1 of 32 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460

OFFICE OF CHEMICAL SAFETY
AND POLLUTION PREVENTION

MEMORANDUM

DATE : 10/13/10

SUBJECT: Flutolanil: Human Health Risk Assessment for Flutolanil on Brassica Leafy Vegetables (Crop Group 5) and Turnip Greens.

PC Code: 128975 DP Barcode: D370200

Decision No.: 419258 Registration No.: 10163-247

Petition No.: 856744 Regulatory Action: Section 3 Registration Risk Assessment Type: Single Chemical Case No.: NA

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

MRID No.: NA 40 CFR: §180.484

FROM: Kristin Rury, Risk Assessor Stephen Funk, Senior Science Advisor Amelia Acierto, Chemist Risk Assessment Branch III (RAB3) Health Effects Division (7509P)

THROUGH: Paula Deschamp, Branch Chief Risk Assessment Branch III (RAB3) Health Effects Division (7509P)

TO: Barbara Madden/Laura Nollen, RM #5 Risk Integration, Minor Use and Emergency Response Branch (RIMUERB) Registration Division (7505P)

The Health Effects Division (HED) has conducted a human health risk asse ssment for the fungicide

flutolanil to estimate the risk to human health that will result from proposed and registered uses of flutolanil. The Interregional Research Project No. 4 (IR-4) has submitted a petition proposing the establishment of permanent tolerances for Brassica (Cole) leafy vegetables (crop group 5) and turnip

greens.

HED has conducted a human health risk assessmen t for these proposed uses. This HED document provides a summary of the findings from the data evaluation and subsequent assessment of human health risk resulting from th is submission. The dietary expo sure assessment was conducted by Kristin Rury (DP#371494, 9/10/2010). The residue chem istry data were reviewed and analyzed by Stephen Funk (DP#381713, 9/7/2010) and Amelia Acierto (DP#371493, 5/12/2010). The drinking2 of 32 water assessment was conducted by Larry Liu (DP#370201, 7/12/2010) of OPP’s Environmental Fate and Effects Division (EFED).3 of 32 Table of Contents

1.0 Executive Summary.............................................................................................................. ........4

2.0 Ingredient Profile............................................................................................................. .............7

2.1 Summary of Registered/Proposed Uses...................................................................................7

2.2 Structure and Nomenclature ....................................................................................................8

2.3 Physical and Chemical Properties............................................................................................9

3.0 Hazard Characterization/Assessment ...........................................................................................9

3.1 Hazard and Dose-Response Characterization..........................................................................9

3.1.1 Database Summary............................................................................................................... 9

3.1.3 Metabolism..................................................................................................................... ....10

3.1.4 Dose-Response.................................................................................................................. .11

3.2 FQPA Safety Factor Considerations......................................................................................11

3.2.1 Evidence of Neurotoxicity.............................................................................................. ....11

3.2.2 Evidence of Immunotoxicity..............................................................................................11

3.2.3 Pre-and/or Postnatal Toxicity: De termination of Susceptibility .......................................11

3.2.4 Safety Factor for Infants and Children...............................................................................12

3.3 Hazard Identification and Toxicity Endpoint Selection ........................................................12

3.4 Endocrine Disruption........................................................................................................... ..13

4.0 Dietary Exposure/Risk Characterization ....................................................................................14

4.1 Pesticide Metabolism and Environmental Degradation.........................................................14

4.1.1 Metabolism in Primary Crops and Livestock.....................................................................14

4.1.2 Metabolism in Rotational Crops ........................................................................................15

4.1.3 Analytical Methodology.....................................................................................................15

4.1.4 Environmental Degradation ...............................................................................................16

4.1.5 Drinking Water Residue Profile.........................................................................................16

4.1.6 Food Residue Profile..........................................................................................................1 7

4.1.7 Proposed Tolerances and Recommended Tolerances........................................................19

4.1.8 International Residue Limits ..............................................................................................20

4.2 Dietary Exposure and Risk ....................................................................................................21

5.0 Residential (Non-Occupationa l) Exposure and Risk..................................................................21

6.0 Aggregate Risk Assessments and Risk Characterization ...........................................................21

7.0 Cumulative Risk Characte rization/Assessment..........................................................................22

8.0 Occupational Exposure/Risk Pathway .......................................................................................22

9.0 Data Needs/Label Recommendations.........................................................................................22 9.1 Toxicology ................................................................................................................ .................23 9.2 Residue Chemistry .......................................................................................................... ............23

9.2.1 Residue Enforcement Analytical Methods ...........................................................................23 9.2.2 Proposed Tolerances ...................................................................................................... .......23 Appendix A: Chemical Structures ............................................................................................... ....24 Appendix B: Toxicology....................................................................................................... ..........26 Appendix C: Toxicology Study Requirements Rationale................................................................314 of 32 1.0 Executive Summary

Flutolanil, N -[3-(1-methylethoxy)phenyl]-2-(t rifluoromethyl)benzamide, is a systemic benzanilide fungicide with both preventative and cu rative actions agai nst powdery scab, Spogospora

subterranean

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

Flutolanil is currently registered for application to peanuts, potatoes, and rice, and as a seed treatment for soybean and cotton. Tolerances have been established for these commodities as well as tolerances for inadvertent residues for soybean and wheat commodities as rotational crops and

tolerances for ruminant commodities. Non-food us es of flutolanil include turf, greenhouse, nursery, and potted ornamentals.

Use Profile The proposed uses on Brassica (Cole) leafy vegetables (crop group 5) and turnip greens are summarized in Table 2.1. These proposed uses /tolerances result in new dietary exposures.

The flutolanil end-use product (EP) relevant to th is registration action is Monocut 70-DF, EPA registration number 10163-301. This dr y flowable (DF) formulation c ontains 70% active ingredient (ai). The flutolanil technical pr oduct relevant to this registrati on is Flutolanil Technical, EPA registration number 10163-247.

The petitioner (IR-4) wishes to amend the pr oduct labels to incorporate new uses on Brassica (Cole) leafy vegetables (crop group 5) and turnip greens.

Proposed Tolerances The proposed tolerances are for residues of the f ungicide flutolanil and th e metabolite desisopropyl, flutolanil (also known as M-4) in/on the fo llowing raw agricultural commodities (RACs):

Vegetable, brassica, leafy group 5.............................. 0.11 ppm Turnip Greens............................................................. 0.11 ppm

Hazard Profile The toxicology database is consid ered complete with the exception of newly required studies for acute neurotoxicity (OPPTS Guideline 870.6200a), subchronic neurotoxicity (OPPTS Guideline 870.6200b), and immunotoxicity (OPPTS Guideline 870.7800) . The toxicological database has been

reviewed and is considered ad equate for the overall hazard profile, endpoint selection, and determination of susceptibility of infants and children as required by the Food Quality Protection Act (FQPA).

In general, the toxicology studies conducted on flutolanil demonstrate few or no biologically significant toxic effects at relati vely low-dose levels in animal studies and only mild or no toxic effects at high doses. The subchronic and chronic toxi city studies showed that at high dose levels ( > 400 mg/kg/day) the frequently obser ved effects of flutolanil were liver effects (characterized by5 of 32 increased liver weight in rats and enlarged livers and hepatic glycogen deposition in dogs) and decreases in body weight. Flutolan il is not neurotoxic, carcinogenic, nor mutagenic. Flutolanil is not a developmental or reproductive toxicant at limit doses (1,000 mg/ kg/day). There is no evidence of increased susceptibility of rat or rabbit fetuses to in utero exposure or rat pups to in utero and postnatal exposure to flutolanil. No toxic effects were observed in studies in which flutolanil was administered by the dermal routes of exposure.

Only a chronic dietary endpoint was identified for flutolanil. HED selected a chronic reference dose (RfD) of 0.50 mg/kg/day (No Observed Adve rse Effect Level (NOAEL) = 50 mg/kg/day; Uncertainty Factor = 100). This chronic RfD is based on the chronic oral toxicity study in dogs in

which increased incidences of clin ical signs (emesis, sa livation, and soft stool) occurred following 65 weeks of exposure.

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

The potential for increased susceptibility of infa nts and children from exposure to flutolanil was evaluated as required by FQPA. Th e FQPA Safety Factor (SF) fo r flutolanil was reduced to 1X because there was no increased sensitivity to fetu ses as compared to maternal animals in the developmental rat and rabbit studies and no increased sensitivity to pup s as compared to adults in a multi-generation reproduction study in rats.

