Document ID: EPA-HQ-OPP-2012-0843-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2012-12-19T05:00Z

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, 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 by establishing tolerances for residues of cloquintocet-mexyl (acetic acid, [(5-chloro-8-quniolinyl)oxy]-, 1-methylhexyl ester)(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 (XDE-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.  Specifically, this pesticide petition proposes to amend the tolerance expression by adding a reference to the new herbicide active ingredient halauxifen-methyl (XDE-729 methyl).  Tolerances are already established for use of cloquintocet-mexyl in conjunction 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 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 metabolism of cloquintocet-mexyl 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 assessment 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 Chromatography with Ultraviolet Detection (HPLC-UV) method REM 138.01 is for the determination of cloquintocet-mexyl (parent) and the HPLC-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 tolerance amendment in barley were generated from several Magnitude of Residue studies on barley and wheat and a processing study in wheat.  Both barley and wheat crops were treated with an end-use water-dispersible granule formulation containing the herbicide XDE-729 methyl and the safener cloquintocet-mexyl (CQM). For barley, fifteen field trials were completed in areas of the U.S. and Canada where barley is grown commercially, 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 were targeted at rates of 4.05 g ae/A XDE-729 acid plus 4.05 g ai/A CQM.

Sample for barley 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 early 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 days prior to earliest maturity, and at approximately 7, 14, 21 and 28 days after earliest maturity.  Samples were analyzed for cloquintocet-mexyl and 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 analysis of CQM and CQA was verified within the study and an LOQ of 0.01 μg/g and an LOD of 0.005 μg/g were reported.

In barley, overall residues were predominantly below quantifiable or detectable levels. For barley grain, residues were non-detectible for all analytes in all samples. In barley straw, residues were at or below LOD for and CQM. For CQA in treated barley straw samples, residues from one trial averaged 0.022 μg/g, and residues in samples from two other trials were between LOD 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 μg/g for CQM and 0.061 μg/g for CQA. Levels were lower in barley hay sampled at 7 DAT, in which no residues above the method LOQ of 0.01 μg/g were detected. In barley hay sampled at more typical intervals of 14 to 33 DAT, residues of all analytes except CQA were below LOQ. 
In wheat, residues were below LOD (ND) in most of the treated samples, particularly at PHIs of 7 days or longer. In grain, all residues were non-detectable. In wheat straw, residues were also non-detectable in most cases; exceptions 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 μg/g, respectively. In wheat forage at 7 DAT, residues of CQM and CQA were at or below LOQ. Analyte 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 PHIs. Wheat hay sampled at 1 DAT within trials demonstrated quantifiable residues of all analytes were found: Average levels in duplicate samples ranged up to 0.03 μg/g for CQM and 0.06 μg/g for CQA. At 7 DAT, analyte residues in wheat hay were near or below LOQ, as in forage. In hay sampled at more typical PHIs of 17 to 31 DAT, residues were below LOD in most cases. However, in a few cases, residues of CQA were slightly above LOQ with CQM residues were below LOD.
Processing data in wheat was collected from one field trial within NAFTA zone 5, in which wheat was treated at two rates of the XDE-729 methyl/cloquintocet-mexyl formulation.  Samples were collected as untreated, 1X or 5X the application rate.  Samples 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-mexyl analytes were below analytical method LODs in wheat grain harvested after application at both the 1X and 5X treatment rates. Residues of both analytes were also below analytical method LODs 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 any analyte residues that may be present in or on wheat grain treated with XDE-729 methyl and cloquintocet-mexyl are not expected to concentrate above detectible 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 received and the nature of the adverse effects caused by cloquintocet-mexyl as well as the no-observed-adverse-effect-level (NOAEL) 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 years only and no appropriate endpoint for acute dietary assessment with the general population and 2) Chronic RfD = cPAD = 0.04 mg/kg/day.  Each of these endpoints uses the typical separate intra and inter-species 10X uncertainty factors (UF), plus an additional database uncertainty factor of 10X.

