EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING 

FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL 

REGISTER (4/9/2010)

EPA Registration Division contact: [Bethany Benbow, (703) 347-8072]

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 and brackets, 

i.e., “[insert company name],” with the information specific to your action.

TEMPLATE:

[Syngenta Crop Protection, Inc.]

[0F7720]

EPA has received a pesticide petition ([0F7720]) from [Syngenta Crop 

Protection, Inc.], [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.

(Options (pick one)

1. by establishing a tolerance for residues of

[Trinexapac-ethyl: 4-(cyclopropyl-α-hydroxy-methylene)-3,5-dioxocyclohexanecarboxylic acid ethyl ester expressed as its primary metabolite CGA179500: 4-(cyclopropyl-α-hydroxy-methylene)-3,5-dioxo-cyclohexanecarboxylic 

acid] in or on the raw agricultural commodity [] at []

Barley, grain at 1.6 parts per million (ppm)

Barley, hay at 0.7 parts per million (ppm)

Barley, straw at 0.35 parts per million (ppm)

Cattle, kidney at 0.05 parts per million (ppm)

Hog, kidney at 0.05 parts per million (ppm)

Sugarcane, cane at 0.8 parts per million (ppm)

Oat, forage at 1.0 parts per million (ppm)

Oat, grain at 4.1 parts per million (ppm)

Oat, hay at 1.3 parts per million (ppm)

Oat, straw at 0.7 parts per million (ppm)
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Wheat, forage at 1.0 parts per million (ppm)

Wheat, grain at 4.1 parts per million (ppm)

Wheat, hay at 1.3 parts per million (ppm)

Wheat, straw at 0.7 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. Syngenta Crop Protection is submitting Analytical Method

GRM020.01A 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. Method validation data using this method on various crop commodities is 

presented in the validation study. The limit of quantitation (LOQ) for CGA-179500 is 

0.01 ppm for all matrices. 

Syngenta Crop Protection is also submitting Analytical Method REM 137.14 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.

ii. Livestock. Because residues in the animal diets indicate that the transfer of

residues will be at or near the limit of detection, Syngenta Crop Protection, Inc. proposes 

that the Nature of Residue study can be used to define the Magnitude of Residue in 

livestock.

3. Magnitude of residues. Complete residue data to support the requested

tolerances for wheat, barley, oats and sugarcane have been submitted. The 

requested tolerances are adequately supported.

i. Wheat. In support of the requested tolerances, a total of twenty (20) field trials 

were conducted on wheat in the United States. One (1) trial was conducted in Virginia 

(EPA Region 2), one (1) trial in Arkansas (EPA Region 4), one (1) trial in Kansas (EPA 

Region 5), one (1) trial in North Dakota (EPA Region 5), one (1) trial in Minnesota 

(EPA Region 5), one (1) trial in Missouri (EPA Region 5), one (1) trial in
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Indiana (EPA Region 5), one(1) trial in Oklahoma (EPA Region 6), three (3) trials in 

North Dakota (EPA Region 7), one (1) trial in South Dakota (EPA Region 7), one (1) 

trial in Nebraska (EPA Region 7), four (4) trials in Texas (EPA Region 8), two (2) trials 

in Oklahoma (EPA Region 8), and one (1) trial in Idaho (EPA Region 11). The trial 

locations satisfy the requirements of OPPTS 860.1500, Crop Field Trials for the number 

of trials and the regional distribution. Trinexapac-ethyl 250EC was applied to wheat as a 

post foliar broadcast spray at a rate of 0.115 lb ai/A and 2-50 GPA (gallons per acre). 