Dietary Exposure A chronic aggregate dietary expos ure and risk assessment was conduc ted using the Dietary Exposure Evaluation Model (DEEM-FCIDTM), Version 2.03, whic h uses food consumption data from the U.S. Department of Agriculture’s Continuing Surveys of Food Intakes by Individuals (CSFII) from 1994- 1996 and 1998. An acute dietary risk assessment wa s not conducted, as an acute dietary endpoint

was not identified.

The chronic dietary analysis include d tolerance level residues, 100% crop treated (CT) estimates, and processing factors (default). The estimated drinking water concentr ation (EDWC) was incorporated directly into the dietary assessmen t (1 in 10 yr annual mean, 8.5 ppb).

The assessment concluded that the chronic dietary exposure estimates are well below HED’s level of concern (<100% cPAD) for the general U.S. popul ation and all population subgroups. The chronic dietary exposure is estimated fo r the U.S. population at 1% of the cPAD and for the most highly exposed population subgroup, children 1- 2 years old, at 1.5% of the cPAD.

Since toxicological endpoints have only been identified for chronic or al exposures, aggregate exposure and risk assessments incl ude only chronic dietary food and wa ter sources of exposure. The aggregate chronic risk estimates were below th e Agency’s level of c oncern for all population subgroups.

Occupational Exposure Workers may be exposed to flutolanil duri ng mixing, loading, applyi ng, and postapplication activities. Based on the proposed application rates and us e scenarios, short- and intermediate-term6 of 32 occupational exposures may occur. However, sin ce short- and intermediate -term endpoints have not been established, an occupational exposure asse ssment is not required. Chronic occupational exposure is not expected; thus, ch ronic occupational exposure risk as sessments are also not required.

Under the Worker Protection Standard (WPS) fo r Agricultural Pesticides, active ingredients classified as acute Toxicity Ca tegories III or IV for these routes are assigned a 12-hour Restricted Entry Interval (REI). Therefore, the 12-hour REI that appears on the proposed label is adequate.

Residential Exposure No residential uses are being requested at this time.

There are existing non-occupational/residential uses a ssociated with flutolanil. Registered products include several for use on turf grass and potted ornamentals which, if not specifically prohibited through label directions, could be used in a reside ntial/public site. Althou gh potential residential handler and post-application expos ures exist, assessments were not conducted because no dermal, oral (incidental), or inhalation t oxicological endpoints at tributable to short- or intermediate-term exposures have been identified, and the current use patterns do not indicate long-term exposure (6 or

more months of continuous e xposure) potential. However, s hould HED identify new regulatory endpoints for risk assessment purposes for flutolanil in the future, th en non-occupational/residential exposures may need to be assessed.

Conclusions

HED recommends for the establishment of tolerances for Brassica (Cole) leafy vegetables (crop group 5) and turnip greens. Residues from the fi eld trials were determined by a data collection method that might understate the residue by measuri ng only flutolanil and its metabolite M4. In the case of the dataset for these crops, HED be lieves the tolerances are adequate for Brassica (Cole) leafy vegetables. A confined rotational crop study indicated that residues in lettuce, a crop similar to the

Brassica (Cole) leafy vegetables, determined by th e enforcement method (common moiety) were 0.08 ppm. This is in agreement with the results of th e subject field trials, where the combined

residues of flutolanil and its me tabolite, M4, were <0.1 ppm.

There are no residue chemistry, toxicology, and/or exposure issues that would preclude granting tolerances and registrations for th e requested use of flutolanil on Brassica (Cole) leafy vegetables (crop group 5) and turnip greens. Ho wever, registrations should be made conditional pending adequate resolution of issues associated with th e fulfillment of new toxico logy data requirements.

Recommended Tolerances Including Revi sions to Petitione d For Tolerances

HED recommends modification of the tolerance expressions for flutolanil according to the new compliance/measurement policy ( Interim Guidance on Tolerance Expressions , Steve Knizner, May 27, 2009) to read as follows:

“HED recommends that the tolerance definition entry in 40 CFR 180.484 be revised as follows: (a) General. Tolerances are established for residues of the fungicide flutolanil, including its metabolites and degradates, in or on the commoditi es in the table below. Compliance with the tolerance levels specified below is to be determ ined by measuring only flutolanil and its metabolites converted to 2-(trifluoromethyl) be nzoic acid and calculated as flut olanil, in or on the commodity.7 of 32 Vegetable, brassica, leafy group 5.............................. 0.11 ppm Turnip Greens............................................................. 0.11 ppm

Environmental Justice Potential areas of environmental ju stice concerns, to the extent possi ble, 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/just ice/eo12898.pdf.

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

conditions or circumstances warrant. Whenever appropriate, nondietary ex posures based on home use of pesticide products and associ ated risks for adult ap plicators and for toddlers, youths, and adults entering or playing on treated ar eas postapplication are evaluate d. Further considerations are currently in development as OPP has committed re sources and expertise to the development of specialized software and models th at consider exposure to bystande rs and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

EPA Review of Human Research Occupational and residential exposur e analyses were considered unnece ssary. Therefore, this risk assessment does not rely on data from Pesticide Handlers Exposure Database (PHED) and Outdoor Residential Exposure Task Force (O RETF) studies in which adult human subjects were intentionally exposed to a pesticide or other chemical.

2.0 Ingredient Profile

2.1 Summary of Registered/Proposed Uses

Flutolanil is currently registered for application to peanuts, potatoes and rice and for use as a soybean and cotton seed treatment. This pe tition is associated with a FI FRA Section 3 amendment of the registration of the EP, Moncut® 70DF Fungici de (EPA Reg. No. 10163-301) , a DF formulation containing 70% flutolanil to include new uses on Brassica (Cole) leafy vegetables crop group 5, and turnip greens as a single in-furrow spray over the seed s at the time of seeding or as directed spray at the base of the transplants at the time or immedi ately after transplanting at the rate of 0.70 – 0.75 lb ai/A. All applications are to be made using ground equipment. Th e use of adjuvant is prohibited. The use of flutolanil is at-plant or at-transplant and is not related to a specific preharvest interval (PHI), as reflected in the wide preharvest interv als of 56-106 days for mature broccoli flower heads, 62-138 days for mature cabbage heads, and 31-63 days for mustard greens in the field trials.8 of 32 Maintenance pesticides and ferti lizers are proposed as necessary to produce commercial quality crops. The proposed use directions for flutolanil as an in-furrow or directed spray to transplants for

Brassica (Cole) leafy vegetables and turn ip greens are presented in Table 2.1.

Table 2.1. Summary of Direct ions for Use of Flutolanil

Trade

Name Application Timing Application

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

(lb ai/A) PHI 2
(days) Use Directions and other

Limitations 3

Brassica (Cole) Leafy Vegetables Crop Group 5, and Turnip Greens.

Moncut ®

70DF in-furrow at planting or directed spray

at the base of transplants at

time of transplant or immediately

after transplanting 0.77 1 none 0.70 – 0.78 Not specified Applications to be made in a minimum of 3 gal/A using ground equipment.

Do not use adjuvant

1 RTI = retreatment interval

2 PHI = preharvest interval

3 Use of oil as carrier or addition of other ad ditives to the finished spray is prohibited

.

2.2 Structure and Nomenclature

The nomenclature of flutolanil is summarized in Table 2.2.

Table 2.2. Flutolanil Nomenclature

Chemical structure

N H O CH 3

CH 3

O

CF 3

Common name Flutolanil
Company experimental name N/A

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

CAS name N -[3-(1-methylethoxy)phenyl]-2-(trifluoromethyl)benzamide
CAS registry number 66332-96-5
End-use product (EP) Moncut 70 DF SC Fungicide (70%% flutolanil); EPA Reg. No. 10163-301)

Chemical structure of common moiety determined by enforcement method

O

CF 3 OH

2-trifluoromethylbenzoic acid (2-TFBA)9 of 32 2.3 Physical and Chemical Properties

The physicochemical properties are summarized in Tabl e 2.3. The chemical names and structures of flutolanil and its transformation pr oducts are presented in Appendix A.

Table 2.3.1. Physicochemical Properties of Flutolanil.

Parameter Value Reference

Melting range 100.4-103.8 °C

pH 5.69

Density 1.325 @ 20-25

Water solubility 6.53 mg/L at 20 °C

Solvent solubility at 20 °C Methanol 232 g/L n-Hexane 0.9 g/L

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

Dissociation constant, pK

a Not applicable

Octanol/water partition coefficient, Log(K OW ) log P OW = 3.74 DP#s 190584 and 190586, 3/24/94, J. Garbus; MRID 42606601

UV/visible absorption spectrum Not available

3.0 Hazard Characterization/Assessment

3.1 Hazard and Dose-Response Characterization

3.1.1 Database Summary A summary of the hazard assessment of flutolanil is provided below. Additional details may be

found in the 2000 Human Health Risk Assessm ent (A. Lowit, DP#268880, 9/11/00) and the 2007 Human Health Risk Assessment (F. Fort, DP#335050, 11/ 27/07). The acute toxicity of flutolanil technical is summarized in Appendix B (Table B.1.) and the toxicity pr ofile of flutolanil is shown in Appendix B (Table B.2.). The following study types were considered.

