


EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER  

EPA Registration Division contact: 

INSTRUCTIONS:  Please utilize this outline in preparing the pesticide petition.  In cases where the outline element does not apply, please insert "NA-Remove" and maintain the outline. Please do not change the margins, font, or format in your pesticide petition. Simply replace the instructions that appear in green, i.e., "[insert company name]," with the information specific to your action.

TEMPLATE:

[Corteva Agriscience
EPA Company No.: 62719]

[Insert petition number]

	EPA has received a pesticide petition ([IN-11655]) from [Corteva Agriscience], [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 a tolerance 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 active ingredient tolpyralate herbicide] in or on the raw agricultural commodity [wheat, grain] at [0.1] parts per million (ppm), [wheat, forage] at [0.2] parts per million (ppm), [wheat, hay] at [0.5] parts per million (ppm), [wheat, straw] at [0.1] parts per million (ppm), [barley, grain] at [0.1] parts per million (ppm), [barley, hay] at [0.1] parts per million (ppm), [barley, straw] at [0.1] parts per million (ppm), [teff, grain] at [0.1] parts per million (ppm), [teff, forage] at [0.2] parts per million (ppm), [teff, hay] at [0.5] parts per million (ppm), [teff, straw] at [0.1] parts per million (ppm).  [Specifically, the proposed amendment is to add a reference to the herbicide active ingredient tolpyralate to the tolerances which are already established under 40 CFR 180.560 for use of cloquintocet-mexyl in conjunction with other herbicides.  This petition will not change the magnitude of the established values but instead specifics a new use partner with tolpyralate.] 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 and wheat were generated from one Magnitude of Residue study on barley and one Magnitude of Residue study on wheat.  Both barley and wheat crops were treated with an end-use suspension concentrate liquid formulation containing the herbicide tolpyralate. The barley study also included the safener cloquintocet-mexyl (CQM). For barley, eighteen field trials were completed in areas of the U.S. and Canada where barley is grown commercially, within NAFTA zones 5, 7, 7A, 9, 11 and 14. For wheat, twenty-two field trials were completed in within NAFTA zones 2, 5, 6, 7, 8, 11 and 14.  Applications were targeted at rates of 0.0357 lb ai/A (40 g ai/ha) tolpyralate in both wheat and barley trials and included 0.0178 lb ai/A (20 g ai/ha) Cloquintocet-mexyl in barley trials.

Samples for barley hay, grain and straw were collected from all trial plots at crop maturity. Barley hay was harvested at a nominal 21-day PHI, at 19 to 23 DAT. Barley grain and straw was harvested at crop maturity, at a nominal 50-day PHI, at 47 to 56 DAT. For wheat, forage, hay, grain and straw samples were collected from all trial plots at early crop maturity. Wheat forage samples were harvested at a 7-day and also at 21-day PHI (19 to 23 DAT), hay samples were allowed to dry for 1 to 9 days until moisture levels were typical for commercial hay. Wheat grain and straw were harvested at a 50-day PHI, 47 to 53 DAT. For both barley and wheat there were an additional two decline trials in barley hay, grain and straw samples and wheat forage, hay and straw samples were also collected. Barley hay samples were cut 14, 18, 21, 24-25, and 28 DAA to assess residue decline.  Decline grain and straw samples were collected 40, 43-45, 50, 54-55, and 58-61 DAA. Wheat forage decline samples were collected 1, 3, 6-7, 9, and 21 DAA.  Wheat hay decline samples were cut 13-14, 16-17, 21, 23-24, and 28-29 DAA, and wheat grain and straw samples were collected 39-40, 45-46, 49-50, 53, and 57-62 DAA. Barley samples were analyzed for cloquintocet-mexyl and its metabolite cloquintocet acid as well as the herbicide tolpyralate and its metabolite MT-2153.  Wheat samples were analyzed for the herbicide tolpyralate and its metabolite MT-2153.  Performance of the method for analysis of tolpyralate and its metabolite, MT-2153, and the method for analysis of cloquintocet-mexyl and its acid metabolite, cloquintocet acid, was verified within both barley and wheat studies and an LOQ of 0.01 ppm and an LOD of 0.003 ppm were reported.

