UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

Date: 06-MAY-2015 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

SUBJECT: Mesotrione. Human Health Risk Assessment in Support of the Section 3 Request 

for Use of Mesotrione on Pome Fruit, Stone Fruit, Citrus, and Tree Nuts. 

PC Code: 122990 DP Barcodes: D41 9616, D419617, D419618 

Decision Nos.: 487 155, 487154, 487156 Registration No.: I 00- 113 l 

Petition No: 4F8240 Regulatory Action: Section 3 

Risk Assessment Type: Single Case No.: 7256 

Chemical/ Aggregate 

TXR No.: NA CAS No.: 104206-82-8 

MRID No.: NA 40 CFR: §180.571 

FROM: 

Thomas 

Sarah J. Levy, 

Bloem

Chemist 

, is ~ 

J ~ 

Monique 

Kelly M. Lowe

M. Perron, 

, Senior 

S.D.

En

, 

v

Toxico

ironrne

logist 

n al Scie

~/Jli.f(/...Ji ntist ~~ ~0iA,,.......,__ Risk Assessment Branch 1 (RAB I) {) 

Health Effects Division (HED, 7509P) 

THROUGH: Thurston Morton, Acting Branch Chief j ' 

George F. Kramer, Ph.D., Senior Chemi t ~~~e~~~-=----

RAB 1, HED (7509P) 

TO: Kathryn Montague/Michael Walsh, PM Team 23 

Registration Division (RD; 7505P) 

The HED of the Office of Pesticide Programs (OPP) is charged with estimating the risk to human 

health from exposure to pesticides. The RD of OPP has requested that HED evaluate hazard and 

exposw-e data and conduct dietary, occupational, residential, and aggregate exposure 

assessments, as needed, to estimate the risk to human health that will result from the proposed 

use of mesotrione on in/on pome fruit, stone fruit, citrus, and tree nuts. 

A summary of the findings and an assessment of human health risk resulting from the 

proposed/registered uses of mesotrione are provided in this document. The risk assessment and 

dietary exposure assessment were provided by Sarah Levy (RAB I), the hazard characterization 

by Monique Perron (RAB I), the residue chemistry data review by Thomas Bloem (RAB I), the 

occupational/residential exposure assessment by Kelly Lowe (RAB I), and the drinking water 

assessment by Iwona Maher of the Environmental Fate and Effects Division (EFED). 

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Mesotrione Human Health Risk Assessment DP# 4 19616 

Table of Contents 

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 Analytical Method ..... .... .... ................ ... .... ............................... ....... ... 6 

2.2.2 Recommended Tolerances ................................. ....... ........ ....... ... ............................ 7 

2.2.3 Revisions to Petitioned-For Tolerances ............................................. ....... ...... .... .... 7 

2.2.4 International Harmonization ................................................ ............. .... ....... ........... 7 

2.3 Label 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 Environmental Justice ........................... .... ....... ........................... 9 

4.0 Hazard Characterization and Dose-Response Assessment ................................... ...... ...... 10 

4.1 Toxicology Studies Avai lable for Analysis ... .... ...................................... .... ...... ... 10 

4.2 Absorption, Distribution, Metabolism, and Excretion (ADME) ............. ...... ....... 10 

4.2.1 Dermal Absorption .. .... .............................................................. ... .... ....... ... ........... 10 

4.3 Toxicological 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 Sensitivity/Susceptibility in the Developing or Young Animal ....... 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 Profile ... ........ .... .... ......... .... .... .... ....... ............................................ 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-Occupational) Exposure/Risk ............................................................... I 9 

6.1 Residential Exposure/Risk Characterization ..... .... .... ... .... ... ........... ....................... 19 

6.2 Spray Drift ................................ ....... ... ... ..... ... .... ...... ................... 21 

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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

Appendix B. Physical/Chemical Properties................................................................................. 31

Appendix C. Review of Human Research ................................................................................... 31
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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 treatments 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 uses 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 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, 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 quantitative 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. 

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, mutagenicity, carcinogenic potential, or immunotoxicity 

in relevant studies.

