i

EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR 

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER 

EPA Registration Division contact: Ms. Kathryn Montague, 703-305-1243

Syngenta Crop Protection, LLC

[4F8240]

EPA has received a pesticide petition (4F8240) from Syngenta Crop Protection, 

LLC, PO Box 18300, Greensboro, NC, 27419 requesting, pursuant to section 408(d) of 

the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 

CFR part 180

by establishing a tolerance for residues of

Mesotrione (2-[4-(methylsulfonyl)-2-notrobenzoyl]-1,3-cyclohexadione) in or on 

the raw agricultural commodities Citrus Fruit, Crop Group 10-10 at 0.01 parts per million 

(ppm), Pome Fruit, Crop Group 11-10 at 0.01 ppm, Stone Fruit, Crop Group 12-12 at

0.01 ppm, Tree Nuts, Crop Group 14-12 at 0.01 ppm, and Almond Hulls at 0.015 ppm. 

EPA has determined that the petition contains data or information regarding the elements 

set forth in section 408 (d)(2) of FDDCA; however, EPA has not fully evaluated the 

sufficiency of the submitted data at this time or whether the data supports granting of the 

petition. Additional data may be needed before EPA rules on the petition.

A. Residue Chemistry

1. Plant metabolism. The metabolism of mesotrione is adequately understood for 

the purpose of the proposed tolerances, based on acceptable cranberry, corn and peanut 

metabolism studies. EPA has determined that, for mesotrione, the residue of concern in 

plants for both enforcement and risk assessment purposes is parent mesotrione.

2. Analytical method. Syngenta has developed and validated analytical 

methodology for enforcement purposes. Practical and specific analytical method RAM 

366/01, utilizing high-performance liquid chromatography (HPLC) with tandem massspectrometry (MS/MS) detection, is available for detecting and measuring the level of 

mesotrione in or on various crop commodities. This method has been submitted to the 

Agency for inclusion in the Pesticide Analytical Manual Volume II (PAM II) as a 

confirmatory method.

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

tolerances are submitted with this petition. The requested tolerances are adequately 

supported. The residue studies were conducted per EPA Test Guidelines 860.1000, 

860.1500, and 860.1520.
2

B. Toxicological Profile

EPA has evaluated the available toxicity data and considered its validity, completeness, 

and reliability as well as the relationship of the results of the studies to human risk. EPA 

has also considered available information concerning the variability of the sensitivities of 

major identifiable subgroups of consumers, including infants and children. The nature of 

the toxic effects caused by mesotrione as well as the no observed adverse effect level 

(NOAEL) and the lowest observed adverse effect level (LOAEL) from the toxicity 

studies reviewed are discussed in the Federal Register of June 21, 2001 (66 FR 33187) 

(FRL – 67877). A summary of the toxicological endpoints for mesotrione used for 

human risk assessment is discussed in Unit III.B of the final rule published in the Federal 

Register of June 21, 2001. The data was reviewed and more recently discussed in Unit 

III of the final rule published in the Federal Register of December 18, 2009 in support of 

newly approved use on soybean.

1. Acute toxicity. The database for acute toxicity of mesotrione is considered to 

be complete. Mesotrione has low acute toxicity (toxicity category IV) via the 

oral, dermal and inhalation routes of exposure. It is a mild eye irritant (toxicity 

category IV), is non-irritating dermally (toxicity category IV) and is not a dermal 

sensitizer. 

2. Genotoxicity. Gene mutation (Guidelines 870.5100 & 870.5300), cytogenetics 

(Guideline 870.5375) and micronucleus (Guideline 870.5395) studies conducted 

with mesotrione have been reviewed and approved by EPA. There is no evidence 

of a mutagenic or cytogenetic effect in vivo or in vitro with mesotrione.

3. Reproductive and developmental toxicity. There is evidence of increased 

susceptibility of rats, mice and rabbits to in utero and/or post-natal exposure to 

mesotrione. However, there is a well characterized NOAEL that is protective of the 

observed effects. A reproduction study in the mouse had a LOAEL of 2.1 mg/kg/day in 

males based on tyrosinemia and ocular discharge in offspring. This endpoint was used to 

establish the point of departure used in risk assessments.

