UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460

MEMORANDUM

DATE: September 12, 2013 O FFIC E OF CH E M I CA L SAF E TY AND
POL LU T I ON P RE VENT I ON

SUBJECT: Trinexapac-ethyl: Human Health Risk Assessment for Registra t ion Review.

PC Code: 1 1 2602

Decision Nos.: 481333

Petition Nos.: NA

Risk Assessment Type: NA

TXRNo.:NA

MRIDNo .: NA DP Barcode: D413570 Registration Nos. : NA Regulatory Action: Reg i stra t ion Review

CaseNo.:NA

CAS No

. : 95266-40-3

40 CFR: §180.662

Shei l a Piper, Chemist/Risk Assessor \ihe..J.tu 

# (J{ pv')

Deborah Smegal, MPH, Toxicologist

. FROM:

Monica H awkins, Ph.D

. , M.P.H., Environmenta l H ealth Scientist

## Jv(_~J.i~~J.A)**~** Risk Assessment Branch V I · Health Effects Division (7509P)



### THROUGH : Felecia Fort, Ch i ef

# 01**o ;~**  Risk Assessment Branch V I 

# Jj

Health Effects Division (7509P)

TO: Kaitlin Keller, Chemica l Rev i ew Manager

Risk Management and Implementation Branch 3

Pesticide Re

- Evaluation D i vision (7508P)

Page I of46Table of Contents

..... .. .. . ... . .. .. .. .. . .. .. .. .. . ... . .. .. .. .. .. . ... . .. .. .. .. .. .. .. .. .. . ... . ... . ... .. .. . .. .. ... .. .. .. .. .. ... .. .. .. .. ... .. .. ... .. ... . 1

1

. 0 Executive Summary

.. . ...... . ............................................................................... . ........................ 4

2.0 HED Recommendations

....... .. .. .. . ... . .. .. . ... . .. .. .. .. .. . .. .. .. ...... .. .. .. .. .. ....... . .. .. .. ... .. .. .. .. ... .. .. .. ... .. .. ... .. .. 7

2.1 Data Deficiencies/Conditions of Registration

.. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. . ... .. .. . .... . ... .. .. .. ... .. ... .. .. ... .. 7

2

. 2 Tolerance Cons i derations

.. ........................................................................................................ 7

2.2.1 Enforcement Analytical Method

.... .. ..................... . ...... .. ...... . .... . ...... . ... .. ... . ... .. ... . ... . ... .. ... .. ... . ... .. ?

2

. 2

. 2 Internationa l Harmonization

.. .. .. .. .. . .. ... . .. .. .. .. .. . .. .......... .. .. .. .. .. .. .. .. .. .. .. .. .. ... . ... .. .. .. ....... .. ... .. .. ... .. .. 8

2

. 2

. 3 Recommended Tolerances

................................................. .. .............. . ....................................... 8

2.3 Label Recommendations

. .. ......... . ... . .. . ... . ... . ...... . ... .. ...... . ....... . ... . ... . ... . ... . ....... . ....... .. .................. . 8

2.3

. 1 Recommendat i ons from Residue Reviews

................................................................................ 8

2.3.2 Recommendations from OccupationaVResidential Assessment..

.............................................. 8

3.0 Ingredient Profile

.. .. .. . .. ...... . .. .. ... . ..................... . .......................... . ......................... . ................... 8

3.1 Chemical Identity

........... . .......... .. .............. . ............. .. ... . .. .. ...... . ... .. .. .. .. .. .. .. ... . ... .. .. .. ... .. .. .. .... .. .. .. 8

3.2 Physical/Chemical Characteristics

............................................................................................ 9

3.3 Summary ofExisting/Proposed Uses

. .. .. .. .. . ... . ... . .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. . ... .. .. .. .. ... .. .. ... . .... . ... .. ... .. 10

3.4 Anticipated Exposure Pathways

............ . ... . .............................................................. . ......... . ... 13

3.5 Consideration of Environmental Justice

. . ... .. .. .. ..................................................... . ................ 13

4.0 Hazard Characterizat i on and Dose-Response Assessment..

... . .. .. .. .. .. .. ................................... 13

4.1 Hazard and Dose-Response Characterization

........................ .. ...... .. ...... ... .. .. ....... . ... .. ... .. ... .. .. . 13

4.1.1 Database Summary

.. .. . ... . .. .. ............................................................................................... ... .. . 14

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)

. .. ... . ... .. . ... . ... .. ... . ... .. ............. 14

4.2.1 Dermal Absorption

....... . .......................................................... . .. ... .. . ... .. .. .. .. .. ... . .. ... .. .. ... .. .. ... ... . 14

4.3 Toxicological Effects

................................ . ... . ............................................ .. ... .. ....... .. .. .. ... ... .. . 15

4.4 Safety factor for Infants and Children (FQPA Safety Factor)

.......................................... .. ... . 16

4.4.1 Completeness ofthe Toxicology Database

. .. .. .. .. . .. .. .. .. .. ...... .. .. .. .. ... . ... . .................................... 17

4.4.2 Evidence ofNeurotoxicity and Immunotoxicity

...................................................... .. ... .. .. .. ... .. l7

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

. .. ... ... . .. ... .. ......... 18

4.4 .4 Residual Uncertainty in the Exposure Database

......................................... .. .. .. .. ... .. .. .. ... ... .. .. . .18

5.0 Dietary Exposure and Risk Assessment

.. . .. .. .. .. .. .. .. .. .. .. .. .. .. . ................................................... 21

5.1 Water Residue Profile

. ........................................................ . ....... . .. .. .. ... .. .. .. .. .. .. .. ... .. .. ... .. ... . .... 21

5.2 Dietary Risk Assessment

... .. .. . .. . ... . .. .. .. . ... .. .. . ... . .. .. .. . ... .. .......................................................... 22

5.2.1 Description ofResidue Data Used in Dietary Assessment

...................................................... 22

5.2.2 Percent Crop Treated Used in Dietary Assessment..

............................................................... 23

5.2.3 Acute Dietary Risk Assessment..

. .. .. .. . .. ... . .. .. .. .. ...... . ... . ... . ... . .. .. ... . ............................................ 23

5 .2.4 Chronic Dietary Risk Assessment

.... . ..................... .. .. .. .. . ... . ... .. .......... . .... . ............................... 23

5.2.5 Cancer Dietary Risk Assessment

............................................................................................. 23

5.2.6 Dietary Summary Table

.. ... . .. .. ............. .. ....................... . .............................. . .. . .... .. ... .. .. .. ... ... .. . 23

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

. . .... . ... . .............................. 24

7.0 Aggregate Exposure/Risk Characterization

..................... . .. .. ... . ... ...... .. .. . ... . ... .. ... . ... .. ... .. .. .. ... .. 32

7.1 Acute Aggregate Risk

.. .. . .. .. .. .. .. . .. .. ... .. . ... ..... . ....... . ...... .. ............... . .......................................... 32

7.2 Short- and Intermediate-Term Aggregate Risk

... ... .. . ... . .. .. .. .. .. .. .. .. .. .. .. ... . ... . ... .. .. .. .. ... .. ... .. ... .. .. 32

7.3 Cancer Aggregate Risk

........................................................................................................... 33

8.0 Cumulative Exposure/Risk Characterization

.. .. .. . ... . ... . ... .. . .. ... . ... . .. ... .. .. .. . .... . ... . ... .. .. .. ... .. ... .. .. . 33

9.0 Occupational Exposure/Risk Pathway

............................................................................. . ...... 34

9.1 Occupational Handler Exposure/Risk Estimates

.................................................................... 34

9.2 Occupationa l Post-application Exposure/Risk Estimates

....................................................... 42

Page 2 of 46Page 3 of 46 9.2.1 Occupational Post-application Inha lation Exposure/Risk Estimates .......................................42

9.2.2 Occupational Post-application Derm al Exposure/Risk Estimates ...........................................42

10.0 References .................................................................................................................... ........... 45Page 4 of 46 1.0 Executive Summary

The Pesticide Re-evaluation Di vision requested that HED prepare a human-health risk assessment for trinexapac-ethyl in support of regi stration review. To address this request, HED cites the most recent trinexapac-ethyl risk as sessment (D3377921, S. Piper, J. Facey, and M. Hawkins, 11/23/11) and has prepared this memo, which updates and expands appropriate sections of the November, 2012 assessment. R ecent changes in dietary consumption data and occupational assessment policies ( e.g., unit exposures, transfer coefficient, and new guidance for requiring/waiving Turf Transfe rrable Residue (TTR) and Dislo dgeable Foliar Residue (DFR) studies) have triggered the need for an updated dietary, residential, and occupational assessment for trinexapac-ethyl. To take into account this new informa tion, the following sections are provided:

1) Updated acute and chronic di etary exposure and risk asse ssment with the 2003-2008 food consumption data from the U.S. Department of Agriculture’s (USDA’s) National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA). 2) Updated residential handlers and post-application asse ssments for turf products. 3) Updated occupational handler a nd post-application exposure to trinexapac-ethyl from the currently registered products

.

Hazard Characterization

Since the previous human health risk assessm ent (D377921), acute and subchronic neurotoxicity studies have been submitted for trinexapac-ethyl. There was no evidence of neurotoxicity in the acute and subchronic neurotoxicity studies in rat at the highest dose tested of 2000 mg/kg and 948/1171 mg/kg/day (male/female), respectively. Therefore, the toxicity database for trinexapac-ethyl is complete under the revised 40 CFR Pa rt 158 data requirements for conventional pesticides.

Endpoints of concern for the incide ntal oral, dermal and inhalati on scenarios for children were not identified from the trinexapac-ethyl toxicity studies (See Section 4.0, Hazard Characterization). For short- a nd intermediate-term dermal and inhalation exposures for adults, the point of departure (POD) is from an or al developmental study in rabbits. The LOAEL (Lowest Observed Adverse Effect Level) fr om this study was 360 mg/kg/day based on a

decrease in the mean number of fetuses/litter and an increase in post-implantation loss. The NOAEL (No Observed Adverse Effect Level) fro m this study was 60 mg/kg/day. A dermal absorption factor of 77.5 % was used for the exposure assessment based on information from a rat dermal penetration study (MRID 42238105). An oral study was selected for the inhalation

route because there was no inha lation study of appropriate dura tion, and based on a review by the Hazard and Science Policy Council (HASPOC; June 20, 2013, TXR 0056699), a routespecific inhalation toxicity study is not required at this time. The level of concern (LOC) for occupational and non-occupational risk is for ma rgins of exposure (MOEs) less (<) than 100. A body weight of 69 kg was used for the inhalati on and dermal assessment since the endpoints were from a developmental toxicity study with fe tal effects. Since the dermal and inhalationPage 5 of 46 scenarios are based on the same study, they can be combined when assessing occupational and residential exposure. Trinexapac-ethyl is clas sified as “Not likely to be carcinogenic to

humans.”

Metabolism/Metabolites and Degradates of Concern

The metabolism of trinexapac-ethyl in plants a nd animals has been adequately delineated. The primary degradation pathway in both livestock and plants involves trin exapac-ethyl rapidly undergoing hydrolysis of the ethyl ester to form trinexapac.

The residue of concern in primary crops, rota tional crops and livestock for both tolerance

enforcement and risk assessment include free an d conjugated residues of both parent trinexpacethyl and its acid metabolite, trin exapac. In drinking water, de gradates of concern for risk assessment are trinexapac-ethyl, trinexapac, 2-(4-cyclopropyl-4-hydr oxy-2-oxobutyl)succinic acid (CGA-313458), an open chain cyclohexane ri ng, and the unidentifie d hydroproduct M3.

Food Residue Profile

The residue profile for the proposed commoditie s is adequate. For all commodities, the registrants submitted adequate field trial data for parent trinexapac-ethyl as trinexapac. Tolerances are currently established for residues of the plant growth inhibi tor, trinexapac-ethyl in/on various plant commodities, at levels rang ing from 0.02 to 40.0 ppm as listed in e-CFR 40 §180.662.

Dietary Exposure and Risk

An updated acute and chronic di etary (food and drinking water) e xposure and risk assessments

were conducted. These unrefined assessments are based on tolerance- level residues, 100% crop treated assumptions for all commodities, and DEEM default processing factors. The acute and chronic dietary risk estimates are belo w HED’s level of concern for all population subgroups, including those comprised of infants and children. Because such conservative assumptions were made in the assessments, HED is confident that the acute and chronic dietary exposure assessments do not underestimate risk to the general U.S. population or any population subgroup.

