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



### MEMORANDUM

Date: 04 -JUN-2 014 OFFICE OF
CHEMICAL SAFETY AND
POLL UTION PREVE NTION



### SUBJECT: Mesotrione. Human-Health Assessment Scoping Document in Support of Regis trat ion Review.

PC Code: 122990 DP Barcode: D417231
Decision No.: 486616 Registration No.: N/ A

P etition No.: N/A Regulatory Action: Regis tration Review Scoping Document
Risk Assessment Type: N/ A Case No.: 7256

TXR N o.: N/A CAS No.: 104206-82 -8

MRIDNo.: N/A 40CFR :**§180 571~** **·**



### FROM: Sarah J. 

### Levy, Chemist

# ;~ 

# q

Kelly M. Lowe, E nvironmental

## Scie~tis Monique Perron

, S.D., Toxico l ogist 

## 171,;

.. ", 

# ..;J**~** Risk Assessment Branch 1 (RABI) 1 

# ....,,0

Health Effects Division (HED, 7509P)

TO: Jolene Trujillo
Pesticide Re-Evaluation Division (PRD) (7508P)

Attached is HED's human-health risk assessment scoping document for mesotrione to support Registra t i on Rev iew.

Page 1 of25

### __ ____**so rio** **n~** 

### Registration Review Huf!!an-Health Assessment Scoping Document



### Table of Contents



### Execut i ve Summary

........................... .... ............................... ......... ................................................. 3

1.0 Introduction

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

2

.

0 Hazard Characterization/ Assessment.

...................................................................................... 5

3.0 Residue Chemistry

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

4.0 Dietary Exposure

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

5.0 Residential Exposure

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

6.0 Aggregate-Risk Assessment

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

7.0 Occupational Exposure

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

8.0 Public Health and Pesticide Epidemiolo gy Data

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

9.0 To l erance Assessment and In ternat i onal Harmonization

...................................................... 11

10.0 Environme n tal J ustice

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

11.0 Cumulative

........................................................................................................................... 12

12.0 Human Studies

.............. . .. ......... ........................................................................................... 12

13.0 Risk-Assessment Updates> Data Deficiencies, and Label Revisions

....... . ........................... 1 3

14.0 References............................................................................................................................ 13

Attachment 1: Chemical Identity Tables

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

Attachment 2: Mesotrione Acute, Subchronic > and Chronic To xicity Profile

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

Attachment 4: Summary of Registered Uses

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

Attachment 5: Mesotrione IRLS Sheet.

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

Page 2 of25Mesotrione Registration Review Human

- Health Assessment Scoping Document

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Page 3 of 25 

### Executive Summary

HED has prepared a scoping document to support Registration Review of mesotrione (2

- [4

- (methylsulfonyl)

- 2

- nitrobenzoyl]

- 1,3

- cyclohexanedione)

. Mesotrione is a triketone herbicide that 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
selective control of annual broadleaf weeds. The most recent quantitative human

- health risk assessment was performed in 2009, and was for the use of mesotrione on soybeans ( Memo, S. Levy et al. , 12

- AUG

- 2009; D357890 )

. HED notes that a qualitative assess ment was conducted for a new use on corn in 2010 (Memo, S. Levy et al. , 20

- JAN

- 2010; D372995). There is currently one pending PRIA action for mesotrione for a new use on mesotrione

- tolerant soybeans.

Mesotrione is formulated as liquid

, granular , and dry

- flowable formulations

, and is currently registered for us e on a variety of crops, with tolerances ranging from 0.01 ppm to 1.5 ppm (40 CFR §180.571 (a)). Mesotrione is also registered for use on turf, including athletic fields, recreational areas, res idential lawns (spot treatments only for liquids), and golf courses. The current registrations include some Special Local Need (SLN) registrations, which include applications to additional use sites (e.g., wildflowers and cuphea).

HED has evaluated the s tatus of the human

- health risk assessments for mesotrione to determine whether sufficient data are available and whether any updates are needed to support Registration
Review. HED has considered all available data and human

- health risk assessments for

mes otrione with respect to its toxicity, exposure, and usage databases, and the most updated Agency science policy and r isk assessment methodologies to determine the scope of work
necessary to support Registration Review.

The toxicity database for mesotrione is complete as required by the 2007 revised 40 CFR Toxicology Data Requirements

. No additional toxicological studies are currently required

. In subchronic and chronic oral studies in the rat, mouse, and dog, mesotrione produced ocular, kidney, and liver effects, which are consistent with the mammalian toxicity profile for HPPD inhibitors caused by high tyrosine levels in the blood

. Body weight decrements were also noted in mice and rats in multiple studies

. Increased susceptibility was seen in developm ental and reproduction toxicity studies with offspring effects observed at doses below maternal/parental toxicity

. As part of Registration Review , the endpoints, doses, and safety factors used in the

most recent human

- health risk assessment will be re

- eva luated according to current HED policy.

The residue chemistry database is adequate to support current Registration Review requirements. Adequate metabolism (crops, livestock, and rotational crops), storage stability, magnitude of the residue, and processing data are available to support the reg istered uses. Adequate methods are available for enforcement of the currently established tolerances.

The dietary

- exposure database is adequate to support current registration requirements. The last risk assessment provided unrefined chronic dietary ( food + drinking water) exposure estimates that are below HED’s level of concern (LOC) for the general U.S. population and all population subgroups (Memo, S. Levy, 05

- AUG

- 2009; D358158); all infants <1 year old were the most highly exposed population (5.8% cPAD). Based on toxicological considerations, assessment of acute dietary exposure is unnecessary. As part of Registration Review, a revised dietary exposure analysis may be required to reflect the most recent dietary exposure models, potentialMesotrione Registration Review Human

- Health Assessment Scoping Document

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Page 4 of 25 

### revised e stimated drinking water concentrations (EDWCs) , and/or changes to the toxicological points of departure (PODs)

.

