation rat 40342910 LC 50 m ales between 0.51 mg/L and 2.04 mg/L

LC 50 f emales ≥ 2.04 mg/L I II

870.2400 Acute eye irritation rabbit 40342912 Minimal irritation IV

870.2500 Acute dermal irritation rabbit 40342915 Not a dermal irritant IV

870.2600 Skin sensitization guinea pig 40342917 Not a dermal sensitizer N/A

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

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile of Flutolanil Technical.

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.3100 90

- Day oral toxicity

(rat) 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 based on changes in absolute and relative liver weights considered adaptive due to absence of supportive clinical chemistry and histopathology findings.

870.3150 90

- Day oral toxicity

(dog) 40342920 (1986)

Acceptable

- Guideline

0, 80, 400, 2000 mg/kg/d NOAEL = 80 mg/kg/day,

LOAEL = 400 mg/kg/day based on increases in

liver weight and severity of hepatic glycogen deposition in both males and females ; elevated alkaline phosphatase and cholesterol levels observed at the next highest dose.

870.3200 21/28

- Day dermal

toxicity (rat) 41841205 (1991)

Acceptable

- Guideline

0, 1000 mg/kg/d Systemic NOAEL = 1000 mg/kg/day

LOAEL not established based on changes in adrenal gland weight (males only) and pulmonary findings considered incidental because they were not observed in any other studies.

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

LOAEL not established based on the absence of

treatment

- related dermal effects at the application

site.Page 29 of 53

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile of Flutolanil Technical.

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.3700a Prenatal

developmental in rat 41850804 (1987)

Acceptable

- Guideline

0, 40, 200, 1000 mg/kg/d Maternal NOAEL = 1000 mg/kg/day

LOAEL not established based on the absence of maternal effects at any dose.

Developmental NOAEL = 1000 mg/kg/day

LOAEL not established based on the absence of developmental effects at any dose.

870.3700b Prenatal

developmental in

rabbit 40342924 (1987)

Acceptable

- Guideline

0, 40, 200, 1000 mg/kg/d Maternal NOAEL = 1000 mg/kg/day

LOAEL not established based on the absence of maternal effects at any dose.

Developmental NOAEL = 1000 mg/kg/day

LOAEL not established based on the absence of developmental effects at any dose.

870.3800 Reproduction and

fertility effects

– 2 generation (rat) 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 = 1625 mg/kg/day

LOAEL not established based on the absence of parental effects at any dose.

Reproductive NOAEL = 1625 mg/kg/day

LOAEL not established based on the absence of reproductive effects at any dose.

Offspring NOAEL = 1625 mg/kg/day

LOAEL no t established based on the absence of effects in the offspring at any dose.

870.4100a Chronic toxicity

(rodents) C ombined chronic / carcinogenicity study available (see below)

870.4100b Chronic toxicity (dog) 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 emesis, salivation, soft sto ol, decreased body weight gains and decreased food consumption.

870.4300a Chronic /

Carcinogenicity

(rat) 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 based on changes in liver weights considered adaptive due to absence of supportive clinical chemistry and histopathology findings.

No evidence of carcinogenicity

870.4200 Carcinogenicity

(mouse) 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 = 3333 (M) and 3676 (F) mg/kg/day

LOAEL = not established based on changes in liver weights (F only) and fatty vacuolation considered adaptive due to absence of supportive clinical chemistry.

No evidence of carcinogenicityPage 30 of 53

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile of Flutolanil Technical.

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.5100 Bacterial Reverse

Mutation Test 40342926 (1981)

Acceptable

- Guideline

0, 10, 50, 100, 500, 1000, 5000, 10000, 25000 ug/plate. Negative with and without metabolic activation

(S9) in Salmonella strains TA98, TA10, TA1535, TA1537, and TA1538 and in E. Coli WP2 uvrA

strain.

870 .5300 In vitro Mouse

Lymphoma Cells Gene

M utations at TK +/

-

L ocus Test 41841207 (1989)

Acceptable

- Guideline

0, 6, 1 5, 30, 60, 80, 100 ug/mL Negative with and without metabolic activation

(S9).

870.5375 In vitro Chinese

Hamster Lung C ell

Chromosome

Aberration Test 40342925 (1986)

Acceptable

- Guideline

0, 37, 75, 150 uM/plate Positive in the presence of S9 metabolic

activation (S9).

870. 53 75 In vitro Human

Lymphocytes

Chromosome

Aberration Test 42606628 (1990)

Acceptable

- Guideline

0, 120, 250, 500, 1000 ug/mL Negative with and without metabolic activation

(S9).

870.5395 Mouse Erythrocyte

Micronucleus Assay 40342927 (1983)

Acceptable

- Guideline

0, 6400, 8000, 10000 mg/kg either in a single dose or 10 gm/kg/day over 4 days. Negative in the bone marrow of M and F

BDF1mice.

870.5550 Unscheduled DNA

Synthesis Assays in

Cultured Primary Rat Hepatocytes 41841206 (1989)

Acceptable

- Guideline

0, 2.67, 27, 53, 80 ug/mL Negative in the induction of unscheduled DNA

synthesis

.

870.6200a Acute neurotoxicity

screening battery 48796402 (2012)

Acceptable

- Guideline

Single dose of 0, 125, 500, or 2000 mg/kg NOAEL = 2000 mg/kg/day

LOAEL = not established based on the lack of

treatment

- related adverse effects up to 14 days after dosing and after pathological examination of

tissues.Page 31 of 53

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile of Flutolanil Technical.

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.6200b Subchronic

neurotoxicity screening battery 48798501 (2012)

Acceptable

- Guideline

Feed Concentration adjusted based on body weight and

estimated food consumption to achieve 0, 62.6, 250, and 1000 mg/kg (M: 0, 62.8, 250.5, and 977.8 mg/kg /day; F: 0, 66.2, 255.8, and 1024.0 mg/kg/day) NOAEL = 1024.0 mg/kg/day

LOAEL = not established based on the lack of

treatment

- related adverse effects during weeks

- 1, 2, 4, 8, and 13 of dosing and after pathological

examination of tissues.

870.7485 Metabolism and

pharmacokinetics (rat) 4260 6602 (1992)

Acceptable

- Guideline

S ingle dose : 20 and 1000 mg/kg

Repeated dose: 20 mg/kg for 14 days No appreciable tissue levels of flutolanil at study

termination (168 hours post

- dose).

Single dose: at 20 mg/kg 4 2

- 45 % of dose

excreted in urine

, 4 1 % in feces ; at 1000 mg/kg 7

- 10% of dose excreted in urine, 67

- 78% in feces.

Repeated dose : at 20 mg/ kg 70

- 71% of dose excreted in urine, 29

- 32% in feces.

No appreciable tissue levels 7 days post

- dose.

Urinary metabolite : N

- (3'

- hydroxyphenyl)

- 2

- (trifluoromethyl) benzamide (aka M

- 4)

Fecal metabolite: Mainly parent chemical with

limited conversion to M

- 4.

870.7800 Immunotoxicity (rat) 48647001 (2011)

Acceptable

- Guideline

0, 750, 3000 or 12,000 ppm (M: 0.0, 61.13, 253.9, 1004.2 mg/kg/day; F: 0.0, 74.6, 253.3, 1026.0 mg/kg/day) NOAEL = 1004.2 mg/kg/day

LOAEL not established based on the absence of systemic or immune system effects at any dose.

