EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER EPA Registration Division contact: Kay Montague , (703) 305 - 124 3 Syngenta Crop Protection , LLC Petition # 4F8254 EPA has received a pesti cide petition ( 4F8254 ) from Syngenta Crop Protection , LLC , P.O. Box 18300 , Greensboro, NC 2741 9 proposing, 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. 662. by establish ing a tolerance for residues of t rinexapac - ethyl: 4 - (cyclopropyl - α - hydroxy - methylene) - 3,5 - dioxo - cyclohexanecarboxylic acid ethyl ester expr ess ed as its primary metabolite CGA - 179500: 4 - (cyclopropyl - α - hydroxy methylene) - 3,5 - dioxo - cyclohexanecarboxylic acid ] in or o n: Rice, bran at 1.5 parts per million (ppm) Rice, grain at 0.4 parts per million (ppm) Rice, straw at 0.07 parts per million (ppm) Rice, wild, grain at 0.4 parts per million (ppm) Rye, bran at 2.5 pa rts per million (ppm) Rye, grain at 2.0 parts per million (ppm) Rye, hay at 0. 8 parts per million (ppm) Rye, straw at 0. 4 parts per million (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 d a ta at this time or whether the data supports granting of the petition. Additional data may be need ed before EPA rules on the petition. A. Residue Chemistry 1. Plant metabolism. The metabolism of trinexapac

- ethyl is adequately understood for the purpose of the proposed tolerances. The metabolism of trinexapac

ethyl has been characterized in grasses grown for seed, spring wheat, and greenhouse grown paddy rice
. The primary metabolic pathway was very similar in these three separate crops . 2. Analytical method. i. Food Syngenta Crop Protection Analytical Method GRM020.01A has been submitted for the Determination of Residues of Trinexapac

- ethyl as CGA

- 179500 in Cro ps by LC

- MS/MS for detecting and measuring levels of trinexapac

- ethyl expressed as its major metabolite CGA

- 179500 , in or on food with a limit of quantitation (LOQ) that allows monitoring of food with residues at or above the levels set in the proposed tol erances. The limit of quantitation (LOQ) for CGA

- 179500 is2

0.01 ppm for all matrices. ii. Livestock Syngenta Crop Protection Analytical Method REM 137.14 has been submitted for the Determination of Residues of Trinexapac Acid (CGA 179500) in Animal Matri ces . The limit of quantification has been set at 0.01 mg/ kg with final analysis by LC MS/MS for egg, kidney, liver, muscle and fat. The limit of quantification has been set at 0.005 mg/ kg for LC

- MS/MS determination for milk. 3. Magnitude of residues. S yngenta conducted adequate magnitude of residue trials on rice under OPPTS 180.1500 to support the requested use of trinexapac

- ethyl
. These residue trials satisfy the requested tolerance on rice
. A tolerance on rye was requested based on the November 25, 2009 ChemSAC decision that provides an allowance for extrapolating residue data for barley and wheat to additional small cereal grains if the use patterns are identical
. Since the directions for use are the same, the requested tolerances on rye are adequ ately supported. B. Toxicological Profile EPA 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. EPA 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 toxic effects caused by trinexapac

- e thyl as well as the no

- observed

- adverse

- effect

- level (NOAEL) from the toxicity studies can be found at the following website: http://edocket.access.gpo.gov/201 2 /201 2

- 4984 .htm . A summary of the toxicological endpoints for trinexapac

- e thyl used for human risk assessment is discussed in Unit III.A and B. of the final rule published in the Federal Register of March 2, 20 12 (7 7 FR pages 12740

- 12746 ) (FRL

- 9337

- 9 ).
C. Aggregate Exposure 1. Dietary exposure. Tier I acute and chronic dietary exposure evaluations were made for trinexapac

- ethyl using the Dietary Exposure Evaluation Model softwa re with the Food Commodity Intake Database (DEEM

- FCID, version 3.16). DEEM

- FCID software incorporates food consumption data from the National Health and Nutrition Examination Survey)/“What We Eat in America” (NHANES/WWEIA) dietary survey conducted in 2003

- 2008. These exposure assessments included all currently registered uses of trinexapac

- ethyl plus proposed foliar uses on rice and barley. Residue data was taken from field trials where trinexapac

- ethyl was applied at the maximum intended use rate and sa mples were harvested at the minimum pre

- harvest interval (PHI) to obtain maximum residue values. Established and proposed tolerance values were used for all commodities in these assessments. Drinking water estimates were included directly into the dietar y exposure assessment using the higher of the estimated drinking water concentrations (EDWCs) for surface and ground water.3

i. Food. Acute exposure
. The acute assessment was only performed for the females (13