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

• Developmental: rat and rabbit developmental toxicity studies (rat, rabbit),

• Reproduction: two-generation repr oduction study (rat),

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

• Other: mutagenicity battery, metabolism.

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

The existing flutolanil database is considered adequate for ha zard characterization, endpoint selection, and assessment. However, the revise d Toxicology Data Requirements for Conventional10 of 32 Pesticides [40 CFR §158.340] now in clude studies which are better ab le to detect any potential immunotoxicity or neurotoxicity. These new study requirements are:

• Acute neurotoxicity [OPPTS Guideline 870.6200a],

• Subchronic neurotoxicity [O PPTS Guideline 870.6200b], and

• Immunotoxicity [OPPTS Guideline 870.7800].

For flutolanil, the above studies are not availa ble, and they are requi red under the new rule.

Based on the available toxicity da tabase and the Agency's current practices, the inhalation risk for flutolanil was not assessed. The Agency may, as appropriate, re-examine and develop new policies and procedures for conducting inha lation risk assessments. If any new policies or procedures are developed, the Agency may revisit the need for an inhalation toxicity study fo r flutolanil and/or reexamine the inhalation toxicity risk assessment.

3.1.2 Toxicological Effects The toxicology studies conduc ted on flutolanil demonstrate few or no biologically significant toxic

effects. Liver effects in rats incl uded increases in absolute and relativ e liver weight in the absence of clinical chemistry and/or histop athology findings. In dogs, there was an elevation in alkaline phosphatase and cholesterol levels t ogether with dose-related increase s in absolute and relative liver weights, slightly enlarged livers, and an increase in severity of glycogen deposition. The increased liver weights are considered to be an adaptive re sponse to flutolanil treatment and not an adverse effect. Based on the lack of evidence of carcinoge nicity and the lack of evidence of mutagenicity,

flutolanil is classified as “not likely to be carcinogenic to humans.”

Evaluation of the available data for flutolanil did not reveal any clinical signs, clinical chemistry changes, and/or histopathology to indicate that it is neurotoxic or that it targets the immune system. It is not a developmental or re productive 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 to post-natal exposure to

flutolanil. No toxic eff ects were observed in studies in whic h flutolanil was administered by the dermal route of exposure at the limit dose. Further, there is no developmenta l or reproductive concern

at dose levels that do not exceed the limit dose. Fo r these reasons, it is concluded that no short-term, intermediate-term, or long-term dermal risk assessment is required.

3.1.3 Metabolism

The available metabolism data show that with single dose oral administration, flutolanil is not completely absorbed and 40% of the administered radioactivity was eliminated in urine and similar percentage was eliminated in feces. With re peated dosing, absorption was improved as shown by 70% of the administered dose eliminated in urine, while approximately 30% in feces. The absorbed flutolanil was eliminated rapidly in the urine and the majority of the urinary elimination occurred within 24 hours post dose. There was no appreciabl e concentration remaining in any tissue. The major metabolite was reported to be M-4. The parental chemical was found to account for the majority of the radioactivity eliminated in the feces.11 of 32 3.1.4 Dose-Response The HED flutolanil risk assessment team previ ously reevaluated the flutolanil database and reaffirmed the lack of an appropriate endpoint fo r the acute RfD and reduction of the FQPA safety factor to 1X. Previous (HED) risk assessments utilized a cRfD of 0.87 mg/kg/day based on the 2- year combined chronic toxicity/carcinogenicity study in rats (Hazard Identification Assessment Review Committee (HIARC) October 14, 1999). Howe ver, more recently the team identified an endpoint from the 2-year chronic dog study as prov iding a more appropriate endpoint for the chronic

RfD. This is based on the conclusion that the li ver effects are considered to be an adaptive, nonadverse response in the absence of clinical chemistry or histopath fi ndings (chronic rat study). In the chronic dog study, the increased incidence of clinical signs (emesi s, salivation, and so ft stool) at 250 mg/kg/day (LOAEL) occurred following 65 weeks of e xposure. The flutolanil risk assessment team then selected a chronic RfD of 0.5 mg/kg/day ( NOAEL of 50 mg/kg/day; 10X interspecies factor; 10X intraspecies fact or; 1X FQPA SF).

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

3.2 FQPA Safety Factor Considerations

The database for flutolanil is ad equate for FQPA consideration.

3.2.1 Evidence of Neurotoxicity A thorough evaluation of the available toxicology data base on flutolanil (including open literature) revealed no clinical signs, clin ical chemistry changes, organ we ights, and histopathology indicating possible neurotoxicity. Included were studies conducted at high doses between 500 mg/kg/day and a 1000 mg/kg/day dose (limit dose), where signs of neur otoxicity were not detected. Based on this analysis, a database uncertainty factor (UF) is not needed to account for the missing neurotoxicity

studies on flutolanil at this time.

3.2.2 Evidence of Immunotoxicity None of the available submitted or open literatu re studies suggested that flutolanil produces hematological effects, effects on the thymus or sp leen indicative of potentia l immunotoxicity. In addition, in most of the repeated or al dosing studies, flut olanil did not produce any adverse effects at the limit dose (1000 mg/kg). At this time, a database uncertainty factor is not needed to account for the missing immunotoxicity study.

3.2.3 Pre-and/or Postnatal Toxicity: Determination of Susceptibility There is no evidence of increased susceptibility. There was no increased sensitivity to fetuses as compared to maternal animals in the developmenta l rat and rabbit studies and no increased sensitivity to pups as compared to adults in a multi-generation reproduction study in rats.12 of 32 3.2.4 Safety Factor for Infants and Children There was no evidence of increased suscep tibility of rat or rabbit fetuses to in utero exposure or rat pups to post-natal exposure to flutolanil. Flutolan il is not a developmental or reproductive toxicant. No maternal, reproductive, or developmental toxicity wa s observed at the limit dose.

EPA has determined that reliable data show the sa fety of infants and children would be adequately protected if the FQPA SF were reduced to 1X. That decision is based on the following findings:

1. The toxicity database for flutol anil is complete except for acu te and subchronic neurotoxicity and immunotoxicity studies. Recent changes to 40 CFR part 158 make acute and subchronic neurotoxicity testing (OPPTS Test Guidelin e 870.6200), and immunotoxi city testing (OPPTS Test Guideline 870.7800) required for pesticide regi stration. However, the available data for flutolanil do not suggest th at the compound produces hematol ogical or thymus/spleen organ

effects indicative of immunotoxic ity. Further, there is no evid ence of neurotoxicity in any study in the toxicity database fo r flutolanil. Therefore, EPA does not believe that conducting neurotoxicity and immunotoxicity studies will result in a NOAEL lower than the NOAEL of 50 milligrams/kilogram/day (mg/kg/day) already established for flutolanil. Consequently, an additional database UF does not need to be applied.

2. There is no indication that flut olanil is a neurotoxic chemical and there is no need for a developmental neurotoxicity study or addi tional UFs to account for neurotoxicity.

3. There is no evidence that flutolanil re sults in increased susceptibility in in utero rats or rabbits in the prenatal developmenta l studies or in young rats in the 2-generation reproduction study.

4. There are no residual uncertainti es identified in the exposure databases. The dietary food exposure assessments were performed based on 1 00% CT and tolerance-level residues. EPA made conservative (protective) assumptions in the ground water and surface water modeling used to assess exposure to flutolanil in drinki ng water. Residential exposure does not pose a concern for flutolanil because (1) chronic re sidential exposure is not expected; and (2) although short-term or intermediate-term reside ntial exposure may occur, no relevant adverse

effects were identified for dermal , incidental oral, or inhalation exposure re lated to residential

use. These assessments will not underestimate the exposure and risks posed by flutolanil.

3.3 Hazard Identification and Toxicity Endpoint Selection

The toxicity endpoints and doses fo r risk assessment were selected based upon the available toxicity data and the use exposure information on flutolanil. The toxicological doses and endpoints selected for various exposure scenarios are summarized in Table 3.3.13 of 32Table 3.3. Summary of Toxicological Doses and Endpoints for Flutolanil for Use in Dietary and NonOccupational Human Risk Assessments

Exposure

Scenario Point of Departure Uncertainty/

FPQA

Factors RfD, PAD,

Level of

Concern for

Risk

Assessment Study and Toxicological Effects

Acute Dietary (All populations) No appropriate toxicological endpoint attributable to a single exposure (dose) was identified from the oral toxicity studies including developmental toxicity studies in rats and rabbits. This

risk assessment is not required.