There is sufficient information available to assess occupational and residential exposure and risk from the registered uses. Residential handl er and post

- application exposure assessments were recently completed based upon HED’s 2012 Residential Standard Operating Procedures (SOPs) and did not identify risk estimates of concern. However, a higher application rate for handheld equipment was ident ified during the label review process for the scoping document . T his higher rate will need to be assessed for residential handlers during Registration Review. The residential
post

- application assessment will not be affected and will not need to be update d, unless policies or toxicological PODs change. The most recent occupational handler and post

- application exposure assessments are reflective of current exposure policies and data, and did not identify risk estimates of concern. These assessments are pr otective of most registered uses, except for uses on sod farms and a SLN use on cuphea (an ornamental). During Registration Review, updated occupational assessments will be conducted to reflect all currently registered uses. In addition, assessments for all uses may be updated if toxicological PODs are revised.

A new aggregate human

- health risk assessment may be required during Registration Review to incorporate revised dietary exposure analyses and/or revised residential exposure assessments.

No data deficiencies were identified for mesotrione. EPA anticipates conducting the following
risk

- assessment updates during Registration Review:

 Toxicology:

o Reevaluate toxicity endpoint/dose selection, along with the Food Quality Protection Act Safety Factor (FQPA SF) based on current HED policy.

 Residue Chemistry:

o None.

 Dietary Exposure:

o A revised dietary

- exposure analysis may be required to reflect the most recent dietary

- exposure models, potential revised EDWCs, and/or changes to the toxicologica l PODs.

 Aggregate Exposure:

o New aggregate risk assessment may be required during Registration Review to incorporate revised dietary exposure analyses

, revised residential exposure

assessments , and/or changes to the toxicological PODs

.

 Occupational/Resident ial Exposure:

o Revised occupational and residential handler assessments will be necessary to reflect maximum application rates.

o Revised occupational post

- application assessments will be necessary to reflect all currently registered uses (including SLN re gistrations).

o Assessments for all residential and occupational uses may be updated if toxicological PODs are revised.

1.0 Introduction

Mesotrione is a triketone herbicide that inhibits the enzyme HPPD, disrupting carotenoid biosynthesis. It is formul ated as liquid, granular, and dry

- flowable formulations, and is currently registered for use on a variety of crops as well as for use on turf, including athletic fields, recreational areas, residential lawns, and golf courses. The current registrations in clude someMesotrione Registration Review Human

- Health Assessment Scoping Document

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### SLN registrations, which include applications to additional use sites (e.g., wildflowers and cuphea). The most recent human

- health risk assessment was performed in 2009 and was for the
use of mesotrione on soybeans ( Memo, S. Levy et al.

, 12

- AUG

- 2009; D357890 ). There is currently one pending PRIA action for mesotrione for a new use on mesotrione

- tolerant soybeans.

2.0 Hazard Characterization/Assessment

Mesotrione acts by inhibiting the HPPD enzyme, which results in decreased carotenoid synthesis and bleaching of target plants. 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, since the formation of HPPA by TAT is reversible,
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.

In a series of rat metabolism studies, 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 with radioactivity also detected in the carcass, GI tract, spleen, bone, and blood. The majority of labele d mesotrione was excreted (predominantly as unchanged parent) via the urine and feces. Biliary excretion was more prominent for males than females. Increasing the dose or repeated doses had little effect on the pattern of excretion.

In subchronic and ch ronic oral studies in the rat, mouse, and dog, mesotrione produced ocular, kidney, and liver effects, which are consistent with the mammalian toxicity profile for HPPD inhibitors caused by high tyrosine levels in the blood. Body

- weight decrements were als o 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 for tyrosine

- mediated toxicological effects (D. Nixon, 27

- MAR

- 2001, TXR# 0051908 ).

There was evidence of increased susceptibility of rats, mice, and rabbits in the developmental studies and mice in the reproduction toxicity study. Offspring effects in the developmental toxicity studies (delayed ossification and ancillary ribs and vertebrae) were seen at doses below those for maternal toxicity (decreased body

- weight gain and food consumption in rats and abortions and clinical signs of toxicity in rabbits; no effects seen in mice). In the mouse reproduction toxicity study, tyrosinemia and ocular discharge were observed in offspring at doses below those for parental toxicity, which was evidenced by increased kidney weights and tyrosi nemia. In the rat reproduction study, offspring susceptibility was not observed. Tyrosinemia was observed in parents and offspring at the same dose level.

Mesotrione 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 irritant.

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

- Health Assessment Scoping Document

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Page 6 of 25 

### There was no evidence of carcinogenic potential in either the rat or mouse carcinogenicity studies and no concern for mutagenicity. Mesotrione is classified as “not likely to be carcinogenic to humans .”

An immunotoxicity study submitted since the last risk assess ment (MRID #48748301) showed no evidence of immunotoxicity.

HED previously requested a subchronic inhalation study to characterize the effects of mesotrione
via the inhalation 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 was not required at this time ( A. Dunbar, 27

- JUN

- 2013; TXR # 0056648 ). The endpoints
and PODs from the last quantitative human

- health risk assessment for mesotrione (S. Levy, 12

- AUG

- 2009 ; D357890 ) can be found in Attachment 3

.

