Page 1 of 78 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460 OFFICE OF CHEMICA L SA FETY AND P O LLUTION PREVENTION MEMORANDUM Date: January 4 , 2011 SUBJECT: Revised Fluazifop - P - Butyl . Amended Human Health Ris k Assessment to Support Use on

Bananas, Citrus, Grapes, Sugar Beets, and the E stablishment of a T olerance on Imported Potatoes. PC Code: 122809 DP Barcode: 385178 Decision No.: 423996 Registration No. : 100 - 1001 Petition No.: 9F7624 & 9E7651 Regul atory Action: New Use Registration Risk Assessment Type: Human Health Case No.: 2285 T XR No.: NA CAS No.: 79241 - 46 - 6 MRID No.: 47874601 - 06 & 47920401 - 05 40 CFR: 180. 411 FROM: Peter Savoia , Chemist

Sey ed Tadayon, Chemist William A. Irwin, PhD, Tox icologist Danette Drew , Chemist R isk Assessment Branch V Health Effects Division (7509P) THRU: Jack Arthur , Branch Chief

Risk Assessment Branch V Health Effects Division (7509P) TO: Kathry

n Montague /Michael Walsh , RM Herbicide Branch Registration Division (750 5 P) This risk assessment revises the September 1, 2010 version (D371092) by providing a more complete characterization of uncertainties/data gaps. Sy ngenta Crop Protection, Inc. has submitted petition No. 9F7624 requesting t o allow for the use of fluazifop - P - butyl (PC Code 122809) on bananas, citrus, grapes, and sugar beets. In addition to these new crop uses, S yn genta has also submitted petition No. 9E7651 which proposes that an import tolerance for fluazifop - P - butyl be est ablished on potatoes. To address these proposed new uses, this document is HED’s amended human health risk assessment incorporating the S yn genta proposed new uses . It therefore contains updated sections of the HED Human Health Risk Assessment of Septembe r 200 8 (DP No. D 347515 , P. Savoia , 0 9 / 18 /200 8 ). In doing so, the following sections which include residue chemistry , drinking water exposure, dietary exposure, aggregate risk assessment, and occupational exposure have been updated to reflect theFluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP No.: 385178

Page 2 of 78 proposed new uses. Information contained in the September 2008 risk assessment remains unchanged unless specificall y noted in this memorandum. Table of Contents 1.0 Executive Summary ................................ ................................ ................................ ............ 4 2.0 Background ................................ ................................ ................................ ....................... 1 1 3.0 Summary

of Proposed Uses ................................ ................................ .............................. 1 1 4.0 Hazard Characterization and FQPA Considerations ................................ ......................... 1 2 4.1 Toxicology

Studies Available for Analy sis ................................ .......................... 1 3 4.2 Absorption, Distribution, Metabolism and Elimination (ADME) ........................ 1 4 4.2.1 Dermal Absorption ................................ ................................ ................................ 1 5 4.3 Toxicological Effects ................................ ................................ ............................ 1 6 4.4 FQPA Safet y Factor ................................ ................................ .............................. 1 7 4.4.1 Completeness of toxicology Database ................................ ................................ .. 1 8 4.4.2 Evidence of Neurotoxicity ................................ ................................ .................... 19 4.4.3 Evidence of Sensitivi ty /Suspectibility

in the Developing or Young Animal ....... 19 4.4.4 Residual Uncertaint y in Exposure Database ................................ ......................... 2 0 4.4.4.1 HED’s Levels of Concern (LOC) ................................ ................................ ......... 2 1 4.5 Tox icity

Endpoint and Point of Departure Selections ................................ .......... 2 1 4.5.1 Dose - Response Assessment ................................ ................................ .................. 2 3 4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment ...... 2 3 4.5.3 Cancer Classification and Risk Assessment Recommendation ............................ 2 3 4.5.3.1 Carcenogenic Potential in Rats ................................ ................................ ............. 2 4 4.5.3.2 Carcenogenicity

S yud y i n Hampsters ................................ ................................ ... 2 6 4.5.3.3 Classification of Carcenogenic Potential ................................ .............................. 2 7 4.5.4 Summary

of Points of Departure And Toxicity Endpoints Used In Human Risk Assessment ................................ ................................ ................................ ............ 2 7 4.6 Endocrine Disruption ................................ ................................ ............................ 2 8 5.0 Metabolism ................................ ................................ ................................ ....................... 29 5.1 Nature of the R esidue - P lants ................................ ................................ .............. 29 5.2 Nature of the R esidue - Animals ................................ ................................ ........... 29 5.3 Meat, M ilk, P oultry and E ggs ................................ ................................ ................. 29 5.4 Analy

tical M eth ods ................................ ................................ ................................ . 3 0 5. 5 Storage S tability Update ................................ ................................ ....................... 3 0 5. 6 Magnitude of R esidue in F ood Update ................................ ................................ . 3 1 5. 7 Processing F actors ................................ ................................ ................................ 3 4 5. 8 Rotationa l C rops ................................ ................................ ................................ ... 3 7 5. 9 Proposed and R ecommended T olerances ................................ ............................ 3 7 6.0 Exposure Characterization/Assessment Section Update ................................ .................. 39 6.1 Dietary E xposure/P athway ................................ ................................ .................... 39 6.1.1 Acute and C hronic D ietary E xposure and R isk Update ................................ ........ 39 7.0 Water Exposure Risk/Pathway ................................ ................................ ......................... 4 1 8.0 Residential Exposure Risk Characterization ................................ ................................ ..... 4 2 9.0 Aggregat e Risk Assessment and Risk Characterization Updates ................................ ..... 4 5 10.0 Occupational Exposure/Pathway Updates ................................ ................................ ........ 4 6 10.1 Handler E xposure and R isk ................................ ................................ .................. 4 6 10.2 Occupational P ost - Application E xposure and R isks ................................ ............ 5 1 11.0 Data Needs and Label Requirements ................................ ................................ ................ 5 3 11.1 Toxicology ................................ ................................ ................................ ............ 5 3 11.2 Residue C hemistry ................................ ................................ ................................ 5 3Fluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP No.: 385178

Page 3 of 78 11.3 Occupational and R esidential E xposure ................................ ............................... 5 3 12.0 References ................................ ................................ ................................ ......................... 5 3 Appendix A Hazard Identification and Endpoint Selection ................................ ...................... 5 7 A.1 Toxicology

Data Requirements ................................ ................................ ............ 5 7 A.2 Toxicity

Profiles ................................ ................................ ................................ .... 59 A.3 Hazard Identification and Endpoint Selection ................................ ...................... 6 8 A.3.1 Acute Reference Dose (aRfD)

– Females Age 13 - 49 ................................ ........... 6 8 A.3.2 Acute Reference Dose (aRfD)

– General Population ................................ ........... 6 8 A.3.3 Chronic reference Dose (cRfD) ................................ ................................ ............ 6 9 A.3.4 In cidental Oral Exposure (Short - and Intermediate - Term) ................................ ... 6 9 A.3.5 Dermal Exposure (Short - , Intermediate - , and Long - Te rm) ................................ .. 70 A.3.6 Inhalation Exposure (Short - , Intermediate - , and Lo ng - Term) .............................. 72 A.4 Executive Summaries ................................ ................................ ............................ 73 A.5 Toxicology

Data Required as a Condition of Regis tration ................................ ... 7 4Fluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP No.: 385178

Page 4 of 78 1.0 Executive Summary Fluazifop - P - butyl [(

R ) - 2 - (4 - ((5 - (trifluorometh yl ) - 2 - py ridinyl)ox y) phenox y)propanoic acid, but yl ester] is a selective herbicide used for the post - eme rgence control of perennial and annual weed grasses. It works b y interfering with fatty acid s ynthesis by inhibiting the enzy

me acet yl CoA carbox yl ase, an adenosine triphosphate (ATP) dependent enzy me. It accumulates in the meristems of roots and shoots, root rhizomes and stolons in susceptible plants. This active ingredient is the resolved isomer (R enantiomer) of fluazifop - butyl (PC code 122805) which has since been cancelled resulting in only fluazifop - P - but yl to be supported for re - registration. Flu azifop - P - butyl end - use products are registered in the United States to Sy ngenta Crop Protection, Inc. under the trade names Fusilade ® , Fusion ® , Oramec ® , Tornado ® , and Ty phoon ®

. F luazifop - butyl isomers are List B chemicals with parent and fluazifop - aci d (free and conjugated) regulated for tolerance expression as the residues of concern used to determine misuse (DP No. D319907, S. L . Kinard, 08/17/20 05). Itis currently registered for use on asparagus, carrot, coffee, cotton, endive (escarole), garlic, macadamia nut, onion, pecan, pepper, rhubarb, soy beans, stone fruits, sweet potato, and yam. It is also currentl y registered for use on lawns as a weed control application . Tolerances are established under 40 CFR §180.411(a) for residues of the herbicid e fluazifop - P - butyl which include both the free and conjugated forms of its resolved isomer expressed as fluazifop. There are no Section 18 emergency exemptions in effect but fluazifop - P - butyl t olerances are likewise established under 40 CFR §180.411(c) wh ich carry regional restrictions expressed as fluazifop. To further develop the use of fluazifop - P - but yl , S yngenta has submitted petition No. 9F7624 for establishing permanent tolerances in/on bananas, citrus, grapes, and sugar beets. The end - use product relevant for this petition request is Fusilade® DX Herbicide (EPA Reg. No. 100 - 1070), an e mulsifiable c oncentrate formulation containing 24.5% ai of fluazifop - P - butyl (equivalent to 2 lb ai/gal). It is proposed for use as multiple foliar or viney ard/orch ard floor applications made at maximum seasonal rates of 1.125 lb ai/A for bananas, grapes, and citrus and 0 .75 lb ai/A for s ugar beets . Applications are to be made with an adjuvant using ground or aerial equipment at P re - H arvest Inter vals (PHIs) which range from 0 day s on treatments made to bananas up to 90 day s for sugar beet s. In addition, petition No. 9E7651 is also being put forward by Sy ngenta which requests that an import tolerance for fluazifop - P - butyl be established on potatoes. The end - use prod ucts relevant for this petition request are the VENTURE L and Fusilade® MAX(X) h erbicide E mulsifiable C oncentrate (EC) formulation s. These end - use products are identical with both of them containing approximately 1 4. 0 % fluazifop - P - butyl active ingredient (ai) equivalent to 125 g ai / L. For this action, Sy ngenta has requested to amend the label of the VENTURE Lproduct by adding this new use on potatoes in Canada . Treatments of these products are to be made as a single foliar spray application not to excee d the maximum labeled rate of 250 g ai/ha timed at PHI s of 45 or 90 day s. T his HED document provides a summary of the findings from the data evaluation and subsequent assessment of human health risk resulting from th ese submission s . Prior actions made to develop the fluazifop - P - butyl herbicide active ingredient (ai) have identified a number of studies that are required for completing data gaps. In accordance, a number of Data Call - In (DCI) submissions have been provided b y the registrant in order to sati sfy these database requirements. These studies are as follows:Fluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP No.: 385178

Page 5 of 78 • Carrot and endive nature of residue studies, test guideline 860.1300. • Ruminant and poultry

nature of residue studies, test guideline 860.1300. • Radiovalidation study

made for the tol erance enforcement method proposed for analyzing plants, test guideline 860.1340. • Method validation study made for the tolerance enforcement method proposed for anal yz ing poultry , eggs and livestock, test guideline 860.1340. • Cattle and poultry

feeding studies, test guideline 860.1480. • Confined rotational crop study , test guideline 860.1850. An assessment of these studies is currentl y in progress and when completed, will be addressed in a separate memorandum. Should the resu lts of the studies submitted in response to the registration DCI impact the conclusions reached in this summation, appropriate changes will be made at that time. Hazard Assessment Fluazifop - P - butyl has low acute toxicity by the oral, dermal and inhalat ion routes, and mildly

irritating to the ey e and skin, and is not a skin sensitizer. Sub - chronic and chronic toxicity

studies with fluazifop - P - butyl show that the rat is more sensitive to toxic effects than the dog, rabbit or hamster, possibly due to longe r retention time of the major metabolite (fluazifop acid) in the rat. The liver and kidney are the target organs and the toxicity

is expressed as liver toxicity in the presence of peroxisome proliferation and exacerbation of age related kidney toxicity . An acute dietary endpoint for females 13 - 49 y ears of age was selected from a developmental toxicity study in rats, based on diaphragmatic hernia (LOAEL=50 mg/kg/day) . No appropriate endpoint attributable to a single dose was identified for the general U.S. p opulation. The short - term incidental oral endpoint was selected from the developmental toxicity studies in rats and is based on maternal body weight gain decrement (NOAEL=100 mg/kg/day) . The chronic dietary

(all populations), intermediate - term dermal and i nhalation, and intermediate term incidental oral en dpoints were selected from the two - generation reproduction study in rats based on decreased spleen, testes and epididy mal weights in males, and decreased uterine and pituitary weights in females (NOAEL=0.7 4 mg/kg/day) . This endpoint was also utilized for the intermediate & long term dermal and inhalation exposures (1 to >6 months). The short - term dermal and inhalation endpoints used in the assessment were selected from the developmental toxicity studies in rats based on decreased fetal weights, hydroureter and delay ed ossification (NOAEL=2 mg/kg/day) . Though this endpoint was selected b y the Hazard Identification Risk Assessment Committee specificall y for females 13 - 49 y ears of age, and a separate, higher, d ose/endpoint was selected for all other population sub - groups from the developmental toxicity studies in rats, based on mate rnal weight gain decrement, HED chose to use the female - specific endpoint for all population sub - groups. By using the lower dose/end point approach for all population sub - groups, the risk assessment is protective of the toxic effects seen at higher doses. Because o ral NOAELs were selected for dermal and inhalation endpoints, d ermal absorption factors, calculated from a dermal absorption and pharmacokinetic study in humans, of 2% for high exposures and 9% for low exposures were used for oral - dermal route - to route extrapolation, and 100% absorption was used for inhalation exposure. Fluazifop - P - butyl is classified as “not likel y t o be carci nogenic to humans” and no mutagenic potential was observed in adequate in vivo and in vitro studies with fluazifop - P - butyl.Fluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP No.: 385178

Page 6 of 78 Though increased susceptibility of offspring was observed in rats, the degree of concern is low. The endpoint of concern (delay ed ossifications) is a well defined endpoint based on five developmental toxicity

studies and the NOAEL/LOAEL(s) are much lower dose levels than resulted in the malformations. A developmental e ndpoint of concern for a single - dose effect (diaphragmatic hern ia) is used for assessing acute dietary risk. However, the 2 - generation reproduction study in rats did not reveal increased susceptibility of the offspring. No increased offspring sensitivity over parent was seen the rabbit pre - natal developmental studies or the post - natal reproduction study Therefore, there is no residual uncertaint y for pre and/or post natal toxicity . The Assessment team concluded that there was not a concern for neurotoxicity resulting from exposure to fluazifop - P - butyl at relevant expos ure levels. There was no evidence of clinical signs indicative of neurotoxicity , neuropathology or immunotoxicity in the available studies. Marginal increases in brain weights at termination were seen in a sub - chronic toxicity study in rats and a carcinoge nicity study in hamsters, but only at high doses. HED concluded that there is not a concern for developmental neurotoxicity resulting fro m exposure to fluazifop - P - butyl . T he Agency concluded that the t oxicolo gy database is complete for FQPA assessment and that outstanding studies are not likely to have an endpoint of less than 0.74 mg/kg/day . T herefore, the FQPA 10X uncertaint y factor need not be retained for susceptibility or data base uncertainty concerns. Residue Chemistry The Fluazifop - P - Butyl Residu e Chapter of the TRED (DP No. 319907, S. L. Kinard, 08/17/2005) concluded that the nature of the residue in soy beans is adequatel y understood. No new plant metabolism studies for the proposed new use crops were submitted as part of the current petition. It has been concluded that for tolerance expression, parent and fluazifop - acid (free and conjugated) are the residues of concern since they are adequate to determine misuse (DP No. D298939, S. L . Kinard, 06/22/2004). For this action, there are no residue chemistry issues that would preclude the conditional registration of the requested uses of fluazifop in/on bananas, citrus, grapes and grape processed commodities, or sugar beet. An unconditional registration may be appropriate upon determination of the a dequacy

of a new citrus processing study . In regard to the establishment of a tolerance for fluazifop - P - butyl in/on imported potato commodities, registration can be granted for this requested use. T here are adequate anal yt ical methods available for carrying out data collection efforts and enforcing all recommended tolerances. Residential Exposure and Risk Estimates Short - term (1 - 30 day s) r esidential exposure may occur from its use in post - emergent control of weed grasses on turf

. For adults, exposure may occur from homeowner appl ication of fluazifop - P - butyl products (dermal and inhalation routes ) and from contact with treated turf (dermal) following a pplication. For children, p ost - application exposures (dermal and incidental oral) can occur from contact with treated turf. Adult applicator and post - application risks were combined in the assessment. Likewise, risks to children from dermal plus hand - to - mouth, object - to - mouth, and soil ingestion exposures were combined for scenarios involving post - applicat ion contact with treated turf . For fluazifop - P - but yl , residential risk estimates were determined using the Margins of Exposure (MOEs) approach made as a ratio of the toxicological point of departure to the body burden. By means of this technique, aggre gate risk estimates were made using the most conservative endpoints, high - end exposures, and worst - case scenarios. Estimated risks for residential handlers and short - term post - application exposures, as well as those involving children, all yielded MOEs ab ove 100 which are not of concern to HED .Fluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP No.: 385178

Page 7 of 78 B ased upon these proposed new uses for this action, the existing residential fluazifop - P - butyl use patterns will not be affected. As a result, HED’s most recent residential risk assessment will require no revisi on with its conclusions remaining relevant and appropriate (DP No. D291905 , M . Collantes, 11/29/2004) . Dietary Exposure and Risk Estimates Revised acute and chronic dietary exposure assessments using the version 2.03 Dietary Exposure Evaluation Mo del (DEEM - FCIDTM) were subsequently conducted for fluazifop - P - butyl (DP No. D3 79452 , S. Tadayon, 0 8 / 09 /20 1 0) . This modeling effort uses food consumption data from the U.S. Department of Agriculture’s Continuing Survey s of Food Intakes by Individuals (CSFII) fr om 1994 - 1996 and 1998 to calculate dietary risk. These analy ses were performed to support the Section 3 registration of fluazifop - P - butyl on bananas, citrus, grapes and grape processed commodities, as well as sugar beets . A lso include d in this determinat ion are all uses which would be relevant to the establishment of an import tolerance made for fluazifop - P - butyl on potatoes . The proposed new crop uses were added into the residue file for all previously registered commodities so that a current evaluation of dietary

exposure could be made. The resulting acute and chronic risk assessments which include both food and water are conservative evaluation s. Tolerance level residues with ratio adjustment to account for additional metabolites of concern were us ed with the a ssumption that 100% of all crops are treated to perform an unrefined acute anal ys is. DEEM 7.81 processing factors were utilized for an y applicable commodities to reflect the possible altering of residue levels through the manufacture of other food forms such as meal and flour. For all other commodities, the default adjustment factor of 1.0 was used to weight the processing effects of alternate food forms. In conjunction, percent crop treated estimates determined by BEAD along with the averag e residue levels observed in the applicable field trial studies with ratio adjustment was used to carry out the refined chronic anal ys is. Default processing factors along with the measured peanut and soy bean processing factors were used to weight the effe cts of alternate food forms for chronic assessment. For both determinations, drinking water considerations we re incorporated directl y into these anal ys e s using the Estimated E nvironmental Concentrations ( EECs) g enerated by

EFED to complete the combined di etary exposure assessment s . The a cute and chronic dietary risk analy ses performed herein with the DEEM - FCIDTM model form a careful evaluation of exposure for f luazifop - P - butyl . The acute dietary assessment was limited to the females 13 - 49 y ears of age population subgroup. This is the only population subgroup for which an appropriate toxic endpoint attributable to a single dose was identified. For females 13 - 49 y ears of age, acute dietary

risk was estimated to be only 13 % of the aPAD with an exposure of 0.0641 mg/Kg/day . In conjunction, the refined chronic analy sis likewise yielded risk estimates wel l below the 100% of the cPAD threshold level of concern for each population subgroup. For the most highly exposed population subgroup , children 1 - 2 y ears of age, chronic dietary risk was estimated to be 40% of the cPAD with an exposure of 0.0030 mg/Kg/day . Inall, the dietary risks for combined food and drinking water exposure from the proposed expanded uses of fluazifop - P - butyl are not of concern.Fluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP No.: 385178

Page 8 of 78 Drinking Water Exposure and Risk Estimates The potential human exposure to fluazifop - P - butyl in drinking water was likewise re - evaluated b y EFED to support the proposed new crop uses being requested b y S yn genta for risk assessment purposes. For this assessment, EECs in both ground and surface water were estimated using the Tier I SCI GROW and Tier II P RZM/EXAMS models, respectivel y (DP No s . D 371093 & D3 7 1094 , W. J Shaughness y , 0 5 /25 /20 1 0) . These modeling efforts indicate that the most significant levels of fluazifop - P - butyl would likely be found in surface water resulting from applications made to bananas and plantains. Corresponding drinking water levels of fluazifop - P - butyl resulted in estimated concentrations of 3 3. 4 μg/L and 6. 6 μg/Lfor acute and chronic exposures respectivel y. As such, these concentration estimates provided b y EFED indicate that the proposed new uses would result in greater water exposures relative to those which were previously determined. However, as stated above, when combined with exposures through food, combined drinking water and food exposures are not of concern. Aggre gate Exposure and Risk Estimates To ensure risk characterization efforts are all inclusive, HED aggregate d the exposures/risks from food, drinking water, and residential (oral, dermal & inhalation) sources. This evaluation is ty pically made b y adding toge ther the exposures from each source for comparison to a quantitative estimate of hazard (NOAEL, PAD, etc.), or just by simpl y aggregating the risks themselves. When aggregating various sources of exposures and risks, HED gives consideration to both the ro ute and duration of exposure. For this action, the proposed new uses of fluazifop - P - butyl were found to slightly increase total exposures through food, and significantly increase exposures through drinking water. Based upon this outcome, the impact on dietary exposure is the only

occurrence which would necessitate updating the current aggregate short - term risk assessment in place for this herbicide. To complete this evaluation, aggregate risk assessments were carried out for the most likely exposur e scenarios resulting from the existing and expanded uses of fluazifop - P - but yl . These scenarios are for combined acute (1 - day) exposures made through food and drinking water, as well as combined chronic exposures occurring through food and drinking water. In addition, the short - term aggregate exposures resulting from food, drinking water, and residential uses were considered. In making this characterization, estimates of aggregate risk from combined acute (1 - day) fluazifop - P butyl expo sures occurring in food and drinking water were determined with DEEM - FCIDTM modeling. DEEM - FCIDTM modeling was also used to determine estimates of aggregate risk from combined chronic fluazifop - P - but yl exposures in food and drinking water as well. A detailed discussion of these findings evaluating the expanded use of f luazifop - P - butyl is therefore provided in the Section 6.1.1 Acute and Chronic Dietary Exposure and Risk Update of this memorandum. As for the short - term (1 - 30 day s in duration) aggregate risk assessment, it was made as an estimate of potential exposures f rom food, drinking water, and home lawns. High - end estimates of exposure resulting from treatment of lawns along with average exposures from food and drinking water were used to form this evaluation . For this short - term aggregate risk assessment, aggregate MOE s of 150 for adults and 250 for children (1

– 2 y ears of age) were obtained which are well above the level of concern of 100 indicating there are no concerns resulting from the proposed expanded uses of fluazifop - P - butyl.Fluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP No.: 385178

Page 9 of 78 Occupational Exposure Estimates The new crop uses proposed with this petition are for the Fusilade® DX Herbicide (EPA Reg. No. 100 - 1070), an EC formulation containing 24.5% ai of fluazifop - P - butyl (equivalent to 2 lb ai/gal). It s expanded use will employ multiple foliar or v ineyard/orchard floor applications at maximum seasonal rates of 1.125 lb ai/A for bananas, grapes, and citrus and 0 .75 lb ai/A for s ugar beets . Applications are to be made using an adjuvant and applied with either ground or aerial equipment. Lab eling ins tructions propose PHIs for the requested new uses which range from 0 day s on treatments made to bananas up to 90 day s for sugar beet applications . Inaccordance, occupational handlers and post application workers can become exposed to fluazifop - P - butyl at short - or intermediate - term durations through its use. For the new crop uses being proposed in this action, the expanded use of fluazifop - P - butyl will support commercial agricultural efforts in controlling grass weeds through limited foliar application. Occupational exposures/risks were addressed in the prior HED human health risk assessment made to support the new uses to dry beans and peanuts (DP No. D347515, P. Savoia, 09/18/2008). For this current action, a new evaluation of the occupational expos ure/risk pathway was performed herein to ensure worker protection safeguards (DP No. D 379451 , S. Tadayon, 0 6 /23 /2008) . Th is accounts for potential exposure to fluazifop - P - butyl during mixing, loading, and application activities pertinent to the existing and proposed new uses . Most occupational activities will involve worker contacts with the herbicide requiring the consideration of dermal and inhalation exposure when evaluating risk. Dermal absorption factors of 2% and 9% were determined for fluazifop - P - but yl depending on high versus low levels of exposure respectivel y. R e - entry

intervals have been assessed using both values . HED believes that prior dermal absorption studies demonstrate saturation of the skin if the mass per unit area exceed s a certai n level . Given this, use of the 9% factor in combination with high levels of exposure would result in a conservative estimate of risk . No long - term exposures are expected for the general agricultural use - patterns of fluazifop - P - butyl , therefore, no long - term risks were assessed. Estimated risks for occupational handlers determined for short - /intermediate - term exposures yielded total MOEs greater than 100 , with some scenarios requiring additional personal protection above baseline (e. g., engineering controls for mixer/loaders) . In reaching or e xceed ing the L OC of 100 , the resulting MOEs indicate these risks are not of conc ern. Most of the proposed new uses are ground directed applications where no crop foliage is being treated. Curr ently , HED has no Transfer Coefficients (TCs) or other data to assess post - application dermal exposures to soil by

occupational workers. As a result, this post - application exposure and risk to occupational workers w as not quantitatively assessed. However , in assessing the applications made to sugar beets and potatoes where workers can come in contact with foliage, these risks are not of concern since the resulting MOEs where found to exceed 100.Fluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP No.: 385178

Page 10 of 78 Environmental Justice Potential areas of envi ronmental 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 L ow - Income Populations," http://www.epa.gov/compliance/resources/policies/ej/exec_order_12898.pdf . The Office of Pesticide Programs (OPP) ty

pically considers the highest potential exposures from the legal use of a pesticide when conducting human health risk assessments, including, but not limited to, people who obtain drinking water from sources near agricultural areas, the variability of diets within the U.S. (including different ages, regio ns, and ethnicities), and people who may be exposed when harvesting crops. Should these highest exposures indicate potential risks of concern, OPP further refines the risk assessments to ensure that the risk estimates are based on the best available information. Cumulative FQPA requires that EPA consider “available information” concerning the cumulative effects of a particular pesticide’s residues and “other substances that have a common mechanism of toxicity .” The Agency considers other substances bec ause low - level exposures to multiple chemical substances that cause a common toxic effect b y a common mechanism could lead to the same adverse health effect, as would a higher level of exposure to any of the substances individually . Risks summarized in thi s document are those that result only from the use of fluazifop . The Food Quality Protection Act (FQPA) requires that the Agency consider “available information” concerning the cumulative effects of a particular pesticide’s residues and “other substances that have a common mechanism of toxicity .” 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 fluazifop and an y other substance s. In addition, fluazifop does not appear to produce a toxic metabolite produced b y other substances which have tolerances in the U.S. Therefore, for the purposes of tolerance reassessment, EPA has not assumed that fluazifop shares a common mechanism of to xicity with other compounds. Recommendations for Tolerances/Registration Provided the petitioner submits revised Sections B and F (see Section 11.0), HED concludes that the toxicological, residue chemistry and occupational/residentia l databases support a conditional registration and establishment of permanent tolerances for the proposed new uses of fluazifop - P - butyl . Tolerances are to be established for residues of the herbicide fluazifop - P - butyl, including its metabolites and degradates, in or on the commodities listed below. Compliance with the tolerance levels specified below is to be determined b y measuring onl y the sum of fluazifop - P - butyl, butyl(R) - 2 - [4 - [[5 - (trifluoromethyl) - 2 - py ridinyl]oxy]phenoxy]propanoate, and the free and c onjugated forms of the resolved isomer of fluazifop, (R) - 2 - [4 - [[5 - (trifluoromethyl) - 2 - py ridinyl]oxy]phenoxy]propanoic acid, calculated as the stoichiometric equivalent of fluazifop, in or on the commodity .