Residential Exposure and Risk

HED determined that there is a potential for residen tial handler and post-application exposure to trinexapac-ethyl from the curren tly registered turf products. An updated residential handler and post-application assessment was conducted because HED recently updated the Standard Operating Procedures for Residential Pesticide Exposure Assessment ( http://www.epa.gov/opp00001/science/EPA- OPP-HED_Residential%20SOPS_Feb2012.pdf ) and body weights to be used in all human health assessments. The combined dermal plus

inhalation risk estimates to resi dential handlers do not exceed HE D’s LOC for all scenarios (i.e.,

MOEs ≥ 100); MOEs ranged from 240 to 21,000,000. Th e short-term dermal residential postapplication MOEs ranged from 450 to 61,000, and therefore, do not exceed HED’s LOC (MOEsPage 6 of 46 ≥ 100). Chemical-specific TTR data are availabl e for trinexapac-ethyl and were used in the residential post-application exposure assessmen t in conjunction with standard default assumptions.

Aggregate Exposure and Risk

The acute (females only) and chronic aggregate ri sks are equivalent to the corresponding dietary (food plus water) risks, which are not of concer n. The short- and intermediate-term dermal and inhalation toxicological endpoints for trinexapac-ethyl are the sa me. The resulting aggregate

short- and intermediate-term risk esti mates for adults and children (MOE ≥ 100); therefore, the short- and intermediate-term aggregate risks of e xposure to trinexapac-ethyl are not of concern.

Occupational Exposure and Risk

HED determined that there is a potential for occupational handler and post-application exposure to trinexapac-ethyl from the currently register ed products. The occupational handler assessment was completed assuming the maximum label application rate for each crop. The occupational handler exposure and risk estimates indicate th at short- and intermed iate-term dermal and

inhalation combined MOEs are not of concern to HED (i.e., MOEs ≥ 100) with baseline attire and/or with the addition of gloves (as required on the labels). With baseline attire and/or gloves, the dermal plus inhalation MOEs range from 140 to 2,100,000.

Chemical-specific TTR data are available for trin exapac-ethyl and were used in the occupational post-application exposure assessment to assess turf scenarios. Chemical-specific DFR data are not available for trinexapac-ethyl in order to assess sugarcane, cereals (wheat, barley, oats, triticale), and grasses grown for seed scenarios. As specified in the revised 40 CFR Part 158 data requirements for conventional pest icides, a DFR study is required for trinexapac-ethyl at this time. The occupational post-appli cation dermal exposure and risk es timates indicate that shortand intermediate-term MOEs are no t of concern to HED (i.e., MOEs ≥ 100) on the day of application, except for hand-harves ting sugarcane (MOE=87) where ri sk estimates are of concern until 2 days after application (MOE=110). The occupational post-application MOEs on the day of application range from 87 to 43,000. Based on HED’s occupational post-application exposure assessment, the restricted-entry interval (REI) for hand-harvesting sugarcane was estimated to be 2 days for short- and intermediate-term expos ure. However, HED does not recommend that sugarcane REI’s be changed on the trinexapac-ethyl labels at this time based on two main issues. One, almost all sugarcane harvesting in the Un ited States is done mechanically. Two, the proposed trinexapac-ethyl labels have a 28-day pre- harvest interval (PHI) for sugarcane, so hand harvesting should not occur until after 28 days wh ich is protective of the estimated REIs. Current trinexapac-ethyl labels have no REI, 0 da ys, or a 4-hour REI. The trinexapac-ethyl

technical material has been classified in Toxici ty Category III for acute dermal, oral, and primary eye irritation, and Category IV for acute inhala tion and primary skin irritation. Therefore, the acute toxicity categories for this chemical require a 12 hour REI under 40 CFR 156.208 (c) (2) (iii).Page 7 of 46 Human Studies

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical . These data, which include studies from PHED 1.1; the AHETF database; the Outdoor Residential Exposure Task Force (ORETF) database; the ARTF database; and the Residential SOPs (Turf/Lawn ) are (1) subject to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable ethics requirements. For certain studi es, the ethics review may have included review by the Human Studies Review Board.

2.0 HED Recommendations

2.1 Data Deficiencies/Conditions of Registration

Dislodgeable Foliar Residue (DFR) In accordance with the updated Part 158 data requi rements (2007), one or more DFR studies are required when a pesticide has residential or occupational uses that could result in postapplication dermal exposure. As part of the recent revision to the Health Effects Division’s 2012 Standard Operating Procedures for Resi dential Pesticide Exposure Assessment , HED analyzed a

number of DFR studies and select ed a new default value for the fr action of the application rate available to be dislodged after a foliar application (F AR ). This default value is 25% and is based on an analysis of 19 DFR studies where the F AR value ranged from 2% to 89%. This value is

recommended for use in both residential and occ upational post-app lication assessments. Of the analyzed DFR studies, the maximum F AR value seen was 89% or 3.6 times higher than the default residue transfer value. Therefore, the HED has decided that a calculated MOE of approximately 4 times higher than the level of concern (e.g., an MOE > 400 if the LOC = 100) using the default dislodged residue values would provide an adequate margin of safety for any potentially higher residues seen in a chemical-specific DFR study ( Guidance for Requiring/Waiving Turf Transfe rrable Residue (TTR) and Disl odgeable Foliar Residue (DFR)

Studies . 6/7/2012, Exposure Science Advisory Counc il). A DFR study will be required for future assessments for trinexapac-ethyl.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

An adequate enforcement method is availabl e for trinexapac-ethyl, Method GRM020.01A, which utilizes high performance liquid ch romatography with triple-quadrupole mass spectrometry (LC-MS/MS). The new method in cludes a strong acid hydrolysis/extraction procedure to release both “free” and “conjugate d” residues of CGA179500 from field grown grass commodities. The reported limit of quant itation (LOQ) is 0.010 ppm. The method has been adequately validated. Also, trinexapac-ethyl was evaluated using the FDA multiresidue method Protocols C and D, and its acid metabolite, trinexapac, was evaluated using Protocol B.Page 8 of 46 These data indicate FDA multi-residue methods ar e not suitable for determining residues of trinexapac-ethyl and trinexap ac in plant commodities.

2.2.2 International Harmonization

There are no established or proposed Codex, Canadian, or Me xican maximum residue limits (MRLs) for trinexapac-ethyl in or on any food or feed crops. Ho wever, a variety of European countries, as well as Argentina, Brazil, Japan, Ko rea, and Australia have established or proposed MRLs for trinexapac-ethyl on cereal grains ( 0.02-0.5 mg/kg), cereal grai n forages and fodders (0.2-3 mg/kg), sugarcane (0.05-0.1 mg/kg), suga r forage and fodder (1 mg/kg), meat (0.02 mg/kg), and/or milk (0.1-0.005 mg/kg).

2.2.3 Recommended Tolerances

Tolerances are established for residues of the plant growth regulator trinexpac-ethyl, including its metabolite and degradate, in or on the co mmodities in the 40CFR 180.662. For plant and livestock commodities, the tolerances should be established as follows:

Tolerances are established for residues of trinexapac-ethyl, includi ng its metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determin ed by measuring both trinexapac-ethyl, ethyl 4- (cyclopropylhydroxymethylene)-3,5-dioxocyclohe xanecarboxylate and the associated metabolite trinexpac, 4-(cyclopropylhydroxym ethylene)-3,5-dioxocyclohexanecarboxylic acid, calculated as the stoichiometric equivalent of trinexapac-ethyl.

2.3 Label Recommendations

2.3.1 Recommendations from Residue Reviews

The label must be modified to specify a 30-day pl antback restriction for ce real grains and leafy vegetables, and prohibit the planting of all other crops not listed on the label.

2.3.2 Recommendations from Occupational/Residential Assessment

PRD should ensure the proper restricted entry inte rvals (REIs) are put in place considering the post-application assessment, the acute toxicity of trinexapac and the cr iteria for 12-hr REIs on the labels to reflect these requirements.

3.0 Ingredient Profile

3.1 Chemical Identity

Table 3.1. Test Compound NomenclaturePage 9 of 46 Table 3.1. Test Compound Nomenclature Compound

Common name Trinexapac-ethyl Company experimental name CGA163935 IUPAC name ethyl ( RS )-4-cyclopropyl( hydroxy)methylene -3,5-dioxocyclohexanecarboxylate CAS name ethyl 4-(cyclopropylhydroxymethylene)-3,5-dioxocyclohexanecarboxylate CAS registry number 95266-40-3 End-use product (EP) 1.0 lb/gal EC (PalisadeTM EC; EPA Reg. No. 100-949) 2.0 lb/gal EC (Palisade 2EC; EPA Reg. No. 100-1241) Regulated Metabolite

Common Name Trinexapac Company Experimental

Name CGA-179500

IUPAC name ( RS )-4-cyclopropyl(hydroxy) methylene-3,5-dioxocyc lohexanecarboxylic acid CAS name 4-(cyclopropylhydroxymethylene)-3,5-dioxocyclohexanecarboxylic acid CAS registry number 104273-73-6

3.2 Physical/Chemical Characteristics

Trinexapac-ethyl has a relatively low octanol/wat er partition coefficient. At pH 5.3, the log K OW value is 2.44 (K OW = 275). Trinexapac-ethyl has a low potenti al to leach into groundwater and is not expected to be volatile because of its low vapor pressure (2.16 x 10 -3 Pa at 25 o C). See Table 3.2 for a listing of trinexapac-ethyl physic al and chemical properties. OH

O O

O

O

C H 3

O

O

O O H OHPage 10 of 46 Table 3.2. Physical and Chemical Properties of Trinexapac-Ethyl.

Parameter Value Reference
Melting point/range 36.1-36.6°C Provided in MRID

46809305 pH 3.3 Density (20oC) 1.215 g/cm 3
Water solubility (g/L at 25°C) 2.8 at pH 4.9 10.2 at pH 5.5 21.1 at pH 8.2 Solvent solubility Acetone 100% Ethanol 100%

Toluene 100% n-octanol 100%

n-hexane 5% Vapor pressure (25oC) 2.16x 10 -3 Pa Dissociation constant, pK

a 4.57 Octanol/water partition coefficient, Log(K O W ) at 25oC 2.44 at pH 5.3

UV/visible absorption spectrum Neutral: 9335 L/mol·cm @ 240.2 nm 13976 L/mol·cm @ 277.4 nm Acidic: 11712 L/mol·cm @ 240.0 nm 12368 L/mol·cm @380.4 nm Basic: 21320 L/mol·cm @ 270.8 nm

3.3 Summary of Existing/Proposed Uses

Trinexapac-ethyl is a cyclohexadion e plant growth regulator that is marketed as an emulsifiable concentrate, wettable powder packed in water-sol uble bags, granule, and as a technical chemical used for formulation only. Syngenta Crop Protecti on has registered trinex apac-ethyl for multiple end-use products on turf areas such as sod farm s, golf courses, sport fields, cemeteries and similar areas, and on grasses grown for seed, sugarcane, and cereals (wheat, barley, oats, triticale). The label-required personal protective equipment ( PPE) for occupational applicators and handlers is a long-sleeved shirt, long pants, shoes, and socks, chemi cal-resistant gloves, and protective eyewear. The currently registered uses and application rates are summarized in Table

3.3.

Table 3.3. Trinexapac-ethyl Use Patterns and Formulations

Applic. Timing, Type, and

Equip. Formulation [EPA Reg. No.] Applic. Rate (lb

ai/A) Max. Seasonal Applic. Rate

(lb ai/A) Max. Applic.

per Season REI Use Directions and

Limitations

Turf

Back Pack, Hand Sprayers, Boom Sprayers, Hand Gun Sprayers 12% ai, EC Primo Liquid (EPA Reg. No. 100-729) 0.36 lb

ai/A (0.017 lb ai/gallon;

0.000008

lb ai/ft 2 ) 0.36 lb ai/A Multiple 0 days Do not apply this product through any type of irrigation
system.

Back Pack, Hand Sprayers, Boom Sprayers, Spray

Gun 25.0 % ai,

Primo WSB

WP in Water Soluble Bag 0.34 lb

ai/A (0.016 lb ai/gallon) 0.34 lb ai/A Multiple 0 days Do not apply this product through any type of irrigation
system.Page 11 of 46 Table 3.3. Trinexapac-ethyl Use Patterns and Formulations

Applic. Timing, Type, and

Equip. Formulation [EPA Reg. No.] Applic. Rate (lb

ai/A) Max. Seasonal Applic. Rate

(lb ai/A) Max. Applic.

per Season REI Use Directions and

Limitations

(EPA Reg. No. 100-752) Turf (Edging/Banding)

Spreader, Shaker

Can .01 %-1.0 % ai, Lawn Primo F, Granule, (EPA Reg. No. 100-931) 0.88 lb

ai/A (0.00002

lb ai/ft 2 ) 0.88 lb ai/A Multiple 0 days Be sure the lawn has adequate fertility before using the product.