The maximum residues were 1.3 ppm in wheat hay, 0.98 ppm in wheat forage, 0.64 ppm 

in wheat straw, and 4.0 ppm in wheat grain. The limit of quantitation (LOQ) for CGA179500 is 0.01 ppm for all matrices.

ii. Barley. In support of the requested tolerances, twelve (12) crop-field trials 

were initiated on barley in the United States. One (1) trial in Pennsylvania (EPA Region 

1), one (1) trial in Iowa (EPA Region 5), one (1) trial in Wisconsin (EPA Region 5), one 

(1) trial in North Dakota (EPA Region 5), four (4) trials in North Dakota (EPA Region 7), 

one (1) trial in Oregon (EPA Region 11), and one (1) trial in Idaho (EPA Region 11). The 

trial locations satisfy the requirements of OPPTS 860.1500, Crop Field Trials for regional 

distribution and number of trials conducted. Trinexapac-ethyl 250EC was applied to 

barley as a post foliar broadcast spray at a rate of 0.115 lb ai/A and 2-50 GPA (gallons 

per acre). The maximum residues were 0.54 ppm in barley hay, 0.29 ppm in barley straw, 

and 1.3 ppm in barley grain. The limit of quantitation (LOQ) for CGA-179500 is 0.01 

ppm for all matrices. 

iii. Oats. A tolerance on oats is requested based on the November 25, 2009 

ChemSAC decision that provides that the timing of applications to these crops 

coincides. Since the use patterns are identical, the wheat and barley data should be 

translatable to oats. Adequate data is being submitted to support the tolerances on oats. 

iv. Sugarcane. In support of the requested tolerances, eight (8) trials were 

conducted on sugarcane in the United States. Three (3) trials were conducted in Florida 

(EPA Region 3), three (3) trials in Louisiana (EPA Region 4), one (1) trials in Texas (EPA 

Region 6) and one (1) trials in Hawaii (EPA Region 13). The trial locations satisfy the 

requirements of OPPTS 860.1500, Crop Field Trials for regional distribution and number of 

trials conducted. Trinexapac-ethyl 250EC was applied to sugarcane as a post foliar broadcast 

spray 28 days prior to the harvest of mature cane at a rate of 0.312 lb ai/A and 2-100 GPA 

(gallons per acre). The maximum residues were 0.43 ppm for sugarcane. The limit of 

quantitation (LOQ) for CGA-179500 is 0.01 ppm for all matrices. 

v. Livestock. A livestock feeding study was conducted at three dosage 

levels, 2.0 ppm, 6.0 ppm, and 20 ppm. Residues of 0.03 ppm were found in the kidney at 

the 1X dose level all other tissues were <0.02 ppm (LOQ). No residues were detected in 

milk, LOQ 0.005 ppm. CGA-179500 is the main metabolite of trinexapac-ethyl. A hen 

feeding study was also conducted. The hens were fed ad libitum for 28 days with 

technical CGA-179500 at three levels – nominally 3.3 ppm (1X), 9.9 ppm (3X), and 33.0 

ppm (10X) in the feed on a dry weight basis. Residues of 0.06 ppm were found in the 

kidney at the 1X dose level all other tissues were <0.01 ppm. No residues were detected 

in eggs, LOQ 0.01 ppm. 
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B. Toxicological Profile

An assessment of toxic effects caused by trinexapac-ethyl is discussed in the 

EPA assessment dated September 5, 2008, Trinexapac-Ethyl: Revised Human 

Health Assessment Scoping Document in Support of Registration Review.

The technical trinexapac-ethyl product is classified in toxicity categories III & IV 

[CAUTION] based on acute oral, dermal, inhalation toxicity and eye/skin 

irritation studies.

1. Acute toxicity. The acute toxicity data of trinexapac-ethyl show that this

chemical is low via the oral, inhalation and dermal routes of exposure (Categories III-IV) 

and it is not a dermal sensitizer. 

2. Genotoxicty. Mutagenicity studies indicate that trinexapac-ethyl is not

mutagenic at doses tested. 

3. Reproductive and developmental toxicity. Reproductive Toxicity: In a rat

developmental toxicity study there was an increased incidence of asymmetrically shaped 

sternebra. The developmental NOEL was ≥200 mg/kg and the Maternal Toxicity NOEL ≥ 1000 

mg/kg. In a developmental toxicity study in New Zealand white rabbits, developmental toxicity

was observed at 360 mg/kg and manifested as a decreased number of live fetuses per litter. 

Developmental NOEL = 60 mg/kg and the Developmental LOEL = 360 mg/kg. Maternal 

toxicity was not observed. A 2-generation reproduction study in rats had a NOEL of 1000 ppm 

and a LOEL of 10,000 ppm based on reduced premating and gestation body weight and/or body

weight gain. 