HDT = Highest Dose Tested; F = females; M = males

A.3 Hazard Identification and Endpoint Selection

This section reflects the 2000 Toxicology Chapter (D262989) and a 2007 reassessment of toxicological endpoints (F. Fort

, 11/27/2007; D334156, page 8).

A.3.1 Acute Reference Dose (aRfD)

- Females age 13

- 49 and General Population

Study Selected: None

Dose and Endpoint for Risk Assessment: No aRfD selected. LOAEL not established based onPage 32 of 53

acute oral LD 50 > 10,000 mg/kg ( Toxicity Category IV ) and no treatment

- related effects in developmental studies up to the limit dose (1000 mg/kg/d ay) for technical grade flutolanil

.

Comments about Study/Endpoint/Uncertainty Factors: T oxic effects observed in oral toxicity studies could not be attributed to a single dose. Additionally, based on the assumption that developmental toxicity could occur in a single exposure, it is common practice in the Agency to use developmental toxicity studies in selecting endpoints for acute dietary risk

assessment. However n o treatment

- related maternal or developmental effects were observed.

A.3.2 Chronic Refer ence Dose (cRfD )

Study Selected : Chronic Toxicity

– Dog

MRID No.: 40342922

Executive Summary : See Appendix A.4, Guideline § 870. 4100b

Dose and Endpoint for Risk Assessment : cRfD = 0.5 mg/kg/day ; cPAD = 0.5 mg/kg/day

. NOAEL = 50 mg/kg/day based on increased incidence of clinical sighs (emesis, salivation and soft stool), decreased body weight gains and decreased food consumption seen at LOAEL = 250 mg/kg/day.

Comments about Study/Endpoint/Uncertainty Factors : This study was selected because it provided the most sensitive endpoint among all available chronic (i.e. 2

- year exposure) feed studies. Uncertainty Factors accounts for both interspecies extrapolation (UF A =10X) and intraspecies variability (UF H =10X). Since the toxicity database for flutola nil is complete,

additional UF D is not required. An FQPA Safety Factor of 1X was applied because there is no evidence that flutolanil results in increased susceptibility of rat or rabbit fetuses or juvenile rats.

A.3.3 Incidental Oral Exposure (Short

- an d Intermediate

- Term)

Study Selected: None

Dose and Endpoint for Risk Assessment: No appropriate endpoint was identified in the

database for these durations and route of exposure.

Comments about Study/Endpoint/Uncertainty Factors: Toxic effects observed in oral toxicity studies could not be attributed to short or intermediate term exposures

.

A.3. 4 Dermal Exposure (Short

- , Intermediate

- and Long

- Term)

Study Selected: None

Dose and Endpoint for Risk Assessment: No appropriate en dpoint was identified in the

database for these durations and route of exposure.Page 33 of 53

Comments about Study/Endpoint/Uncertainty Factors: In a 21

- day repeated dose dermal toxicity study in rats (MRID No. 41841205), no systemic or dermal toxicity was observed a t 1000 mg/kg/day, the highest dose tested (limit dose). The likelihood of toxic effects resulting from repeated dermal exposure to flutolanil is quite low.

A.3. 5 Inhalation Exposure (Short

- , Intermediate

- and Long

- Term)

Study Selected: None

Dose and Endpoint for Risk Assessment: No appropriate endpoint was identified in the

database for short

- or intermediate

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

- term inhalation exposure potential.

Comments about Study/Endpoint/Uncertainty Factors: On 2/20/2013 HASPOC concluded

, based on a WOE approach, that a subchronic inhalation toxicity study is not required for flutolanil. This approach included all of the available hazard and exposure information for

flutola nil, such as: 1) the low vapor pressure of flutolanil (4.87 x 10 - 8 mm Hg @ 25°C); 2) the low acute inhalation toxicity of flutolanil (Toxicity Category IV); and 3) the low subchronic toxicity of flutolanil, with rat, rabbit and dog studies all showing no t oxicity evident up to the Limit dose; and low chronic toxicity, in which the principal adverse effects up to the Limit Dose are liver and body weight changes and 5) if an oral PODs would have been used, MOEs for

residential handlers would have been greate r than the Agency’s level of concern.

A.4 Executive Summaries

This section contains the most recent executive summary or conclusion for each study. In some cases, they incorporate recent changes as explained in Supplementary Data Evaluation Records.

T he document source is indicated in parenthesis by the study title.

A.4.1 Subchronic Toxicity

870.3100 90

- Day Oral Toxicity

– Rat (P. Chin 3/25/2008, TX R 0053361)

In a subchronic oral toxicity study (MRID 40342919), flutolanil [97.5% a.i.; Lot No. 54325 1 (36)] was administered in the diet to groups of 10 male and 10 female CD (Sprague

- Dawley derived) rats at concentrations of 0, 500, 4000, and 20000 ppm for 90 days. The dietary concentrations were equivalent to 0, 37, 299, and 1512 mg/kg/day, respective ly, for males and 0, 44, 339, and 1743 mg/kg/day, respectively, for females.

No treatment

- related changes in ophthalmoscopic, hematological, clinical chemistry, gross pathology, or histopathology parameters were observed in either sex. At 1512 mg/kg/day (HDT), the absolute liver weights in females were increased (19%) over control and the relative liver weights in males and females were increased (14

- 20%) over control. At 299 mg/kg/day, the absolute and relative liver weights in females were increased (8

- 11%) over control. The increase in liver weights was considered to be an ada ptive response to flutolanil treatment because these effects were not supported by clinical chemistry or histopathology findings.Page 34 of 53

The NOAEL was 1512 mg/kg/day (HDT) and the LOAEL was not established.

This study is classified acceptable/guideline and satisfies the guideline requirement (OPPTS 870.3100a; OECD 408) for a subchronic oral toxicity study in the rat.

870.3150 90

- Day Oral Toxicity

– Dog (M. Mercado

- Feliciano 8/20/2013, TX R

0056766 )

In a 90

- day oral toxicity study (MRID 40342920) te chnical grade flutolanil (Lot No. 543251(36); purity: 97.5%) was administered to 4 beagle dogs sex/dose in capsules at dose levels of 0, 80, 400, or 2000 mg/kg bw/day for 95

- 98 days. At study termination, all animals were sacrificed and subjected to gross pathological examination and histological examination of selected tissues.

There were no unscheduled deaths or significant clinical observations at any dose level. Levels of alkaline phosphatase in blood were elevated in high dose males (123%, p<0.01) a nd females (83%, p<0.05) at study end, and in high dose males (92%, p<0.01) at 1.5 months of dosing. Absolute and relative (to bw) liver weights were increased in high dose males (29% and 26%, respectively; p<0.01). Absolute liver weight was increased (3 2%, p< 0.05) in high dose females. While glycogen deposition in the liver was observed in the same number of animals in each dose group, severity increased with dose: from minimal

- to

- mild in control and low dose groups, to mild in the mid dose group and m ild

- to

- moderate in the high dose group; the same trend was observed in males and females. These results suggest adaptive changes in the liver. Since no

adverse treatment

- related effects were seen in this study, a LOAEL could not be

established. The obse rved NOAEL in male and female dog was 2000 mg/kg bw/day.