4. Subchronic toxicity. In a 90-day dietary study in rats with mesotrione, corneal 

lesions were observed in males at 0.63 mg/kg/day; the NOAEL was 0.41 mg/kg/day for 

males and 0.47 mg/kg/day for females. In another 90-day dietary study in rats, corneal 

lesions in both sexes and decreased body weight gain in males was observed at 11 

mg/kg/day in males and 13 mg/kg/day in females; the NOAEL was 0.09 and 0.10

mg/kg/day in males and females, respectively. Ninety-day oral studies with mesotrione 

in both the mouse and dog have been accepted by EPA; no effects were observed in 

males and females at the highest doses tested (1212/1537 mg/kg/day [M/F] in mice and 

1000 mg/kg/day [M & F] in dogs).

5. Chronic toxicity. Chronic studies have been conducted with mesotrione in the 

rat, mouse and dog. Major adverse effects were ocular lesions, liver and kidney effects, 

increased plasma tyrosine levels and body weight decreases. The chronic reference dose
3

used for risk assessment purposes is 0.007 mg/kg/day and is protective of the effects 

observed.

6. Animal metabolism. Animal metabolism studies have shown that mesotrione is 

readily absorbed and almost totally eliminated within 72 hours following oral or 

intravenous administration in rats and mice. Parent compound, mesotrione, was the 

major compound identified in excreta. Minor metabolites identified were 4-OHmesotrione, 5-OH-mesotrione, MNBA and AMBA.

7. Metabolite toxicology. The metabolism of mesotrione has been well 

characterized in standard FIFRA metabolism studies. The residue of concern in plants, 

livestock and drinking water is parent mesotrione.

8. Endocrine disruption. Mesotrione does not belong to a class of chemicals 

known or suspected of having adverse effects on the endocrine system. Developmental 

toxicity studies in the rat, rabbit, and mouse, and reproduction studies in rats and mice 

gave no indication that mesotrione would have any effect on endocrine function related to 

development and reproduction. Furthermore, histological investigations of endocrine 

organs (adrenals, thyroid, and pituitary) in the long-term studies in dog, rat, and mouse 

did not indicate that the endocrine system is targeted by mesotrione, even when animals 

were treated at maximally tolerated doses over chronic time periods. Due to the rapid 

degradation of the product in the environment, there is no risk that mesotrione will 

bioaccumulate. Based on these results and the comprehensive database, mesotrione is not 

expected to interfere with the endocrine system in humans or wildlife.

C. Aggregate Exposure

1. Dietary exposure. Tier II short-term and chronic dietary exposure evaluations 

were completed for mesotrione using the Dietary Exposure Evaluation Model software 

with the Food Commodity Intake Database (DEEM-FCID, version 3.16). DEEM-FCID 

software incorporates food consumption data from the National Health and Nutrition 

Examination Survey “What We Eat in America” (NHANES/WWEIA) dietary survey 

conducted in 2003-2008. In addition to all currently registered uses of mesotrione 

(asparagus, berry Crop Group (Crop Group 13), field corn, sweet corn, popcorn, 

cranberry, flax, grasses grown for seed, millet, oat, okra, rhubarb, sorghum, and 

sugarcane), and the pending reinstatement of aerial applications for corn and sugarcane 

and the pending use on herbicide (mesotrione) tolerant soybeans (HT soybeans), this 

exposure assessment included proposed crop uses on citrus fruits (Crop Group 10-10), 

pome fruits (Crop Group 11-10), stone fruits (Crop Group 12-12) and tree nuts (Crop 

Group 14-12). The definition of the residue for tolerance enforcement and risk 

assessment purposes for crops is parent mesotrione. The assessments utilized residue 

data from field trials in which mesotrione was applied at the maximum intended use rate 

and samples were harvested at the minimum pre-harvest interval (PHI) to obtain 

maximum residues. Percent of crop treated values were estimated based upon economic, 

pest, and competitive pressures for the proposed uses. Secondary residues in animal 

commodities were estimated based on “maximum reasonably balanced diets” and transfer 

information from metabolism studies. Drinking water estimates were incorporated 
4

directly into the dietary exposure assessment using the higher of the estimated drinking 

water concentrations (EDWCs) for surface and ground water. 

i. Food. Acute Exposure. Mesotrione is not considered to be acutely toxic and an 

acute toxicological endpoint was not selected by the Agency.

