
                                                                               

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

2F8086

	EPA has received a pesticide petition 2F8086 from Dow AgroSciences LLC, 9330 Zionsville Road, Indianapolis, IN 46268 requesting, 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 Halauxifen-methyl, including its metabolites and degradates, in or on the commodities listed below.  Compliance with the tolerance levels specified is to be determined by measuring the combined residues of halauxifen-methyl (Methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate) and halauxifen (4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylic acid) expressed as halauxifen-methyl (parent) equivalents in or on the raw agricultural commodity barley, grain at 0.01 parts per 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 byproducts at 0.01 ppm; goat, fat at 0.01 ppm; goat, meat at 0.01 ppm; goat, meat byproducts at 0.01 ppm; horse, fat at 0.01 ppm; horse, meat at 0.01 ppm; horse, meat byproducts at 0.01 ppm; milk at 0.01 ppm; sheep, fat at 0.01 ppm; sheep, meat at 0.01 ppm; sheep, meat byproducts at 0.01 ppm; wheat, forage at 0.5 ppm; wheat, grain at 0.01 ppm; wheat, hay at 0.04 ppm; wheat, straw at 0.015 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 the 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 adequately understood 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 halauxifen-methyl and halauxifen, expressed as halauxifen-methyl.

	2. Analytical method. The residue profile of halauxifen-methyl and halauxifen is adequately understood and an acceptable analytical method is available for enforcement purposes.  The DAS analytical method study number 110004 outlining the Method Validation for the Determination of Residues of Halauxifen-methyl Ester and Halauxifen in Agricultural Commodities and Wheat Processed Products using Offline Solid-Phase Extraction and Liquid Chromatography with Mass Spectrometry Detection was validated on a variety 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 significant 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 not show significant statistical differences across geographies, varieties, or cultural practices.  Therefore, it is adequate to propose and support harmonized MRLs.

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 halauxifen-methyl plus 0.0089 lb ai/A of the safener cloquintocet.  The Limit of Detection (LOD) and Limit of Quantification (LOQ) values were validated for the analytical method as 0.001 ppm and 0.003 ppm, respectively for each analyte in grain, straw, forage and hay.  Observed residues support a suite of proposed US tolerances at the limit of quantitation (LOQ) for most commodities.

For barley, residues of halauxifen-methyl and halauxifen 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 halauxifen-methyl and halauxifen ranged from non detectable (< LOD) to <LOQ, in/on barley grain,  barley straw harvested at normal commercial harvest (NCH) and barley hay harvested at 17-33 DAA.

For wheat, residues of halauxifen-methyl and halauxifen were determined following one foliar application for 27 field locations.  Grain and straw samples were collected at harvest, 42 to 73 days 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 halauxifen-methyl and halauxifen ranged from 0.036 to 0.389 ppm and from below the LOD to <LOQ in wheat forage.  For wheat hay, residues of halauxifen-methyl and halauxifen ranged from below the LOD to 0.026 ppm and from below the LOD to <LOQ, respectively.  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 would 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 (LOQ). However, taking a conservative precautionary approach, Dow AgroSciences is proposing cow, sheep, goat and horse meat, meat products and milk tolerances at the LOQ (0.01 mg/kg).


B. Toxicological Profile  A complete set of core toxicology studies were conducted on halauxifen and a bridging package of toxicology studies was conducted on halauxifen-methyl to demonstrate toxicological equivalence.  This set of bridging toxicology studies conducted on halauxifen-methyl demonstrated that although having different NOAELs and target organs with high dose repeat exposure, halauxifen-methyl and halauxifen are toxicologically equivalent up to 10 mg/kg bw/day (mkd).

	1. Acute toxicity.  Halauxifen and halauxifen-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 halauxifen and halauxifen-methyl in the acute inhalation test; therefore, they were not conducted.  Skin and eye irritation studies with halauxifen and halauxifen-methyl showed minimal irritation that cleared in 72 hours or less.  Halauxifen and halauxifen-methyl were negative for sensitization potential.

	2. Genotoxicty. Halauxifen and halauxifen-methyl were negative in a series of in vitro genotoxicity studies; halauxifen was also negative in an in vivo mouse micronucleus assay.

	3. Reproductive and developmental toxicity. Halauxifen 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. 

Halauxifen-methyl was assessed 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 NOAEL was 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 halauxifen in rats, mice, and dogs. The primary target organs of halauxifen are the kidney 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 days.

      Sub-chronic dietary toxicity studies were conducted with halauxifen-methyl in rats, with the primary target organ identified as the liver, with secondary effects observed in the thyroid and the thymus. The NOAEL in rats was 10 mkd (males) and 52 mkd (females) after 28 days and 10 mkd (males and females) after 90 days.]

	5. Chronic toxicity. The NOAELs for the rat 2-year study and the mouse 18-month study with halauxifen were based on kidney and urinary bladder effects. No tumors were observed in mouse and rat. Halauxifen-methyl is proposed as not likely to be carcinogenic to humans, based on the lack of evidence of carcinogenicity in rat and mouse studies with halauxifen, and the absence of a mutagenicity concern.