4. Subchronic toxicity. Subchronic Oral Toxicity: A 13-week rat feeding study

had a NOEL of 500 ppm. A 13-week dog feeding study had a NOEL of 15,000 ppm. A 

21-day dermal study in rabbits had a NOEL of 10 mg/kg/day based on various 

biochemical parameters and microscopic observations of the skin.

5. Chronic toxicity. Chronic Oral Toxicity: In a combined oral oncogenicity/chronic 

study in rats, the LOEL for systemic toxicity = 10,000 ppm and the systemic toxicity NOEL 

= 3,000 ppm. Trinexapac-ethyl is not likely to be an oncogen. 

6. Animal metabolism. The metabolism of cyprodinil in rats is adequately

understood. As discussed in the EPA assessment dated September 5, 2008, TrinexapacEthyl: Revised Human Health Assessment Scoping Document in Support of Registration 

Review, Trinexapac-ethyl is rapidly, extensively absorbed (both sexes) with >95% of the

administered dose being absorbed. There is little potential for accumulation with >85% 

eliminated within 12 hours via urine and 2% via feces within 24 hours. There is very little 

or no biliary excretion and no sex difference. The free acid derivative resulting from 

hydrolysis of the ester bond of parent compound is the major component in urine and 

feces. The only other component was parent which was found in the feces. 
5

7. Metabolite toxicology. The residue of concern for tolerance setting purposes is

CGA-179500. CGA-179500 is the only animal metabolite of trinexapac-ethyl. Its 

toxicological properties are therefore fully assessed by the animal studies performed with 

trinexapac-ethyl. Other metabolites are considered to be of equal or lesser toxicity than 

the parent. 

8. Endocrine disruption. An extensive toxicity database exists for trinexapacethyl, including acute, subchronic, chronic, developmental, reproductive, and 

carcinogenicity toxicology studies. While no special studies have been conducted to 

investigate the potential for endocrine effects, the existing studies do not show evidence 

of compound-related endocrine-mediated effects or pathology of the endocrine organs. 

Consequently, it is concluded that trinexapac-ethyl does not possess endocrine 

disrupting properties. 

C. Aggregate Exposure 

1. Dietary exposure. Acute (Tier I) and chronic (Tier II) dietary exposure evaluations

were made for trinexapac-ethyl using the Dietary Exposure Evaluation Model software 

with the Food Commodity Intake Database (DEEM-FCIDTM, version 2.16) from

Exponent. All consumption data for these assessments were taken from the USDA’s

Continuing Survey of Food Intake by individuals (CSFII) with the 1994-96 consumption 

database and the Supplemental CSFII children’s survey (1998) consumption database.

These exposure assessments included all currently registered uses of trinexapac-ethyl

plus the proposed foliar uses on wheat, barley, triticale, oats, grasses grown for seed and 

sugarcane. 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 preharvest interval (PHI) to obtain maximum residue values. Wheat residue data was used 

as a surrogate for barley residue data. Anticipated residues in meat and milk were 

calculated by constructing theoretical nutritionally balanced diets. 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.

i. Food. Acute exposure. 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 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 31,059 

(0.3 % 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
6

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

and an uncertainty factor of 100X. The 100X uncertainty factor includes a 100X safety 

factor for intra- and inter-species 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 659,434 (0.0% 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 210,671 (0.0% 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. No cancer risk assessment was performed for trinexapac-ethyl.

ii. Drinking water. The EPA uses FIRST (FQPA Index Reservoir Screening Tool) as a

Tier I screening model to estimate pesticide concentrations in surface water, and SCIGROW (Screening Concentration In Ground Water) as a Tier I screening model to 

estimate pesticide concentrations in ground water. These models do not consider the 

impact that processing (mixing, dilution, or treatment) would have on the removal of 

pesticides from the water source prior to distribution as drinking water. The primary use 

of these models is to provide a conservative approximation of the Estimated Drinking 

Water Concentrations (EDWCs) of specific pesticides in drinking water. These models 

were used by Syngenta to calculate the highest EDWCs for trinexapac-ethyl from 

existing uses on turf and ryegrass grown for seed as well as proposed uses on wheat, 

barley, and sugarcane. Maximum EDWCs were calculated based on the turf use (4 

applications x 0.6875 lb ai/A, 56 day interval). For surface water the peak (acute) 

EDWC for the combined residue of trinexapac-ethyl and its free acid degradate (CGA179500) is estimated to be 49.725 ppb, and the annual average (chronic) EDWC is 

estimated to be 1.909 ppb. For ground water the EDWC is estimated to be 0.0130 ppb. 