Banana ................................ ................................ .................. 0.01 ppm Fruit, c itrus , group 10 ................................ ........................... 0.03 ppm Citrus, oil ................................ ................................ ............ 30.0 ppm Citrus, dried pulp ................................ ................................ . 0. 40 ppm Citrus, juice ................................ ................................ .......... 0.06 ppm Grape ................................ ................................ .................... 0.01 ppm Beet, sugar, root ................................ ................................ ... 0.25 ppm Beet, sugar, dried pulp ................................ ......................... 1.0 ppmFluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP No.: 385178

Page 11 of 78 Beet, sugar, molasses ................................ ........................... 3.5 ppm Potato ................................ ................................ ................... 1.0 ppm P otato, chips ................................ ................................ ......... 2.0 ppm P otato, granules/flakes ................................ ......................... 4.0 ppm Registrati on of these tolerances should be made conditionally until the remaining data deficiencies described in Section 11.0 are satisfied. An unconditional registration may be appropriate upon determination of the adequacy of a new citrus processing study ( see re quirements under Processed Food and Feed). 2.0 Background In August of 2005, HED completed a human health risk assessment of the fluazifop - P - butyl herbicide active ingredient for Tolerance Reassessment Eligibility Decision (DP No. D316891, D. Locke, 0 8/29/2005). Following this risk assessment, Sy ngenta Crop Protection, Inc. s ubmitted petition No. 7F7289 which requested to allow for the post - emergence use of fluazifop - P - butyl on dry beans and peanuts. Along with these two new crop uses, the registrant a lso proposed in this petition to allow fluazifop - P - butyl treatments made on soy beans to include post - bloom application. In response to this action, HED has conducted a subsequent risk assessment to support all existing uses as well as the new crop treatments which were requested (DP No. D347515, P. Savoia, 09/18/2008). For this current registration action, new data characterizing the magnitude of the residue in plants were appropriatel y provided by the registrant to support the additional crop uses whi ch are being proposed. T here were no new toxicological studies, public health, residential, or occupational data provided in the Sy ngenta submission. Therefore, the presentation of the toxicity database, points of departure, and hazard characterization p resented in section 4.0, while more streamlined, are substantively the same as those appearing in recent previous assessments. The assessment of residential exposures and risks are similarly based upon the relevant information provided in the August 2005 tolerance reassessment (DP No. D316891, D. Locke, 08/29/2005). T o establish permanent tolerances for residues of fluazifop - P - butyl on banana , citrus, grape , and sugar beet RACs as well as an import ed potatoes, this memorandum updates the prior risk ass essments noted . It provides residue chemistry , dietary exposure, aggregate risk assessment, and occupational risk assessment updates to reflect the new crop uses which are being proposed. In doing so, all information and/or conclusions contained in the August 2005 and September 2008 HED human health risk assessment s will therefore remain unchanged unless otherwise noted in this memorandum. 3.0 Summary of Proposed Uses The expanded use of fluazifop - P - butyl will utilize the Fusilade® DX Herbicide for multipl e foliar or viney ard/orchard floor applications at maximum seasonal rates of 1.125 lb ai/A for bananas, grapes, and citrus and 0 .75 lb ai/A for s ugar beets . This product can be applied with an adjuvant using ground or aerial equipment at PHI s which range from 0 day s on treatments made to bananas up to 90 day s for sugar beet applications . For the new use requested on potatoes, the VENTURE Lproduct will be utilized as a single foliar spray not to exceed the maximum labeled rate of 250 g ai/ha timed at a PH I of 45 or 90 day s. In using this product , spray mist and drift is to be avoided with applications never to be made b y aircraft or within 15 m of fish bearing waters. A detailed summary of the proposed new uses on bananas, grapes, citrus, potatoes and su gar beets is presented below in Table 1 for review .Fluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP No.: 385178

Page 12 of 78 Table 1 . Summary of Directions for Use of Fl uazifop - P - butyl . Applic. Timing, Type, and Equip. Formulation

[EPA Reg. No.] Maximum

Applic. Rate (lb ai/A) Max. No.

Applic. per Season Max. Seasona l

Applic. Rate (lb ai/A) PHI

(days) Use Directions and

Limitations Banana Ground and Aerial. Fusilade® DX Herbicide, 2 lb/gal EC [100 - 1070] 0.375 3 1.125 0 A minimum 30 - day RTI is specified . Citrus Ground and Aerial. Fusilade® DX Herbicide, 2 lb/gal EC [100 - 1070] 0.375 3 1.125 14 A minimum 21 - day RTI is specified. Grape Ground and Aerial. Fusilade® DX Herbicide, 2 lb/gal EC [100 - 1070] 0.375 3 1.125 50 A minimum 14 - day RTI is specified. Sugar Beet Ground and Aerial. Fusilade® DX Herbicide, 2 lb/gal EC [100 - 1070] 0.375 2 0.75 90 A minimum 14 - day RTI is specified. Potato Post - emergence Ground. Venture L® Herbicide, 125 g ai/L EC [ Canadian Reg. No.: 21209 ] 0.275 1 0.275 45 or 90 May be mixed with Lexone or sencore formulations for early post emergent application. The general label use directions of the Fusilade® DX Herbicide specify that: (1) adjuvants (crop oil concentrate, non - ionic surfactant, or other approved adjuvants) plus liquid nitrogen fertilizer may be used on soy

beans; (2) ground and a erial applications are to be made in a minimum of 5 gal/A; (3) for chemigation (sprinkler irrigation), adjuvants are not to be used in the manner described for use in conventional applications or applied with a s ys tem connected to a public water s ys tem; an d (4) the restricted - entry

interval is 12 hours. Rotational grass crops such as corn, sorghum and cereals are not to be planted within 60 day s of last application. For the VENTURE L product, general label use directions specify that it will be less effec tive when weeds are not growing rapidly because of stress from lack of moisture, excessive moisture, flooding, low temperature and/or very low humidity . Treatments should be applied to activel y growing grass weeds that have 3 to 5 fully developed leaves f

or best results. Spray

mist and drift is to be avoided with applications never to be made b y aircraft or within 15 m of fish bearing waters. The use of adjuvants (crop oil concentrate, non - ionic surfactant, or other approved adjuvants) plus liquid nitrog en fertilizer may

be used on specified crops such as soy beans and potatoes . 4.0 Hazard Characterization and FQPA Considerations The 2005 risk assessment contained a thorough description of toxicology profile for fluazifop - P - but yl (DP No. D316891, D. Lo cke, 08/29/2005). The data base is adequate for FQPA assessment, endpoint selection, and do se - response evaluation for fluazifop - P - butyl and the fluazifop mixed isomers.Fluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP No.: 385178

Page 13 of 78 4.1 Toxicology Studies Available for Analysis The toxicity

data base on fluazifop - butyl is essentially complete with sufficient toxicity data on fluaz ifop - P - butyl to show similar responses in animal toxicity studies. The toxicity database is adequate for FQPA assessment, endpoint selection and dose - response evaluation of both products. F luazifop - P - butyl has low volatility , is not an ey e or skin irritant in acute or 21 - day dermal studies, and is not a skin sensitizer. Fluazifop - P - but yl is likely to show similar toxicity

by the inhalation route and the oral route, because it is metabolized by blood to the acid form and excreted as the acid form. The use pattern and exposure pattern for the residential handler show high MOEs, well above the level of concern using endpoints based on oral exposure. The data are relativel y consistent among th e rat with fluazifop - butyl and fluazifop - P - butyl, dog with fluazifop - butyl, and the hamst er with fluazifop - P butyl , probabl y with some within - animal variation, although all endpoints were not ev aluated with all species with fluazifop - P - butyl and its mixed isomers . Data from the following studies were used to evaluate the hazard potential of fluazifop - P - butyl: Acute: Oral, Dermal, Inhalation, Ey e and skin irritation, Dermal sensitization with

fluazifop - butyl and fluazifop - P - butyl Subchronic: Oral rat wi th fluazifop - butyl and fluazifop - P - but yl, Oral dog with fluazifop butyl, Dermal 21 - day

rabbit with fluazifop - butyl, Inhalation - no studies available. Chronic: Chronic/Cancer rat with fluazifop - butyl, Cancer hamster with fluazifop - P - butyl,

Oral dog with fluazifop - butyl Developmental: Two in the Sprague Dawley rat with fluazifop - butyl and three in the Wistar rat with fluazifop - P - butyl. One in the NZW Rabbit with fluazifop - butyl and one in the NZW rabbit with fluazifop - P - butyl. Reproduction: Two - generati on in rats with fluazifop - butyl Metabolism: Rat, human and dog with fluazifop - butyl and comparative in the rat with

fluazifop - butyl and fluazifop - P - butyl, and hamsters with fluazifop - P - butyl. Dermal Penetration: Hum an study (ethics of study

cleared) Literature Studies: Literature studies regarding information for which similar, but more detailed,

reports were submitted to the Agency .Fluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP No.: 385178

Page 14 of 78 4.2 Absorption, Distribution, Metabolism, & Elimination (ADME) Fluazifop - butyl is a herbicide with mixed iso meric [RS] content, while fluazifop - P - butyl is the purified [R] enantiomer, the only herbicide supported for re - registration. Metabolism studies have been conducted in the rat with fluazifop - butyl, and absorption, excretion and confirmatory metabol ism stu dies in the dog with fluazifop - butyl, and hamster with fluazifop - P - butyl. Comparative metabolism studies in the rat show that both fluazifop - P - butyl and fluazifop - butyl mixed isomers are rapidly hydrol yz ed to fluazifop acid and the [S] enantiomer is rapid ly converted to the [R] enantiomer in the blood, yielding similar toxicities within animal variation. Incharacterizing this herbicide active ingredient, fluazifop - P - butyl is the purified (R) enantiomer of the mixed isomeric (RS) fluazifop - butyl product. F luazifop - but yl (PC code 122805) has since been cancelled resulting in only fluazifop - P butyl (PC code 122809) currentl y being supported for re - registration. In vivo, the S - isomer quickly converts to the R - isomer. A 50:50 mixture of the two isomers quickl y converts to 97% R - isomer in vivo. Given this distinction, the toxicological data - base on fluazifop - but yl is complete with sufficient data available showing equivalence of f luazifop - butyl ( FB, PC code 122805) for fluazifop - P - but yl (FPB, PC code 122809) in animal toxicity . The toxicity data - base is therefore adequate to carry out FQPA assessment, endpoint selection, and dose - response evaluation for both chemicals. Peroxi some proliferation was shown in rat and mouse, and to a lesser extent in the hamster, i n vivo, and human liver cells, in vitro . Oral dog and female rat studies show similar results. Fluazifop - butyl is rapidly absorbed through the gut after oral dosing and the ester linkage is h ydroly zed to produce the fluazifop acid in the blood. No pare nt fluazifop - ester was detected in plasma at any time. Male rats show similar fluazifop acid excretion to the female, but excretion is slower because fluazifop is excreted in the bile, resulting in a higher % in the feces of males rats. The greater toxici ty in male rats may

be due to the longer retention time. In rats, the blood half - lives after intravenous administration ranged from 2.7 - 43 hours for 1 mg/kg and 1000 mg/kg doses, respectivel y. B ased on radio activity recovered in the urine after 1 mg/kg ora l dosing in rats, absorption was extensive in females (75 - 89%), but was less so in males (49 - 51%). Furthermore, excretion in the urine was rapid in females, 66 - 83% dose within 1 day post - dose. Conversel y, excretion was slower in males, largel y taking pla ce over a 3 day period post - dose in urine (41 - 43% dose) and feces (26 - 27% dose). Over the 7 day post - dose period in rats , relativel y little of the dose was excreted in the feces of females (3 - 11%), while 35% dose was excreted in the feces of males. Resid

ual fluazifop acid appears to be retained in the body fat (<1% to 8% in the rat) and speculated to be esterified to mono - or di - gl yc erides. This small amount of residual material , if released, was too low to be accuratel y detectable in the urine. This re sidual material is relativel y immobile and may

be toxicologically

insignificant, s ince multiple dosing studies show that fluazifop butyl does not accumulate in the body and is not a carcinogen. In hamsters dosed orall y , 72 - 82% of the administered radioacti vity was excreted by

males and 82 - 88% b y females within 12 hours of dosing. Over the 72 - hour collection period, the majorit y of the radiolabel was excreted in the urine (70 - 83% for males; 76 - 93% for females) and feces (11 - 24% for males; 10 - 16% for females ), irre spective of dose. The hamsters had low levels of radiolabel in the tissues and carcasses (0.18 - 0.43% of the given dose).Fluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP No.: 385178

Page 15 of 78 In a metabolism study

(MRID# 00131464)(Fluazifop - butyl, 99.6% a.i, Y00083/012/003) were administered to 3 male humans i n a single dose in corn oil on a sugar cube at a dose level of 0.07 mg/kg. The results from the study were consistent with the studies in rats and dogs. That fluazifop butyl is rapidl y absorbed, hydrol yz ed to the free acid and excreted mostly in the urin e as the free acid, with minor amounts of conjugates of the free acid (conjugates unidentified in humans). The one - half life in the men studied was closer to that found in female rats, which lacked the delay ed excretion characteristic of male rats possibl y being due to bi liary recycling in male rats. If the toxicity of fluazifop - butyl is related to delay ed excretion time seen in male rats, then the rapid excretion in men in the current study

may suggest that the toxicity

in men is more closel y related to the dog and female rats where the excretion time is also short. In toxicity studies in rats, toxicity

in males was alway s more severe than in females. Only hydrol yz ed fluazifop - butyl or the free acid was detectable in plasma and the free acid and its co njugate were detected in urine. The excretion of the test material was complete within 7 days, with plasma levels being undetectable within 72 - 144 hours (3 - 6 day s) and with urine levels being undetectable at 96 - 144 hours (4 - 6 day s). Total recoveries of f luazifop as the conjugate and the free acid in the urine from each of the 3 men were 80%, 93% and 92% (Mean 88.3%) of the dose and 1 - 4%, 6% and 23% as a conjugate, respectivel y. The ethics of this human study was cleared in the memo “Ethics Review of Fluazifop - But yl Absorption, Distribution and Metabolism Study” (K Sherman, August 13, 2010). 4.2.1 Dermal Absorption In a dermal absorption and pharmacokinetic study in humans (MRID# 46082918, ethics of study cleared, Lowe MF, Carley JM, June 10, 2006), six men/dose (age 18 - 45; weight 60 - 90 kg) were exposed dermally

with 2 mg or 200 mg of 0.05% or a 5.0% (w/v) solution of fluazifop - butyl in a formulation. The washes, T - shirts, plasma and urine samples were analyzed for fluazifop - but yl or fluazifop acid. Mos t of the applied dose appeared to be in the stratum corneum and easily removed (the unrecovered test material was speculated to be in the outer lay ers of the skin). Recovery of test material was good, a mean of 93.4% ± a standard deviation of 13% at the 2 mg dose and mean of 83.2% ± a standard deviation of 21% at the 200 mg dose. Peak plasma levels were shown to occur 24 to 31 hours after application in these men. The one half - life for excretion was about 18 hours. In the 2005 risk assessment, HED (D31689 1) modified the study author’s percentage absorption via scaling the amount recovered material to 100%, yielding absorption factors of 8.6% and 1.9% at the 2 mg dose and 200 mg dose, respectively .Fluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP No.: 385178

Page 16 of 78 4.3 Toxicological Effects Fluazifop - P - butyl herbicidal specificit y is by inhibiting acetyl CoA carbox ylase (a key enzy me in plant fatty

acid s ynthesis and required for maintaining membranes in functioning condition). Fluazifop - P - butyl has low volatility proving no indication of being an ey e or skin irritant in acute or 21 - day dermal studies, and is not a skin sensitizer. Fluazifop - P - butyl show s similar toxicity by both the inhalation and oral routes because of its metabolization by blood into the acid form and excretion in this manner. The liver an d kidney have demonstrated to be its target organs expressed for the most part as liver toxicity

in the presence of peroxisome proliferation and exacerbation of age - related kidney toxicity . These data are reasonabl y consistent among the rat with fluazifop - butyl and fluazifop - P - butyl, dog with fluazifop - butyl, and hamster with fluazifop - P - butyl. Although all endpoints were not tested in all species using both compounds, some disparities may be evident probably within animal variation. In general, there we re no carcinogenicity concerns in any acceptable studies in the rat with fluazifop - butyl or in the hamster for fluazifop - P - butyl. The hamster was selected for cancer study because liver peroxisome prolifieration more closely resembled what was found for human liver cells. There were no mutagenicity concerns evident for fluazifop - but yl or fluazifop - P - butyl. The current risk assessment is based on the mo st s ensitive endpoints (decreased testes and epididy mal weights in male rats and decreased pituitary an d uterine weights in females) in the most sensitive species. The reproduction study male/female NOAEL s are 0.74 and 0.88 mg/kg/day while the LOAELs are 5.8 and 7.1 mg/kg/day , respectivel y. A rat developmental study exhibiting diaphragmatic hernia effects was used as the basis to select the acute dietary

endpoint for females 13 - 49 y ears of age. In contrast, there was no appropriate endpoint which correlated to a single dose identifiable for the general U.S. population. The short - term incidental oral endp oint was selected based upon a maternal body weight gain decrement exhibited in the developmental toxicity studies performed on rats. The chronic dietary (all populations), intermediate - term dermal and inhalation, as well as the intermediate - term incident al oral endpoints, were selected from the 2 - generation reproduction study in rats. This study

was significant in exhibiting decreased testes, and epididym al weights in males along with decreased uterine and pituitary weights in females. In regard to the short - term dermal and inhalation endpoints used in this assessment, the developmental toxicity studies performed on rats were used as the basis for endpoint selection. These studies were notable in exhibiting decreased fetal weights, as well as h ydrourete r and delay ed ossification effects. In summarizing the available toxicity data on fluazifop - P - butyl, the established toxicity endpoints for risk assessment are presented below in Appendix A2 for review (DP No. D316891, D. L ocke, 08/29/2005). The re were no concerns for neurotoxicity resulting from fluazifop - P - butyl which were evident at relevant exposure levels. There was also no evidence of clinical signs which would indicate neurotoxicity

or neuropathology

in the available studies, however, the Revised Part 158 Data Requirements list the acute and 90 - day neurotoxicity

studies as mandatory . Marginal increases in brain weights at termination were observed in a sub - chronic toxicity study in rats, and in a carcinogenicity

study performed on hamster s, but only at higher doses.Fluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP No.: 385178

Page 17 of 78 For fluazifop, there were some indications of potential immunotoxicity in the form of th ym ic involution, altered spleen weights, l ymphadenopathy and bone marrow m ye logram changes in dogs treated orally

(capsule) with 25 m g/kg/day (mid - dose) and 125 mg/kg/day (high - dose) fluazifop for 55 weeks. However, these effects are not of concern because: (1) th ym ic involution was of slight severity in only 1 female treated with the mid - dose. In addition, the response was equivocal in the males as there was no dose - response relationship (incidence and severit y) and controls also exhibited thy mic involution. One control dog had severe th ym ic involution. Also, the colony of dogs used in the study had excessive health problems that may have impacted normal immune status; (2) the statistical and biological significance of the alterations in spleen weights could not be assessed because of the large variation of the weights in control dogs. Also, the alterations were inconsistent between dogs that died (these dogs display ed increased adrenal weights) and dogs that survived (these dogs display ed decreased adrenal weights); (3) ly mphadenopathy

was observed only

at the high dose (125 mg/kg/day) and the response is questionable since the colo ny of dogs used in the study had excessive health problems that included lymphadenopath y; (4) the bone marrow m yelogram changes were discounted by an HED Peer Review Committee which determined that the changes were small and variable and not dose related. In addition, the colony of dogs used in the study exhibited health problems that may have impacted the normal immune sy stem; and (5) none of the potential immunological signs in the dog were seen in a chronic study of the rat, the most sensitive species. HED considered the results of the chronic dog stud y to be unreliable due to fact that the animals were unhealthy, so that apparent immunotoxic effects were observed in some untreated control animals. Moreover, no immunotoxic effects were observed in the sub - chronic dog study ; a study where healthy

animals were used. HED therefore believes that the available data do not warrant an additional 10X be applied to the uncertaint y factor used for estimating risk at this time. An immunotoxicity study (870.7800) must be performed on fluazifop - P - butyl, under 40 CFR Part 158, so that its immunotoxic potential can be fully evaluated. 4.4 FQ PA Safety Factor No increased offspring sensitivity over parent was seen the rabbit pre - natal developmental studies or the post - natal reproduction study and no evidence of neurotoxicity was observed. Although malformed fetuses were seen at high dose levels in the absence of maternal toxicity in the rat developmental toxicity

studies, the definitive developmental endpoint in five developmental studies was selected based delayed ossification and fetal weight decrement at much lower doses (100 fold lower). T here is an adequate toxicity database for fluazifop - P - butyl and exposure data are complete or are estimated based on data that reasonably account for potential exposures. There is no evidence of susceptibility

following in utero and/or post - natal exposure in the 2 - generation rat reproduction study (parental NOAEL=0.74 mg/kg/day and offspring NOAEL=7.1 mg/kg/day) . There are no r e sidual uncertainties pertaining to pre - and post - natal toxicity and no developmental neurotoxicity or immunotoxicity concerns were revealed in past studies . The chronic dietary (food and drinking water) exposure assessments are conservative. The dietary and residential assessments are based on reliable data and will not underestimate exposure/risk. Based on these data and conclusions, the FQPA Safety Factor can be reduced to 1X . 90 - Day dermal and inhalation toxicity studies are also required to confirm the PODs selected for assessing dermal and inhalation exposures based on route - to - route extrapolations from oral studies. Fluazifop - P - butyl is expected to show similar toxicity by the inhalation and oral routes because of itsFluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP No.: 385178

Page 18 of 78 metabolism by

blood into the acid form and excretion in this manner. The NOAEL from the available 28 - day dermal study

is considerabl y higher (100 mg/kg/day). Although a point of departure from an oral study was used to assess residential handler inhalation risks for fluazifop - P - butyl, EPA does not believe this aggregate risk assessment is under - protective of adult handlers. Handler MOEs based on the extrapolated endpoint are quite high ( 14,000 to 1.1 million ) , and the contribution of residential exposure to aggregate risk is small . Therefore, even if an inhalation study were to provide a lower point of departure than the oral stud y, it’s not expected to have a significant impact on aggregate risk. 4.4.1 Completeness of the Toxicology Database The toxicity

database for fluazifop - P - butyl is complete except for acute and sub - chronic neurotoxicity studies and immunotoxicity testing. Recent changes to 40 CFR §158 make these studies (OPPTS Guideline 870.7800) required for pesticide registration. A 90 - day dermal study and 90 - day inha lation study have also been requested for purposes of further evaluation and confirmation of the oral PODs route - to - route extrapolations used for these potential exposure routes. Fluazifop - P - butyl is likely to show similar toxicity

by both the inhalation and oral routes because of its metabolization by blood into the acid form and excretion in this manner. The short - term dermal and short - term inhalation endpoints utilized the developmental toxicity study data with a NOAEL of 2.0 mg/kg/day , since it was mor e protective than the 28 - day dermal study

endpoint of 100 mg/kg/day . Although neurotoxicity studies have not yet been submitted, there is no evidence of neurotoxicity in an y study in the toxicity database for fluazifop - P - but yl . In the absence of specific immunotoxicity studies, EPA has evaluated the available fluazifop - P - butyl toxicity database to determine whether an additional database uncertainty factor is needed to account for potential immunotoxicity . No evidence of immunotoxicity was found in the mos t sensitive species, as described previ ously . The complete description for the lack of immunotoxicity testing not warranting a 10X FQPA factor is described in the memo “ Fluazifop - P Butyl . Rationale for Reducing the 10X Safet y Factor to 1X for Lack of an I mmunotoxicity Study . Addendum to Fluazifop - P - Butyl Risk Assessment for Dry Beans, Peanuts, and Soy beans [D347515, P. Savoia et al. , 19 - SEP - 2008], J. L iccione, January 23, 2009 , DP Barcode: 359779 . Due to the lack of evidence of neurotoxicity and immunoto xicity

for fluazifop - P - butyl, EPA does not believe that conducting immunotoxicity and acute and sub - chronic neurotoxicity testing will result in a NOAEL less than that to derive the current cRfD of 0.0074 mg/kg bw/day . Likewise, the oral POD selected for residential dermal and inhalation routes of exposure (Developmental NOAEL = 2.0 mg/kg/day) is beli e ved to be protective. Residential MOEs are large (14,000) and fluazifop - p - but yl is expected to show similar toxicity by both the inhalation and oral routes be cause of its metabolization by blood into the acid form and excretion in this manner . Consequently , the EPA believes the existing data are sufficient for endpoint selection for exposure/risk assessment scenarios and for evaluation of the requirements unde r the FQPA, and an additional database uncertainty factor does not need to be applied. In the case of fluazifop - p - butyl, the 2008 risk assessment included a table that listed decreased spleen weights in male rats in the two - generation reproduction rat stu dy as one of the effects observed at the LOAEL for several endpoints. However, upon closer examination of the effects seen, HED has determined that the spleen weight effect should not be cited as a toxicological effect at the study LOAEL for the following reasons: 1) the apparent spleen effect was marginal, only observed in one generation of male rats, and relativel y independent of dose, 2) the apparent spleen effect was notFluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP No.: 385178