This 90

- day oral toxicity study in the dog is acceptable (guideline) and satisfies the guideline requirement for a 90

- day oral toxicity study (OPPTS 870.3150; OECD 409) in non

- rodent species.

870 .3200 21/28

- Day Dermal Toxicity

– Rat ( M. Mercado

- Feliciano 8/20 /2013,

TX R 0056766 )

In a 21

- day dermal toxicity study (MRID 41841205), flutolanil (97.6% a.i., lot # 543251) was applied to the shaved skin of 5 Sprague

- Dawley derived CD® rats /sex/dose at dose levels of 0, or 1000 mg/kg bw/day, 6 hours/day for 5 days/week during a 21

- day period. At study termination, all animals were sacrificed and subjected to gross pathological examination, clinical chemistry, hematology and histological examination of s elected tissues.

There were no compound related effects on mortality, clinical signs, body weight, food consumption, hematology, clinical chemistry, or gross and histologic pathology. Mean absolute and relative adrenal weights were decreased in males (19 %, p≤0.01, and 20%, p≤0.05, respectively). Alveolar emphysema and perivascular lymphocytes were observed in the lungs of two treated males and one treated female; however these effects may be due to the ether

anesthesia and not treatment

- related. Since n o adverse treatment

- related effects were seen in this study, a LOAEL could not be established. The observed NOAEL in male and femalePage 35 of 53

rats was 1000 mg/kg bw/day.

This 21

- day dermal toxicity study in the rat is acceptable (guideline) and satisfies the guideline requirement for a 21/28

- day dermal toxicity study (OPPTS 870.3200 ; OECD 410) in rat.

A.4.2 Prenatal Developmental Toxicity

870.3700a Prenatal Developmental Toxicity Study

– Rat (M. Mercado

- Feliciano

8/20 /2013, TX R 0056766 )

In a developmental toxicity study (MRID 41850804) flutolanil (97.5%% a.i ., lot # 543251) was administered to 22 female Sprague

- Dawley, CD®] rats/dose by gavage] at dose levels of 0, 40, 200, or 1000 mg/kg bw/day from days 6 through 15 of gestation.

There were no treatment

- related effects on survival, clinical signs, body wei ght, food consumption, or cesarean parameters. Post

- implantation loss increased from 6.5% in the control to 8.1% (+25%) at 1000 mg/kg/day; however it was within the historical control range (1.7

- 12.7%). Since no adverse treatment

- related effects were see n in this study, a maternal LOAEL could not be established. The observed maternal NOAEL is 1000 mg/kg bw/day.

There were no treatment

- related effects in developmental parameters. The incidence of incomplete ossification was increased compared to contro ls on a per fetus basis, but not on a litter basis; therefore it was not considered to be compound related. Since no adverse

treatment

- related effects were seen in this study, the developmental LOAEL could not be established. The developmental NOAEL is 10 00 mg/kg bw/day.

The developmental toxicity study in the rat is classified acceptable (guideline) and satisfies the guideline requirement for a developmental toxicity study (OPPTS 870.3700; OECD 414) in the

rat.

870.3700b Prenatal Developmental Toxici ty Study

– Rabbit (M. Mercado

Feliciano 8/20 /2013, TX R 0056766 )

In a developmental toxicity study (MRID 40342924) Flutolanil (97.5% a.i ., lot No. 543251(36)) was administered to 16 females New Zealand white rabbits /dose in by gavage at dose levels of 0, 40, 200, or 1000 mg/kg bw/day from days 6 through 18 of gestation.

There were no treatment

- related effects on survival, clinical signs , body weight, food consumption, or cesarean parameters. The number of resorptions was increased in the mid and high doses (1 resorption in a total of 14 control dams, 0 for 15 dams at 40 mg/kg/day, 4 for 13 dams at 200 mg/kg/day, 7 for 13 dams at 1000 mg /kg/day). However, control and treated group had similar number of live fetuses per dam (7.4, 6.6, 7.8 and 7.3 for the 0, 40, 200 and 1000 mg/kg/day groups, respectively), and there was no altered growth (as evidenced by pup weight

and skeletal ossificati on), and no treatment

- related effects on anomalies and no treatment

- related

malformations. Consequently, the increase in resorptions is not considered biologically significant. Since no adverse treatment

- related effects were seen in this study, a materna lPage 36 of 53

LOAEL could not be established. The observed maternal NOAEL is 1000 mg/kg bw/day.

Since no adverse there no treatment

- related effects in developmental parameters were seen in this study, a developmental LOAEL could not be established. The developmenta l NOAEL is 1000 mg/kg bw/day.

The developmental toxicity study in the rabbit is classified acceptable (guideline) and satisfies the guideline requirement for a developmental toxicity study (OPPTS 870.3700; OECD 414) in

rabbits.

A.4.3 Reproductive Toxi city

870.3800 Reproduction and Fertility Effects

– Rat (M. Mercado

- Feliciano 8/20 /2013,

TX R 0056766 )

In a 2

- generation reproduction study (MRID 41850805) Flutolanil (98% a.i., lot # 543251 and 90706) was administered to 30 Sprague

- Dawley Crl:CD ® rats /sex/dose in diet at dose levels of 0, 200, 2000, or 20,000 ppm (equivalent to 0, 16, 161, 1636 mg/kg bw/day for males and 0, 19, 188, 1917 mg/kg bw/day for females). On lactation Day 4, litters were culled to 4 pups/sex when possible. Pups were w eaned on Day 21 of lactation.

No compound

- related mortality, clinical signs, or effects on body weight, gross or histopathology were observed for either sex or generation. At 20,000 ppm, mean relative liver weights were increased in F0 generation males ( 8%) and females (16%) and F1 generation females (9%) compared to controls. These results suggest adaptive changes in the liver. Since

no adverse treatment

- related effects were seen in this study, a parental systemic LOAEL

could not be established. The p arental systemic NOAEL is 20,000 ppm (1636 mg/kg bw/day in males, 1917 mg/kg bw/day in females).

No compound

- related reproductive effects were observed at any dosage level. F0 live birth index at both 2000 and 20,000 ppm was significantly lower (97%) tha n control (100%); however this was not considered compound

- related because (1) the control group had unusually high pup viability, and (2) the F1 live birth index for all dosed groups was comparable to control, despite longer exposure to the compound. Sin ce no adverse treatment

- related effects were seen in this study, an offspring LOAEL could not be established. The offspring NOAEL is 20,000 ppm (1917 mg/kg bw/day).

This study is acceptable (guideline) and satisfies the guideline requirement for a 2

- gen eration reproductive study (OPPTS 870.3800); OECD 416 in rats

A.4.4 Chronic Toxicity

870.4300 Combined Chronic T oxicity/ C arcinogenicity F eeding

– R at (P. Chin

3/25/2008 , TX R 0053361 )

In a combined chronic toxicity/carcinogenicity feeding (MRID No. 40342921), flutolanil (97.5

-Page 37 of 53

99.8% a.i.; lot # 2, 6, 7, 9, 11 and 14) was administered in the diet to groups of 50 male and 50 female SD [Crj:CD (SD) SPF] rats at concentrations of 0, 40, 200, 2000, and 10000 ppm for 2 years. The dietary concentrations wer e equivalent to 0, 2, 9, 87, and 460 mg/kg/day, respectively, for males and 0, 2, 10, 103, and 536 mg/kg/day, respectively, for females.