Conclusions : The toxicity database for mesotrione is complete as required by the 2007 revised 40 CFR Toxicology Data Requirements. No additional toxicological studies are currently required. As part of registration review, the endpoints, doses, and safety factors used in the most
recent risk assessment will be re

- evaluated according to current HED policy.

3.0 Residue Chemistry

Permanent tolerances are established for residues of mesotrione , including its metabolites and degradates in/on a variety of crops, with tolerances ranging from 0.01 ppm to 1.5 ppm (40 CFR §180.571 (a)). There are currently no tolerances established for mesotrione in/on livestock
commodities or for indirect/inadvertent residues in rotational crops.

The HED Metabolism Assessment Review Committee (MARC) reviewed and discussed field
corn, peanut, cranberry ( cyclohexane

- 2

- 14 

### C label only)

, livestock, rotational crop, and drinking
water studies for the he rbicide mesotrione, as well as toxicological and environmental fate data, for determination of the residues of concern (Memo, S. Levy, et al. , 26

- APR

- 2001; D274111). Subsequent to this decision, registration for application of mesotrione to asparagus,

cra nberry (Section 18), berry crop group (group 13), lingonberry, flax, grass grown for seed, oats, okra, rhubarb, sorghum (grain and sweet), and sugarcane were approved by HED. HED concluded that for these crops, the residue of concern for risk assessment a nd tolerance enforcement is mesotrione (Memo, S. Levy, 05

- DEC

- 2007; D335364).

The nature of the residue in ruminants and poultry has been adequately defined based on previously reviewed cattle and hen studies. HED previously concluded that the residue of concern in livestock commodities is mesotrione (HED MARC, 26

- SEP

- 2001). In the last risk assessment for soybeans, HED noted that there was no reasonable expectation of quantifiable mesotrione residues of concern in eggs, milk, and the meat, fat, or mea t byproducts of poultry and ruminants [40 CFR Category 180.6(a)(3)] as a result of any registered use.

An acceptable high

- performance liquid chromatography (HPLC) method with tandem mass

spectrometry detection (MS/MS), Method RAM 366/01

, is available to analyze residues of mesotrione and metabolite ( 4

- methanesulfonyl

- 2

- nitro

- benzoic acid (MNBA)

. This method was previously reviewed and has been forwarded to the U.S. Food and Drug Administration (FDA) for inclusion in the Pesticide Analyti cal Manual (PAM) Volume II as a confirmatory method. The method was adequately validated in conjunction with the analysis of several field trial and processing study samples. Based on the lowest level of method validation (LLMV), the limit ofMesotrione Registration Review Human

- Health Assessment Scoping Document

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Page 7 of 25 

### quantitatio n (LOQ) was 0.01 ppm for each analyte in all soybean and corn commodities. It was previously determined that multiresidue method s (MRM s ) are not adequate for tolerance
enforcement.

Adequate field trial and processing data are available to support the use of mesotrione on the registered crops . An adequate number of trials w ere conducted in the appropriate geographical regions using the appropriate formulation applied at the maximum use rate. These studies are also supported by adequate storage stability data.

Adequate confined and field rotational crop data are available. HED previously concluded that the residue of concern in rotated crops is mesotrione. Based on the currently registered uses and PBIs, residues in rotational crops are expected to be insignificant.

Conclusions : The residue chemistry database is adequate to support current Registration Review data requirements. Adequate metabolism (crops, livestock, and rotational crops), storage stability, magnitude of the residue, and processing data are available to support the registered uses. Adequate methods are available for enforcement of the currently established tolerances.

4.0 Dietary Exposure

The HED MARC concluded that the residue of concern in drinking water is mesotrione (Memo, S. Levy, APR

- 2001; D274111). All metabolites identified were present at low levels, and are not expected to be more toxic than the parent.

No toxic effects attrib utable to a single exposure to mesotrione have been identified; therefore, an acute reference dose (aRfD) was not established for mesotrione , and an acute dietary exposure assessment was not required. HED ha s previously conducted a chronic dietary exposur e analysis, which considered all currently registered uses (Memo, S. Levy, 05

- AUG

- 2009; D358158). The analysis was conducted using the Dietary Exposure Evaluation Model

– Food Consumption Intake Database (DEEM

- FCID, ver. 2.03), which incorporates the food consumption data from the United States Department of Agriculture (USDA) Continuing Surveys of Food Intakes by Individuals (CSFII; 1994

- 1996 and 1998) and assumed tolerance

level residues and 100% crop treated.

Dietary risk estimates were determined by considering exposures from both food and EDWCs. These EDWC values were provided in a 2008 memo from the Environmental Fate and Effects Division (EFED; Memo, K. Moore, 25

- NOV

- 2008; D354510). EDWCs resulting from an experimental use permit ( EUP ) soybean a pplication scenario w as used as it resulted in greater
EDWC values than from any other use s (i.e., more conservative). The EUP soybean application use rate is also the highest registered or proposed u se rate for mesotrione.

