### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON

, D.C

. 20460



### MEMORAN D UM

Date: 06-MAY-2015 OFFIC E OF C HEMICAL SAFETY AND POLLUT I ON PREVENTION



### SUBJECT: Mesotrione. Human Health Ri s k Assessment in Support of the Sect i on 3 R equest for Us e of Mesotrione on Pom e Fruit

, Stone Fruit

, Citrus, and Tree Nuts.



### PC Code : 1 22990 

### DP Barcodes: D41 96 16

, D419617

, D419 618 

### Decision Nos

. : 487 1 55

, 487154

, 487156 

### Registratio n No .: I 00- 1 1 3 l 

### Petit i on No: 4F8240 

### R egu l a tory Ac tion: Sec tion 3 

### Ri s k Assess m e nt T y p e : Single 

### Case No.: 7256 C h emical / Aggregate 

### TXR No.: NA 

### CAS No.: 104206-8 2 -8 

### MRID No. : NA 40 

### CF R : §180.57 1



### FROM: Sa r a h 

### J. Levy, Chemist J**~** Thomas Bl oem ,

### is**~** Kell y M. Lowe

, Senior En v ironrn e n al Scie nti s t

### ~~ Monique M. P erron, S .D.

, Toxico l ogist

## ~/Jli.f(/...Ji**~0iA,,....... ,__**  Ri sk Assessme nt Branch 1 (RAB I ) {)
H eal th Effec t s Divi s ion (HED

, 7 509P)



### THR O UGH: Thurston Morton

, Acting Branch Ch ief 

# j '
Georg e F. Kramer

, Ph.D.

, Senior Chemi t**~~~e ~~** **~-=----** RAB 1

, H E D (7509 P )



### TO: Kathr y n Mo nta gue/M i c ha e l Walsh

, P M Team 23 R eg i stration Di v i s ion ( RD ; 7505P)

The HED of the Offic e of P es ticid e Program s (O PP ) i s charged w i th es tim a tin g t h e ri s k to human h ea lth from expo s ur e to pe s ticides. Th e RD of OPP has r eq uest ed that HED e va l uat e ha zard and

ex po s w-e data and conduc t dietary

, occupational

, r es idential

, a nd aggregate exposure

assess ments
, as ne e d ed, t o es timat e the ri s k to human health that w ill r es ult from th e proposed

u s e of me sot rion e o n in/on p o m e fruit

, stone fruit

, c itru s, and tree nut s

.

A s umm ary of the findings a nd an assessmen t o f human health risk r esu ltin g fr o m the proposed/registe r ed uses of m eso tri o ne are pr ovided in thi s document. The risk assess ment and dietary exposure assess m e nt were pro v ided b y Sa r a h Levy (RA B I ), the h aza rd c h arac teri za tion by Monique Perron (RAB I )

, th e residue chemistry d a ta r ev i ew b y Thom as Bloem (RA B I)

, the

occ upational/re s identi a l ex po s ure assessment by K e ll y Lowe (RAB I)

, and t h e drinking water

assess ment by I wona M a h e r of the Environm e nt a l Fa t e and Effects Divi s ion ( E FED).
P

age I of3 IMesotrione Human Health Risk Assessment DP # 4 1 9616



### Tab l e of C on te n ts

1.0 Executive Summary

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

### 2.0 Recommendations

................................. ... .. .. .. .. .. .. .. .. .. .. .. .. .. .. . .. .............................. .. .. . . . ...... . 6 

### 2.1 Data Deficiencies / Data Needs

...... .. .. .. .. .. ....... .. .. . .. . .... . ....................................... . .. .. 6 

### 2.2 Tolerance Considerations

.. .. .. .. .. .. .. .. .. . .... .. .. .. .. .. .. . ................................. .. .. .. . .. .. .. ...... 6 

### 2.2. l Enforcement Analytica l Method

... .. . ... .. .. .. . ........ . .. .. . .. .. .. . .. ....................... . .. .. .. . .. .. . .. 6 

### 2.2.2 Recommended Tolerances

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

### 2.2.3 Revisions to Petitioned-For Tolerances

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

### 2.2.4 Internationa l Harmonizat i on

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

### 2.3 Labe l Recommendations

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

### 3.0 Introduction

... .. . ... . .. . .. .. .. . .. .. .. .. .. .. .. .............................................. .. . .. ...... . . .. .. .. .. . ................... 8 3 .1 Chemical Identity

....................... .. .. .. .. ... .. .. .. .. . ... .. .. .............................. . .. .. .... .. .. . ...... 8 3

. 2 Physical/Chemical Characteristics

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

### 3.3 Pesticide Use Pattern

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

### 3.4 Anticipated Exposure Pathways

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

### 3.5 Consideration of Environmenta l Justice

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

### 4.0 Hazard Characterization and Dose-Response Assessment

................................. .. .... .. ...... 

### 10 4

. 1 Toxicology Studies Avai l able for Analysis

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

### 4

. 2 Absorpt i on, D i str i bution

, Metabolism, and Excretion (ADME)

.... .. ..... .. .... .. ....... 

### 10 4.2.1 Dermal Absorption

.. . . .. ...... .. .................................................... .. . .. .. .. . .. .. .. . .. .. . ........ 

### 10 4.3 Toxicologica l Effects

................................................... .. .. .. .... .. ............................. 

### 11 4.4 Safety Factor for Infants and Children (FQPA SF)

....................................... .. ..... 

### 11 4.4

. l Completeness of the Toxicology Database

...... .. ...... .. ....................................... .. .. 

### 12 4.4

. 2 Evidence ofNeurotoxicity

................... ... .. .. .. .. ..... .. .. .. ....................................... .. . . 

### 12 4.4.3 Evidence of Sens i t i vity / Susceptibility in the Developing or Young Anima l

...... . 

### 12 4.4.4 Residual Uncertainty in the Exposure Database

...................... . ... .. ....................... 

### 12 4

. 5 Toxicity Endpoint and Point of Departure Selections

.............................. .. ........ .. 

### 12 4.5.1 Dose-Response Assessment..

............................................... .. .. .. . .. .. .. . .. .. . .. .. .. . .. . .... 

### 13 4

. 5

. 2 Recommendation for Combining Routes of Exposures for Risk Assessment..

.... 

### 13 4.5.3 Cancer Classification and Risk Assessment Recommendation

..... .. ..... .. .... . ........ . 

### 13 4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk Assessment.

................................................................................. .. .. . ... . .. .. . .. .. .. . . ...... .. ........ 14 5 .0 Dietary Exposure and Risk Assessment

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

### 5

. 1 Residues of Concern Summary and Rationale

...................................................... 

### 15 5.2 Food Residue Profile

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

### 5

. 3 Water Residue Profi l e

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

### 5.4 Dietary Risk Assessment

......................................... . ........ .. .. .. ........ .. .. . .. .. ............. 

### 18 5.4

. 1 Description of Residue Data Used in Dietary Assessment..

..................... .. ........ .. 

### 18 5.4.2 Percent CT Used in Dietary Assessment

.................. .. ..... .. .. . .. .. ..... .. ..................... 

### 18 5.4.3 Acute Dietary Risk Assessment

. ... .. ....... .. .. .. .. .. ...... . .............................................. 

### 18 5.4.4 Chronic Dietary Risk Assessment

.......................................... . ............ . .. .. .. .. ........ 

### 18 5.4.5 Cancer Dietary Risk Assessment..

..................................... .. ..... .. .. .. ........ .. .. .. .... .. .. 

### 18 5.4.6 Sumn1ary Table

.................... . .......... .. ... . .. ... .. .. .. .. .. .. . .. .. .. . .. .. .. . .. .. .. .. . .................... 

### 189 6.0 Residential (Non-Occupationa l ) Exposure / Risk

....................................................... .. ..... . I 9 

### 6.1 Residential Exposure / Risk Characterization

. .. .. .. .. .. .. . .. .. .. . .. ...... . .. .. ....................... 

### 19 

### 6.2 Spray Drift

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

Page 2 of3 IMesotrione Human Health Risk Assessment DP # 419616

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Page 3 of 31 

### 6.3 Residential Bystander Post

- Application Inhalation Exposure

.............................. 21 7.0 Aggregate Exposure/Risk Characterization

................................ ................................ ...... 22 7.1 Acute Aggregate Risk

................................ ................................ ........................... 22 7.2 Short

- and Intermediate Term Aggregate Risk

................................ ..................... 22 7.3 Chronic (Long

- Term) Aggregate Risk

................................ ................................ .. 23 7.4 Cancer Risk

................................ ................................ ................................ ........... 23 8.0 Cumulative Risk Characterization/Assessment

................................ ................................ 23 9.0 Occupational Exposure/Risk Characterization

................................ ................................ . 24 9.1 REI

................................ ................................ ................................ ........................ 25 10.0 References

................................ ................................ ................................ ......................... 25 Appendix A. Toxicology Profile

................................ ................................ ................................ .. 26 A.1 Toxicology Data Requirements for Mesotrione.

................................ ....................... 26 A.2 Toxicity Profiles.

................................ ................................ ................................ ....... 27 Appe ndix B. Physical/Chemical Properties

................................ ................................ ................. 31 Appendix C. Review of Human Research

................................ ................................ ................... 31Mesotrione Human Health Risk Assessment DP # 419616

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Page 4 of 31 

### 1.0 Executive Summary

Mesotrione (2

- [4

- (methylsulfonyl)

- 2

- nitrobenzoyl]

- 1,3

- cyclohexanedione) is a triketone herbicide which inhibits the enzyme p

- hydroxyphenyl

- pyruvate dioxygenase (HPPD), disrupting carotenoid biosynthesis. This process leads to the destruction of chlorophyll, resulting in a bleaching effect in susceptible plants. Mesotrione is intended for preemergence and postemergence use for the selective control of annual broadleaf weeds. Mesotrione is currently registered for application to asparagus, berry group 13, field corn, seed corn, yellow popcorn, sweet corn, cranberry, flax, grasses grown for seed, lingonberry, pearl millet, oat, okra, rhubarb, sorghum (sweet and grain), soybean, and sugarcane with tolerances for residues of mesotrione

per se of 0.01

- 1.5 ppm. Mesotrione is also registered for use on turf, including athletic fields, recreational areas, residential lawns (spot treat ments only for liquids), and golf courses. It is noted that a risk assessment was recently completed by HED for mesotrione

- tolerant soybeans (Memo, S. Levy et al.

, 22

- OCT

- 2014; D410250). Syngenta is currently proposing postemergent soil application to pome fruit, stone fruit, citrus, and tree nut orchards. The new use s will be added to the Callisto ® 

### Herbicide product label (EPA Reg. # 100

- 1131), which is a liquid formulation (suspension

- concentrate) of mesotrione

.