In barley and wheat, overall residues of cloquintocet-mexyl, its metabolite cloquintocet acid, herbicide tolpyralate and its acid MT-2153 were predominantly below quantifiable or detectable levels. For barley grain, residues were non-detectible for all analytes in all samples. maximum tolpyralate residue in grain collected 47-56 DAA was <LOD (0.003 ppm) (mean of per-trial averages = 0.01 ppm), and maximum MT-2153 residue in grain was <LOQ (0.01 ppm) (mean of per-trial averages = 0.01 ppm). Maximum cloquintocet-mexyl residue in grain collected 47-56 DAA was <LOQ (0.01 ppm) (mean of per-trial averages = 0.01), and maximum 5-chloro-8-quinolinoxyacetic acid (cloquintocet acid) residue in grain was <LOQ (0.01 ppm) (mean of per-trial averages = 0.01 ppm). 
In barley straw, maximum tolpyralate residue in straw collected 47-56 DAA was 0.0691 ppm (mean of per-trial averages = 0.0147 ppm), and maximum MT-2153 residue in straw was  0.115 ppm (mean of per-trial averages = 0.0157 ppm).  Maximum cloquintocet-mexyl residue in straw collected 47-56 DAA was <LOD (0.003 ppm) (mean of per-trial averages = 0.01 ppm), and maximum 5-chloro-8-quinolinoxyacetic acid residue in straw was 0.0315 ppm (mean of per-trial averages = 0.0145 ppm). In barley hay, maximum tolpyralate residue in hay collected 19-23 DAA was 0.190 ppm (mean of per-trial averages = 0.0297 ppm), and maximum MT-2153 residue in hay was 0.166 ppm (mean of per-trial averages = 0.0286 ppm). Maximum cloquintocet-mexyl residue in hay collected 19-23 DAA was 0.0118 ppm (mean of per-trial averages = 0.0101 ppm), and maximum 5-chloro-8-quinolinoxyacetic acid residue in hay was 0.0745 ppm (mean of per-trial averages = 0.0165 ppm).
Decline information for barley was obtained from two trial sites where hay, grain and straw samples were collected. Barley hay samples were cut 14, 18, 21, 24-25, and 28 DAA to assess residue decline.  Tolpyralate residues in hay decreased from 0.0804 ppm at 14 DAA to <LOQ at 28 DAA.  MT-2153 residues in hay decreased from 0.0748 ppm at 14 DAA to <LOQ ppm at 28 DAA.  Cloquintocet-mexyl residues in hay were <LOD at all sampling events.  5-chloro-8-quinolinoxyacetic acid residues in hay were fairly stable (slightly above or slightly below the LOQ) across the 14 day sampling period, and showed a slight decline over the total 28 day period. Barley grain and straw samples were collected 40, 43-45, 50, 54-55, and 58-61 DAA to assess residue decline.  Tolpyralate, MT-2153, cloquintocet-mexyl, and 5-chloro-8-quinolinoxyacetic acid residues in grain were <LOD, <LOD, <LOD, and ND, respectively, at all sampling events.  Tolpyralate residues in straw were at the LOQ (0.0104 ppm) at 40 DAA and declined to <LOQ at 45 DAA. Cloquintocet-mexyl residues in straw were <LOD and ND, respectively, at all sampling events.  MT-2153 residues in straw were <LOQ at all sampling events, but declined slightly across the 21 day sampling period.  5-chloro-8-quinolinoxyacetic acid residues in straw decreased slightly from 0.0188 ppm at 40 DAA to <LOQ at 50 DAA.  