Mesotrione EDWCs in groundwa ter were estimated using the Tier 1 model SCI

- GROW (Screening Concentration in Ground Water). EDWCs in surface water were estimated using the linked Tier 2 models Pesticide Root Zone Model (PRZM v3.12beta, 24

- MAY

- 2001) and Exposure Analysis Modeling Syste m (EXAMS v2.98.04, 18

- AUG

- 2002), coupled with the input shell pe5.pl (16

- NOV

- 2006). The surface water EDWC of 5.1 ppb (greater than the groundwater number) was incorporated in the DEEM

- FCID into the food categories “water, indirect, all sources,” and “wat er, direct, all sources.” In the 20 09 assessment , dietary exposure was estimated at 0.000140 mg/kg/day for the U.S. population (2.0% of the cPAD) and 0.000403Mesotrione Registration Review Human

- Health Assessment Scoping Document

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Page 8 of 25 

### mg/kg/day (5.8% of the cPAD) for the most highly exposed population subgroup (all infants, <1

ye ar old)

Conclusions : The dietary

- exposure database is adequate to support current registration requirements. In the most recent risk assessment, chronic dietary exposures were not of concern to HED. However, as part of Registration Review, a revised dietary exposure analysis may be required to reflect the most recent dietary exposure models, potential revised EDWCs, and/or changes to the toxicological PODs.

5.0 Residential Exposure

Mesotrione is currently registered for use on turf, including athletic fields, recreational areas, residential lawns (spot treatments only for liquids), and golf courses. Both liquid and granular formulations are registered. Attachment 4 includes a summary of the use sites for mesotrione, including those related to residential areas. Residenti al exposures from the registered residential uses have been assessed in the most recent occupational and residential exposure (ORE) assessment for mesotrione (Memo, K. Lowe, 23

- OCT

- 2013; D415329).

For residential handlers, the following scenarios were a ssessed:

 M ixer /loader/applicator (M/L/A) of liquids with manually

- pressurized handwand,

 M/L/A of liquids with sprinkler can,

 M/L/A of liquids with backpack sprayer, and

 L/A of granulars with push

- type spreader.

For residential post

- application exposu re, the following scenarios were assessed:

 Dermal exposure for adults and children from high

- contact lawn activities, mowing, and golfing; and

 Incidental oral post

- application exposure for children (1 to <2 years old) from high

contact lawn activities.

A chemical

- specific turf transferable residue (TTR) study was submitted for mesotrione and used in the residential assessment. None of the residential handler or post

- application scenarios assessed resulted in risk estimates of concern (i.e., all margins of exposure (MOEs) ≥ the LOC of 300). Based on a review of the registered labels for mesotrione for this scoping document, a slightly higher rate for application of liquid formulations to turf was identified for handheld equipment. This higher rate will need to be assessed for residential handlers during Registration Review. The post

- application assessment will not be affected and will not need to be updated, unless policies or toxicological PODs change.

Spray Drift/Bystander Exposure Residential expos ures resulting from off

- site transport (e.g., spray drift or volatilization) may occur as a result of applications of mesotrione

. In the most recent ORE assessment (Memo, K. Lowe, 23

- OCT

- 2013; D415329), potential exposures from spray drift were evaluated, and it was determined that a quantitative spray drift assessment for mesotrione was not required because the maximum application rate for a crop/target site multiplied by the adjustment factor for drift was less than the maximum direct spray residential t urf application rate

. Therefore, the turf post

application MOEs are protective for any potential exposures related to spray drift for the currently registered uses of mesotrione. The Agency is in the process of evaluating bystanderMesotrione Registration Review Human

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Page 9 of 25 

### exposures resulting fr om volatilization, and the need for volatilization risk assessment for mesotrione will be examined during registration review

.

Conclusions : The residential exposure database is adequate to support the Registration Review process for mesotrione. Residential handler and post

- application exposure assessments were recently completed based upon HED’s Residential SOPs; however, a higher applicatio n rate for handheld equipment was identified during the label review process. This higher rate will need to be assessed. The post

- application assessment and spray drift assessment will not be affected and will not need to be updated, unless policies or t oxicological PODs change.

6.0 Aggregate

- Risk Assessment

The most recent aggregate

- risk assessment was performed in conjunction with the 20 09 HED
human

- health risk assessment ( Memo, S. Levy et al. , 1 2

- AUG

- 20 09 ; D3 57890 ). Since an acute dietary endpoint was not identified, an acute aggregate assessment was not performed. Separate
short

- term and intermediate

- term aggregate assessment s w ere conducted for mesotrione. T he
short

- and intermediate

- term aggregate risks were made up of dietary and non

- dietary (residential
turf use) sources of exposure

, and were not of concern to HED. Chronic (long

- term) aggregate risk is made up only of dietary sources; therefore, the chronic dietary exposure estimates represents chronic aggr egate exposure, and were not of concern to HED. Aggregate cancer risk
was not calculated because mesotrione was classified as “not likely to be carcinogenic to
humans.”

Conclusions : A n ew aggregate risk assessment may be required during Registration Review to incorporate revised dietary exposure analyses and/or revised residential exposure assessments

.

7 .0 Occupational Exposure

Occupational handler and post

- application exposures are expected based on the registered agricultural uses of mesotrione. Attachment 4 provides a summary of the occupational use
pattern. The current registrations include some SLN registrations, which include applications to additional use sites (e.g., wildflowers and cuphea) and/or differen t application methods than those currently on registered labels (e.g., aerial application to corn for dry flowable formulations). Current formulations include liquid, granular, and dry flowable products. The application rates range from 0.078

– 0.25 lb a i/A, and applications can be made pre

- plant, pre

emergence, or early post

- emergence.

