**EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR**

**PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER EPA**  **Registration Division contact:**  **Mindy Ondish (703)605 -**  **0723** Dow AgroSciences , LLC 2F8085 EPA has received a pesticide petition ( 2F8085 ) from Dow AgroSciences , LLC , 9330 Zionsville Road, In dianapolis, 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 by

establishing tolerance s for residues of cloquintocet - mex yl(acetic acid, [(5 - chloro - 8 - quniolinyl)oxy] - , 1 - methylhex ylester)(CAS Reg. No. 99607 - 70 - 2) and its acid metabolite (5 - chloro - 8 - quinlinoxyacetic acid) for use as a safener in combination with the new active ingredient halauxifen - methyl ( X DE - 729 methyl ) in or on the raw agricultural commodities barley , grain at 0.1 parts per million (ppm); barley, hay at 0.1 ppm; barley , straw at 0.1 ppm; wheat, forage at 0.2 ppm; wheat, grain at 0.1 ppm ; wheat, hay at 0.5 ppm; and wheat, straw at 0.1 ppm. Specificall y , th is pesticide petition proposes to amend the tolerance expression by a dding a reference to the new herbicide active ingredient halauxifen - methyl ( XDE - 729 methyl ) . Tolerances are already established for use of cloquintocet - mex ylin conjunct ion with other herbicides. This petition will not change the established tolerance levels. 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 eval uated 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 metabolism of cloquintocet - mex yl in grains has been covered in previous EPA tolerance decisions , with more detailed discussion in Federal Register 70, 74679, December 16, 2005, (FRL - 7753 - 4) . Per D313217 EPA - HQ - OPP 2007 - 0555 - 0004: The nature of the residue in wheat, barley, livestock, and rotational crops is adequately understood. The HED Metabolism Assessment Review Committee (MARC) previously determined for the purpose of the conditional registration that the residues of concern for the tolerance expression and risk ass essment for plants, livestock, and rotational crops are cloquintocet- mexyl and its {acid} metabolite . 2. Analytical method. Adequate enforcement methodology is available to enforce the tolerance expression ( Federal Register 76, 38035 June 29, 2011; (FRL - 8877 - 2) ) . There are two enforcement methods available. The High Performance Liquid Chromatograph y with Ultraviolet Detection (HPLC - UV) method REM 138.01 is for the determination of cloquintocet - mex yl(parent) and the HPL C - UV Method REM 138.10 allows determination of its acid metabolite (also known as CGA - 153433) . 3. Magnitude of residues. The residue data in support of the proposed tolerance2

amendment in barley

were generated from several M agnitude of R esidue studies on barley and wheat and a proces sing study in wheat . Both barley

and wheat crops were treated with an end - use water - dispersible granule formulation co ntaining the herbicide XDE - 729 methyl and the safener cloquintocet - mexyl (CQM ). For barley , f ifteen field trials were completed in areas of the U.S. and Canada where barley is grown commerciall y, within NAFTA zones 1, 5, 7, 9, 11 and 14. For wheat, twenty field trials were completed in within NAFTA zones 2, 5, 6, 7, 8, 11 and 14. Applications wer e targeted at rates of 4.05 g ae/A XDE - 729 acid plus 4.05 g ai/A CQM. Sample for b arley

grain and straw were collected from all trial plots at crop maturity , harvested at 43 to 74 DAT. For wheat, grain and straw samples were collected from all trial plots at earl y crop maturity and harvested at 42 to 73 DAT. For both barley and wheat there were an addition two decline trials in which grain and straw samples were also collected at 7 day s prior to earliest maturit y, and at approximately 7, 14, 21 and 28 day s after earliest maturity . Samples were anal yz ed for cloquintocet - mex yland its metabolite cloquintocet acid (CQA) as well as the herbicide XDE - 729 methyl (XDE 729M) and XDE - 729 acid (XDE - 729A). Performance of the method for analy sis of CQM and CQA was ve rified within the study and an LOQ of 0.01 μ g/ g and an LOD of 0.005 μ g/g were reported . In barley , o verall r esidues were predominantly below quantifiable or detectable levels. For barley

grain, residues were non - detectible for all anal yt es in all samples. Inbarley straw, residues were at or below LOD for and CQM. For CQA in treated barley straw samples, residues from one trial averaged 0.022 μ g/ g, and residues in samples from two other trials were between L OD and LOQ, while levels were non - detectible in samples from all other trials. Decline information for barley hay sampled at 1 day