Backpack Sprayers, Hand Sprayers, Boom Sprayers, Spray

Guns 12% ai, EC Primo Liquid (EPA Reg. No. 100-729) 0.73 lb

ai/A 0.73 lb ai/A Multiple 0 days Do not apply this product through any type of irrigation
system.

Back Pack, Hand Sprayers, Boom Sprayers, Spray

Gun 25.0 % ai, Primo WSB,

WP in Water Soluble Bag (EPA Reg. No. 100-752) 0.68 lb

ai/A 0.68 lb ai/A Multiple 0 days Do not apply this product through any type of irrigation
system.

Turf and Edging/Banding

Spreader, Shaker

Can 0.39% ai,

The Andersons

0.39%Trinexapacethyl + Fertilizer, Granule, (EPA Reg. No.

9198-246) 0.88 lb

ai/A 0.88 lb ai/A Multiple 0 days Do not apply this product to grasses not listed on the label.

Sod Farm

Back Pack, Hand Sprayers, Boom Sprayers, Hand Gun Sprayers 12% ai, EC Primo Liquid (EPA Reg. No. 100-729) 0.36 lb

ai/A 0.36 lb ai/A Multiple 0 days Do not apply this product through any type of irrigation
system.

Back Pack, Hand Sprayers, Boom Sprayers, Spray

Gun, Aerial, Chemigation 25.0 % ai, Primo WSB,

WP in Water Soluble Bag (EPA Reg. No. 100-752) 0.34 lb

ai/A 0.34 lb ai/A Multiple 0 days Do not apply this product through any type of irrigation
system.

Golf Course Fairways

Spreader, Shaker

Can 0.39% ai,

The Andersons

0.39%Trinexapacethyl + Fertilizer, Granule, (EPA Reg. No. 0.44 lb

ai/A 0.44 lb ai/A 0 days Do not apply this product to grasses not listed on the label.Page 12 of 46 Table 3.3. Trinexapac-ethyl Use Patterns and Formulations

Applic. Timing, Type, and

Equip. Formulation [EPA Reg. No.] Applic. Rate (lb

ai/A) Max. Seasonal Applic. Rate

(lb ai/A) Max. Applic.

per Season REI Use Directions and

Limitations

9198-246)

Back Pack, Hand Sprayers, Boom Sprayers, Hand Gun Sprayers 12% ai, EC Primo Liquid (EPA Reg. No. 100-729) 0.18 lb

ai/A 0.18 lb ai/A Multiple 0 days Do not apply this product through any type of irrigation
system.

Back Pack, Hand Sprayers, Boom Sprayers, Spray

Gun 25.0 % ai, Primo WSB,

WP in Water Soluble Bag (EPA Reg. No. 100-752) 0.17 lb

ai/A 0.17 lb ai/A Multiple 0 days Do not apply this product through any type of irrigation
system.

Golf Course Greens

Back Pack, Hand Sprayers, Boom Sprayers, Hand Gun Sprayers 11.3% ai,

Microemulsion

Concentrate

Primo Maxx (EPA Reg. No. 100-937) 0.07 lb

ai/A 0.07 lb ai/A Multiple 0 days Do not apply this product through any type of irrigation
system.

Spreader, Shaker

Can .01 %-1.0 % ai, Lawn Primo F, Granule, (EPA Reg. No. 100-931) 0.07 lb

ai/A 0.07 lb ai/A Multiple 0 days Be sure the lawn has adequate fertility before using the product.

Back Pack, Hand Sprayers, Boom Sprayers, Spray

Gun 25.0 % ai, Primo WSB,

WP in Water Soluble Bag (EPA Reg. No. 100-752) 0.05 lb

ai/A 0.05 lb ai/A Multiple 0 days Do not apply this product through any type of irrigation
system.

Grasses Grown For Seed

Aerial, Ground,

Chemigation 12 % Palisade EC, EC, (EPA Reg. No. 100-949) 0.5 lb ai/A 0.5 lb ai/A 2 12 hours PHI = 35 days

Sugarcane

Aerial, Ground,

Chemigation 12 % Palisade EC, EC, (EPA Reg. No. 100-949) 0.31 lb

ai/A 0.31 lb ai/A 2 12 hours PHI = 28 days

Cereals (Wheat, Barley, Oats, Triticale)

Aerial, Ground,

Chemigation 12 % Palisade EC, EC, (EPA Reg. No. 100-949) 0.1 lb ai/A 0.11 lb ai/A 2 12 hours PHI = 45 days.

Several of the trinexapac-ethyl labels did not provide th e pounds (lb) active ingredient (ai) per gallon of product; therefore, HED made assumptions in order to convert the rates to lb ai/A.Page 13 of 46 3.4 Anticipated Exposure Pathways

PRD requested that HED perform an assessment of human health risk to support for trinexapacethyl on cereal grains, sugarcane, turf grass, sod farms, golf c ourses, and residential lawns in support of registration review. Hu mans might be exposed to trin exapac-ethyl in food and drinking water because trinexapac-ethyl ma y be applied directly to grow ing crops. In addition, these applications can result in trinexapac-ethyl r eaching surface and groundwater, both of which can serve as sources of drinking water. The uses on tu rf grass result in the potential for both residential and occupational exposures. In addition, because of the agricultural uses, applicators might be exposed while handling the pesticide prior to appl ication, mixing/loading the pesticide, and during application. There is a potential for post-application exposure for work ers re-entering treated fields.

3.5 Consideration of Environmental Justice

Potential areas of environmental ju stice concerns, to the extent possi ble, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, “Federal Actions to Address Environmental Justice in Minority Populations and Low-Income Populations,” ( http://www.eh.doe.gov/oepa/ guidance/justice/eo12898.pdf . As a part of every pesticide risk assessment, OPP considers a large variety of c onsumer subgroups according to well-established procedures. In line with OPP policy, HED estimates risks to p opulation subgroups from pesticide exposures that are based on patte rns of that subgroup’s food and wa ter consumption, and activities

in and around the home that involv e pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the USDA unde r the Continuing Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categor ized by subgroups based on ag e, season of the year, ethnic group, and region of the country. Additionall y, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure as sessments are performed when conditions or circumstances warrant. Whenever appropriate , non-dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated ar eas postapplication are evaluate d. Further considerations are currently in development as OPP has committed re sources and expertise to the development of specialized software and models th at consider exposure to bystande rs and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0 Hazard Characterization and Dose-Response Assessment

4.1 Hazard and Dose-Response Characterization

The acute toxicity for trinexapac- ethyl technical formulation was cl assified as Toxicity Category III for acute oral, dermal, and eye irritation, and IV for acute inhalation and skin irritation. Table 4.1 presents a summary of the acute toxi city information fo r trinexapac-ethyl.Page 14 of 46 Table 4.1. Acute Toxicity Profile - Trinexapac-ethyl (97%)

Guideline

No. Study Type MRID Results Toxicity Category

870.1100 Acute oral [rat] 41563901 ♂ LD 50 = 4613 mg/kg ♀ LD 50 = 4212 mg/kg

Combined LD 50 = 4458 mg/kg III

870.1200 Acute dermal [rabbit] 41563910 LD 50 > 4000 mg/kg III 870.1300 Acute inhalation [rat] 41563912 LC 50 ≥ 5.3 mg/L IV 870.2400 Acute eye irritation [rabbit] 41563914 Minimal irritant; cleared by 72 hours III 870.2500 Acute dermal irritation [rabbit] 41563916 Slightly irritating; cleared by day 7 IV 870.2600 Skin sensitization [guinea pig] 41869522 Not a dermal sensitizer N/A

4.1.1 Database Summary

The toxicology database for trin exapac-ethyl is complete for ri sk assessment in support of registration review. Available to xicity studies are detailed in the following section and a brief summary of the findings is discussed in section 4.3, Toxicological Effects.

4.2 Absorption, Distribution, Met abolism, & Elimination (ADME)

Absorption: Trinexapac-ethyl was rapidly and extens ively absorbed in both sexes of rat following single or repeat low-dose (0.97 mg/k g bw) administration and single high-dose (166 mg/kg bw) administration. Greater than 95% of the administered dose was absorbed following single or repeat low-dose administration and singl e high-dose administration. Data suggests that there was very little or no biliary absorption. Distribution: The highest residue levels were observed in the fat, lungs, kidneys and liver; however, mean recovery of radioactivity in tissues/carcass at sacrifice (at 168 h post-dosing) was less than 0.3% of administered dose for all dose groups indicating little potential for accumulation. Metabolism: The major component in

urine and fecal extracts was identified as 4-cyclopropyl-

 (hydroxy-methylene)-3,5-dioxocyclohexanecarboxylic acid, the free acid deri vative of trinexapac-ethyl resulting from hydrolysis of the ester bond of the parent compound accounting for approximately 82–91.6% of the administered dose. The only other residue found (found in fecal extrac t only) was identified as the parent compound, accounting for less than 0.1% of the administered dose. Excretion: Excretion was rapid, with the majority of radio activity being eliminated within 12 h post-dosing

via urine (greater than 85% of the administered dose at the low and high dose) and within 24 h post-dosing via feces (0.56–1.43 and 0.80–2.01% at th e low and high dose, respectively). The major route of excretion was vi a urine, accounting for approximate ly 95% of administered dose

at both dose levels. Fecal excr etion accounted for approximate ly 1.0–2.4% of administered dose at both dose levels. By 72 hr less than 0.01% of the administered dose was recovered in expired air. Data suggest that there was very little or no biliary excretion. Significant qualitative

differences were not found in ab sorption, distribution, metabolism or excretion of trinexapacethyl between the sexes, between single and re peat low-dose administration, or between single low-dose and high-dose administration. These results indicate that toxici ty of both the parent and acid metabolite has been accounted for in the submitted toxicity studies.

4.2.1 Dermal AbsorptionPage 15 of 46 A single dermal dose of 0.01, 0.1, or 1.0 mg/cm 2 14 C-trinexapac-ethyl administered to male rats was rapidly absorbed, distributed and e liminated (MRID 42238105). The amount absorbed increased with duration of exposure. The average 14 C- trinexapac-ethyl absorbed within 24 hours was 56.8, 66.7, and 33.8% of the applied dose for the low-, mid-, and high- dose groups, respectively. Recovery of the applied dose was 97-117% and most was recovered from the skin washes and urine. A dermal absorption fact or of 77.5% was estimated based on the sum of

56.5% absorbed after 10 hours in the low dose group (0.01 mg/cm2), in addition to 21% of applied dose that was associated with the application site after wash.

4.3 Toxicological Effects

The acute toxicity of the technical material is low via the oral, dermal, or inhalation routes of exposure (Categories III-IV), and it is not a dermal sensitizer.

Trinexapac-ethyl is a low acute toxicity chemi cal with systemic effects occurring at or well above 300 mg/kg/day in subchronic and lifetime dos ing studies. There is, however, evidence of increased qualitative and quantitative suscepti bility in the rat (inc reased incidence of asymmetrical sternebrae) and rabbit (decreased nu mber of live fetuses/litter and increased postimplantation loss) developmental studies, but only at relatively high doses (300 – 1,000 mg/kg/day). Qualitative sensitivity was observe d in the 2-generation reproduction study but only above the limit dose (1,000 mg/kg/day). Decrease d pup survival when analyzed with sexes

combined resulted in statistical significance (5-7%), but was not significant when analyzed separately. Further evaluation of the individual litters suggested th at one or two li tters were not the cause of the reduced pup survival at the hi ghest dose tested. Repr oductive toxicity was not observed up to the limit dose. Refer to Table 4.3 for a comparison of the effects across toxicity

studies.