Occupational Handlers There is the potential for dermal and inhalation exposure to occupational handlers from the currently registered use pattern of mesotrione. In th e most recent exposure assessment for mesotrione (Memo, K. Lowe, 23

- OCT

- 2013, D415329), assessments were conducted for mixers/loaders, applicators and flaggers for aerial, groundboom and chemigation applications of a liquid formulation. The assessment was based on the latest HED exposure policies and data, maximum application rates (~ 0.25 lb ai/A), and maximum area treated per day or gallons handled for the proposed uses. Handler' exposure and risk s were calculated at baseline (long pants, a long

- sleeved shirt, no chemical

- resistant gloves, and no respirator) and with personal

protective equipment (PPE) when necessary (e.g., chemical

- resistant gloves, respirators, and engineering controls).Mesotrione Registration Review Human

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Page 10 of 25 

### Dermal and inhalation risk estimates were not of concern (i.e. , MOEs ≥ 300) with the use of
chemical

- resistant gloves as specified on the proposed labels for the action. Based on a review of the registered labels for mesotrione for this scoping document, it appears that this recent
assessment covers most of the occu pational handler scenarios anticipated for the registered uses of mesotrione; however, there were a couple of use patterns identified that will need to be assessed during Registration Review:

1) For turf (including golf courses, residential lawns, athletic fields, and non

- residential turf areas), there is a higher rate that was identified for handheld equipment that has not been
assessed. 2) There are SLN registrations for corn that allow for aerial applications of dry flowable
formulations. This scenario h as not been assessed previously. 3) There is a SLN registration for applications to cuphea (an ornamental) that has not been assessed previously. 4) There is a SLN registration for applications to wildflowers that has not been assessed previously.

Occupational Post

- Application There may be the potential for post

- application dermal exposure to workers following applications of mesotrione to agricultural crops and commercial use sites. In the most recent exposure assessment for mesotrione (Memo, K. Lowe, 23

- OCT

- 2 013, D415329), occupational
post

- application assessments were conducted for the proposed crops for early

- season activities since most applications are made early post

- emergence. The assessment was based on the latest HED exposure policies and data and max imum application rates (~ 0.25 lb ai/A). A pilot dislodgeable foliar residue (DFR) study was submitted for mesotrione which was deemed acceptable for use in risk assessment. Using chemical

- specific residue data, no risk estimates of
concern were identifi ed for mesotrione (i.e., all MOEs ≥ 300) on the day of application.

Based on a review of the registered labels for mesotrione for this scoping document, it appears that this recent assessment covers the occupational post

- application scenarios anticipated for most of the registered uses; however, there were a couple of use patterns identified that will need to be assessed during Registration Review: 1) For sod farms, there are post

- application activities (e.g., maintenance activities, harvesting of sod, and transplanting/planting sod) that have a higher exposure potential than what has been assessed previously. 2) For the SLN on cuphea (ornamentals), a post

- application assessment for nursery crops
will need to be conducted.

Conclusions : The occupational exposure database is adequate to support the Registration Review process for mesotrione. The most recent occupational handler and post

- application exposure assessment is reflective of current exposure policies and data, and did not ident ify risks of concern. This assessment is protective of most registered uses, except for uses on sod farms and a SLN use on cuphea (an ornamental). During Registration Review, updated occupational assessments will be conducted to reflect all currently reg istered uses. In addition, assessments for all uses may be updated if toxicological PODs are revised.

8.0 Public Health and Pesticide Epidemiology Data

The OPP Incident Data System (IDS) and the Centers for Disease Control and Prevention/National Institute for Occupational Safety and Health (CDC/NIOSH) Sentinel EventMesotrione Registration Review Human

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Page 11 of 25 

### Notification System for Occupational Risk

- Pesticides (SENSOR) databases were consulted fo r pesticide incident data on the active ingredient mesotrione (PC code: 122990). The purpose of the database search was to identify potential patterns in the frequency and severity of the health effects attributed or potentially attributed to mesotrione e xposure. Mesotrione is not included in the Agricultural Health Study (AHS).

For the Main IDS (which contains incidents resulting in higher severity outcomes and provides more detail with regard to case specifics), there were two incidents reported for th e single chemical active ingredient mesotrione in the database from January 1, 200 9 to January 1 5

, 201 4

. The s e two incident s were reported as moderate severity . There were 13 additional incidents reported involving more than one chemical. One incident w as classified as major severity and 12 incidents were classified as moderate severity

. In Aggregate IDS (which contains incidents resulting in less severe human incidents (minor, unknown, or no effects outcomes)), there were 20 reported incidents involvin g mesotrione from January 1, 200 9 to January 15 , 201 4 . These incidents were all classified as minor severity. Overall, there are few incidents involving mesotrione reported to IDS. A query of SENSOR

- Pesticides from 1998

- 20 10 identified 4 cases, stemming from 3 events, involving mesotrione. Multiple active ingredients were implicated in all 4 cases. Three of the cases were classified as low severity and one case was reported as moderate

. The low frequency and low severity of acute poisoning cases (also referred to as human incident data) reported for mesotrione in both the IDS and
SENSOR

- Pesticides does not trigger an EPA concern at this time. The Agency will continue to monitor the incident information, and if the magnitude and frequency of reported ac ute poisoning events increases, additional analysis will be performed.

Conclusions : The Agency has reviewed the available incident data for mesotrion e. Based on the low frequency and generally low severity of incident cases reported for mesotrione to either the
IDS or SENSOR

- Pesticides, there does not appear to be a concern at this time that would warrant further investigation. The Agency will continue to monitor the incident information and if a concern is triggered additional analysis will be conduc ted during Registration Review.

9 .0 Tolerance Assessment and International Harmonization

U.S. permanent tolerances (listed in 40 CFR 180. 57 1 ) are summarized in Attachment 5. All U.S.
tolerances/ Canadian maximum residue limits (MRLs) are harmonize d

, w ith the exception of cranberries. The U.S. cannot harmonize with Canada as the method LOQ (0.02 ppm in the U.S.) is higher than the Canadian MRL (0.01 ppm). During Registration Review, HED may lo ok int o the possibility of harmonizing with Canada for the cranberry tolerance.