Chronic Exposure. The mesotrione chronic dietary (food only) risk assessment was 

performed for all population subgroups with a chronic reference dose of 0.007 mg/kgbw/day based on a mouse reproduction study with a Lowest Observable Adverse Effect 

Level (LOAEL) of 2.1 mg/kg-bw/day and an uncertainty factor of 300X. The 300-fold 

safety factor includes intra- and interspecies variations (100X) and an additional FQPA 

safety factor of 3X (absence of NOAEL). For the purpose of the aggregate risk 

assessment, exposure values were expressed in terms of margin of exposure (MOE), 

which was calculated by dividing the LOAEL by the exposure for each population 

subgroup. In addition, exposure was also expressed as a percent of the reference dose 

(%RfD). Chronic (food only) exposure to the U.S. population resulted in a MOE of 

129,636 (0.2% of the chronic RfD of 0.007 mg/kg-bw/day). The most sensitive subpopulation was children (1-2 years old) with a MOE of 49,607 (0.6% of the chronic 

RfD). The benchmark MOE for this assessment was 300.

Cancer. Mesotrione is considered “not likely to be a human carcinogen”. Therefore, no 

cancer risk assessment was performed for mesotrione.

ii. Drinking water. The Estimated Drinking Water Concentrations (EDWCs) of 

mesotrione were determined using Tier l SCI-GROW and PRZM-GW which estimate 

pesticide concentration in ground water and Tier II PRZM/EXAMS which estimates 

pesticide concentration in surface water. Currently registered and pending (HT soybeans) 

plus proposed uses on citrus fruit, pome fruit, stone fruit and tree nuts were assessed. 

Based on the PRZM-GW modeling, the currently registered Experimental Use Permit 

(EUP) on soybeans provided a groundwater chronic EDWC of 16.6 ppb. Based on Tier 

II PRZM/EXAMS modeling for surface water, the soybean EUP provided a chronic 

EDWC of 5.1 ppb. Since the ground water EDWC exceeds the surface water EDWC, the 

ground water value was used for risk assessment purposes and will be considered 

protective for any surface water exposure concerns. 

Chronic Exposure from Drinking Water. The chronic ground water EDWC of 16.6 ppb 

was input directly into the DEEM-FCID software as “water, direct and indirect, all 

sources” to model the chronic drinking water exposures. Chronic drinking water 

exposure to the U.S. population resulted in a MOE of 6,042 (5.0% of the cRfD of 0.007 

mg/kg-bw/day). Chronic drinking water exposure to the most exposed sub-population 

(all infants, <1 year old) resulted in a MOE of 2,343 (12.8% of the cRfD of 0.007 mg/kgbw/day). The benchmark MOE for this assessment was 300.

2. Non-dietary exposure. Currently the herbicide used on turfgrasses containing 

mesotrione is formulated as a liquid and marketed under the trade name TenacityTM, 

0.08% Mesotrione on Fertilizer, 0.19% Mesotrione on Fertilizer, and 0.25% Mesotrione 
5

on Fertilizer. These products are used for selective contact and residual control of weeds 

in turfgrasses for golf courses and sod farms. TenacityTM is labeled for use only by 

professional applicators; therefore, residential handler application scenarios were not 

assessed. Residential (non-occupational) risk assessments were conducted for potential 

post-application exposure to adults and youth on treated golf courses. 

The post-application exposures on treated golf courses include dermal exposures due to 

contact activities with the treated areas. Risks due to short-term exposures (1-30 days) 

were assessed using the Margin of Exposure (MOE) approach. Based on the use pattern 

of mesotrione on turf, intermediate-term exposures (1 to 6 months) are unlikely and longterm exposures (greater than six months) are not expected. Therefore, intermediate-term 

and long-term risks were not assessed.