Looking across the available toxicity studies, the dog appears to be the most sensitive species. In adult animals, no systemic adverse effects were seen in rats, rabbits, or mice below the limit dose (1,000 mg/kg/day) following subchronic or chro nic oral exposure. In the dogs, however, decreased body weight gain and food consumpti on, diffuse thymic atrophy, and changes in the epithelial cells of the renal tubules were seen in the 90-day dog study at 516/582 mg/kg/day (males/females). Following chronic exposure, do se-related neuropathology of the brain was seen

at ≥ 365/357 mg/kg/day in male and female dogs, respec tively. The lesions remained confined to the supporting cells in the central nervous system and did not progress to more advanced or more extensive damage of the nervous tissue. They we re not associated with other neuropathological findings or overt neurological signs, so their biological signifi cance is unknown. Similar lesions

were not observed in the rat or mouse followi ng subchronic or chronic dietary exposure, and there was no other evidence in any other species tested to indicate a neurotoxicity potential. There was no evidence of neurotoxicity in the acute and subchronic rat neurotoxicity studies. Furthermore, the brain lesions observed in the ch ronic dog study are not likely to develop from a short-term exposure and were not observed in e ither the rat or mouse short-term studies. The combined chronic toxicity/carcinogenicity study in the rat did not demons trate an increase in any tumor type that would be relevant to human s. The observation of squamous cell carcinomas in the non-glandular portion of the stomach of two males at 806 mg/kg/day does not providePage 16 of 46 reasonable evidence of a possible deleterious eff ect of trinexapac-ethyl on the pharynx and/or esophagus (non-glandular areas) of the human becau se trinexapac-ethyl would not be in contact with the human tissues for a significant period of time compared to the length of time with which it would have been in contact with the rat stomach. Follicular adenocarcinoma of the thyroid was significantly increased in ma les (5%) at 806 mg/kg/day, but was within the historical control range. In the mouse, there was no evidence of car cinogenicity. The mutagenicity database is complete, with no evidence of mu tagenicity. The cancer classifi cation for trinexapac-ethyl is “Not likely to be carcinogenic to humans.”

Table 4.3. Comparison of NOAELs/LOAELs for co nsideration in risk assessment for trinexapacethyl

Study NOAEL mg/kg/day LOAEL mg/kg/day Endpoint

Rat Developmental

Maternal 1000 >1000 none

Developmental 200 1000 Based on increased incidence of asymmetrically-shaped sternebrae

Rabbit Developmental

Maternal 360 (HDT) >360 none

Developmental 60 360 (HDT) Based on a decrease in the mean numberof fetuses/litter and an increase in postimplantation loss

2-Generation Reproduction- Rat

Parental 594 1212 Based on reduced premating and gestation body weight/body-weight gain and food consumption

Offspring 594 1212 Based on decreased F1 postnatal survival and reduced pup body weights in both generations [both sexes].

Chronic Dog

Adult males and

females 31.6 357 Based on elevated serum cholesterol values in females, mucoid feces in females and bloody feces in both sexes, and minimal, focal vacuolation of the dorsal medial hippocampus and/or lateral

midbrain in both sexes.

4.4 Safety factor for Infants and Children (FQPA Safety Factor)Page 17 of 46 The existing use pattern for trinexapac-ethyl coul d potentially result in dietary (various crops) and residential (turf) exposure to infants and children. Thus, FQPA hazard considerations were

addressed in HED’s evaluation of the toxico logy database. HED recommends that the 10x FQPA Safety Factor (for the protection of infants and child ren) be reduced to 1x. The toxicological database for trinexapac-ethyl is comp lete with regard to pr e-and postnatal toxicity, immunotoxicity and neurotoxicity studies, and ther e are no residual uncertainties. Additionally, the dietary exposure assessment is based on cons ervative, health-protective assumptions that ensure that exposures to trin exapac-ethyl are not u nderestimated. These assumptions include

tolerance-level residues and 100% crop treated estimates for all commodities. Furthermore, conservative, upper-bound assumptions were used to determine exposure through drinking water and residential sources, such that these exposures have not been underestimated.

4.4.1 Completeness of the Toxicology Database

The toxicology database for trin exapac-ethyl is complete for risk assessment. There are acceptable studies available for toxicity endpoint selection; they include:

The Hazard and Science Policy Council ( HASPOC; June 20, 2013, TXR 0056699) concluded based on a weight of evidence (W OE) approach that a subchronic inhalation study is not needed

at this time.

There are no residual uncertainties in the toxicological database and EPA has determined that an additional database uncertainty factor for lack of all guideline studies is not needed at this time. The rationale is based on the following: 1) alt hough there is evidence of brain neurotoxicity in the chronic dog study, there are clear NOAELs/LOAELs for this effect; 2) there is a large dose spread in the chronic dog study such that th e PoD or NOAEL from the chronic dog study is 10-

fold lower than the dose at which neuropathol ogy is observed and therefore sufficiently protective; 3) there are no concerns for children via incidental oral inge stion exposures since no endpoint of concern (i.e. non in-utero ) was identified in the available studies; and 4) the registrant has submitted the acute neurotoxicity study (in review) and is currently conducting the subchronic neurotoxicity study. Both the ACN and SCN showed no signs of neurotoxicity at the highest doses tested (NOAELs of2000 mg/ kg, and 948/1171 mg/kg/day, respectively).

Currently, an oral toxicity study is being used to assess inhalationa l exposure. However, with the oral NOAEL currently used for inha lation risk assessment, all of the occupational and residential

inhalation MOEs are well above the LOC and th e conventional 100X safety factor has been applied to inhalation risk assessments. Therefore, even if an inhalation study were to provide a lower point of departure than the oral study, it's not expected to have a significant impact on aggregate risk.

4.4.2 Evidence of Neurotoxicity and Immunotoxicity

There was no evidence of neurotoxicity in the ac ute and subchronic neurotoxi city studies in rats at the highest dose tested of 2000 mg/kg and 948/1171 mg/kg/day (male/female), respectively.Page 18 of 46 Dose-related neuropathology characterized as foca l bilateral vacuolation of the dorsal medial hippocampus and/or lateral midbr ain in both sexes was observed at study termination in the chronic dog study at the two highe st doses tested (356 mg/kg/da y: 3/8 dogs and 727 mg/kg/day: 8/8 dogs in the mid- and high dose groups, respec tively). The vacuolation was associated with the astrocytes and oligodendrocyt es. The lesions remained confined to the supporting cells in the CNS and did not progress to more advanced or more extensive damage of the nervous tissue.

The lesions were not associated with other neuropathological findings or overt neurological signs. The biological significance of these lesions is not known. Si milar microscopic lesions in the brain were not reported in the 90-day dog st udy, although, there was an inconsistency in the level of screening of the brain in the 90- day study. It is highl y unlikely, however, that lesions would develop within a short-term (1-30 days) pe riod of exposure. Furthermore, similar lesions

were not observed in the rat or mouse followi ng subchronic or chronic dietary exposure, and there was no other evidence in any species test ed to indicate a neurot oxicity potential.

An immunotoxicity study (MRID 48444101) in mice was submitted for trinexapac-ethyl. This study satisfies the guideline requirement fo r an immunotoxicity study (OPPTS 870.7800). There

were no treatment related effects on mortalit y, clinical observations, body weights, food consumption, thymus and spleen weights, or macroscopic findings in the splenic antibodyforming cell (AFC) and the Natu ral Killer cell ( NKC) groups.

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

Evidence of increased qualitative and quantitative susceptibility of the offspring was seen only at high doses in the developmenta l rat and rabbit studies, and re production study. Developmental toxicity in the rat was only observed at the limit dose (increased incidence of asymmetrical sternebrae at 1,000 mg/kg) in the absence of maternal toxicity. In the rabbit, no maternal toxicity was demonstrated at the highest dose tested [360 mg/kg/day], but there was a decrease in the

mean number of fetuses/litter a nd an increase in post-implantation loss at this dose level. However, clearly identified no effect levels were established in both the rat and rabbit developmental studies. Reproductiv e toxicity was not observed in the rat reprodu ction study, but decreased pup survival and decreased pup body wei ght/body-weight gain during lactation were observed above the limit dose with only reduc ed body weight and food consumption observed in the parental animals (>1200 mg/kg/day).

Although, there is evidence of sus ceptibility in the rat and rabbit developmental studies and in the 2-generation rat reproduction study, these effect s only occurred at the highest doses tested (360-1200 mg/kg/day), for each study, and ther e were clearly identified NOAELs (60-593 mg/kg/day) for each fetal/offspring effect.

4.4.4 Residual Uncertainty in the Exposure Database

There are no residual uncertainti es in the exposure database. Since the dietary and non-dietary exposure estimates were based on several conser vative assumptions, HED does not believe that the exposure estimates are underestimated. The dietary exposure assessment is based on conservative, health-prot ective assumptions that en sure that exposures to trinexapac-ethyl are not underestimated. These assumptions include to lerance-level residues and 100% crop treatedPage 19 of 46 estimates for all commodities. Actual exposures and risks from trinexapac-ethyl will likely be lower. Furthermore, conservative, upper-bound assumptions were used to determine exposure through drinking water and reside ntial sources, such that th ese exposures have not been

underestimated.

4.4.5 Dose-Response Assessment

The short- and intermediate-term dermal and i nhalation endpoints select ed for adults are not applicable to children because the adult endpoints are based on in utero effects. HED reviewed the full toxicological database for trinexapac-ethyl in an attempt to select endpoints for children for the dermal and inhalation exposure scenar ios; however, no appropr iate endpoints were identified for these scenarios based on the following reasons:

 dermal irritation effects ar e mild after 21/28 days of exposure in the rabbit study,

 dermal irritation effects after a singl e exposure disappear after seven days,

 there are no systemic effects up to th e limit dose in the de rmal rabbit study,

 there are no adverse toxicological effect s (at doses close to the limit dose of 1000 mg/kg/day) in the 2-ge neration reproductive study in rats or in the chronic/carcinogenicity studi es in rats and mice,

 there is no maternal toxicity in the devel opmental toxicity studies in both rats and rabbits, and

 there are no identifiable endpoints for th e oral studies in the rat or rabbit.

An endpoint for children for the incidental oral exposure scenario was also not identified from the available trinexapac-ethyl toxi city studies and the rationale fo r this conclusion is based on the following weight of evid ence considerations:

 the toxicity observed during the appropriate duration of concern (short/intermediate term) were observed only at high dose s [LOAELs = 900 mg/kg/day in the dog, 1000 mg/kg/day in the rat, and 1212 mg /kg/day in the reproduction study],

 the brain lesions observed in the chroni c dog study are not appropriate for this

scenario since the brain lesions were seen only at termination (i .e. after exposure for 1-year) and toxicity observed after chronic exposur e is not appropriate for application to the short/intermediate term scenarios,

 the brain lesions observed in the chronic st udy are not expected to occur after short term exposure due to the lack of similar lesi ons or associated toxi city (i.e., clinical neurologic signs) in the 90-da y studies in rats or dogs,

 the cause for concern for the brain lesions is low because of the minimal lesion severity, lack of associated changes (i.e ., gliosis, myelin loss astrocyte hypertrophy, neuronal necrosis etc), and the non-speci fic nature of the lesions (i.e., focal vacuoles),

 the overall toxicity profile of this chemical clearly show s that toxicity is observed only at high doses (lowest LOAEL = 360 mg /kg/day in the chronic dog study), and

 the in utero endpoint identified in the rabbit st udy is not appropriate for this population of concern (children) (D392798, M.Hawkins, 11/23/2011).Page 20 of 46 The toxicological doses and e ndpoints for trinexapac-ethyl are shown in Table 4.4.5 below.

Table 4.4.5. Summary of Toxicolo gical Doses and Endpoints for Trinexapac-ethyl for use in

Human Health Risk Assessments. Exposure/

Scenario Point of Departure Uncertainty/ FQPA Safety

Factors RfD, PAD,

Level of

Concern for

Risk

Assessment Study and Toxicological Effects

Acute Dietary (General Population, including

Infants and Children) No appropriate endpoint for the general population including infants and children

Acute Dietary (Females 13-49 years of age) NOAEL = 60 mg/kg UF A = 10x

UF H = 10x FQPA SF=

1x Acute RfD = 0.6 mg/kg

aPAD = 0.6 mg/kg Developmental rabbit study

MRID 41869524

LOAEL = 360 mg/kg, based on a

decrease in mean number of

fetuses/litter and an increase in post-implantation loss

Chronic Dietary (All Populations) NOAEL=

31.6 mg/kg/day UF A = 10x

UF H = 10x FQPA SF=

1x Chronic RfD =

0.32 mg/kg/day

cPAD = 0.32 mg/kg/day Chronic oral toxicity study – dog

MRID 42779402/ 42779401

LOAEL = 357 mg/kg/day, based

on elevated serum cholesterol values in females, mucoid feces in females and bloody feces in both sexes, and minimal, focal

vacuolation of the dorsal medial hippocampus and/or lateral

midbrain in both sexes

Incidental

Oral (Short and

IntermediateTerm ) No appropriate endpoint for the inci dental oral scenario for childrenPage 21 of 46 Table 4.4.5. Summary of Toxicolo gical Doses and Endpoints for Trinexapac-ethyl for use in

Human Health Risk Assessments. Exposure/

Scenario Point of Departure Uncertainty/ FQPA Safety

Factors RfD, PAD,

Level of

Concern for

Risk

Assessment Study and Toxicological Effects

Dermal &

Inhalation

Short- and

Intermediateterm (adults only) NOAEL=

60 mg/kg/day

Dermal absorption

rate = 77.5%

of oral absorption

Inhalation absorption

rate assumed

to be equivalent to

oral UF A = 10x

UF H = 10x FQPA SF=

1x Residential

LOC for MOE

= 100

Occupational

LOC for MOE

= 100 Developmental rabbit study

MRID 41869524

LOAEL = 360 mg/kg, based on a

decrease in mean number of

fetuses/litter and an increase in post-implantation loss

Dermal &

Inhalation

Short- and

Intermediateterm No appropriate endpoint for the dermal and inhalation scenario for children

Cancer (oral, dermal, inhalation) Classification: “Not likely to be Carcinogenic to Humans”

Point of Departure (POD) = A data point or an estimated poin t that is derived from observed dose-response data and used to mark the beginning of extrapolation to determine risk associated with lower en vironmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intra species). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level

of concern.