Page 19 of 78 observed in the chronic carcinogenicit y rat study, and 3) histological examination of the spleen tissue did not indicate that any

changes were occurring on a cellular level. Based on these detailed considerations, HED now concludes that it is inappropriate to list spleen weight as a toxicological effect at the LOAEL of the two - generati on rat reproduction study . The Assessment team concluded that the toxicology database for fluazifop - butyl and fluazifop - P - butyl is complete for FQPA evaluation and that the current NOAEL of 0.74 mg/kg/day is sufficiently protective, since no immun o toxicity nor neurotoxicity were observed in previous studies . Acceptable developmental toxicity

studies in rats and rabbits on fluazifop - butyl and fluazifop - P - butyl are available in addition to an acceptable 2 - generation reproduction stud y in rats. Studies on f luazifop butyl may

be used to support fluazifop - P - butyl due to equivalency in toxicity . A more comprehensive description of these data needs is listed in Appendix A3. 4.4.2 Evidence of Neurotoxicity The assessment team concluded that there was not a conc ern for neurotoxicity resulting from exposure to fluazifop - P - butyl at relevant exposure levels. There was no evidence of clinical signs indicative of neurotoxicity

or neuropathology

in the available studies. Marginal increases in brain weights at termination were seen in a sub - chronic toxicity study in a rats and a carcinogenicity study in hamsters, but only at high doses. A developmental neurotoxicity study is not required at this time. 4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Y oung Animal There is no concern for increased susceptibility to offspring following pre - and postnatal exposure to rats or in utero exposure in rabbits. There is no indication of developmental neurotoxicity resulting from exposure to fluazifop - P - butyl with the current data sets, so this study will not be requested at this time. Evidence that supports not requiring a DNT study

include there was no developmental or central nervous sy stem malformations seen in an y of the developmental toxicity studies with r ats or rabbits and no evidence of neurotoxicity or neuropathology

in adult animals in the available studies. The toxicological significance of the marginal increases in brain weights at high doses is unknown in the absence of corroborative histopathologica l lesions. The assessment team concluded that there is not a concern for developmental neurotoxicity resulting from exposure to fluazifop - but yl or fluazifop - P - butyl. The toxicology

database is adequate for hazard characterization and endpoint selection. Therefore, no database uncertainty

factors are needed for an y database deficiencies. The data base included 7 developmental toxicity studies: 2 with fluazifop - butyl in Sprague - Dawley rats; 3 with fluazifop - P - butyl in Wistar rats; 1 with fluazifop - butyl in New Zealand rabbits; and 1 with fluazifop - P - butyl in New Zealand rabbits. These studies are summarized below: The NOAEL/LOAEL in the five rat developmental toxicity studies was determined by a weight of evidence criteria mainly

around consistency

of del ay ed ossification, delay ed development of the urinary tract, and diaphragmatic hernias. Although, delay ed ossification was seen in some studies at lower doses, they

were inconsistent (i.e., low incidence of delay ed ossification in controls compared to his torical controls, large variation in historical controls, the delayed ossification was not clearly dose related, and litter incidence was not statisticall y significant).Fluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP No.: 385178

Page 20 of 78 The LOAEL is 5.0 mg/kg/day based on decreased fetal weight and increased incid ence of h ydroureter in fetuses and litters, and delay ed ossification in a 160 litter/group developmental toxicity study (MRID# 00088858). This L OAEL is also supported by a dose - related increased fetal incidence in partially ossified sternebrae and sterneb rae bipartite, 5th (MRID# 46082913, 46082903), and statistically

significant increased incidence of fetuses and litters with interparietals, occipitals and parietals partiall y ossified, calcaneum not ossified and increased manus and pes scores at 5.0 mg/kg/day

(MRID# 46082903 and 46158401). The NOAEL of 1.0 mg/kg/day in the 160 litter per group stud y was not selected and a NOAEL of 2.0 mg/kg/day from the Wistar rat studies was selected. Since apparent effects noted at 0.05 and 1.0 mg/kg/day were either no t dose related, concurrent controls were low, the effects were lower than the historical control range, or were not statistically significant in litters, and 2 developmental studies that included a 2 mg/kg/day dose group failed to elicit a dose dependant r esponse, a NOAEL of 2.0 mg/kg/day was selected. The overall rat studies showed a NOAEL/LOAEL of 2.0/5.0 mg/kg/day . The NOAEL/ LOAEL was chosen from among MRID# 0008858, 46082903, 46082913 and 46518401. For a single dose effect, the NOAEL/LOAE Ls are 50/2 00 mg/kg/day based on the diaphragmatic hernia malformations. The maternal toxicity

NOAEL/L OAEL of 100/300 mg/kg/day was based a combination of factors. There was a clear effect on maternal weight decrement at 300 mg/kg/day in the Wistar rat studies and a clear NOAEL at 100 mg/kg/day in the Wistar rat studies. Although, the maternal weight decrement in the Sprague Dawley

rat was shown to be due to gravid uterine weight decrement, it was not completely

clear that maternal toxicity was not expressed at 200 mg/kg/day . Therefore the maternal NOAEL was chosen among the three Wistar rat developmental toxicity studies to remove this ambiguit y in maternal toxicity . While there was quantitative evidence of increased susceptibility in the fetuses of rats exposed in utero to fluazifop - butyl and fluazifop - P - butyl , the degree of concern is low based on the following considerations: the endpoint of concern (delay ed ossifications) is considered to be a developmental delay as opposed to a malformation or variation which is considered to be more serious in nature; there were considerable variations in the incidences among the five studies; the NOAELs/LOAELs for this effect were well defined and consistent across these studies; and a developmental endpoint of concern (diap hragmatic hernia) is used for assessing acute dietary risk. Also, in a two - generation reproduction toxicity

study in rats, there was no evidence (quantitative or qualitative) of increased susceptibility

following in utero exposures to rabbits or following pre - and/or post - natal toxicity . Therefore, there is no residual uncertaint y for pre and/or post natal toxicity . 4.4.4 Residual Uncertainty in the Exposure Database There are no residual uncertainties in the exposure database. Since the dietary and non - d ietary exposure estimates were based on several conservative assumptions, HED does not believe that the exposure estimates are underestimated.Fluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP No.: 385178

Page 21 of 78 The acute and chronic dietary assessments are conservative evaluations. The acute assessment utilized tol erance level residues for all crops. In addition, default processing factors were assumed for all commodities. One hundred percent crop treated was assumed for all commodities. A more refined anly sis was performed for the chronic assessment, using perce nt crop treated, average field trial residue levels and default processing factors. Both the acute and chronic food plus water analy ses were performed with the DEEM - FCIDTM model, which assumes that all drinking water will contain fluazifop - P - butyl at the highest estimated drinking water concentration (EDWC) levels modeled by EFED for ground water or surface water. For these reasons it can be concluded that the dietary anal ys is does not underestimate risk from exposure to fluazifop - P - butyl. 4.4.4.1 HED’s Levels of Concern (LOC) Summary of HED’s LOCs for risk assessment . MOEs that are less than the LOCs are of concern. Route Duration Short - Term (1 - 30 Days) Intermediate - Term (1 - 6 Months) Long - Term (> 6 Months) Occupational (Worker) Exposure Dermal 100 100 100 Inhalation 100 100 100 Resi dential (Non - Dietary) Exposure Oral 100 100 N/A Dermal (All Populations) 100 100 100 Inhalation (All Populations) 100 100 100 For Occupational exposure: This is based on the conventional uncertainty factor of 100X (10X for interspecies extrapolation and 10X for intra - species variation). For Residential exposure: This is based on the conventional uncertainty factor of 100X (1X for FQPA, 10X for interspecies extrapolation and 10X for intra - species variation). 4.5 Toxicity Endpoint and Point of Departure Selections The details for selecting toxicity endpoints and points of departure for various exposure scenarios are presented in the appendix A2. An acute dietary

endpoint for females 13 - 49 y ears of age was selected from a developmental tox icity study in rats, based on diaphragmatic hernia. No appropriate endpoint attributable to a single dose was identified for the general U.S. population. The short - term incidental oral endpoint was selected from the developmental toxicity studies in rats and is based on maternal bod y weight gain decrement. The chronic dietary

(all populations), intermediate - term dermal and inhalation, and intermediate - term incidental oral endpoints were selected from the 2 - generation reproduction study in rats based on d ecreased testes and epididy mal weights in males, and decreased uterine and pituitary weights in females. The short - term dermal and inhalation endpoints used in the assessment were selected from the developmental toxicity studies in rats based on decreased fetal weights, hydroureter and delay ed ossification. Though this endpoint was selected by the Hazard Identification Risk Assessment Committee specifically

for females 13 - 49 y ears of age, and a separate, higher, dose/endpoint was selected for all other po pulation subgroups from the developmental toxicity studies in rats, based onFluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP No.: 385178

Page 22 of 78 maternal weight gain decrement, the fluazifop - P - butyl assessment team chose to use the female specific endpoint for all population subgroups for initial screening. By using the l ower dose/endpoint approach for all population subgroups, the risk assessment is protective of the toxic effects seen at higher doses. This approach is particularly appropriate as a screening level assessment to determine if there are an y potential risks of concern. Oral NOAEL s were selected for dermal and inhalation endpoints. Dermal absorption factors, calculated from a dermal absorption and pharmacokinetic study in humans, of 1.9% for high exposures and 8.6% for low exposures were used for oral - dermal route to - route extrapolation, and 100% absorption was used for inhalation exposure. Fluazifop - P - but yl is classified as “not likel y t o be carcinogenic to humans” and no mutagenic potential was observed in adequate in vivo and in vitro studies with fluazif op - butyl and fluazifop - P - butyl. 4.5.1 Dose - Response Assessment The decreased testes weight and decreased epididymal weight in PO and F1 adult rats showed a marginally

adequate dose response. The statistically significant decrease in both organs could pot entially

have resulted from a decreased sperm count. The cancer study in hamsters showed a good dose - response in testes weight decrement. Since the statistically significant effects were seen in the male P0 and F1 parents and in the hamster study , the ef fects were considered treatment related. The testicular endpoint from the reproduction study was selected for the chronic RfD, intermediate - term oral incidental exposure, intermediate and long - term dermal and inhalation exposure. Other studies showed tes tes weight decrement and epididy mal effects at higher dose levels, but there were only equivocal histological effects shown. Although extensive short - term studies on the testes weight decrement and epidid ym al effects were conducted, all failed to show that the effect was incidental or find an explanation for the effect. However, the more sensitive studies on sperm parameters, such as sperm motility

and sperm count, were not among the extra studies conducted. An acceptable negative study of sufficient dur ation on sperm parameters would add confidence to the possibility that the testes and epididy

mal weight decrement seen in the rat reproduction study were incidental and not reproducible. The uterine weight decrement seen in the reproduction study showed a good dose - response and was supported by

a dose - response in the pituitary weight decrement at the same doses. In addition, in the hamster, h yperplasia in the ovary was seen at high dose levels. One of the sub - chronic studies in the rat with fluazifop - P - butyl showed testicular weight decrement, while the other one with fluazifop butyl did not at approximately the same doses as in the reproduction study (at the highest dose tested in the sub - chronic stud y with fluazifop - butyl absolute testes weights were increased 30%). The reason is unknown, but may

be due to animal variation or other unknown factors such as edema. The testes and epidid ym al weight decrement and uterine and ovarian effects suggest possible endocrine related effects. However, negative i n vitro studies suggest estrogen and androgen hormones were not involved. Agonistic and antagonistic studies with fluazifop - butyl, fluazifop - P - butyl and the fluazifop acid metabolite were conducted in ye ast cells containing human estrogen and androgen rec eptors. No receptor activity was found with any

of the test materials over a sufficientl y wide concentration range.Fluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP No.: 385178

Page 23 of 78 The acute RfD and short - term incidental oral, and short - term dermal and inhalation exposure endpoints were selected from the dev elopmental data base which includes 7 developmental toxicity studies: 2 with fluazifop - butyl in Sprague - Dawley rats; 3 with fluazifop - P - butyl in Wistar rats; 1 with fluazifop - butyl in New Zealand rabbits; and 1 with fluazifop - P - butyl in New Zealand rabbits . There was evidence (quantitative) of increased susceptibility in the fetuses of two strains of rats exposed in utero to fluazifop - butyl. Diaphragmatic hernia was seen at the highest dose tested in the Sprague Dawley rat and other developmental toxicity , characterized as delay s in skeletal ossifications, were seen in the absence of maternal toxicity relativel y consistently

in all five rat studies. However, the concern is low for the increased susceptibility seen in the rats based on the endpoint of conc ern (delay ed ossifications). This developmental delay occurred at a lower dose level than the malformations. The delayed ossification in a given parameter showed considerable variation in the incidence among the five studies requiring a weight of evidenc e to determine the appropriate NOAEL/LOAEL among the five rat studies. There was no evidence (quantitative or qualitative) of increased susceptibility

following in utero exposures to rabbits. The dose - related liver and kidney toxicity shown in the older sub - chronic and chronic studies was expressed as exacerbation of age related kidney toxicity . Tests show that this toxicity was in the presence of peroxisome proliferation. However, the extensive and age related nephropath y in control groups complicate this conclusion with regard to the kidney . A possible treatment related slight increase in chronic nephropathy was noted onl y atthe highest dose tested in the more recent study of reproduction in the rat. The uncertainty

factors used with all endpoints were 10X for inter - species extrapolation and 10X for intra - species variation for a total of 100X. 4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment As per FQPA, 1996, when there are potential residential exposures to the pesticid e, aggregate risk assessment must consider exposures from three major routes: oral, dermal and inhalation. The fluazifop - P - butyl team chose to aggregate high - end exposures using conservative endpoints for a screening level assessment. I f the resulting as sessment showed risks of concern, further refinements would have been incorporated into the assessment but, it was not necessary . 4.5.3 Cancer Classification and Risk Assessment Recommendation The assessment team, in accordance with the 1999 Draft Carc inogen Risk Assessment Guideline (April, 1999) classified fluazifop - butyl and fluazifop - P - butyl as “Not likely to be carcinogenic in humans,” based on the lack of evidence of carcinogenicity in rats and hamsters. Progressive chronic nephropath y was observ ed in both rats and hamsters, but there was no statistically significant incidence of malignant and/or benign tumors seen at any dose in either study . A carcinogenicit y study in mice was not conducted. Peroxisome proliferation in the mouse was at levels much higher than in the hamster at comparable dose levels. Therefore, a carcinogenicity study in hamsters was conducted instead. The hamster was chosen because peroxisome proliferation in vivo and in vitro was more comparable to that found in human cell culture.Fluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP No.: 385178

Page 24 of 78 The assessment team concluded that there is not a concern for mutagenicity resulting from exposure to fluazifop - P - butyl. The database for mutagenicit y is considered adequate based on pre - 1991 guidelines. No mutagenic potential was seen in ade quatel y conducted pre - 1991 guideline mutagenicity

studies (in vivo and in vitro) on fluazifop - P - butyl or fluazifop - butyl. A structural analogue {halox yfop - methyl [methyl 2 - [4 - [[3 - chloro - 5 - (trifluromethyl) - 2 - py ridinyl] oxy]phenoxy]propinonate]} of fluazif op - P - butyl also showed no mutagenic potential. 4.5.3.1 Carcinogenic Potential in Rats In a combined chronic/carcinogenicit y study (MRID# 41563703) PP009 (fluazifop - butyl, 94.8% a.i., batch/lot # 14, Reference C4915, CTLY00082/001/005)] was administered to [(60 Wistar rats/sex/group in the diet at dose levels of 0, 2, 10, 80 or 250 ppm (equivalent to 0, 0.10, 0.51, 4.15 or 12.29 mg/kg bw/day

for males and 0.127, 0.65, 5.20 or 16.0 for females) for 106 or 107 day s, respectivel y. Additional groups of 10 rats/sex/group were administered the test material in an analogous manner for 52 weeks prior to an interim sacrifice. Clinical signs were characteristic of rats, except respiratory distress, nasal and ocular discharge were seen among some males at 80 and among some males and females at 250 ppm from week 29 to 55. These signs were accompanied b y bod y weight loss and death in the seriously affected males at 80 and 250 ppm and in the seriously affected females at 250 ppm. Bod y weight gain of males and f emales, not dying, were increased significantly up to week 28 at 80 (14% in males and 19% in females) and 250 ppm (10% in males and 20% in females) and in males week 29 - 44 at 250 ppm (26%), thereafter body weight gain was nominall y i ncreased in males at 10 , 80 and 250 ppm and nominally increased in females from week 29 - 108 at 2, 10, 80 and 250 ppm. There was an overall nominal body weight gain increase in males and females at the three top dose levels for the 106 weeks of the study. However, male ( - 79 g t o - 123 g versus - 101 in control males) and female ( - 9 g to - 24 g versus - 24g in control females) rats lost body weight between week 81 - 85 and at the end of the study . No differences from control were seen in food consumption, food efficiency , water consumption or urinaly sis among the groups. There appeared to be a dose related increased mortality among males at 80 and 250 ppm (33% at 80 ppm and 34% at 250 ppm versus 14% in control) and among females (21% at 250 ppm versus 4% in control) during the first 52 weeks of the stud y. Overall mortality at cumulative termination appeared to be increased in males at 80 and 250 ppm (88% - 86% versus 68% in control) and in females at 250 ppm (65% versus 45% in controls). The report stated that the death occurring up t o week 52 was caused b y respiratory problems exacerbated b y t est material related nephropathy (all grades) in nearly 100% of the affected males dying at 80 and 250 ppm and 87% of the affected females dying at 250 ppm. No dose - related mortality was seen fr om week 52 to termination. Dose - related nephropathology , slight, moderate and marked, but not otherwise specified was seen in the animals dying or killed in extremis during the first 52 weeks of the study . This nephropathy was seen in control, 2, 10, 80 and 250 ppm group animals; 9/10, 9/9, 6/6, 22/23, and 24/24, respectively in males and 0/3, 0/1, 1/6, 1/ 2 and 13/15, respectively in females dying or killed in extremis. Treatment may have exacerbated the nephropath y. In animals sacrificed at terminati on, geriatric nephropathy was seen in nearl y all surviving animals [23/24 (96%) HDT versus 30/31 (97%) in control males] and [20/24 (83%) HDT versus 19/24 (79%) control females]. Gastrointestinal tract lesions appeared to be increased slightl y at 250 ppm in males and females.Fluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP No.: 385178

Page 25 of 78 At ophthalmological examination, increased keratitis was seen in males (5/20) at 250 ppm. Since this observation was not seen in females and did not appear to be dose related at lower dose levels, the study authors questioned th e toxicological significance of the finding. Hematological parameters showed slight changes in males at 80 and 250 ppm. Decreased hematocrit (6 - 8%), hemoglobin concentration (3 - 4%) and ery throcy te count (6 - 8%) were slightly but statistically signifi cant at week 12 and 25 and nominally decreased at week 78 at 80 ppm and 250 ppm. Hemosiderosis was found only in the spleens of one female each in control, 2, 80 and 250 ppm groups. Blood chemistries showed increased cholesterol (about 85% to 107%) at various times of anal ys es up to 78 weeks in males and females, but not after 100 weeks in females at 250 ppm; males showed a nominal decrease in cholesterol after 100 weeks at the same dose. Albumin showed statistically significantl y decreases of about 24% in males and females at 250 ppm. Bone smears on males and female rats were similar to controls at week 52 or 106, but many smears in all groups could not be evaluated. Decreased absolute (16%) and relative (17%) liver weights were statistically significant in males at 250 ppm at terminal sacrifice, and increased absolute (40%) and relative (37%) ovarian weights were significant at termination at 250 ppm; animals with ovarian cy sts and masses were excluded from these calculations. Testes and seminal vesicl e weight did not differ from control weight at terminal sacrifice, but were nominally decreased at 250 ppm. At the 52 week interim sacrifice, absolute and relative kidney

(Abs. 29%) and th yroid (Abs. 33%) weights were significantly increased in males, but not in females at 250 ppm. Absolute (31%) and relative (24%) testes weight showed a treatment related decrease at 250 ppm at the 52 week sacrifice. Ovarian weights were nominally increased at 250 ppm and 52 weeks. Ovaries, possibly enlarged by

cy sts, appeared to have an increased incidence in the 250 ppm group than in control. The LOAEL in males is 80 ppm (4.15 mg/kg/day) based on increased mortality and nephropath y from start to week 52 of the study . The NOAEL is 10 ppm (0.51 mg/kg/day in males). The LOAEL in females is 250 ppm (16.0 mg/kg/day) based on increased morality and nephropathy

during the first 52 weeks of the stud y and increased ovarian weight and ovarian cy sts at termination. The NOAEL was 80 ppm (5.2 mg/kg/day) for females. At the doses tested, there was no treatment related increase in tumor incidence when compared to controls. The only

statistically

significant neoplasia seen in the study was an increase in male adrenal phaeochromocy

tomas at 80 ppm, but not at 250 ppm. The incide nce of adrenal phaeochromocy toma bearing males (left or right adrenal was calculated from the individual animal data) in control, 2, 10, 80 or 250 ppm were, respectivel y, 5/70, 3/70, 2/70, 11*/70 and 7/70 for males that died or were sacrificed. [* Signific ant at p < 0.019 by a Peto analy sis, when the 80 ppm group was compared with control] None of these adrenal tumors were seen at the interim sacrifice. This chronic/carcinogenicit y s tudy in the rat is ACCEPTABLE (GUIDELINE) and satisfies the guideline requirement for a chronic/carcinogenicity study OPPTS 870.4300); OECD 453] in the rat. This study was upgraded from supplementary (TXR#009746) to acceptable by a 3/12/1996 peer review committee (TXR# 011840). The confusion in TXR# 009746 over which enant iomer was studied is corrected from [R] in TXR# 009746 to [RS]. The test material studied was PP009, the [RS] racemic mixture. The conclusions take precedence over previous conclusions.Fluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP No.: 385178

Page 26 of 78 4.5.3.2 Carcinogenicity Study in Hamsters In a carcinogenici ty

study (MRID# 45345401, 46082905) [fluazifop - P - butyl, 91.6% a.i., batch/lot# P23] was administered to 63 Golden Sy rian hamsters/sex/dose in the diet at dose levels of 0, 0, 200, 750 or 3000 ppm (mean of measured test material consumption equivalent to 0, 0, 12.5, 47.4 or 193.6 mg/kg bw/day

for males and 0, 0, 12.1, 45.5 or 181.4 mg/kgbw/day for females, page 25 of 45345401) for 80 weeks. Of these animals, 12/sex/group were designated for interim sacrifice on week 53. Two control groups were included. T here were no significant definitive body weight changes or meaningful food consumption or food efficiency differences from control in males or females during the study . There was an increased frequency of a clinical observation at 3000 ppm (“thin”) (13 ve rsus 5 in control). Survival was unchanged statisticall y, but females showed a slight nominal decrease at 3000 ppm (70.6% versus 78.5% in pooled control). Probably no biologicall y - significant hematological effects were seen in the study . Statistically significant decreases in white cell count in interim sacrificed males (22% - 23%) at 750 ppm and 3000 ppm and in terminal females (17%) at 3000 ppm were observed. The remaining statistically significant hematological changes at 3000 ppm were minor and prob ably not biologicall y significant. No clinical chemistry

analy sis was conducted. Testes weights were decreased at 750 and 3000 ppm and liver and kidney weights were increased in males and females at 3000 ppm. In males, absolute and adjusted testes weights were decreased in a dose related manner and statistically significantly

reduced (p < 0.01) at 750 (abs 8% and adj 10%) and 3000 ppm (abs 20% and adj 19%). In males, adjusted liver weight was statistically significantl y elevated at 750 (5%) and 3000 pp m (7%), but the absolute weight was not elevated at any dose level. In males and females, a kidney weight (males 11% and females 9%) and adjusted kidney weights (males 11% and females 9%) were statistically significantly

elevated in the 3000 ppm group, on ly . In females absolute liver weight was statisticall y significantly elevated at all dose levels (9% - 38%), but adjusted liver weights (34%) were significantl y el evated onl y at 3000 ppm. Slight absolute and adjusted brain weight increases (2.5% and 1.6%) respectivel y in males and females at 3000 ppm are of unknown biological significance. Non - neoplastic microscopic histological findings were increased in the epididy mis, testes, ey es, livers and gall bladder in males and in females, ovarian stroma cel l/sex cord hy perplasia was increased at 750 and 3000 ppm. In males dose related incidences were seen at 750 ppm of reduced spermatozoa in epididy mis (24% versus 8% in pooled controls), increased incidences of testicular tubule degeneration (37% versus 7% in pooled controls), increased incidences of ey e cataract changes (31% in males at 750 ppm versus 16% in pooled controls), increased incidences of male liver mononuclear cell infiltration (35% versus 20% in pooled controls) and increased incidences of gall bladder stones (73% versus 31% in pooled controls) in males and in females at 3000 ppm (41% versus 13% in pooled controls). The incidence of chronic nephropath y was nominally increased in males and females at all dose levels. In females dose - related inc reased incidences were seen at 750 ppm in ovarian stroma/sex cord h yperplasia (14%versus 6% in pooled controls).Fluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP No.: 385178

Page 27 of 78 The LOAEL for s ys temic effects is 750 ppm (equivalent to 47.4 mg/kg/day in males and 45.5 mg/kg/day

in females) based on increased incidenc e of males with reduced sperm, testicular degeneration, ey e cataract changes, liver inflammation and gall stones and in females increased incidences of ovarian stroma cell/sex cord hy perplasia. The NOAEL is 200 ppm (equivalent to 12.5 mg/kg/day

in males and 12.1 mg/kg/day in females. No dose - related tumors were seen in males. Benign ovarian stroma cell/sex cord tumors were statistically

significantly

elevated at the 3000 ppm 5/51 (9.8%) versus 3/103 (2.9%) in pooled controls. However, when the inciden ce s of malignant and benign tumors were combined, no significant differences were seen at any dose. It was concluded that fluazifop - butyl, [R] isomer is not carcinogenic at the dose levels studied. Dosing was adequate in males and females as indicated by the kidney

weight increase and histological findings in ey es [cataracts], liver [inflammation], gall bladder [gall stones], the testes [tubular degeneration] and epididy mis [reduced spermatozoa] of males, and in females b y the ovarian findings [hyperpla sia and adenomas], gall bladder [gall stones] and the severit y of progressive chronic nephropathy at 3000 ppm (HDT). The carcinogenicit y stud y [MRID#46082901, but not 45345401] in the hamster is ACCEPTABLE (guideline) and does satisfy the guideline require ment for a carcinogenicity study [OPPTS 870.4200; OECD 451] in hamsters. 4.5.3.3 Classification of Carcinogenic Potential The assessment team, in accordance with the 1999 Draft Carcinogen Risk Assessment Guideline (April, 1999) classified fluazifop - butyl and fluazifop - P - butyl as “Not likely to be carcinogenic in humans,” based on the lack of evidence of carcinogenicity in rats and hamsters. 4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk Assessment Table 1 a Summar y of Toxicological Doses and Endpoints for Fluazifop - P - butyl + Exposure Scenario Dose Used in Risk