10 .0 Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in the

most recent mesotrione 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 a



### . ” The OPP typically considers the highest potential exposures from the lega l use of a pesticide when conducting human

- health risk assessments, including, but not limited to, people who obtain drinking water from sources near agricultural areas, the variability of diets within the U.S., and people who may be exposed when harvestin g crops. Should these

a http://www.epa.gov/compliance/environmentaljustice/resources/policy/exec_order_12898.pdfMesotrione Registration Review Human

- Health Assessment Scoping Document

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Page 12 of 25 

### highest exposures indicate potential risks of concern, OPP further refines the risk assessments to
ensure that the risk estimates are based on the best available information.

11.0 Cumulative

The Hazard and Science Policy Council ( 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 marked di fferences 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 toxicity ind uced 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 tyrosine aminotransferase ( 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 th e 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 childho od but is often sustained throughout patient’s lifetime. The human experience indicates that a therapeutic 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 di et. This observation indicates that an HPPD inhibitor in it and of itself cannot easily overwhelm the tyrosine

- clearance mechanism in humans.

T herefore, exposures to environmental residues of HPPD

- inhibiting herbicides are unlikely to result in the high blood levels of tyrosine 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, assessments 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.

1 2

. 0 Human Studies

Past mesotrione risk assessments rely in part on data from studies in which adult human subjects were intentionally exposed to a pesticide to determine their dermal and inhalation exposure. Many such studies, involving exposure to many different pesticide s, comprise generic pesticide exposure databases such as the Pesticide Handlers Exposure Database (PHED) , the Outdoor Residential Exposure Task Force (ORETF) Database, and the Agricultural Reentry Task Force (ARTF) Database. EPA has reviewed all the studies supporting these multi

- pesticide generic exposure databases, and has found no clear and convincing evidence that the conduct of any of them was either fundamentally unethical or significantly deficient relative to the ethical standards prevailing a t the time the research was conducted. All applicable requirements of EPA’s Rule for the Protection of Human Subjects of Research (40 CFR Part 26) have been satisfied, and there is no regulatory barrier to continued reliance on these studies.Mesotrione Registration Review Human

- Health Assessment Scoping Document

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Page 13 of 25 

### 1 3 .0 Risk

- Assessment Updates, Data Deficiencies, and Label Revisions

No data deficiencies were identified for mesotrione. EPA anticipates conducting the following
risk

- assessment updates during Registration Review:

 Toxicology:

o Reevaluate toxicity endpoint/dose selection, along with the Food Quality Protection Act Safety Factor (FQPA SF) based on current HED policy.

 Residue Chemistry:

o None.

 Dietary Exposure:

o A revised dietary

- exposure analysis may be required to reflect the most recent dietary

- exposure models , potential revised EDWCs, and/or changes to the toxicological PODs.

 Aggregate Exposure:

o New aggregate risk assessment may be required during Registration Review to incorporate revised dietary exposure analyses

, revised residential exposure

assessments , an d/or changes to the toxicological PODs

.

 Occupational/Residential Exposure:

o Revised occupational and residential handler assessments will be necessary to reflect maximum application rates.

o Revised occupational post

- application assessments will be necessary to reflect all currently registered uses (including SLN registrations).

o Assessments for all residential and occupational uses may be updated if toxicological PODs are revised.

1 4 .0 References

HED Memoranda Relevant to Registration Review.

Author Barcode Date Title

K. Lowe D415329 10/23/13 Mesotrione. REVISED Occupational and Residential Exposure Assessment for Proposed Label Amendments Affecting Registered Uses on Corn, Sugarcane, Grasses Grown for Seed, Cranberry, Grain Sorghum, and Soybeans, and a Reassessment
of Residential Uses.

K. Lowe D342065 10/9/07 HED’s Review of “Determination of Transferable Turf Residue Dissipation from Tur f Treated with Mesotrione.

H. Podall D263245 2/24/00
E. Evans and
S. Recore D417803 2/6/14 Mesotrione : Tier I Review of Human Incidents

.

S. Levy D335364 12/5/07 S. Levy et al. D357890 8/12/09 S. Levy et al. D372995 1/20/10 S. Levy D358158 8/5/09

D. Nixon TXR# 0051908 3/27/01
A. Dunbar TXR#0056648 6/27/13 S. Levy D274111 4/26/01 S. Levy D335364 12/5/07

HASPOC NR 12/17/07 The Mode of Action and Human Relevance of HPPD

- Inhibiting

H erbicides

– Revised Interim Policy.Mesotrione Registration Review Human

- Health Assessment Scoping Document

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Page 14 of 25 

### Attachments:

Attachment 1: Chemical Identity Table s

. Attachment 2: Mesotrione Acute, Subchronic, and Chronic Toxicity Profile

. Attachment 3: Mesotrione Endpoint Selection Tables. Attachment 4: Summary of Register ed Uses

. Attachment 5: Mesotrione International Residue Limit Status (IRLS) Sheet.

cc: S. Lowe (RAB1), K. Lowe (RAB1), M. Perron (RAB1)
RDI: RAB1 ( 2 /2 6 /1 4 ), C

. Smith ( 2 / 26 /1 4 ) , D. Vogel (3/5/14) S. Levy :S1095 3 :PY

- S:(703)305

- 07 3 :7509P:RAB1Mesotrione Registration Review Human

- Health Assessment Scoping Document

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Page 15 of 25 

### Attachment 1: Chemical Identity Table s

.