5 .0 Dietary Exposure and Risk Assessment

5.1 Water Residue Profile

The drinking water residues used in the di etary risk assessment were provided by the
Environmental Fate and Effects Divisi on (EFED) in the following memorandum: “ TrinexapacEthyl Drinking Water Assessmen t to Support Registration Review ” (C. Koper, D409833, 03/11/13) and incorporated directly into the dietary assessment.Page 22 of 46 A Tier II screening-level drinking water asse ssment was conducted to support the human

health risk assessment for the first food use registration for tr inexapac-ethyl on cereals (wheat, barley, oats) and sugarcane. Since there are no recent actions, the estimated drinking water concentrations (EDWCs) generated for turf use still hold precedence. For surface water, a foliar ground application to Penns ylvania turf yielde d the highest EDWCs. The 1-in-10 yr annual peak (acute) concentration was 12.61 μg /L, the 1-in-10 yr annual mean (chronic) concentration was 1.56 μg/L and the 30-year annua l mean (cancer chronic) concentration was 1.04 μg/L. For groundwater, based on the highes t annual use rate for turf, the SCI-GROW model estimated the trinexapac ethyl concentration at 0.009 μg/L.

Based on the ROCKS memorandu m (D390121, 7/12/11), the parent ester including its free acid CGA-179500, CGA-313458, an open chain cycl ohexane ring and an unidentified hydroproduct M3 should be included in a Total Toxic Residue (TTR) approach for the drinking

water assessment.

Water residues were incorporated in the DEEM -FCID into the food categories “water, direct, all sources” and “water, indirect , all sources.” Table 5.1 provides a summary of the Tier 2 modeled drinking water concentrations. The mode l and its description are available at the EPA
internet site: http://www.epa.gov/oppefed1/models/water/

.

Table 5.1. Trinexapac-Ethyl Estimated Drinking Water Concentrations (EDWCs) 1 for Surface Water and Ground Water based on Selected Crop Scenarios

Label Use PRZM/EXAMS

Scenario 1
(first app date) Method 2 Maximum Application Rate (interval between

applications) 1-in-10

year
acute
( μg/L ) 1-in-10

year chronic
( μg/L ) 30- year

average ( μg/L )

Primo ® WSB

Surface Water

Turf FL Turf (Feb 15 – foliar) G 8 app @ 0.34 lb a.i./acre 10.16 1.22 0.84

PA Turf (April 15 – foliar) G 8 app @ 0.34 lb a.i./acre 12.61 1.56 1.04

Ground Water

SCIGROW Turf -- 8 app @ 0.34 lb a.i./acre 0.009 0.009 0.009

1 For surface water (PRZM/EXAMS), EDWC values adjusted w ith a Percent Cropped Area (PCA) factor of 1.0. For ground water (SCI-GROW), no PCA adjustment was utilized.

2 G = ground application.

Bold numbers denote maximum EDWC values.

5.2 Dietary Risk Assessment

5.2.1 Description of Residue Data Used in Dietary AssessmentPage 23 of 46 Acute and chronic aggregate di etary (food and drinking water) exposure and risk assessments were conducted using the Dietary Exposure Evaluation Model DEEM-FCIDTM, Version 3.16 which uses food consumption data from the U. S. Department of Ag riculture’s (USDA’s)

National Health and Nutrition Examina tion Survey, What We Eat in America (NHANES/WWEIA).

The acute and chronic analyses are based on tolerance-level residues, 100% crop treated assumptions for all commodities and default processing factors. The drinking water estimates provided by EFED are modeled estimates, and we re generated using the most conservative model available for the registered crops. HED is confident that the acu te and chronic dietary exposure assessments significantly overestimate ri sk to the general U.S. population and various population subgroups.

5.2.2 Percent Crop Treated Used in Dietary Assessment

As stated above, the acute and chronic assessm ents were both based on the assumption that

100% of all commodities with trinexapac-ethyl recommended tolerances will be treated.

5.2.3 Acute Dietary Risk Assessment

The acute dietary exposure was estimated for females 13-49 years old only, since an acute endpoint of concern was not identified for the general U.S. population. The acute dietary exposure estimate for females 13-49 years old is 0.014057 mg/kg/day (2% of the acute population adjusted dose (aPAD)).

5.2.4 Chronic Dietary Risk Assessment

The chronic dietary exposure and risk estimates ar e conservative since they assume that 100% of crops are treated and that the residues are present at the recommended tolerance levels. Combined chronic dietary exposure estimates fo r food and drinking water are well below HED’s level of concern. Using the DEEM-FCID soft ware, dietary exposure is estimated at 0.007535 mg/kg/day for the general U.S. population, which is equivalent to 2% of the chronic population adjusted dose (cPAD), and 0.019416 mg/kg/day, equiva lent to 6% of the cPAD for children 1-2 years old, the population subgroup with the highest estimated chronic dietary exposure to trinexapac-ethyl. Results for all population subgroup are summarized in Table 5.2.6, below.

5.2.5 Cancer Dietary Risk Assessment

Trinexapac-ethyl is classified as “Not Likely to be Carcinogenic to Humans.” Therefore, a cancer dietary exposure assessment was not conducted.

5.2.6 Dietary Summary Table

Table 5.2.6. Summary of Dietary (Food and Drinking Water) Exposure and Risk for Trinexapac-ethylPage 24 of 46 Population Subgroup Acute Dietary 1
(95 th % Percentile) Chronic Dietary Cancer

Dietary Exposure (mg/kg/day) %

aPAD Dietary Exposure (mg/kg/day) % cPAD Dietary Exposure (mg/kg/day) Risk

General U.S. Population 0.007535 2

N/A N/A All Infants (< 1 year old) 0.006360 2

Children 1-2 years old 0.019416 6

Children 3-5 years old 0.018520 6

Children 6-12 years old 0.013294 4

Youth 13-19 years old 0.007701 2

Adults 20-49 years old 0.006093 2

Adults 50+ years old 0.005137 2

Females 13-49 years

old 1 0.014057 2 0.005741 2

1 aPAD=0.6 mg/kg/day for females 13-49 only (no appropriate endpoint for general US population including infants and children) and cPAD=0.32 mg/kg/ day. Not likely to be Carcinogenic to Humans

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

Trinexapac-ethyl is currently registered for use on turf; updated residential handler and residential post-application exposure assessments were conducted according to HED’s 2012 Residential Standard Oper ating Procedures (SOPs) 1

.

6.1 Residential Handler Expo sure/Risk Characterization

HED uses the term “handlers” to describe those individuals who are involved in the pesticide application process. HED believes that there are distinct tasks related to applications and that exposures can vary depending on the specifics of each task. Residential handlers are addressed somewhat differently by HED as homeowners are assumed to complete all elements of an application without use of any protective equipment.

The quantitative exposure/risk a ssessment developed for reside ntial handlers is based on the following scenarios:

1 Available: http://www.epa.gov/pesticides/science/residential

‐ exposure

‐ sop.htmlPage 25 of 46  Mixing/Loading/Applying Liquid with Hose-End Sprayer,

 Mixing/Loading/Applying Liquid with Manually-Pressurized Hand-wand,

 Mixing/Loading/Applying Li quid with Sprinkler Can,

 Mixing/Loading/Applying Liquid with Backpack,

 Mixing/Loading/Applying Wettable Powders in Water-Soluble Pack aging with Hose-end Sprayer,

 Mixing/Loading/Applying Wettable Powder s in Water-Soluble Packaging with Manually-Pressurized Hand-wand,

 Mixing/Loading/Applying Wettable Powder s in Water-Soluble Packaging with Backpack,

 Applying Granules with Pu sh-Type Rotary Spreader,

 Applying Granules with Belly Grinder,

 Applying Granules with Spoon,

 Applying Granules with Cup,

 Applying Granules with Hand Dispersal,

 Applying Granules with Shaker Can.

The combined dermal and inhalation MOEs fo r residential handlers ranged from 240 to 21,000,000. The MOEs for all of the scenarios exceed the LOC of 100 which indicate that the residential handler exposure risk estimates are not of concern. The residential handler exposures

and MOEs are calculated as detailed in Table 6.1.1.Page 26 of 46Table 6.1.1. Residential Handler Non-cancer Exposure and RiskEstimates for Trinexapac-ethyl.Exposure ScenarioLevel ofConcernDermal UnitExposure(mg/lb ai)InhalationUnitExposure(mg/lb ai)MaximumApplicationRate1Area Treated orAmountHandled Daily2DermalInhalationTotalDose(mg/kg/day)3MOE4Dose(mg/kg/day)5MOE6MOE7Mixer/Loader/ApplicatorLawns/Turf Liquid withHose-End Sprayer100 13.4 0.022 0.36 lb ai/A 0.5 acres 0.027 2,200 0.0000581,000,0002,200Lawns/Turf Liquid withManually-PressurizedHandwand100 63 0.0180.017 lbai/gallon5 gallons 0.06 1,000 0.0000222,700,0001,000Lawns/Turf Liquid withSprinkler Can100 13.4 0.0220.000008 lbai/ft21,000 ft20.0012 50,000 0.000002624,000,00050,000Lawns/Turf Liquid withBackpack100 130 0.140.017 lbai/gallon5 gallons 0.12 480 0.00017350,000480Lawns/Turf Liquid withBackpack(Edging/Banding)100 130 0.140.034 lbai/gallon5 gallons 0.2482 240 0.00034170,000240Lawns/Turf WettablePowders in WaterSoluble Packaging withHose-End Sprayer100 6.26 0.034 0.34 lb ai/A0.5 acres 0.012 5,000 0.000084720,0005,000Lawns/Turf WettablePowders in WaterSoluble Packaging withManually-PressurizedHandwand100 63 0.0180.016 lbai/gallon5 gallons 0.057 1,100 0.0000212,900,0001,100Lawns/Turf WettablePowders in WaterSoluble Packaging withBackpack100 63 0.0180.016 lbai/gallon5 gallons 0.057 1,100 0.0000212,900,0001,100Lawns/Turf Granulewith Push-Type RotarySpreader100 0.81 0.0026 0.88 lb ai/A0.5 acres 0.004 15,000 0.0000173,600,00015,000Lawns/Turf Granulewith Belly Grinder100 360 0.0390.00002 lbai/ft21,200 ft20.097 620 0.0000144,400,000620Lawns/Turf Granulewith Spoon100 6.2 0.0870.00002 lbai/ft2100 ft20.00014 430,000 0.000002524,000,000420,000Lawns/Turf Granule100 0.11 0.013 0.00002 lb 100 ft20.0000025 24,000,000 0.00000038160,000,00021,000,000Page 27 of 46Table 6.1.1. Residential Handler Non-cancer Exposure and RiskEstimates for Trinexapac-ethyl.Exposure ScenarioLevel ofConcernDermal UnitExposure(mg/lb ai)InhalationUnitExposure(mg/lb ai)MaximumApplicationRate1Area Treated orAmountHandled Daily2DermalInhalationTotalDose(mg/kg/day)3MOE4Dose(mg/kg/day)5MOE6MOE7with Cupai/ft2Lawns/Turf Granulewith Hand Dispersal100 160 0.380.00002 lbai/ft2100 ft20.0036 17,000 0.0000115,400,00017,000Lawns/Turf Granulewith Shaker Can100 0.11 0.0130.00002 lbai/ft2100 ft20.0000025 24,000,000 0.00000038160,000,00021,000,0001 Based on currently registered trinexapac-ethyl labels.2 Based on HED’s 2012 Residential SOPs (http://www.epa.gov/pesticides/science/residential-exposure-sop.html).3 Dermal Dose = Dermal Unit Exposure (mg/lb ai) × Application Rate (lb ai/acre or gal) × Area Treated or AmountHandled (A/dayor gallons/day) × Dermal Absorption Factor(77.5%) ÷ Body Weight (69 kg).4 Dermal MOE = Dermal NOAEL (60 mg/kg/day) ÷ DermalDose (mg/kg/day).5 Inhalation Dose = Inhalation Unit Exposure(mg/lb ai) × Application Rate(lb ai/acre or gal) × Area Treated or Amount Handled(A/day or gallons/day) ÷ Body Weight (69 kg).6 Inhalation MOE = Inhalation NOAEL (60 mg/kg/day) ÷ Inhalation Dose (mg/kg/day).7 Total MOE = NOAEL (60 mg/kg/day)÷ (Dermal Dose + Inhalation Dose)Page 28 of 46 6.2 Residential Post-application Exposure/Risk Characterization

There is the potential for post-ap plication exposure fo r individuals exposed as a result of bein g an environment that has been pr eviously treated with trinexapac-ethyl. Although there is the potential for dermal and oral post-application exposure to children, no dermal or oral exposur e endpoints were identified (see rationale in Section 4.0, Hazard Charac terization above). Therefore, quantitative dermal and incidental oral post-application assessments for children w not conducted.

