T opramezone Human-Health Assessment Scoping Document 0425613 

UNITED STATES ENVIRONMENT AL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

OFFICE OF CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

MEMORANDUM 

Date: 

Subject: 

July IO, 20 15 

Topramezone. Human-Health Assessment Scoping Document in Support of 

Registratio n Review. 

PC Code: 123009 

Decision No.: 49992 1 

Petition No.: NA 

DP Barcode: D425613 

Registration No.: NA 

Regulatory Action: Registration Review 

Risk Assessment Type: NA Case No.: NA 

TXR No.: NA CAS No.: 2 1063 1-68-8 

MRID No.: NA 40 CFR: § 180.6 12 

From: 

Thru: 

To: 

Cassi L. Walls, Ph.D., Senior Biologist{l/i>v< .. Z~ Sa

Monique 

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Josh Godsha ll, Biologist 5 

Risk Assessment Branch 1 (RAB 1) 

Health Effects Division (HED, 7509P) / ------

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George F. 

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Acting 

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#J-~ ~ RAB l/HED (7509P) 

Jose Gayoso, Chemical Review Manager 

RMIB2/Pesticidc Re-Evaluation Division (PRO) (7508P) 

Office of Pestic ide Programs 

Attached is HED's human-health risk assessment scoping document for topramezone ([3-(4,5-

dihydro-3-isoxazolyl)-2-methyl-4-(methylsul fonyl)phenyl](S-hydroxy-1-methyl- l H-pyrazol-4-

yl)methanone) submitted in support of Registratio n Review. To evaluate the scope of work 

necessary to support Registration Review, HED has considered recent risk assessments for 

topramezone, updates to its toxicity, exposure and usage databases, and the latest Agency science 

policy and risk assessment methodologies. The most recent risk assessment for topramezone 

was conducted in 2013 for a new use on non-crop aquatic sites (0400310 and D404014, C. 

Rodriguez. 05/30/20 13). 

Pagt: I of25 
Topramezone Human-Health Assessment Scoping Document 0425613 

Executive Summary 

Topramezone is a pre- and post-emergence herbicide used to control broad leaf weeds and 

grasses by inhibition of the enzyme 4-hydroxyphenylpyruvate dioxygenase (HPPD) and blocks 

the pathway of phenylquinone biosynthesis in plants. lt is currently registered for use on 

residential turf grass, golf courses, sod farms, non-crop ornamentals, rights-of-way, tree 

plantations, aquatic vegetation, and other non-crop areas, as well as for appl ication to corn (field, 

pop, seed, and sweet) with tolerances ranging from 0.01 to 0.80 ppm ( 40 CFR § 180.612). 

The toxicity database for topramezone is complete as required by the 2007 revised 40 CFR 

Toxicology Data Requirements. No additional toxicological studies are currently required. As 

part of Registration Review, the endpoints, doses. and safety factors used in the most recent risk 

assessment will be re-evaluated according to current I-I ED policy. 

The residue chemistry database is sufficient to support the current registrations of lopramczone. 

The nature of the residue in the registered primary crops and li vestock has been adeq uately 

defined. Adequate field trial/processing data, storage stability data, rotational crop data, and 

enforcement methods are available. 

New dietary exposure and aggregate risk assessments are not anticipated during Registration 

Review, unless there are significant increases to the drinking water exposure estimates that need 

to be incorporated and/or there are updates to the toxicity endpoints or safety factors. 

New residential handler and post-application residential exposure and risk assessments arc not 

anticipated to be needed during Registration Review unless there are updates to the toxicity 

endpoints or safety fac tors. Occupational handler and post-application exposure and risk 

assessments are needed during Registration Review lo account for recent changes in exposure 

assessment assumptions, including body weight, amount treated, and transfer coefficients. as 

well as any updates to the toxicity endpoints or safety factors. 

Aggregate exposure to topramezone is currently not of concern to HED. New aggregate 

assessments are not anticipated to be needed during Registration Review, unless there arc 

changes in uses. procedures, drinking water exposure estimates, toxicity endpoints, and/or safety 

factors. 

The Agency will examine the need for spray drift and volatilization assessments during 

Registration Review for topramezone based on the potential for exposure to bystanders from 

agricultural applicatio ns. 