- 49 years old) subpopulation as this subpopul ation was the only one for which an acute endpoint was determined. The acute dietary risk assessment was performed with an acute reference dose (aRfD) of 0.6 mg/kg

- bw/day based on an acute rabbit study with a no observed adverse effect level (NOAEL) of 60 mg/kg/day and an uncertainly factor of 100X. The 100X safety factor includes intra

- and interspecies variations. No additional FQPA safety factor was applied. The acute assessment was run using DEEM

- FCIDTM software using established and proposed toleran ce residue values and 100% CT values. For the purpose of the aggregate risk assessment, the exposure value was expressed in terms of margin of exposure (MOE), which was calculated by dividing the NOAEL by the exposure for the females (13

- 49 years old) sub group. In addition, exposure was expressed as a percent of the acute reference dose (% aRfD). Acute food exposure to the females (13

- 49 years old) subpopulation resulted in a MOE of 4,340 (2.3 % of the aRfD of 0.6 mg/kg

- bw/day). Since the Benchmark MOE for this assessment was 100 and since the EPA generally has no concern for exposures below 100% of the aRfD, Syngenta believes that there is a reasonable certainty that no harm will result from acute dietary (food) exposure to residues arising from the cur rent and proposed uses for trinexapac

ethyl. Chronic exposure. The trinexapac

- ethyl chronic dietary risk assessment was performed for all population subgroups with a chronic reference dose of 0.32 mg/kg/day based on a chronic dog study with a no observab le adverse effect level (NOAEL) of 31.6 mg/kg/day and an uncertainty factor of 100X. The 100X uncertainty factor includes intra

- and inter

species variations. No additional FQPA safety factor was applied. For the purpose of aggregate risk assessment, t he exposure values were expressed in terms of margin of exposure (MOE), which was calculated by dividing the NOAEL by the exposure for each population subgroup. In addition, exposure was expressed as a percent of the reference dose (% cRfD). Chronic diet ary (food only) exposure to the U.S. population resulted in a MOE of 4,151 (2.4% of the chronic RfD of 0.32 mg/kg/day). The most sensitive sub

population was children (1

- 2 years old) with a MOE of 1,611 (6.1% of the chronic RfD of 0.32 mg/kg/day). Since the benchmark MOE for this assessment is 1,000 and since the EPA generally has no concern for exposures below 100% of the RfD, Syngenta believes that there is a reasonable certainty that no harm will result from dietary (food only) exposure to residues ari sing from the current and proposed uses of trinexapac

- ethyl. Cancer
. Trinexapac

- ethyl is classified as “Not likely to be carcinogenic to humans.” ii. Drinking water. The Estimated Drinking Water Concentrations (EDWCs) of trinexapac

- ethyl (determined as total toxic residues of trinexapac

- ethyl and its acid degradate, CGA179500) were determined using Tier l model SCI

- GROW which estimates pesticide concentration in ground water, Tier II PRZM/EXAMS which estimates pesticide concentration in surface water fo r terrestrial uses and Modified Tier 1 Rice Model which estimates pesticide concentration in surface water for aquatic uses. EDWCs of trinexapac

- ethyl from the currently registered uses as well as a proposed use on rice were determined. For ground water, SCI

- GROW provided an EDWC of 0.00746 ppb (acute and chronic) based on the currently registered use on turf. For surface water,4

PRZM/EXAMS provided an acute EDWC of 10.2 ppb and a chronic EDWC of 1.24 ppb based on the currently registered use on turf. S urface water EDWCs were corrected for 0.95 Percent Cropped Area. T he surface water EDWCs were used for risk assessment purposes. Acute Exposure from Drinking Water : The acute surface water EDWC of 10.2 ppb was input directly into the DEEM

- FCIDTM software as “water, direct and indirect, all sources” to model the acute drinking water exposures. Exposure contributions at the 95%

- ile of exposures were determined by taking the difference between the aggregate (food + drinking water) exposures and the food (al one) exposures for each population subgroup. Acute drinking water exposure to the females (13

- 49 years old) subpopulation resulted in a MOE of 229,008 (<0.1% of the aRfD of 0.6 mg/kg

- bw/day). Since the Benchmark MOE for this assessment was 100 and since the EPA generally has no concern for exposures below 100% of the aRfD, Syngenta believes that there is a reasonable certainty that no harm will result from acute drinking water exposure to residues arising from the current and proposed uses for trinexapac

- ethyl
. Chronic Exposure from Drinking Water : The chronic surface water EDWC of 1.24 ppb was input directly into the DEEM

- FCIDTM software as “water, direct and indirect, all sources” to model the chronic drinking water exposures. Chronic drinking water ex posure to the U.S. population resulted in a MOE of 10 x 10 6 (<0.1% of the cRfD of 0.32 mg/kg