In wheat, residues were below LOD (ND) in most of the treated samples. In wheat grain, maximum tolpyralate residue in grain collected 47-58 DAA was <LOD (0.003 ppm) (mean of per-trial averages = <LOQ (0.0100 ppm)), and maximum MT-2153 residue in grain was <LOQ (0.0100 ppm) (mean of per-trial averages = <LOQ (0.0100 ppm)).  In wheat straw, maximum tolpyralate residue in straw collected 47-58 DAA was 0.0236 ppm (mean of per-trial averages = 0.0106 ppm), and maximum MT-2153 residue in straw was 0.0166 ppm (mean of per-trial averages = 0.0105 ppm). In wheat forage, maximum tolpyralate residue in forage collected 6-8 DAA was 0.458 ppm (mean of per-trial averages = 0.0555 ppm), and maximum MT-2153 residue in forage was 0.0740 ppm (mean of per-trial averages = 0.0166 ppm). Maximum tolpyralate residue in forage collected 20-23 DAA was 0.0161 ppm (mean of per-trial averages = 0.0105, and maximum MT-2153 residue in forage was 0.0106 ppm (mean of per-trial averages =  <LOQ (0.0100 ppm). In wheat hay, maximum tolpyralate residue in hay collected 20-23 DAA was 0.0445 ppm (mean of per-trial averages = 0.0133 ppm), and maximum MT-2153 residue in hay was 0.0374 ppm (mean of per-trial averages = 0.0126 ppm).
Decline information for wheat was obtained from two trial sites where wheat forage, grain and hay samples were collected. Forage samples were collected at 1, 3, 6-7, 9, and 21 DAA to assess residue decline.  Decline hay samples were cut 13-14, 16-17, 21, 23-24, and 28-29 DAA, and decline grain and straw samples were collected 39-40, 45-46, 49-50, 53, and 62 DAA. Mean tolpyralate residues in forage decreased from 3.02 ppm at 1 DAA to <LOQ ppm at 21 DAA.  Tolpyralate residues in hay decreased from 0.0134 ppm at 1 DAA to <LOQ ppm at 28 DAA. Tolpyralate residues in grain were <LOQ.   Tolpyralate residues in straw decreased from 0.0233 ppm at 40 DAA to <LOQ ppm at 62 DAA. Mean MT-2153 residues in forage decreased from 0.221 ppm at 1 DAA to <LOQ ppm at 21 DAA.   MT-2153 residues in hay decreased from 0.0115 ppm at 1 DAA to <LOQ ppm at 28 DAA.  MT-2153 residues in grain were <LOQ.  MT-2153 residues in straw decreased from 0.0259 ppm at 40 DAA to <LOQ ppm at 62 DAA.
Plots were established to examine the need for processing data within both the barley and wheat studies with exaggerated rates of 3X and 5X plots however quantifiable residues were not detected within the raw agricultural commodities (cereal grain) therefore the need for processing data was determined not to be necessary. The results from processing trials show that after one foliar application of Tolpyralate 400 SC at a 5x rate of 0.179 lb ai/A +- 5% (equivalent to 200 g ai/ha) containing cloquintocet-mexyl safener at a rate of 0.0890 lb ai/A +-5% (equivalent to 100 g ai/ha) made 50 days prior to normal crop maturity, maximum tolpyralate, MT-2153,  cloquintocet-mexyl, and 5-chloro-8-quinolinoxyacetic acid (cloquintocet acid) residues in the grain were <LOQ.]

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 August 2, 2016, June 29, 2011, March 31, 2010, 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 81, 50630 August 2, 2016; (FRL-9947-78).]

	2. Genotoxicty. [Cloquintocet-mexyl was negative in all genotoxicity tests and is considered by the Agency to not be genotoxic, per Federal Register 81, 50630 August 2, 2016. (FRL-9947-78).]

	3. Reproductive and developmental toxicity. [There is no evidence of developmental or reproductive toxicity for cloquintocet-mexyl (Federal Register 81, 50630 August 2, 2016. (FRL-9947-78). 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 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 81, 50630 August 2, 2016. (FRL-9947-78).  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 81, 50630 August 2, 2016. (FRL-9947-78).]

	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 tolpyralate 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 March 17, 2016 is considered applicable.  

	1. Dietary exposure. [Per D406460 of March 17, 2016, 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 D406460 of March 17, 2016, 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 D406460 of March 17, 2016, 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.

 Acute Dietary (food and drinking water)
For acute exposure, food and drinking water exposures were considered in previous assessment D406460. 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.

 Chronic Dietary (food and drinking water)
For chronic exposure, food and drinking water exposures were considered in previous assessment D406460. 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 tolpyralate on barley or wheat.  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 D406460, EPA-HQ-OPP-2012-0843-0004, March 17, 2016 the estimated dietary (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 tolpyralate 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 (D406460, EPA-HQ-OPP-2012-0843-0004, March 17, 2016).  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, 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.]