No data defi ciencies were identified for topramezone. HED notes the following risk assessment 

updates may be needed during Registration Review: 

• Toxicology: Endpoints, doses, and safety factors used in the most recent risk 

assessment will be re-evaluated according to cun-ent I !ED policy 

• Residue Chemistry/Dietary Exposure: A revised dietary-exposure analysis may be 

required to reflect significant changes to the drinking water exposure estimates, 

and/or updates to the toxicity endpoints or safety factors. 

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 Occupational/Residential Exposure: Residential handler and post-application 

residential exposure and risk assessment may be updated to reflect changes in toxicity 

endpoints or safety factors. Updated occupational handler assessments will be 

required using current ORE policies as well as any changes to the toxicity endpoints 

or safety factors. Additionally, the need for spray drift and volatilization risk 

assessments will be examined during Registration Review. 

 Aggregate Exposure: An updated aggregate assessment may be needed if there are 

changes in uses, procedures, drinking water exposure estimates, toxicity endpoints 

and/or safety factors.

1.0 Introduction

Topramezone is currently registered for weed post-emergence application to aquatic areas/water, 

Christmas tree plantations, corn (field, pop, sweet, and seed), nonagricultural uncultivated 

areas/soil, nursery stock, and turf (sod farms, ornamental, golf course, recreational, residential); 

for application to agricultural fallow/idle-land/conservation reserve; and for post-transplant

application to forest trees (hardwood and broadleaf trees). Topramezone end use products are 

formulated as suspended concentrates (SC). Applications can be made with ground, aerial, and 

hand held spray equipment. The most recent risk assessment for topramezone was conducted in

2013 for a new use on non-crop aquatic sites (D400310 and D404014, C. Rodriguez, 

05/30/2013). Refer to Attachment 1 for the chemical identity of topramezone. A summary of 

the use patterns is provided in Attachment 6.

2.0 Hazard Identification/Toxicology

Topramezone is an inhibitor of the enzyme HPPD and blocks the pathway of phenylquinone 

biosynthesis in plants. Topramezone has a structural and toxicological profile that is similar to 

mesotrione. For mesotrione, a wealth of mechanistic data are available both experimentally and 

in the literature which thoroughly characterize its molecular initiating event and adverse outcome 

pathway. 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. Although extensive mechanistic data are not available for topramezone, 

there is strong evidence of tyrosinemia in its database including dose-dependent increases in 

serum tyrosine measured in prenatal developmental toxicity studies (mice and rabbits). 

Similar to other HPPD inhibiting chemicals, the rat was the most sensitive species and males 

were found to be more sensitive than females (in rats and dogs). In rat subchronic and chronic 

oral studies, topramezone produced ocular (corneal vascularization, opacity, and keratitis) and 

kidney (microscopic findings and increased organ weights) effects, which are consistent with the 

mammalian toxicity profile for HPPD inhibitors caused by high tyrosine levels in the blood. 

Histopathological findings in the thyroid were frequently observed in rats and dogs following 

topramezone exposure. Thyroid tumors via a non-linear mode of action involving thyroid 

hormone disruption were seen in the rat; however, topramezone is classified as “not likely to be 

carcinogenic to humans at doses that do not alter rat thyroid hormone homeostasis.” Additional 
Topramezone Human-Health Assessment Scoping Document D425613

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histopathological findings were seen in the pancreas of rats and the urinary bladder in dogs. 

Body weight decrements were also noted in all species, including the mouse, which did not 

exhibit any other adverse effects in the database. 

There is evidence of increased prenatal susceptibility following in utero exposures to rats and 

rabbits. In rats and rabbits, fetal skeletal variations and abnormalities were observed in all 

developmental toxicity studies and are consistent with those reported in the toxicological 

databases for other HPPD inhibiting chemicals. No increased susceptibility was observed in the 

rat reproduction toxicity study. A developmental neurotoxicity study (DNT) in rats is also 

available for topramezone. Offspring effects included neurobehavioral and neuropathological 

changes while toxicity in maternal animals was limited to corneal opacity. Although these 

offspring effects are indicators of potential neurotoxicity, there were no effects seen in the acute 

neurotoxicity study (ACN) up to the limit dose and effects in the subchronic neurotoxicity study 

(SCN) were consistent with the rest of the database (ocular effects and histopathological findings 

in the pancreas and thyroid). In the mouse, elevated tyrosine blood levels were noted in maternal 

animals; however, there were no developmental effects observed. 

Topramezone is classified as having low acute toxicity (Toxicity Category III or IV) via the oral, 

dermal, and inhalation routes). It was found to be a slight eye and dermal irritant, but it was not 

found to be a dermal sensitizer. 