after treatment (DAT) indicated quantifiable residues ranged up to 0.015 μ g/g for CQM and 0.061 μ g/g for CQA. Levels were lower in barley hay sampled at 7 DAT, in which no residues above the method L OQ of 0.01 μ g/g were detected. In barley hay sampled at more ty

pical intervals of 14 to 33 DAT, residues of all anal yt es except CQA were below LOQ. In wheat, residues were below LOD (ND) in most of the treated samples, particularl y at PHI s of 7 day s or longer. In grain, all residues were non - detectable. In wheat straw, residues were also non - detectable in most cases; excep tions were four samples in which CQA was detected between LOD and LOQ. In wheat forage sampled at 1 DAT, residues of CQM and CQA were above LOQ, at levels up to 0.085 and 0.064 μ g/ g, respectivel y. In wheat forage at 7 DAT, residues of CQM and CQA were at or below LOQ. Anal yt e residues were all non - detectable in wheat forage sampled at 14 to 28 DAT. Results for wheat hay

showed a similar pattern of residue decline as in wheat forage, except for a few detections at longer PHI s. Wheat hay sampled at 1 DAT within trials demonstrated quantifiable residues of all analy tes were found: Average levels in duplicate samples ranged up to 0.03 μ g/g for CQM and 0.06 μ g/ g for CQA. At 7 DAT, anal yt e residues in wheat hay

were near or below LOQ, as in forage. In hay sampled at more ty

pical PHI s of 17 to 31 DAT, residues were below LOD in most cases. However, in a few cases, residues of CQA were slightl y above LOQ with CQM residues were below L OD. Processing data in wheat was collected from one field trial within NAFTA zone 5 , in which wheat wa s treated at two rates of the XDE - 729 methyl /cloquintocet - mex yl3

formulation . Samples were collected as untreated, 1X or 5X the application rate. S amples were processed into fractions by procedures which simulate commercial processing for : Bran, Total bran, Flour (dry mill), Whole meal flour, Flour - 550, Bread (white), Whole grain bread, Middlings, Shorts, Germ, Gluten, Gluten Feed Meal, Starch, Aspirated Grain Fractions. Residues of the cloquintocet - mex yl anal yt es were below anal yt ica l method LODs in wheat grain harvested after application at both the 1X and 5X treatment rates. Residues of both anal yt es were also below anal yt ical method L ODs in all samples of processed fractions derived from the 5X - treated wheat grain. These results do not allow calculation of quantitative concentration or dilution factors. They indicate, however, that an y anal yt e residues that may be present in or on wheat grain treated with XDE - 729 methyl and cloquintocet - mex yl are not expected to concentrate above de tectible levels in processed fractions derived from processing of wheat grain

. B. Toxicological Profile . The Agency

has evaluated the available toxicity data and considered its validity , completeness, and reliability as well as the relationship of the results of the studies to human risk. The Agency

has also considered available information concerning the variability

of the sensitivities of major identifiable subgroups of consumers, including infants and children. Specific information on the studies rec eived and the nature of the adverse effects caused b y cloquintocet - mex ylas well as the no - observed - adverse - effect level (NOAE L) and the lowest - observed - adverse - effect - level (LOAEL) from the toxicity studies are discussed in the final rules published on March 5, 2008, December 16, 2005 and June 22, 2000. Relevant cloquintocet - mexyl endpoints are: 1) an Acute RfD = aPAD = 1.0 mg/kg/day

for Females 13 to 49 y ears onl y and no appropriate endpoint for acute dietary assessment with the general population and 2) Chronic RfD = cPAD = 0.0 4 mg/kg/day . Each of these endpoints uses the ty pical separate intra and inter - species 10X uncertaint y factors (UF), plus an additional database uncertainty factor of 10X. 1. Acute toxicity. Cloquintocet - mex ylhas low acute oral, dermal and inhalation toxicity (Acute Toxicity