Food Quality Protection 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 all 
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exposure scenarios for use of a lowest-observed adverse-effect level (LOAEL) from the mouse 

reproduction toxicity study since the effect (ocular 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 developmental 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-recommended tolerances. There 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 was 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 analysis assumed 100% crop treated (CT), DEEM 7.81 default processing 

factors, and tolerance-level residues for all foods. Drinking water was incorporated directly into 

the dietary assessment using 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 

population-adjusted dose (cPAD)]. The chronic dietary risk estimate for the highest exposed 

population subgroup, all infants (<1 year old), is 17% 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 previously (using the revised 2012 Residential Standard 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 chronic 

(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 children (6 to <11 

years old), children (11 to <16 years old), or adults from residues on turfgrass; therefore, this 

exposure scenario was not factored into the short-and intermediate-term aggregate risk 
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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, 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. 

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 quantitative 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. 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 Low-Income Populations," 

http://www.epa.gov/compliance/environmentaljustice/resources/policy/exec_order_12898.pdf.

This risk assessment relies in part on 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 data deficiencies were identified for the current petition. It is noted that the requirements for 

plant metabolism data in three dissimilar crops have 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 stored 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 currently-established plant tolerances is a high-performance 

liquid chromatography (HPLC) method with fluorescence detection (Method TMR0882B; 
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D245477, S. Levy, 6-Jun-2001; D283827, W. Cutchin, 12-Jan-2005). The confirmatory method 

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 were 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/seasonal application rates 3X 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. 
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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. 

Table 3.1. Test Compound Nomenclature.

Chemical structure

O

O

O

S

N

+

O

O

CH3

O O

–

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 lbs ai/gal SC)

Chemical structure

N

+

O O

–

S

CH3

HO

O

O

O

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 Kow, and Henry’s law constant (5.1 x 10-7 Pa m3/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 liquid 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 applications are prohibited 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.
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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)

Comments1

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

-Applied 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 may 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 

pesticide 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 food 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 and are used in pesticide risk 

assessments for all registered food uses of a pesticide. These data are analyzed and categorized 
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by subgroups based on age, season of the year, ethnic group, and region of the country. 

Additionally, OPP is able to assess dietary 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 models 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 immunotoxicity 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 mesotrione via the inhalation route. Since that request, the 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. Dunbar, 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 

radioactivity 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 or 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 results of an in vivo

dermal absorption study in rats (P.V. Shah, 23-OCT-2007, TXR#0054622). This dermalabsorption factor is applied for converting oral doses to dermal-equivalent doses in order to 

assess the potential risk associated with dermal exposures of mesotrione.
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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 organ 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 because 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 doses 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 most 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/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 SF should be reduced 

to 3X for all exposure scenarios for use of a LOAEL from 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, but 
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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 developmental 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 effects 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 for 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 

fetal/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 reproduction 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 residues 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 models and associated modeling 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 Endpoint 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).
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4.5.1 Dose-Response Assessment

Acute Dietary Endpoint (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 reduced to 3X to 

incorporate an uncertainty factor (UFL) 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/UFL 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/UFL). For dermal exposure scenarios, a dermalabsorption factor of 1% should be applied.

Inhalation Endpoints (all durations): The reproduction 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/UFL). 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 potential 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 

effects. 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 mesotrione 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. 
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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 NonOccupational Human Health Risk Assessments.

Exposure/ 

Scenario POD

Uncertainty/FQPA 

SFs

RfD, PAD, LOC 

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

UFA = 10X

UFH = 10X

FQPA SF/UFL = 

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 

IntermediateTerm (1-6 

months)

LOAEL = 

2.1 mg/kg/day

UFA = 10X

UFH = 10X

FQPA SF/UFL = 

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), 

IntermediateTerm (1-6 

months) and 

Long-Term (>6 

months)

LOAEL = 

2.1 mg/kg/day

UFA = 10X

UFH = 10X

FQPA SF/UFL = 

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), 

Intermediateterm (1-6 

months) and 

Long-Term (>6 

months)

LOAEL = 

2.1 mg/kg/day

Inhalation 

assumed 

equivalent to 

oral

UFA = 10X

UFH = 10X

FQPA SF/UFL = 

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-effect level. LOAEL = lowest-observed adverse-effect level. UF = uncertainty factor. UFA = extrapolation 

from animal to human (interspecies). UFH = potential variation in sensitivity among members of the human population 