Chronic Dietary (All populations) NOAEL=

50 mg/kg/day UF A =10X

UF H =10X

FQPA SF =

1X cRfD = 0.5 mg/kg/day

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

MRID no. 40342922 LOAEL = 250 mg/kg/day based on increased incidence of clinical toxic signs (emesis, salivation, and soft stool)

Incidental Oral,

Short- and Intermediate-Terms;

Dermal and Inhalation, Short

and intermediate

terms No appropriate endpoint was identified in the database for these durations of exposure.

Dermal and

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

Cancer (oral, dermal, inhalation) Classification: “Not likely to be Carcinogenic to Humans” based on the absence of significant tumor increases in two adequate rodent carcinogenicity studies.

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

3.4 Endocrine Disruption

As required under FFDCA section 408(p), EPA has developed the Endocrine Disruptor Screening Program (EDSP) to determine whether certain su bstances (including pest icide 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, and or t hyroid (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 w ill determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 tes ting is designed to identify any adverse endocrine14 of 32 related effects caused by the subs tance, and establish a dose-respons e relationship between the dose and the E, A, or T effect.

EPA issued test orders/data call-i ns for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 iner t ingredients. This list of chemical s was selected based on the potential for human exposure through pathways such as food a nd water, residential activity, and certain postapplication agricultural s cenarios. This list should not be construed as a list of known or likely endocrine disruptors.

Flutolanil is among the group of 58 pe sticide active ingredients on the in itial list to be screened under the EDSP. The Agency will review the EDSP Tier 1 data and any “other scientifically relevant information” submitted in response to test orders. Based on this review the Agency will determine the need for additional testing. For further inform ation on the status of the EDSP, the policies and procedures, the list of 67 chemicals, the test guide lines and the Tier 1 screen ing battery, please visit our website: http://www.epa.gov/endo/.

4.0 Dietary Exposure/Risk Characterization

References: Chronic Aggregate Dietary (Food and Drinking Wa ter) Exposure and Risk Assessment for the Section 3 Registration Action (Brassica Leaf y Vegetables, Crop Group 5). K. Rury, DP#371494,

9/10/10.

Petition for Establishment of Tolerances for Use on Brassica (Cole) Leafy Vegetables Crop Group 5 and Turnip Greens. Summary of Analytical Ch emistry and Residue Data. A. Acierto, DP#371493,

5/12/10.

Petition for Establishment of Tolerances for Use on Brassica (Cole) Leafy Vegetables Crop Group 5 and Turnip Greens. Summary of Analytical Chemistry and Residue Data. S. Funk, DP#381713: Revision of DP# 371493, 9/07/10.

Estimated Environmental Concentr ations (EECs) of Flutolanil on Sugar Beets, Brassica Leafy Vegetables, Turnip Greens, and Ginseng. L. Liu, D370201, DP#376798, 7/21/10.

4.1 Pesticide Metabolism and Environmental Degradation

4.1.1 Metabolism in Primary Crops and Livestock No new plant metabolism data were submitted in conjunction with the subject petitions. The nature of the residue in plants is adequately unders tood based on acceptable metabolism studies submitted previously on rice, cucumber leaves, and peanuts. Flutolanil is metabolized via O -deisopropylation, hydroxylation, and methylation to yield N -(3'-hydroxyphenyl)-2-(trifluor omethyl)benzamide (M4),

and N -(4'-hydroxy-3'-methoxy)phenyl-2-(trifluoromethyl)ben zamide (M7). Most of the metabolites are found bound or conjugated. The major identifi ed components in plants were parent and

metabolite M4. HED’s Metabolism Committee concl uded that the parent compound and metabolites containing the common moiety, 2-trif luoromethyl benzanilide, need to be included in the tolerance expression.15 of 32 No livestock metabolism data were submitted in c onjunction with the subject petition since there are

no livestock feed commodities associ ated with the proposed uses.

See Appendix A for chemical structures of flutolanil and metabolites.

4.1.2 Metabolism in Rotational Crops The nature of the residue in rotational crop co mmodities is adequately understood based on an acceptable confined rotati onal crop study with lettuce, radish, and oat/sorghum conducted with [U14 C-aminophenoxy]flutolanil. The major residue co mponents were flutolanil and metabolites M-4 and M-5 ( N -[3',4'-(dihydroxy)phenyl]-2- (trifluoromethyl)b enzamide). The residues of concern for tolerance expression and dietary risk assessment for rotational crops are flutolanil and metabolites containing the common moiety, 2-tr ifluoromethyl benzanilide.

4.1.3 Analytical Methodology A gas chromatography-mass spectrometry (GC/MS ) enforcement method (AU/95R/04) originally submitted by AgrEvo USA Company has undergone a successful independent validation with nutmeat, peanut and hay, rice grain, milk, eggs, beef muscle, and beef fat. The method was found adequate for data collection based on acceptable r ecovery data. Method AU/95R/04 analyzes for the flutolanil residues of concern for tolerance expres sion and risk assessment. However, it was noted that a confirmatory method is required because the method is a common moiety method. In addition,

HED noted that the method must be rewritten to incl ude instructions for analysis of additional crops including cotton and soybeans.

Nichino America submitted a liquid chromatogr aphy-mass spectrometry (LC/MS/MS) method XAM65 as a data collection method and proposed th is method to replace the AU/95R/04 enforcement method. The proposed XAM-65 method was not found acceptable as a data collection method and not suitable as a replacement for the enforcement method because it may not determine the flutolanil residues of concern for the tolerance expressi on and dietary risk assessment. The AU/95R/04 analytical method would be expected to determin e higher residues of flutol anil-derived residues,

since it determines all metabolites converted to 2-TFBA (including M-2, M-3, and M-7 (Appendix A)) in addition to flutolanil and M-4 (F. Fort , DP#335050, 11/26/07). Method XAM-65 is acceptable as a confirmatory enforcement method (S. Funk, DP#364462, 01/25/10).

HED recommends for the establishment of tolerances for Brassica (Cole) leafy vegetables (crop group 5) and turnip greens. Although residues from the field trials were determined by a data collection method that in general might understate the residue by m easuring only flutolanil and its metabolite M4, in the case of the data set for these crops HED believes the tolerances are adequate

for Brassica (Cole) leafy vegetables. The use is at-plant/at-transplant to the soil and is therefore very

similar to the conditions of a rota tional crop trial. A confined rotational crop study indicated that residues in lettuce, a crop similar to the Brassica (Cole) leafy vegetables, determined by the enforcement method (common moiety) were 0.08 ppm. This is in ag reement with the results of the subject field trials, where the combined residue of flutolanil and metabolite M4 were <0.1 ppm.

Flutolanil was proposed for use on ginseng but ginseng has been removed from the revised Section F. HED notes for possible future requests that ginse ng samples must be analyzed by the common moiety16 of 32 method. Other acceptable approaches would be (1 ) to demonstrate that the common moiety method (AU/95R/04) and the LC/MS/MS method XAM-65 yield similar quantitative resu lts on a variety of crop matrices with incurred resi dues; OR (2) to dem onstrate that method XAM-65 modified to use the extraction solvents of the pl ant metabolism studies, including a new extract hydrolysis step gives

similar results as unmodified method XAM-65.

4.1.4 Environmental Degradation Flutolanil has a very low solubility, has a low propens ity to volatilize, is resi stant to hydrolysis, and practically resistant to photolysis. Flutolanil is relatively resistant to aerobic and anaerobic degradation in soils and aquatic e nvironments with half-lives of more than 200 days in soils and greater than one year in water.

Flutolanil and the most significant transformation product DIP (desisopropyl flutolanil) do have the potential to leach based on their K

oc values. Flutolanil and its degrad ate DIP, may be transported to surface water through erosion of soil particles containing bound residues or dissolved in runoff water.

In all fate studies, no major transformation products were identified. In th e aerobic soil metabolism study, three minor degradates were identified. 3' -hydroxy- 2-trifluoromethyl-benzanilide (DIP) was formed at no more than 3% of the applied. Two other degradates were formed in minor amounts (<1%): 3'-methoxy-2-trifluoromethyl-ben zanilide (MDP) and 4'-hydroxy-3-methoxy-2- trifluoromethyl-benzanilide (HMD ). Flutolanil was observed to degrade faster under anaerobic conditions during the flooded stage of the study. Two minor degradat es not identifie d under aerobic conditions were observed: 3'-(hydroxymethy1et hoxy)-2-trifluoromethyl-benzanilide (HIP) and 4'- hydroxy-3'-isopropoxy-2-triflouromet hyl-benzanilide (HFT).