Category III) and is slightly

irritating to eyes. It is not a skin irritant. However, it is a skin sensitizer (per Federal Register 76, 38035 June 29, 2011; (FRL - 8877 - 2)) . 2. Genotoxicty. Cloquintocet - mex ylwas negative in all genotoxicity tests and is considered b y the Agency to not be genotoxic, per Federal Register 61, 16017 March 31, 2010. (FRL - 8816 - 3) . 3. Reproductive and developmental toxicity. There is no evidence of developmenta l or reproductive toxicity for c loquintocet - mex yl(per Federal Register 76, 38035 June 29, 2011; (FRL - 8877 - 2) . Previousl y assessed data demonstrate no increased sensitivity

of rat s or rabbits to in utero or early post - natal exposure to cloquintocet mex yl . NOAELs for maternal/paternal toxicity were either less than or equal to the NOAELs for fetal or reproductive toxicity (per D313217, EPA - HQ - OPP - 2007 - 0555 - 0004, November 29, 2005). The Agency has concluded that there is no concern for4

increased susceptibility

in offspring to cloquintocet - mex yl , and the additional FQPA 10 - fold safet y factor for the protection of infants and children has been reduced to 1X based on the available data (per Federal Register 73, 11816 March 5, 2008. (FRL - 8350 - 8)) . 4. Subchronic toxicity. Per D313217, EPA - HQ - OPP - 2007 - 0555 - 0004, November 29, 2005, the sy stemic toxicity of cloquintocet - mexyl has been reviewed and is understood by

the Agency ; the primary target organs for subchronic exposure are the liver and the renal s ys tem. In a 90 - day feeding study

in rats, increased incidence of urinary bladder hy

perplasia and increased serum bilirubin were observed in males at doses >1000 ppm (equivalent to 64 mg/kg/ day). This observation was supported by a 28 - day oral gavage study

in rats where renal papillary necrosis and inflammation with fibrosis were observed at doses >100 mg/kg/day . In a 28 - day dermal toxicity

study in rats, mottled or reddish livers accompanied by histopathological changes including necrosis and fibrosis were observed in two of five females exposed to 1000 mg/kg/day of cloquintocet - mex yl . In a 90 - day feeding study

in dogs, liver toxicity

was evidenced by observations of liver necrosis and periva scular inflammatory cell infiltration. In the one ye ar dog study , increased relative liver weight and increased chronic interstitial nephritis were observed . 5. Chronic toxicity. Inaccordance with the US EPA Proposed EPA weight of evidence Categories, August 1999, the HIARC classified c loquintocet - mexyl as “not likely to be a human carcinogen”, per Federal Register 76, 38035 June 29, 2011; (FRL 8877 - 2) . Per D313217, EPA - HQ - OPP - 2007 - 0555 - 0004, November 29, 2005, in the two ye ar chronic toxicity

study in rats, no renal or liver toxicity was reported; however, there was an increase in l ymphoid hy perplasia of the th ymus in male rats and an increase in thy roid follicular epithelial hy perplasia in female rats at 73 mg/kg/day . 6. Animal metabolism. Per D31321 7, EPA - HQ - OPP - 2007 - 0555 - 0004, November 29, 2005, m etabolism studies in rats indicated approximately 40% of the administered dose of cloquintocet - mexyl was absorbed through the gastrointestinal tract and subsequently

excreted via the urine. Fecal excretion accounted for approximately 60% of the administered dose. The chemical was rapidly eliminated via feces and urine within 48 hours post - dosing . 7. Metabolite toxicology . The main metabolite for cloquintocet - mex ylis 5 - chloro 8 - quin - linoxyacetic acid and t esting on the metabolite is part of the toxicology database for cloquintocet - mex yl(per Federal Register 76, 38035 June 29, 2011; (FRL - 8877 - 2) . 8. Endocrine disruption . The Agency is required under the FFDCA, as amended by FQPA, to develop a screening program to determine whether certain substances (including all pesticide active and other ingredients) “may have an effect in humans that is similar to an effect produced b y a naturall y occurring estrogen, or other such endocrine effects as the Administrat or may designate”. Following the recommendations of its Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC), the Agency determined that there was scientific basis for including, as part of the program, the androgen and th yr oid hormone sy s tems, in addition to the estrogen hormone sy stem (per D313217, EPA - HQ - OPP - 2007 - 0555 - 0004, November 29, 2005) . A special study has5

been conducted to investigate a histological finding of h yp erplasia of thy roid gland epithelium noted in the female rat in the standard life time combined chronic toxicity and carcinogenicity

study (Federal Register 65, 20972 April 19, 2000). No effect was noted on the level of th yroid hormones at an y of the treatment levels. C. Aggregate Exposure . The proposed use of cloquint ocet - mex ylwith XDE - 729 methyl will cause no numerical change to the tolerances for the specific barley and wheat commodities sought. Therefore, the last risk assessment conducted b y the Agency in the March 31, 2010 is considered applicable . 1. Dietary exposure. Per D313217 of November 29, 2005, the acute dietary endpoint is applicable to the population subgroup females 13 - 49 years old only . The chronic dietary