Assessment, UF FQPA SF and Level

of Concern for Risk Assessment Study and Toxicological Effects Acute Dietary * (Females 13 - 49 years of age) NOAEL = 50

mg/kg/day UF = 100 Acute RfD = 0.50 mg/kg/day FQPA SF = 1X aPAD = 0.50 mg/kg/day Developmental Toxicity in Rats Developmental LOAEL = 200 mg/kg/day based on diaphragmatic hernia. Acute Dietary (General population including infants and children) An appropriat e endpoint attributable to a single dose was not identified in the available studies including the

developmental toxicity studies. Chronic Dietary (All populations) NOAEL= 0.74

mg/kg/day UF = 100 Chronic RfD = 0.0074 mg/kg/day FQPA SF = 1X cPAD = 0.007 4 mg/kg/day Tw o - Generation Reproduction in Rats LOAEL = 5.8 mg/kg/day in males and 7.1 in females based on decreased testes & epididymal weights in males, and uterine & pituitary weights in females . Short - Term Incidental Oral (1 - 30 days) Maternal

NOAEL = 100 mg/kg/day Residential LOC for MOE = 100 Occupational = N/A Developmental Toxicity in Rats Maternal LOAEL = 300 mg/kg/day based on maternal body weight gain decrement during GD 7 - 16. Intermediate - Term Incidental Oral (1 - 6 months) Parental/Systemic

NOAEL = 0.74 mg/kg/day Residential LOC for MOE = 100 Occupational = N/A Tw o - Generation Reproduction in Rats LOAEL = 5.8 mg/kg/day in males and 7.1 in females based on decreased testes & epididymal weights in males, and uterine & pituitary weights in females .Fluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP No.: 385178

Page 28 of 78 Table 1 a Summar y of Toxicological Doses and Endpoints for Fluazifop - P - butyl + Exposure Scenario Dose Used in Risk

Assessment, UF FQPA SF and Level

of Concern for Risk Assessment Study and Toxicological Effects Short - Term Dermal (1 to 30 days) Developmental NOAEL = 2.0 mg/kg/day Residential LOC for MOE = 100 Occupational LOC for MOE = 100 Developmental Toxicity in Rats LOAEL = 5.0 mg/kg/day based on fetal w eight decrement, hydroureter, and delayed ossification. Intermediate - & Long Term Dermal (1 to >6 months) a Parental/Systemic

NOAEL = 0.74 mg/kg/day Residential LOC for MOE = 100 Occupational LOC for MOE = 100 Tw o - Generation Reproduction in Rats LOAEL = 5.8 mg/kg/day in males and 7.1 in females based on decreas ed testes & epididymal weights in males, and uterine & pituitary weights in females . Short - Term Inhalation (1 to 30 days) b Developmental NOAEL

= 2.0 mg/kg/day Residential LOC for MOE = 100 Occupational LOC for MOE = 100 Developmental Toxicity in Rats LOAEL = 5.0 mg/kg/day based on fetal w eight decrement, hydroureter, and delayed ossification. Intermediate - & Long Term Inhalation (1 to >6 months) b Parental/Systemic

NOAEL = 0.74 mg/kg/day Residential LOC for MOE = 100 Occupational LOC for MOE = 100 Tw o - Gen eration Reproduction in Rats LOAEL = 5.8 mg/kg/day in males and 7.1 in females based on decreased testes & epididymal weights in males, and uterine & pituitary weights in females . Cancer (oral, dermal, inhalation) Not likely to be carcinogenic to humans. * Selected by the Assessment team for Females 13 - 49 years of age. + Table taken from DP Barcode: 359779 , J Liccione, Jan. 23, 2009 a Use either 9% (low exposure scenario) or 2% (high exposure scenario) for route - to - route extrapolations b Absorption via the inhalation route is presumed to be equivalent to oral absorption. UF = uncertainty factor, FQPA SF = FQPA safety factor, NOAEL = no observed adverse effect level, LOAEL = lowest observed adverse effect level, PAD = population adjusted dose (a = acute, c = chronic) RfD = reference dose, MOE = margin of exposure, LOC = level of concern, NA = Not Applicable 4.6 Endocrine Disruption In the available studies on fluazifop

–P - butyl, there was no estrogen, androgen and/or thy roid mediated toxicity shown. No androgen/estrogen agonist or antagonist activity was detected for fluazifop - P butyl or its acid metabolite. Fluazifop - P - butyl is not among the group of 58 pesticide active ingredients on the initial list to be screened under the Endocrine Disr uption Screening Program. As required under FFDCA section 408(p), EPA has developed the Endocrine Disruptor Screening Program (EDSP) to determine whether certain substances (including pesticide active and other ingredients) may

have an effect in humans o r wildlife similar to an effect produced by a “naturall y occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP employ s a two - tiered approach to making the statutorily required determinations. Tier 1 consists of a battery of 11 screening assay s to identify the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal sy stems. Chemicals that go through Tier 1 screening and are found to have the potential to interac t with E, A, or T hormonal sy stems 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 effect s caused by

the substance, and establish a dose - response relationship between the dose and the E, A, or T effect.Fluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP No.: 385178

Page 29 of 78 Between October 2009 and February 2010, EPA has issued test orders/data call - ins for the first group of 67 chemicals, which contains 58 pesti cide active ingredients and 9 inert ingredients. This list of chemicals was selected based on the potential for human exposure through pathways such as food and water, residential activit y, and certain post - application agricultural scenarios. This list s hould not be construed as a list of known or likely endocrine disruptors. For further information on the status of the EDSP, the policies and procedures, the list of 67 chemicals, the test guidelines and the Tier 1 screening battery , please visit the webs ite: http://www.epa.gov/endo/. 5.0 Metabolism 5. 1 Nature of the R esidue – P lants

N F 3 C O O H C H 3 O O C 4 H 9 ( n ) Fluazifop - P - butyl The Fluazifop - P - Butyl Residue Chapter of the TRED (DP No. 319907, S. L. Kinard, 08/17/2005) concluded that the nature of the residue in so ybeans is adequatel y understood. No new plant metabolism studies for the proposed new use crops were submitted as part of the current petition. T he MARC has determined that for tolerance expression, parent and fluazifop - acid (free and conju gated) are the residues of concern since they are adequate to determine misuse. The MARC also concluded that the residues of concern in plants for risk assessment are parent, fluazifop - acid (free and conjugated), 5 - trifluoromethyl - 2 - py ridone, and 2 - (4 - hydrox yphenox y) propionic acid (free and conjugated). 5.2 Nature of the R esidue - A nimals Th e MARC has concluded that for tolerance expression and risk assessment, parent and fluazifop - acid (free and conjugated) are the residues of concern since they are adequate to determine misuse . 5.3 Meat, M ilk, P oultry, and E ggs In evaluating the data provided to support this petition, the establishment of tolerance limits will be recommended for several RACs commonly recognized for use as liv estock feedstuffs. This would include establishing tolerance limits for sugar beet tops, citrus dried pulp and potato es as requested in part with this action. A lthough in the assessment of prior actions sugar beet tops would have comprised a large portio n of the beef and dairy cattle diet , it is no longer a factor for consideration in the calculation of dietary

burden. For the citrus dried pulp commodity , the tolerance of this livestock feed is being tentativel y s et following the concentration factor of 4x determined from the processing data that were provided. In comparing the resulting limit of 0. 40 ppm for this commodity to the 2.5 ppm residue level of the soy bean roughage now being fed, a net increase in the contribution of dietary burden to livestoc k will not result. Inregard to potato RACs, this use will be only established as an import tolerance which will not result in making this commodity a contributor to the dietary burden of cattle.Fluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP No.: 385178

Page 30 of 78 Given these circumstances , it will not be necessary to pr ovide a re - calculation of dietary burden in support of this action. The prior calculations tentatively depicting the secondary

transfer of fluazifop P - butyl residues to meat, milk, poultry , and eggs made for the uses established on dry beans and peanuts r emain current (DP No. D348246, D. Soderberg, 09/16/2008) . 5.4 Analytical M ethods There are adequate residue anal yt ical methods listed in PAM II for tolerance enforcement and data collection. For the enforcement of tolerances for fl uazifop - P - butyl residues of concern, a High Performance Liquid Chromatograph y/Ultra - Violet Spectrometry (HPL C/UV) method is available for crop commodities. In conjunction, HPL C/UV and Gas Chromatograph y/ Mass Spectrometry (GC/MS) methods are available for milk and animal commodities. The stated quantitation limits are 0.02 - 0.05 ppm for crop commodities, 0.01 ppm for milk, and 0.02 ppm for animal tissues. In addition, the FDA PESTDATA database dated 11/01 (PAM Volume I, Appendix I ) indicates that fluazifop - butyl (onl y) is completely

recovered using Multiresidue Methods Sections 302 (Luke Method; Protocol D) and 303 (Mills, Onley , and Gaither Method; Protocol E, nonfatty food). It is important to note that n one of the se methods can distinguish the optical i somers of fluazifop - butyl or fluazifop . To support PP#9F7624, the banana, citrus, grape, and sugar beet field trial samples were anal yz ed for residues of total fluazifop (fluazifop - P - butyl, fluazifop free and conjugated) using either a GC/MS or Fluorine - 1 9 Nuclear Magnetic Resonance ( 19 F NMR) protocol. These procedures provide a total determination by

hydrolyzing the fluazifop ester or acid conjugates and then derivatizing them to form the fluazifop methyl ester for quantitation with residues being report ed as fluazifop . For PP#9E7561, the potato field trial samples were anal yz ed for residues of total fluazifop using a High Performance Liquid Chromatograph y/ Mass Spectrometry /Mass Spectrometry

(HPLC/MS/MS) protocol. This procedure is a common moiety metho d which works by

hydrolyzing the fluazifop ester or acid conjugates so that a total determination can be made. In all, these protocols are adequate for data collection based upon acceptable method validation and concurrent method recoveries. 5.5 Storag e S tability U pdate Storage stability

data have been reviewed in conjunction with earlier actions undertaken for fluazifop P - butyl which indicate that its residues are stable in a number of crop commodities. As such, its stability has been investigated in a wide variet y of frozen crop commodities and documented in several prior reports generated b y S yn genta. These reports demonstrate that residues of fluazifop are stable in/on soy

beans, sugar beets, green beans, strawberries, oilseed rape, coffee, caulifl ower, onions, potatoes, peanuts, macadamia nuts, tomatoes, endive, and celery for durations of 3 to 28 months (DP No. D 348246 , D. Soderberg , 0 9/16/20 08). Given the results obtained from the se prior studies , th ese data are adequate in directly supporting o r can be translated to corroborate the sample storage intervals incurred in th ese field trials. Although no data were provided to substantiate the holding times that were incurred for man y of the processed commodities tested, none are needed since these anal ys es were made within thirty

(30) day s of production. As such, the re are adequate data to support all of the sample storage conditions and durations that were incurred for all of the RACs tested in part for these petition requests ( PP#9F7624 & PP#9E756 1 ). However, no data were provided to substantiate the holding times that were incurred for an y of the potato processed commodities which were analyzed. Data are available which demonstrate fluazifop - P - butyl is stable in a wide variet y of frozen crop commodities including potatoes. As such, HED expects fluazifop to be stable in the frozen potato processed commodities noted but data should be provided to confirm its stability in these fractions.Fluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP No.: 385178

Page 31 of 78 5.6 Magnitude of R esidue in F ood U pdate The data described below are from the HED residue chemistry chapter made for PP#9F7624 which requests to allow new uses of fluazifop - P - but yl to be made on bananas, citrus, grapes, and sugar beets (DP No. D380017, P. Savoia, 08/ 31 /2010). Inaddition, data are also prese nted from the accompan yi ng HED residue chemistry chapter made for PP#9E7651 which proposes the establishment of an i mport tolerance for fluazifop - P - butyl on potatoes (DP No. D372408, P. Savoia, 08/ 31 /2010). These results are adequate to support each of th e proposed new crop uses put forward in these petition requests. Banana results To determin e the magnitude of fluazifop - P - but yl residue , f ive (5) field trials were conducted in/on bagged and unbagged bananas in the United States during the 1999 growing se ason. The trials were conducted in Zone 3 (1 trial in Florida) and Zone 13 ( 4 trials in Hawaii ). For each trial, three applications of the 2 lb/gal EC formulation of fluazifop - P - butyl were made at a target rate of 0.375 lbs fluazifop - p - butyl/acre for a t otal seasonal rate of 1.125 lb a.i./acre . All applications were made in spray volumes of 17 to 29 gal/A (GPA) using ground - based equipment. An adjuvant was added to the spray mixture for all applications (non - ionic surfactant or crop oil concentrate). E ach test site consisted of a control and treated plot for both bagged and unbagged bananas . Applications were made b y broadcast spray to the soil at 60, 30, and 0 days prior to normal harvest. Banana whole fruit samples were collected at the normal harve st which was immediately fo llowing the last application ( PHI of 0 day s ). The banana field trial results demonstrate the application of the fluazifop - P - butyl herbicide made at the 1x maximum directed labeled use rate. It was appropriatel y carried out in line with the requirements set forth in the OPPTS 860.1500 Residue Chemistry Test Guidelines for bananas . Following three applications of fluazifop - p - but yl at a seasonal target application rate of 1.125 lbs ai/A, residue level s (reported as total fluazif op) were below the LOQ (0.01 ppm) in all bagged and unbagged samples of whole bananas (PHI of 0 day s). Based on concurrent recoveries, an acceptable method was used for the quantitation of total fluazifop in/on unbagged and bagged bananas. Adequate stabi lity data available for other similar crops can be translated to substantiate the storage conditions and durations that were incurred in this study . These data which were reported are adequate to support the proposed seasonal use pattern on bananas (MRID No. 47874601, P. Savoia, 08/ 31 /2010) .Fluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP No.: 385178

Page 32 of 78 Citrus results To determin e the magnitude of fluazifop - P - but yl residue in/on citrus RACs, twenty - three (23) field trial studies were provided by the registrant in support of this petition request. In accordance, MRID No. 41373705 contains 15 field trials and MRID No. 47874602 provides an additional 8 more to satisfy the data requirement for a total of 23 studies in all. For the data submission which contain ed the 15 field trials , these studies were conducted in the United States during the 1986 g rowing season. It is comprised of 5 trials made for oranges (zone 3; Florida) along with 5 trials each carried out for grapefruits and lemons (2 trials in zone 3; Florida, 1 trial zone 6; Texas & 2 trials in zone 10; California & Arizona). The treated test plots in this study received 2 to 3 applications of the 2 lb/gal EC formulation of fluazifop - P - butyl made at 21 day RTI s fo r a total seasonal rate of 1.5 lb ai/acre to 2.25 lb ai/acre . In regard to the data submission contain ing the 8 field trials that were made , these studies were conducted in the United States during the 2000 growing season. Itconsist ed of 7 trials made for oranges (3 trials in zone 3; Florida, 1 trial in zone 6; Texas & 3 trials in zo ne 10; California & Arizona) along with 1 trial carried out on grapefruit (1 trial in zone 3; Florida). The treated test plots in this study

each received 3 applications of the 2 lb/gal EC formulation of fluazifop - P - butyl at 19 - 21 day RTIs for a total sea sonal rate of 1.125 lb ai/acre. The number and locations of the fie ld trials were made in accordance with OPPTS Guideline 860.1500 for oranges, grapefruit, and lemons. The trials generall y reflect the proposed maximum seasonal use pattern, although the trials made in 1986 (MRID No. 41373705) were performed at a 1.3x and 2x greater rate. For the data submission which contained the 15 field trials carried out in 1986, an 19 F NMR instrumental technique was used to carry out these anal ys es. Following th e tr eatment program made at a seasonal target application rate of 1. 5 lbs ai/A to 2.25 lb ai/A , residue levels (reported as total flu azifop) were below the LOQ (0.03 ppm) in oranges, grapefruit and lemon (PHI 14 day s). In regard to the data submission contain ing the 8 field trials that were made, a GC/MS instrumental technique was used to carry out these analy ses. F o r this treatment program of 3 applications made at a seasonal target ed rate of 1.125 lbs ai/A, residue level s (reported as total fluazifop) were below the LOQ (0.01 ppm) in oranges and grapefruit (PHI of 12 to 14 day s). Based on concurrent recoveries of fortified oranges, grapefruit, and lemons, the methods used for these anal ys es were adequate for data collection. Adequate stability data availab le for other similar crops can be translated to substantiate the storage conditions and durations that were incurred in this study . These data which were reported are adequate to support the proposed seasonal use pattern on citrus commodities (MRID No. 47 87460 2 , P. Savoia, 08/ 31 /2010) . Grape re s ults To determin e the magnitude of fluazifop - P - but yl residue in/on grapes, twelve (12) were conducted in the United States during the 2000 growing season. For this study , the trials were carried out in zone 1 (2 trials; New York), zone 10 (8 trials: California), and zone 11 (2 trials; Oregon & Washington). Separate untreated control and treated test plots wer e e stablished at each trial site. At each test location, three b roadcast spray applications of the 2 lb/g al E C formulation of fluazifop - P - butyl were made to the viney ard floor beneath the grape vines at a target application rate of 0.375 lb ai/A/application, for a total target seasonal rate of 1.125 lb ai/A. Applications were made 12 to 15 day s apart in spra y volumes of 10 to 30 gal/A at 9 trial sites and 8 to 10 gal/A at 3 trial sites. Adjuvants (non - ionic surfactant or crop oil concentrate) were used at all the sites and the g rapes subsequently harvested at a PHI of 49 - 50 day s.Fluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP No.: 385178

Page 33 of 78 The grape field trial r esults demonstrate the application of the fluazifop - P - butyl herbicide made at the 1x maximum directed labeled use rate. It was appropriatel y carried out in line with the requirements set forth in the OPPTS 860.1500 Residue Chemistry Test Guidelines for gr apes . Following the last of three viney ard floor applications made with the 2 lb/gal EC formulation at a total rate of 1.11 to 1.16 lb ai/A/season , residue levels (reported as total fluazifop) were <LOQ (0 . 01 ppm) in/on grapes (PHI of 49 to 50 day s ). B as ed upon acceptable method validation and concurrent method recoveries , the protocol used for these analy ses was adequate for data collection. Adequate stability data available for other similar crops can be translated to substantiate the storage condition s and durations that were incurred in this study . These data which were reported are adequate to support the proposed seasonal use pattern on grape commodities (MRID No. 47874604, P. Savoia, 08/ 31 /2010) . Sugar beet results To determin e the magnitude of f luazifop - P - but yl residue in/on sugar beets, twelve (12) field trials were conducted in the United States d uring the 2000 growing season . For this study , trials were carried out in zones 5 (2 trials; Minnesota, 2 trials; North Dakota & 1 trial; Wisconsin), 7 (1 trial: Nebraska), 8 (1 trial; Kansas), 9 (1 trial; Montana), 10 (2 trials; California), and 11 (2 trials; Idaho & Washington). Separate untreated control and treated test plots were established at each trial site. At each test location, two foliar b roadcast spray applications of the 2 lb/gal E C formulation of fluazifop P - butyl were made to sugar beet s at a target application rate of 0.375 lb ai/A/application, for a total target seasonal rate of 0.75 lb ai/A. Applications were made at 12 - to 14 - day retreatment interval s in spray volumes of 10 to 30 gal/A at 9 trial sites and 8 to 10 gal/A at the other 3 trial sites. Adjuvants (non - ionic surfactant or crop oil concentrate) were used at all sites and the sugar beet s subsequently harvested at a PHI of 89 to 90 day s. The sugar beet field trial results demonstrate the application of the fluazifop - P - butyl herbicide made at the 1x maximum directed labeled use rate. It was appropriatel y carried out in line with the requirements set forth in the OPPTS 860 .1500 Residue Chemistry Test Guidelines for sugar beets . For the application program tested, samples were harvested 89 to 90 day s after the last of two broadcast foliar applications made with the 2 lb/gal EC formulation at total rates of 0.747 - 0.764 lb ai /A/season. In accordance, m aximum residues of total fluazifop were found to be 1.45 ppm in/on sugar beet tops and at 0.2 3 ppm for the roots. B ased upon acceptable method validation and concurrent method recoveries , the protocol used for these anal ys es wa s adequate for data collection. Adequate stability data are available for this RAC to substantiate the storage conditions and durations that were incurred for this study . These data which were reported are adequate to support the proposed seasonal use pattern on sugar beet commodities (MRID No. 47874603, P. Savoia, 08/ 31 /2010) .Fluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP No.: 385178

Page 34 of 78 Potato results To establish a new import tolerance for the residues of fluazifop - P - butyl in/on potatoes, field trial studies were conducted wi thin the various geographic/climatological production regions of Canada. In accordance, MRID No. 47920402 contains 13 field trials and MRID No. 47920403 provides an additional 3 more to satisfy the Canadian requirement for a total of 16 studies in all. For the data submission which contained the 13 field trials, these studies were carried out in Canadian growing zones 1, 1A, 5, 5B, 7A, 12 and 14 during the 2008 growing season. As such, two trials were held at New Glasgow, Elm Creek, and Malden along with single ones made at Al bany , Branchton, St. Marc sur - Richeilieu, Taber, Abbotsford, Minto, and Innisfall. Inregard to the data submission containing the 3 field trials that were made, these studies were held at Hunter River (2 trials) and Portage la Prairie (1 trial) in Canada during the 2007 growing season. Each trial site was managed according to the practices routinel y followed by Canadian commercial producers for cultivating potatoes. Test plots were sufficiently

large enough to provide a 1 Kg sample of mature potato tube rs to be collected from at least six (6) different plants. At each study location, market quality potato samples were cultivated using both untreated control and treated test plots. Each treated test plot received a single application of the VENTURE Len d - use product applied at the maximum labeled rate of 250 g ai/ha so that late seasonal treatments made at a PHI of 45 day s could be evaluated. The potato field trial results demonstrate the application of the fluazifop - P - butyl herbicide made at the 1x m ax imum directed labeled use rate. The number and location of field trials were sufficient in scope since they were undertaken in line with the requirements set forth in the PMRA Regulatory Directive to evaluate this use. Following a single treatment of the VENTURE L EC formulation of fluazifop made at the maximum seasonal rate of 250 g ai/ha, t otal residue levels were observed ranging at levels between <0.0033 - 0.61 ppm (P HIof 45 day s ± 1 day). The treatment regimen also appropriatel y included two (2) residue decline studies made at the New Glasgow and Elm Creek sites with samples collected at - 7, 0, +7, +14 and +21 day s of normal commercial harvest. The results generated in the two decline studies illustrate demonstrate that concentrations of fluazifo p will in fact decrease as greater PHIs for treatment are followed. B ased upon acceptable method validation and concurrent method recoveries , the protocol used for these analy ses wa s adequate for data collection. Adequate stability data are available to show that fluazifop residues are stable in frozen potatoes stored at - 18°C for 18 months which substantiate the storage conditions and durations that were incurred in these studies. These data which were reported are adequate to support the proposed seaso nal use pattern on sugar beet commodities (MRID No s . 47 920402 & 47920403 , P. Savoia, 08/ 31 /2010) . 5.7 Processing F actors The data described below are from the HED residue chemistry chapter made for PP#9F7624 which requests to allow new uses of fluazifop - P - but yl to be made on bananas, citrus, grapes, and sugar beets (DP No. D380017, P. Savoia, 08/ 31 /2010). Inaddition, data are also presented from the accompan yi ng HED residue chemistry chapter made for PP#9E7651 which proposes the establishment of an imp ort tolerance for fluazifop - P - butyl on potatoes (DP No. D372408, P. Savoia, 08/ 31 /2010). These results are adequate to determine residue concentration factors for processed fractions to support the new crop uses put forward in these petition requests.Fluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP No.: 385178

Page 35 of 78 Citrus processed commodity results T o determine residue concentration factors in citrus processed fractions , a single trial on oranges was conducted in F lorida during the 1986 growing season using the 2 lb/gal EC formulation of fluazifop - P butyl. For this test program, three applications were made at the nominal rate of 3.75 lb ai/A/application, for a total seasonal rate of 11.25 lb ai/A (10x the maximum proposed seasonal rate for citrus). Applications were made at 21 day intervals using ground equipme nt, with the spray directed to the ground beneath and around the trees. Samples of oranges were harvested 14 day s after the last application and processed into chopped peel, dried pulp, molasses, juice, and oil. Total fluazifop residues were <LOQ (0.03 p pm) in/on the whole oranges treated with fluazifop - P - butyl at a total of 11.25 lb ai/A. Following processing of the whole oranges, total fluazifop residues were 1.7 ppm in chopped peel, 2.6 ppm in dried pulp, 0.09 ppm in molasses and oil, and <LOQ (0.03 p pm) in juice. Based on these data, processing factors would be 87x in dried pulp, 3x in oil, and <1x in juice. However, the Petitioner states that processing factor in dried pulp in unreasonable considering that oranges contain about 86% water. Therefor e, the Petitioner calculated processing factors b y assuming that the residue in the whole oranges was 0.65 ppm, as calculated from the total residue found in the processed commodities and the weight of the starting oranges. The resulting reported processi ng factors were 4x for dried pulp, 2.6x for peel, 1.7x for molasses, and 0.14x for oil. EPA previously

concluded that proposed tolerances in citrus fruit and dried citrus cannot be determined (DEB No. 6343, M. J. Bradley , 08/15/1990). Rather then attempt ing to upgrade these results, it would be prudent for the petitioner to provide a new study given the age of this data submission. To satisfy

the establishment of tolerances for the citrus processed commodities, the theoretical concentration factors are therefore used for setting the pertinent limits on juice (2x) and oil (1000x). These factors along with the citrus HAFT of 0.03 ppm, determine that an appropriate fluazifop - P - butyl tolerance for citrus juice would be 0.06 ppm and 30.0 ppm for the oil fract ion. In regard to citrus dried pulp, there is no theoretical concentration factor determined for this processed commodity . However, in a recent action made for chlorantraniliprole, a snap - shot of 27 pesticides having citrus dried pulp limits was made to determine a practical maximum concentration factor for this processed commodity (DP No. D361791, D. Rate, 01/08/2010) . This determination found that concentration factors range between 2 - 13x for the citrus dried pulp tolerances which were examined. There fore, using the maximum concentration factor of 13x for fluazifop, a resulting tolerance of 0.40 ppm should be set for the citrus dried pulp processed commodity (D385205, P. Savoia, 01/04/11) Grape processed commodity result s T o determine residue concentration factors in grape processed fractions , a single field trial was conducted during the 2000 growing season in Zone 1 0 (1 trial in CA). Separate untreated control and treated test plots were established at the trial site. Three b roadcast spray applications of the 2 lb/gal EC formulation of fluazifop - P - butyl were made to the viney ard floor beneath the grape vines to conduct this trial. Treatments were made at a target application rate of 1.875 lb ai/A/application, with a 14 - day retreatment inter

val (RTI), for a total target seasonal rate of 5.6 3 lb ai/A (5 x the maximum application rate). Grapes were harvested 50 day s after final treatment. The grape RACs were processed into grape juice and raisins.Fluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP No.: 385178

