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**EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER**  **EPA Registration**  **Division contact:**  **Maggie Rudick 703**  **- 347**  **- 0257**  **; rudick.maggie@epa.gov**  **TEMPLATE:** Dow AgroSciences LLC 9330 Zionsville Road Indianapolis, IN 46268 - 1054 2F8086EPA has received a pesticide petition 2F8086 from Dow AgroSciences LLC , 9330 Zionsville Road, Indianapolis, IN 46268 request ing, pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180 1. by establishing a tolerance for residues of the herbicide H alaux ifen - methyl , including its metabolites and degradates, in or on the commodities listed below. Compliance with the tolerance levels specified is to be determined b y measuring the combined residues of halaux ifen - methyl (Methyl 4 - amino 3 - chloro - 6 - (4 - chloro - 2 - fluoro - 3 - m ethox yphen yl )py r idine - 2 - carbox yl ate) and halaux ifen (4 - amino - 3 - chloro - 6 - (4 - chloro - 2 - fluoro - 3 - methoxy phenyl)py

ridine - 2 - c arboxylic acid) expressed as halaux ifen - methyl (parent) equivalents in or on the raw agricultural commodity barley , grain at 0.01 parts p er million (ppm) ; barley , hay at 0.01 ppm; barley , straw at 0.01 ppm; cattle, fat at 0.01 ppm; cattle, meat at 0.01 ppm; cattle, meat by products at 0.01 ppm; goat, fat at 0.01 ppm; goat, meat at 0.01 ppm; goat, meat by products at 0.01 ppm; horse, fat at 0.01 ppm; horse, meat at 0.01 ppm; horse, meat by products at 0.01 ppm; milk at 0.01 ppm; sheep, fat at 0.01 ppm; sheep, meat at 0.01 ppm; sheep, meat b yproducts at 0.01 ppm; wheat, forage at 0.5 ppm; wheat, grain at 0.01 ppm; wheat , hay at 0.0 4 ppm; wheat , straw at 0.01 5 ppm . EPA has determined that the petition contains data or information regarding the elements set forth in section 408 (d)(2) of FDDCA; however, EPA has not fully evaluated the sufficiency of the submitted data at this time or whether th e data supports granting of the petition. Additional data may be needed before EPA rules on the petition. A. Residue Chemistry 1. Plant metabolism. The nature of the residue in plants is adequatel y understood2

for the purpose of establishing the proposed tolerances. Based on the findings from metabolism studies in wheat and turnips , the residue of concern in plants is the combined residue of halaux ifen - methyl and halaux ifen, expressed as halaux ifen - methyl. 2. Analytical method. The residue profile of halaux ifen - methyl and halaux ifen is adequatel y understood and an acceptable anal yt ical method is available for enforcement purposes. The DAS analy tical method study

number 110004 outlining the Method Validation for the Determinatio n of Residues of Halauxifen - methyl Ester and Halauxifen in Agricultural Commodities and Wheat Processed Products using Offline Solid - Phase Extraction and L iquid Chromatograph y wi th Mass Spectrometry Detection was validated on a variet y of plant matrices. The method was validated over the concentration range of 0.01 - 1.00 mg/kg with a limit of quantitation of 0.01 mg/kg. 3. Magnitude of residues. Good Agricultural Practices (GAP) for each crop have been harmonized as much as possible across countries. A s ignificant number of supervised residue trials have been carried out at the critical GAP on wheat and barley in Australia, New Zealand, United States, and Canada to provide harmonized data for MRL setting. Data on oats was also generated in Australia, where it is a required representative crop. There were thirty - nine trials conducted on wheat, twenty - two trials conducted on barley , and four trials conducted on oats. Residues in food and feed commodities were rather homogeneous within each crop, and did n ot show significant statistical differences across geographies, varieties, or cultural practices. Therefore, it is adequate to propose and support harmonized MRL s . Trials from NAFTA regions during the 2010 and 2011 growing seasons are summarized for the purpose of the US petition. For both barley and wheat, applications were made at the BBCH 39 growth stage at a target rate of 0.0089 lb a.e./A of applied halaux ifen methyl plus 0.0089 lb ai/A of the safener cloquintocet. The Limit of Detection (L OD) and L imit of Quantification (LOQ) values were validated for the anal yt ical method as 0.001 ppm and 0.003 ppm, respectivel y for each anal yt e in grain, straw, forage and hay . Observed residues support a suite of proposed US tole rances at the limit of quantitation (LOQ) for most commodities. For barley , residues of halaux ifen - methyl and halaux ifen were determined following 1 foliar application for 18 field locations. Grain and straw samples were collected at harvest, 43 to 83 days after treatment (DAT); hay was harvested 19 to 33 DAT and dried before collection. Residues of both halaux ifen - methyl and halaux ifen ranged from non detectable (< LOD) to <LOQ, in/on barley grain, barley