- bw/day). Chronic drinking water exposure to the most exposed sub

population (infants, <1 year old) resulted in a MOE of 472,001 (<0.1% of the cRfD of 0.32 mg/kg

- b w/day). Since the Benchmark MOE for this assessment was 100 and since the EPA generally has no concern for exposures below 100% of the cRfD, Syngenta believes that there is a reasonable certainty that no harm will result from chronic drinking water exposu re to residues arising from the current and proposed uses for trinexapac

ethyl
. 2. Non

- dietary exposure
. A residential exposure and risk assessment was performed for trinexapac

- ethyl using the endpoints and uncertainty factors established by the EPA in a recent assessment (September 12, 2013). Residential exposure and risk assessments were performed for trinexapac

- ethyl uses on turf at the maximum single application rate of 0.88 lb ai/A. Trinexapac

- ethyl is registered for non

- food uses by homeowners and professional applicators on turf grasses. As such, residential assessments included handler exposure for adults and post

- application exposure risks for adults and children. The highest predicted exposure for adults mixing, loading and applying product b y backpack spray application to turf resulted in a combined (dermal plus inhalation) short

- term margin of exposure (MOE) of 519. The post

- application dermal exposure to adults, following use of granules on lawns, from high contact activity is MOE = 901. Children’s post application dermal plus non

- dietary oral aggregate exposure to trinexapac

- ethyl from lawn products had a short

- term MOE of 220. Direct ingestion of granules is not aggregated with other routes of exposure for children because it is conside red to be a one

- time episodic event. The MOEs for all residential scenarios do not exceed the EPA’s level of concern (Benchmark MOE of 100) and there is a reasonable certainty that no harm will result from the residential uses of trinexapac

- ethyl.5

D. Cum ulative Effects Cumulative Exposure to Substances with a Common Mechanism of Toxicity. 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”. The EPA does not have, at this time, available data to determine whether trinexapac

- ethyl has a common mechanism of toxicity with oth er substances or how to include this pesticide in a cumulative risk assessment. For the purposes of this tolerance action, the EPA has not assumed that trinexapac

- ethyl has a common mechanism of toxicity with other substances. E. Safety Determination 1
. U.S. population. The acute dietary exposure analysis (food plus water) showed that exposure from all registered and proposed trinexapac

- ethyl crop uses would result in a MOE of 4,259 (2.3% of the aRfD) for the females (13

- 49 years old) subpopulation, whic h exceeds the benchmark MOE of 100. A short

- term aggregate exposure analysis (food, water and residential) was required for adults because there are residential exposure scenarios as a result of mixing, loading, and application to turf. The corresponding MOEs were aggregated using the inverse MOE approach. For short

- term exposures the dietary (food plus drinking water) exposure was aggregated with the residential exposure resulting in a short

- term aggregate MOE of 494 for the females (13

- 49 years old). Th e chronic dietary exposure analysis (food plus water) showed that exposure from all registered and proposed trinexapac

- ethyl crop uses resulted in a MOE of 4,149 (2.4% of the cRfD) which exceeds the benchmark MOE of 100. Since the worst
- case aggregate MOE of 494 exceeds the benchmark MOE of 100, and based on the completeness and reliability of the toxicity data supporting these petitions, Syngenta believes that there is a reasonable certainty that no harm will result from aggregate exposure to residues ari sing from all current, pending and proposed trinexapac

- ethyl crop uses, including anticipated dietary exposure from food, water, and all other types of non

occupational exposures. 2. Infants and children
. The chronic dietary exposure analysis (food plus d rinking water) showed that exposure from all established and proposed uses of trinexapac

- ethyl result in a MOE of 1,608 (6.1% of the cRfD ) for the most sensitive population subgroup, children (1

- 2 years old). Based on the completeness and reliability of t he toxicity data supporting these petitions, Syngenta believes that there is a reasonable certainty that no harm will result to infants and children from aggregate exposure to residues arising from all registered and proposed trinexapac

- ethyl crop uses, in cluding anticipated dietary exposure from food, water, and all other types of non

- occupational exposures. F. International Tolerances There are no established or proposed Codex, Canadian, or Mexican maximum residue limits (MRLs) for residues of trinexapa c - ethyl in or on any food or feed crops. However, a variety of European countries, as well as Argentina, Brazil, Japan, Korea, and Australia6

have established or proposed MRLs for trinexapac

- ethyl on cereal grains (0.02

- 0.5 mg/kg), cereal grain forages and fodders (0.2

- 3 mg /kg), sugarcane (0.05

- 0.1 mg/kg), sugarcane forage and fodder (1 mg/kg), meat (0.02 mg/kg), and/or milk (0.1

- 0.005 mg/kg).