4.1.5 Drinking Water Residue Profile

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

EFED does not have monitoring data available to perform a quantitative drinking water risk

assessment for flutolanil at this time. Therefor e, the Agency is presently relying on computergenerated estimated drinking wate r concentrations (EDWCs). Ground and surface water exposure

estimates for use of flutolanil on rice were provided by EFED (L. Liu, D3702101, D376798, 7/21/2010). For surface water and gr ound water, EDWCs were generate d from Pesticide Root Zone Model and Exposure Analysis Modeling System (PRZM-EXAMs) and from a Tier I Screening Concentration In Ground Water (SCI-GROW) analysis , respectively. At the time the EDWCs were generated, flutolanil was propos ed for use on sugar beets, Brassica (Cole) leafy vegetables, turnip greens and ginseng, with the highest application rate for flutolanil proposed on ginseng. The mean surface water concentration of 8.5 ppb from applica tion to ginseng was entered as a conservative point estimate in the chronic resi due file editor for DEEM-FCID TM . While the proposed use of flutolanil on ginseng has been withdrawn, the dr inking water analysis incorporating the use of flutolanil on ginseng was used in the dietary assessment as a conserva tive, screening level analysis.17 of 32 Table 4.1.5. Summary of Estimate d Surface Water and Ground water Concentrations for Flutolanil.

Scenario Surface Water Conc., ppb a Ground water Conc., ppb b

Acute 12.7

Chronic (non-cancer) 8.5 0.7

a From the Tier II PRZM-EXAMS - Index Reservoir model. Input parameters are based on ...

b From the SCI-GROW model.

4.1.6 Food Residue Profile IR-4 has submitted magnitude of residue data for cabbage, mustard greens, broccoli and ginseng in support of the requested uses and proposed tole rances. The results from these studies are

summarized below:

Cabbage (MRID#47832601) IR-4 submitted crop field data for cabbage from ni ne field trials conducted in the United States during the 2005 growing season. Mature cabbage h eads were harvested 62- 138 days after treatment and analyzed for residues of flutolanil [ N -[3-(1-methylethoxy)-phenyl ]-2-(trifluoromethyl)- benzamide] and its metabolite M-4 [ N -(3’hydroxyphenyl)-2-(trifluoromet hyl)bezamide]. Adequate storage stability data are available to support the st orage conditions and durations of the cabbage field samples. No residues of flutolanil or M-4 were de tectable in any of the tr eated field samples above

the calculated lowest level of method valida tion (LLMV) (0.05 ppm) following 62-138 days after

treatment. No residues were found in a ny of the untreated control samples.

Mustard Greens (MRID#47832602) IR-4 submitted crop field trial data on mustard greens from 10 trials conducted during the 2006 growing season. The number and geographical distribut ion of the supervised field trials on mustard greens are adequate. The storage stability data ar e also adequate to suppo rt the storage conditions and durations of the field samples. No residues of flutolanil or metabolite M- 4 were detectable above the LLMV (0.05 ppm) in any of the treated samples except samples from the California trial (CA67) where 0.05 and 0.06 ppm of flutolanil we re found in 2 treated samples.

Broccoli (MRID#47832602) IR-4 submitted crop field trial data on broccoli fr om 11 field trials conducted across the United States during the 2006 growing season. The number and geogr aphical distribution of the supervised field trials on broccoli are adequate.

Residues of flutolanil or metabolite M-4 were not detected above the LLMV (0.05 ppm) in any of the treated and untreated samples except samples fr om the Ohio trial (OH*11) where ~0.02 ppm flutolanil residue was found in the control sample and apparent residues at or below the calculated LOD (0.01 and 0.009 ppm) were found in the treated samples.

No residues of flutolanil or metabolite M-4 were detectable above the LLMV in any of the treated samples or untreated samples except for the sample s from Ohio (OH#11) wher e apparent flutolanil residues of 0.02 ppm were found in the untreated control and 0. 01 and 0.009 ppm in the treated samples.18 of 32 The available data are adequate to support the sample storage c onditions and intervals from the

broccoli field trials.

Ginseng (MRID#47832602) IR-4 submitted crop field trial data on ginseng from 3 field trials in Wisconsin during the 2006 growing season.

Flutolanil residues in the treated samples ranged from 0.65 – 2.17 ppm. Residues of M-4 were not detected above the LLMV (0.05 ppm) in any of th e treated samples except in one treated sample (MI17 trial) where apparent re sidues of about 0.02 ppm were found. No detectable residues were found in the untreated samples except for a sample that was verified to have been switched.

The available data are adequate to support the sample storage condi tions and intervals for ginseng

roots.

Field Trials

Table 4.1.6 summarizes the residue data in the field trials of flut olanil on cabbage, mustard greends, broccoli and ginseng.

TABLE 4.1.6. Summary of Residue Data on Cabbage, Mustard Greens, Broccoli and Ginseng Field

Trials with Flutolanil.

Residue Levels (ppm) Commodity Total Applic.

Rate (lb ai/A) PHI (days) Analyte

n Min. Max. HAFT 1 Median (STMdR) Mean (STMR) Std.

Dev.

Flutolanil 18 < 0.05 < 0.05 < 0.05 < 0.05 < 0.05 NA 2 Cabbage 0,72 – 0.788 62 -

138 M-4 18 < 0.05 < 0.05 < 0.05 < 0.05 < 0.05 NA

Total <0.10 <0.10 <0.01 <0.05 <0.05 NA

Flutolanil 20 < 0.05 < 0.05 0.06 < 0.05 < 0.055 0/007 Greens,

Mustard 0,195– 0.784 31 -

63 M-4 20 < 0.05 < 0.05 < 0.05 < 0.05 < 0.05 NA

Total 20 <0.1 <0.11 <0.11 <0.1 <0.105 NA

Flutolanil 23 < 0.05 < 0.05 <0.05 < 0.05 < 0.05 NA Broccoli 0,411 – 0.775 54 -

106 M-4 22 < 0.05 < 0.05 < 0.05 < 0.05 < 0.05 NA

Total 20 <0.1 <0.1 <0.1 <0.01 <0.1 NA

Flutolanil 6 0.65 2.17 1.80 1.25 1.28 0.52 Ginseng 0,674 – 0.717 61

M-4 6 < 0.05 < 0.05 < 0.05 < 0.05 < 0.05 NA 2

Total 6 <0.07 <2.22 <1.85 <1.30 <1.32 NA

1 HAFT = Highest Average Field Trial.

2 NA = not applicable.

For the requested minor uses on Brassica (cole) leafy vegetables (cr op group 5), turnip greens, and ginseng (in the original request ), there was a major issue that precluded granting Section 3 registration of Moncut® 70DF and permanent to lerances for the proposed crops (A. Acierto, DP#371493, 5/12/2010). The data collection method used determines flutolanil (M1) and metabolite M4 only and may not adequately determine the to tal residue as currentl y defined for tolerance

enforcement. The current residue definition includes flutolanil and all meta bolites converted to the common moiety 2-trifluoromethyl benzanilide vi a harsh base hydrolysis of the extract.19 of 32 The at-plant trials with cabbage, broccoli, and mustard greens yielded resi dues of <0.05 ppm each of flutolanil and M4, or <0.1 ppm total.

Although the total residue as defined for tolera nce enforcement was not determined, there is supplemental information that demonstrates that for the Brassica (Cole) leafy vegeta bles situation the residues will be below the limit of quantitation of the data collection method (<0.10 ppm). In a confined rotational crop study (G. Kramer , DP#193608, 08/03/1993), aminophenoxy-ring-labeled

14 C-flutolanil was applied to soil at a rate of 2.4 lb ai/A. Lettuce, a leafy vegetable, was seeded into the treated soil 30 days later. At normal harvest, the extractable TRR of th e lettuce leaves was 0.09 ppm, including 0.03 ppm free and 0.05 ppm c onjugated radiolabeled residue. Analysis of the lettuce by the common moiety enfor cement method yielded 0.08 ppm. This is comparable to the proposed atplant use of flutolanil for Brassica (Cole) leafy vegetables and turnip s, where flutolanil is applied infurrow at seeding at a rate of 0.78 lb ai/acre or to the base of transpla nts at 0.78 lb ai/acre. Thus, the

results of the Brassica (Cole) leafy vegetable field trials with residues <0.10 ppm and the confined rotational crop study with residues of 0.08 ppm are in agreement.

Storage Stability Storage stability data submitted previously are ade quate to support the sample storage conditions and intervals for cabbage, mustard greens, broccoli an d ginseng roots submitted in conjunction with this petition. However, the petitioner is reminded that zero-day data should be submitted in future petitions as required in Guideline OPPTS 860.1300.