The endpoints and points of departure (PODs) from the last quantitative human-health risk 

assessment for topramezone (C. Rodriguez; 30-MAY-2013; D400310 and D404014) can be 

found in Attachment 4. Since the last assessment, an acceptable immunotoxicity study in mice 

has been submitted and reviewed for topramezone with no effects seen up to the highest dose 

tested (1615 mg/kg/day). A subchronic inhalation toxicity study is not available for 

topramezone, as required in accordance with the current 40 CFR Part 158 Toxicology Data 

Requirements; however, the Hazard and Science Policy Council (HASPOC) concluded, using a 

weight-of-evidence approach, that this study is not required for topramezone at this time (K. 

Rury; 01/30/13; TXR 0056531). 

Conclusions: The toxicity database for topramezone is complete as required by the 2007 revised 

40 CFR Toxicology Data Requirements. No additional toxicological studies are currently 

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

most recent risk assessment will be re-evaluated according to current HED policy.

3.0 Residue Chemistry/Dietary Exposure

Tolerances are currently established under 40 CFR §180.612 for residues of topramezone, 

including its metabolites and degradates. Compliance with the tolerance levels are to be 

determined by measuring only topramezone. Tolerances for corn commodities range from 0.01-

0.05 ppm and for fish and livestock meat byproducts from 0.02-0.80 ppm.

The qualitative nature of topramezone residues in corn and ruminants is adequately understood 

based on acceptable corn and goat metabolism studies; an adequate confined rotational crop 

study has also been submitted. HED previously concluded that topramezone per se is the residue 

of concern, for purposes of tolerance enforcement and risk assessment, in corn, rotational crops, 

and ruminants. An adequate poultry metabolism study has also been submitted. Based on these 
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data and the current dietary burden, residues in poultry are expected to be negligible. HED 

indicated that if a future proposed use significantly increases the poultry dietary burden, then a

poultry feeding study, which monitors for residues of parent and metabolite M670H02, may be 

required. Adequate analytical enforcement methods are available. Additionally, adequate field 

trial, processing, and storage stability data are available.

Unrefined acute and chronic aggregate dietary (food and drinking water) exposure and risk 

assessments were conducted for topramezone using the Dietary Exposure Evaluation Model 

software with the Food Commodity Intake Database (DEEM-FCID) Version 3.16, which uses 

food consumption data from the U.S. Department of Agriculture’s National Health and Nutrition 

Examination Survey, What We Eat in America, (NHANES/WWEIA). The assessments assumed 

tolerance-level residues, DEEM 7.81 default processing factors, and 100% crop treated (%CT) 

for all registered commodities (S. Levy, 05/15/13; D400947). The drinking water residues used 

in the dietary risk assessment were provided by the Environmental Fate and Effects Division 

(EFED) (J. Wolf, 01/29/13; D408687) and incorporated directly into the acute and chronic 

dietary assessments. The highest topramezone estimated drinking water concentrations (EDWC)

is expected to result from the direct aquatic applications. The EDWCs were based on the 

registered use for water bodies with functional potable water intakes, which cannot exceed 45 

ppb.

The acute and chronic dietary assessments show that the acute and chronic dietary risk estimates 

are below HED’s level of concern (i.e., <100% of the acute or chronic population adjusted doses 

(aPAD or cPAD). The acute dietary risk estimate for females 13-49 years old at the 95th

percentile of exposure was 50% of the aPAD. For the general US population and the most 

highly exposed population subgroup (all infants <1 year old), the risk for food and drinking 

water utilized 32% and 98% of the aPAD, respectively. For the general US population, the risk 

for food and drinking water utilized 25% of the cPAD. The chronic dietary risk estimate for the 

highest reported exposed population subgroup, all infants <1 year old, utilized 62% of the cPAD. 

Conclusions: The residue chemistry and dietary-exposure database is adequate to support 

current registration requirements. No additional data are required at this time. In the most recent 

risk assessment, acute and chronic dietary exposures were not of concern to HED. Therefore, a

new dietary exposure assessment is not anticipated to be needed during Registration Review 

unless there are significant increases to the drinking water exposure estimates and/or there are 

updates to the toxicity endpoints or safety factors.

4.0 Residential Exposure

Topramezone is currently registered for residential/public area uses on turf (sod farms, golf 

courses, recreational, residential) and aquatic areas/water (ponds, lakes, reservoirs, and 

shoreline). There is potential for short-term residential exposure to topramezone during handling 

(mixing, loading, and applying) and post-application activities. 