The quantitative exposure/risk a ssessment for residential post-a pplication exposures is based o the following scenarios:

 Adults (dermal) performing high c ontact yard work on treated turf,

 Adults (dermal) mowing treated turf, and

 Adults (dermal) playing golf on treated turf.

 Child 11 to < 16 years old (dermal) playing golf on treated turf

 Child 11 to < 16 years old (d ermal) mowing treated turf

The residential post-application dermal MOEs ranged from 450 to 61,000 and therefore do n o exceed HED’s LOC (MOEs ≥ 100). A summary of the residential post-application exposures/risk estimates is presented in Table 6.2.1.

Table 6.2.1 Residential Post-applic ation Non-Cancer Exposure and Risk Estimates for Trinexapac-eth y

Lifestage Post-application Exposure

Scenario TTR (ug/cm 2 ) 1 Dose (mg/kg/day) 2 MOEs 3

Use Site Activity / Route of Exposure
Sprays

Child 11 to < 16 years old Turf Golf Course (Dermal) 0.008 0.002 31,000

Child 11 to 16 years old Turf Mowing (Dermal) 0.016 0.001 61,000

Adult Turf High Contact

Lawn Activities (Dermal) 0.016 0.049 1,200

Mowing (Dermal) 0.016 0.001 61,000

Golf Course

(Dermal) 0.008 0.002 31,000

Granular Formulation

Child 11 to < 16 years old Turf Golf Course (Dermal) 0.020 0.005 13,000

Child 11 to 16 years old Turf Mowing (Dermal) 0.040 0.002 25,000

Adult Turf High Contact

Lawn Activities (Dermal) 0.040 0.135 450

Mowing (Dermal) 0.040 0.002 24,000Page 29 of 46 Table 6.2.1 Residential Post-applicat ion Non-Cancer Exposure and Risk Estimates for Trinexapac-ethyl.

Lifestage Post-application Exposure

Scenario TTR (ug/cm 2 ) 1 Dose (mg/kg/day) 2 MOEs 3

Use Site Activity / Route of Exposure

Golf Course

(Dermal) 0.020 0.005 13,000

1 TTR= chemical-specific data from MRID 45260201 for the Georgia s ite adjusted for differences in application rates (0.36 lb ai /A for

residential turf and 0.18 lb ai/A for golf courses). 2 Dose (mg/kg/day) equations 3 MOE = POD (60 mg/kg/day) ÷ Dose (mg/kg/day).

6.3 Residential Risk Estimates fo r Use in Aggregate Assessment

Table 6.3.1 reflects the residential risk estimates that are recommended for use in the aggregate assessment for trinexapac-ethyl.

 The recommended residential exposure for use in the adult aggregate assessment reflects dermal and inhalation exposure from handler ex posure to sprays that are applied on turf with backpack sprayers (edging/banding) , which resulted in a MOE of 240.

 The recommended residential exposure use in the child aggregate assessment reflects dermal exposure from mowing turf that has been treated with a granular formulation, which resulted in a MOE of 13,000.Page 30 of 46Table 6.3.1. Recommendations for the Residential Exposures for the Trinexapac-ethyl Aggregate Assessment.1LifestageResidential HandlerResidential Post-applicationDose (mg/kg/day)2MOE3Dose (mg/kg/day)4MOE5DermalInhalationTotalDermalInhalationTotalDermalInhalationOralTotalDermalInhalationOralTotalShort-TermAdult Female 0.2482 0.00034 0.249 240 170,0002400.135 N/A N/A 0.135 450 N/A N/A 450Child 11 to 16years oldN/A N/A N/A N/A N/A N/A 0.005N/A N/A 0.005 13,000 N/A N/A13,0001 Bolded risk estimates should contribute to the residential exposure portion of the aggregate assessment.2 Residential Handler Dose = the highest handler dose for each applicable lifestage of all scenarios assessed from Table 5.1.1.Total = dermal + inhalation.3 Residential Handler MOE = the MOEs associated with the highestdoses identified in Table 5.1.1. Total = 1 ÷ (1/Dermal MOE) +(1/Inhalation MOE).4 Residential Post-application Dose = thehighest post-application dose for each applicable lifestage of all scenarios assessedfrom Table 5.2.1. Total = dermal+ inhalation + incidental oral, whereapplicable.5 Residential Post-application MOE = the MOEsassociated with the highest doses identified in Table 5.2.1. Total = 1 ÷ (1/Dermal MOE) + (1/Inhalation MOE) +(1/Incidental oral MOE).Page 31 of 46 6.4 Spray Drift

Off-target movement of pesticides can occur vi a many types of pathways and it is governed by a variety of factors. Sprays that are released and do not deposit in the application area end up offtarget and can lead to exposures to those it may directly cont act. They can also deposit on

surfaces where contact with residues can ev entually lead to indirect exposures ( e.g. , children playing on lawns where residues ha ve deposited next to treated fields). The potential risk

estimates from these residues can be calculate d using drift modeling coupled with methods employed for residential risk assessments for turf products.

The approach to be used for quantitatively incorp orating spray drift into risk assessment is based on a premise of compliant applications which, by definition, should not result in direct exposures to individuals because of existing label languag e and other regulatory requirements intended to prevent them. 2 Direct exposures would include inhala tion of the spray plume or being sprayed directly. Rather, the exposures addressed here are thought to occur indirectly through contact with impacted areas, such as residential lawn s, when compliant applications are conducted. Given this premise, exposures for children (1 to 2 years old) and adults who have contact with turf where residues are assumed to have deposited via spray drift thus re sulting in an indirect exposure are the focus of this analysis anal ogous to how exposures to turf products are

considered in risk assessment.

Several trinexapac-ethyl products have existing labels for use on turf, thus it was considered

whether the risk assessment for th at use may be considered prot ective of any type of exposure that would be associated with spray drift. It s hould be noted that the regi stered residential uses on turf result in exposure greater than potenti al exposure from spray drift; therefore, no new residential assessment for spray drift needs to be completed. If the maximum application rate on crops adjusted by the amount of dr ift expected is less than or e qual to existing tu rf application rates, the existing turf assessmen t is considered protective of sp ray drift exposure. The proposed maximum single application rate of trinexapac-ethyl on grasses grown for seed is 0.5 lb ai/acre. According to the Tier 1 output from the groundb oom spray profile of the AgDrift model, trinexapac-ethyl passed the spra y drift screening because the maxi mum application rate to a crop target site (grasses grown for seed) multiplied by the adjustment factor for drift of 0.26 is less than the direct spray residential tu rf application ra te (0.36 lb ai/A) 3 . The turf post-application MOEs have been previously assessed and are based on the re vised SOPs for Residential Exposure Assessment (see above in Section 6.2).

6.5 Residential Bystander Post-Application Inhalation Exposure

Based on the Agency's current practices, a quant itative post-application inhalation exposure assessment was not performed for trinexapac- ethyl at this time primarily because of the low acute inhalation toxicity (Toxicity Category III and IV). However, volatilization of pesticides may be a source of post-application inhalati on exposure to individua ls nearby pesticide applications. The Agency sought expert advice an d input on issues relate d to volatilization of

2 This approach is consistent with the requirements of the EPA’s Worker Protection Standard and the language
proposed in the PR Notice 2009 which, when included on all labels, precludes direct exposure pathways.

3 0.5 lb ai/A x 0.26 = 0.13 lb ai/APage 32 of 46 pesticides from its Federal Insecticide, Fungicide , and Rodenticide Act Scie ntific Advisory Panel (SAP) in December 2009, and received th e SAP’s final report on March 2, 2010 4 . The Agency is in the process of evaluating the SAP report a nd may, as appropriate, develop policies and procedures to identify the need for and, subseq uently, the way to inco rporate post- application inhalation exposure into the Agen cy's risk assessments. If new policies or procedures are developed, the Agency may revisit the need for a quantitative post- application inhalation exposure assessment for trinexapac-ethyl.

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or th e risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED consider s both the route and duration of exposure.

7.1 Acute Aggregate Risk

Acute aggregate risk results from exposure to re sidues in food and drinking water alone. The acute dietary exposure analysis included both food and drinki ng water. Therefore, acute aggregate risk is equivalent to the acute dietary risk, as disc ussed in Section 5.2.3, above. All

risk estimates are below HED’s level of concern.

7.2 Short- and Intermediate-Term Aggregate Risk

The short- and intermediate-term toxicological endpoints for trinexapac-e thyl are the same for each route of exposure. Therefore, for resident ial exposure scenarios, onl y short-term exposures were assessed, and are consider ed to be protective of interm ediate-term exposure and risk. Exposures from these scenarios are aggregated with chronic dietary e xposure from food and water which is considered to be background expo sure. The LOC for these exposure routes are

all 100.

For the adult short- and intermediate-term aggr egate risk assessment, chronic dietary exposure was added directly to the adult and children 11- 16 years old post-application exposure estimate. To be health protective, the post-application scenario was used in the aggregate because it resulted in higher exposure than the handler scen ario. The chronic dietary exposure estimate for females 13-49 years old and youth 13-19 years old were used to determine the aggregate risk

estimate.

Short-term aggregate margins of exposure for ad ult and children exceed HED’s level of concern of 100 and are not of concern (MOEs > 100). Short and intermediate estimated exposure and

risks are shown below in Table 7.2.a.

4 Available: http://www.epa.gov/scipoly/SAP/m eetings/2009/120109meeting.htmlPage 33 of 46 Table 7.2.a Short-Term and/or Intermediate Term Dermal Aggregate Risk Calculations

Short- or Intermediate-Term Scenario
Population NOAEL mg/kg/day LOC 1 Max

Allowable Exposure mg/kg/day 2 Average

Food and

Water Exposure mg/kg/day 3 Residential

Postapplication

Dermal Exposure mg/kg/day 4 Total Exposure mg/kg/day 5 Aggregate MOE (food, water, and residential) 6

Sprays

Child 11- 16 yrs old 60 100 0.60 0.007701 0.002 0.009701 6,200

Adult

Female 0.005741 0.049 0.054741 1,100

Granular Formulation

Child 11- 16 yrs old 60 100 0.60 0.007701 0.005 0.012701 4,700

Adult

Female 0.005741 0.135 0.140741 430

1 An UF of 100x was applied to account for inters pecies extrapolation (10x) and intraspecies variation (10x) and no additional uncertainty factors/safety factors are required.

2 Maximum Allowable Exposure (mg/kg/day) = NOAEL/ (60 mg/kg/day)/LOC (100)

3 Average food and water exposure from chronic dietary exposure for youth 13-19 yrs old and females 13- 49 yrs old. See Table 5.2.6

4 Residential Exposure = Dermal exposure from treated turf (see table 6.2.1).

5 Total Exposure = Avg Food & Water Exposure + Residential Exposure

6 Aggregate MOE = [NOAEL

 / (Avg Food & Water Exposure + Residential Exposure)]

7.3 Cancer Aggregate Risk

The CARC classified trinexapac-ethyl as “not like ly to be carcinogenic to humans.” The chronic dietary risk assessment is protec tive of cancer effects and, therefore, cancer risk resulting from exposure to trinexapac-et hyl is not of concern.

8.0 Cumulative Exposure/Risk Characterization

The Food Quality Protection Act (FQPA) requires th e Agency to consider the cumulative risks of chemicals sharing a common mechanism of toxic ity. The Agency determined that there was insufficient evidence to suggest trinexapac-ethyl shares a common mechanis m of toxicity with

other chemical substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity a nd to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s Office of Pesticide Program concerning common mechanism determinations and procedur es for cumulating effects from substancesPage 34 of 46 found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

9.0 Occupational Exposure/Risk Pathway

9.1 Occupational Handler Ex posure/Risk Estimates

HED uses the term handlers to describe those individuals who are invo lved in the pesticide application process. HED believe s that there are distinct job functions or tasks related to applications and exposures can vary depending on the specifics of each task. Job requirements (amount of chemical used in each application), the kinds of equipment used, the target being treated, and the level of protection used by a ha ndler can cause exposure levels to differ in a manner specific to each application event.