No treatment

- related changes in ophthalmoscopic, hematological, clinical chemistry, urinalysis, gross pathology, or histopathology parameters were observed in either sex. In 460 mg/kg/day male rats only, body weight gain relative to the control was decreased up to 10% during the first 13 weeks. Following the initial 13 weeks, the body weight gain differences between t he high dose and control were less apparent. At 460 mg/kg/day, the relative liver weights in males were increased (12

- 14%) over control at 3 and 24 months. In females, absolute liver weights were increased (15

- 18%) over control at 3, 12, and 24 months an d relative liver weights were increased (10

- 11%) over control at 3 and 12 months. However, the increase in liver weights in male and female rats at 460 mg/kg/day was considered to be an adaptive response to flutolanil because these effects were not suppor ted by clinical chemistry or histopathology findings. There

was not a treatment

- related increase in tumor incidence in any treated groups when compared to

controls. Dosing was considered adequate to assess the chronic toxicity and the carcinogenic

potent ial of the test substance based on findings from the 90

- day study (MRID 40342919). In

the 90

- day study, the NOAEL was 1512 mg/kg/day (HDT) and the LOAEL was not established. At 1512 mg/kg/day, the liver weights were increased over control, however, the i ncrease in liver weights was considered to be an adaptive response to flutolanil treatment because these effects were not supported by clinical chemistry or histopathology findings.

The NOAEL in this chronic toxicity/carcinogenicity study in the rat was 4 60 mg/kg/day (HDT)

and the LOAEL was not established.

This chronic toxicity/carcinogenicity study in the rat is classified acceptable/g uideline and satisfies the guideline requirement for a chronic toxicity/carcinogenicity study in the rat [OPPTS 870.4300); OECD 453].

870.4100b Chronic Toxicity

– Dog (P. Chin 3/25/2008, TXR 0053361)

In a chronic oral toxicity study (MRID 40342922), flutolanil ( 97.5

- 99.8% a.i., Lot No. 2, 6, 8, 9, 11, 12, 14, 15, and 16) was administered orally, by gelatin capsule, to 6 male and 6 female beagle dogs/group at dose levels of 0, 50, 250, and 1250 mg/kg/day for 2

- years. All dogs survived until study termination. No treatment

- related changes in ophthalmoscopic, hematological, clinical chemistry, organ weights, gross pathology, or histopathology parameters

were observed in either sex.

Following 65 weeks of exposure, there was a dose

- related increase in the incidenc e of clinical signs (emesis, salivation, and soft stool) in both sexes at 250 and 1250 mg/kg/day, which continued until study termination. In addition, at 1250 mg/kg/day, decreased body weight gains (from the 82nd week in males and from the 81st week in f emales) and decreased food consumption (from the 79th week in males and from the 74th week in females) were observed. The LOAEL was 250 mg/kg/day based on increased incidence of clinical toxic signs (emesis, salivation, and soft stool). The NOAEL was 50 mg/kg/day.Page 38 of 53

This chronic study in dogs is classified acceptable/g uideline and it satisfies the guideline requirement (870.4100b) for a chronic oral toxicity study in a nonrodent. NOTE: This abbreviated DER provides a revised Executive Summary to upgrade t he original DER.

A.4.5 Carcinogenicity

870.4200b Carcinogenicity (Feeding)

– Mouse (M. Mercado

- Feliciano 8/20 /2013, TX R

0056766 )

In a carcinogenicity study (MRID 41850803 ) Flutolanil (97.6% a.i., lot # 543251 was administered to 52 CD

- 1 (ICR)BR mice /sex/dose in diet at dose levels of 0, 300, 1500, or 7000, or 30,000 ppm (equivalent to 0, 32, 162, 735, 333 3 mg/kg bw/day males and 0, 34, 168, 839,

3676 mg/kg bw/day females) for 79 weeks

.

Survival, clinical signs, body weights, food consumption and he matology parameters were similar in treated groups and controls, except for a non

- dose

- responsive increase in percent survival in all female treatment groups compared with controls

. Mean relative (to bw) l iver weight was increased (33%, p< 0

. 0 l ) in high

- dos e females (but not in males) when compared to

controls. There were no other treatment

- related changes in organ weights or gross pathology.

There were no treatment

- related neoplastic lesions. There were positive dose

- related trend s (p<0.05) in periacinar fatty vacuolation in males and centriacin ar fatty vacuolation in females

. These results suggest adaptive changes in the liver. Since no adverse treatment

- related effects were seen in this study, a LOAEL could not be established. The observed NOAEL s were 3333 mg/kg /day in male s and 3676 mg/kg /day in female s.

At the doses tested, there was no treatment related increase in tumor incidence when compared to controls. Dosing was considered adequate based on the observed adaptive changes in the liver

.

This carcinogenicity study in mice is acceptable (guideline) and satisfies guideline requirement for a carcinogenicity study [OPPTS 870.4200; OECD 451] in mice.

A.4.6 Mutagenicity

Gene Mutation

870.5100, Salmonella and E. coli reverse mutation assays

MRID 40342926 Acceptable N egative up to 25 mg/ plate both in the presence and absence of metabolic

activation

. (S.C. Dapson 6/16/1988, TX R 006673)

870.5195

, Mutation Assay at TK+/

- Locus in Mouse Lymphoma Cells

MRID 418412 0 7
Acceptable Negative up to 100 μg/ml (>50% cytotoxicity) in the presence and absence of

metabolic activation. (S.C. Dapson 5/7/1993, TX R 010239)Page 39 of 53

Cytogenetics

870.5375, Chromosomal Aberration Assay in Cultured Mammalian Cells

MRID 403429 25 Acceptable Test was positive at 150 μ M (48.5 μg /m l) only in the presence of metabolic

activation ; this dose also produced about 50% reduction in colony formation

. Higher doses were cytotoxic. (S.C. Dapson 6/16/1988, TX R 006673)

870.5395, Mouse Erythrocyte

Micronucleus Test in Vivo

MRID 403429 27 Acceptable The test was negative up to 10 g/kg. (S.C. Dapson 6/16/1988, TX R 006673)

870.5375

, Chromosomal Aberration in

Cultured Human L ymphocytes

MRID 42606628 Acceptable The test was negative up to 1 mg/mL (S.C. Dapson 8/6 /1993, TX R 010470 )

870.5550 , U nscheduled DNA Synthesis in Primary Male Rats Hepatocytes

MRID 41841206 Acceptable The test was negative up to 80 μ g/mL

. Precipitation occurred at
concentrations ≥ 80 g/mL

. (S.C. Dapson 5/7/1993, TX R 010239)

A.4.7 Neurotoxicity

870.6200 Acute Neurotoxicity Screening Battery (M.S. Ottley 3/26/2013, TX R

0056619 )

In an acute neurotoxicity study (MRID 48796402), four groups of 20 HsdHan:WIST rats (10/sex/group; 8 weeks of age) were administered a single dose of 0, 125, 500, or 2000 mg/kg bw (mg/kg ) of Flutolanil Technical [98.7% (Batch No. 9AE0011P) in 1% methylcellulose] by gavage dose and observed for 14 days. Neurobehavioral assessment [functional observational battery (FOB) and motor activity (MA) testing] were performed on 10 rats/sex/group on days 1, 7, and 14. At study termination, 5 rats/sex/group were euthanized and perfused in situ for neuropathological examination. The remaining animals were sacrificed and selected tissues were taken for microscopic examination.