	1. Acute toxicity.  Cloquintocet-mexyl has 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-mexyl was negative in all genotoxicity tests and is considered by 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 developmental or reproductive toxicity for cloquintocet-mexyl (per Federal Register 76, 38035 June 29, 2011; (FRL-8877-2). Previously assessed data demonstrate no increased sensitivity of rats or rabbits to in utero or early post-natal exposure to cloquintocet-mexyl. 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 for increased susceptibility in offspring to cloquintocet-mexyl, and the additional FQPA 10-fold safety 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 systemic 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 system. In a 90-day feeding study in rats, increased incidence of urinary bladder hyperplasia 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-mexyl. In a 90-day feeding study in dogs, liver toxicity was evidenced by observations of liver necrosis and perivascular inflammatory cell infiltration. In the one-year dog study, increased relative liver weight and increased chronic interstitial nephritis were observed.

	5. Chronic toxicity. In accordance with the US EPA Proposed EPA weight of evidence Categories, August 1999, the HIARC classified cloquintocet-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-year chronic toxicity study in rats, no renal or liver toxicity was reported; however, there was an increase in lymphoid hyperplasia of the thymus in male rats and an increase in thyroid follicular epithelial hyperplasia in female rats at 73 mg/kg/day.

	6. Animal metabolism. Per D313217, EPA-HQ-OPP-2007-0555-0004, November 29, 2005, metabolism 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-mexyl is 5-chloro-8-quin-linoxyacetic acid and testing on the metabolite is part of the toxicology database for cloquintocet-mexyl (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 by a naturally occurring estrogen, or other such endocrine effects as the Administrator 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 thyroid hormone systems, in addition to the estrogen hormone system (per D313217, EPA-HQ-OPP-2007-0555-0004, November 29, 2005). A special study has been conducted to investigate a histological finding of hyperplasia of thyroid 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 thyroid hormones at any of the treatment levels.

C. Aggregate Exposure. 

      The proposed use of cloquintocet-mexyl with 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 by 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 analyses for cloquintocet-mexyl are Tier 1 assessments (assuming 100% crop treated and tolerance level residues), because no additional data have been used to refine the analysis.

	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-mexyl and 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-year mean) concentrations of cloquintocet-mexyl and CGA-153433 in water at 0.186 ppb and 0.005 ppb, respectively.

      a. Acute Dietary (food 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.  Values less than 100% are below the Agency's level of concern.

      b. Chronic Dietary (food 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-mexyl, additional risk assessments beyond food and water are not required.

D. Cumulative Effects

	Unlike other pesticides which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, the Agency has not made a common mechanism of toxicity finding as to cloquintocet-mexyl and any other active substance, and the chemical does not appear to produce a toxic metabolite produced by other substances. The Agency has previously assumed that cloquintocet-mexyl does 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 certainty that no harm will result to the general population from aggregate exposure to cloquintocet-mexyl or 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 uses are already covered by the existing Tier 1 assessment for cloquintocet-mexyl which 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 Safety Factor Committee (SFC) met on March 6, 2000 to evaluate the hazard and exposure data for cloquintocet-mexyl and recommended that the FQPA factor be reduced to 1X.  This is supported by the toxicity data base for cloquintocet-mexyl being complete (i.e. developmental toxicity studies 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 recently stated (Federal Register 61, 16017 March 31, 2010. (FRL-8816-3): The dietary (food and drinking water) 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 therefore non-occupational exposure is not expected.).  The risk assessments for exposure to cloquintocet-mexyl or its metabolite when used with XDE-729 methyl on barley or wheat are considered indicate there were no risk concerns for infants and children.  This is because this type of use is already covered by the existing Tier 1 assessment for cloquintocet-mexyl which assumes 100% percent crop treated (D313217, EPA-HQ-OPP-2007-0555-0004, November 29, 2005).  Food and water exposure occupies 1% of the cPAD for 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 MRLs for cloquintocet-mexyl of 0.1 ppm in wheat and barley grain.  No Codex MRLs are established for cloquintocet-mexyl.