	6. Animal metabolism. Halauxifen and halauxifen-methyl were rapidly and highly absorbed after oral administration in the rat and mouse.  Halauxifen is poorly metabolized and readily eliminated in urine and feces.  Data suggest rapid hydrolysis of halauxifen-methyl in vivo, and the systemic exposure is predominantly to the halauxifen.  Minor metabolites of both test materials consisted of the acyl-glucuronide conjugate of halauxifen, demethylated halauxifen-methyl and halauxifen and their corresponding sulfate and glucuronide conjugates. Halauxifen and halauxifen-methyl do not accumulate in tissues.
	7. Metabolite toxicology. The primary mammalian metabolite and main form of systemic exposure following dietary administration of halauxifen-methyl is halauxifen and there is a complete set of toxicology studies demonstrating limited toxicity.  Other mammalian metabolites observed include demethylated halauxifen-methyl and demethylated halauxifen and their sulfate and glucuronide conjugates following dietary administration of halauxifen-methyl. The demethylated metabolites have been co-investigated in the mammalian 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 halauxifen, and there was no evidence of any endocrine-related effects. Bridging toxicology studies with halauxifen-methyl demonstrated systemic exposure was to halauxifen and metabolites with negligible or no halauxifen-methyl found in blood, urine and fetuses. For this reason, the weight of evidence suggests halauxifen and halauxifen-methyl are not endocrine modulators.

C. Aggregate Exposure

	1. Dietary exposure. A Dietary Assessment was conducted using the Dietary Exposure Evaluation Model(TM) (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 by EPA/USDA FCID recipe set as of February 2012.  This assessment evaluates potential risks due to chronic dietary exposures of the U.S. population subgroups to residues of halauxifen-methyl.  These analyses cover all proposed tolerances, including meat and milk.

	i. Food. a). Acute exposure.  No appropriate toxicological endpoint attributable to a single exposure was identified in the available toxicology studies on halauxifen-methyl and halauxifen. 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 (health protective) risk estimates.  Chronic assessments were conducted to evaluate potential risks due to chronic dietary exposure of the U.S population and sensitive subpopulations to residues of halauxifen-methyl against the proposed chronic reference dose (cRfD) of 0.1 mg/kg/day based on a NOAEL of 10 mg/kg/day from the halauxifen-methyl 90-day rat toxicity study and an uncertainty factor of 100 (10X for intra-species variation and 10X for inter-species variation).  The proposed FQPA Safety Factor (SF) = 1X; therefore, the proposed chronic population adjusted dose (cPAD) = cRfD.

	ii. Drinking water. Because halauxifen-methyl is a new active ingredient there are no water-related data from monitoring to complete a quantitative drinking water exposure analysis 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 was 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 distribution 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 which would exceed human health levels of concern.

a). Acute exposure and risk. No acute dietary endpoint is proposed by Dow AgroSciences.  Therefore, 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 halauxifen-methyl and halauxifen, as both theoretically could be found in the environment. The highest calculated water concentration was for halauxifen in surface water at 0.029 ppb. As a conservative approach, this water concentration was used in the DEEM-FCID(TM) dietary risk assessment for all direct and indirect 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 2 years 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-treated information and/or anticipated residue values would yield lower estimates of chronic dietary exposure.

	2. Non-dietary exposure. Halauxifen-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 halauxifen-methyl and halauxifen in food and drinking water will not contribute significantly to human exposure and that the chronic aggregate exposure from halauxifen-methyl residues in food and drinking water will not exceed the proposed level of concern (100% of the chronic PAD) for any population subgroup.  The Agency generally has no concern for exposures 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 considering 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 halauxifen-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, halauxifen-methyl does not appear to produce a toxic metabolite produced by other substances.  For the purposes of this tolerance action, therefore, it is assumed that halauxifen-methyl does not have a common mechanism of toxicity with other substances.

E. Safety Determination

	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 cRfD for the U.S. general population. EPA generally 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 certainty that no harm will result to the U.S. general population or any subpopulation from aggregate exposure to halauxifen-methyl residues.

	2. Infants and children. The toxicology data available includes acceptable developmental studies in both rats and rabbits conducted using halauxifen-methyl and acceptable developmental studies (on rats and rabbits) and a two generation reproduction study using halauxifen.  A complete toxicity database is available for to jointly support halauxifen-methyl and halauxifen.  Exposure estimates are highly 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 halauxifen-methyl from the proposed new tolerances will utilize 0.5% of the cPAD for infants and children. The Agency generally has no concern for exposures 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. 
Based on these risk assessments, Dow AgroSciences concludes that there is a reasonable certainty that no harm will result to infants and children from aggregate exposure to halauxifen-methyl residues.  The risk assessment is conservative in nature and results in a risk profile of halauxifen-methyl that is very protective of human health.

F. International Tolerances

	There are no existing international MRLs in other countries at this time.  The same tolerances values proposed in the USA have also been proposed as harmonized MRLs 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).  Specifically, the animal meat and milk tolerances are helpful for global harmonization with Australia's MRL requirements for trade export.