straw harvested at normal commercial harvest (N CH) and barley h ay harvested at 17 - 33 DAA. For wheat, residues of halaux ifen - methyl and halaux ifen were determined following one foliar application for 27 field locations. Grain and straw samples were collected at harvest, 42 to 73 day s after treatment ( DAT); forage was collected 1 DAT and hay was harvested 17 to 31 DAT and dried before collection. For wheat grain, all residues were below the LOD. For wheat straw, all residues were below the LOQ. Residues of halaux ifen - methyl and halaux ifen ranged from 0.036 to 0.389 ppm and from below the LOD to <LOQ in wheat forage. For wheat hay , residues of halaux ifen - methyl and3

halaux ifen ranged from below the LOD to 0.026 ppm and from below the LOD to < LOQ, respectivel y. Processed wheat commodities were also generated; results indicate that residues are not expected to concentrate above detectable levels in processed fractions derived from the processing of wheat grain. Because the proposed tolerances cover crops commonly used as feed for livestock, a proposal for animal commodity milk and meat tolerances at the LOQ of 0.01 ppm is included. The estimated animal burden was calculated based on NAFTA feeding diets in order to determine if these uses woul d result in detectable residues in meat and meat product commodities. The maximum dietary burden in ruminants estimated from proposed uses on potential feed crops was compared with the doses tested in the cattle feeding study conducted by Dow AgroSciences . All calculated residue levels in meat, meat products and milk were below the level of quantitation (L OQ). However, taking a conservative precautionary approach, Dow AgroSciences is proposing cow, sheep, goat and horse meat, meat products and milk toleran ces at the LOQ (0.01 mg/kg). B. Toxicological Profile A complete set of core toxicology studies were conducted on halaux ifen and a bridging package of toxicology studies was conducted on halaux ifen methyl to demonstrate toxicological equivalence. This set of bridging toxicology studies conducted on halaux ifen - methyl demonstrated that although having different NOAELs and target organs with high dose repeat exposure, halaux ifen - methyl and halaux ifen are toxicol ogically equivalent up to 10 mg/kg bw/day (mkd). 1 . Acute toxicity. H alaux ifen and halaux ifen - methyl exhibited low acute oral and dermal toxicity

with an LD50 >5000 mg/kg bw for all studies. An adequate test atmosphere was not able to be generated for halaux ifen and halaux ifen - methyl in the acute inhalation test; therefore, they were not conducted. Skin and eye irritation studies with halaux ifen and halaux ifen - methyl showed minimal irritation that cleared in 72 hours or less. H alaux ifen and halaux ifen - methyl were negative for sensitization potential. 2. Genotoxicty. H alaux ifen and halaux ifen - methyl were negative in a series of in vitro genotoxicity

studies ; halaux ifen was also negative in an in vivo mouse micronucleus assay . 3. Reproductive and developmental toxicity. H alaux ifen was assessed in a two generation reproduction study in rats and developmental studies in both rats and rabbits. There were no adverse, treatment - related effects on reproduction or development. H alaux ifen - methyl was asse ssed in developmental studies with both rats and rabbits. No treatment - related developmental toxicity was observed in rats. In the rabbit developmental study , there were no treatment - related fetal malformations in any group. The developmental NOAELwas based on a treatment - related decrease in fetal body weights and associated secondary effects at the high dose . 4. Subchronic toxicity. Sub - chronic dietary toxicity studies were conducted with halaux ifen in rats, mice, and dogs . The primary target organ s of halaux ifen are the kidney4

in rats and dogs, and the urinary bladder in mice . No toxicity was observed at the limit dose with dermal administration in rats (NOEL > 1000 mkd) after 28 day s. Sub - chronic dietary