Page 36 of 78 Total fluazifop residues were found to b e <LOQ (0.01 ppm) in/on the grape RAC harvested 50 day s after the last of three treatments made at a 5x seasonal application rate (5.64 lb ai/A/season). Total fluazifop residues were also found to be <LOQ (0.01 ppm) in/on the grape juice and raisin proces sed grape fractions. As such, the observed processing factors for grape juice and raisins are less than the theoretical concentration factor of 4.7x for raisins (based on the loss of water on processing grapes into raisins ; OPPTS 860.1520, Table 1) and 1. 2x for grape juice (based on separation of components; OPPTS 860.1520, Table 3). The se data indicate that total fluazifop residues do not appear to concentrate in raisins or grape juice. T hese data are adequate for determining residue concentration facto rs for the grape processed commodities (MRID No. 47874605, P. Savoia, 08/ 31 /2010) . Sugar beet processed commodity result s T o determine residue concentration factors in sugar beet processed fractions , a single field trial was conducted during the 2000 growing season in Zone 11 (1 trial in WA). Separate untreated control and treated test plots were established at the trial site. Two foliar b roadcast spray applications using the 2 lb/gal EC formulation of fluazifop - P - butyl were made to sugar beet s to con duct this trial. Treatments were made at a target application rate of 1.875 lb ai/A/application, with a 14 - day RTI , for a total target seasonal rate of 3.75 lb ai/A (5 x the maximum application rate). Sugar beet s were harvested 90 day s after final treatme nt. The sugar beet RAC was processed into refined sugar, dry pulp and molasses. Average total fluazifop residues were found to be 0.86 ppm in/on the sugar beet RAC (root) harvested 90 day s after the last of two broadcast foliar treatments made at a 5x se asonal application rate (3.79 lb ai/A/season). In processed sugar beet fractions, average total fluazifop residues were found to be 0.31 ppm in refined sugar, 3.35 ppm in the dry pulp, and 1 2 ppm in molasses. A comparison of the residues in the RAC with those in each processed fraction resulted in concentration factors of 0.36x for refined sugar, 3.9x for dry pulp, and 14x for molasses. These concentration factors are consistent with the theoretical concentration factor of 12.5x for sugar (based on separ ation of components; OPPTS 860.1520, Table 3) and the maximum observed concentration factor of 20x (OPPTS 860.1520, Table 4) for dry

pulp and molasses. The se data indicate that total fluazifop residues do not appear to concentrate in sugar beet refined su gar, but may concentrate in sugar beet dried pulp and sugar beet molasses (MRID No. 47874606, P. Savoia, 08/ 31 /2010). P otato processed commodity results T o determine residue concentration factors in potato processed fractions , ZENECA AGRO based in Frankfurt held six (6) field trials at separate sites within Germany to cultivate potatoes during the 1993 growing season. No details concerning the varieties of potatoes that were grown, the use of an y maintenance pesticides and fertilizers, soil chemistry , weather data, or the use of supplemental irrigation was provided. The data submission only noted that each test location received an application of the Fusilade end - use product formulation of fluazifop - P - butyl applied at a late seasonal Pre - Harvest Interval (PHI) of six weeks. These treatments were made at the targeted amount of 375 g ai/ha in order to provide each test plot with a total seasonal application that was equivalent to 1.5x the maximum labeled use rate. For this program, the field samples from the two trials observed with the highest residues of total fluazifop were processed into potato peels, cooked potatoes, chips and dried flakes for testing.Fluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP No.: 385178

Page 37 of 78 The results in this data submission provide a determination of residue concentration factors for fluazifop - P - butyl in potato processed commodities. It was appropriatel y carried out in line with the recommendations set forth in the OPPTS 860.1520 Residue Chemistry Test Guidelines for evaluating the concentration of residues in processed commoditie s. Processing of the potato RAC bearing quantifiable residues of fluazifop resulted in no concentration of residues in the peel (1.1x processing factor). However, total fluazifop residues were found to concentrate in potato chips and dried flakes at a pr ocessing factor of 3.3x, and 6.4x, respectivel y. The se results indicate that total fluazifop residues do not appear to concentrate in the potato peels , but may do so in the chips and granules/flakes processed fractions. In all, these data are adequate fo r determining residue concentration factors for potato processed commodities (MRID No. 47920405, P. Savoia, 08/ 31 /2010). 5.8 Rotational C rops For th ese actions (PP# 9F7624 & PP#9E7651 ), no new rotational crop data are required. 5.9 Proposed and R ecomm ended T olerances In a meeting on March 3, 2004, the MARC concluded that for tolerance expression, parent and fluazifop - acid (free and conjugated) are the residues of concern since they are adequate to determine misuse (DP No. D298939, S. L . Kinard, 06/22/2004). An acceptable so yb ean metabolism study is available along with new studies made to a root crop and leafy vegetable which are currently undergoing Agency

review. In accordance, t olerances are established under 40 CFR §180.411(a)(1) and (c)(1) for r esidues of fluazifop - butyl, including free and conjugated fluazifop, expressed as fluazifop . F or fluazifop - P - butyl , including free and conjugated fluazifop (R isomer), tolerances are likewise established under 40 CFR §180.411(a)(2) and (c)(2) with residue s e xpressed as fluazifop . Its registered uses include dry beans, carrot, cotton, endive (escarole) , macadamia nut, onion, peanut, pecan, soy

bean, spinach, stone fruit, and sweet potato . It also carries tolerances with regional registrations on asparagus, coffee, pepper, and rhubarb along with being registered for use on lawns as a weed control application. For PP#9F7624, field trials on bananas, citrus, grapes, and sugar beets along with corresponding studies made on the relevant processed commodities we re submitted to support this action. In evaluating the field trials provided b y the registrant, these studies were found to be adequate in satisfying these residue chemistry data requirements. Inregard to the banana, grape, and citrus RACs, residues lev els in all of the treated samples anal yzed were found to be below the LOQ of the test method. As such, the proposed tolerance of 0.01 ppm specified b y the registrant for bananas and grapes is acceptable. Following this approach a revised tolerance of 0.0 3 ppm for citrus based upon the corresponding LOQ of the test method is therefore recommended instead of the 0.05 ppm level proposed b y the registrant. Total fluazifop residues in/on sugar beet RACs were found to be readily quantifiable at levels greater then the LOQ of the test method. The residue data for sugar beet s were entered into the Agency ’s tolerance spreadsheet as specified by the Guidance for Setting Pesticide Tolerances Based on Field Trial Data SOP to determine an appropriate tolerance level (Appendix I). The spreadsheet provides a best estimate of a tolerance at 0.25 ppm for sugar beet roots. In regard to sugar beet tops, no tolerance will be required for this commodity since it is no longer considered to be a significant food or feed item.Fluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP No.: 385178

Page 38 of 78 In evaluating of the corresponding processing study data that were provided, it can be concluded that no additional tolerances are needed for grape juice and raisins as well as sugar beet refined sugar. However, residues of fluazifop were found to con centrate in sugar beet dry pulp (3.9x) and sugar beet molasses (14x). Based on the sugar beet root HAFT of 0.22 ppm and the processing factor s calculated for dried pulp and molasses, expected residues in these fractions are 0.86 ppm and 3. 1 ppm , respectiv el y. As a result, the tolerances of 1.0 ppm in dried pulp and 3.5 ppm for molasses proposed by the registrant are adequate for these sugar beet processed commodities. For the citrus processed commodities, the p etitioner has also proposed tolerances of 0.40 ppm in dried pulp along with 0.05 ppm in juice and oil. However, EPA previousl y concluded that proposed tolerances in citrus fruit and dried citrus cannot be determined (DEB No. 6343, M. J. Bradley , 08/15/1990). Rather then attempting to upgrade the se results, it would be prudent for the petitioner to provide a new study

given the age of this data submission. To satisfy the establishment of tolerances for the citrus processed commodities, the theoretical concentration factors are therefore used for setting the pertinent limits on juice (2x) and oil (1000x). These factors along with the citrus HAFT of 0.03 ppm, determine that an appropriate fluazifop - P - butyl tolerance for citrus juice would be 0.06 ppm and 30.0 ppm for the oil fraction. In regard to citrus dried pulp, there is no theoretical concentration factor determined for this processed commodity . Using the maximum concentration factor of 13x calculated in the recent chlorantraniliprole action along with the citrus HAFT of 0.03 ppm, setting a f luazifop - P - butyl tolerance of 0. 40 for dried pulp would be relevant for this fraction. For PP#9E7651, field trials on potatoes along with a corresponding study made on its pertinent processed commodities were submitted to support this action. In evaluati ng the field trials provided by the registrant, these studies were found to be adequate in satisfying these residue chemistry data requirements. Total fluazifop residues in/on the potato RAC were found to be readil y quantifiable at levels greater then the LOQ of the test method. In accordance, the Agency ’s Guidance for Setting Pesticide Tolerances Based on Field Trial Data was utilized for determining appropriate tolerance levels for potato tubers . Based on these calculations, the proposed potato toleran ce of 0.25 in roots is adequate and a limit of 1.0 ppm for top s is recommended . In regard to the corresponding processing study data that were provided, it can be concluded that no additional tolerances are needed for the peel. However, residues of fluaz ifop were found to concentrate in potato chips (3.3x) and dried flakes (6.4x). Based on the potato HAFT of 0. 55 ppm and the processing factor s calculated for chips and dried flakes , expected residues in these fractions are 1.82 ppm and 3.52 ppm , respectiv el y. As a result, the tolerances of 2.0 ppm in chips and 4.0 ppm for dried flakes are recommended for these potato processed commodities. Th e available residue data provided for fluazifop - P - butyl are adequate to support the establishment of permanent tol erance s on bananas, citrus, grapes, and sugar beets along with an import limit on potatoes. There are no Codex, Canadian or Mexican established M aximum R esidue L imits (MRL s) for residues of fluazifop - P - butyl in/on bananas, citrus, grapes, sugar beets, and potatoes. However, PP#9E7651 is being put forward as a request for the establishment of import tolerances on potato commodities which will be cultivated in Canada. As noted, there are no established MRL s for residues of fluazifop - P - butyl in/on potatoes in Canada but the promulgation of regulatory levels by PMRA are in the process of being finalized. As a result, international harmonization with Canada is a consideration for this data evaluation concerning the establishment of import tolerances on potato commodities. Inall, the proposed tolerances should therefore be revised to re flect the recommended tolerance levels and correct commodity definitions specified below in Table 2 .Fluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP No.: 385178

Page 39 of 78 Table 2 . Tolerance Summary for Fluazifop - P - butyl. Commodity Established Tolerance (ppm) Proposed

Tolerance (ppm) Recommend

ed Tolerance (ppm) Comments; Correct Commodity

Definition Tolerances Proposed for 40 CFR §180.411(a)(1) Bananas -- 0.01 0.01 Citrus -- 0.05 0.03 Fruit, citrus, group 10 Citrus, oil -- 0.05 30.0 Citru s, dried pulp -- 0.40 0. 40 Citrus, juice -- 0.05 0.06 Grape -- 0.01 0.01 Beet, sugar, root -- 0.25 0. 25 Beet, sugar, top -- 1.5 None Removed from Table 1 F eedstuffs, June 2008 Beet, sugar, dried pulp -- 1.0 1.0 Beet, sugar, molasses -- 3.5 3.5 Potato, tubers -- 1.1 1.0 Potato Potato, chips -- 3.0 2.0 Potato, granules/flakes -- 5.0 4.0 Note; the establishment of a tolerance on banana includes the plantain raw agricultural commodity. 6.0 Exposure Characterization/Assessment Section Update 6.1 Dietary E xposure/ P athway 6.1.1 Acute and C hronic D ietary E xposure and Risk U pdate Revised acute and chronic dietary exposure assessments using the version 2.03 Dietary Exposure Evaluation Model (DEEM - FCIDTM) were conducted for fluazifop - P - but yl (DP No. D 379452 , S. Tadayon, 0 8 / 09 /20 1 0) . This modeling effort uses food consumption data from the U.S. Department of Agriculture’s Continuing Survey s of Food Intakes by Individuals (CSFII) from 1994 - 1996 and 1998 to calculate dietary

risk. These anal ys es w ere performed to support the Section 3 registration of fluazifop - P - butyl on bananas, citrus, grapes and grape processed commodities, as well as sugar beets . Also included in this determination are all uses relevant to the establishment of an import tolerance made for fluazifop - P - butyl on potatoes. T he se new crop uses were incorporated into the residue data of file inputs for all other registered commodities to render a current evaluation of dietary exposure. The resulting acute and chronic risk assessm ents which include both food and water are conservative evaluation s. For the a cute dietary exposure assessment, tolerance level residues with a ratio adjustment to account for additional metabolites of concern were used with the a ssumption that 100% of al l crops are treated . Where applicable, DEEM 7.81 processing factors were utilized for the applicable commodities to reflect the possible altering of residue levels through the manufacture of other food forms such as meal and flour. For all other commodit ies, the default adjustment factor of 1.0 was used to weight the processing effects of alternate food forms.Fluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP No.: 385178

Page 40 of 78 In contrast, percent crop treated estimates determined by BEAD along with the average residue levels observed in the applicable field trial stu dies with ratio adjustment was used to carry out the refined chronic analy sis. Default processing factors along with the measured potato processing factors were used to weight the effects of alternate food forms for chronic assessment. For both determinations, drinking water estimates were incorporated directly into these analy s e s using the EECs g enerated by EFED to complete the combined dietary exposure assessment s . Results of Acute and Chronic Dietary Exposure Analy sis Acute and chronic dietary risk analy ses were made with the DEEM - FCIDTM model to form a careful evaluation of exposure for fluazifop - P - butyl. The acute dietary assessment focuses on the population subgroup, females 13 - 49 y ears of age. This is the only population subgroup for which an ap propriate toxic endpoint attributable to a single dose was identified. For this population subgroup, female 13 - 49 ye ars of age, acute dietary risk was estimated to be only 1 3 % of the aPAD with an exposure of 0.0641 mg/Kg/day . No acute dietary endpoint attributable to a single dose was identified for general population including infants and children. This assessment concludes that for all supported registered commodities and new uses, the acute food plus water dietary risk estimates are below the Agency ’ s level of concern (<100 % aPAD). In conjunction, the refined chronic analy sis performed concludes that for all commodities, the resulting food plus water dietary risk is below the Agency ’s level of concern (<100 %cPAD) for the U.S. population ( 12 % cPAD with an exposure of 0.009 mg/kg/day) and all population subgroups. The most highly

exposed population subgroup in the chronic dietary exposure analy sis performed was for children 1 - 2 y ears of age ( 40 % cPAD with an exposure of 0.00 3 mg/kg/day). An overvie w summarizing the results of the acute and chronic dietary assessments with the population subgroup having the highest exposure being noted in bold is presented below in Table 3. Table 3 . Summary of Acute & Chronic Dietary Exposure for Fluazifop - P - buty l 1 Population Subgroup Acute Dietary2 (95 th Percentile) Chronic Dietary3 Dietary Exposure (mg/kg/day) % aRfD Dietary Exposure (mg/kg/day) % cRfD General U.S. Population N/A4 N/A 0.00 09 12 All Infants 0.00 1 5 20 Children 1 - 2 years old 0.00 3 40 Children 3 - 5 years old 0.00 22 30 Children 6 - 12 years old 0.00 14 19 Youth 13 - 19 years old 0.00 08 11 Adults 20 - 49 years old 0.00 7 8.9 Adults 50+ years old 0.00 06 8.7 Females 13 - 49 years old 0.0641 1 3 0.00 06 8.6 1 Fluazifop - P - butyl is not a l ikely human carcinogen based on lack of evidence of carcinogenicity in rats and mice; therefore, a dietary cancer exposure and risk analysis was not conducted. 2 Acute dietary analysis derived from a 0. 5 0 mg/kg/day aRfD. 3 Chronic dietary analysis deriv ed from a 0. 00 74 mg/ kg/day cRfD. 4 N/A

– None Applicable.Fluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP No.: 385178

Page 41 of 78 7.0 Water Exposure Risk/Pathway To address the proposed new crop uses for this action (PP# 9F7624 ), the potential human exposure to fluazifop - P - butyl in drinking water was subsequently re - evaluated ( DP No s . D 371093 & D3 7 1094 , W. J Shaughnessy , 0 5 /25 /20 1 0 ). Th is modeling was updated to reflect updated application rates based on acid equivalents, applications with two and four total applications, and half - lives calculated using the linear/natural log equation. Itwas carried out by EFED to support risk assessment efforts for the Section 3 registration of fluazifop - p - butyl for use on bananas, citrus, grapes, and sugar beets . Ground water EECs were modeled using Tier I SCI GROW (version 2.3, dated July 29, 2003) and surface water EECs with Tier II PRZM ( P esticide R oot Z one M odel; vers. 3.12.2, May 12, 2005) and EXAMS ( EXposure Analy sis M odeling S ys tem; Vers. 2.98.04.06). The resulting EECs represent exposure to fluazifop - acid, with assumptions that flu azifop - acid may be present in the R or S form or as a mixture of the enantiomers. Fluazifop - but yl (PC Code 122805) was detected in both surface water and ground water samples at low concentrations in Spain (<0.2 μg/L) indicating that exposure to fluazifop - butyl in drinking water is possible . H owever, based on the metabolism studies fluazifop acid is still expected to be the primary component present in drinking water (Martinez et al. 2000). Fluazifop - acid was not detected in a non - targeted ground water m onitoring study (MRID No. 40439401). The results of this updated modeling analy s e s performed by EFED is presented below in Table 4 for review . The results of current assessment are higher than 2008 assessment (DP No. D347521, K. White, 08/04/2008) . For aerial applications the highest surface water EECs reported for peak, 1 in 10 ye ar average, and the 30 y ear average as estimated by PRZM/EXAMS for all crop use scenarios were 33.4, 6.6 ppb, and 4.4 ppb, respectivel y. For ground applications the highest EE Cs for peak, 1 in 10 ye ar average, and the 30 y ear average were 32.1 ppb, 5.8 ppb, and 3.1 ppb, respectivel y. SCI - GROW estimated the concentration of fluazifop - acid in shallow ground water sources to be 1.56 ppb . The difference between the 2008 and curre nt assessment results can be attributed to a proposed increase in the maximum number of allowable applications (i.e., 3 vs. 2), and differences in crop use scenarios used in the two assessments.Fluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP No.: 385178

Page 42 of 78 Table 4. Summary of the highest predicted surface an d ground water concentrations for the drinking water assessment for the use of fluazifop - p - butyl on bananas , plantains, citrus, grapes, and sugar beets . Use Estimated Drinking Water Concentration of Fluazifop - Acid (  g/L) Acute or Peak 1 in 10 year Aver age

(Noncancer Chronic) 30 year Average (Cancer Chronic) Aerial Applications Surface Water Bananas & Plantains 33.4 6.2 3. 2 Citrus 28.5 5.4 3.7 Grapes 19.8 6.6 4.4 Sugar Beets 13.0 4.8 3.3 Ground Applications Surface Water Bananas & Plantains 32.1 5.8 2.7 Citrus 27.3 5.1 2.8 Grapes 16.6 5.3 3.1 Sugar Beets 10.6 3.9 2.3 Ground Water All Uses 1.56 1.56 1.56 The resulting modeling estimates indicate that the most significant levels of fluazifop - P - butyl would likely be found in surface water r esulting from applications made to bananas and plantains . These new EECs were then appropriatel y used to complete this updated risk assessment. 8.0 Residential Exposure Risk Characterization Non - dietary , non - occupational exposure was ad dressed in the HED tolerance reassessment made for the fluazifop - P - butyl herbicide in August 2005 (DP No. D316891, D. L ocke, 08/29/2005). Upon completion of this human health risk assessment, no new information on residential exposure has been submitted. For this action, the existing residential application of fluazifop - P - butyl will not be impacted because the proposed new uses will onl y augment commercial agricultural practices. Sections of the prior residential anal ys es made for fluazifop - P - butyl are therefore repeated to allow for the transparent calculation of aggregate risk required to support the proposed new uses. Non - Occupational (Residential) Handler Exposure and Risks Fluazifop - P - butyl is a registered herbicide for residential use on turfgrass and broadleaf ornamentals for the post - emergent control of weed grasses. It is used in this manner as a total grass weed control in a number of outdoor environments such as on lawns, walks, driveways, and ornamental planting beds. Homeowners that apply fluazifop - P - butyl products may therefore be come e xposed for short - term durations via the dermal and inhalation routes. There are several residential handler exposure scenarios given the t yp es of equipment and techniques for appl yi ng fluazifop - P - butyl base d upon anticipated use patterns and current labeling instructions. The exposure scenarios developed for residential handlers of fluazifop - P - butyl are as follows:Fluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP No.: 385178

Page 43 of 78 1. Liquid Concentrate: Low Pressure Handwand. 2. Liquid Concentrate: Hose - end Spray er. 3. Li quid Concentrate: Watering Can. 4. Ready - to - Use (RTU) Formulations: Sprinkling Application. 5. Ready - to - Use (RTU) Formulations: Trigger - pump Spray er. The results for residential handlers of fluazifop - P - butyl were found to yi eld MOEs above 100 which indicate no risks are of concern. The results from these exposure and risk calculations are presented below in Table 5 which are taken from the HED August 2005 tolerance reassessment. Table 5. Summary of Residential Handler Risks fromFluazifop - P - butyl. Exposure Sc enario Target Appl. Rate a Area

Treated Daily b Dermal Unit Exposure (mg/lb ai) Inhalation

Unit Exposure (g/lb ai) Dermal

Dose (mg/Kg/day) Inhalation

Dose (mg/Kg/day) MOE (HED’s level

of concern = 100) Derd Inhl.

e Der + Inhl. Mi xer/Loader/Applicato r Mixing/Loading /Applying Liquid Conc. with Low Press. Handwand (1) Walks,

drives, patios & fences 0.0056

lb ai/gal 5 gallons 56 3.8 0.0024 0.0000018 850 1.1 x 10 6 850 Mixing/Loading /Applying Liquid Conc. with Hose - end Sprayer (2) Walks,

drives, patios, fences & lawns 0.98 lb

ai/acre 0.5 acre 11 17 0.0081 0.00014 250 1400 0 240 Mixing/Loading /Applying Liquid Conc. with Watering Can (3) Walks,

drives, patios & fences 0.0056

lb ai/gal 5 gallons 11 17 0.00046 0.0000079 430 0 2500 00 4300 Loading/ Applying RTU Liquid with Watering Can (4) In/around

ornamental plants & ground cover 0.04 lb

ai/gal 1 gallon 11 17 0.00066 0.000011 300 0 1800 00 3000 Loading/ Applying RTU Liquid with Trigger Pump Sprayer (5) In/around

ornamental plants & ground cover 0.04 lb

ai/gal 1 gallon 13.5 123 0.00081 0.000082 250 0 2400 0 2200

a Application rates are the maximum application rates determined from EPA registered labels for fluazifop - P - butyl. b Amount handled per day values are EPA estimates. Attire is short - sleeve shirt, short pants, and no gloves and no respirator. c Dermal MOE = NOAEL (2 mg/kg/day) / dermal daily dose (mg/kg/day), where dermal dose = daily unit exposure (mg/lb ai) x application rate amount handled per day / body weight (60 kg female adult). d Inhalation MOE = NOAEL (2 mg/kg/day) / inhalation daily dose (mg/kg/day), where inhalation dose = daily unit exposure (μg/lb ai) x application rate x amount handled per day x conversion factor (1 mg/1,000 g)/body weight (60 Kg adult female). Residential Post - Application Exposure and Risks Fluazifop - P - butyl can be used in a number of residential areas which may be frequented by

the general population such as on home lawns. This provides the potential for dermal (adults and children) and incidental oral exposur e (children) following residential applications of fluazifop - P - butyl. For these purposes, exposure and risk estimates were derived using the HED Standard Operating Procedures for Residential Exposure Assessments (draft December 18, 1997). In accordance, the following fluazifop - P - butyl post - application risk scenarios were assessed for children: 1. Residential Turf (High Contact Activities). 2. Hand to Mouth Activity on Turf.Fluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP No.: 385178

Page 44 of 78 3. Object to Mouth Activity on Turf. 4. In cidental Soil Ingestion. The results for resident ial post - application exposures were found to yi eld MOEs above 100 which indicate that no risks are of concern. The results from these exposure and risk calculations are presented below in Table 6 which are taken from the HED August 2005 tolerance reassessm ent. Table 6 . Fluazifop - P - butyl Post - Application Risk Estimates for Children. Exposure Scenario Route of Exposure Application Rate (lb

ai/acre) MOE on Day 0 (HED’s level of concern = 100) Residential Turf (High Contact Activities) Dermal 0.98 (lawn r enovation) 260 0.09 (established turf) 2,900 0.075 (turf) 170,000 Hand to Mouth Activity on Turf Oral 0.98 (lawn renovation) 6,800 0.09 (established turf) 74,000 0.075 (turf) 89,000 Object to Mouth Activity on Turf Oral 0.98 ( lawn renovation) 27,000 0.09 (established turf) 300,000 0.075 (turf) 360,000 Incidental Soil Ingestion Oral 0.98 (lawn renovation) 2,000,000 0.09 (established turf) 22,000,000 0.075 (turf) 26,000,000 Fluazifop - P - butyl Post - Appli cation Risk Estimates for Adults . High Contact La wn Activities Derm al 0.98 (law n renovation) 380 0.09 (established turf) 4,200 0.075 (turf) 5,000 Mowing Turf Derm al 0.09 (established turf) 26,000 0.075 (turf) 32,000 Golf Course Derm al 0.09 (established turf) 13,000 0.075 (turf) 16,000 Spray Drift Spray drift is alway s a potential source of exposure to residents who may be nearb y to spraying operations. This is particularly the case with aerial application, but could als o be a potential source of exposure from ground application method s to a lesser extent. L abeling instructions for f luazifop - P butyl specify that it is registered for use on several major agricultural crops, including cotton, soy beans, fruit/nut trees, and vegetable crops. As such, it may be applied with aircraft, ground - boom, or air - blast equipment. As indicated in this assessment, fluazifop - P - butyl can be d irectl y applied to residential turf

, which will not r esult in exposures of concern. Based on thi s assessment, HED believes that it is unlikely that there is a higher potential for risk from exposure to spray drift from agricultural uses of this active ingredient.Fluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP No.: 385178