(intraspecies). UFL = 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. 
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Table 4.5.4.2. Summary of Toxicological Doses and Endpoints for 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), 

IntermediateTerm (1-6 

months) and 

Long-Term (>6 

months)

LOAEL = 

2.1 mg/kg/day

UFA = 10X

UFH = 10X

UFL = 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), 

Intermediateterm (1-6 

months) and 

Long-Term (>6 

months)

LOAEL = 

2.1 mg/kg/day

Inhalation 

assumed 

equivalent to 

oral

UFA = 10X

UFH = 10X

UFL = 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-effect level. LOAEL = lowest-observed adverse-effect level. UF = uncertainty factor. UFA = extrapolation 

from animal to human (interspecies). UFH = potential variation in sensitivity among members of the human population 

(intraspecies). UFL = use of a LOAEL 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-MAY2015; 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.
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Plants (Primary Crops): Field corn (preemergent and foliar application) and peanut 

(preemergent application) metabolism studies conducted with [cyclohexanedione-2-

14C]mesotrione and [14C-phenyl]mesotrione and a cranberry (foliar application) metabolism 

study conducted with [14C-phenyl]mesotrione were previously submitted and reviewed (Memo, 

S. Levy, 06-JUN-2001; D245477; Memo, W. Cutchin, 12-JAN-2005; D283827; and Memo, S. 

Levy, 02-MAR-2007; D326898). The studies conducted with [14C-phenyl]mesotrione (field 

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-

14C]mesotrione (field corn and 

peanut) indicate that the cyclohexanedione ring may be degraded to CO2 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 because metabolism data 

reflecting application with [cyclohexanedione-2-

14C]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, for 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 future 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 proposed 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 crop 

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 assumes that the registered labels adhere to the HEDrecommended 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 cyclohexanedione2-

14C]mesotrione and [14C-phenyl]mesotrione has been previously submitted and reviewed

(Memo, S. Levy, 06-JUN-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 may 
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occur with the cyclohexanedione 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 metabolism 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 inches 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 drinking 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 millet, 

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 

insignificant. 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 estimated drinking water concentrations (EDWCs) used in the dietary exposure risk 

assessment were provided by EFED in a memorandum dated 23-NOV-2013 (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 ground water. The proposed maximum annual 

application rates (0.376 lbs ai/A) for the proposed uses are much lower than the previouslymodeled EUP use on soybeans (1.5 lbs ai/A/year). Although the EUP has expired, HED did not 

request revised EDWCs, since the estimate from the EUP scenario did not result in risks of 

concern. Furthermore the EUP scenario has a higher application rate than the other 
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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 lbs ai/A) 38.1 5.1 2.2

Groundwater (PRZM-GW) Soybean-EUP (1.5 lbs ai/A) 26.2 18.4 <18.4

Groundwater (SCI-GROW) Soybean-EUP (1.5 lbs ai/A) 0.54 <0.54 <0.54

The ground water EDWC of 18.4 ppb 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 tolerancelevel residues for all commodities (Memo, S. Levy, 06-MAY-2015; D420018). Drinking water 

was incorporated directly into the dietary assessment using the concentration 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 (aRfD) was not 

established. 

5.4.4 Chronic Dietary Risk 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 17% of the cPAD. A summary table of 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 processing 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.
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5.4.6 Summary Table

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

Population Subgroup1

Chronic Dietary

Dietary Exposure

(mg/kg/day) % cPAD

General U.S. Population 0.000457 6.5

All Infants (<1 year old) 0.001170 17

Children 1-2 years old 0.000834 12

Children 3-5 years old 0.000677 9.7

Children 6-12 years old 0.000453 6.5

Youth 13-19 years old 0.000346 4.9

Adults 20-49 years old 0.000436 6.2

Adults 50-99 years old 0.000425 6.1

Females 13-49 years old 0.000434 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; D426691 (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 turf, 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 section 

as they are applicable to aggregate 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 

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 1 to <2 years old aggregate 

assessment reflects combined dermal plus incidental oral (hand-to-mouth) postapplication exposure from high contact activities on home lawns treated with a granular 

formulation.
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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/A
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Table 6.1.2. Recommendations for the Residential Exposures for the Mesotrione Aggregate Assessment.

