Document ID: EPA-HQ-OPP-2017-0591-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2018-03-22T04:00Z

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

EPA Registration Division contact: [insert name and telephone number with area code]

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:

[Interregional Research Project No. 4 (IR-4)]

[Insert petition number]

EPA has received a pesticide petition ([insert petition number]) from [Interregional Research Project No. 4],  Rutgers, The State University of New Jersey, 500 College Road East, Suite 201 W, Princeton, NJ 08540] 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 an inert ingredient (safener) in combination with existing listed active ingredients in or on the raw agricultural commodities [Teff, forage] at [0.2] ppm; [Teff, grain] at [0.1] ppm; [Teff, straw] at [0.1] ppm; [Teff, hay] at [0.5] 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 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. [Teff has been proposed and validated for crop group 15 Cereal Grains at the 2002 IR-4 / USDA International Crop Grouping Symposium, and is scheduled to be included in a crop group submission to the EPA. The use rate for clouintocet mexyl on wheat is the same as it's  proposed use on teff.  Based on the existing residue tolerances for cloquintocet mexyl and it's acid metabolite (40 CFR 180.560) on wheat, IR-4 proposes that EPA establish a tolerance for cloquintocet mexyl and it's acid metabolite in or on teff. 
The nature of the residues of cloquintocet mexyl is adequately understood, and an acceptable analytical method is available for enforcement purposes
.]

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 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 

Dietary exposure. [The existing assessments which include wheat are requested to be extrapolated to teff for dietary exposure-see below. The last assessment which included wheat was conducted by the Agency in the March 31, 2010(Federal Register 61, 16017 March 31, 2010. (FRL-8816-3)) and is expected to remain valid with teff  included in the tolerance expression. 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.]

 Food.  [Tolerances have been established (40 CFR 180.560) for the residues of cloqintocet mexyl and it's acid metabolite in or on wheat and barley. In this petition, tolerances for teff as raw agricultural commodities (RAC) are being proposed based on bridging to the tolerances already set for wheat (RAC).

Contribution through food items from teff flour is negligible to the dietary exposure evaluation for this petition for proposed addition of the commodity teff. Using residue levels in teff numerically equivalent to wheat a theoretical exposure evaluation was completed using DEEM FCID version 3.14 to evaluate the impact of adding the commodity teff flour to total population exposure. During our assessment we found no numerical difference in total exposure to any population subgroup in mg/kg/body wt/day to five decimal points when the exposure model was initially run with wheat flour only and then with wheat flour plus teff flour. Contribution from teff to the dietary intake is negligible over intake from existing crop uses as detailed below and will continue to provide large margins of safety to the public health.

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.

 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.

 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 when the proposed use on teff in considered in addition to current uses in barley and wheat.  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 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, 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.]