Hazard Assessment In subchronic and chronic oral studies in the rat, mouse, and dog, mesotrione produced ocular (ocular discharge and corneal abnormalities and lesions), kidney (increased organ weights), and liver effects (increased organ weights and hepatocyte fat vacuolation), which are co nsistent with the mammalian toxicity profile for HPPD inhibitors caused by high tyrosine levels in the blood. Body

- weight decrements and decreased food consumption were also noted in mice and rats in multiple studies. Even though the rat was found to be the most sensitive species for these effects, the mouse was identified as a more appropriate model for assessing human risk due to similar activity in mice and humans of an enzyme involved in tyrosine catabolism.

There was evidence of increased quantitati ve susceptibility of rats and mice in the developmental and reproduction toxicity studies. Offspring effects in the developmental toxicity studies were evidenced by delayed ossification and ancillary ribs and vertebrae at doses below or in the absence of maternal toxicity in both species . In the reproduction toxicity studies, tyrosinemia and ocular discharge were observed in offspring at doses below those for parental toxicity, which was evidenced by increased organ weights (liver in the rat and kidney in the mouse) and tyrosinemia.

M esotrione was classified as having low acute toxicity via the oral, dermal, and inhalation routes (Toxicity Categories III or IV). It is classified as a mild eye irritant, but it is not a dermal sensitizer or dermal irrita nt.

There was no evidence of neurotoxicity, mutagenicity, carcinogenic potential, or immunotoxicity in relevant studies.

Food Quality Pr otection Act (FQPA) Assessment The toxicological database is adequate for FQPA assessment. There is no evidence of neurotoxicity, evidence of offspring susceptibility/sensitivity is protected for by the selected endpoints, and there is no uncertainty in the exposure database. The RAB1 risk assessment team for mesotrione determined that the FQPA Safety Factor (SF) should be reduced to 3X for allMesotrione Human Health Risk Assessment DP # 419616

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Page 5 of 31 

### exposure scenarios for use of a lowest

- observed adverse

- effect level (LOAEL) from the mouse reproduction toxicity study since the effect (ocula r discharge) provided a highly conservative endpoint, there is low concern for susceptibility in the developmental and reproduction studies in mice (the relevant species for human health risk assessment), and the selected endpoints are protective of develo pmental effects observed in the rat and rabbit developmental toxicity studies.

Food Residue Profile The nature of the residue in plants is adequately understood in the subject crops. Organization for Economic Co

- operation and Development (OECD) tolerance

- calculation procedures and the submitted residue data sets were used to calculate the HED

- recommende d tolerances. T here are no residue chemistry issues that would preclude establishing unconditional tolerances for residues of mesotrione , as outlined in Table 2.2.2

.
Exposure/Risk Assessment Characterization Dietary: A chronic dietary risk assessment w a s conducted using the Dietary Exposure Evaluation Model

- Food Consumption Intake Database (DEEM

- FCID, ver. 3.16) which incorporates consumption data from United States Department of Agriculture (USDA) National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA; 2003

- 2008). The chronic analysi s assumed 100% crop treated (CT), DEEM 7.81 default processing factors, and tolerance

- level residues for all foods. Drinking water was incorporated direc tly into the dietary assessment usi ng the groundwater concentration generated using the Experimental Use Permit (EUP) use pattern on soybeans and the PRZM

- GW model

. The chronic dietary risk assessment shows that the chronic dietary risk estimates are not of concern [ i.e., <100% chronic
pop ulation

- adjusted dose ( cPAD) ]

. The chronic dietary risk estimate for the highest exposed population subgroup, all infants (<1 year old), is 1 7 % of the cPAD.

Residential: The proposed uses are not expected to result in residential exposure; however, there are existing residential uses (e.g., golf course turf, homes lawns, and recreational turf). These

uses were reassessed p reviously (using the revised 2012 Residential Stan dard Operating Procedures (SOPs) ). All residential risk estimates (both handler and post

- application) are greater than 3,000 [level of concern (LOC ) = 300 ]

.
Aggregate: An acute aggregate risk assessment was not necessary since an appropriate endpoint for the assessment of acute dietary risk was not identified (no acute hazard is present). A c hronic (long

- term) aggregate assessment was conducted; however, the assessment only considers food and drinking water (see dietary exposure section above for more details) . An aggregate cancer risk assessment was not performed because mesotrione was classified as “not likely to be carcinogenic to humans.”

The short

- and intermediate

- term toxicological points of departure ( PODs ) for mesotrione are the same for each route of exposure. Therefore, for residential exposure scenarios, only short

- term exposures were assessed, and are considered to be protective of intermediate

- term exposure and risk. Short

- term aggregate risk results from dietary (food and drinking water) and non

- dietary sources of exposure (for this assessment, turf). Incidental oral exposure was factored into the short

- term aggregate risk calculations for children (1

- <2 years old) , as incidental oral exposure is possible for this population. Incidental oral exposure is not expected for ch ildren (6 to <11 years old) , children (11 to <16 years old), or a dults from residues on turfgrass; therefore, this exposure scenario was not factored into the short

- and intermedi ate

- term aggregate riskMesotrione Human Health Risk Assessment DP # 419616

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Page 6 of 31 

### calculations

. Short

- term aggregate margins of exposures (MOEs) for the adult and children population subgroups were assessed, and are not of concern to HED ( i.e., MOEs >300).

Occupational: Based on the proposed use pattern, expos ures are anticipated for occupational handlers only (mixing/loading and applying via groundboom). Post

- application exposure is not anticipated since the label directions indicate contact with the crop foliage is to be avoided. HED did not conduct specifi c occupational handler assessments for this action since it has been determined that these new uses are not uniquely different from previously assessed uses for this active ingredient; therefore, a quantitative assessment is not necessary. An exposure ass essment was previously assessed for mesotrione (Memo, K. Lowe, 1 3

- OCT

- 2013 ; D415329 ) for uses on corn, sugarcane, cranberry

, and soybeans. These risk estimates are representative of higher application rates than the proposed uses, and were not of concern to HED; therefore, the proposed new uses are not of concern to HED.

Environmental Justice Potential areas of environmental justice concerns, to the extent possible, 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 Lo w

- Income Populations," http://www.epa.gov/compliance/environmentaljustice/resources/policy/exec_order_12898.pdf

.
This risk assessment relies in part o n data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. Please refer to Appendix C for a discussion of the human study data used in this risk assessment.

2.0 Recommendations

Provided the petitioner submits revised Section F, there are no other residue chemistry, occupational, or toxicology data deficiencies that would preclude the establishment of permanent tolerances as outlined in Section 2.2.2.

2.1 Data Deficiencies /Data Needs

No da ta deficiencies were identified for the current petition

. It is noted that the requirements for plant metabolism data in three dissimilar crops ha ve not been fulfilled and livestock feeding studies have not been submitted. To support uses on future crops , additional plant metabolism and/or livestock feeding studies may be required. In addition, although adequate storage stability data are available to validate the employed intervals, the study authors indicated that data are forthcoming demonstrating the stability of mesotrione in/on orange fruit, orange juice, and almond nutmeat sto red frozen for 12 months (Syngenta Study TK00661099); these data should be submitted/evaluated so as to confirm the conclusion made here concerning stability in citrus and tree nuts.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

The enforcement method for the curr ently

- established plant tolerances is a high

- performance liquid chromatography (HPLC) method with fluorescence detection (Method TMR0882B;Mesotrione Human Health Risk Assessment DP # 419616

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Page 7 of 31 

### D245477, S. Levy, 6

- Jun

- 2001; D283827, W. Cutchin, 12

- Jan

- 2005). The confirmatory m ethod for tolerance enforcement is the same as the current data

- collection method (Syngenta Method RAM 366/01). Since the magnitude of the residue data were generated using the confirmatory method and since adequate validation data w ere submitted, HED concludes that the confirmatory method is sufficient to enforce the tolerances recommend herein.

2.2.2 Recommended Tolerances

Table 2.2.2 is a summary of the petitioner

- proposed and HED

- recommended tolerances for residues of mesotrione per se ; HED is requesting a revised Section F specifying the correct tolerance value or commodity definition. Other than almond hulls, the field trial studies resulted in less than limit of quantitation ( < LOQ) residues; therefore, LOQ

- level tolerances are being recommended. For almond hulls, the OECD tolerance

- calculation procedure recommended for a 0. 015

- ppm tolerance; based on the method LOQ of 0.01 ppm, HED is recommending for a tolerance in/on almond hulls of 0.02 ppm (method not valid to the thousandths place ). Tolerances in/on the processed commodities were determined to be unnecessary as the processing studies, which employed single/seasona l application rates 3 X that proposed, resulted in residues ≤LOQ (LOQ = 0.01 ppm) in all of the processed commodities.

Table 2.2.2

. Tolerance Summary for Mesotrione

.
Commodity Proposed Tolerance (ppm) HED

- Recommended

Tolerance (ppm) Comments ( correct commodity definition )
citrus fruit, crop group 10 0.01 0.01 fruit, citrus, group 10

- 10 pome fruit, crop group 11 0.01 0.01 fruit, pome, group 11

- 10 stone fruit, crop group 12 0.01 0.01 fruit, stone, group 12

- 12 tree nuts, crop group 14 0.01 0.01 nut, tree, group 14

- 12

almond, hulls 0.015 0.02 Tolerance of 0.015 ppm was determined to be inappropriate as the method LOQ is 0.01 ppm.



### 2.2.3 Revisions to Petitioned

- For Tolerances

The commodity definition for citrus, pome fruit, stone fruit, and tree nuts should be revised to conform with HED’s preferred terms. In addition, based on the method LOQ of 0.01 ppm, HED is recommending for a tolerance in/on almond hull of 0.02 ppm rather than 0.015 ppm.

2.2.4 International Harmonization

There are no Codex or Mexican maximum residue limits (MRLs) in/on the proposed commodities . Therefore, tolerance harmonization is not an issue for this petition.

2.3 Label Recommendations

None

.Mesotrione Human Health Risk Assessment DP # 419616

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Page 8 of 31 

### 3.0 Introduction

3.1 Chemical Identity

The chemical structure and nomenclature of mesotrione and its metabolite 2

- nitro

- 4

- (methylsulfonyl)benzoic acid ( MNBA ) are presented in Table 3.1.

T able 3.1. Test Compound Nomenclature.