4.1.7 Proposed Tolerances and Recommended Tolerances HED previously concluded that the residues of c oncern for tolerance expr ession and dietary risk assessment for crops are flutolanil and metabolites containing the co mmon moiety, 2-trifluoromethyl

benzanilide. HED recommends m odification of the tolerance expres sions for flutolanil according to the new compliance/measurement policy ( Interim Guidance on Tolerance Expressions , Steve Knizner, May 27, 2009) to read as follows:

“HED recommends that the tolerance definition entry in 40 CFR 180.484 be revised as follows: (a) General. Tolerances are established for residues of the fungicide flutolanil, including its metabolites and degradates, in or on the commoditi es in the table below. Compliance with the tolerance levels specified below is to be determ ined by measuring only flutolanil and its metabolites converted to 2-(trifluoromethyl) be nzoic acid and calculated as flut olanil, in or on the commodity.

Table 4.1.7. Tolerance Summary for Flutolanil

Commodity Proposed Tolerance (ppm) Recommended Tolerance (ppm) Comments Correct Commodity Definition Brassica leafy vegetables (crop group 5), 0.11 0.1

Turnip greens 0.11 0.1 Until the regulations have been finalized in the Federal Register to move turnip greens from the leaves of root and tuber vegetables crop group (group 2) to the Brassica leafy greens subgroup 5B, a separate20 of 32 Table 4.1.7. Tolerance Summary for Flutolanil

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

tolerance is needed at the same level

as the Brassica Leafy Greens, subgroup 5B. 1

1 Memorandum, B. Schneider, 6/14/02.

4.1.8 International Residue Limits Codex Maximum Residue Limits (MRLs) are es tablished for residues of flutolanil in rice commodities at 1-10 ppm, and in livestock comm odities at 0.05-0.2 ppm. No Canadian or Mexican

MRLs have been established.21 of 32 4.2 Dietary Exposure and Risk

A chronic dietary exposure assessment (using tole rance-level residues and assuming all crops are treated (100 %CT) and using default concentr ation factors for processed commodities) was conducted for the general U.S. population and various population subgroups. The results reported in Table 4.2 are for the general U.S. Population, all infants (<1 year old), children 1-2, children 3-5, children 6-12, youth 13-19, females 13-49, adults 20- 49, and adults 50+ years. Tolerance-level residues, 100 % CT, and DEEM TM 7.81 default processing factors were used to determine the chronic dietary exposure and risk estimates. This assessm ent showed that for all included commodities, the chronic risk estimates were below the Agency’s le vel of concern (<100% cPAD) for the general U.S. population (<1% of the cPAD) and all population subgroups (<2% cPAD) listed in Table 4.2. The most highly exposed population s ubgroup was children 1 – 2 years of age at 1.5% of the cPAD.

Table 4.2 Summary of Dietary (Food and Drinking Water) Exposure and Risk for

Flutolanil

Chronic Dietary

Population Subgroup Dietary Exposure (mg/kg/day) % cPAD

General U.S. Population 0.003127 <1

All Infants (< 1 year old) 0.007005 1.4

Children 1-2 years old 0.007530 1.5

Children 3-5 years old 0.006337 1.3

Children 6-12 years old 0.004258 <1

Youth 13-19 years old 0.002850 <1

Adults 20-49 years old 0.002818 <1

Adults 50+ years old 0.001964 <1

Females 13-49 years old 0.002418 <1

5.0 Residential (Non-Occupational) Exposure and Risk

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

6.0 Aggregate Risk Assessments and Risk Characterization22 of 32 In accordance with the FQPA, the Agency must consider aggregate pesticide exposures and risks from three major sources: food, drinking water, a nd residential exposures. In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or th e risks themselves can be aggregated. When aggregating exposures and risks from various so urces, the Agency considers both the route and duration of exposure. In the case of flutolanil, aggregat e risk assessments were performed for chronic aggregate exposure (food + drinki ng water) only. Short- and inte rmediate-term aggregate risk assessments were not performed because toxico logical endpoints from dermal and inhalation exposures were not identified. Additionally, the Agency does not expect residential exposure durations that would result in long term exposures. A cancer aggregate risk assessment was also not performed because flutolan il is not carcinogenic.

The chronic aggregate risk assessment takes into account average exposure estimates from dietary consumption of flutolanil (food and drinking water) a nd residential uses. However, due to the use patterns, no chronic residential e xposure is expected. Therefor e, the chronic aggregate risk assessment will consider exposure from food and dri nking water only. The chronic dietary exposure estimates in Table 4.2 for food and drinking water are below HED’s level of concern (<100% cPAD) for the general U.S. population (<1% of th e cPAD) and all population subgroups (< 1.5% cPAD). Therefore, the chronic aggregate risk associated with the proposed a nd registered uses of flutolanil

does not exceed HED’s level of concern for the general U.S. population or any population subgroups.

7.0 Cumulative Risk Char acterization/Assessment

Unlike other pesticides for which EPA has followe d a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to flutolanil and any other substances and flutolanil does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolera nce action, therefore, EP A has not assumed that flutolanil has a common mechanism of toxicity w ith other substances. For information regarding

EPA’s efforts to determine which chemicals have a common mechanism of toxi city and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s Office of Pesticide Programs concerning common mechanism de terminations and pro cedures for cumulating

effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

8.0 Occupational Exposure/Risk Pathway

Workers may be exposed to flutolanil duri ng mixing, loading, applyi ng, and postapplication activities. Based on the proposed application rates and us e scenarios, short- and intermediate-term occupational exposures may occur. However, sin ce short-and intermediate-term endpoints have not been established, an occupational exposure asse ssment is not required. Chronic occupational exposure is not expected; thus, ch ronic occupational exposure risk as sessments are also not required.

9.0 Data Needs/Label Recommendations23 of 32 9.1 Toxicology

The revised Toxicology Data Requirements for Conventional Pesticides [40 CFR §158.340] now

includes studies which are better ab le to detect toxicities that ar e outside the scope of standard subchronic and chronic assays. These new study requirements are:

Acute neurotoxicity [OPPTS Guideline 870.6200a]; Subchronic neurotoxicity [OPPTS Guideline 870.6200b]; Immunotoxicity [OPPTS Guideline 870.7800]

See Appendix C.

9.2 Residue Chemistry

HED has examined the residue chemistry databa se for flutolanil (A. Acierto, DP#371493, 05/12/10). There are no residue chemistry issues that woul d preclude granting an unc onditional registration of the end-use product Moncut® 70DF (EPA Reg. No.10163-301) for at-pla nt/at-transpla nt use in/on

Brassica (Cole) leafy vegetables crop group 5 and turnip greens.

The available data, which reflect a single in-furrow or directed spray at the base of transplants of

Brassica (Cole) leafy vegetables crop group 5, and turnip greens, combined with the data from the confined rotational crop study, will support the proposed new minor uses. Although the residues resulting from the proposed uses were determined by a method that does not co mply with the current residue definition and that might understate the residue, a confined rotational crop study conducted at 3X the proposed rate for Brassica (Cole) leafy vegetables and tu rnip greens yielded residues of 0.08 ppm in a leafy vegetable (lettuce), where the sa mples were analyzed by the existing enforcement

method.

9.2.1 Residue Enforcement Analytical Methods Ginseng has been removed from the revised Section F. HED notes for possible future requests that ginseng samples must be analyzed by the comm on moiety method. Other acceptable approaches would be (1) to demonstrate that the common moiety method (AU/95R/04) and the LC/MS/MS method XAM-65 yield similar quantitative results on a variety of crop ma trices with incurred residues; OR (2) to demonstrate that method XAM-65 modified to use the extr action solvents of the plant metabolism studies and including a new extr act hydrolysis step give s similar results as

unmodified method XAM-65.