Residential exposures were assessed assuming a one-time maximum application rate of 

0.25 pounds of active ingredient per acre (0.25 lb a.i./A or 5.74E-06 lbs a.i./ft2) per 

application of TenacityTM, 0.19% Mesotrione on Fertilizer, and 0.25% Mesotrione on 

Fertilizer. Residential exposures were assessed assuming a one-time maximum 

application rate of 0.15 pounds of active ingredient per acre (0.15 lb a.i./A or 3.44E-06 

lbs a.i./ft2) per application of 0.08% Mesotrione on Fertilizer. The absorbed dose was 

assumed to be 1% for dermal exposure. Dermal risks were assessed against a lowest 

observed adverse effect level (LOAEL) of 2.1 mg/kg-bw/day from a mouse reproduction 

study. 

Residential handler risks were calculated for granular application of mesotrione. The 

short-term MOEs were 8,129 (Granular Open Pour Belly Grinder Loader Applicator) and 

164,815 (Push Spreader Loader Applicator). Since the calculated residential hander 

exposures were found to be well above the EPA’s level of concern (MOEs>300), there 

does not appear to be an unacceptable level of risk to residential handlers resulting from 

applications of mesotrione products to turf.

Post-application dermal exposure risks for adults and youths due to physical activities on 

turf, mowing, and golfing were calculated for mesotrione using the calculated TTR value 

of 0.0056 μg/cm2. The short-term MOEs for high contact dermal exposure resulting from 

activities on turf were 9,983 (adults 26-81 years old), and 5,084 (children 1-2 years old). 

The short-term MOEs for mowing were 544,553 (adults 26-81 years old) and 474,215 

(youths 11-16 years old). The short-term MOEs for golfing were 141,276 (adults 26-81 

years old), 121,248 (youths 11-16 years old), and 103,277 (youths 6-11 years old). The 

calculated post-application exposures were found to be well above the EPA’s level of 

concern (MOEs > 300).

Post-application dermal exposure risks for adults and youths due to physical activities on 

turf, mowing, and golfing were calculated for TenacityTM using the calculated TTR value 

of 0.083 μg/cm2

. The short-term MOEs for high contact dermal exposure resulting from 

activities on turf were 2,219 (adults 26-81 years old), and 1,121 (children 1-2 years old). 

The short-term MOEs for mowing were 108,911 (adults 26-81 years old) and 94,843 

(youths 11-16 years old). The short-term MOEs for golfing were 28,255 (adults 26-81 
6

years old), 24,250 (youths 11-16 years old), and 20,655 (youths 6-11 years old). The 

calculated post-application exposures were found to be well above the EPA’s level of 

concern (MOEs > 300).

D. Cumulative Effects

Cumulative Exposure to Substances with a Common Mechanism of Toxicity. Section 

408(b)(2)(D)(v) requires that, when considering whether to establish, modify, or revoke a 

tolerance, the Agency consider “available information” concerning the cumulative effects 

of a particular pesticide’s residues and “other substances that have a common mechanism 

of toxicity”. The EPA does not have, at this time, available data to determine whether 

mesotrione has a common mechanism of toxicity with other substances or how to include 

this pesticide in a cumulative risk assessment. For the purposes of this tolerance action, 

the EPA has not assumed that mesotrione has a common mechanism of toxicity with 

other substances.

E. Safety Determination

1. U.S. population. The chronic dietary exposure analysis (food plus water) 

showed that exposure from all registered, pending and proposed mesotrione crop uses 

result in a MOE of 5,769 (5.2% of the chronic RfD) for the general U.S. population. 

2. Infants and children. The chronic dietary exposure analysis (food plus water) 

showed that exposure from all registered, pending and proposed mesotrione uses would 

result in a MOE of 2,266 (13.2% of the chronic RfD) for infants less than one year old 

(the most sensitive population subgroup). A short-term aggregate MOE of 338 (LOC = 

300) was determined for children (1-6 years old). All aggregate MOEs exceed the 

benchmark MOE of 300.

F. International Tolerances

There are currently no Maximum Residue Limits (MRLs) set for mesotrione for crops by 

the Codex Alimentarius Commission. International MRLs for the herbicide mesotrione 

have been established for various agricultural commodities in a number of countries 

including Argentina, Austria, Belgium, Brazil, Czech Republic, Denmark, France, 

Germany, Greece, Hungary, Italy, Luxembourg, Morocco, Netherlands, Serbia and 

Montenegro, Slovak Republic, Slovenia, South Africa, and the United States.