Chemical structure

Common name Mesotrione Company experimental name ZA1296 IUPAC name 2

- (4

- mesyl

- 2

- nitrobenzoyl)cyclohexane

- 1,3

- dione CAS name 2

- [4

- (methylsulfonyl)

- 2

- nitrobenzoyl]

- 1,3

- cyclohexanedione CAS registry number 104206

- 82

- 8 End

- use product (EP) Callisto ® Herbicide; EPA Reg. No. 100

- 1131 ( 4 lb s ai/gal SC )

Chemical structure

Common name MNBA/NOA 437130 Chemical name 2

- nitro

- 4

- (methylsulfonyl)benzoic acid



### 3.2 Physical/Chemical Characteristics

Mesotrione has a low vapor pressure, Log K ow 

### , and Henry’s law constant (5.1 x 10

- 7 

### Pa m 3 

### /mol). See Appendix B for details.

3.3 Pesticide Use Pattern

The new use will be added to the Callisto ® 

### Herbicide product label (EPA Reg. # 100

- 1131), which is a li quid formulation. The supplemental label provided with the petition indicates the product is to be applied postemergence, for control of weeds in citrus fruit (orange), pome fruit (apple), stone fruit (nectarine, peach, plum) and tree nuts (almond, walnut , pistachio). The proposed label indicates the product should be applied towards the ground/weeds, avoiding contact with crop foliage, stems

, or fruit. Applications are to be made by ground equipment only; chemigation and aerial application s are prohibit ed by the label.

Table 3.3.1 is a summary of the proposed formulated product and Table 3.3.2 is a summary of the proposed application scenario. The proposed label is adequate.Mesotrione Human Health Risk Assessment DP # 419616

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Page 9 of 31 Table 3.3.1. Summary of Proposed Formulated Product. Name (EPA Reg. No .) Formulation ai Concentration Weeds Controlled
Callisto ® Herbicide (EPA Reg. No. 100

- 1131) suspension

- concentrate (SC) 4 lbs ai/gallon annual broadleaf weeds

Table 3.3.2. Summary of Application Scenarios.

Crop Formulation Method Rate (lbs ai/acre) RTI

( days) Preharvest

Interval (PHI; days) Comments 1

pome fruit,

stone fruit, citrus, and tree
nuts SC

4 lbs ai/gallon (see Table 3.3.1) Apply as a

directed or shielded spray to the orchard floor. Banded application is also permitted. 0.094 or

0.188 5 months between applications at 0.188 lbs ai/acre

6 weeks between applications at 0.094 lbs ai/acre or 0.188 lbs ai/acre and subsequent applications at 0.094 lbs ai/acre. pome fruit,

stone fruit, and tree nuts

- 30 days

citrus

- 1 day - Appl ied after trees have been established

for a minimum of 12 months.

- Application through irrigation equipment is prohibited.

- Do not exceed 0.375 lbs ai/acre per year or in a 12

- month period.

- Do not exceed 3 applications per year or in a 12

- month period.

- Do not apply using aerial equipment.

- Do not apply when the nuts or fruit are on the ground at harvest.

- If weeds are emerged at the time of application, the addition of a NIS or COC is recommended as well as AMS.

1 NIS = nonionic surfactant; COC = crop oil concentrate; AMS = ammonium sulfate.



### 3.4 Anticipated Exposure Pathways

Humans may be exposed to mesotrione in food and drinking water, since mesotrione may be applied directly to growing crops and application m ay result in mesotrione reaching surface and ground water sources of drinking water. There are also residential uses of mesotrione , so exposure in residential or non

- occupational settings can occur . In an occupational setting, applicators may be exposed while handling the pesticide prior to application, as well as during application.

This risk assessment considers all of the aforementioned exposure pathways based on the proposed new use of mesotrione , but also considers the existing registered uses as well.

3.5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, 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://epa.gov/compliance/ej/resources/policy/exec_order_12898.pdf ). As a part of every pestici de risk assessment, OPP considers a large variety of consumer subgroups according to well

- established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s f ood and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the U.S. Department of Agriculture (USDA) under the NHANES/WWEIA; 2003

- 2008 a nd are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorizedMesotrione Human Health Risk Assessment DP # 419616

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Page 10 of 31 

### by subgroups based on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to assess die tary exposure to smaller, specialized subgroups and exposure assessments 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 areas post

- application are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and mode ls that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0 Hazard Characterization and Dose

- Response Assessment

In mammals, the amino acid tyrosine is catabolized by the tyrosine aminotransferase (TAT) enzyme to form the substrate 4

- hydroxyphenylpyruvic acid (HPPA), which is then further catabolized by the HPPD enzyme for excretion. Inhibition of HPPD leads to the build

- up of HPPA and this build

- up results in elevated levels of tyrosine in the blood (tyrosinemia). Tyrosinemia in laboratory animals results in ocular, developmental, liver, and kidney effects. TAT activity can vary depending on the species; therefore

, the degree of tyrosine accumulation differs among species.

4.1 Toxicology Studies Available for Analysis

The toxicological database for mesotrione is adequate for hazard characterization, toxicity endpoint selection, and FQPA SF evaluation. An immun otoxicity study (MRID #48748301) has been submitted since the last risk assessment and the results are incorporated into the current assessment. HED previously requested a subchronic inhalation study to characterize the effects of mesotri one via the inhal ation route. Since that request, t he HED Hazard and Science Policy Council (HASPOC) concluded using a weight

- of

- evidence approach that the subchronic inhalation study is not required at this time ( Memo, A. Dun bar, 27

- JUN

- 2013; TXR #0056648).

4.2 Absorption, Distribution, Metabolism, and Excretion (ADME)

A series of rat metabolism studies with radiolabeled mesotrione indicated mesotrione was readily absorbed and distributed throughout the body after single and repeated doses. Concentrations of

ra dioactivity were highest in the liver and kidney

, with radioactivity also detected in the carcass, GI tract, spleen, bone, and blood. Repeated dosing resulted in reduced accumulation of radiolabeled mesotrione in tissues (0. 44X lower). Within 72 hours of administering a single oral dose at 1 mg/kg, both sexes excreted 54.2

- 55.9% and 23.8

- 24.5% of the administered dose via the urine and feces, respectively. The major component excreted in urine, feces, and bile was unchanged parent. Increasing the dose o r repeated doses had little effect on the pattern of excretion. Biliary excretion was a more prominent route of excretion for males than females.

4.2.1 Dermal Absorption

A dermal

- absorption factor of 1% was estimated for mesotrione based on the result s of an in vivo dermal absorption study in rats (P.V. Shah, 23

- OCT

- 2007, TXR#0054622). This dermal

absorption factor is applied for converting oral doses to dermal

- equivalent doses in order to assess the potential risk associated with dermal exposures of mesotrione.Mesotrione Human Health Risk Assessment DP # 419616

________________________________________________________________________ ______ ______________

Page 11 of 31 

### 4.3 Toxicological Effects

In subchronic and chronic oral studies in the rat, mouse, and dog, mesotrione produced ocular (ocular discharge and corneal abnormalities and lesions), kidney (increased organ weights), and liver effects (increased o rgan weights and hepatocyte fat vacuolation), which are consistent with the mammalian toxicity profile for HPPD inhibitors caused by high tyrosine levels in the blood. Body

- weight decrements and decreased food consumption were also noted in mice and rats in multiple studies. Even though the rat was found to be the most sensitive species for these effects, HED’s Mechanism of Toxicity Science Advisory Review Committee ( MTSARC ) concluded that the mouse is a more appropriate model for assessing human risk be cause TAT enzyme activity in the mouse and human are similar ( Memo, D. Nixon, 27

- MAR

- 2001 ; TXR# 0051908 )

.
There was evidence of increased susceptibility of rats and mice in the developmental and reproduction toxicity studies. Offspring effects in the developmental toxicity studies were evidenced by delayed ossification and ancillary ribs and vertebrae at dose s below or in the absence of maternal toxicity. In the reproduction toxicity studies, tyrosinemia and ocular discharge were observed in offspring at doses below those for parental toxicity, which was evidenced by increased organ weights (liver in the rat and kidney in the mouse) and tyrosinemia.

Mesotrione is classified as having low acute toxicity via the oral, dermal, and inhalation routes (Toxicity Categories III or IV). It is classified as a mild eye irritant, but it is not a dermal sensitizer or dermal irritant.

There was no evidence of neurotoxicity or neuropathology seen in the acute and subchronic neurotoxicity studies.

There was no evidence of carcinogenic potential in either the rat or mouse carcinogenicity studies and no concern for mutagenicity.

An immunotoxicity study submitted since the mos t recent risk assessment showed no evidence of immunotoxicity.

4.4 Safety Factor for Infants and Children (FQPA SF)

The toxicological database is adequate for FQPA assessment. There is no evidence of neurotoxicity, evidence of offspring susceptibility/s ensitivity is protected for by the selected endpoints, and there is no uncertainty in the exposure database.

The RAB1 risk assessment team for mesotrione determined that the FQPA SF should be reduced to 3X for all exposure scenarios for use of a LOAEL fro m the reproduction toxicity study. This conclusion is based on the following:

 The ocular discharge seen in the reproduction toxicity study in mice provided a highly conservative endpoint. The LOAEL for this study is currently the lowest dose tested. The incidence of ocular discharge lacked a clear dose response, butMesotrione Human Health Risk Assessment DP # 419616

________________________________________________________________________ ______ ______________

Page 12 of 31 

### an effect was evident at the highest dose tested indicating that the choice of LOAEL in this study may also be conservative.

 There is low concern for susceptibility seen in the developmen tal and reproduction toxicity studies in mice (the relevant species for human health risk assessment) because the doses and endpoints selected are protective of effects seen in these studies. The doses and endpoints are also protective of developmental ef

fects observed in the rat and rabbit developmental toxicity studies (see Section 4.4.3).

4.4.1 Completeness of the Toxicology Database

The existing toxicological database is adequate for characterizing mesotrione toxicity and quantification of hazard f or dietary and occupational exposures. The developmental toxicity studies in rats, mice, and rabbits, two

- generation reproduction toxicity studies in rats and mice, and acute and subchronic neurotoxicity studies in rats are available to assess potential f etal/offspring sensitivity.

4.4.2 Evidence of Neurotoxicity

There is no evidence of neurotoxicity from mesotrione exposure.

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

There was evidence of quantitative susceptibility to offspring in developmental and reproduction toxicity studies in mice and rats (see Section 4.3). Concern is low since: 1) the basis for the points of departure (ocular discharge in the mouse reproductio n toxicity study) provides a highly conservative endpoint for risk assessment; and 2) the doses and endpoints selected for risk assessment are protective of the offspring effects seen in mice (the relevant species for human health risk assessment ) as well as the developmental effects observed in rats.

4.4.4 Residual Uncertainty in the Exposure Database

There are no additional residual uncertainties with respect to exposure data. The dietary food exposure assessment utilizes recommended tolerance

- level re sidues and 100% CT information for all commodities. By using these screening

- level assessments, acute and chronic exposures/risks will not be underestimated. The dietary drinking water assessment utilizes values generated by model s and associated modelin g parameters that are designed to provide conservative, health

- protective, high

- end estimates of water concentrations that will not likely be exceeded

. The residential handler and post

- application exposure assessments are based upon the residential SOPs. The residential SOPs are based upon reasonable worst

- case assumptions and are not expected to underestimate risk. These assessments of exposure are not likely to underestimate the resulting estimates of risk from exposure to mesotrione

.

4.5 Toxicity End point and Point of Departure Selections

No changes have been made to toxicity endpoints and points of departure since the last risk assessment for mesotrione ( Memo, S. Levy et al.