toxicity studies were conducted with halaux ifen - methyl in rats, with the primary target organ identified as the liver , with secondary effects observed in the thy roid and the thymus. The NOAEL in rats was 10 mkd (males) and 52 mkd (females) after 2 8 day s and 10 mkd (males and females) after 90 day s. ] 5. Chronic toxicity. The NOAEL s for the rat 2 - ye ar study and the mouse 18 - month study with halaux ifen were based on kidney and urinary bladder effects. No tumors were observed in mouse and rat. H alaux ifen - methyl is proposed as not likely to be carcinogenic to humans , based on the lack of evidence of carcinogenicity i n rat and mouse studies with halaux ifen , and the absence of a mutagenicity concern. 6. Animal metabolism. H alaux ifen and halaux ifen - methyl were rapidly and highl y absorbed after oral administration in the rat and mouse. H alaux ifen is poorly metabolized and r eadil y eliminated in urine and feces. Data suggest rapid hydrol ys is of halaux ifen methyl in vivo , and the sy stemic exposure is predominantly to the halaux ifen . Minor metabolites of both test materials consisted of the acyl - glucuronide conjugate of halaux ifen , demethylated halaux ifen - methyl and halaux ifen and the ir corresponding sulfate and glucuronide conjugates. H alaux ifen and h alaux ifen - methyl do not accumulate in tissues. 7. Metabolite toxicology . The primary mammalian metabolite and main form of sy stemic exposure following dietary administration of halaux ifen - methyl is halaux ifen and there is a complete set of toxicology studies demonstrating limited toxicity . Other mammalian metabolites observed include demethylated halaux ifen - methyl and demethylated halaux ifen and their sulfate and glucuronide conjugates following dietary administration of halaux ifen - m eth yl . T he demethylated metabolites have been co investigated in the m ammali an toxicology studies and both metabolites are considered to be of no toxicological significance. 8. Endocrine disruption . A complete set of toxicology studies were conducted with halaux ifen , and there was no evidence of an y endocrine - related effects. Bridging toxicology

studies with halaux ifen - methyl demonstrated s ys temic exposure was to halaux ifen and metabolites with negligible or no halaux ifen - methyl found in blood, urine and fetuses. For this reason, the weight of evidence suggests halaux ifen and halaux ifen methyl are not endocrine modulators. C. Aggregate Exposure 1. Dietary exposure. A Dietary Assessment was conducted using the Dietary Exposure Evaluation ModelTM (DEEM - FCID, ver. 3.14) software which contains food consumption data based on NHANES 2 - day food Consumption data for 2003 to 2008 and food translation to RACs, as indicated b y EPA/USDA FCID recipe set as of February 2012. This assessment evaluate s potential risks due to chronic dietary exposures of the5

U.S. population subgroups to residues of halaux ifen - methyl . These anal ys es cover all proposed tolerances , including meat and m ilk . i. Food. a) . Acute exposure . No appropriate toxicological endpoint attributable to a single exposure was identified in the available toxicology studies on halaux ifen - methyl and halaux ifen . Since no acute toxicological endpoints are proposed, no acute assessment was performed . b). The current chronic dietary assessment is an unrefined Tier I assessment using tolerance values and 100% crop - treated assumption to estimate dietary exposure. These results are conservative (he alth protective) risk est imates . Chronic assessments were conducted to evaluate potential risks due to chronic dietary exposure of the U.S population and sensitive subpopulations to residues of halaux ifen - methyl against the proposed chronic reference dose (cRfD) of 0.1 mg/kg/day based on a NOAELof 10 mg/kg/day

from the halaux ifen - methyl 90 - day rat toxicity

study and an uncertaint y factor of 100 (10X for intra - species variation and 10X for inter - species variation). The proposed FQPA Safet y Factor (SF) = 1X; there fore, the proposed chronic population adjusted dose (cPAD) = cRfD. ii. Drinking water. Because halaux ifen - methyl is a new active ingredient there are no water - related data from monitoring to complete a quantitative drinking water exposure anal ys is and risk assessment . Screening level exposure levels to water were estimated from the Agency ’s water models. The Index Drinking Water Reservoir (FIRST) was used to calculate estimated concentrations in surface waters. The screening concentration in ground water wa s estimated using the Screening Concentrations In Ground Water model (SCI - GROW). These models take into account the use patterns and the environmental profile of the pesticide, but do not include consideration of the impact that processing raw water for di stribution as drinking water would likely have on the removal f pesticides from the source water. The primary use of these models is to provide a coarse screen for assessing whether a pesticide is likely to be present in drinking water at concentrations wh ich would exceed human health levels of concern. a). Acute exposure and risk. No acute dietary endpoint is proposed by