endpoint applies to all population subgroups including infants and children . i. Food. Per D313217 of November 29, 2005, Both acute and chronic dietary exposure anal ys es for cloquintocet - mex ylare Tier 1 assessment s (assuming 100% crop treated and tolerance level residues), because no additional data have been used to refine the anal ys is. ii. Drinking water. Per D313217 of November 29, 2005, EFED has previously provided computer - generated estimated environmental concentrations EECS for the combined residues of cloquintocet - mex yland the acid metabolite using the GENEEC and SCI - GROW water models . EFED reported that the highest EECs from the current and proposed uses were the GENEEC estimates acute (peak) and chronic (56 - ye ar mean) concentrations of cloquintocet - mex yland CGA - 153433 in water at 0.186 ppb and 0.005 ppb, respectivel y. a. Acute Dietary ( f

ood and drinking water) For acute exposure, food and drinking water exposures were considered in previous assessment D313217. The estimated dietary exposure (food and water) for females aged 13 - 49 years old accounts for <1% of the aPAD. Va lues less than 100% are below the Agency ’s level of concern . b. Chronic Diet ary (f

ood and drinking water) For chronic exposure, food and drinking water exposures were considered in previous assessment D313217. The chronic dietary endpoint applies to all population subgroups including infants and children. Food and water exposure occupies <1% of the cPAD for the US population and 1% of the cPAD for children 3 - 5 years old, the subgroup with the highest exposure. Values less than 100% are below the Agency ’s level of concern . 2. Non - dietary exposure . Since there are no residential uses of cloquintocet mex yl , additional risk assessments beyond food and water are not required .6

D. Cumulative Effects Unlike other pesticides which EPA has followed a cumulativ e risk approach based on a common mechanism of toxicity , the Agency has not made a common mechanism of toxicity

finding as to cloquintocet - mex yland any other active substance, and the chemical does not appear to produce a toxic metabolite produced b y othe r substances. The Agency

has previousl y assumed that cloquintocet - mex yldoes not have a common mechanism of toxicity with other substances . E. Safety Determination 1. U.S. population. The aggregate risk assessments support a finding that there is a reasonable certaint y that no harm will result to the general population from aggregate exposure to cloquintocet - mex ylor its metabolite for exposure from use with XDE - 729 methyl on barley

or wheat are considered . This is based on fact that barley and wheat use s are alread y covered by the existing Tier 1 assessment for cloquintocet - mex ylwhich assumes 100% percent crop treated . Per D313217, EPA - HQ - OPP - 2007 - 0555 - 0004, November 29, 2005 the estimated dieatary (food and water) exposure for female aged 13 - 49 is <1% of the acute PAD and the chronic dietary assessment for the US general population also indicates <1% of the cPAD ; hence there are no risk concerns. 2. Infants and children . The FQPA Safet y Factor Committee (SFC) met on March 6, 2000 to evaluate the hazard and exposure data for cloquintocet - mex yland recommended that the FQPA factor be reduced to 1X. This is supported by the toxicity data base for cloquintocet - mex ylbeing complete (i.e. developmental toxicity stud ies in rats and rabbits; 2 - generation reproduction study in rats) and there is no indication of quantitative or qualitative increased susceptibility of rats or rabbits in the toxicity data . In addition the EPA has recentl y stated (Federal Register 61, 160 17 March 31, 2010. (FRL - 8816 - 3): The dietary (food and drinking w ater) exposure assessments will not underestimate the potential exposures for infants and children from the use of cloquintocet- mexyl (currently there are no proposed residential uses and the refore non occupational exposure is not expected .). The risk assessments for exposure to cloquintocet - mex ylor its metabolite when used with XDE - 729 methyl on barley or wheat are considered indicate there were no risk concerns for infants and children. T his is because this t ype of use is alread y covered b y the existing Tier 1 assessment for cloquintocet - mex ylwhich assumes 100% percent crop treated (D313217, EPA - HQ - OPP 2007 - 0555 - 0004, November 29, 2005). Food and water exposure occupies 1% of the cPAD fo r children 3 - 5 years old, the subgroup with the highest exposure. F. International Tolerances Per the USDA FASOnline, USDA Pesticide Database ( http://www.mrldatabase.com/ ) , Australia, Russia, and Japan have established harmonized MRL s for cloquintocet - mex ylof 0.1 ppm in wheat and barley grain. No Codex MRL s are established for cloquintocet - mexyl

.