9.2.2 Proposed Tolerances

HED recommends that the tolerance definition en try in 40 CFR 180.484 be revised as follows: (a)

General. Tolerances are established for residues of the fungicide flutolanil, including its metabolites and degradates, in or on the commod ities in the table below. Comp liance with the tolerance levels specified below is to be determined by measurin g only flutolanil and its me tabolites converted to 2- (trifluoromethyl) benzoic acid a nd calculated as flutolanil, in or on the commodity.24 of 32 Appendix A: Chemical Structures

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

Common name; Company code Chemical name Chemical structure

Flutolanil; M1 N-[3'-(1-m ethylethoxy)p henyl]-2- (trifluoromethyl)benzamide

N H O CH 3

CH 3

O

CF 3
M-2 N-[4'-hydroxy-3'-(1- methylethoxy)phenyl]-2- (trifluoromethyl) benzamide

N H O CH 3

CH 3

O

CF 3 OH

M-3 N-[3'-(2-hydroxy-1-methylethoxy) phenyl]-2- (trifluoromethyl)benzamide

N H O CH 3

O

CF 3 OH

M-4 N-(3'-hydroxyphenyl)-2- (trifluoromethyl)benzamide

N H OH

O

CF 325 of 32 Table A. 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

N H OH

O

CF 3 OH

M-6 N-(3'-methoxy)phenyl -2- (trifluoromethyl)benzamide

N H O

O

CF 3 CH 3

M-7 N-(4'-hydroxy-3'-methoxy)phenyl - 2-(trifluoromethyl)benzamide

N H O

O

CF 3 CH 3

OH

M-11 2-[[3-[2-(trifluoromethyl)benzoyl]- amino]phenoxy]propanoic acid

N H O CH 3

O

CF 3 O

O H

2-TFBA: 2-trifluoromethyl benzoate

O

CF 3 OH26 of 32 Appendix B: Toxicology

B.1 Toxicology Data Requirements

The requirements (40 CFR 158.500) for food use for fl utolanil are in Table B.1. Use of the new guideline numbers does not imply that the new (1998) guideline pr otocols were used.

Table B.1. Toxicology Da ta Requirements for Food Use

Technical Test

Required Satisfied

870.1100 Acute Or al Toxi city ......................................................
870.1200 Acute Derm al Toxi city .................................................
870.1300 Acute Inha lation Toxi city............................................. 870.2400 Primary Ey e Irritation................................................... 870.2500 Primary Derm al Irritation .............................................
870.2600 Dermal Sensitiza tion..................................................... yes

yes

yes

yes

yes

yes yes

yes

yes

yes

yes

yes

870.3100 Oral Subc hronic (Rat)................................................... 870.3150 Oral Subchronic (Dog) ................................................. 870.3200 21-Day Dermal ............................................................. 870.3250 90-Day Dermal ............................................................. 870.3465 90-Day Inhalation ......................................................... yes

yes

no

no

no yes

yes

yes

-

-

870.3700a Developmenta l Toxicity (Rat) ...................................... 870.3700b Developmental Toxicity( Rabbit) ................................. 870.3800 Repr oduction ................................................................ yes

yes

yes yes

yes

yes

870.4100a Chronic To xicity (Rat)..................................................
870.4100b Chronic To xicity (Dog) ................................................ 870.4200a Oncogeni city (Rat) ....................................................... 870.4200b Oncogeni city (Mouse) ..................................................
870.4300 Chronic/Onco genicity (Rat).......................................... yes

yes

yes

yes

yes 1

yes

1

yes

yes

870.5100 Mutagenicity—Gene Mutation - bacterial.................... 870.5375 Mutagenicity—Gene Mutation - mammalian............... 870.5385 Mutagenicity—Structural Chromosomal Aberrations .. 870.5395 Mutagenic ity—Micronuc leus ....................................... yes

yes

yes

yes yes

yes

yes

yes

870.6100a Acute Delaye d Neurotox. (Hen) ................................... 870.6100b 90-Day Neur otoxicity (Hen).........................................
870.6200a Acute Neurotox. Sc reening Battery (Rat)..................... 870.6200b 90 Day Neuro. Sc reening Battery (Rat)........................
870.6300 Develo p. Neuro............................................................. no

no

yes

yes

no -

-

no

no

-

870.7485 General Metabolis m...................................................... 870.7600 Dermal Penetration .......................................................
870.7800 Immunotoxicity ............................................................ yes

no

yes yes 2

no

Special Studies for Ocular Effects................................................... no - 1 = a chronic/onocgenicity study is available for the rat, thus separate chronic and oncogenicity are not necessary. 2 = study classified as unacceptable.27 of 32 Table B.2. Acute Toxicity of Flutolanil Technical 1

GDLN Study Type MRID nos. Results Tox Category

§81-1 Acute Oral 40342905 LD 50 > 10,000 mg/kg IV

§81-2 Acute Dermal 40342906 LD 50 > 2,000 mg/kg III

§81-3 Acute Inhalation 40342910 LC 50 > 5.98 mg/L (4 hours) IV

§81-4 Primary Eye Irritation 40342912 Minimal irritation IV

§81-5 Primary Skin Irritation 40342915 Not a dermal irritant IV

§81-6 Dermal Sensitization 40342917 Not a dermal sensitizer N/A

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

Table B.3. Toxicity Profile of Flutolanil Technical

Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

870.3100 (82-1) 90-day Oral Toxicity Rat - diet 40342919 (1986)/ Acceptable-Guideline/ 0, 500, 4000, 20000 ppm (M: 0, 37, 299, 1512 mg/kg/d; F: 0, 44, 339, 1743 mg/kg/d) NOAEL = 1512 mg/kg/day (HDT),

LOAEL = not established.
At 1512 mg/kg/day (HDT): increased absolute liver weights (males), increased relativ e liver weights (males and females), slight decrease in b ody weights (males) and slight increases in absolute, and relative thyroid/parathyroid weights were observed. No treatment-related changes in ophthalmoscopic, hematological, clinical chemistry, gross pathology, or histopathology parameters were observed. Therefore, the increased liver weights are considered to be an adaptive response to flutolanil treatment.

870.3150 (82-1) 90-day Oral Toxicity In Nonrodents (Dog) - gelatin capsule 40342920 (1986)/ Acceptable-Guideline/ 0, 80, 400, 2000 mg/kg/d NOAEL = 80 mg/kg/day, LOAEL = 400 mg/kg/day based on enlarged livers and increased severity of hepatic glycogen deposition in both

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

observed.

870.3200 (82-2) 21-day Dermal Toxicity - Rat 41841205 (1991)/ Acceptable-Guideline/ 0, 1000 mg/kg/d Systemic NOAEL= 1000 mg/kg/day (limit dose), Systemic LOAEL > 1000 mg/kg/day.
Dermal irritation NOAEL= 1000 mg/kg/day (limit dose), Dermal irritation > 1000 mg/kg/day.

870.3250 90-day Dermal Toxicity Not available Not available.28 of 32 Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

870.3465 90-day Inhalation Toxicity Not available Not available.

870.3700a(83-3a)

Prenatal Developmental In Rat - oral gavage 41850804(1987)/ Acceptable-Guideline/0, 40, 200, 1000 mg/kg/d Maternal NOAEL = 1000 mg/kg/day, LOAEL > 1000 mg/kg/day. Developmental NOAEL= 1000 mg/kg/day, LOAEL > 1000 mg/kg/day.

870.3700b(83-3b)

Prenatal Developmental In Rabbit - oral gavage 40342924(1987)/ Acceptable-Guideline/ 0,40,200,1000 mg/kg/d Maternal NOAEL= 1000 mg/kg/day, LOAEL > 1000 mg/kg/day. Developmental NOAEL = 1000 mg/kg/day, LOAEL > 1000 mg/kg/day.

870.3800(83-4) Reproduction And Fertility Effects In

Rat - 2 Generation -

diet 41850805(1992)/ Acceptable-Guideline/ 0,200,2000,20000 ppm (M: 0,16,159,1625 mg/kg/d; F: 0,19,190,1936 mg/kg/d) Parental/Systemic NOAEL = 1000 mg/kg/day, LOAEL > 1000 mg/kg/day. Reproductive NOAEL = 1000 mg/kg/day, LOAEL > 1000 mg/kg/day. Offspring NOAEL = 1000 mg/kg/day, LOAEL > 1000 mg/kg/day.

870.3800(83-4) Reproduction And Fertility Effects In

Rat - 3 Generation -

diet 40342923(1982)/ Unacceptable / 0, 1000, 10000 ppm (M: 0, 63, 661 mg/kg/d; F: 0, 86, 880 mg/kg/d) Parental/Systemic NOAEL = 661 mg/kg/day, LOAEL > 661 mg/kg/day. Reproductive NOAEL = 661 mg/kg/day, LOAEL > 661 mg/kg/day.

870.4100a Chronic Toxicity

Rodents See combined chronic / carcinogenicity study available (see below)

870.4100b (83-1) Chronic Toxicity Dogs- gelatin capsule 40342922(1982)/ Acceptable-Guideline/ 0, 50, 250, 1250 mg/kg/d NOAEL = 50 mg/kg/day, LOAEL = 250 mg/kg/day based on increased incidence of clinical toxic signs (emesis, salivation, and soft stool)

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

in males and from 74 th week in females) were observed.
No treatment-related changes in ophthalmoscopic, hematological, clinical chemistry, organ weights, gross pathology, or histopathology parameters were observed.