Based on the anticipated use patterns and curr ent labeling, types of equipment and techniques that can potentially be used, occupational handl er exposure is expected from the currently registered uses. The quantitative exposure/ris k assessment developed for occupational handlers is based on the following scenarios:

 Mixing/Loading Granules for Tractor Drawn Spreader Applications

 Mixing/Loading Liquids fo r Aerial Applications

 Mixing/Loading Liquids for Chemigation

 Mixing/Loading Liquids fo r Groundboom Applications

 Mixing/Loading Wettable Powders in Water Soluble Bags for Aerial Applications

 Mixing/Loading Wettable Powders in Wa ter Soluble Bags for Chemigation

 Mixing/Loading Wettable Powders in Water Soluble Bags for Groundboom Applications

 Applying Sprays for Aerial Applications

 Applying Sprays for Groundboom Applications

 Applying Granules for Tractor Drawn Spreader Applications

 Flagging (Sprays) during Aerial Applications

 Mixing/Loading/Applying Liquids for Backpack Applications

 Mixing/Loading/Applying Liquids for Manua lly-Pressurized Handw and Applications

 Mixing/Loading/Applying Liquids for Mech anically-Pressu rized Handgun Applications

 Mixing/Loading/Applying Wettable Powders in Water Soluble Bags for Backpack Applications

 Mixing/Loading/Applying Wettable Powders in Water Soluble Bags for ManuallyPressurized Handwand Applications

 Mixing/Loading/Applying Wettable Powders inWater Soluble Bags for MechanicallyPressurized Handgun Applications

 Loading/Applying Granules for Belly Grinder Applications

 Loading/applying granules for Ro tary Spreader Applications

The short- and intermediate-term risk estimates for occupational handlers are included in Table 9.1.1. All dermal and inhalation occupational ha ndler scenarios are above HED’s LOC (MOEs

≥ 100) with baseline attire and/ or gloves and engineering contro l (i.e., enclosed cockpits) forPage 35 of 46 aerial applications. With baseline attire and/or gloves, the dermal plus inhalation MOEs range from 140 to 2,100,000.Page36of46Table 9.1.1. Occupational Handler Non-Cancer Exposure and RiskEstimates for Trinexapac-ethyl.Exposure ScenarioCrop or TargetDermal UnitExposure (μg/lbai)1Inhalation UnitExposure (μg/lbai)1MaximumApplicationRate2AreaTreated orAmountHandledDaily3DermalInhalationTotalMitigation LevelMitigation LevelDose(mg/kg/day)4MOE5Dose(mg/kg/day)6MOE7MOE8Mixing/Loading GranulesTractor-Drawn SpreaderApplicationGolf Course(Fairways,Tees, Greens)8.4 1.7 0.44 40 0.00166 36,000 0.000433 140,000 29,000Golf Course(Tees andGreens Only)8.4 1.7 0.44 5 0.000208 290,000 0.0000542 1,100,000 230,000Mixing/Loading LiquidsAerial ApplicationSod220 0.219 0.36 350 0.314 190 0.000404 150,000 190Grasses GrownFor Seed220 0.219 0.5 350 0.432 140 0.000555 110,000 140Sugarcane220 0.219 0.31 350 0.268 220 0.000345 170,000 220Cereals (Wheat,Barley, Oats,Triticale)220 0.219 0.11 1200 0.326 180 0.000419 140,000 180Chemigation ApplicationSod220 0.219 0.36 350 0.314 190 0.000404 150,000 190Grasses GrownFor Seed220 0.219 0.5 350 0.432 140 0.000555 110,000 140Sugarcane220 0.219 0.31 350 0.268 220 0.000345 170,000 220Cereals (Wheat,Barley, Oats,Triticale)220 0.219 0.11 350 0.0951 630 0.000122 490,000 630Groundboom ApplicationGolf Course(Tees andGreens Only)220 0.219 0.07 5 0.000865 69,000 0.00000111 54,000,000 69,000Golf Course(Fairways,Tees, Greens)220 0.219 0.18 40 0.018 3,300 0.000023 2,600,000 3,300Sod220 0.219 0.36 80 0.072 830 0.0000925 650,000 830Grasses GrownFor Seed220 0.219 0.5 80 0.0988 610 0.000127 470,000 610Page37of46Table 9.1.1. Occupational Handler Non-Cancer Exposure and RiskEstimates for Trinexapac-ethyl.Exposure ScenarioCrop or TargetDermal UnitExposure (μg/lbai)1Inhalation UnitExposure (μg/lbai)1MaximumApplicationRate2AreaTreated orAmountHandledDaily3DermalInhalationTotalMitigation LevelMitigation LevelDose(mg/kg/day)4MOE5Dose(mg/kg/day)6MOE7MOE8Sugarcane220 0.219 0.31 80 0.0613 980 0.0000787 760,000 980Cereals (Wheat,Barley, Oats,Triticale)220 0.219 0.11 200 0.0544 1,100 0.0000699 860,000 1,100Mixing/Loading Wettable PowdersIn Water Soluble PackagingAerial Application Sod9.8 (EC) 0.24 (EC) 0.34 350 0.0131 (EC)4,600(EC)0.000414 (EC)140,000 (EC) 4,500 (EC)Chemigation Application Sod9.8 (EC) 0.24 (EC) 0.34 350 0.0131 (EC)4,600(EC)0.000414 (EC)140,000(EC)4,500 (EC)GroundboomGolf Course(Tees andGreens Only)9.8 (EC) 0.24 (EC) 0.05 50.0000275(EC)2,200,000(EC)0.00000087(EC)69,000,000(EC)2,100,000(EC)GroundboomGolf Course(Fairways,Tees, Greens)9.8 (EC) 0.24 (EC) 0.17 400.000748(EC)80,000(EC)0.0000236(EC)2,500,000(EC)78,000(EC)Groundboom Sod9.8 (EC) 0.24 (EC) 0.34 80 0.003 (EC)20,000(EC)0.0000946(EC)630,000(EC)19,000(EC)Appling SpraysAerial ApplicationSod2.08 (EC) 0.0049 (EC) 0.36 3500.00298(EC)20,000(EC)0.00000904(EC)6,600,000(EC)20,000(EC)Grasses GrownFor Seed2.08 (EC) 0.0049 (EC) 0.5 3500.00409(EC)15,000(EC)0.0000124(EC)4,800,000(EC)15,000(EC)Sugarcane2.08 (EC) 0.0049 (EC) 0.31 3500.00254(EC)24,000(EC)0.00000771(EC)7,800,000(EC)24,000(EC)Cereals (Wheat,Barley, Oats,Triticale)2.08 (EC) 0.0049 (EC) 0.11 12000.00309(EC)19,000(EC)0.00000938(EC)6,400,000(EC)19,000(EC)Groundboom ApplicationGolf Course(Tees andGreens Only)78.6 0.34 0.07 5 0.000309190,000 0.00000172 35,000,000190,000Golf Course(Fairways,Tees, Greens)78.6 0.34 0.18 40 0.006429,300 0.0000359 1,700,0009,200Page38of46Table 9.1.1. Occupational Handler Non-Cancer Exposure and RiskEstimates for Trinexapac-ethyl.Exposure ScenarioCrop or TargetDermal UnitExposure (μg/lbai)1Inhalation UnitExposure (μg/lbai)1MaximumApplicationRate2AreaTreated orAmountHandledDaily3DermalInhalationTotalMitigation LevelMitigation LevelDose(mg/kg/day)4MOE5Dose(mg/kg/day)6MOE7MOE8Sod78.6 0.34 0.36 80 0.0257 2,300 0.000143 420,0002,300Grasses GrownFor Seed78.6 0.34 0.5 80 0.0353 1,700 0.000197 300,0001,700Sugarcane78.6 0.34 0.31 80 0.0219 2,700 0.000122 490,0002,700Cereals (Wheat,Barley, Oats,Triticale)78.6 0.34 0.11 200 0.0194 3,100 0.000108 560,0003,100Applying GranulesTractor-Drawn SpreaderApplicationGolf Course(Fairways,Tees, Greens)9.9 1.2 0.44 40 0.00195 31,000 0.000306 200,00027,000Tractor-Drawn SpreaderApplicationGolf Course(Tees andGreens Only)9.9 1.2 0.44 5 0.000245240,000 0.0000383 1,600,000210,000FlaggerAerial ApplicationSod11 0.35 0.36 350 0.0157 3,800 0.000646 93,000 3,700Grasses GrownFor Seed11 0.35 0.5 350 0.0217 2,800 0.000888 68,000 2,700Sugarcane11 0.35 0.31 350 0.0134 4,500 0.000551 110,000 4,300Cereals (Wheat,Barley, Oats,Triticale)11 0.35 0.11 350 0.00476 13,000 0.000196 310,000 12,000Mixing/Loading/Appling LiquidsBackpack ApplicationLandscapingTurf (Lawns,Athletic Fields,Parks, etc.)8260 2.58 0.017 40 0.0631 950 0.0000254 2,400,000 950Manually –PressurizedHandwandLandscapingTurf (Lawns,Athletic Fields,Parks, etc.)100000(baseline)30 0.017 400.764(baseline)79(baseline)0.000296 200,00079(baseline)430(with gloves)0.00328(with gloves)18,000(with17,000(withPage39of46Table 9.1.1. Occupational Handler Non-Cancer Exposure and RiskEstimates for Trinexapac-ethyl.Exposure ScenarioCrop or TargetDermal UnitExposure (μg/lbai)1Inhalation UnitExposure (μg/lbai)1MaximumApplicationRate2AreaTreated orAmountHandledDaily3DermalInhalationTotalMitigation LevelMitigation LevelDose(mg/kg/day)4MOE5Dose(mg/kg/day)6MOE7MOE8gloves) gloves)Backpack ApplicationEdging/Bandingfor LandscapingTurf (Lawns,Athletic Fields,Parks, etc.)8260 2.58 0.03 40 0.11 540 0.0000449 1,300,000 540Manually –PressurizedHandwandEdging/Bandingfor LandscapingTurf (Lawns,Athletic Fields,Parks, etc.)100000(baseline)30 0.03 401.35(baseline)44(baseline)0.000522 110,00044(baseline)430(with gloves)0.0058(with gloves)10,000(withgloves)9,200(withgloves)Mechanically-PressurizedHandgunGolf Course(Tees andGreens Only)1140 1.9 0.07 5 0.00448 13,0000.00000964 6,200,000 13,000Mechanically-PressurizedHandgunGolf Course(Fairways,Tees, Greens)1140 1.9 0.18 5 0.0117 5,1000.0000251 2,400,000 5,100Mechanically-PressurizedHandgunLandscapingTurf (Lawns,Athletic Fields,Parks, etc.)1140 1.9 0.36 5 0.0233 2,6000.0000501 1,200,000 2,600Mechanically-PressurizedHandgunEdging/Bandingfor LandscapingTurf (Lawns,Athletic Fields,Parks, etc.)1140 1.9 0.73 5 0.0467 1,300 0.000101 590,000 1,300Mixing/Loading/ApplyingWettable Powders In Water Soluble PackagingBackpack ApplicationLandscapingTurf (Lawns,Athletic Fields,Parks, etc.)8260 2.58 0.016 40 0.0594 1,000 0.0000239 2,500,000 1,000Manually –PressurizedHandwandLandscapingTurf (Lawns,Athletic Fields,100000(baseline)30 0.016 400.719(baseline)83(baseline)0.000278 220,00083(baseline)430 0.00309 19,000 17,000Page40of46Table 9.1.1. Occupational Handler Non-Cancer Exposure and RiskEstimates for Trinexapac-ethyl.Exposure ScenarioCrop or TargetDermal UnitExposure (μg/lbai)1Inhalation UnitExposure (μg/lbai)1MaximumApplicationRate2AreaTreated orAmountHandledDaily3DermalInhalationTotalMitigation LevelMitigation LevelDose(mg/kg/day)4MOE5Dose(mg/kg/day)6MOE7MOE8Parks, etc.) (with gloves) (with gloves) (withgloves)(withgloves)Backpack ApplicationEdging/Bandingfor LandscapingTurf (Lawns,Athletic Fields,Parks, etc.)8260 2.58 0.03 40 0.11 540 0.0000449 1,300,000 540Manually –PressurizedHandwandEdging/Bandingfor LandscapingTurf (Lawns,Athletic Fields,Parks, etc.)10000030 0.03 401.35(baseline)44(baseline)0.000522 110,00044(baseline)430(with gloves)0.0058(with gloves)10,000(withgloves)9,200(withgloves)Mechanically-PressurizedHandgunGolf Course(Tees andGreens Only)1350 18 0.05 5 0.0038 16,000 0.0000652 920,000 16,000Mechanically-PressurizedHandgunGolf Course(Fairways,Tees, Greens)1350 18 0.17 5 0.0129 4,700 0.000222 270,000 4,600Mechanically-PressurizedHandgunLandscapingTurf (Lawns,Athletic Fields,Parks, etc.)1350 18 0.34 5 0.0258 2,300 0.000443 140,000 2,300Mechanically-PressurizedHandgunEdging/Bandingfor LandscapingTurf (Lawns,Athletic Fields,Parks, etc.)1350 18 0.68 5 0.0516 1,200 0.000887 68,000 1,200Loading/Applying GranulesBelly Grinder ApplicationLandscapingTurf (Lawns,Athletic Fields,Parks, etc.)10000 62 0.88 1 0.0988 610 0.000791 76,000 610Rotary SpreaderApplicationGolf Course(Tees and440 10 0.44 5 0.0109 5,500 0.000319 190,000 5,300Page41of46Table 9.1.1. Occupational Handler Non-Cancer Exposure and RiskEstimates for Trinexapac-ethyl.Exposure ScenarioCrop or TargetDermal UnitExposure (μg/lbai)1Inhalation UnitExposure (μg/lbai)1MaximumApplicationRate2AreaTreated orAmountHandledDaily3DermalInhalationTotalMitigation LevelMitigation LevelDose(mg/kg/day)4MOE5Dose(mg/kg/day)6MOE7MOE8Greens Only)Rotary SpreaderApplicationGolf Course(Fairways,Tees, Greens)440 10 0.44 5 0.0109 5,500 0.000319 190,000 5,300Rotary SpreaderApplicationLandscapingTurf (Lawns,Athletic Fields,Parks, etc.)440 10 0.88 5 0.0218 2,800 0.000638 94,000 2,7001Based on the “Occupational Pesticide HandlerUnit Exposure Surrogate Reference Table” (March 2013); Level of mitigation: Baseline (single layerof clothing, no gloves,no respirator), Baselinewith gloves, or Eng. Controls (EC; closed cockpit) for aerial applicators.2Based on currently registered labels.3 Exposure Science Advisory Council Policy #9.1.4 Dermal Dose = Dermal Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre orgal) × Area Treated or Amount Handled (A or gal/day) × DAF (77.5%) ÷ BW(69 kg).5 Dermal MOE = Dermal NOAEL (60 mg/kg/day) ÷ Dermal Dose (mg/kg/day).6 Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A or gal/day) ÷ BW (69 kg).7 Inhalation MOE = Inhalation NOAEL (60 mg/kg/day) ÷ InhalationDose (mg/kg/day).8 Total MOE = NOAEL (60 mg/kg/day)÷ Dermal Dose + Inhalation Dose.Page 42 of 46 9.2 Occupational Post-applicat ion Exposure/Risk Estimates