There were no mort alities or toxicologically significant clinical observations at any dose level.

There were no treatment

- related or statistically significant differences in body weight or body weight gain in males or females observed at any dose level. There were no treat ment

- related, toxicologically significant, or statistically significant findings in any of the neurological endpoints examined in the study. Macroscopic and microscopic examination of tissues showed

no treatment

- related findings.

No treatment

- related adve rse effects were seen in this study and the NOAEL in male and female HsdHan:WIST rats was 2000 mg/kg bw/day. The LOAEL was not established.

This neurot oxicity study is classified as acceptable/guideline and satisfies the guideline requirement for an acut e neurotoxicity study in rats (870.6200; OECD 424).Page 40 of 53

870.6200 Subchronic Neurotoxicity Screening Battery (M.S. Ottley 3/26/2013, TX R 0056619)

In an subchronic neurotoxicity study (MRID 48798501), four groups of 20 HsdHan:WIST rats (10/sex/group; 6 weeks of age) were administered Flutolanil Technical [98.7% (Batch No. 9AE0011P) in the diet in concentrations designed to deliver doses of 0, 62.6, 250, or 1000 mg/kg bw (mg/kg) for 13 weeks. Achieved doses were 0, 62.8, 250.5, an d 977.8 mg/kg/day for males, and 0, 66.2, 255.8, and 1024.0 mg/kg/day for females. Neurobehavioral assessment [functional observational battery (FOB) and motor activity (MA) testing] was performed on 10 rats/sex/group during weeks

- 1, 2, 4, 8, and 13. At s tudy termination, 5 rats/sex/group were euthanized and perfused in situ for neuropathological examination. The remaining animals were sacrificed and selected tissues were preserved. Only tissues prepared for neuropathological

examination from the control and high

- dose groups were evaluated microscopically.

There were no mortalities or toxicologically significant clinical observations at any dose level.

There were no treatment

- related or statistically significant differences in food consumption, body

we ight or body weight gain in males or females observed at any dose level. There were no

treatment

- related, toxicologically significant, or statistically significant findings in any of the neurological endpoints examined in the study. Macroscopic and micro scopic examination of

tissues showed no treatment

- related findings.

No treatment

- related adverse were seen in this study and the NOAEL was 977.8 mg/kg/day for males and 1024.0 mg/kg/day for females. The LOAEL was not established.

This neurotoxicit y stud y is classified as acceptable/guideline and satisfies the guideline requirement for a subchronic neurotoxicity study in rats (870.6200; OECD 424).

A.4.8 Metabolism

870.7485 Metabolism

– Rat (T.F. McMahon 4/18/1995, TXR 0011495 ; T.F. McMahon 10/23/1995, TX R 0011701; M. Mercado

- Feliciano 8/20 /2013, TXR 0056766 )

Disposition and metabolism of 14 C

- Flutolanil was investigated ( MRID 426066 0 2 ) in male and female rats at a low oral dose of 20 mg/kg, repeated low oral doses of 20 mg/kg x 14 days, and a single high dose of 1000 mg/kg. Absorption of Flutolanil was incomplete at the single low and high oral doses, but appeared to be increased after repeated low oral dosing. There were no appreciable tissue levels of Flutolanil at study termination. At the single low oral dose, excretion in urine and feces was equivalent, with approximately 40% of an administered dose excreted via

each route in male and female rats. Repeated low oral dosing resulted in an increased percentage in urine (about 70%) with a corresponding decrease in fecal excretion. At the single high dose, the majority of radioactivity (66

- 78%) was excreted via the feces, with less t han 10% found in

urine. Identification of urinary and fecal metabolites by TLC showed the presence of one major metabolite in urine, M

- 4 (structure not identified) in all dose groups. In feces, radioactivity was excreted mainly as parent chemical, with l imited conversion to M

- 4. This study was originally

classified as c ore

- s upplementary d ata since it did not satisfy the g uideline requirements ( 40 CFRPage 41 of 53

158.340, 85

- 1) for a metabolism study in rats. The registrant has adequately addressed the remaining defi ciency with regard to the original metabolism study. Based o n the review of these submitted data, the original study is now upgraded to acceptable (guideline)

.

A.4.9 Immunotoxicity

870.7800 Immunotoxicity (Y.G. Yang 6/26/2012, TX R 0056378)

In a 28

- day dietary immunotoxicity study (MRID 48647001), Flutolanil TGAI, (98.7% a.i., Lot No. 9AE0011P) was administered in the diet to Crl:CD® (SD) rats (10/sex/group) at dietary concentrations of 0, 750, 3000 or 12,000 ppm (0.0, 61.13, 253.9, or 1004.2 mg/kg/day for males and 0.0, 74.6, 253.3, or 1026.0 mg/kg/day for females, respectively) for 28 days. Animals in the positive control group (5/sex) received intraperitoneal injections of cyclophosphamide (25 mg/kg) at a dose volume of 10 mL/kg (2.5 mg/mL ) for four consecutive days prior to scheduled sacrifice. Animals in all study groups were immunized with sheep red blood cells (SRBC) by intravenous injection (0.5 mL/animal, 4 x 108 SRBC/mL) four days prior to the scheduled sacrifice. On Day 29, all an imals were fasted overnight and anesthetized with sodium pentobarbital, exsanguinated, and necropsied. Spleens were harvested for evaluation of T

- cell dependent antibody response (TDAR) with an antibody forming cells (AFC) assay. Other parameters evaluat ed were: clinical observations, mortality, body weight, body weight gain, and food consumption, select organ weights (i.e. brain, spleen and thymus), and macropathology investigations.

There were no test substance

- related effects on mortality, clinical ob servations, mean body weight, body weight gain, food consumption, terminal body weight, and brain, spleen or thymus weights in any group.

For systemic toxicity, the NOAEL is 12,000 ppm (1004.2 mg/kg/day in males and 1026.0 mg/kg/day in females); the LOAEL was not determined.

Evaluation of immune function using an antibody forming cell (AFC) assay indicated that Flutolanil had no significant effect on anti

- SRBC antibody response (AFC/106 cells and AFC/spleen). A high inter

- individual variability was noted in all the treatment groups as well as in the control group. Evaluation of individual animal data of this study did not show any trend or distribution that would demonstrate significant suppression of anti

- SRBC AFC response.

Positive control animals had statistically significant decreases in immune function parameters (AFC/spleen, AFC/106 splenocytes, and absolute splenocyte cellularity); decreases in mean absolute spleen and thymus weights also noted when compared to vehicle control group. The positive control group confirmed the ability of the test system to detect immunosuppressive effects and confirmed the sensitivity of the study design.

The Natural Killer (NK) cells activity was not evaluated in this study. The toxicology database

for Flutolanil d oes not reveal any evidence of treatment

- related effects on the immune system. The overall weight of evidence suggests that this chemical does not directly target the immune system. Under HED guidance, a NK cell activity assay is not required at this time

.Page 42 of 53

Under conditions of this study, the immunotoxicity NOAEL is 12,000 ppm (1004.2 mg/kg/day in males and 1026.0 mg/kg/day in females). The LOAEL was not determined.