Residential Handlers 

Since topramezone is not a restricted-use pesticide (RUP) a residential handler exposure 

assessment was previously performed (D388367, K. Lowe, 02/02/12). Spot or broadcast 

applications can be made using handheld spray equipment to turf. The residential handler 
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assessment was only conducted resulting in total (dermal + inhalation) margins of exposure 

(MOEs) ranging from 1,800 to 3,900 and are not of concern (MOE > 100). 

Residential Post-Application 

Short-term dermal and incidental oral exposure and risk estimates were assessed using the 2012 

Residential Standard Operating Procedures (SOPs) in the latest topramezone occupational and 

residential exposure (ORE) assessments (D388367, K. Lowe, 02/02/12 and D400310/D404014, 

C. Rodriguez, 05/30/13). These assessments considered post-application exposures to treated 

turf and aquatic environments. A turf transferrable residue (TTR) study has been submitted, 

reviewed, and found to be acceptable for risk assessment (MRID 48379401). These data were

incorporated into the most-recent post-application exposure assessment to treated turf in place of 

default assumptions for residue transfer. 

Post-application MOEs were not of concern (MOEs >100) for any of the registered residential 

uses of topramezone. The short-term adult dermal post-application MOEs range from 480 to 

9,100,000. The short-term combined incidental oral and dermal MOE for children 1 to <2 years 

old is 210. 

Spray Drift or Volatilization

Residential bystander exposures resulting from off-site transport (e.g., spray drift or 

volatilization) may occur as a result of applications of topramezone. The potential for spray drift 

will be 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. In terms of volatilization, the agency has developed a Volatilization Screening Tool and a 

subsequent Volatilization Screening Analysis 

(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 topramezone.

Conclusions: The registered residential uses of topramezone have been assessed using the 

maximum application rates and revised 2012 Residential SOPs. New residential handler and 

post-application residential exposure and risk assessments are not anticipated to be needed 

during Registration Review unless there are updates to the toxicity endpoints or safety factors. 

Further, the Agency will examine the need for a volatilization assessment, as well as evaluate the 

potential topramezone exposure from spray drift during Registration Review.

5.0 Aggregate Risk Assessment

Aggregate assessments consider exposures from food, drinking water, and residential uses. 

Since there are residential uses of topramezone, aggregate risk considers residential handler and 

post-application exposures, food, and drinking water.

In the most recent human health risk assessment (D400310 and D40414, C. Rodriguez, 

05/30/2013), an acute aggregate risk assessment, which is equivalent to the acute dietary risk 

assessment, was not of concern to HED. Chronic exposure from the residential pathway is not 
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anticipated based on the current topramezone use pattern. Therefore, the chronic aggregate risk 

(food and drinking water) is equivalent to the chronic dietary (food and drinking water) exposure 

estimate, which was not of concern to HED. An aggregate cancer risk assessment was not 

performed since topramezone is classified as “not likely to be carcinogenic to humans at doses 

that do not alter rat thyroid hormone homeostasis”.

A short-term aggregate risk assessment was conducted for adults and children. For adults, the 

pathways assessed for aggregate exposure include oral dietary (background), and postapplication dermal (primary) routes. For children, the pathways assessed for aggregate exposure 

include oral dietary (background), incidental oral, and dermal (primary) routes from postapplication exposure. The adult and children short-term aggregate dietary and residential MOEs 

are 220 and 120, respectively (LOC = 100).

Conclusions: Aggregate exposure to topramezone is currently not of concern to HED. New 

aggregate assessments are not anticipated to be needed during Registration Review, unless there 

are changes in uses, procedures, drinking water exposure estimates, toxicity endpoints, and/or 

safety factors.

6.0 Occupational Exposure

Topramezone is registered for weed control in post-emergence application to aquatic areas/water, 

Christmas tree plantations, corn (field, pop, sweet, and seed), nonagricultural uncultivated 

areas/soil, nursery stock, and turf (sod farms, ornamental, golf course, recreational, residential); 

for fallow application to agricultural fallow/idle-land/conservation reserve; and for posttransplant application to forest trees (hardwood and broadleaf trees). There is potential for shortand intermediate-term occupational exposure to topramezone during handling (mixing, loading, 

and applying) and post-application activities.