HED uses the term post-application to describe exposures that occur when individuals are present in an environment that has been previously treated with a pe sticide (also referred to as reentry exposure). Such exposures may occur when workers enter previously treated areas to perform job functions, including ac tivities related to crop producti on, such as scouting for pests or harvesting. Post-application e xposure levels vary over time and depend on such things as the type of activity, the nature of the crop or target that was trea ted, the type of pesticide application, and the chemical’s degradation properties. In addition, the timing of pesticide applications, relative to harvest activities, can greatly reduce the potential for post-application exposure.

9.2.1 Occupational Post-application I nhalation Exposure/Risk Estimates

Based on the Agency's current practices, a quant itative post-application inhalation exposure assessment was not performed for trinexapac-ethy l at this time primarily because of the low acute inhalation toxicity (T oxicity Categor y III and IV). However, there are multiple potential sources of post-application i nhalation exposure to individual s performing post-application activities in previously treated fields. These potential sources in clude volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides. The Agency sought expert advice and input on issues related to volatilization of pe sticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 5 . The Agency is in the process of evaluating the SAP report as well as available post-applic ation inhalation exposure data generated by the ARTF and may, as appropriate, develop policies and procedures, to iden tify the need for and, subsequently, the way to incorporate occupational post-application inhala tion exposure into the Agency's risk assessments. If new policies or procedures are put into place, the Agency may

revisit the need for a quantitative occupational post-applic ation inhalation exposure assessment for trinexapac-ethyl.

Although a quantitative occupational post-applic ation inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commercial handlers. Handler exposure resultin g from application of pesticides outdoors is likely to result in higher exposure than post -application exposure. Therefore, it is expect ed that these handler inhalation exposure estimates would be protec tive of most occupatio nal post-application inhalation exposure scenarios.

9.2.2 Occupational Post-application Dermal Exposure/Risk Estimates

A series of assumptions and exposure factors serv ed as the basis for completing the occupational post-application risk assessments. Each assumpti on and factor is detailed in Table 9.2.2.1 below

on an individual basis.

5 Available: http://www.epa.gov/scipoly/SAP/m eetings/2009/120109meeting.htmlPage 43 of 46 Table 9.2.2.1. Anticipated Po st-Application Activities and Dermal Transfer Coefficients.

Crops Policy Crop Group Category Crop Height Foliage Density Transfer

Coefficients

(cm 2 /hr ) Activities

Golf Course Turf/sod Low Full 3700 Maintenance

Golf Course Turf/Sod Low Full 2500 Maintenance, greens only

Sod Turf/Sod Low Full 6700 Maintenance, Slab Harvesting, Transplanting/Planting

Sugarcane Sugarcane High Full 1100 Scouting

Sugarcane Sugarcane High Full 8800 Hand Harvesting

Sugarcane Sugarcane Low Minimum 70 Hand Weeding

Cereals (Wheat,

Barley, Oats,

Triticale) Field/row

crop, low/medium Low Full/Minimum 1100 Scouting

Cereals (Wheat,

Barley, Oats,

Triticale) Field/row

crop, low/medium Low Full/Minimum 70 Hand Weeding

Grasses Grown For

Seed Field/row

crop, low/medium Low Full 1900 Hand Set Irrigation

Grasses Grown For

Seed Field/row

crop, low/medium Low Minimum 1100 Scouting

Dislodgeable Foliar Residues

In accordance with the updated Part 158 data requi rements (2007), one or more DFR studies are required when a pesticide has residential or occupational uses that could result in postapplication dermal exposure. As part of the recent revision to the Health Effects Division’s 2012 Standard Operating Procedures for Resi dential Pesticide Exposure Assessment , HED analyzed a

number of DFR studies and select ed a new default value for the fr action of the application rate available to be dislodged after a foliar application (F AR ). This default value is 25% and is based on an analysis of 19 DFR studies where the F AR value ranged from 2% to 89%. This value is

recommended for use in both residential and occ upational post-app lication assessments. Of the analyzed DFR studies, the maximum F AR value seen was 89% or 3.6 times higher than the default residue transfer value. Therefore, the HED has decided that a calculated MOE of approximately 4 times higher than the level of concern (e.g., an MOE > 400 if the LOC = 100) using the default dislodged residue values would provide an adequate margin of safety for any potentially higher residues seen in a chemical-specific DFR study ( Guidance for Requiring/Waiving Turf Transfe rrable Residue (TTR) and Disl odgeable Foliar Residue (DFR)

Studies . 6/7/2012, Exposure Science Advisory Counc il). A DFR study will be required forPage 44 of 46 future assessments since there are dermal MOEs less than 4 times the LOC based on default values for the fraction of application rate av ailable for transfer af ter a foliar application.

Chemical-specific TTR data are available for trin exapac-ethyl and were used in the occupational post-application exposure assessment to assess turf in conjunction w ith standard default assumptions to assess sugarcane, cereals (wheat, barley, oats, triticale) , and grasses grown for seed. Therefore, the assessment uses surface resi dues from the day of application (assume that individuals could be exposed to resi dues immediately after application) for occupational turf

uses.

The short- and intermediate-term occupationa l post-application derm al exposure and risk

estimates indicate that the MOEs are not of concern to HED (i.e., MOEs ≥ 100) on the day of application, except for hand-harves ting sugarcane (MOE=87) where ri sk estimates are of concern until 2 days after application (MOE =110) as detailed in Table 9.2.2.2.

Table 9.2.2.2. Occupational Post-application Non-Cancer Exposure and Risk Estimates for Trinexapacethyl.

Crop/Site Activities Transfer Coefficient (cm 2 /hr) DFR/TTR 1 Dermal Dose (mg/kg/day) 2 MOE 3

Short-term/Intermediate-term

Granular Formulation

Golf Course (Turf/Sod) Main tenance 3700 0.015 0.005 12,000

Golf Course (Turf/Sod) Maintenance, Greens Only 2500 0.015 0.003 18,000

Liquid Formulations

Golf Course (Turf/Sod) Main tenance 3700 0.006 0.002 29,000

Golf Course (Turf/Sod) Maintenance, Greens Only 2500 0.006 0.001 43,000

Sod (Turf/Sod) Maintenance, Harvesting, Slab,

Transplanting 6700 0.012 0.008 8,000

Sugarcane Scouting 1100 0.87 0.086 700

Sugarcane Hand Harvesting 8800 0.87 0.688 87 (MOE=110 at Day 2 after treatment)

Sugarcane Hand Weeding 70 0.87 0.005 11,000

Cereals (Wheat, Barley, Oats, Triticale) Scouting 1100 0.31 0.030 2,000

Cereals (Wheat, Barley, Oats, Triticale) Hand Weeding 70 0.31 0.002 31,000

Grasses Grown For

Seed Hand Set Irrigation 1900 1.40 0.239 250

Grasses Grown For

Seed Scouting 1100 1.40 0.139 430

1 DFR = Application Rate × F × (1-D) t × 4.54E8 μg/lb × 2.47E-8 acre/cm 2 ; where F = 0.25 and D = 0.10 per day or TTR = chemical-specific

data from MRID 45260201 for the Indiana site ad justed for differences in application rates 2 Daily Dermal Dose = [DFR (μg/cm 2 ) × Transfer Coefficient × 0.001 mg/μg × 8 hrs/day × dermal absorption (77.5%)]  BW (69 kg).
3 MOE = POD (60 mg/kg/day) / Daily Dermal Do se. Daily Dermal Dose = [DFR/TTR (μg/cm 2 ) × TC × 0.001 mg/μg × 8 hrs/day × dermal

absorption factor (77.5%)]  BW (69 kg).Page 45 of 46 Restricted Entry Interval

The REI specified on the currently registered labels is based on the acute toxicity of trinexapac ethyl. Trinexapac-ethyl is classi fied as Toxicity Cate gory III via the dermal route and Toxicity Category IV for skin irritation potential. It is no t a skin sensitizer. Short- and intermediate-term post-application risk estimates were not a conc ern on day 0 (12 hours following application) for all post-application activities. Under 40 CFR 156.208 (c) (2) (iii ), ai’s classified as Acute III or IV for acute dermal, eye irrita tion and primary skin irrigati on are assigned a 12-hour REI. Therefore, the [156 subpart K] Worker Protecti on Statement interim REI of 12 hours is adequate to protect agricultural workers from post-application exposures to trinexapac-ethyl.

10.0 References

DP#: 377921 Subject: Trinexapac-ethyl: Human Health Risk Assessment for the Section 3 Registration Action on Cereal Grains, Sugarcan e, and Grasses Grown for Seed. From: S. Piper, J. Facey, and M. Hawkins To: B. Benbow and K. Montague

Date: 11/23/11

MRIDs: NA

DP#: 409833 Subject: Trinexapac-ethy Drinking Water A ssessment to Support Registration Review. From: C. Koper To: A. Jakob, C. Olinger, and S. Piper

Date: 03/11/13

MRIDs: NA

DP#: 413986 Subject: Trinexapac-ethyl : Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments to Support Registration Review From: S. Piper

To: K. Keller

Date: 09/12/2013

MRIDs: NA

DP#: 463873 Subject: Trinexapac-ethyl. Preliminary O ccupational and Residential Exposure/Risk Assessment for Registration Review

From: M. Hawkins To: S. Piper and K. Keller

Date: 08/01/13

MRIDs: NAPage 46 of 46 DP#: 392798 Subject: Trinexapac-ethyl: Occupational an d Residential Exposure/Risk Assessment for Proposed Uses on grasses grown for seed, sugarcane, and cereals (wheat, barley, and oats).

From: M. Hawkins

To: M. Waller and T. Stowe

Date: 08/31/11

MRIDs: NA