Table 1. 1. Test Compound Nomenclature.
Compound

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) 4 lb/gal SC (Callisto® Herbicide; EPA Reg. No. 100

- 1131)
Compound

Common name MNBA

Chemical name 4

- (methylsulfonyl)

- 2

- nitrobenzoic acid

Table 1.2 . Physicochemical Properties of the Technical Grade Test Compound Mesotrione

. Parameter Value Reference
Melting range 148.7

- 152.5°C RD Memo, H. Podall, 2/24/2000; D263245. pH 3.4 (1% dispersion in water; 25°C)
Density 1.46 g/mL, 20°C
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 4.3 x 10

- 8 torr, 20°C
Dissociation constant, pK
a 3.12, 20°C
Octanol/water partition coefficient 20°C log P OW = 0.11 in unbuffered water log P OW = 0.90 in pH 5 buffer log P 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.Mesotrione Registration Review Human

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Page 16 of 25 

### Attachment 2: Mesotrione Acute, Subchronic, and Chronic Toxicity Profile

.

2 .1 Toxicology Data Requirements

.

Study requirements (40 CFR 158.340) for use of mesotrione are below . 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 ris k assessment ; therefore

, this deficiency is not considered a data gap at this time.

3 The combined chronic toxicity/carcinogenicity study satisfies the requirement of the study.



### 2.2 Toxicity Profiles

.

Table 2.2.1 . Acute Toxicity Data for Mesotrione

. Guideline No./Study Type MRID# 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

---Mesotrione Registration Review Human

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Page 17 of 25 Table 2 .2.2

. Subchronic, Chronic and Other Toxicity Profile for 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 and decreased body

- weight gain 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

.

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
maternal body

- weight gains and decreased 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

.Mesotrione Registration Review Human

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Page 18 of 25 Table 2 .2.2

. Subchronic, Chronic and Other Toxicity Profile for Mesotrione.

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

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 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
and 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 and dosing was initiated in several groups prior to completion of implantation

.

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 signif icantly increased plasma tyrosine 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 kidn ey 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 > 145 5.5/1652.3

.

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 870.4300Mesotrione Registration Review Human

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Page 19 of 25 Table 2 .2.2

. Subchronic, Chronic and Other Toxicity Profile for Mesotrione.

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

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) (The 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 lesions, 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

.

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.

870.7800 Immunotoxicity 48748301 (2012) Acceptable/guideline 0, 110, 332 or 1168 mg/kg/day NOAEL = 5000 ppm

.

LOAEL not established

.Mesotrione Registration Review Human

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Page 20 of 25 

### Attachment 3: Mesotrione Endpoint Selection Tables (from 20 09 Risk Assessment)

.

Table 3 .1

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

Occupational Human

- Health Risk Assessments

.

Exposure/
Scenario Point of

Departure Uncertainty/FQPA

Safety Factors RfD, PAD, L O C
for Risk
Assessment Study and Toxicolog ical 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 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 d eparture (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

- effe ct 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 LOAEL 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 Registration Review Human

- Health Assessment Scoping Document

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Page 21 of 25 Table 3 .2

. Summary of Toxicological Doses an d Endpoints for Mesotrione for Use in Occupational Human

Health Risk Assessments

.

Exposure/
Scenario Point of

Departure Uncertainty Factors L O C 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 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 d eparture (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

- effect level.
LOAEL = lowest

- observed adverse

- effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF L = use of a LOAEL to extrapolate a NOAEL. MOE = margin of exposure. LOC = level of concern.Mesotrione Registration Review Human

- Health Assessment Scoping Document

_____________________________________________________________________________________________________________________________ __________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ ___________________________________________________________________

Page 22 of 25 

### Attachment 4: Summary of Registered Uses

.

Crop/Use Site Formulation Application
method Maximum App Rate (lb ai/A) REI

Asparagus Liquid Aerial, Groundboom, Chemigation Preemergence: 0.24 lb aiA; Postemergence: 0.09 lb ai/A 12 hr

Bush and Caneberries Liquid Aerial, Groundboom, Chemigation Pre

- bloom post

- directed spray: 0.19 lb
aiA 12 hr

Low

- bush Blueberry (SLN) Liquid Groundboom and chemigation (Aerial prohibited) Preemergence and early postemergence:
0.125 lb ai/A 12 hr

Corn Liquid Aerial, Groundboom, Chemigation Preemergence: 0.24 lb ai/A and

Postemergence: 0.078

- 0.23 lb ai/A (depends on timing) 12

- 24 hr

Dry
Flowable Groundboom

(Aerial and Chemigation prohibited) Preemergence: 0.18

- 0.24 lb ai/A and

Postemergence: 0.078

- 0.24 lb ai/A (depends on timing) 12 hr

Corn (SLN) Dry
Flowable Allows for Aerial

application 0.078 lb ai/A 12 hr

Cranberries Liquid Aerial, Groundboom, Chemigation 0.25 lb ai/A 12 hr

Cuphea (ornamental; SLN) Liquid Groundboom and
Handheld Postemergence: 0.094 lb ai/A or 0.0098 lb ai/gal 12 hr

Flax Liquid Aerial, Groundboom, Chemigation Preemergence only: 0.19 lb aiA 12 hr

Golf courses Granular Groundboom and
Handheld 0.25 lb ai/A

12 hr Liquid Groundboom

(Aerial and Chemigation prohibited) 0.25 lb ai/A; 0.0058 lb ai/1000 ft2; 0.0116 lb ai/gal