, 22

- OCT

- 2014; D410250 ).Mesotrione Human Health Risk Assessment DP # 419616

________________________________________________________________________ ______ ______________

Page 13 of 31 

### 4.5.1 Dose

- Response Assessment

Acute Dietary Endp oint (all populations) : There were no effects observed attributable to a single dose. Therefore, an endpoint was not selected for this exposure scenario.

Chronic Dietary Endpoint (all populations) : The chronic reference dose (cRfD) was established based on the LOAEL (2.1 mg/kg/day) from the mouse reproduction toxicity study. The LOAEL is based on tyrosinemia and ocular discharge in offspring. The study and endpoint are appropriate for the route and duration of exposure. The FQPA SF has been reduc ed to 3X to incorporate an uncertainty factor (UF L 

### ) for use of a LOAEL to extrapolate a no

- observed adverse

- effect level (NOAEL) (see Section 4.4).

Short

- and Intermediate

- Term Incidental Oral Exposure : The reproduction toxicity study in mice was chosen for evaluating incidental oral exposures. The LOAEL of 2.1 mg/kg/day is based on tyrosinemia and ocular discharge in offspring. The FQPA SF/UF L 

### has been reduced to 3X (see Section 4.4).

Dermal Endpoints (all durations) : The reproduction toxicity study in mice was chosen for evaluating dermal exposures. The LOAEL of 2.1 mg/kg/day is based on tyrosinemia and ocular discharge in offspring. The use of a POD based on offspring effects is highly conservative for adults. The LOC for dermal exposures is for MOEs <300 (10X for interspecies, 10X for intraspecies extrapolation and 3X for FQPA SF/UF L 

### ). For dermal exposure scenarios, a dermal

absorption factor of 1% should be applied.

Inhalation Endpoints (all durations) : The rep roduction toxicity study in mice was chosen for evaluating inhalation exposures. The LOAEL of 2.1 mg/kg/day is based on tyrosinemia and ocular discharge in offspring, which is highly conservative for adults. The LOC for inhalation exposures is for MOEs < 300 (10X for interspecies, 10X for intraspecies extrapolation and 3X for FQPA SF/UF L 

### ). Inhalation exposure is assumed to be equivalent to oral exposure.

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

When there are potentia l occupational and residential exposures to a pesticide, the risk assessment must address exposures from three major sources (oral, dermal, and inhalation) and determine whether the individual exposures can be combined if they have the same toxicological

e ffects. For short

- and intermediate

- exposures, dermal, inhalation, and incidental oral exposures can be combined since the same endpoint was chosen for all routes.

4.5.3 Cancer Classification and Risk Assessment Recommendation

The Agency classified meso trione as “not likely to be carcinogenic to humans” by all routes of exposure based upon lack of evidence of carcinogenicity in rats and mice; therefore, a cancer risk assessment is not required.Mesotrione Human Health Risk Assessment DP # 419616

________________________________________________________________________ ______ ______________

Page 14 of 31 

### 4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk Assessment

Table 4.5.4.1. Summary of Toxicological Doses and Endpoints for Mesotrione for Use in Dietary and Non

Occupational Human Health Risk Assessments

. Exposure/ Scenario P O D Uncertainty/FQPA SFs RfD, PAD, L O C

for Risk Assessment Study and Toxicological Effects

Acute Dietary (All Populations) Not applicable Not applicable Not applicable No adverse effects attributable to a single dose were observed. As a result, no hazard was identified and an endpoint was not selected to assess this exposure scenario.

Chronic Dietary (All Populations) LOAEL =

2.1 mg/kg/day UF A = 10X

UF H = 10X

FQPA SF/UF L = 3X cRfD = 0.007

mg/kg/day

cPAD = 0.007 mg/kg/day Reproduction Study (mouse)

Offspring LOAEL = 2.1/2.4 mg/kg/day (M/F) based on tyrosinemia and ocular discharge

.

NOAEL not established

.

Incidental Oral Short

- Term (1

- 30 days) and Intermediate

Term (1

- 6 months) LOAEL =

2.1 mg/kg/day UF A = 10X

UF H = 10X

FQPA SF/UF L = 3X Residential LOC

for MOE = 300 Reproduction Study (mouse)

Offspring LOAEL = 2.1/2.4 mg/kg/day (M/F) based on tyrosinemia and ocular discharge

.

NOAEL not established

. Dermal Short

- Term (1

- 30 days), Intermediate

Term (1

- 6 months) and Long

- Term (>6 months) LOAEL =

2.1 mg/kg/day UF A = 10X

UF H = 10X

FQPA SF/UF L = 3X Residential LOC

for MOE = 300 Reproduction Study (mouse)

Offspring LOAEL = 2.1/2.4 mg/kg/day (M/F) based on tyrosinemia and ocular discharge

.

NOAEL not established

. Inhalation Short

- Term (1

- 30 days), Intermediate

term (1

- 6 months) and Long

- Term (>6 months) LOAEL =

2.1 mg/kg/day

Inhalation assumed equivalent to oral UF A = 10X

UF H = 10X

FQPA SF/UF L = 3X Residential LOC

for MOE = 300 Reproduction Study (mouse)

Offspring LOAEL = 2.1/2.4 mg/kg/day (M/F) based on tyrosinemia and ocular discharge

.

NOAEL not established

. Cancer (oral, dermal, inhalation) Classified as “not likely to be carcinogenic to humans” based upon lack of evidence of

carcinogenicity in rats and mice

.
Point of departure (POD) = A data point or an estimated point that is derived from observed dose

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL =

no

- observed adverse

- effec t 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 (intraspecies). UF L = use of a LOAE L to extrapolate a NOAEL. FQPA SF = FQPA Safety Factor. PAD = population

- adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern.Mesotrione Human Health Risk Assessment DP # 419616

________________________________________________________________________ ______ ______________

Page 15 of 31 Table 4.5.4.2. Summary of Toxicological Doses and Endpoints fo r Mesotrione for Use in Occupational Human Health Risk Assessments. Exposure/ Scenario POD Uncertainty SFs LOC for Risk Assessment Study and Toxicological Effects

Dermal Short

- Term (1

- 30 days), Intermediate

Term (1

- 6 months) and Long

- Term (>6 months) LOAEL =

2.1 mg/kg/day UF A = 10X

UF H = 10X

UF L = 3X Occupational LOC

for MOE = 300 Reproduction Study (mouse)

Offspring LOAEL = 2.1/2.4 mg/kg/day (M/F) based on tyrosinemia and ocular discharge

.

NOAEL not established

. Inhalation Short

- Term (1

- 30 days), Intermediate

term (1

- 6 months) and Long

- Term (>6 months) LOAEL =

2.1 mg/kg/day

Inhalation assumed equivalent to oral UF A = 10X

UF H = 10X

UF L = 3X Occupational LOC

for MOE = 300 Reproduction Study (mouse)

Offspring LOAEL = 2.1/2.4 mg/kg/day (M/F) based on tyrosinemia and ocular discharge

.

NOAEL not established

. Cancer (oral, dermal, inhalation) Classified as “not likely to be carcinogenic to humans” based upon lack of evidence of

carcinogenicity in rats and mice

.
Point of departure (POD) = A data point or an estimated point that is derived from observed dose

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL =

no

- observed adverse

- effec t 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 (intraspecies). UF L = use of a LOAE L to extrapolate a NOAEL. MOE = margin of exposure. LOC = level of concern.



### 5.0 Dietary Exposure and Risk Assessment

Memo, T. Bloem

, 30

- APR

- 2015 ; D420017 (residue chemistry summary for the current action) Memo, S. Levy

, 06

- MAY 2015 ; D420018 (dietary exposure analysis for the current action)



### 5.1 Residues of Concern Summary and Rationale

Table 5.1. Summary of Metabolites and Degradates to be Included in the Risk Assessment. Matrix Tolerance Expression Residues for Risk Assessment Registered Crops Mesotrione Mesotrione Livestock Mesotrione Mesotrione Rotational Crops Mesotrione Mesotrione Drinking Water NA* Mesotrione * NA = not applicable.Mesotrione Human Health Risk Assessment DP # 419616

________________________________________________________________________ ______ ______________

Page 16 of 31 

### Plants (Primary Crops ): Field corn (preemergent and foliar application) and peanut (preemergent application) metabolism studies conducted with [cyclohexanedione

- 2

- 14 

### C]mesotrione and [ 14 

### C

- phenyl]mesotrione and a cranberry (foliar application) metabolism study conducted with [ 14 

### C

- phenyl]mesotrione were previously submitted and reviewed ( Memo, S. Levy, 0 6

- J UN

- 2001; D245477; Memo, W. Cutchin, 12

- J AN

- 2005; D283827; and Memo, S. Levy, 0 2

- M AR

- 2007 ; D326898 ). The studies conducted with [ 14 

### C

- phenyl]mesotrione (fiel d corn, peanut, and cranberry) indicate that the major metabolic pathway involves cleavage of the cyclohexanedione ring to yield MNBA, which is further reduced to its amino analog, AMBA. Mesotrione may also undergo hydroxylation to form 4

- OH

- mesotrione. The results of metabolism studies reflecting application of [cyclohexanedione

- 2

- 14 

### C]mesotrione (field corn and peanut) indicate that the cyclohexanedione ring may be degraded to CO 2 

### which is incorporated into natural products, and the cyclohexanedione ring may be oxidized to form 4

- OH

- mesotrione which is further metabolized to form multiple metabolites.

The field corn and peanut studies were deemed acceptable, and the results were shown to be similar. However, the cranberry data were deemed incomplete b ecause metabolism data reflecting application with [cyclohexanedione

- 2

- 14 

### C]mesotrione were not submitted. Based on these data, HED concluded that the residue of concern in the currently

- registered crops, including cranberry and the berry crop group 13, fo r tolerance expression and risk assessment purposes is mesotrione per se . It was noted that the requirements for plant metabolism data in three dissimilar crops had not been fulfilled, and that additional plant metabolism data may be required to support f

uture uses on additional crops.

For the following reasons, HED concludes that the currently

- available metabolism data are adequate for the requested crops and the residue of concern for tolerance enforcement and risk assessment purposes, in/on the propo sed crops is mesotrione per se : (1) the metabolism of phenyl

- labeled mesotrione was similar in cranberry, peanut, and corn, suggesting that the metabolic routes for mesotrione are similar in all three crops; (2) results from the corn and peanut metabolism studies reflecting application of cyclohexanedione

- labeled mesotrione indicate that additional residues of concern are unlikely to be found following application of cyclohexanedione

- labeled mesotrione to cranberries; and (3) results from the submitted cro p field trials for the proposed crops indicate that residues of mesotrione and MNBA were below the LOQ in/on all samples following treatment according to the proposed use patterns. It is noted that additional metabolism data may be required in

- support of future petitions.