This 28

- day dietary immunotoxicity study in the rat is acceptable/guideline and satisfies guideline requirement for an immunotoxicity study (OPPTS 870.7800).Page 43 of 53

Appendix B. Nomenclature and Physicochemical Properties of Fl utolanil

.

Table B.1. Chemical Names and Structures of Flutolanil and Metabolites.

Common name; Company code Chemical name Chemical structure

F lutolanil ; M1 N

- [3'

- (1

- methylethoxy)phenyl ]

- 2

- (trifluoromethyl)benzamide

M

- 2 N

- [4'

- hydroxy

- 3'

- (1

- methylethoxy)phenyl ]

- 2

- (trifluoromethyl)benzamide

M

- 3 N

- [3'

- (2

- hydroxy

- 1

- methylethoxy)phenyl]

- 2

- (trifluoromethyl)benzamide

M

- 4 N

- (3'

- hydroxyphenyl)

- 2

- (trifluoromethyl)benzamidePage 44 of 53

Table B.1. Chemical Names and Structures of Flutolanil and Metabolites.

Common name; Company code Chemical name Chemical structure

M

- 5 N

- [3',4'

- (dihydroxy)phenyl ]

- 2

- (trifluoromethyl)benzamide

M

- 6 N

- (3'

- methoxy)phenyl

- 2

- (trifluoromethyl)benzamide

M

- 7 N

- (4'

- hydroxy

- 3'

- methoxy)phenyl

- 2

- (trifluoromethyl)benzamide

M

- 11 2

- [ [3

- [2

-

(trifluoromethyl)benzoyl]

- amino]phenoxy]propanoic acid

2

- TFBA: 2

- ( trifluoromethyl ) benzo ic

acidPage 45 of 53

Table B.2. Physicochemical Properties of Flutolanil

. Parameter Value Reference

Molecular weight (g/mole) 323.3 DP#s 190584 and 190586, 3/24/94, J. Garbus; MRID

42606601 Melting range 100.4

- 103.8 °C

pH 5.69
Density (g/cm 3 ) 1.325 @ 20

- 25 °C
Water solubility 6.53 mg/L at 20 °C
Solvent solubility (g/L) at 20 °C

Acetone 1440

Methanol 232

n

- Hexane 0.9

Toluene 57 Ethyl acetate 675

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

Dissociation constant, pK

a Not applicable
Octanol/water partition coefficient, Log(K OW ) log P OW = 3.74

Soil half

- life (aerobic soil metabolism) 256.65 days (mean)Page 46 of 53

Appendix C . Incident Report ( e

- mail dated 7/30/13 from Shanna Recore)

TEB has been asked to review the incidents in IDS and NIOSH SENSOR

- Pesticides for the

flutolanil preliminary risk assessment due August 2013. Flutolanil incidents were previously analyzed 2008 ( Updated Review of Flutolanil Incident Reports , M. Hawkins and J Cordova, 07/24/2008). There was one incident identified in the Main Incident Data System from 2000 to July 24, 2008. This incident update is being provided via e

- mail for following reasons : 1) the previous incident analysis was prepared in the last 5 years; 2) the incidents did not warrant further analysis; and 3) the current incident analysis is consistent with the previous analysis.

Updated incident analyses of the Main and Aggregate Incident Data System (IDS) from January 1, 2008 to May 8, 2013, and the National Institute of Occupational Safety and Health Sentinel Event Notification System for Occupational Risks (NIOSH SENSOR) from 1998 to 2008 are consistent with the previous analysis. The results are as follows:

 From January 1, 2007, to May 8, 2013, there was one incident reported to Main IDS that involved flutolanil that was part of a lawsu it and will not be considered in this update. There were three incidents identified Aggregate IDS that involve flutolanil. These incidents were classified as minor severity.

 From 1998 to 2009, one incident was identified in SENSOR involving flutolanil. This case involved multiple active ingredients. The case occurred in New York in 2006, was moderate in severity and included the following details in the report:

“Former farmhand was loading bins for "cutting potatoes" (process of separating good potatoes from bad). This is done in an enclosed area. When the door to this area is opened, the wind blows in. This stirs up the air flow and causes product to blow back on him. RUP was used by an unsupervised, uncertified applicator. He had no barrier on his hands to protect himself from coming into contact with product. Other recommended PPE also not worn.”

The medical record states that the “symptoms started in early spring after products are used repeatedly 5 days/week. Symptoms got progressively worse

over the next 7 months. He is repeatedly seen through ED or PCP with complaints of chest pain, sore throat, nausea”

Based on the continued low frequency and severity of incident cases reported for flutolanil, there does not appear to be a concern at this time that would warrant further investigation. The Agency will continue to monitor the incident information and if a concern is triggered, additional analysis will b e conducted.Page 47 of 53

Appendix D . Food Residue Profile Details

Processing studies : Of the registered crops , processed commodities are associated with cotton, peanut, potato, rice, soybean, and wheat. Adequate processing data are available as discussed

below.

Cotton: For the seed treatment use (D364462, S. Funk, 1/25/10), a cotton processing study was not required because of low residues in the cotton seed.

Peanut: The processed commodities for peanut are meal and refined oil. Flutolanil concentrates

2.2x in meal but does not concentrate (0.29x) in refined oil ( D190879, G. F. Kramer, Ph.D.,

1/12/94 and D207486 , G.F. Kramer, Ph.D., 11/3/94).

Potato: The processed commodities for potato are granules/flakes, chips and wet peel. There is no concentration in granules/flakes and chips but residues concentrate 1.7x in wet peel (D226667, M. Xue, 2/1/00).

Rice: The processed commodities for rice are polished rice and bran. Residues concentrate 3.5x in rice hulls and 1.4x in rice bran, but do not concentrate in polished rice (D201704, J. Garbus, Ph.D., 5/9/94 and D226667, M. Xue, 2/1/00).

Soybean: The processed commodities for soybean are meal, hull s, and refined oil. An adequate processing study (D335050, F. Fort, 11/26/07) indicated that residues do not concentrate in soybean hulls, meal, and oil.

Wheat: The processed commodities for wheat are bran, flour, germ, middlings, and shorts. An adequat e processing study was submitted (D335050, F. Fort, 11/26/07) that indicated that residues do not concentrate in wheat flour, germ, middlings, and shorts, but do concentrate in bran. Residues from the submitted rotational crop field trials were <0.05 ppm in wheat grain but averaged 0.16 ppm in bran. HED concluded in the risk assessment (D335050 F. Fort, 11/26/07 )

that a tolerance of 0.2 0 ppm is appropriate for indirect or inadvertent residues in wheat bran.

Storage Stability : Adequate storage stability data are available to support the field trials of the primary (treated) crops for existing uses and the rotational crop wheat as discussed below and

shown in Table D.1.

Brassica (cole) leafy vegetables and turnip greens: Adequate storage stability data are available

for flutolanil and its metabolite M

- 4 in/on cabbage, mustard greens, and broccoli. The data

indicate that residues of flutolanil and its metabolite M

- 4 are stable in frozen storage up to 297 days in cabbage, 519 days in mustard greens, and 5 69 days in broccoli.