Since the surface water EDWCs exceed the ground water EDWC, the surface water 

values should be used for comparison purposes and are considered protective for any

ground water concentration concerns

Acute Exposure from Drinking Water: The acute EDWC of 49.725 ppb was used to

calculate the acute drinking water exposure values for the females (13-49 years old) 

subpopulation as this subpopulation was the only one for which an acute endpoint was 

determined. Acute drinking water exposure to for the females (13-49 years old)
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subpopulation resulted in a MOE of 33,426 (0.3% of the aRfD of 0.6 mg/kg/day; 

Benchmark MOE = 100). Since the Benchmark MOE for this assessment is 100 and 

since 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 EDWC of 1.909 ppb was used to

calculate the chronic drinking water exposure values for the U.S. Population and 

population subgroups. Chronic drinking water exposure to the U.S. Population resulted 

in a MOE of 785,346 (or <0.01% of the cRfD of 0.32 mg/kg/day); Benchmark

MOE = 100). The most sensitive sub-population was infants (<1 year old) with a MOE of 

239,543 (<0.01% of the cRfD of 0.32 mg/kg/day; Benchmark MOE = 100). Since the 

Benchmark MOE for this assessment is 100 and since 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 dietary (drinking water) exposure 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 5, 2008). 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 belly

grinder application to turf resulted in a combined (dermal plus inhalation) short-term 

margin of exposure (MOE) of 1,092. The post-application dermal exposure to adults, 

following use of granules on lawns, from high contact activity is MOE = 325. Children’s 

post application dermal plus non-dietary oral aggregate exposure to trinexapac-ethyl

from lawn products had a short-term MOE of 225. Incidental ingestion of granules on 

treated lawns by children, calculated based on the short-term incidental oral NOAEL (no 

acute endpoint identified), had a MOE of 9,736. 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.

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
8

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 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 358,452 (<0.1% of the chronic RfD of 0.32 mg/kg/day) for the general U.S. 

population. A short-term aggregate exposure analysis (food, water and residential) was 

required for adults because there are residential post-application exposure scenarios. 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 o 325 for the adults (20-49 

years old). An intermediate-term aggregate exposure analysis (food, water and 

residential) was not required for adults because residential lawn applications scenarios 

are not expected to occur for longer than a short-term time frame. Since the worst-case 

aggregate MOE of 325 exceeds the benchmark MOE of 100, Syngenta believes that there 

is a reasonable certainty that no harm will result from aggregate exposure to residues 

arising from all current and proposed trinexapac-ethyl 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 drinking water)

showed that exposure from all established and proposed uses of trinexapac-ethyl result in 

a MOE of 150,657 (0.1% of the chronic RfD of 0.32 mg/kg/day) for the most sensitive 

population subgroup, children (1-2 years old). A short-term aggregate exposure analysis 

(food, water and residential) was required for toddlers because there are residential postapplication dermal and oral exposure scenarios. 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 225 for children (1-6 years old). An intermediate-term 

aggregate exposure analysis (food, drinking water and residential) was not required for 

children because residential lawn applications scenarios are not expected to occur for 

longer than a short-term time frame. Since the worst-case aggregate MOE of 225 

exceeds the benchmark MOE of 100, Syngenta believes that there is a reasonable 

certainty that no harm will occur to infants and children from aggregate exposure to 

residues arising from all current and proposed trinexapac-ethyl uses, including 

anticipated dietary exposure from food, water and all other types of non-occupational 

exposures. 

F. International Tolerances

There are no Codex maximum residue levels (MRLs) established for residues of 

trinexapac-ethyl in or on grasses grown for seed. Codex MRLs have been established for 

sugarcane, rape, and cereal crops and in animal commodities including milk and beef 

kidney.