Plants (Rotational Crops): Since citrus, pome fruit, stone fruit, and tree nuts are not rotated, a discussion concerning the nature of the residue in rotated crops is unnecessary. For the registered crops, the current assessment assume s that the registered labels adhere to the HED

re commended plant

- back intervals (PBIs).

Livestock: Ruminant (dietary burden of ~10 ppm; 7 consecutive days) and poultry (dietary burden of ~10 ppm; 10 consecutive days) metabolism studies conducted with cyc lohexanedione

2

- 14 

### C]mesotrione and [ 14 

### C

- phenyl]mesotrione has been previously submitted and reviewed ( Memo, S. Levy, 0 6

- J UN

- 2001; D245477, and Memo, W. Cutchin, 12

- JAN

- 2005 ; D283827 ). Based on the results of the dairy cow metabolism studies, it was proposed that mesotrione is metabolized by the reduction of the nitro group to an amino group, leading to the formation of the metabolite AMBA. In addition, separation of the phenyl and cyclohexanedione rings mayMesotrione Human Health Risk Assessment DP # 419616

________________________________________________________________________ ______ ______________

Page 17 of 31 

### occur with the cyclohexane dione ring metabolized and incorporated into natural products such as lactose. In the poultry metabolism study, mesotrione was the primary residue found in eggs and edible tissues; however, incorporation into natural components such as palmitic, oleic, and stearic acid was also demonstrated. HED concluded that for tolerance expression and risk assessment purposes the residue of concern in/on livestock commodities is mesotrione per se

.
Drinking Water: Mesotrione is absorbed through the soil by emerging weeds and through the foliage of emerged weeds. The active ingredient is mobile (Koc: 16.5 to 390 L/kg) and presents limited persistence in soil and aquatic environments. In soil, mesotrione dissipates through aerobic metabol ism with rates from 5.5 days to 32 days that are dependent on the pH of the system (increasingly rapid in acidic environments). In field studies, mesotrione dissipated rather rapidly with half

- lives ranging from 2 to 14 days and was not detected below 6 i nches indicating that it is not likely to leach to ground water. Mesotrione may reach surface water through drift, runoff, and/or erosion

. In aquatic environments, mesotrione is stable to hydrolysis and has limited photolysis but degrades rapidly through aerobic and anaerobic metabolism. Based on physicochemical properties, mesotrione is not expected to bioconcentrate. Likewise, it is not expected to volatilize from soil. HED concluded that for risk assessment purposes the residue of concern in drinkin g water is mesotrione per se

.

5.2 Food Residue Profile

Mesotrione is currently registered for application to asparagus, berry group 13, field corn, seed corn, yellow popcorn, sweet corn, cranberry, flax, grasses grown for seed, lingonberry, pearl mille t, oat, okra, rhubarb, sorghum (sweet and grain), soybean, and sugarcane with tolerances for residues of mesotrione per se in/on the food commodities associated with these crops of 0.01

- 0.05 ppm (LOQ = 0.01 ppm). The residue data submitted in conjunction with the current petition were similar with residues of mesotrione per se in/on the proposed crops at ≤0.014 ppm. The orange, apple, and plum processing studies resulted in a reduction in mesotrione per se residues for all processed commodities excluding orange juice where residues were at the LOQ following treatment at 3.0x the proposed rate (<LOQ in the RAC). Based on the current livestock dietary burdens and the results of the ruminant and poultry metabolism studies, residues in livestock will be insig nificant. Also, based on the rotational crop PBIs and the result of the confined and field rotational crop studies, residues in rotational crops will be insignificant.

5.3 Water Residue Profile

The e stimated d rinking w ater c oncentrations (EDWCs) used in the dietary exposure risk assessment were provided by EFED in a memorandum dated 23

- NOV

- 201 3 ( Memo, I. Maher; D415369 )

. Water residues were incorporated directly into the DEEM

- FCID in the food categories “water, direct, all sources” and “water, indirect, all sources.”

The EDWCs were estimated using the Pesticide Root Zone Model and Exposure Analysis Modeling System (PRZM/EXAMS) in surface water and with Screening Concentration in Ground Water (SCI

- GROW) and PRZM

- GW for groun d water. The proposed maximum annual application rates (0.376 lb s ai/A) for the proposed uses are much lower than the previously

modeled EUP use on soybeans (1.5 lbs ai/A/year). Although the EUP has expired, HED did not request revised EDWCs, since the e stimate from the EUP scenario did not result in risks of

concern

. Furthermore the EUP scenario has a higher application rate than the otherMesotrione Human Health Risk Assessment DP # 419616

________________________________________________________________________ ______ ______________

Page 18 of 31 

### registered/

proposed uses. EFED confirmed the use of the EUP soybean EDWCs ( electronic correspondence, I. Maher to S. Levy

, 23

- SEP

- 2014 ).

Table 5.3. Maximum EDWCs of Mesotrione.
Drinking Water Source (model) Use

(Maximum Annual Rate) Upper

- Bound EDWC (ppb) Acute (1

- in

- 10 year) Chronic

(1

- in

- 10 year) Chronic

(30

- year average)
Surface Water (PRZM/EXAMS) Soybean

- EUP (1.5 lb s ai/A) 38.1 5.1 2.2
Groundwater (PRZM

- GW) Soybean

- EUP (1.5 lb s ai/A) 26.2 18.4 < 18.4 Groundwater (SCI

- GROW) Soybean

- EUP (1.5 lb s ai/A) 0.54 < 0.54 < 0.54



### The ground water EDWC of 18.4 pp b was used in the chronic analysis, as this value was the highest and provided a more conservative approach.

5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

The unrefined chronic analysis assumed DEEM 7.81 default processing factors and tolerance

level residues for all commodities (Memo, S. Levy, 06

- MAY

- 201 5 ; D4 20018 ) . Drinking water was incorporated directly into the dietary assessment using the concentratio n for groundwater generated by SCI

- GROW and PRZM

- GW for ground water modeling based on a previously registered EUP on soybeans.

5.4.2 Percent CT Used in Dietary Assessment

The chronic dietary analyses assumed 100% CT for all commodities.

5.4.3 Acute Dietary Risk Assessment

An acute dietary assessment was not conducted for mesotrione because an endpoint of concern attributable to a single dose was not identified; therefore, an acute reference dose ( a RfD) was not established.

5.4.4 Chronic Dietary R isk Assessment

The chronic dietary risk for food and drinking water utilized 6. 5 % of the cPAD for the U.S. population. The chronic dietary risk for the highest exposed population subgroup, all infants (<1 year old), is 1 7 % of the cPAD. A summary table o f chronic dietary exposure and risk for mesotrione can be found in Section 5.4.6. Although further refinement to the analysis is not required at this time, future assessments could be refined using anticipated residue estimates , use of empirical processin g factors, incorporation of %CT data, or monitoring data.

5.4.5 Cancer Dietary Risk Assessment

A cancer dietary assessment was not conducted because HED’s Hazard Identification Assessment Review Committee (HIARC) classified mesotrione as “not likely to be carcinogenic to humans,” based upon lack of evidence of carcinogenicity in rats and mice.Mesotrione Human Health Risk Assessment DP # 419616

________________________________________________________________________ ______ ______________

Page 19 of 31 

### 5.4.6 Summary Table

Table 5.4.6. Summary of Dietary (Food + Drinking Water) Exposure and Risk for Mesotrione.

Population Subgroup 1 Chronic Dietary Dietary Exposure (mg/kg/day) % cPAD
General U.S. Population 0.0004 57 6. 5 All Infants (<1 year old) 0.001 170 1 7 Children 1

- 2 years old 0.000 834 12 Children 3

- 5 years old 0.000 677 9.7 Children 6

- 12 years old 0.0004 53 6.5 Youth 13

- 19 years old 0.0003 46 4. 9 Adults 20

- 49 years old 0.0004 36 6. 2 Adults 50

- 99 years old 0.0004 25 6.1 Females 13

- 49 years old 0.0004 34 6. 2

1 The value of the highest exposed population is bolded.



### 6.0 Residential (Non

- Occupational) Exposure/Risk

Memo, K. Lowe, 06

- MAY

- 2015 ; D 426691 (ORE memo for the current action)



### 6.1 Residential Exposure/Risk Characterization

The proposed uses are not expected to result in residential exposure; however, there are existing residential uses that are registered for mesotrione (e.g., golf course tur f, homes lawns, and recreational turf). These residential uses were assessed previously using the 2012 Residential SOPs (Memo, K. Lowe, 13

- OCT

- 2013 ; D415329 ). The relevant results are shown in this s ection as they are applicable to a ggregate assessment.

Both liquid and granular formulations are registered, resulting in potential residential handler (dermal and inhalation) and post

- application (dermal and incidental oral) exposures. Residential risk estimates were not a concern, with the lowest MOE of 3,000 resulting from combined dermal and incidental oral exposure to children from the granular formulation (LOC = 300)

. Recommendations for the residential input of the aggregate remain unchanged from the previous memo. They are as follows:

 The recommended residential exposure for use in the adult aggregate assessment reflects combined residential handler dermal plus inhalation exposure from mixing/loading/ applying liquids with a backpack sprayer.

 The recommended residential exposure for use in the children 11 to <16 years old aggregate assessment reflects dermal post

- application exposure from golfing on turf that has been treated with a granular formulation.

 The recommended residential exposure for use in the children 6 to <11 years old aggregat e assessment reflects dermal post

- application exposure from golfing on turf that has been treated with a granular formulation.

 The recommended residential exposure for use in the children 1 to <2 years old aggregate assessment reflects combined dermal plus incidental oral (hand

- to

- mouth) post

application exposure from high contact activities on home lawns treated with a granular formulation.Mesotrione Human Health Risk Assessment DP # 419616

________________________________________________________________________ ______ ______________

Page 20 of 31 

### Summaries of the residential exposure/risk estimates and recommendations for aggregate are provided in Tables 6.1.1 and 6.1.2.

Table 6.1.1. Summary of Residential Exposure/Risk Estimates.