Cotton: Storage stability data were not required for cotton because of the short storage duration (D364462, S. Funk, 1/25/10).Page 48 of 53

Peanuts: Adequate storage stability data are available for flutolanil and its metabolite M

- 4 in/on

peanu t commodities. The data indicate that residues of flutolanil and its metabolite M

- 4 are stable in frozen storage for up to 3 years in/on peanut nutmeat, oil, hulls.

Potato: Potato samples were stored for 3.5 years (D268880, A. Lowit, 9/11/00). MRID

457 56604 indicated that flutolanil and M

- 4 are stable in potatoes after 54 months (4.5 years) and 67 months (5.6 years) frozen storage at

- 10 to

- 20°C.

Rice: Adequate storage stability data were previously submitted for flutolanil and its metabolite

M

- 4 in/ on rice commodities. The data indicate that residues of flutolanil and its metabolite M

- 4 are stable in frozen storage (

- 20 °C) for up to ~31 months in/on rice grain and straw.

Soybean: Storage stability data were not required for soybean because of the short storage duration (D364462, S. Funk, 1/25/10).

Wheat: Flutolanil (parent) has been shown to be stable in wheat grain stored frozen (

- 20 o C) for 207 days (MRID 42606611). Matrices of the rotational crop wheat in the field rotational crop study (MRID 43175803) were stored frozen (

- 20 o C) for the following intervals: grain for 334

- 369 days; forage for 496

- 675 days; straw for 352

- 443 days; and hay for 418 days.

Table D

. 1. Summary of Storage Conditions and Durations of Samples from Crop Field Trials.

Matrix [MRID] Storage Temperature (°C) Actual Storage Duration (days) Interval of Demonstrated

Storage Stability

Broccoli [47832603]

- 4 to

- 22 o C 357 to 564 569 days

Cabbage [47832601]

- 29 to

- 10oC 48 to 293 297 days

Mustard greens [47832602]

- 4 to

- 22 o C 299 to 511 519 days

Peanuts [42742004] frozen 904

– nutmeat
916

- hay 3 years in/on nutmeat, oil,

and hulls

Peanuts [43175801] frozen 407

– nutmeat and hay

Potato [439714

- 20,

- 21,

- 22] frozen 3.5 years 54 months (4.5 years) and 67 months (5.6 years) (MRID 45756604)

Rice [48092301]

- 20 ± 5°C 32

- 84 days 1

(1.1

- 2.8 months) 931 days ( ~31 months or

2.5 yrs) in/on rice grain and

straw (MRID 44526202)

Rice [44529502] frozen 1200 days (3.3 years) 931 days (2.5 years)

Wheat [4 3175803 ]

- 20°C 334

- 369 grain

496

- 675 forage

353

- 443 straw 418 hay 207 days in/on wheat grain

(MRID 42606611); 931 days in/on rice grain & straw (MRID 44526202); 519 days in/on mustard

greens

Meat, Milk, Poultry, and Eggs

Acceptable feeding studies with dairy cattle and poultry were previously reviewed. No

detectable residues of flutolanil and its m etabolites M

- 2, M

- 4, or M

- 7 were found in the whole milk, cream, skim milk, muscle, and fat of dairy cows sacrificed after dos ing for 28 days at 29.4Page 49 of 53

(2.9x), 85.0 (8.5x), and 286 ppm (29x) in the feed. Detectable residues were found in liver at 0.05, 0.06, and 0.21 ppm at the 29.4, 85 .0 , and 286 ppm feeding levels and in kidney at 0.06, 0.15, and 0.82 ppm at the 29.4, 85 .0, and 286 ppm feeding levels.

A feeding study on laying hens is available in which hens were dosed with flutolanil for 28 days

at levels of 1.29 (0.8 0x), 3.87 ( 2 .4x), and 12.9 ppm ( 8 .0 x) in the diet . Eggs were collected throughout the feeding study. Samples of tissue (liver, breast muscle, thigh muscle, fat, skin) and egg (white, yolk) were analyzed by GC/MS for flutolanil (M

- 1), and its major metabolites,

M

- 2, M

- 4, and M

- 7. Except for one residue of 0.12 ppm in liver at the highest feeding level, no

detect able residues of parent or any metabolite were found.

Adequate storage stability data are available on livestock matrices stored frozen (

- 20 o C) (MRID 43175811 and 43175812) to support the livestock feeding studies as reported in T able D.2

below.

Table D

. 2. Summary of Storage Conditions and Durations of Samples from Livestock Feeding Studies.

Livestock Matrix [MRID] Storage Temperature (°C) Actual Storage Duration Interval of Demonstrated Storage Stability 1

Beef fat [ 43175808 ] frozen 119 days 92 days (av g. 51%

recovery in beef fat ) Chicken fat [42606612] frozen ~5 months

Beef kidney [ 43175808 ] frozen 119 days 127 days in beef muscle

Beef liver [ 43175808 ] frozen 112 days 122 days in chicken liver

Beef muscle [ 43175808 ] frozen 111 days

Chicken liver [ 42606612 ] frozen ~5 months

Chicken muscle [ 42606612 ] frozen ~5 months

Eggs [ 42606612 ] frozen ~5 months 125 days

Milk [43175808] frozen 114 days 115 days

1 MRIDs 43175811 and 43175812

Livestock dietary burdens are calculated in Table D.3 below.

Table D.3. Calculation of Dietary Burdens of Flutolanil Residues to Livestock.

Feedstuff Type 1 % Dry

Matter 2 % Diet 2 Recommended Tolerance (ppm) Dietary Contribution

(ppm) 3

Beef Cattle

Cotton, cotton gin byproducts R 90 5/0 0.20 0.00

Cotton, meal PC 89 5 0.20 0.00

Cotton, hulls R 90 5/0 0.20 0.011

Soybean forage R 35 15/25 8.00 3.42

Rice, grain CC 88 20 7.00 1.59

Soybean, meal PC 92 15/5 0.20 0.011

TOTAL BURDEN

-- -- 55

-- 5.03

Dairy Cattle

Cotton, undelinted seed PC 88 10 0.20 0.023

Cotton, meal PC 89 10/0 0.20 0.00Page 50 of 53

Table D.3. Calculation of Dietary Burdens of Flutolanil Residues to Livestock.

Feedstuff Type 1 % Dry

Matter 2 % Diet 2 Recommended Tolerance (ppm) Dietary Contribution

(ppm) 3

Soybean forage R 35 25 8.00 5.71

Soybean hay R 30 5 2.5 0.42

Peanut hay R 85 15 12.89 (HAFT) 2.27

Rice, grain CC 88 20 7.00 1.59

Soybean, meal PC 92 15/0 0.20 0.00

TOTAL BURDEN

-- -- 75

-- 10.01

Poultry

Cotton, meal PC 89 20/5 0.20 0.011

Rice, grain CC 88 20 7.00 1.40

Peanut, meal PC 85 20 1.00 0.20

TOTAL BURDEN

-- -- 45

-- 1.61

Swine

Cotton, meal PC 89 15/0 0.20 0.00

Rice, grain CC 88 20 7.00 1.40

Wheat, milled byproducts CC 88 50 0.20 0.10

Peanut, meal PC 85 15 1.00 0.15

Soybean, meal PC 92 5/0 0.20 0.00

TOTAL BURDEN

-- -- 85

-- 1.65

1 R: Roughage; CC: Carbohydrate concentrate; PC: Protein concentrate.

2 OPPTS 860.1000 Table 1 Feedstuffs (06/30/2008). First entry is maximum for the particular commodity; second entry is assigned per the total for maximum reasonably based diet.