Grass grown for seed Liquid Aerial, Groundboom, Chemigation Preemergence and Postemergence: 0.19 lb
aiA 12 hr

Oats Liquid Aerial, Groundboom, Chemigation Preemergence: 0.19 lb aiA; Postemergence: 0.09 lb ai/A 12 hr

Okra Liquid Aerial, Groundboom, Chemigation Preemergence: 0.19 lb aiA; Postemergence: 0.09 lb ai/A 12 hr

Pearl Millet Liquid Aerial, Groundboom, Chemigation Preemergence only: 0.19 lb aiA 12 hr

Residential
lawns/Recreational
areas/Athletic Fields Granular Handheld 0.25 lb ai/A 12 hr

Liquid Handheld 0.25 lb ai/A; 0.0058 lb ai/1000 ft2; 0.0116 lb ai/gal None

Non

- residential turf areas (airports, cemeteries, commercial buildings, and similar sites) Liquid Groundboom or Handheld (Aerial and Chemigation prohibited) 0.25 lb ai/A; 0.0058 lb ai/1000 ft2; 0.0116 lb ai/gal None

Rhubarb Liquid Aerial, Groundboom, Chemigation Preemergence only: 0.19 lb aiA 12 hrMesotrione Registration Review Human

- Health Assessment Scoping Document

_____________________________________________________________________________________________________________________________ __________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ ___________________________________________________________________

Page 23 of 25 Crop/Use Site Formulation Application
method Maximum App Rate (lb ai/A) REI

Sod farms Granular Groundboom and
Handheld 0.25 lb ai/A

12 hr Liquid Groundboom

(Aerial and Chemigation prohibited) Broadcast: 0.25 lb ai/A

Sorghum Liquid Aerial, Groundboom, Chemigation 0.2 lb ai/A 12

- 24
hr

Soybean Liquid Aerial, Groundboom, Chemigation Preemergence: 0.2 lb ai/A; Postemergence: 0.11 lb ai/A 12 hr

Sugarcane Liquid Aerial, Groundboom, Chemigation Preemergence: 0.24 lb aiA; Postemergence: 0.09 lb ai/A 12 hr

Wildflowers (SLN) Liquid Groundboom or
Handheld Preemergence (applied after seeding in

fall): 0.125 lb ai/A in 30 gal water/A = 0.0042 lb ai/gal; Postemergence (in March or April the year following fall wildflower seeding): 0.094 lb ai/A or 0.0031 lb ai/gal 12 hrMesotrione Registration Review Human

- Health Assessment Scoping Document

_____________________________________________________________________________________________________________________________ __________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ ___________________________________________________________________

Page 24 of 25 

### Attachment 5 : Mesotrione IRLS Sheet

.

Summary of US and International Tolerances and Maximum Residue Limits

. Residue Definition : US Canada Mexico 1 

### Codex

40 CFR 180.571:
Plant: M esotrione (2

- [4

- (methylsulfonyl)

- 2

- nitrobenzoyl]

- 1,3

- cyclohexanedione), including its metabolites and degradates.

Livestock: None 2

- [4

- (methylsulfonyl)

- 2

- nitrobenzoyl]

- 1,3

- cyclohexanedione None



### Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico 1 

### Codex
Asparagus 0.01 0.01

Berry, group 13 0.01 0.01 aronia berries, buffalo currants, Chilean guavas, cranberries,currants, elderberries, European barberries, gooseberries, highbush blueberries, highbush cranberries honeysuckle, huckleberries, jostaberries, lingonberries, lowbush blueberries, native currants,

sa lal berries, saskatoon berries (juneberries), sea buckthorn Corn, field, forage 0.01 Corn, field, grain 0.01 0.01 Corn, field, stover 0.01 Corn, pop, grain 0.01 0.01 Corn, pop, stover 0.01 Corn, sweet, forage 0.5 Corn, sweet, kernel plus cob with
husks removed 0.01 0.01

Corn, sweet, stover 1.5 Cranberry 0.02 0.01 Flax, seed 0.01 0.01 Grass, forage 0.01 Grass, hay 0.01 Grass, seed screenings 0.10 Grass, straw 0.10 Lingonberry 0.01 0.01 Millet, forage 0.01 Millet, grain 0.01 0.01 pearl millet, proso millet Millet, hay 0.02 Millet, straw 0.02 Oat, forage 0.01 Oat, grain 0.01 0.01 Oat, hay 0.01 Oat, straw 0.01
Okra 0.01
Rhubarb 0.01 0.01 Sorghum, grain, forage 0.01 Sorghum, grain, grain 0.01 0.01 sorghum Sorghum, grain, stover 0.01Mesotrione Registration Review Human

- Health Assessment Scoping Document

_____________________________________________________________________________________________________________________________ __________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ _____________________________________________________________________________________________________________________________ ______ _____________________________________________________________________________________________________________________________ ___________________________________________________________________

Page 25 of 25 Sorghum, sweet 0.01 0.01 sorghum Sorghum, seed 0.01 Sugarcane, cane 0.01 0.01

MRLs With NO US Equivalent Dry soybeans 0.01 Eggs 0.01

Meat byproducts of cattle 0.01 Meat byproducts of goats 0.01 Meat byproducts of hogs 0.01 Meat byproducts of horses 0.01 Meat byproducts of poultry 0.01 Meat byproducts of sheep 0.01
Meat of cattle 0.01 Meat of goats 0.01 Meat of hogs 0.01
Meat of horses 0.01 Meat of poultry 0.01 Meat of sheep 0.01

Milk 0.01

Completed: M. Negussie; 02/06/14

1 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.