Exposure Scenario Route Dose (mg/kg/day) MOE

(LOC = 300) Total MOE

(LOC = 300)
Outdoor Turf Use Residential Handler Mixing/loading/applying liquids with manually pressurized handwand Dermal 0.0001 21,000 20,000 Inhalation 0.0000029 720,000 Mixing/loading/applying liquids with

sprinkler can Dermal 0.0000044 480,000 410,000 Inhalation 0.00000072 2,900,000 Mixing/loading/applying liquids with

backpack sprayer Dermal 0.00021 9,900 9,000 Inhalation 0.000023 92,000 Loading/applying granules with push

- type

spreader Dermal 0.000013 170,000 130,000 Inhalation 0.0000041 520,000 Residential Post

- application

Adults high contact

lawn activities Liquid

Dermal 0.0001 21,000

N/A mowing 0.0000021 1,000,000 golfing 0.000008 260,000 high contact lawn activities Granules 0.00019 11,000
mowing 0.0000034 610,000 golfing 0.000013 160,000

Children (11 to <16 years) mowing Liquid 0.0000024 890,000

golfing 0.0000093 230,000 mowing Granules 0.0000039 530,000 golfing 0.000015 140,000 Children (6 to <11 years) golfing Liquid 0.000011 190,000

Granules 0.000018 120,000

Children (1 to <2 years) high contact

lawn activities Liquid Dermal 0.0002 10,000 3,400 Incidental Oral

- HtM 0.00041 5,100 Incidental Oral

- OtM 0.00001 170,000 N/A Incidental Oral

– Soil Ingestion 0.0000085 250,000 N/A

Granules Dermal 0.00037 5,700 3,000

Incidental Oral

- HtM 0.00034 6,200 Incidental Oral

- OtM 0.00002 100,000 N/A Incidental Oral

– Soil Ingestion 0.0000085 250,000 N/AMesotrione Human Health Risk Assessment DP # 419616

________________________________________________________________________ ______ ______________

Page 21 of 31 Table 6. 1 .2. Recommendations for the Residential Exposures for the Mesotrione Aggregate Assessment.
Lifestage Dose (mg/kg/day) 2,4 MOE 3,5
Dermal Inhalation Oral Total Dermal Inhalation Oral Total
Short

- term Residential Handler Adult (Backpack Sprayer) 0.00021 0.000023 N/A 0.00023 9,900 92,000 N/A 9,000

Short

- term Residential Post

- application Adult (high contact activities/turf/granules) 0.00019

N/A N/A 0.00019 11,000

N/A N/A 11,000

Child (11 to <16 years) (golfing/turf/granules) 0.000015 0.000015 140,000 140,000

Child (6 to <11 years) (golfing/turf/granules) 0.000018 0.000018 120,000 120,000

Children (1 to <2 years) (high contact activities/turf/granules) 0.00037 0.00034 0.00071 5,700 6,200 3,000



### 6. 2 Spray Drift

Spray drift is a potential source of exposure to those nearby pesticide applications

. This is particularly the case with aerial application, but, to a lesser extent, spray drift can also be a potential source of exposure from the ground application methods (e.g., groundboom and airblast) employed for mesotrione

. The agency has been working with the Spray Drift Task Force (a task force composed of various regis trants which was developed as a result of a Data Call

- In issued by EPA), EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the agency’s Spray Drift website for more information). [1 ] 

### The agency has also developed a policy on how to appropriately consider spray drift as a potential source of exposure in risk assessments for pesticides

. The potential for spray drift will be quantitatively evaluated for each pestic ide during the Registration Review process, which ensures that all uses for that pesticide will be considered concurrently

. The approach is outlined in the revised (2012) Standard Operating Procedures For Residential Risk Assessment (SOPs)

- Residential E xposure Assessment Standard Operating Procedures Addenda 1: Consideration of Spray Drift

. This document outlines the quantification of indirect non

- occupational exposure to drift.

6. 3 Residential Bystander Post

- Application Inhalation Exposure

Volatilization of pesticides may be a source of post

- application inhalation exposure to individuals nearby pesticide applications

. The agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fu ngicide, and Rodenticide Act (FIFRA) Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/SAP/meet ings/2009/120109meeting.html ). The agency has evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis

[1] Available: http://www.epa.gov/opp00001/factsheets/spraydrift.htmMesotrione Human Health Risk Assessment DP # 419616

________________________________________________________________________ ______ ______________

Page 22 of 31 

### ( http://www.regulations.gov/#!docketDetail;D=EPA

- HQ

- OPP

- 2014

- 0219 ). During Registration Review, the agency will utilize this analysis to determine if data (i.e., flux studies, route

- specific inhalation toxicological studies) or further analysis is requ ired for mesotrione.

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, H ED must consider and aggregate pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. In an aggregate

asse ssment, exposures from relevant sources are added together and compared to quantitative estimates of hazard, or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure. Since there are residential uses registered, HED conducted a residential aggregate assessment for mesotrione.

7.1 Acute Aggregate Risk

An endpoint of concern was not identified to quantify acute

- dietary risk to the general population

or to any population subgroup. Since an acute dietary endpoint was not identified, an acute hazard does not exist and an acute aggregate assessment was not performed.

7.2 Short

- and Intermediate Term Aggregate Risk

The short

- and intermediate

- term toxicologica l PODs for mesotrione are the same for each route of exposure. Therefore, for residential exposure scenarios, only short

- term exposures were assessed, and are considered to be protective of intermediate

- term exposure and risk.

Short

- and intermediate

- term aggregate risk is made up of dietary and non

- dietary sources of exposure. Since mesotrione has residential uses on golf course turf, as well as turf for commercial and residential sites, post

- application residential exposure is expected. Short

- and inte rmediate

- term aggregate risk is made up of average dietary exposures from food and drinking water sources, dermal and oral (children only) residential exposures. Post

- application inhalation exposure is not expected and was not included in the aggregate ri sk estimates.

Dietary (food + drinking water) exposure estimates are based on a conservative, unrefined chronic dietary exposure assessment (see Table 5.4.6). Residential exposure estimates are conservative estimates due to the standard assumptions tha t were built into the calculations (see Section 6.0). Incidental oral exposure was factored into the short

- and intermediate

- term aggregate risk calculations for children (1 to <2 years old), as incidental oral exposure is possible for this population. In cidental oral exposure is not expected for ch ildren (6 to <11 years old)

, children (11 to <16 years old), or a dults from residues on turfgrass; therefore, this exposure scenario was not factored into the short

- and intermediate

- term aggregate risk calculati ons.Mesotrione Human Health Risk Assessment DP # 419616

________________________________________________________________________ ______ ______________

Page 23 of 31 Table 7.2. Short

- and Intermediate

- Term Aggregate Risk Calculations.

Population Food + Water Exposure 1 (mg/kg/day) Residential Exposure 2, 3, 4 (mg/kg/day) Aggregate MOE 5
Children (1 to <2 years) 0.000 834 0.00071 1 , 4 00 Child (6 to <11 years) 0.000 4 53 0.000018 4, 5 00 Child (11 to <16 years) 0.000346 0.000015 5,800 Adults 6 0.000 4 36 0.00023 3,200

1 Dietary exposure from Table 5 .4. 6

. Note the subpopulation “youth 13

- 19 years old from the dietary exposure assessment was used for the child (11 to <16 years) aggregate assessment as this was the closest comparable ages.

2 C ombination of dermal plus incidental oral (hand

- to

- mouth) post

- application exposure from treated lawns (See Table 6. 1

. 2 ).

3 P ost

- application dermal exposure from golfing (See Table 6. 1

. 2 ).

4 C ombination of dermal (handler) plus inhalation exposure from mixing/loading/applying based on the turf scenario (See Table 6. 1

. 2 ).

5 Aggregate MOE = Short

- term LOAEL (2.1 mg/kg/day)/(food + water exposure) + (residential exposure). LOC = 300.

6 Adult dietary exposure is represented by Adults 20

- 49 years old.



### As can be seen in Table 7 .2, all short

- and intermediate

- term aggregate MOEs are not of concern to HED.

7 .3 Chronic (Long

- Term) Aggregate Risk

A c hronic (long

- term) aggregate assessment was conducted; however, the assessment only considers food and drinking water (see Section 5.4 for details) . Long

- term aggregate assessment did not include residential post

- application exposure as long

- term duration (more than 6 months) is not expected based on the potential residential use pattern of mesotrione.

7. 4 Cancer Risk

Aggregate cancer risk was not calculated because mesotrione was classified as “not likely to be carcinogenic to humans.”

8.0 Cumulative Risk Characterization/Assessme nt

The HASPOC met on June 28, 2007 to discuss the mode of action and human relevance of HPPD inhibiting herbicides

. The following is a summary of their decision regarding the need for a cumulative risk assessment (HASPOC Memo, 17

- DEC

- 2007).

There are ma rked differences among species in the ocular toxicity associated with inhibition of HPPD. Ocular effects following treatment with HPPD inhibitor herbicides are seen in the rat but not in the mouse. Monkeys also seem to be recalcitrant to the ocular toxic ity induced by HPPD inhibition. One explanation for this species

- specific response in ocular opacity may be related to species differences in the clearance of tyrosine. A metabolic pathway exists to remove tyrosine from the blood that involves the liver enzyme TAT. In contrast to rats where ocular toxicity is observed following exposure to HPPD

- inhibiting herbicides, mice and humans are unlikely to achieve the levels of plasma tyrosine necessary to produce ocular opacities because the activity of TAT in these species is much greater compared to rats.

HPPD inhibitors (e.g., nitisinone) are used as an effective therapeutic agent to treat patients suffering from rare genetic diseases of tyrosine catabolism. Treatment starts in childhood but is often susta ined throughout patient’s lifetime. The human experience indicates that a therapeuticMesotrione Human Health Risk Assessment DP # 419616

________________________________________________________________________ ______ ______________

Page 24 of 31 

### dose (1 mg/kg/day dose) of nitisinone has an excellent safety record in infants, children, and adults and that serious adverse health outcomes have not been observed in a population followed for approximately a decade. Rarely, ocular effects are seen in patients with high plasma tyrosine levels; however, these effects are transient and can be readily reversed upon adherence to a restricted protein diet. This observation indicates that an HPPD inhibitor in it and of itself cannot easily overwhelm the tyrosine

- clearance mechanism in humans.

Therefore, exposures to environmental residues of HPPD

- inhibiting herbicides are unlikely to result in the high blood levels of tyros ine and ocular toxicity in humans due to an efficient metabolic process to handle excess tyrosine. The Agency continues to study the complex relationships between elevated tyrosine levels and biological effects in various species. In the future, assessme nts of HPPD

- inhibiting herbicides may consider more appropriate models and cross species extrapolation methods. Therefore, EPA has not conducted cumulative risk assessment with other HPPD inhibitors.

9.0 Occupational Exposure/Risk Characterization

Based on the proposed use pattern, exposures are anticipated for occupational handlers only (mixing/loading and applying via groundboom). Post

- application exposure is not anticipated since the label directions indicate contact with the crop foliage is to be avoided. However, HED did not conduct specific occupational handler assessments for this action since it has been determined that these new uses are not uniquely different from previously assessed uses for this active ingredient; therefore, a quantitat ive assessment is not necessary.

An exposure assessment was previously assessed for mesotrione (Memo, K. Lowe, 13

- OCT

2013 ; D415329 ) for uses on corn, sugarcane, cranberry and soybeans

. Exposures during aerial, groundboom, and chemigation applications were assessed at maximum application rates of 0.2 to 0.25 lb s ai/A. Combined (dermal + inhalation) risk estimates for groundboom applications ranged from 1,500 to 3,500 for mixer/loaders, and 3,100 to 7,600 for applicators. These exposure calculations we re conducted using a dermal and inhalation LOAEL of 2.1 mg/kg/day (dermal absorption factor of 1% and body weight of 80 kg). The LOC is 300 ( 10X interspecies factor, 10X intraspecies factor, 3 X FQPA safety factor for use of a LOAEL) . These risk estimates are representative of higher application rates than the proposed uses, and are not of concern to HED; therefore, the proposed uses are not of concern to HED.