Dow AgroSciences. T herefore, no acute assessment was conducted and it is proposed that there is a reasonable certainty of no harm from acute exposure from drinking water. b). Chronic exposure and risk. Tier I screening level exposure assessments were conducted using SCI - GROW and FIRST. The models were run with input data for both halaux ifen - methyl and halaux ifen , as both theoretically co uld be found in the environment. The highest calculated water concentration was for halaux ifen in surface water at 0.029 ppb. As a conservative approach, this water concentration was used in the DEEM - FCIDTM dietary

risk assessment for all direct and indirec t water sources . The Tier - I DEEM exposure for food and water with proposed tolerances resulted in an estimated exposure of 0.0001 mg/kg bw/day for the US general population which is 0.1% of the chronic RfD . For the most highly exposed population subgroup, children 1 to 26

ye ars old, the estimated exposure is 0. 0.0005 mg/kg/day at 0.5% of cPAD. These results are conservative (health protective) risk estimates. Refinements such as use of percent crop - treat ed information and/or anticipated residue values would yield lower estimates of chronic dietary

exposure. 2. Non - dietary exposure . H alaux ifen - methyl does not have any proposed residential non - food uses . Therefore , there is no non - dietary acute, chronic, short or intermediate - term exposure and the dietary assessment alone serves to cover the aggregate assessment. Dow AgroSciences concludes that residues of halaux ifen - methyl and halaux ifen in food and drinking water will not contribute significantly to hum an exposure and that the chronic aggregate exposure from halaux ifen - methyl residues in food and drinking water will not exceed the proposed level of concern (100% of the chronic PAD) for an y population subgroup. The Agency generall y has no concern for exp osures below 100% of the cPAD because the cPAD represents the level at or below which daily

aggregate dietary

exposure over a lifetime will not pose appreciable risks to human health . D. Cumulative Effects Section 408(b)(2)(D)(v) requires that, when con sidering whether to establish, modify , or revoke a tolerance, 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 .” EPA does not have, at this time, available data to determine whether halaux ifen - methyl has a common mechanism of toxicity with other substances or how to include this pesticide in a cumulative risk assessment. Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity , halaux ifen - me thyl does not appear to produce a toxic metabolite produced b y other substances. For the purposes of this tolerance action, therefore, it is assumed that halaux ifen - methyl does not have a common mechanism of toxicity with other substances . E. Safety Dete rmination 1. U.S. population. The unrefined chronic dietary exposure for food and water (which covers the aggregate exposure) occupies up to 0.1% of the c RfD for the U.S. general population . EPA generall y has no concern for exposures below 100% of the chronic cRfD, because the cRfD represents the level at or below which daily dietary exposure over a lifetime will not pose appreciable risks to human health. Dow AgroSciences concludes that there is a reasonable certaint y that no harm will result to the U.S. general population or an y subpopulation from aggregate expos ure to halaux ifen methyl residues. 2. Infants and children. The to xicology data available includes acceptable developmental studies in both rats and rabbits conducted using halaux ifen - methyl and acceptable developmental studies (on rats and rabbits) and a two generation reproduction study using halaux ifen . A complete toxicity database is avai lable for to jointly support7

halaux ifen - methyl and halaux ifen . Exposure estimates are highl y conservative and protective and complete. Based on the completeness of the database and the lack of prenatal and postnatal toxicity , Dow AgroSciences proposes that an additional safety factor is not needed for the protection of infants and children (FQPA SF = 1X) . Since no acute toxicological endpoints are proposed by Dow AgroSciences , the acute aggregate risk is considered to be negligible. Using the exposure assumptions described above, Dow AgroSciences has concluded that chronic dietary exposure (food and water) to halaux ifen - methyl from the proposed new tolerances will utilize 0.5% of the cPAD for infants and children. The Agency generall y has no concern for exposures below 100% of the cPAD because the cPAD represents the level at or below which dail y aggregate dietary exposure over a lifetime will not pose appreciable risks to human health. Based on these risk assessments, Dow AgroSciences concludes that there is a reasonable certaint y that no harm will result to infants and children from aggregate exposure to halaux ifen - methyl residues. The risk assessment is conservative in nature and results in a risk profile of halaux ifen - methyl that is very protective of human health . F. International Tolerances There are no existing international MRL s in other countries at this time. The same tolerances values proposed in the USA have also been proposed as harmonized MRL s the countries that have generated data for the global residue package ( Canada, Australia). In addition for Australia , MRLs are proposed for the small grain subgroup (grain at 0.01 ppm, straw at 0.015 ppm, forage, at 0.8 ppm and hay at 0.04 ppm ) . Specificall y, the animal meat and milk tolerances are helpful for global harmonization with Australia’s MRLrequirements for trade export .