Page 45 of 78 9.0 Aggregate Risk Assessment and Risk Characterization Updates In compliance with FQ PA, HED must consider and aggregate (add) the risks whenever there are potential residential exposures to a pesticide active ingredient. In doing so, the pesticide risks from the three (3) major potential sources of exposure (food, drinking water & reside ntial use) are evaluated collectively . This assessment is made by adding together the exposures from these relevant sources and comparing them to quantitative estimates of hazard (NOAEL, PAD, etc.) , or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED will routinely consider both the route and duration of exposure. For the proposed new uses put forward in th ese petition s (PP# 9F7624 & PP# 9E7651 ), there are potential exposure s to fluazifop - P - butyl which c an occur through food, drinking water, and r esidential use s (turf & ornamental application) . For the most part, identical hazards were identified via the oral, dermal, and inhalation routes over the short - and intermediate - time durations . Short - term resi dential exposures are anticipated but intermediate - and long - term residential exposures are not. Therefore, this aggregate risk assessment will consider potential short - term residential exposures plus those averaged for food and drinking water estimated w ith DEEM - FCIDTM modeling described beforehand. Estimated drinking water concentrations provided by EFED were directl y i ncorporated into the assessment. Acute and Chronic Aggregate Risk Assessments (Food & Drinking Water) For a detailed discussion of the acute and chronic aggregate risk assessments of food and drinking water exposure, r efer to S e c tion 6.1.1 in this memorandum for the anal ys es made with DEEM - FCIDTM modeling. Th ese assessment s conclude d that for all supported registered commodities and new uses, the food plus water dietary risk estimates for acute and chronic exposure are both below the Agency’s level of concern (<100 % of the aPAD & cPAD) . Short - Term Aggregate Risk Assessments Short - term aggregate risk assessments are made to estimate th e potential effects from exposures which can occur from 1 to 30 day s in duration. For fluazifop - P - butyl, there are a number of short - term exposure scenarios which could be aggregated. In doing so, onl y the most likely occurrences were combined so that a conservative (high - end) determination would be made. F or adults, HED combined the average chronic food and drinking water exposures with handler (dermal and inhalation) and postapplication exposure s on treated turf (dermal). For children, HED combined th e average chronic food and drinking water exposures with postapplication dermal and incidental oral (hand - to - mouth, object - to - mouth, soil ingestion) from contact with treated turf . The results from this assessment are presented below in Table 7 for review . These results indicate that short - term aggregate risks are not of concern for fluazifop - P - butyl. Table 7. Short - TermAggregate Risk Population Short - Term Scenario 1 Aggregate MOE (food and residential) 7 HED’s Aggregate LOC 2 MOE

food + water 3 MO E

incid ental oral 4 MOE

dermal 5 MOE inhalation 6 Gen. U.S. Population 100 110,000 NA 150 14,000 150 Adult Female 100 170,000 NA 150 14,000 150 Child 100 33,000 5,500 260 NA 2 50 1 Le vel of Concern (LOC) along with the Margin of Exposure (MOE) for incidental oral, dermal, and inhalation see DP No. D316891, D. Locke, 08/29/2005. MOE for food + water see Table 3 of this memorandum.Fluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP No.: 385178

Page 46 of 78 2 Le vel of Concern (LOC) is 100 based on 10X for inter - species extrapolation and 10X for intra - species variation. 3 MOE food + water = [(short - term oral NOAEL 100 mg/kg/day)/(chronic dietary exposure)] Chronic dietary exposure: General U.S. Pop.= 0.002309 mg/kg/day; Females 13 - 49 yrs = 0.001823 mg/kg/day; Children 1 - 2 yrs. = 0.005994 mg/kg/day. 4 MOE incid ental oral = [(short - term incidental oral NOAEL 100 mg/kg/day)/(child residential exposure)] Child residential exposure: Hand - to - mouth = 0.015 mg/kg/day; Object - to - mouth = 0.0037 mg/kg/day; I ncidental soil ingestion = 0.000049 mg/kg/day. 5 MOE dermal = [ (short - term dermal NOAEL 2 mg/kg/day)/(high - end dermal residential exposure)] Dermal exposure: Adults = handler 0.0081 mg/kg/day + postapp 0.0053 mg/kg/day; Child = 0.0076 mg/kg/day. 6 MOE inhalation = [(inhalation NOAEL 2 mg/kg/day)/(high - end inhalation residential exposure)] I nhalation exposure: Adult = handler 0.00014 mg/kg/day. 7 Aggregate MOE (food + water + residential) = 1÷[ [(1÷MOE food + water) + (1÷MOE incidental oral) + (1÷MOEdermal) + (1÷MOE inh alation)]]. Intermediate - Term Aggregate Risk Ass essments All residential/recreational exposures are anticipated to be short - term in duration (DP No. D316891, D. L ocke, 08/29/2005) . Long - Term Aggregate Risk Assessments Long - term aggregate risks are captured under the chronic dietary risk assessment prev iously discussed. As stated above, no long - term residential exposures are anticipated for fluazifop - P - but yl . 10.0 Occupational Exposure/Pathway The new crop uses which are proposed will be made with the Fusilade® DX Herbicide (EPA Reg. No. 100 - 1070) EC formulation contain ing 24.5% fluazifop - P - butyl ai (equivalent to 2 lb ai/gal) . Its expanded use will employ multiple foliar or vineyard/orchard floor applications at maximum seasonal rates of 1.125 lb ai/A for bananas, grapes, and citrus and 0 .75 lb a i/A for s ugar beets . Applications are to be made with an adjuvant using ground or aerial equipment at P re - H arvest Inter vals (PHIs) which range from 0 day s on treatments made to bananas up to 90 day s for sugar beets. In accordance, occupational handlers and post - application workers can become exposed to fluazifop - P - butyl at short or intermediate - term durations through its use. For the new crop uses being proposed in this action, the expanded use of fluazifop - P - butyl will support commercial agricultural efforts in controlling grass weeds through limited foliar application. Occupational exposures/risks were not addressed in the prior HED human health risk assessment to support tolerance reassessment (DP No. D31 6891 , D . Lo cke , 08/29 /20 05) . An evaluation of the occupational exposure/risk pathway was performed herein to ensure worker protection safeguards (DP No. D 379451 , S. Tadayon, 0 6 /23 /20 1 0) . 10.1 Handler Exposure and Risk For the new crop uses being proposed, agricultural workers may likel y become exposed to fluazifop P - butyl through a number of different application activities. There is a potential for exposure to fluazifop - P - butyl during mixing, loading, and application activities. As such, a short - /intermediate term risk assessment to evaluate exposure using the applicable endpoints selected by the HIARC (06/15/2004) was performed. In doing so, the following worker scenarios were identified for the uses being proposed: Mixer/Loader: 1. Mixing/L oading L iquid Concentrates for Aerial Applications (PHED) 2. Mixing Loading Liquid Concentrates for Chemigation Applications (PHED) 3. Mixing Loading Liquid Concentrates for Groundboom Applications (PHED)Fluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP No.: 385178

Page 47 of 78 Applicators 1. Applying Spray s via Aerial Equipment (PHED) 2. Applying Spray s via Groundboom Equipment (PHED) Mixer/Loader/Applicator 1. Mixing/L oading/Applying with Handgun Spray er (ORETF data) Flaggers 1. Flagging for Aerial Spray Applications (PHED) To estimate risks from occupational exposures associated with these new uses, HED used dermal absorption data f

rom a study

involving human volunteers (Woolen, BH, 1991, "Fluazifop - butyl - Dermal Absorption and Pharmacokinetics in man following single dose of 2 mg and 200 mg"). This study has had the appropriate ethical review and been deemed acceptable for use in human health risk assessment (Lowe, MF, June 10, 2006, Initial Ethics Review of a Human Study of Dermal Absorption and Pharmacokinetics of Fluazifop - But yl "). This study provides two estimates of dermal absorption for fluazifop - but yl , 2% and 9 %. The stud y indicates that the rate of absorption of fluazifop - butyl through the skin is dependent on the level of exposure or dose applied to the skin. Specificall y, low levels of exposure result in higher rates of absorption (9%), and high levels of exposure resu lt in lower rates of absorption (2%). HED's HIARC determined that the data were acceptable and both factors could be used for risk assessment (Report of the Hazard Identification Assessment Review Committee for Fluazifop - P - but yl , D. Anderson, 0 5/20/20 04). HED's TOX SAC met on 0 8/28/20 08 to reconsider the use of both factors in risk assessment. The TOX SAC reconfirmed the appropriateness of the use of both factors for risk assessment because there is high confidence in the data as they come from a study using humans. In addition, the TOX SAC concurred that the use of the 9% dermal absorption factor across all scenarios is conservative given the results of the dermal absorption study in humans, which indicates that as exposures to fluazifop - butyl on the skin increase, the skin becomes saturated and the percentage of dermal absorption decreases. More specificall y, a high dose results in a chemical build up on the skin. This chemical build up acts as a shield and therefore prevents further absorption of the chemical. As a result, there is a lowering of the dermal absorption factor (2%) at higher doses. Conversel y, a scenario in which there is a low daily dose allows the chemical to absorb into the skin without the shielding effect from chemical build up. As a result, a higher dermal absorption factor (9%) is observed at low daily doses. Following this approach, a range of risk estimates (MOEs) for occupational exposures associated with the new uses, one set of MOEs based on 9% dermal absorption and a se cond set of MOEs based on 2% dermal absorption were determined. The TOX SAC considered this a unique circumstance in which available human data could be used to provide a range of risk estimates. In this manner, the use of 2% absorption is considered a r efinement. The non - cancer risk or margin of exposure (MOE) for all time durations was calculated as follows: MOE = NOAEL (mg/K g/day)

Dermal or Inhalation Daily Dose (mg/K g/day)Fluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP No.: 385178

Page 48 of 78 The levels of concern for occupational workers are MOEs of 100 for dermal and inhalation risk. The adverse effects seen i n both the dermal and inhalation studies were similar; therefore, the MOEs were combined to identify a total risk. All short/intermediate - term MOEs calculated for the mixer/loader are greater than 100 at the engineering control level. These MOEs do not e xceed HED’s level of concern. In characterizing these risks, the dermal toxicity study associates a 9% dermal absorption factor with a dermal dose of 0.02 mg/Kg/day , and a 2% dermal absorption factor with a dermal dose of 2.6 mg/Kg/day . As a result, occu pational exposures for the new uses of fluazifop - P butyl were found to range from a high of 0.07 mg/Kg/day to a low of 0.006 mg/Kg/day . To illustrate these findings, the results of occupation handler risk assessment are presented below in Tables 8 and 9 f or review . This anal ys is has determined that exposures greater thean 0.1 mg/Kg/day represent high doses and the use of the 2% dermal absorption factor would be most appropriate for these exposure scenarios (high pressure handwand). Alternatel y, exposures less than 0.1 mg/Kg/day represent low doses and application of the 9% dermal adsorption factor for these scenarios (all other scenarios) would be more appropriate.Fluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP No.: 385178

Page 49 of 78 Table 8 . Short - Term Fluazifop - P - butyl Occupational Handler Risks Exposure Scenario Crop o r Target Application Rate a ( lb ai/A) Area

Treated Daily b ( A /gal ) Dermal Dose (mg/Kg/day) Dermal

Absorption Factor Total MOE c

Baseline+ Glove d Eng Cont e Mi xer/Loader Mixing/L oading L iquid for Aerial and Applications Potato, sugar beet 0. 375 350 4. 53E - 03 9% 280 NA Mixing/L oading L iquid for chemigation Applications Potato, sugar beet 0. 375 350 4.53E - 03 9% 280 NA Mixing/L oading L iquid for Groundboom Applications Potato, sugar beet, citrus, grape, banana, plantains 0. 375 80 1.04E - 03 9% 1223 NA A pplicator Applying Spray s via Aerial Equipment Potato, sugar beet 0.375 350 9.84E - 04 9% No Data 1765 Applying Spray s via Groundboom Equipment Potato, sugar beet, citrus, grape, banana, plantains 0. 375 80 6.30E - 04 9% 2000 NA Mi xer/Loader/Applicator Handgun Spray er (ORETF ) C itrus, grape, banana, plantains 0.375 25 6.33E - 03 9% 303 NA Flagger Flagging for Aerial Spray Applications Potato, sugar beet 0.375 350 2.17E - 03 9% 682 NA NA Not assessed since an acceptable risk is achieved a Application rates are the maximum application rates determined from proposed labels for fluazifop - P - butyl b Amount handled per day values are HED estimates of acres treated per day based on Exposure SAC SOP #9 “Standard Values for Da ily Acres Treated in Agriculture,” indu stry sources, and

HED estimates. c Short - term I

nhalation and dermal MOE = NOAEL (2.mg/kg/day) / inhalation or dermal daily dose (mg/kg/ day), where ; Dermal dose = daily unit exposure (μg/lb ai) x application rate x amount handled per day x 9% dermal ab sorption factor (since all the dermal dose values were less then 0.1 mg/Kg/day a value of 9% dermal absorption factor was used)/body weight (60 Kg). Inhalation dose = daily unit exposure (μg/ lb ai) x application rate x amount handled per day x conversio n factor (1 mg/1,000 μg/body weight (60 Kg). Total MOE = NOAEL / (Dermal dose + I nhalation Dose) d PPE - long pants, long sleeved shirt shoes and glove . e Engineering Controls is closed mixing/loading system, enclosed cab, or enclos ed cockpit.Fluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP No.: 385178

Page 50 of 78 Table 9 . Intermediate - Term Fluazifop - P - butyl Occupational Handler Risks Exposure Scenario Crop or Target Application Rate a lb ai/A Area

Treated Daily b ( A/gal) Dermal

Dose (mg/Kg/day) Dermal

Absorption Factor Total MOE c

Baseline+ Glove d Eng

Cont e Mi xer/Loader Mixing/L oading L iquid for Aerial and Applications Potato, sugar beet 0.375 350 3.88E - 03 9% 114 NA Mixing/L oading L iquid for Chemigation Applications Potato, sugar beet 0. 375 350 3.88E - 03 9% 114 NA Mixing/L oading L iquid s for Groundboom Applications Potato, sugar beet, citrus, grape, banana, plantains 0. 375 80 8.87E - 04 9% 198 NA Applicator Applying Spray s via Aerial Equipment Potato, sugar beet 0. 375 350 8.44E - 04 9% No Data 746 Applying Spray s via Groundboom Equipment Potato, sugar beet, citrus, grape, banana, plantains 0. 375 80 5.40E - 04 9% 813 NA Mi xer/Loader/Applicator Handgun Spray er (ORETF ) Citrus, grape, banana, plantains 0.375 25 5.42E - 03 9% 130 NA Flagger Flagging for Aerial Sprays Applications Potato, su gar beet 0.375 350 1.86E - 03 9% 282 NA NA Not assessed since an acceptable risk is achieved a Application rates are the maximum application rates determined from proposed labels for fluazifop - p - butyl b Amount handled per day values are HED estimates of a cres treated per day based on Exposure SAC SOP #9 “Standard Values for Daily Acres Treated in Agriculture,” , and HED estimat es. c Intermediate - term i nhalation and dermal MOE = NOAEL (0.74mg/Kg/day) / inhalation or dermal daily dose (mg/Kg/ day), where ; Dermal dose = daily unit exposure (μg/ lb ai) x application rate x amount handled per day x 9% dermal absorption factor (since all the dermal dose values were less then 0.1 mg/Kg/day a value of 9% dermal absorption factor was used)/body weight (70 Kg). Inhalation dose = daily unit exposure (μg/ lb ai) x application rate x amount handled per day x conversion factor (1mg/1,000 μg / body weight (70 Kg). Total MOE = NOAEL / (Dermal dose + I nhalation Dose) d Baseline attire is single layer and no gloves/no respirator. e Engineering Controls is closed mixing/loading system, enclosed cab, or enclosed cockpit.Fluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP No.: 385178

Page 51 of 78 10.2 Occupational P ost - A pplication E xposure and Risks Most of the proposed new uses of fluazifop - P - butyl are ground - directed applications where no crop foliage is treated. Currently , HED has no TCs or other data to assess post - application dermal exposures to soil by

occupational workers. For citrus, grape s, bananas, and plantains, the fluazifop P - butyl label prohibits spraying on the foliage. Consequently , for these proposed soil - directed uses, post - application exposures and risks to occupational workers were not quantitatively assessed. Alternatel y, for potatoes and sugar beets, the fluazifop - P - butyl label allows for spraying on the foliage to occur. Therefore, for these proposed uses, post - application exposures and risks to occupational workers were quantitativel y assessed. HED’s post - application exposure estimates are based on a surrogate approa ch due to the lack of chemical - specific data for fluazifop - P - butyl. The maximum application rate is used in this assessment, while assumptions regarding D islodgeable F oliar R esidues (DFR) and workday duration are believed to be average values. Twenty per cent of the residues are assumed available for transfer. Dissipation of foliar residues is assumed to occur at the rate of 10% of the application rate per day . The workday

duration is assumed to be 8 hours. These risk estimates are characterized as central to high - end. Most post - application activities will involve frequent contacts made with the foliage of treated crops requiring the consideration of dermal exposure when evaluating re - entry risks. For any

given activity , the extent of exposure will dep end on the amount of residue on the foliage, the intensity of the contact made with the foliage, and the duration of contact. Dermal absorption factors of 2% and 9% were determined for fluazifop - P - butyl depending on low versus high exposures, respectivel y . R e - entry intervals have been assessed using both values . HED believes that prior dermal absorption studies demonstrate saturation if the mass per unit area exceed s a certain level . Given this, use of the 9% factor in combination with high levels of exposure would result in providing a conservative estimate of risk . The determination of both short - and intermediate - term dermal MOEs for post - application exposure were found to range from 100 to 8900. In reaching or exceeding the LOC of 100, the resulting MOEs indicate these risks are not of concern. The results of this post - application assessment indicate that MOEs are greater than 100 for short - and intermediate - term scouting activities at day 0 when the 2% dermal absorption factor is used . Nevertheless, the MOEs are ≥ 100 for short - and intermediate - term scouting activities with REI s of 3 and 10 day s, respectively , when a conservative dermal absorption factor of 9% is assumed. A summary of the Post - application Exposure and Risk Assessment made herein is presented below in Table 10 for review.Fluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP No.: 385178

Page 52 of 78 Table 10. Fluazifop - P - butyl Exposure and Risk Assessment for Occupational Post - A pplication Activities . Crops 1 Applicati

on Rate (lb ai/A) Dislodgeable

Foliar Residue (ug/cm 2 ) 2 Dermal Transfer

Coefficient 3 (cm 2 /hr) Short - Term (2% DAF ) 4 Intermediate - Term 4 (2% DAF ) MOE REI

(days) MOE REI (days) Potato, sugar beet 0.375 0.84 (day 0) 0.61 (day 3) 0.29 (day 10) High end activities Scouting

2500 360 0 155 0 Low end activities (Irrigation) 100 8900 0 3800 0 Dermal Transfer Coefficient (cm 2 /hr) Short - Term (9% DAF ) Intermediate - Term (9% DAF ) MOE REI

(days) MOE REI (days) High end activities Scouting

2500 110 3 100 10 Low end activities (Irrigation) 100 1985 0 875 0 1. Crop ty pes are taken from the HED Science Advisory Council (SAC) for Exposure Policy 003.1 (August 2000). 2. Dislodgeable Foliar Residue Postapplication day (ug/cm 2 ) = Application rate (lb ai/A) x Fraction of ai Retained on the Foliage x (1 - Fraction of Residue that Dissipates Daily) postapplication day x 4.54E+8 ug/lb x 4.7E - 9 A/cm 2 3. Transfer coefficients are taken from the HED Science Advisory Council (SAC) for Exposure Policy 003.1 (August 2000), which include data supplied b y the Agricultural Reentry Task Force . 4. For short - and intermediate - term dermal risk assessment, the dermal absorption factor of 2% and 9% were applied because the endpoint chosen for this risk assessment was derived from an oral toxicity study .Fluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP N o.: 385178

Page 53 of 78 1 1 .0 Data Needs and Label Requirements 11.1 Toxicology See Appendix A.5 for list of studies and rational for requirements. 11.2 Residue C hemistry 860.1 2 00 Directions for Use The submitted bridgi ng study data made for the Venture L and Fusilade Maxx EC formulation s show that when they

are applied to potatoes at 1x the maximum seasonal rate, the resulting residues will be similar. If the registrant so chooses, a revised section B could be submitte d which includes this use for both product formulations. 860.1 380 Storage Stability Adequate storage stability data are available to support sample storage conditions that were incurred for the potato RAC, but none have been provided for the processed c ommodities. This is required since the processed commodities do not appear to have been anal yzed within thirty (30) day s of production. 860.1520 Processe d Food and Feed The submitted citrus processing stud y is not acceptable having been previously conclu ded b y the Agency to be inadequate (DEB No. 6343, M. J. Bradley , 08/15/1990). Rather then attempting to upgrade these results, it would be prudent for the petitioner to provide a new study given the age of this data submission. 860.1550 Proposed Toleranc es The proposed tolerances should be revised to reflect the recommended tolerance levels and correct commodity

definitions as specified in Table 2 of this memorandum . 1 1 .3 Occupational and R esidential E xposure None 12.0 References DP No.: D347515 Subject: Fluazifop - P - But yl . Amended Human Health Risk Assessment to Support Use on

Dry Beans, Peanuts, and the Post - Bloom Application to Soy beans. From: P. Savoia To: J. Miller & J. Stone Dated: 09/19/200 8 MRID Nos.: 47285501 - 47285505Fluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP N o.: 385178

Page 54 of 78 DP No.: D319907 Subject: Fluazifop - P - butyl. REVISED TRED

– Report on FQPA Tolerance Reassessment

Progress and Interim Risk Management Decisions. Residue Chemistry Considerations. Case No. 2285. From: S. L . Kinard To: D. L ocke Dated: 08/17/2005 MRID Nos.: 00093840 - 1, 00093843, 00093845, 00137763, 00144014, 00151494, 00157191,

001517193, 40140401, 40241901, 40341601, 40361104, 40361108, 40361111, 40693108, 40725701, 40831303 - 5, 40831307, 40831309 - 10, 41018001, 41373703. DP No.: D298939 Subject: Fluazifop - P - butyl. Report of the Metabolism Assessment Review Committee. From: S. L . Kinard To: Y. Donovan Dated: 0 3 / 17 /20 0 4 MRID No.: None DP No.: D291905 Subject: Fluazifop - P - butyl: Revised Residential Exposure Assessment and

Rec ommendations for the Tolerance Reassessment Eligibility Decision (TRED) Document. From: M. Collantes To: D. L ocke Dated: 08/ 10 /20 0 4 MRID No.: None DP No.: D379452 Subject: Fluazifop - P - butyl Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk assessment for the Section 3 Registration Action to add uses on Banana, Plantains, Citrus, Grapes, Potato and Sugar beet. From: S. Tadayon To: P. Savoia Dated: 0 8 / 09 /20 1 0 MRID No.: None DP No s .: D 371093 and D371904 Subject: Drinking Wat er Assessment for the Section 3 registration of Fluazifop - P - butyl for

New Use on Bananas, Plantains, Citrus, Grapes, and Sugar Beets From: Wm. J. Shaughnessy To: J. Miller and M. Walsh Dated: 0 5 /25 /201 0 MRID No.: NoneFluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP N o.: 385178

Page 55 of 78 DP No.: D 379451 Subject: Occupational Risk Assessment to Support Request for a Section 3 registration of

New Uses of Fluazifop - P - butyl From: S . Tadayon To: P. Savoia Dated: 0 6 /23 /20 1 0 MRID No.: None DP No.: D316891 Subject: Fluazifop - P - butyl. REVISED HED Chapter of the Tolerance Reassessment

Eligibility

Document (TRED). PC Code: 122809, Case #2285, DP No. D316891. From: D. L ocke To: L. Wormell Dated: 08/17/20 05 MRID No.: None DP No.: D 348246 Subject: Fluazifop - P - But yl . Section 3 Registration Request to Add New Uses on Beans

(Dry), Peanuts and Soy

beans. Summary

of Analy tical Chemistry

and Residue Data. From: D. Soderberg To: J. Miller Dated: 09/16/2008 MRID Nos.: 47285501 - 05; 46412503 DP No.: D38 5205 Subject: Fluazifop - P - But yl . Amended Section 3 Registration Request to Add New Uses on

Bananas, Citrus, Grapes, and Sugar beets. Summary of Anal yt ical Chemistry

and Residue Data. From: P. Savoia T o: K. Montague and M. Walsh Dated: 01 / 0 4 /201 1 MRID Nos.: 47874601 - 47874606 DP No.: D372408 Subject: Fluazifop - P - But yl . Request for the Registratio n of a Reduced Pre - Harvest Interval

for Application of the Venture L End - Use Product on Potatoes. Summary of Analy tical Chemistry

and Residue Data. From: P. Savoia To: K. Montague and M. Walsh Date: 08/31/2010 MRID Nos.: 47920401 - 47920401Fluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP N o.: 385178

Page 56 of 78 MRID No.: 4787 4601. Kleinschmidt M., M.M. Miller. (2000) Fluazifop - P - But yl

– Residue

Levels in Banana from Trials Carried Out in the United States During 1999 (Final Report). Report Number RR 00 - 43B. Study Number FLUA - 99 - MR - 01. Unpublished study

prepared by

Sy ngenta Crop Protection, Inc. 79 pages. MRID No.: 47874602. Stewart, ER. (2001) Fluazifop - P - but yl

– Residue Levels on Citrus from

Trials Conducted in the United States During 2000 (Final Report). Report Number RR 00 - 63B. Study

Number FLUA - 00 - MR - 03. Unpublish ed study prepared by Sy ngenta Crop Protection, Inc. 126 pages. MRID No.: 47874604. Stewart, E. (2001) Fluazifop - P - Butyl - Residue Levels on Grapes from

Trials Conducted in the United States During 2000 (Final Report). Report Number RR 00 - 062B. Study Number FLUA - 00MR - 02. Unpublished study prepared by Sy ngenta Crop Protection, Inc. 158 pages. MRID No.: 4787 46 03. Stewart, E. (2001) Fluazifop - P - Butyl - Residue Levels on Sugar Beet s

from Trials Conducted in the United States During 2000 ( Final Report ) . Report Number RR 00 - 066B . Study Number FLUA - 00 - MR - 06 . Unpublished study prepared b y Sy

ngenta Crop Protection, Inc . 177 pages. MRID No.: 47920402 Sagan, K. (2009) Fluazifop EC (A12791B)

– Residue Levels on

Potatoes from Trials Conducted in Canada During 2008; Final Report. Laboratory Project ID Report Number: CER02608/08. Task Number: TK0021556. Unpublished study

prepared by

ALS Laboratory

Group Canada, Atlantic Agri Tech., Inc., ICMS, Inc., and Sy ngenta Crop Protection, Inc. 194 pages. MRID No. : 47920403 Sagan, K. (2008) Fluazifop EC (A12791B)