It is HED policy to use the best available data to assess exposure. Several sources of generic data were used in the assessment as surrogate data in the absence of chemical

- specific data, including Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1) ; the Agricultural Handler Exposure Task Force (AHETF) database; the Outdoor Residential Expo sure Task Force (ORETF) database; the Agricultural Reentry Task Force (ARTF) database; the Residential SOPs (turf/lawns), and a chemical

- specific turf transferable residue study (MRID 47172301 ) and a dislodgeable foliar residue study (MRID 47190101) . Some of these data are proprietary, and subject to the data protection provisions of FIFRA.Mesotrione Human Health Risk Assessment DP # 419616

________________________________________________________________________ ______ ______________

Page 25 of 31 

### 9. 1 REI

The restricted

- entry interval (REI) specified on the proposed label is based on the acute toxicity of mesotrione. M esotrione is classified as Toxicity Category III via the dermal route and Toxicity Category IV for skin and eye irritation potential. It is not a skin sensitizer. Short

- and intermediate

- term post

- application risk estimates were not a concern on day 0 (12 hours following application) for a ll post

- application activities. Under 40 CFR 156.208 (c) (2) (iii), ais classified as Acute III or IV for acute dermal, eye irritation and primary skin irrigation are assigned a 12

- hour REI. Therefore, the [156 subpart K] Worker Protection Statement inte rim REI of 12 hours is adequate to protect agricultural workers from post

- application exposures to mesotrione.

10.0 References

RD Memo, H. Podall ; 24

- FEB

- 2000; D263245 Memo, D. Nixon, 27

- MAR

- 2001 ; TXR# 0051908 Memo, S. Levy, 06

- JUN

- 2001; D245477 Memo, W. Cutchin, 12

- JAN

- 2005; D283827 Memo, S. Levy, 02

- Mar

- 2007; D326898 HASPOC Memo, 17

- DEC

- 2007 Memo, S. Levy et al. , 12

- AUG

- 2009; DP#357890 Memo, A. Dunbar, 27

- JUN

- 2013 ; TXR #0056648 Memo, K. Lowe, 13

- OCT

- 2013; D415329 EFED Memo, I. Maher, 23

- NOV

- 2013; D415369 Memo, T. Bloem, 30

- APR

- 201 5 ; D 420017 Memo, S. Levy, 06

- MAY

- 201 5 ; D420018 Memo, K. Lowe, 06

- MAY

- 2015; D 426691

List of Appendices: Appendix A. Toxicology Profile Appendix B. Physical/Chemical Properties Appendix C. Review of Human Research

cc: S. Levy (RAB1) RDI: RAB1 ( 1 0 / 2 2 /1 4 ) ; Kramer ( 1 0 / 17 /14) S. Levy :S1095 3 :PY

- S:(703)305

- 07 83 :7509P:RAB1Mesotrione Human Health Risk Assessment DP # 419616

________________________________________________________________________ ______ ______________

Page 26 of 31 

### Appendix A

. Toxicology Profile

A.1 Toxicology Data Requirements for Mesotrione

.
Study requirements (40 CFR 158.340) for use of mesotrione are in Table A. 1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Study Technical Required Satisfied 870.1100 Acute Oral Toxicity

................................ ....................... 870.1200 Acute Dermal Toxicity

................................ .................. 870.1300 Acute Inhalation Toxicity

................................ .............. 870.2400 Acute Eye Irritation

................................ ....................... 870.2500 Acute Dermal Irritation

................................ ................. 870.2600 Skin Sensitization

................................ .......................... yes yes yes yes yes yes yes

yes yes yes yes yes 870.3100 90

- Day Oral Toxicity in Rodents

................................ .. 870.3150 90

- Day Oral Toxicity in Nonrodents

............................. 870.3200 21/28

- Day Dermal Toxicity

................................ .......... 870.3250 90

- Day Dermal Toxicity

................................ ............... 870.3465 90

- Day Inhalation Toxicity

................................ ........... yes yes yes

no

no 1 yes

yes yes

--

-- 870.3700a Prenatal Developmental Toxicity (rodent)

.................... 870.3700b Prenatal Developmental Toxicity (nonrodent)

.............. 870.3800 Reproduction and Fertility Effects

................................ yes yes yes yes

no 2

yes 870.4100a Chronic Toxicity (rodent)

................................ .............. 870.4100b Chronic Toxicity (nonrodent)

................................ ........ 870.4200a Carcinogenicity (rat)

................................ ...................... 870.4200b Carcinogenicity (mouse)

................................ ............... 870.4300 Combined Chronic Toxicity/Carcinogenicity

............... yes yes yes yes yes yes

yes yes 3

yes yes 870.5100 Mutagenicity

— Bacterial Reverse Mutation Test

.......... 870.5300 Mutagenicity

— Mammalian Cell Gene Mutation Test

.. . 870.5xxx Mutagenicity

— Structural Chromosomal Aberrations

.. . 870.5xxx Mutagenicity

— Other Genotoxic Effects

....................... yes yes yes yes yes

yes yes yes 870.6200a Acute Neurotoxicity Screening Battery (rat)

................. 870.6200b 90

- Day Neurotoxicity Screening Battery (rat)

.............. 870.6300 Developmental Neurotoxicity

................................ ....... yes yes

no yes

yes

-- 870.7485 Metabolism and Pharmacokinetics

................................ 870.7600 Dermal Penetration

................................ ........................ 870.7800 Immunotoxicity

................................ ............................. yes

no yes yes

-- yes
1 HED HASPOC concluded that the subchronic inhalation study was not required at this time (A. Dunbar, 27

- JUN

2013, TXR#0056648).

2 Study is classified as unacceptable/not upgradable, but the rabbit is not considered the relevant species for human health ri sk assessment therefore this is not considered a data gap at this time.

3 The combined chronic toxicity/carcinogenicity study satisfies the requirement of the study.Mesotrione Human Health Risk Assessment DP # 419616

________________________________________________________________________ ______ ______________

Page 27 of 31 

### A.2 Toxicity Profiles

.

Table A.2.1

. Acute Toxicity Profile

– Mesotrione.

Guideline No. Study Type MRID(s) Results Toxicity Category

870.1100 Acute oral 44373512 LD 50 > 5000 mg/kg IV

870.1200 Acute dermal 44373514 LD 50 > 2000 mg/kg III

870.1300 Acute inhalation 44373516 LC 50 > 4.75 mg/L IV

870.2400 Acute eye irritation 44373518 Mild eye irritant IV

870.2500 Acute dermal irritation 44373520 Not a dermal irritant IV
870.2600 Skin sensitization 44373522 Not a dermal sensitizer

---

Table A.2.2. Subchronic, Chronic, and Other Toxicity Profile

– Mesotrione.

Guideline No. Study Type MRID No. (year)/ Classification/Doses Results

870.3100 90

- Day Oral

Toxicity in Rodents (rat) 44505020 (1997)

Acceptable/guideline 0, 2.5, 5, 7.5, or 150 ppm M: 0, 0.21, 0.41, 0.63, or 12.46 mg/kg/day F: 0, 0.23, 0.47, 0.71, or 12.46 mg/kg/day NOAEL = 0.41/0.47 mg/kg/day (M/F)

.
LOAEL = 0.63/0.71 mg/kg/day (M/F) based upon corneal lesion in males

.

870.3100 90

- Day Oral

Toxicity in Rodents (rat) 44505019 (1995)

Acceptable/guideline 0, 1, 125, 1250, or 12500
ppm M: 0, 0.09, 11, 112, or 1111 mg/kg/day F: 0, 0.10, 13, 126, or 1213 mg/kg/day NOAEL = 0.09/0.10 mg/kg/day (M/F)

.
LOAEL = 11/13 mg/kg/day (M/F) based upon corneal abnormalities in both sexes in males

.

870.3100 90

- Day Oral

Toxicity in Rodents (mouse) 44505022 (1997)

Acceptable/guideline 0, 10, 50, 350, or 7000
ppm M: 0, 1.7, 8.4, 61.5, or 1212 mg/kg/day F: 0, 2.4, 12.4, 80.1, or 1537 mg/kg/day NOAEL = 1212/1537 mg/kg/day (M/F)

.
LOAEL >1212/1537 mg/kg/day (M/F)

. No effects noted

.

870.3150 90

- Day Oral

Toxicity in Non

Rodent (dog) 44505023 (1997)

Acceptable/guideline M & F: 0, 100, 600, or 1000 mg/kg/day NOAEL = 1000 mg/kg/day (M/F)

.
LOAEL >1000 mg/kg/day (M/F)

. No effects noted

.

870.3200 21

- Day Dermal

Toxicity (rabbit) 44505024 (1997)

Acceptable/guideline M & F: 0, 10, 500

, or 1000 mg/kg/day NOAEL = 1000 mg/kg/day (M/F)

.
LOAEL >1000 mg/kg/day (M/F)

. No systemic effects noted

.Mesotrione Human Health Risk Assessment DP # 419616

________________________________________________________________________ ______ ______________

Page 28 of 31 Table A.2.2. Subchronic, Chronic, and Other Toxicity Profile

– Mesotrione.

Guideline No. Study Type MRID No. (year)/ Classification/Doses Results

870.3700a Prenatal

Developmental in Rodent (rat) 44920801 (1999)

Acceptable/guideline F: 0, 100, 300, or 1000 mg/kg/day Maternal NOAEL = 100 mg/kg/day

. LOAEL = 300 mg/kg/day based upon decreased body weight gain and food consumption

.
Developmental NOAEL not established

. LOAEL = 100 mg/kg/day based upon delays in skeletal ossification and changes in manus/pes ossification assessments

.

870.3700a Prenatal

Developmental in Rodent (mouse) 44920802 (1997),

44901708 (1999) Acceptable/guideline F: 0, 10, 60, 150, or 600 mg/kg/day Maternal NOAEL = 600 mg/kg/day

. LOAEL >600 mg/kg/day; No effects noted

.
Developmental NOAEL = 150 mg/kg/day

. LOAEL = 600 mg/kg/day based upon decreased ossification of the cervical vertebrae centra

.

870.3700b Prenatal

Developmental in Non

- Rodent (rabbit) 44901707 (1999),

44505032 (1999) Unacceptable/not upgradable F: 0, 100, 250, or 500 mg/kg/day Maternal: NOAEL = 100 mg/kg/day

. LOAEL = 250 mg/kg/day based upon late abortions and clinical signs of toxicity

.
Developmental: NOAEL not established

. LOAEL = 100 mg/kg/day based upon delayed ossification of the 7 th cervical transverse process

a nd odontoid and increases in extra full 13 th rib and 27 pre

- sacral vertebra

.
Study classified as unacceptable because a developmental NOAEL was not established, dosing was initiated in several groups prior to completion of implantation, and insufficient n umber of females mated.