Lifestage Dose (mg/kg/day)2,4 MOE3,5

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 registrants 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 pesticide 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 Exposure 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, Fungicide, 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/meetings/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.htm
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(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 required for mesotrione.

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate pesticide exposures and risks 

from three major sources: food, drinking water, and residential exposures. In an aggregate 

assessment, exposures from relevant sources are added together and compared to quantitative 

estimates of hazard, 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 toxicological 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 

intermediate-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 risk 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 that 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. Incidental oral exposure is not expected for children (6 to <11 years old), 

children (11 to <16 years old), or adults from residues on turfgrass; therefore, this exposure 

scenario was not factored into the short-and intermediate-term aggregate risk calculations.
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Table 7.2. Short- and Intermediate-Term Aggregate Risk Calculations.

Population Food + Water Exposure1

(mg/kg/day)

Residential Exposure2, 3, 4

(mg/kg/day) Aggregate MOE5

Children (1 to <2 years) 0.000834 0.00071 1,400

Child (6 to <11 years) 0.000453 0.000018 4,500

Child (11 to <16 years) 0.000346 0.000015 5,800

Adults6 0.000436 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

 Combination of dermal plus incidental oral (hand-to-mouth) post-application exposure from treated lawns (See Table 6.1.2).

3

 Post-application dermal exposure from golfing (See Table 6.1.2).

4

 Combination 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 chronic (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/Assessment

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 marked 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 toxicity 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 sustained throughout patient’s lifetime. The human experience indicates that a therapeutic 
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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 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. 

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 quantitative assessment is not necessary. 

An exposure assessment was previously assessed for mesotrione (Memo, K. Lowe, 13-OCT2013; 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 lbs 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 were 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, 3X 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 Exposure 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.
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9.1 REI

The restricted-entry interval (REI) specified on the proposed label is based on the acute toxicity 

of mesotrione. Mesotrione 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 all 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 interim 

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-2015; D420017

Memo, S. Levy, 06-MAY-2015; D420018

Memo, K. Lowe, 06-MAY-2015; D426691

List of Appendices:

Appendix A. Toxicology Profile

Appendix B. Physical/Chemical Properties

Appendix C. Review of Human Research

cc: S. Levy (RAB1)

RDI: RAB1 (10/22/14); Kramer (10/17/14)

S. Levy:S10953:PY-S:(703)305-0783:7509P:RAB1
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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

no1

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

no2

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

yes3

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-JUN2013, TXR#0056648). 

2 Study is classified as unacceptable/not upgradable, but the rabbit is not considered the relevant species for human

health risk 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.
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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 LD50 > 5000 mg/kg IV

870.1200 Acute dermal 44373514 LD50 > 2000 mg/kg III

870.1300 Acute inhalation 44373516 LC50 > 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 NonRodent (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.
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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 7th cervical transverse process 

and odontoid and increases in extra full 13th 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 number 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 F2 males.

Offspring/Systemic: NOAEL not established.

LOAEL = 0.3 mg/kg/day (M/F) based upon 

significantly increased plasma tyrosine levels in F2

male pups.

Reproductive: NOAEL = 0.3 mg/kg/day.

LOAEL = 1.1/1.2 mg/kg/day (M/F) based upon 

decreased F2 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 F1

males.

Offspring/Systemic: NOAEL not established. 

LOAEL = 2.1/2.4 mg/kg/day (M/F) based upon 

tyrosinemia and ocular discharge in the F1 and F2

offspring.

Reproductive: NOAEL = 1455.5/1652.3 

mg/kg/day (M/F).

LOAEL >1455.5/1652.3 mg/kg/day (M/F).
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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) (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.
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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/cm2 or 4781 

μg/cm2

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/cm2 or 4818 

μg/cm2

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/cm2 or 4818 

μg/cm2

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 10-8torr

Dissociation constant, pKa (20°C) 3.12

Octanol/water partition 

coefficient, Log(KOW) (20°C)

log KOW = 0.11 in unbuffered water

log KOW = 0.90 in pH 5 buffer

log KOW <-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) subject 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 website1. 

 

1 http://www.epa.gov/pesticides/science/handler-exposure-data.html and 

http://www.epa.gov/pesticides/science/post-app-exposure-data.html