– Residue Levels on

Potatoes from Trials Conducted in Canada During 2007; Final Report. Laboratory Project ID Report Number: CER02606/07. Task Number: TK0021557. Unpublished study

prepared by

ALS Labo ratory

Group Canada, Atlantic Agri Tech., Inc., ICMS, Inc., and Sy ngenta Crop Protection, Inc. 118 pages. DP No.: None Subject: PP#0F3842/FAP#0H5596. Fluazifop - P - butyl on Citrus. Evaluation of Analy tical Methods and Residue Data . MRID Nos. 41373701 - 06 . DEB No. 6343. HED Project No. 0 - 0683. From: M. J. Bradley To: J. Miller Dated: 08/1 5 / 1990 MRID Nos.: 41373701 - 41373706 .Fluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP N o.: 385178

Page 57 of 78 DP No.: D361791 Subject: Chlorantraniliprole. Amended Section 3 Registration Request for Uses on Various

Field, Vegetable, and F ruit Crops and Discussion of Future Registration and Tolerance Requests. Summary of Anal yt ical Chemistry

and Residue Data. From: D. Rate To: V. Eagle and K. Davis Dated: 01/08/2010 MRID Nos.: 47588201 - 11 and 47588214 - 29 MRID No.: 47874605. Stewart, E. ( 2001) Fluazifop - P - Butyl - Residue Levels on Grape Juice

and Raisins from a Trial Conducted in the United States in 2000 (Final Report). Report Number RR 00 - 067B. Study Number FLUA - 00 - PR - 01. Unpublished study prepared b y S yn genta Crop Protection, Inc. 1 24 pages. MRID No.: 4787 4 606. Stewart, E. (2001) Fluazifop - P - Butyl - Residue Levels on Sugar beet

Sugar (Refined), Dry

Pulp and Molasses from a Trial Conducted in the United States During 2000 ( Final Report ) . Report Number RR 00 - 070B . Study Number FLUA - 00 - PR - 04. Unpublished study prepared by Sy

ngenta Crop Protection, Inc . 134 pages. MRID No.: 47920405 Sagan, K. (1994) Determination of Residues of Total - Fluazifop

(Fluazifop - P - Butyl + Fluazifop - P) in Potatoes and their Processed Products Federal Repub lic of German y 1993. L aboratory Project ID Report Number: ICI - 9301. Study Number: Az. 13430/93. Task Number: TK0022593. Unpublished study prepared b y Dr. Specht & Partner Chemische Laboratorien GMBH, and Syngenta Crop Protection, Inc. 66 pages. Fluazi fop, a grass - selective herbicide which inhibits acet yl - CoA carboxylase in sensitive plant species. Walker KA , Ridley SM , Lewis T , Harwood JL . , Biochem J. 1988 Aug 15;254(1):307 - 1 0. Initial Ethics Review of a Human Study of Dermal Absorption and Pharmacokinetics of Fluazifop Butyl ( MRID 46082918 ). L owe MF, Carley JM, June 10, 2006 Ethics Review of Fluazifop - But yl Absorption, Distribution, and Metabolism Study (MRID 00131464). Sherman K, August 13, 2010 Fluazifop - P - But yl . Rationale for Reducing the 10X Safet y Factor to 1X for Lack of an Immunotoxicity

Study . Addendum to Fluaz ifop - P - Butyl Risk Assessment for Dry Beans, Peanuts, and Soy beans [D347515, P. Savoia et al. , 19 - SEP - 2008], J. L iccione, January 23, 2009 DP Barcode: 359779 Appendix A Toxicology Data Requirements and Profile A . 1 Toxicology Data Requirements The requirements (40 CFR 158.500) for food and non - food use for fluazifop - P - butyl are in Table A1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.Fluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP N o.: 385178

Page 58 of 78 Table A1: Toxicology Data Requirements Technical Re quired 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 Sub - chronic (rodent) ................................ ..... 870.3150 Oral Sub - chronic (nonrodent) ............................... 870.3200 21 - Day Dermal ................................ ..................... 870.3250 90 - Day Dermal ................................ ..................... 870.3465 90 - Day/28 - Day Inhalation ................................ .... yes yes yes R R yes

yes yes no no 870.3700a Developmental Toxicity (rodent) ......................... 87 0.3700b 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)

..................... ............................. 870.4200b Oncogenicity (hamster) ................................ ........ 870.4300 Chronic/Oncogenicity

(rat)........................................... yes yes yes yes no yes yes a

yes yes no b yes yes 870.5100 Mutagenicity

— Gene Mutation - bacterial ............ 870.53 00 Mutagenicity

— Gene Mutation - ma mmalian ....... 870.5375 Mutagenicity

— Structural Chromosomal Aberrations ................................ ........................... 870.5395 Mutagenicity

— Other Genotoxic Effects .............. yes yes yes yes yes

yes yes yes 870.6100a Acute Delayed Neurotox. (hen) ............................ 870.6100b 90 - Day Neurotoxicity (hen) ................................ .. 870.6200a Acute Neurotox. Screening Battery (rat) .............. 870.6200b 90 - Day Neuro. Screening Battery (rat) ................. 870.6300 Developmental Neurotoxicity ............................... R R yes yes R yes c

yes c no no no 870.7485 General Metabolism ................................ ............. 870.7600 Dermal Penetration ................................ ............... yes no yes

y es 870.7800 Immunotoxicity............................................................. yes no

a Guideline 870.4300 satisfies this requirement. b The study in the hamster satisfies this requirement. c Required for organo phosphates only . d Reserved. R: RequiredFluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP N o.: 385178

Page 59 of 78 A . 2 Toxicity Profiles

Table A.2.1 Acute Studies with Fluazifop - P - butyl (PC 122809) Guideline No./ Study Type MRID No. Results Toxicity Category 870.1100 Acute oral toxicity /rats (PP00 5; 93.7% & 86.3% ) 00162440 (1984) LD 50 = 3680 mg/kg for males rats LD 50 = 2451 mg/kg for female

rats III

III 870.1200 Acute dermal toxicity /rabbits (PP005; 93.7% & 86.3%) 00162440 (1984) LD 50 > 2000 mg/kg or >1.73 mL/kg III 870.1300 Acute inhalation 1 toxicity /rats (PP005; 24.6%) CTL/P/3331 41917904 (1991) LC 50 > 1.7 mg/L III 870.2400 Acute ey e irritation/rabbit (PP005; 86.3%) CTL/P/856 00162441 (1983) Mild irritation, cleared within 3 day s IV 870.2500 Acute dermal irritation/rabb it (PP005; 86.3%) CTL/P/856 00162441 (1983) Slight irritation, cleared within

72 hours IV 870.2600 Skin sensitization/GP (PP005; 99.6%) 80/ILK026/349 00162441 (1983) Not a skin sensitizerFluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP N o.: 385178

Page 60 of 78 Table A.2.2 Subchronic, Chronic, Developm ental, Reproductive and Other Toxicity Profile on

Fluazifop - butyl [FB] and Fluazifop - P - butyl [FPB]. Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results 870.3100 90 - Day oral toxicity (rat) with FB 00093820 (1980)

Acceptable /guideline 0, 10, 100, 2000 ppm M: 0, 0.7, 7.1, 144.5 mg/kg/day F; 0, 0.8, 8.0, 161.9 mg/kg/day NOAEL=0.7 mg/kg/day

LOAEL=7.1 mg/kg/day based on liver and kidney

histopathology.

870.3100 90 - Day oral toxicity (rat) with FPB 46158402 (1985)

Acceptable/ guideline 0, 10, 100, 2000 ppm

—F: 0, 0.5, 5, 100 mg/kg/day NOAEL=0.5 mg/kg/day

LOAEL=5 mg/kg/day based on decreased spleen weight and decreased hematological parameters in males. Dose related testicular weight decrement and cholesterol depression were also seen. 870.3150 90 - Day oral toxicity (dog) with FB 00093821 (1980)

Acceptable/guideline 0, 5, 25, 125/250 mg/kg/day NOAEL = 25 mg/kg/day

LOAEL = 125/250 mg/kg/day based on multiple pathologies in 3 dogs (2 males and 1 female) killed at 1 month d osed at 250 mg/kg/day. Also seen were body weight loss gut lesions, severe eye lesions and hepatotoxicity. In remaining surviving dogs dosed at 125 mg/kg/day, mild to equivocal liver lesions were

seen. 870.3150 90 - Day oral toxicity (hamster) with FPB 46082902 (2001)

Acceptable/guideline Males: 0, 19.5, 78.3 or 291.9 mg/kg/day Females: 0, 19.9, 79.0 or 319.6 mg/kg/day NOAEL = M/F: 78.3/79.0 mg/kg/day

LOAEL = M/F: 291.9/319.6 mg/kg/day based on decreased body weight/body weight gain and food efficienc y in males and evidence of liver toxicity; centrilobular eosinophilia/loss of glycogen in males and females. 870.3200 21/28 - Day dermal toxicity (rabbit) with FB 00093819 (1980)

Acceptable/guideline 0, 100, 500, 2000 mg/kg/day NOAEL = 100 mg/kg/day

LOA EL = 500 mg/kg/day based on death in 1 male and at 2000 mg/kg/day, death 4 males and 5 females,

possibly due to kidney failure. 870.3700a Prenatal developmental in (Sprague Dawley rats) with FB 0008857, 92067047 (1981) Acceptable/guideline 0, 10, 50, 20 0 mg/kg/day Maternal NOAEL = 200 mg/kg/day

LOAEL = None based on maternal weight decrement due to gravid uterine weight decrement. Developmental NOAEL=none LOAEL=10 mg/kg/day based on delayed ossification. Malformations NOAEL = 50 mg/kg/day LOAEL = 200 m g/kg/day based on diaphragmatic

hernia.Fluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP N o.: 385178

Page 61 of 78 Table A.2.2 Subchronic, Chronic, Developm ental, Reproductive and Other Toxicity Profile on

Fluazifop - butyl [FB] and Fluazifop - P - butyl [FPB]. Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results 870.3700a Developmental toxicity (Sprague Dawley rat) with FB 00088858, 92067048,

92967020 (1981) Acceptable/guideline 0, 1.0, 5.0, 10, 200 mg/kg/day with FB Maternal NOAEL=200 mg/kg/day. LOAEL=None based on mat ernal weight decrement partially explained by gravid urine weight decrement. Developmental NOAEL=1 mg/kg/day. LOAEL=5 mg/kg/day based on fetal weight decrement and increased incidence of small fetuses

and delayed ossification. Malformations NOAEL= 10 mg/k g/day LOAEL=200 mg/kg/day based on increased incidence

of diaphragmatic hernia. 870.3700a Developmental toxicity (Wistar rats) with FPB 46158401 (1991)

Acceptable/guideline 0, 0.5, 1.0, 20, 300 mg/kg/day Maternal NOAEL=20 mg/kg/day

LOAEL=300 mg/kg/day based on body weight gain

decrement. Developmental NOAEL=1.0 mg/kg/day LOAEL=20 mg/kg/day based on delayed ossification in skull bones, cervical arches and centrum in fetuses and litters and delayed ossification in the manus and

pes.

870.3700a Deve lopmental Toxicity (Wistar rats) with FPB 46082903 (1989)

Acceptable/guideline 0, 2, 5 or 100 mg/kg/day Maternal NOAEL=100 mg/kg/day LOAEL= None based no maternal toxicity. Developmental NOAEL=2.0 mg/kg/day LOAEL=5.0 mg/kg/day based on based on dose re lated delayed ossification in skull bones [occipital and parietal] in fetuses and litters.

870.3700a Developmental Toxicity (Wistar rats) with FPB 46082013 (1990)

Acceptable/guideline 0, 2.0, 5.0, 100 mg/kg/day Maternal NOAEL=100 mg/kg/day LOAEL= No ne based on no toxic effects Developmental NOAEL=2.0 mg/kg/day LOAEL=5.0 mg/kg/day based on delayed ossification in skull bones, sternebrae bipartite, sternebrae and calcenum unossifided in fetuses and litters. The overall conclusions based on a weight o f evidence on the five studies of developmental toxicity in the rat were a NOAEL/LOAEL = 2.0/5.0 mg/kg/day based on fetal weight decrement and delayed ossification.Fluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP N o.: 385178

Page 62 of 78 Table A.2.2 Subchronic, Chronic, Developm ental, Reproductive and Other Toxicity Profile on

Fluazifop - butyl [FB] and Fluazifop - P - butyl [FPB]. Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results 870.3700b Developmental toxicity (NZW rabbit) with FB 00088856, 92067049,

92067021 (19 81) Acceptable/guideline 0, 10, 30, 90 mg/kg/day Maternal NOAEL=30 mg/kg/day LOAEL=90 mg/kg/day based on abortions. Developmental NOAEL=30 mg/kg/day LOAEL=90 mg/kg/day based on nominal increases in delayed ossification, total litter loss, abortions, smal l fetuses, cloudy eyes all above mean or range of

historical controls 870.3700b Developmental toxicity (NZW rabbits) with FPB 46082904 (1993)

Acceptable/guideline 0, 2, 10, 50 mg/kg/day Maternal NOAEL=10 mg/kg/day LOAEL=50 mg/kg/day based death, abort ions and

body weight loss Developmental NOAEL=10 mg/kg/day LOAEL=50 mg/kg/day based on increased incidence of 13 th rib and delayed ossification in sternebrae 2. 870.3800 Reproduction and fertility effects (rats) with FB 00088859, 92067050 (1981) Acceptable/guideline 0, 10, 80, 250 ppm M/F: 0/0, 0.74/0.88, 5.8/7.1, 21.7/17.5 mg/kg/day Parental/Systemic NOAEL = M/F 0.74/7.1 mg/kg/day LOAEL = M/F 5.8/ 21.7 mg/kg/day based on decreased spleen wt. in males & increased absolute & relative liver & kidney wts . & geriatric nephropathy

in females. Offspring NOAEL = 7.1 mg/kg/day LOAEL = 21.7 mg/kg/day based on pup viability in f1 and f2 pups during lactational day 1, 4, 11, 18 & 25 and decreased f2 pup weight on lactational day 25. Reproductive NOAEL = M/F 0.74/ 0.88mg/ kg/day LOAEL = M/F 5.8/7.1 mg/kg/day based on decreased abs. & rel testes & epididymal weight and in females decreased pituitary & uterine weights. Sperm counts

not available. Conclusions on the 2 - generation study on reproduction in the Sprague D awley rat: The cause of the dose related testes wt decrease in the P0 and F1 generations has not been demonstrated, but no sperm counts, morphology, motility have been conducted to date. Extensive short term studies on testes weight, testes histopathology , and endocrine effects (MRID# 46082911, 46082916, 46082917, 46082920 & 46082920, see table 4.1d) failed to find the reason for the testes weight decrement in the rat and hamster. However, since the most sensitive tests for effects on sperm were not condu cted (sperm count, motility and morphology as indicated in the 1996 guidelines), it is concluded that testes weight decrement from possible decrements in sperm seen in the rat reproduction and the chronic study in hamsters have not been adequately eliminat ed. The histology on the testes does not support an

effect, but histology is insufficiently sensitive to detect a slight effect. 870.4100a Chronic toxicity (rats) 870.4300 satisfies the

requirementFluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP N o.: 385178

Page 63 of 78 Table A.2.2 Subchronic, Chronic, Developm ental, Reproductive and Other Toxicity Profile on

Fluazifop - butyl [FB] and Fluazifop - P - butyl [FPB]. Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results 870.4100b Chronic toxicity (dog) with FB 001 31462, 00131463,

92067018 (1982) Acceptable/guideline 0, 5, 25, 125 mg/kg/day NOAEL = 5 mg/kg/day LOAEL = 25 mg/kg/day based on marginally increased incidence adrenal fatty vacuolation & increased incidence of thymic involution and at 125 mg/kg/day death of 4/6 males and 2/6 females, eye, gastrointestinal tract lesions, adrenal and bone marrow pathology & thymic involution. 870.4200 Carcinogenicity (hamster) with FPB 4534501, 46082905 (2001) Acceptable/guideline 0, 0, 200, 750, 3000 ppm M: 0, 0, 12.5, 47.4, 193.6 mg/kg/day F: 0, 0, 12.1, 45.5, 181.4 mg/kg/day NOAEL =M/F 12.5/12.1 mg/kg/day

LOAEL = 47.5/45.5 mg/kg/day based on based on increased incidence of males with reduced sperm, testicular degeneration, eye cataract changes, liver inflamation and g all stones and in females, increased incidence of ovarian stroma cell/sex chord

hyperplasia. No evidence of carcinogenicity 870.4300 Chronic/Carcinoge nicity (rat) with FB 41563703 (1985)

Acceptable/guideline 0, 2, 10, 80, 250 ppm M: 0, 0.10, 0.51, 4.15, 12.3 mg/kg/day F: 0, 0.13, 0.65, 5.2, 16.0 mg/kg/day NOAEL =M/F 0.51/5.2 mg/kg/day LOAEL =M/F 4.15/16.0 mg/kg/day based on increased mortality & nephropathy exacerbated by respiratory stress, and in females possible increased basal and/or follicular/lut eal cysts. No evidence of carcinogenicity 870.6100a Acute neurotoxicity in hens with FB 00093818 (1981)

Acceptable/guideline 0, 3750, 7500 or 15000 or 15000 mg/kg Fluazifop - butyl exposed hens showed no evidence of delayed neurotoxicity. 870.7485 Me tabolism and pharmacokinetics (rats) with FB 00093822 through

00093828 (1981) Acceptable/guideline 1 mg/kg and 1000 mg/kg Fluazifop - butyl is rapidly hydrolyzed to fluazifop acid

by blood enzymes and excreted as the acid and its conjugates in the urine of males and females. Due to biliary excretion parent compound, fluazifop acid and its conjugates are excreted in the feces of males at much higher proportions than in feces of the female. Excretion was complete in 7 days, with the exception of small amo unts in the fat in some rats. 870.7600 Dermal penetration (human) 46082918 A human study/NG satisfies guideline 870.7600. Ethics of study cleared.Fluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP N o.: 385178

Page 64 of 78 Table A.2.2 Subchronic, Chronic, Developm ental, Reproductive and Other Toxicity Profile on

Fluazifop - butyl [FB] and Fluazifop - P - butyl [FPB]. Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results NG Comparative metabolism with FB and FPB in rats 00162445, 0012446

(1983) Acceptable/NG 1 mg/k g FB is hydrolyzed and the [S] enantiomer is converted

to the [R] enantiomer. Whether fluazifop - butyl [RS] (50:50) or fluazifop - P - butyl [S] (90:10) is administered, within a hour the blood contained a mixture composed of fluazifop acid in a ratio of [R] 95% and [S] 3%. The two products behaved similarly and reached the same equilibrium within experimental

error. NG Plasma level time course with FB and FPB in rats 46082910 (1998) Acceptable/NG 200 mg/kg The time course of plasma levels and elimination of

the acid metabolite were similar for both fluazifop butyl and fluazifop - P - butyl. Plasma levels of the acid from both isomers were much higher in males than in females. The data support previous studies. NG Absorption and excretion study in hams ters with FPB 46082923 (2002) Acceptable/NG 0, 200, 750, 3000 ppm The study was conducted in two phases, Phase 1 - single dose followed by 3 days of unlabeled test material and Phase 2 - 24 hour feeding of labeled test material followed by 3 day of unla beled test material. Data were consistent with excretion data from other species. The system appeared saturated, since the ratio of the 3000/200 ppm dose levels was much lower than the ratio of respective plasma levels,

especially for males. NG Absor

ption, excretion and tissue retention in mice with FB 46082925 (1992)

Acceptable/NG 1 and 150 mg/kg Male mice excreted proportionally more in feces and

less in urine than females. Although males excreted more than females in the feces and females excre ted more than males in the urine, the difference between males and female mice was smaller than with male and female rats. The study showed individual variability in excretion, similar to that found in the rats and dogs, although analytical deviation may have

explained part of the variation. NG Absorption and excretion in dogs with FB 0093829 (1981)

Acceptable/NG 1 mg/kg One dog showed delayed absorption. Excretion rate

similar to females rats. No evidence of biliary

excretion. NG Peroxisome proliferation in mice, rats, hamsters and humans with FPB 46082919 (1988) Acceptable/NG 0, 80, 250, 1000 or 2000 ppm In vivo and in vitro peroxisome proliferation was

studied in the mouse, rat and hamster and in vitro human hepatocytes. Proliferation in hepatocytes from the greatest to the smallest was: mice > rats > hamster >> human. No increase in cell replication was seen at any dose.Fluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP N o.: 385178

Page 65 of 78 Table A.2.2 Subchronic, Chronic, Developm ental, Reproductive and Other Toxicity Profile on

Fluazifop - butyl [FB] and Fluazifop - P - butyl [FPB]. Guideline No./ Study Type MRID No. (year)/

Classification /Doses Results NG Androgen/estrogen activity with FPB & acid; FB & acid metabolite 46082916 (2001)

Acceptable/NG No agonis t or antagonist activity was detected for FPB or FB or their acid metabolites. Using recombinant yeast strains expressing human androgen receptor or estrogen receptor, the intrinsic androgenic, anti - androgenic, estrogenic, anti - estrogenic activity of FPB, FB and their respective acid metabolites have been assessed by absorbance in a transcription assay. Positive antagonists were hydrotamoxifen and flutamide, which induced appropriate antagonic activity. Agonistic activity assessed by comparison to 17β - es tradiol and dihydrotestosterone; antagonic activity was assessed by inhibition of 17βestradiol and dihydrotestosterone activity. No agonist or antagonic activity was found within 7 orders of magnitude (oom) greater than the conc. of estradiol transcriptio n, 4 oom greater for inhibition of estradiol transcription and 6 oom for agonistic activity of dihydrotestosterone and up to 156 μM antagonist activity by a dose related decrease in dihydrotestosterone - mediated androgenic activity. NG Dermal absorption i n humans with FB 46082918

Acceptable/NG 2 mg & 200 mg/person Dermal absorption was 8.6% at 2 mg/person and 1.9% at 200 mg/person, Ethics of study clearedFluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP N o.: 385178

Page 66 of 78 Table A2.3: Mutagenicity Data Summaries on Fluazifop - butyl (FB) and fluazifop - P - butyl (FPB) Adequacy of data base for Mutagenicity : No mutagenic potential was seen in adequately conducted pre - 1991 guideline mutagenicity studies ( in vivo and in vitro ) on fluazifop - P - butyl [FPB] or fluazifop butyl [FB]. A structural analogue {hal oxyfop - methyl [methyl 2 - [4 - [[3 - chloro - 5 - (trifluromethyl) - 2 - pyridinyl] oxy]phenoxy]propinonate]} of fluazifop - P - butyl showed no mutagenic potential. 1. Gene Mutation Guideline 870.5100, Am es/Salmonella typhimurium, reverse mutation MRID#00162443 Acce ptable Test material [FB] In a reverse gene mutation assay in bacteria (MRID#00162443, 92067023), histidine deficient strains TA98, TA100, TA1535, TA1537, TA1538 of S. typhimurium were exposed to fluazifop - butyl (96.8% a.i., batch/lot# P25) in the prese nce and absence of mammalian metabolic activation by plate incorporation. Negative with and without S9 up to the limit dose of 5000 μg/plate. Guideline 870.5100, Am es/Salmonella typhimurium, reverse mutation MRID#00162442 Acceptable Test material [FPB] In a reverse gene mutation assay in bacteria (MRID#00162442, 92067013), histidine deficient strains TA98, TA100, TA1535, TA1537, TA1538 of S. typhimurium were exposed to fluazifop - butyl (93.6% a.i., batch/lot# P8) in the presence and absence of mammalian metabolic activation by plate incorporation. Negative with and without S9 up to the limit dose of 5000 μg/plate (insoluble at 5000μg/plate). Guideline 870.5300, Mouse lymphoma cell test Acceptable Test material [FB] In a mammalian cell gene mutation assay (MRID# 00116678), heterozygous TK+/ - P 388 mouse lymphoma cells cultured in vitro were exposed to fluazifop - butyl, (99.6% a.i., batch/lot # ADGM/1021/79) at concentrations of 0, 0.25, 2.5, 25, 250 or 2500 μg/mL in the presence an d absence of mammalian metabolic activation, S9, for 30 minutes. Negative with and without S9 up to cytotoxic doses. Guideline 870.5300, Mouse lymphoma L5178Y TK+ test Acceptable Test material [FPB] In a mammalian cell gene mutation assay (MRID#46082906), mouse lymphoma L5178Y TK+ cells in vitro were exposed 4 hr to fluazifop P - butyl at 0, 100, 200, 500, 700, 1000 or 1500 μg/mL with and without S9 activation. In second assay the cells were exposed to 0, 100, 200, 500, 700 or 1000 μg/mL w ith and without S9 activation. Test was negative with and without S9 activation up to and including excessive precipitation. 2. CytogeneticsFluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP N o.: 385178

Page 67 of 78 Table A2.3: Mutagenicity Data Summaries on Fluazifop - butyl (FB) and fluazifop - P - butyl (FPB) Guideline 870.5375; In vitro chromosomal aberrations in human blood lymphocytes. (1985) Acceptable Test mat erial: [FPB] In independently performed mammalian cell cytogenetic assays (chromosome aberration) (MRID#41555202), lymphocyte cultures prepared from human peripheral blood were exposed to fluazifop -p butyl (R - enantiomer, 93.8% a.i.; CTL reference # Y02746 /001/008) in dimethyl sulfoxide for 4 hours at concentrations of 0, 1, 10, 100, 500, or 1000 μg/mL both in the presence and absence of S9 - activation. Cells were harvested at 27 hours after initiation of treatment. The was no evidence of chromosome aberration induced over background in the presence or absence of S9 - activation at toxic doses. Guideline 870.5385, In vivo rat mammalian cytogenetics; bone marrow chromosomal aberrations (1980) Acceptable Test material: [FB] In independent bone marrow chromosome aberration assays (MRID#00088861), 10 male CD rats/dose were treated via oral gavage (10 mL/kg) either once (acute) or daily for 5 consecutive days (sub acute) with fluazifop - butyl (94.5% a.i.; Lot/Batch #: CTL Compound code: Y00083/001/006), i n corn oil at doses of 0, 21.0, 67.2, or 210.0 mg/kg. Bone marrow cells were harvested at 6 or 24 hours after treatment in the acute study, and at 6 hours after treatment in the sub acute study. There was no evidence of chromosome aberration ind uced over background at toxic doses. Guideline 870.5450, Mouse Dominant lethal test (1980) Unacceptable: Top dose not sufficiently toxic Test material: [FB] In a dominant lethal assay (MRID#00088862) [PP009, fluazifop - butyl (97.0% a.i., batch/lot # 310 M)] was administered to 25 CD - 1 m ale mice/group by corn oil gavage (10 mL /kg) at dose levels of 0, 28.7, 91.8 or 287 mg/kg/day for 5 days for the first mating. Based on the results of the first mating, subsequent matings were based on 15 of the 25 dosed males. These 15 males were mated with 30 females in 8 sets and the females examined for dominant lethal effects (resorptions) at day 15 of pregnancy. The investigators reported that fluazifop - butyl does not cause dominant lethal effects in CD - 1 mice up t o and including 287 mg/kg/day for 5 days. No toxicity demonstrated. 3. Other Genotoxicity Guideline 870.5395; In vivo mouse micronucleus test (1983) Acceptable Test material: [FB] and [FPB] Acceptable In an in vivo mammalian cell mouse micronucle us assay (MRID# 0016244,92068014), C57BL/6J mice were administered FB or FPB at doses of 250 or 400 mg/kg and bone marrow removed after 24, 48 or 72 hours to determine the frequency of MPCEP. FB and FPB were tested up to 80% and 50% of the LD50 in mice. There were no adequate evidence of a positive response of increased micronuclei over background with either fluazifop - butyl [FB] or fluazifop - P - butyl [FPB] at toxic doses.Fluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP N o.: 385178

Page 68 of 78 A.3 Hazard Identification and Endpoint Selection A.3.1 Acute Referen ce Dose (aRfD) - Females age 13 - 49 In a developmental toxicity study (MRID# 00088857), fluazifop - butyl was administered to 22 female CD Sprague Dawley strain rats/group in a corn oil (2 ml/kg) gavage at dose levels of 0, 10, 50 or 200 mg/kg bw/day

from da ys 6 through 20 of gestation. Diaphragmatic hernia was seen in 1 fetus at 10 mg/kg/day , none at 50 mg/kg/day and in 3 fetuses at 200 mg/kg/day . No diaphragmatic hernia was seen in 2970 historical control fetuses. In a subsequent study (discussed below) w ith a larger number of litters (160 litter/group) diaphragmatic hernias were seen in 3 of 1113 control fetuses, 1 of 1081 fetuses at 1 mg/kg/day , 3 of 1073 fetuses at 5 mg/kg/day , 2 of 1064 fetuses at 10 mg/kg/day

and in 59 of 1064 fetuses (and 45/159 litters)at 200 mg/kg/day . Since this anomaly was seen at a higher incidence (3 fetuses) in the controls in this study and was not replicated at the same dose in the second study , the single incidence of diaphragmatic hernia at 10 mg/kg/day was considered to be an aberration and not attributable to treatment. In an another developmental toxicity study (MRID# 00088858) fluazifop - butyl was administered to 159 or 160 female CD Sprague Dawley strain rats/group in a corn oil (2 ml/kg) gavage at dose levels of 0, 1 .0, 5.0, 10 or 200 mg/kg bw/day from day 6 through 20 of gestation. There was an increased incidence of diaphragmatic hernia were seen in fetuses (5% versus 0.13% in control) and litters (43.4% versus 1.9%) at 200 mg/kg/day . Dose and Endpoint for Establi shing aRfD: NOAELis 50 mg/kg/day based on the increased incidence of diaphragmatic hernia at 200 mg/kg/day. Uncertaint y Factor (UF) : 100. This includes 10X for inter - species extrapolation and 10X for intra species variation. Comments about Study

/End point/Uncertaint y Factor: The NOAEL selected is based on the combined results of the two studies. In the two studies conducted in the same strain of rats with an identical dosing regimen, diaphragmatic hernias were seen at 200 mg/kg/day in both studies; n one were seen at 50 mg/kg/day in the second study

(MRID# 00088858); and a single incidence was seen at 10 mg/kg/day

in the first study

(MRID# 00088857). The single incidence in the first study was not considered to be treatment - related since the incidence was lower than that seen in the control fetuses in the second study and was not replicated at the same dose in the later study . Therefore, based on the combined doses tested, 0, 1, 5, 10, 50, or 200 mg/kg/day, for this effect, the NOAEL is 50 mg/kg/day an d the LOAEL is 200 mg/kg/day . These values differ from the study NOAE L/ LOAEL. This particular developmental effect is presumed to occur after a single exposure and thus is appropriate for this population subgroup (Females 13 - 49).