870.3800 Reproduction and

Fertility Effects (rat) 44505033 (1997)

Acceptable/guideline 0, 2.5, 10, 100

, or 2500
ppm M: 0, 0.3, 1.1, 11.7, or 287.7 mg/kg/day F: 0, 0.3, 1.2, 12.4, or 311.4 mg/kg/day Parental/Systemic: NOAEL not established

. LOAEL = 0.3 mg/kg/day (M/F) based upon significantly increased plasma tyrosine levels and increased liver weights in F 2 males

.
Offspring/Systemic: NOAEL not established

. LOAEL = 0.3 mg/kg/day (M/F) based upon significantly increased plasma t yrosine levels in F 2 male pups

.
Reproductive: NOAEL = 0.3 mg/kg/day

. LOAEL = 1.1/1.2 mg/kg/day (M/F) based upon decreased F 2 mean litter size

.

870.3800 Reproduction and

Fertility Effects (mouse) 44505034 (1997)

Acceptable/guideline 0, 10, 50, 350, 1500 or 7000 ppm M: 0, 2.1, 10.1, 71.4, 306.7

, or 1455.5 mg/kg/day F: 0, 2.4, 11.7, 82.5, 362.7

, or 1652.3 mg/kg/day Parental/Systemic: NOAEL = 10.1/11.7 (M/F)

. LOAEL = 71.4/82.5 mg/kg/day (M/F) based upon increased kidney weights and tyrosinemia in the F 1 males

.
Offspring/Systemic: NOAEL not established

. LOAEL = 2.1/2.4 mg/kg/day (M/F) based upon tyrosinemia and ocular discharge in the F 1 and F 2 offspring

.
Reproductive: NOAEL = 1455.5/1652.3 mg/kg/day (M/F ). LOAEL >1455.5/1652.3 mg/kg/day (M/F).Mesotrione Human Health Risk Assessment DP # 419616

________________________________________________________________________ ______ ______________

Page 29 of 31 Table A.2.2. Subchronic, Chronic, and Other Toxicity Profile

– Mesotrione.

Guideline No. Study Type MRID No. (year)/ Classification/Doses Results

870.4100a Chronic Toxicity

(mouse) 44505026 (1997)

Acceptable/guideline 0, 10, 50, 350

, or 7000
ppm M: 0, 1.5, 7.8, 56.2

, or 1114 mg/kg/day F: 0, 2.1, 10.3, 72.4

, or 1494.5 mg/kg/day NOAEL = 56.2/72.4 mg/kg/day (M/F)

.
LOAEL = 1114/1494.5 mg/kg/day (M/F) based upon decreases in body weight gain and food utilization in males

.

870.4100b Chronic Toxicity

(dog) 44505027 (1997)

Acceptable/guideline M & F: 0, 10, 100

, or 600 mg/kg/day NOAEL was not established

.
LOAEL = 10 mg/kg/day based upon evidence of tyrosinemia in both sexes and increased incidence of erythrophagocytosis in the mesenteric lymph nodes of females

.

870.4200a Carcinogenicity (rat) See 870.4300 See 870.4300

870.4200b Carcinogenicity

(mouse) 44505028 (1997)

Acceptable/guideline 0, 10, 350 or 7000 ppm M: 0, 1.4, 49.7

, or 898 mg/kg/day F: 0, 1.8, 63.5

, or 1103 mg/kg/day NOAEL = 49.7/63.5 mg/kg/day (M/F)

.
LOAEL = 898/1103 mg/kg/day (M/F) based upon decreased body weight, body weight gain, and food efficiency in males

.

No evidence of carcinogenicity

.

870.4300 Combined Chronic

Toxicity/Carcinogen icity (rat) 44505035 (1997),

44505036 (1998) Acceptable/guideline 0, [1.0, 2.5], 7.5, 100 or 2500 ppm M: 0, [0.06, 0.16], 0.48, 6.48

, or 159.9 mg/kg/day F: 0, [0.08, 0.19], 0.57, 7.68, or 189.5 mg/kg/day NOAEL = 0.16/0.19 mg/kg/day (M/F) ( t he NOAEL only applies to ocular lesions; a NOAEL was not determined for kidney and liver weights or hepatocyte fat vacuolation in males)

.
LOAEL = 0.48/0.57 mg/kg/day (M/F) based upon ocular lesi ons, increases in kidney and liver weights, and hepatocyte fat vacuolation in males

.
No evidence of carcinogenicity

.

870.5100 Bacterial reverse

mutation 44373526 (1993)

Acceptable/guideline There was no evidence of induced mutant colonies over background

.

870.5300 In vitro mammalian

cell gene mutation 44373525 (1994)

Acceptable/guideline There were no treatment

- related increases in mutant frequency in the presence or absence of S9 activation

.

870.5375 In vitro mammalian

cytogenetics assay 44373524 (1994)

Acceptable/guideline Not clastogenic with S9 activation and equivocal for clastogenic activity without S9 activation

.

870.5395 Bone marrow

micronucleus (mouse) 44373527 (1994)

Acceptable/guideline There was no significant increase in the frequency of micronucleated polychromatic erythrocytes in bone marrow after any treatment time.

870.6200a Acute Neurotoxicity

Screening Battery (rat) 44505017 (1997),

44505018 (1997) Acceptable/guideline M & F: 0, 20, 200

, or 2000 mg/kg/day NOAEL = 2000 mg/kg/day (M/F)

.
LOAEL >2000 mg/kg/day (M/F)

. No effects noted

.Mesotrione Human Health Risk Assessment DP # 419616

________________________________________________________________________ ______ ______________

Page 30 of 31 Table A.2.2. Subchronic, Chronic, and Other Toxicity Profile

– Mesotrione.

Guideline No. Study Type MRID No. (year)/ Classification/Doses Results

870.6200b Subchronic

Neurotoxicity Screening Battery (rat) 44505025 (1997)

Acceptable/guideline M: 0, 0.2, 8.25

, or 403 mg/kg/day F: 0, 0.23, 9.29

, or 467 mg/kg/day NOAEL = 0.20/0.23 mg/kg/day (M/F)

.
LOAEL = 8.25/9.29 mg/kg/day (M/F) based upon corneal opacities and/or vascularization of the cornea of the eye in males

.

870.7485 Metabolism and

Pharmacokinetics 44505101 (1995)

44505102 (1996) 44505103 (1996) 44505104 (1996) 44505105 (1996) 44505106 (1996) Acceptable/guideline 1 or 100 mg/kg single oral dose 1 mg/kg single iv dose 1 mg/kg repeated dose 50 mg/kg single oral dose Radiolabeled mesotrione was readily absorbed and distributed throughout the body after single and repeated doses. Concentrations of radioactivity were highest in the liver and kidney. Majority of labeled mesotrione was excreted via the urine and feces. The major component in urine and feces was unchanged parent. Biliary excretion was more prominent for males than females. Increasing the dose or repeated doses had little effect on the pattern of excretion.

870.7600 Dermal Absorption

In vivo rat 46951723 (2004)

Acceptable/guideline 4.8 μg/cm 2 or 4781 μg/cm 2 10 hrs of exposure Sacrifice at 10, 24

, and 48 hr Mean dermal absorption values ranged from 0.12

- 0.52% for the high dose and from 0.31

- 1.83 for the low dose. With the exception of the 10

- hour duration, amount absorbed decreased with increased dose indicating skin is approaching saturation of penetration at higher doses. For the low dose, percent of dose remaining in/on skin decreased while percent absorbed increased with time after the 10 hour , 24 and 48 hour washes indicating that some of the material remaining in/on the skin continued to be absorbed post

- wash.

870.7600 Dermal Absorption

In vitro rat 46951721 (2004)

Acceptable/non

- guideline 4.86 μg/cm 2 or 4818 μg/cm 2 10 or 24 hrs of exposure Mean amount of applied dose remaining in the rat epidermis for the 10

- hour exposure was 0.36% for the high dose and 17.6% for the low dose. For the 24

- hour exposure period, mean percent of applied dose remaining in the epidermis was 0.32% for the high dose and 20.9% for the low dose.

870.7600 Dermal Absorption

In vitro human 46951722 (2004)

Acceptable/non

- guideline 4.86 μg/cm 2 or 4818 μg/cm 2 10 or 24 hrs of exposure Mean amount of applied dose remaining in the stratum corneum was 0.09% for the high dose and 0.29% for the low dose for the both exposure periods. Mean amount in the remaining epidermis for the 10 hour exposure was 1.71% for the low dose and 0.06% for the high dose. For the 24

- hour exposure, mean percent of dose in the epidermis was 1.83% for the low dose and 0.02% for the high dose.

870.7800 Immunotoxicity 48748301 (2012) Acceptable/guideline 0, 110, 332

, or 1168 mg/kg/day NOAEL = 5000 ppm

.

LOAEL not established

.Mesotrione Human Health Risk Assessment DP # 419616

________________________________________________________________________ ______ ______________

Page 31 of 31 

### Appendix B. Physical/Chemical Properties

Table B.1.Physicochemical Properties of the Technical Grade Test Compound Mesotrione. Melting range 148.7

- 152.5°C

RD Memo; H. Podall, 24

- Feb

- 2000 ; D263245 pH (25°C) 3.4 (1% dispersion in water) Density (20°C) 1.46 g/mL

Water solubility (20°C) 160 ppm, unbuffered water 0.22 g/100 mL, pH 4.8 1.5 g/100 mL, pH 6.9 2.2 g/100 mL, pH 9

Solvent solubility (20°C) 0.37 g/100 mL, methanol 1.7 g/100 mL, ethyl acetate 0.27 g/100 mL, toluene 10.4 g/100 mL, acetonitrile <0.03 g/100 mL, heptane 8.1 g/100 mL, acetone Vapor pressure (20°C) 4.3 x 10

- 8 torr Dissociation constant, pK a (20°C) 3.12
Octanol/water partition coefficient, Log(K OW ) (20°C) log K OW = 0.11 in unbuffered water log K OW = 0.90 in pH 5 buffer log K OW <

- 1 at pH 7 and 9 buffered water
UV/visible absorption spectrum Absorption maximum in methanol at 256 mu, with a molar extinction coefficient of 2.24 x 104 M cm.



### Appendix C. Review of Human Research

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 the PHED 1.1, the AHETF database, and the ARTF database are (1) subj ect to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable ethics requirements. For certain studies, the ethics review may have included review by the Human Studies Review Board. Descriptions of data sources, as well as guidance on their use, can be found at the Agency website 1



### .

1 http://www.epa.gov/pesticides/science/handler

- exposure

- data.html and http://www.epa.gov/pestici des/science/post

- app

- exposure

- data.html