3 Contribution = ([tolerance /% DM] X % diet) for beef and dairy cattle; contribution = ([tolerance] X % diet) for poultry and swine.

Conclusions. T olerances are established for residues of flutolanil and its metabolites converted

to 2

- TFBA in ruminant (cattle, goat, horse, and sheep) commodities at 0.05 ppm for milk, 0.10 ppm for fat, 1.00 ppm for kidney, 2.00 ppm for liver, and 0.05 ppm for meat and meat byproducts, and in poultry commodities at 0.05 ppm for egg, fat, meat, and meat byproducts. Feeding studies are available on lactating cows and laying hens. Based on the feeding studies and the maximum reasonably balanced diets for livestock, t he e stablished livestock tolerances are adequate.

Rotational crops :

In the confined rotational crop study t he total radioactive residues (TRR) were 0.01

- 0.04 ppm in all raw agricultural commodities (RACs) of mature crops at the 366 DAT (days after treatment ) plantback interval. Residue levels were highest at the 30 DAT interval and declined by 90% or more by the 366 DAT interval.

Field rotational crop studies were previously reviewed for winter wheat, corn, soybeans, and cotton planted 2, 3, or 4 months (wheat) or 8

- 10 months (corn, cotton, and soybean) following

the harvest of flutolanil

- treated peanuts. In addition, field rotati onal crop studies were submitted and reviewed for soybean and grain sorghum following the harvest of flutolanil

- treated rice.Page 51 of 53

More recently, Nichino America, Inc. s ubmitted the results of a field rotational crop study on

corn and cotton. For this latt er study, samples of corn and cotton matrices were stored frozen for

7.5

- 8 years from harvest to analysis. HED concluded that the field rotational study on corn and cotton is unacceptable because no storage stability data are available which demonstrate t hat

residues of flutolanil and M

- 4 are stable in corn forage, fodder and grain and cotton seed stored frozen for up to 8 years and because the analytical method did not deter mine the residue of

concern.

A field rotational crop study was also reported on s oybeans and wheat concurrently with the above study on corn and cotton. Crops were planted 29

- 36 days following application of the 70% WDG formulation at 2.0 lb ai/A (1x the maximum registered seasonal rate for any crop) to

bare soil. Detectable flutolan il

- derived residues were found in all crop samples of soybean and wheat except wheat grain, where residues were <0.05 ppm.

Tolerances for indirect or inadvertent residues are established for wheat commodities in 40 CFR 180.484 (a).

Rotational crop restrictions are included on the established Flutolanil 40SC label ( EPA Reg. No.

71711

- 28 ) . Plantback restrictions on the established 40SC label are 0 days for cotton, peanuts, potatoes, rice, and soybeans; 30 days for wheat; 150 days for leafy vegetables and small grain crops other than wheat; 240 days for corn and sorghum; and 365 days for all other crops.

Rotational crop restrictions on the established Moncut® 70

- DF label (EPA Reg. No. 10163

- 301 ) are 0 days for cotton, peanuts, potatoes , rice, soybeans, turnip greens, and Brassica (cole) leafy vegetables; 30 days for wheat; 150 days for leafy vegetables and small grain crops other than wheat; 240 days for corn and sorghum; and 365 days for all other crops.

Conclusions . Rotational cro p restrictions and inadvertent residue tolerances have been

established on the Flutolanil 40SC label ( EPA Reg. No. 71711

- 28 ) based on the available

confined and field accumulation studies

.

Since Brassica (cole) leafy vegetables and turnip greens are being registered on the 40SC label, the rotational crop restrictions for the Flutolanil 40SC label (EPA Reg. No. 71711

- 28 ) should be

amended to include Brassica (cole) leafy vegetables and turnip greens under the 0

- day rotational crop restriction interval.

Sin ce no tolerance is established for sugar beet, the 0

- day rotational crop restriction for sugar beet on the Artisan Fungicide label (EPA Reg. No. 71711

- 17) should be removed.Page 52 of 53

Appendix E . International Residue Limits Status Sheet

Table E .1 . Summary of US and International Tolerances and Maximum Residue Limits

US Canada Mexico 1 Codex 2

Residue Definition: 40 CFR180.484 (a) flutolanil, N

- (3

- (1

- methylethoxy)phenyl)

- 2

- (trifluoromethyl)benzamide, and its

metabolites converted to 2

- (trifluoromethyl)benzoic acid and

calculated as flutolanil. None For plant commodities, flutolanil. For animal commodities, flutolanil and transformation products containing the 2

- trifluoromethyl

benzoic acid moiety, expressed as

flutolanil.

Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg) Commodity US Canada Mexico 1 Codex 2

Cattle, fat 0.10 None Cattle, kidney 1.00 0.1
Cattle, liver 2.00 0.2

Cattle, meat byproducts 0.05

Cattle, meat 0.05 0.05 (*) Cotton, gin byproducts 0.20
Cotton, undelinted seed 0.20 Egg 0.05 0.05 (*)
Goat, fat 0.10 Goat, kidney 1.00 0.1
Goat, liver 2.00 0.2 Goat, meat byproducts 0.05
Goat, meat 0.05 0.05 (*) Hog, fat 0.10 Hog, kidney 1.00 0.1 Hog, liver 2.00 0.2 Hog, meat byproducts 0.05 Hog, meat 0.05 0.05 (*)
Horse, fat 0.10 Horse, kidney 1.00

Horse, liver 2.00

Horse, meat byproducts 0.05
Horse, meat 0.05 0.05 (*)

Milk 0.05 0.05 (*)

Peanut 0.5 Peanut, hay 20.0
Peanut, meal 1.0

Potato 0.20 Potato, wet peel 0.30 Poultry, fat 0.05 Poultry, meat 0.05 0.05 (*) Poultry, meat byproducts 0.05 0.05 (*)
Rice, bran 10.0 10 (unprocessed)

Rice, grain 7.0 2 husked 1 polished
Rice, hulls 25.0Page 53 of 53

Table E .1 . Summary of US and International Tolerances and Maximum Residue Limits

US Canada Mexico 1 Codex 2

Rice, straw 10.0 10 Sheep, fat 0.10 Sheep, kidney 1.00 0.1 Sheep, liver 2.00 0.2 Sheep, meat 0.05 0.05 (*) Sheep, meat byproducts 0.05 Soybean, forage 8.0 Soybean, hay 2.5 Soybean, seed 0.20 Turnip, greens 0.20 Vegetable, brassica, group 5 0.20

Residue Definition: 40CFR180.484 (d)

indirect or inadvertent residues of the fungicide flutolanil, N

- (3

- (1

- methylethoxy)phenyl)

- 2

- (trifluoromethyl)benzamide, and

its metabolites converted to 2

- (trifluoromethyl)benzoic acid and

calculated as flutolanil None None

Wheat, bran 0.20 Wheat, forage 2.5 Wheat, grain 0.05 Wheat, hay 1.2
Wheat, straw 0.20

1 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.

2 * = absent at the limit of quantitation.