EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR 

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER 

EPA Registration Division contact: Kay Montague, (703) 305-1243

Syngenta Crop Protection, LLC

Petition# 4F8254

EPA has received a pesticide petition (4F8254) from Syngenta Crop Protection, 

LLC, P.O. Box 18300, Greensboro, NC 27419 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 establishing a tolerance for residues of trinexapac-ethyl: 4-

(cyclopropyl-α-hydroxy-methylene)-3,5-dioxo-cyclohexanecarboxylic acid ethyl 

ester expressed as its primary metabolite CGA-179500: 4-(cyclopropyl-α-hydroxymethylene)-3,5-dioxo-cyclohexanecarboxylic acid] in or on: 

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 parts 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 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 trinexapac-ethyl is adequately 

understood for the purpose of the proposed tolerances. The metabolism of trinexapacethyl 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 Crops 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 tolerances. The limit of quantitation (LOQ) for CGA-179500 is 
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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 Matrices. 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. Syngenta 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 

adequately 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-ethyl 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/2012/2012-4984.htm. A summary of the toxicological 

endpoints for trinexapac-ethyl 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, 2012 (77 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 software 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 samples 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 dietary exposure assessment using the higher of the estimated drinking water 

concentrations (EDWCs) for surface and ground water.
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i. Food. Acute exposure. The acute assessment was only performed for the females (13-

49 years old) subpopulation as this subpopulation 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 tolerance 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) subgroup. 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 current and proposed uses for trinexapacethyl.

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 observable adverse effect level (NOAEL) of 31.6 mg/kg/day 

and an uncertainty factor of 100X. The 100X uncertainty factor includes intra- and interspecies variations. No additional FQPA safety factor was applied. For the purpose of 

aggregate risk assessment, the 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 dietary (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 subpopulation 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 arising 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 for 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, 
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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. Surface water EDWCs were corrected for 

0.95 Percent Cropped Area. The 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 (alone) 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 

exposure to the U.S. population resulted in a MOE of 10 x 106(<0.1% of the cRfD of 

0.32 mg/kg-bw/day). Chronic drinking water exposure to the most exposed subpopulation (infants, <1 year old) resulted in a MOE of 472,001 (<0.1% of the cRfD of 

0.32 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 cRfD, Syngenta 

believes that there is a reasonable certainty that no harm will result from chronic drinking 

water exposure to residues arising from the current and proposed uses for trinexapacethyl.

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 by 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 considered 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.
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D. Cumulative 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 other 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, 

which 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).The 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 arising from all current, pending and proposed trinexapac-ethyl crop 

uses, including anticipated dietary exposure from food, water, and all other types of nonoccupational exposures.

2. Infants and children. The chronic dietary exposure analysis (food plus drinking 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 the 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, including 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 trinexapac-ethyl in or on any food or feed crops. However, 

a variety of European countries, as well as Argentina, Brazil, Japan, Korea, and Australia 
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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).