870.4300 (83-1 & 83-5)

Chronic/ Carcinogenicity

Rats - diet 40342921 (1982)/ Acceptable-Guideline/ 0, 40, 200, 2000, 10000

ppm (M: 0, 2, 9, 87, 460 mg/kg/d F: 0, 2, 10, 103, NOAEL = 460 mg/kg/day,

LOAEL = not established. At 460 mg/kg/day (HDT), increased absolute and relative liver weights (males and females) were observed in the absence of clinical chemistry or histopathology findings. Therefore, the increased liver weights are considered to be29 of 32 Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

536 mg/kg/d) an adaptive response to flutolanil treatment.

870.4300(83-2) Carcinogenicity

Mice - diet 41850803(1990)/ Acceptable-Guideline/ 0, 300, 1500, 7000, 30000 ppm (M: 0,32,162,735,3333 mg/kg/d; F: 0, 34, 168, 839, 3676 mg/kg/d) NOAEL = 735 (M) and 168 (F) mg/kg/day, LOAEL = 3333 (M) and 839 (F) mg/kg/day based on decreased body weight gains.

Gene Mutation 870.5375 (84-2), In

vitro Chromosomal Aberration Assay in

Cultured

Mammalian Cell 40342925(1986)/ Acceptable-Guideline/0, 37, 75, 150 uM/plate Positive finding, flutolanil induced chromosomal aberrations in cultured Chinese hamster lung cells in the presence of metabolic activation (S9).

Gene Mutation 870.5100 (84-2),

Reverse Mutation Assay 40342926(1981)/ Acceptable-Guideline/0, 10, 50, 100, 500, 1000, 5000, 10000, 25000 ug/plate. Negative (with and without S-9 metabolic activator) at doses up to 25 mg/plate in the increase in revertant colonies using

Salmonella strains TA98, TA10, TA1535, TA1537, and

TA1538 and in the E. Coli WP2 uvrA strain.

Gene Mutation 870.5375 (84-2),

Gene Mutation in

Cultured

Mammalian Cells (Mouse Lymphoma Cells) 41841207(1989)/ Acceptable-Guideline/0, 6, 15, 30, 60, 80, 100 ug/mL. Negative (either in the presence or absence of S9 activation)

for the induction of forward mutations at the TK+/- locus in L5178Y mouse lymphoma cells.

Cytogenetics 870.5395 (84-2),

Mouse
Micronucleus 40342927(1983)/ Acceptable-Guideline/0, 6400, 8000, 10000 mg/kg either in a single dose or 10 gm/kg/day over 4 days by gastric intubation to

BDF1 mice (6/sex/group). Negative up to a dose of 10000 mg/kg in the induction of micronuclei in the bone marrow erythrocytes of male and

female mice.

Cytogenetics 870.5385 (84-2),

Mammalian Cells in

Culture Cytogenetics Assay

in Human Lymphocytes 42606628(1990)/ Acceptable-Guideline/0, 120, 250, 500, 1000 ug/mL. Negative in the structural chromosome assay. There was no significant increase in the frequency of aberrations with any treatment levels, either with or without activation.

Other Genotoxicity Effects 84-2, In

Vitro Unscheduled DNA Synthesis 41841206(1989)/AcceptableNonguideline/0, 2.67, 27, 53, 80 ug/mL. Negative in the induction of unscheduled DNA synthesis in primary rat hepatocytes.30 of 32 Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results

Assays in Primary Rat Hepatocytes

870.6200a Acute Neurotoxicity Screening Battery Not available Not available. Required.

870.6200b

Subchronic Neurotoxicity Screening Battery Not available Not available. Required.

870.6300 Developmental Neurotoxicity Not available Not available. Conditionally required.

870.7485

Metabolism And

Pharmacokinetics -

Rat 42606602(1992)/ Acceptable-Guideline/ single oral dose of 20 and 1000 mg/kg and
repeated oral doses of 20 mg/kg for 14 days No appreciable tissue levels of flutolanil at study termination (168 hours post-dose). 20 mg/kg: urine (40%) and feces (40% of dose). Repeated dose of 20 mg/kg: urine (70%) and feces (10%) 1000 mg/kg: urine (10% ) and feces (66-78%) Urinary metabolite by TLC: M-4 [N-(3'-hydroxyphenyl)-2- (trifluoromethyl) benzamide] Fecal metabolite by TLC: Main ly parent chemical with

limited conversion to M-4.

870.7600 Dermal penetration

- Rat Not available Not available.

870.7800 Immunotoxicity Not available. Immunotoxicity Required.31 of 32 Appendix C: Toxicology St udy Requirements Rationale

Guideline Number: 870.6200 Study Title : Neurotoxicity Battery (Acute and Subchronic Studies)

Test Substance: Flutolanil Rationale for Requiring the Data

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

The Neurotoxicity Screening Batte ry (OPPTS 870.6200) is designed to evaluate the potential adverse effects on the nervous system from exposure to pes ticide chemicals. The Ag ency believes that the guideline studies are inadequate in their assessment of behavioral effects and do not use optimal methods to evaluate the potential toxicity to the ne rvous tissue structure and function. To detect and characterize these potential effects more fully, a battery of more sensitive testing is required. The objective of this neurotoxicity battery testing is to evaluate the incidence and severity of the functional and/or behavioral effects, the level of motor activit y, and the histopathology of the nervous system. The

acute neurotoxicity study is required to detect possible eff ects resulting from a single exposure. The subchronic neurotoxicity study is intended to detect possible effects resulting from repeated or longterm exposures.

Practical Utility of the Data

How will the data be used?

The acute and subchronic neurotoxicity studies provi de critical scientific information needed to characterize potential hazard to the human populatio n on the nervous system from pesticide exposure. These studies can provide data on a wide range of functional tests for evaluating neurotoxicity including sensory effects, neuromuscular effects, learning and memory and histopathology of the nervous system For example, animal studi es with organophosphorous chemicals have shown neurotoxicity to be the primary toxic endpoints (e.g ., cholinesterase inhibition) of concern in rodents

and non-rodents. These animal studies can be u sed to select endpoints and doses for use in risk assessment of all exposure scenarios and are consider ed a primary data source for reliable reference dose calculation. The Agency has established an or al reference dose (RfD) for assessing dietary risks for a number of chemicals (e.g., organophosphates and carbamates) where neurotoxicity was the most sensitive endpoint of concern.

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

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

If the Agency does not have this data, a 10X database uncertainty factor may be applied when conducting a risk assessment using the currently available studies.32 of 32 OPPTS Guideline Number: 870.7800 Study Title: Immunotoxicity

Test Substance: Flutolanil Rationale for Requiring the Data The immunotoxicity study is a new data requi rement under 40CFR §158 as a part of the data requirements for registration of a pesticide (food and non-food uses). The Immunotoxicity Test Guideline (OPPTS 870.7800) prescribes functional immunotoxicity testing, and is designed to evaluate the potential of a repeated chemical exposure to produce adverse effects (such as suppression) on the immune system. Immunosuppression is a deficit in the ability of the immune system to respond to a challenge of bacteria l or viral infections, such as tuberculosis (TB), Severe Acquired Respiratory Syndrome (SARS), or neoplasia. Because the immune system is highly complex, studies not specifically conducted to assess immunotoxic endpoints are inadequate to characterize a pesticide’s potential immunotoxicity . While data from hematology, lymphoid organ weights, and histopathology in routine chronic or subchronic toxicity studies may offer useful information on potential immunotoxic effects, th ese endpoints alone are insufficient to predict immunotoxicity. Practical Utility of the Data

How will the data be used? Immunotoxicity studies provide critical scientific information needed to characterize potential hazard to the human population on the immune system from pesticide exposure. Since epidemiologic data on the effects of chemical exposures on immune parameters are limited, and are inadequate to characterize a pesticide’s potential immunotoxicity in humans, animal studies are used as the most sensitive endpoint for risk assessme nt. These animal studies can be used to select endpoints and doses for use in risk assessment of all exposure scenario s, and are considered a primary data source for reliable reference dose calculation. For example, an imal studies have demonstrated that immunotoxicity

in rodents is one of the more sensitive manifesta tions of TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) among developmental, reproductive and endocrinolog ic toxicities. Additionally, the EPA has established an oral reference dose (RfD) for tributyltin oxide (TBT O), based on observed immunotoxicity in animal studies (IRIS, 1997).

How could the data impact the Agency's future decision-making? If the immunotoxicity study shows that the test material poses either a greater or a diminished risk than that given in the interim decision’s conc lusion, the risk assessments for the test material may need to be revised to reflect the magnitude of potential risk derived from the new data. If the Agency does not have these data, a 10X database UF may be applied for conducting a risk

assessment from the available studies.