A.3.2 Acute Reference Dose (aRfD) - General Population An appropriate endpoint attributable to a single dose was not available in the database including the developmental toxicity studies. Acute RfD (Female 13 - 49) = 50 mg/kg (NOAEL) /100 (UF) = 0.50 mg/kgFluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP N o.: 385178

Page 69 of 78 A.3.3 Chronic Refe rence Dose (cRfD) See Section 4.2.4 for a descriptive summary of the Two - Generation Reproduction Study in rats (MRID# 00008859, 92067022 & 92067050). Dose and Endpoint for Establishing cRfD: NOAELis 0.74 mg/kg/day based on decreases in absolute and re lative testes and epididy mal weights in males at 5.8 mg/kg/day (LOAEL). Uncertaint y Factor(s): 100X (10X for inter species extrapolation and 10X for intra species variation. Comments about Study

/Endpoint/Uncertaint y Factor : The study /dose/endpoint is appropriate for the route (oral) and duration (chronic) of concern. Although the endpoint of concern in based on male reproductive effects, decreases in pituitary and uterine weights were seen in females at a comparable NOAEL (0.88 mg/kg/day) and LOAEL ( 7.1 mg/kg/day).

A.3.4 Incidental Oral Exposure (Short - and Intermediate - Term) Short - Term Incidental Oral Exposure (1 - 30 days) See Section 4.2.3 for a descriptive summary of the Developmental Toxicity Studies in rats (MRID# 46082913, 46158401, 46082903). A brief summary relevant to the endpoint selected is presented below. In a developmental toxicity study (MRID# 4608 2913) fluazifop - P - butyl was administered to Aderl y Park strain of Wistar rats b y gavage at dose levels of 0, 2.0, 5.0 or 100 mg a.i./kgday from day s 7 through 16 of gestation. No evidence of maternal toxicity was seen at any

dose level. For maternal toxic ity , the NOAELis 100 mg/kg/day (HD T) and a LOAEL wa s not established. In another developmental toxicity study (MRID# 46158401) fluazifop - P - butyl was administered to Alderly Park strain of Wistar rats by gavage at dose levels of 0, 0.5, 1.0, 20, or 300 mg/kg /day from day s 7 through 16 of gestation. Maternal toxicity at 300 mg/kg/day

was indicated by

a bod y weight gain decrement of 19% during the dosing period, GD 7 - 16. Food consumption was decreased statisticall y significantly at the same dose and food efficiency decreased 13%. For maternal toxicity , the NOAELis 20 mg/kg/day and the L OAEL is 300 mg/kg/day based on decreases in bod y weight gain maternal animals. In another developmental toxicity study (MRID# 46028903) fluazifop - P - butyl was administered to Alderly Park strain of Wistar rats by gavage at dose levels of 0, 2, 5 or 100 mg a.i./kgday from day s 7 through 21 of gestation. No maternal toxicity was seen. For maternal toxicity , the NOAEL is 100 mg/kg/day

(HDT) and a LOAEL is not established. Chronic RfD = 0.74 mg/kg/day (NOAEL)/100 (UF) = 0.0074 mg/kg/dayFluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP N o.: 385178

Page 70 of 78 D ose and Endpoint for Risk Assessment: Maternal NOAEL of 100 mg/kg/day based on decreases in body weight gain in maternal animals during the dosing period (GD 7 - 16) at 300 mg/kg/day (LOAEL). Comments about Study

/Endpoint: The maternal NOAEL is selected ba sed on the combined results of the two studies with support from the third study . The first two studies were conducted in the same strain of rats (Wistar) with identical dosing regimen (dosing during GD 7 - 16) in the same laboratory . The lower NOAEL (20 mg/kg/day) in the second study (46158401) is an artifact of dose selection. Additionally , the NOAEL is supported by another study

conducted in the same strain of rats with a slightly longer dosing period (GD 7 - 21) where no maternal toxicity was seen at 100 mg/kg/day , the highest dose tested (MRID# 46082903). This dose/endpoint is appropriate for the population (infants and children) and duration (1 - 30 day s) of concern. Intermediate - Term Incidental Oral Exposure (1 - 6 months) See Section 4.2.4 for a descriptive summary of the Two - Generation Reproduction Study in rats (MRID# 00008859, 92067022 & 92067050). Dose and Endpoint for Establishing cRfD: NOAEL is 0.74 mg/kg/day based on decrease s in absolute and relative testes and epidid ym al weights in males at 5.8 mg/kg/day (LOAEL). Comments about Study

/Endpoint : The endpoint of concern was seen after approximately 13 - 16 weeks of exposure and thus is appropriate for the duration (1 - 6 months ) of concern. Although the endpoint of concern in based on male reproductive effects, decreases in pituitary and uterine weights were seen in females at a comparable NOAEL (0.88 mg/kg/day) and L OAEL (7.1 mg/kg/day). This endpoint is appropriate for the p opulation (infants and children) of concern. A.3.5 Dermal Exposure (Short - , Intermediate - and Long - Term) In a dermal absorption and pharmacokinetic study in humans (MRID# 46082918), six men (age 18 - 45; weight 60 - 90 kg)/dose were dosed dermally with 2 mg or 200 mg of 0.05% or a 5.0% (w/v) solution of fluazifop - butyl in a formulation. Four ml of each solution was spread over 800 cm 2 of the backs of 6 men/dose level, allowed to dry and left un - occluded for 8 hours. Plasma and urine was collected in multip le samples over a 264 hour period. Plasma was collected hourl y for 4 hours, every

2 hours for 12 hours and every 24 hours to the end. Urines were collected every 4 hours for 12 hours and then every 24 hours to the end. After 8 hours, the application sit e was washed with water using cotton swabs and 3% Teepol and covered with a T - shirt over the application site until morning. At 24 hours after application the site was again washed with a 3% solution of Teepol. The washes, T - shirts, plasma and urine samp les were analyzed for fluazifop butyl or fluazifop acid.Fluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP N o.: 385178

Page 71 of 78 Most of the applied dose appeared to be in the stratum corneum and easily removed. Recovery

of test material was good, a mean of 93.4% ± a standard deviation of 13% at the 2 mg dose and mean of 83.2% ± a standard deviation of 21% at the 200 mg dose. Peak plasma levels were shown to occur 24 to 31 hours after applicat ion in these men. The one half - life for excretion was about 18 hours. In arriving at these percentage s of recovery , the study author s added a correction to the amount excreted in the urine (i.e. to the amount excreted up to 120 hours was added the amount excre ted after 120 hours through a 2 - compartment pharmacokinetic model ) . However, this latter correction was insignificantly smal l amounting about 0.008% of the 200 mg applied to the skin. HED modified the study

author’s percentage absorption by scaling the recovered material to 100% . The modified dermal absorption was calculated by two methods; (1) Unrecovered added to absorbed m aterial, and (2) Scaling recovered material to100%. Method (1) yielded absorption factors of 18.4% and 14.6% at the 2 mg dose and 200 mg dose, respectively. Method (2) yi elded absorption factors of 8.6% and 1.9% at the 2 mg dose and 200 mg dose, respecti vely . Method (2) appeared to be more reasonable because residual material (unrecovered) may have been relativel y immobile. The unrecovered test material was speculated to be in the outer layers of the skin and appeared to be easily

removed. Short - Term D ermal Exposure (1 - 30 days) See Sections 4.4.1 and 4.4.4 for a descriptive summary of the Developmental Toxicity Studies in rats (MRID# 00088858, 46082903, 46082913, 46158401). Though the Assessment t eam chose two short - term dermal endpoints, one for females of child - bearing age based on concerns for in utero effects, and another for all other population subgroups, for regulatory purposes, the dose and endpoint for the most sensitive population was use d in the risk assessment for all population subgroups. Since females of child - bearing age cannot be excluded or treated separatel y from the general population should regulatory and/or mitigation measures be necessary , it is incumbent upon the Agency

to ad dress the potential risks of the most sensitive population as representative of the entire population. The short - term dermal endpoint that the assessment team chose for the general population, including infants and children, was selected from 3 developmental toxicity studies in rats (MRID# 46158401, 46082913 and 46082903). See a description under Section 4.4.4 Short - term Incidental Oral above. The dose/endpoint chosen is the maternal NOAEL of 100 mg/kg/day based on decreases in bod y weight gain in matern al animals during the dosing period (GD 7 - 16) at 300 mg/kg/day

(LOAEL). For the reasons stated above, the risk assessment was conducted using the short - term dermal endpoint selected for females 13 - 49 y ears of age. Dose and Endpoint for Risk Assessment : D evelopmental NOAEL is 2.0 mg/kg/day based on fetal weight decrement, increased incidence of h ydroureter and delayed ossification at 5.0 mg/kg/day (LOAEL). Comments about Study

/Endpoint: The in utero effects are appropriate to assess dermal risks for the p opulation subgroup, Females 13 - 49 from exposure to fluazifop - butyl. This endpoint was selected because of the developmental toxicity concerns seen consistently in rats and rabbits via the oral route. The team did not select the 21 - day dermal toxicity

stu dy in rabbits due to the concern for developmental toxicity which is not evaluated in the dermal study . In addition, dermal study would not address the developmental concerns since the NOAEL (100 mg/kg/day) in thatFluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP N o.: 385178

Page 72 of 78 study is considerably

higher than the de rmal equivalent dose (22 mg/kg/day) obtained using the oral dose (2.0 mg/kg/day) with a 9% dermal absorption factor (2.0  0.09 = 22). Since an oral NOAEL was selected, an appropriate dermal absorption factor (i.e., 2% or 9%, exposure depended) was used for route - to - route extrapolation. Intermediate and Long - Term Dermal Exposure (1 - 6 months & > 6 months) See Section 4.2.4 for a descriptive summary of the Two - Generation R eproduction Study in rats (MRID# 00008859, 92067022 & 92067050). Dose and Endpoint for Risk Assessment: NOAEL is 0.74 mg/kg/day based on decreases in absolute and relative testes and epidid ym al weights in males at 5.8 mg/kg/day (LOAEL). Comments about Study

/Endpoint : The endpoint of concern was seen after approximately 13 - 16 weeks of exposure and thus is appropriate for the duration (1 - 6 months) of concern. Although the endpoint of concern in based on male reproductive effects, decreases in pituitary and uterine weights were seen in females at a comparable NOAEL (0.88 mg/kg/day) and L OAEL (7.1 mg/kg/day). These endpoints are appropriate for the general population including infants and children. Since an oral NOAEL was selected an appropriate dermal absorption factor (i.e., 2% or 9%, exposure depended) was used for route - to - route extrapolation. A.3.6 Inhalation Exposure (Short - , Intermediate - and Long - Term) Short - Term Inhalation Exposure (1 - 30 days) See Sections 4.4.1 and 4.4.4 for a descriptive summary of the Developmental Toxicity Studies in rats (MRID# 00088858, 46082903, 46082913, 46158401). Again, though the Assessment team chose two short - term inhalation endpoints, one for females of child - bearing age based on concerns for in utero effects, and another for all other population subgroups, for regulatory purposes, the dose and endpoint for the most sensitive population was used in the risk assessment. Dose and Endpoint for Risk Assessm ent : Developmental NOAEL is 2.0 mg/kg/day based on fetal weight decrement, increased incidence of h ydroureter and delayed ossification at 5.0 mg/kg/day (LOAEL) Comments about Study

/Endpoint: The in utero effects are appropriate to assess inhalation risks for the population subgroup, Females 13 - 49 y ears from exposure to fluazifop - P - butyl. This endpoint was selected because of the developmental toxicity concerns seen consistently in rats and rabbits via the oral route. The Assessment team noted the absence of a repeated exposure inhalation toxicity study . For route - to - route extrapolation, absorption via the inhalation route is assumed to be equivalent to oral absorption. Intermediate - and Long - Term Inhalation Exposure (1 - 6 months & > 6 months) See Section 4.2.4 for a descriptive summary of the Two - Generation Reproduction Study in rats (MRID# 00008859, 92067022 & 92067050).Fluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP N o.: 385178

Page 73 of 78 Dose and Endpoint for Risk Assessment: N OAEL is 0.74 mg/kg/day based on decreases in absolute and relative testes and epidid ym al weights in males at 5.8 mg/kg/day (LOAEL). Comments about Study

/Endpoint : The endpoint of concern was seen after approximately 13 - 16 weeks of exposure and thus i s appropriate for the duration (1 - 6 months) of concern. Although the endpoint of concern is based on male reproductive effects, decreases in pituitary and uterine weights were seen in females at a comparable NOAEL (0.88 mg/kg/day) and L OAEL (7.1 mg/kg/day) . These endpoints are appropriate for the general population including infants and children. Again, the Assessment team noted the absence of a repeated exposure inhalation toxicity study . For route - to - route extrapolation, absorption via the inhalation r oute is assumed to be equivalent to oral absorption. A.4 Executive Summaries A detailed summary

of the various study

executive summaries are listed in the document “ Fluazifop - P - but yl : Revised HED Chapter of the Tolerance Reassessment Eligibility Docume nt (TRED) ” ( August 29, 2005, PC Code: 122809, Case # 2285, DP Barcode: D316891 ).Fluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP N o.: 385178

Page 74 of 78 A.5 Toxicology Data Required as a Condition of Registration Guideline Number: 870.3250 Study Title: 90 - Day Dermal Toxicity Rationale for Requir ing the Data As well as food uses, fluazifop - P - butyl has non - food, commerical and residential uses, including roadsides, turf and shrub applications. The sub - chronic (90 - day) dermal toxicity study is a new data requirement under 40 CFR Part 158 as a part of the data requirements for registration of a pesticide for non - food use. The dermal toxicity Test Guidelines (OPPTS.870.3250) is intended to evaluate the toxic effects associated with continuous or repeated exposures to a test substance for a period of 90 - days. The Agency requests a 90 - day dermal toxicity study for non - food use pesticides because the dermal route will be the primary route of exposures for che micals designated with this use pattern (i.e., non food). The Agency believes that this study i s required because the longer term oral studies (i.e., chronic or carcinogenicity studies) which are required for food - use pesticides are usually not required for non food use pesticides. A 21/28 day dermal toxicity test is insufficient to identify potent ial hazards for non - food use pesticides because of the concern for the longer duration exposure associated with this use pattern. For example, professional applicators may be subjected to repeated exposure during the 3 month p eriod of peak summer usage . F or this type of increased exposure, professional applicators may not be adequately protected using data from a 21/28 - day study. Additionally, the 28 - day dermal study revealed adverse responses such as an animal death at the study LOAEL, suggesting that fur ther dermal testing is required to determine whether longer exposure may decrease the dermal LOAEL and NOAEL values. Practical Utility of the Data How will the data be used? A route specific (i.e., dermal) study will provide critical scientific infor mation needed to characterize potential hazard to the human population exposed to the pesticide by the dermal route. This study will provide a dose and a toxicological endpoint of concern for quantification of risks for dermal exposures. This study would eliminate the uncertainties associated with the use of an oral study with a default (100% oral equivalent) dermal absorption factor. In many cases, toxicity observed via the dermal route will be different than toxicity observed via oral exposure, due t o absorption and distribution of the toxic agent after exposure or differences in metabolism (i.e., systemic versus local). This means that the route - to - route extrapolation (i.e., use of an oral dose/endpoint) in risk assessment could result in under or o ver estimation of risks from the dermal route. How could the data impact the Agency’s future decision - making? If the dermal toxicity study indicates that the test material poses either a greater or lesser risk than that calculated using an oral dose, (a s used in the interim decision), the risk assessment would be revised to reflect the magnitude of potential risk derived from the new data. Also, the requested data would allow the Agency to determine if the risks were over - estimated or under - estimated. I f the risks were under estimated, additional risk mitigation measures could be required. If the risks were over - estimated, risk mitigation measures could be reduced.Fluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP N o.: 385178

Page 75 of 78 Guideline Number: 870.3465 Study Title: 90 - Day/28 - Day Inhalation Toxicity Ration ale for Requiring the Data C onducting the inhalation study for 90 days, is requested by the Agency because intermediate - term exposure to workers is expected based on fluazifop - P - butyl 's use pattern. A longer - term inhalation study is required in situation s in which a specific concern exists for increased hazard related to exposure via the inhalation route. The 28 - day inhalation toxicity study evaluates the potential hazard of a pesticide chemical following repeated inhalation exposures. This study is imp ortant for pesticides such as fluazifop - P - butyl with use patterns in which there is potential for repeated human exposures (e.g., professional applicators, green house use, etc.) of periods of 28 days or more . The study des ign simulates one route of human exposure (inhalation) to a pesticide, the animals are exposed (nose/whole body) to aerosol concentrations of the test material for 6 hours/day, 5 days/week for 90/ 28 days. A detailed toxicological examination including the histopathology of the respiratory system is conducted. This route - specific study would provide data for hazard characterization, dose response assessment, and a dose and endpoint for assessing potential risks via the inhalation route. Practical Utility of the Data How will the data be used? This study will identify hazard (i.e., provide a dose and endpoint) following repeated inhalation exposures. The results will be used in risk assessments as appropriate. How could the data impact the Agency’s decision - making? A sub - chronic inhalation study could provide scientific information to characterize potential hazard to the human respiratory system from pesticide e xposure. In the case of fluazifop - P - butyl , there is no acceptable inhalation study available. A 90/ 28 - day repeated exp osure study that follows the Test Guidelines (870.3465) will characterize hazard and provide data for a more refined inhalation risk assessment. Exposure time may be reduced 28 days pending exposure patterns, plateauing of effects and considering the overa ll toxicity potential of fluazifop .Fluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP N o.: 385178

Page 76 of 78 Guideline Number: 870.6200 Study Title : Neurotoxicity Battery (Acute and Sub - Chronic Studies) Rationale for Requiring the Data This is a new data requirement under 40 CFR Part 158 as a part of the data requirements for registration of a pesticide (food and non - food uses). The Neurotoxicity Screening Battery (OPPTS 870.6200) is designed to evaluate the potential adverse effects on the nervous system from exposure to pesticide chemicals. The Agency believes that the guideline studies are inadequate in their assessment of behavioral effects and do not use optimal methods to evaluate the potential toxicity to the nervous tissue structure and function. To detect and characterize these potential effects more fully, a battery of more sensitive testing is required. The objective of this neurotoxicity battery testing is to evaluate the incidence and severity of the functional and/or behavioral effects, the level of motor activity, and the histopathology of the nervous system. The acute neurotoxicity study is required to detect possible effects resulting from a single exposure. The sub - chronic neurotoxicity study is intended to detect possible effects resulting from repeated or long term exposures. Practical Utility of the Data How will the data be used? The acute and sub - chronic neurotoxicity studies could provide scientific information to characterize potential hazard to the human population on the nervous system from pesticide ex posure. These studies can provide data on a wide range of functional tests for evaluating neurotoxicity including sensory effects, neuromuscular effects, learning and memory and histopathology of the nervous system For example, animal studies with organop hosphorous chemicals have shown neurotoxicity to be the primary toxic endpoints (e.g., cholinesterase inhibition) of concern in rodents and non - rodents. These animal studies can be used to select endpoints and doses for use in risk assessment of all exposure scenarios and are considered a primary data source for reliable reference dose calculation. The Agency has established an oral reference dose (RfD) for assessing dietary risks for a number of chemicals (e.g., organophoshates and carbamates) where ne urotoxicity was the most sensitive endpoint of concern. How could the data impact the Agency's future decision - making? If the acute or sub - chronic neuroto xicity studies show that fluazifop - P - butyl poses either a greater or a diminished risk than that gi ven in the interim decision’s conclusion, the risk assessment for fluazifop P - butyl may need to be revised to reflect the magnitude of potential risk derived from the new data. If the Agency does not have th ese data, a 10X database uncertainty factor may be applied when conducting a risk assessment using the currently available studies.Fluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP N o.: 385178

Page 77 of 78 Guideline Number: 870.7800 Study Title : Immunotoxicity Rationale for Requiring the Data This is a new data requirement under 40 CFR Part 158 as a part of the data requirements for registration of a pesticide (food and non - food uses). The Immunotoxicity

Test Guideline (OPPTS 870.7800) prescribes functional immunotoxicity testing and is designed to evaluate the potential of a repeated chemical exposure to prod uce adverse effects (i.e. suppression) on the immune sy stem. Immunosuppression is a deficit in the ability of the immune s ys tem to respond to a challenge of bacterial or viral infections such as tuberculosis (TB), Severe Acquired Respiratory Sy ndrome (SARS ), or neoplasia. Because the immune sy stem is highl y complex, studies assess ing functional immunotoxic endpoints are helpful in fully characteriz ing a pesticide’s potential immunotoxicity . These data will be used in combination with data from hematology , ly mphoid organ weights, and histopathology in routine chronic or sub - chronic toxicity studies to characterize potential immunotoxic effects. 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 pe sticide’s potential immunotoxicity in humans, animal studies are used as the most sensitive endpoint for risk assessment. These animal studies can be used to select endpoints and doses for use in risk assessment of all exposure scenarios and are considere d a primary

data source for reliable reference dose calculation. For example, animal studies have demonstrated that immunotoxicity in rodents is one of the more sensitive manifestations of TCDD (2,3,7,8 - tetrachlorodibenzo - p - dioxin) among developmental, rep roductive, and endocrinologic toxicities. Additionally , the EPA has established an oral reference dose (RfD) for tributyltin oxide (TBTO) based on observed immunotoxicity in animal studies (IRI S, 1997). How could the data impact the Agency's future decis ion - making? If the immunotoxicity

study shows that the test material poses either a greater or a diminished risk than that given in the interim decision’s conclusion, the risk assessments for the test material may

need to be revised to reflect the magnit ude of potential risk derived from the new data. If the Agency

does not have this data, a 10X database uncertaint y factor may be applied for conducting a risk assessment from the available studies. Appendix B . Review of Human ResearchFluazifop - P - But yl Human Health Risk Assessment to Support New Uses DP N o.: 385178

Page 78 of 78 Past fluazifo p - P - butyl risk assessments rel y in part on data from studies in which adult human subjects were intentionally exposed to a pesticide to deter mine their dermal exposure and pharmacokinetics . Many such studies, involving exposure to many different pesticide s, comprise generic pesticide exposure databases such as the Pesticide Handlers Exposure Database (PHED), the Agricultural Reentry

Task Force (ARTF) Database, and the Outdoor Residential Exposure Task Force (ORETF) Database. EPA has reviewed all the studi es supporting these multi - pesticide generic exposure databases, and has found no clear and convincing evidence that the conduct of any of them was either fundamentally unethical or significantl y deficient relative to the ethical standards prevailing at the time the research was conducted. All applicable requirements of EPA’s Rule for the Protection of Human Subjects of Research (40 CFR Part 26) have been satisfied, and there is no regulatory

barrier to continued reliance on these studies. The fluazifop - butyl human dermal study

( MRID 46082918 ) utilized in this risk assessment was cleared for use in the memo “ Initial Ethics Review of a Human Study of Dermal Absorption and Pharmacokinetics of Fluazifop - But yl ”, Lowe MF, Carley JM, June 10, 2006.