Occupational Handlers

The registered topramezone labels require occupational handlers to wear long sleeved shirts, 

long pants, shoes, socks, chemical resistant gloves, and in some cases goggles, face shield, or 

safety glasses. Applications can be made using ground, aerial, and handheld spray equipment. 

Mixer/loaders supporting aerial applications to aquatic areas are required to employ closed 

systems. The updated occupational exposure assessment policies and body weight assumptions 

were incorporated into the non-crop terrestrial, aquatic, and turf topramezone exposure 

assessments, however updated assessments will be needed for occupational handlers of 

topramezone for the treatment of corn and all exposure scenarios if there are changes in the 

toxicity endpoints or safety factors. All current occupational handler MOEs are not of concern 

(MOE > 100). 

Occupational Post-Application

Occupational post-application short- and intermediate-term dermal exposures are possible for 

workers contacting treated crops. Although the MOEs in the most recent occupational postapplication exposure assessment for corn are not of concern (MOE > 100), it did not incorporate 

updated exposure assessment policies utilizing changes in transfer coefficients and body weight 

assumptions (M. Dow, D317065, 05/09/05). Therefore, an updated occupational postapplication exposure assessment will be required during Registration Review for the 

topramezone use on corn and all exposure scenarios if there are changes in the toxicity endpoints 
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or safety factors. 

Dislodgeable Foliar Residue (DFR): In accordance with 40CFR §158, DFR data are required

for all occupational (e.g., crop, nursery, greenhouse use sites) or residential (e.g., ornamental and 

vegetable gardens, pick your own farms, retail tree farms) uses that could result in postapplication exposure to foliage. In the absence of chemical-specific DFR data, EPA uses default 

values. The 2012 Standard Operating Procedures for Residential Pesticide Exposure 

Assessment includes an analysis of a number of DFR studies, which resulted in the selection of a 

revised default values for the fraction of the application rate available for transfer after a foliar 

application (FAR). These values are based on an analysis of 19 DFR studies. Since that time, the 

Agricultural Re-entry Task Force (ARTF) has submitted information (MRID 49299201) that 

corrects an application rate error made in the original submission of “ARF039 – Determination 

of Dermal and Inhalation Exposure to Reentry Workers During Chrysanthemum Pinching in a 

Greenhouse” (EPA MRID 45344501). As a result, the range of FAR values was revised from 2% 

- 89% to 2% - 47%. In the data, a large range of transferability is observed and this variability 

can potentially be attributable to many factors such as active ingredient; formulation; field 

conditions in the studies; weather conditions (e.g., humidity); or many other difficult to quantify 

factors. Although witnessed across multiple chemicals, this range in FAR values is not expected 

when considering DFR data for a single chemical. At this time, the ARTF submission did not 

alter the selection of 25% as the reasonable, high-end default value. Because DFR data are not 

available for topramezone EPA is using the default value of 25%. Although there may be a 

small degree of uncertainty in the use of the default DFR value for topramezone (i.e., there is a 

small chance that the FAR value may exceed the applicable default value), it is likely that the 

health-protective aspects of EPA’s occupational post-application assessment methodology will 

more than compensate for this potential uncertainty. For example, when assessing residential 

and occupational post-application exposure to gardens and ornamentals, EPA assumes the 

following: exposures occur to zero-day (i.e., day of application ) residues every day of the 

assessed exposure duration (i.e., EPA assumes that no dissipation or degradation occurs, it 

doesn’t rain, etc); individuals perform the same post-application activities performed in the 

transfer coefficient study day after day (e.g., weeding, harvesting, pruning, etc.); and individuals 

engage in these post-application activities for a high-end amount of time every day (represented 

by data reflecting time spent gardening based on survey data).

Given the conservatisms discussed above and the potential compounding nature of these 

conservatisms, EPA is able to rely upon the calculated exposure estimates with confidence that 

exposure is not being underestimated. Therefore, DFR studies are not anticipated to be needed at 

this time.

Conclusions: There is sufficient information available to assess occupational handler and postapplication exposures. There is an acceptable TTR study available to evaluate the postapplication exposure to topramezone on turf. Updated occupational handler and post-application 

exposure assessments will be conducted during Registration Review for topramezone use on 

corn and all exposure scenarios if there are changes in the toxicity endpoints or safety factors. 

Based on existing and anticipated occupational post-application risk estimates and the current 

toxicological PODs, DFR studies are not anticipated to be needed at this time.

7.0 Public Health and Pesticide Epidemiology Data
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Based on the low frequency and severity of incident cases reported for topramezone in both the 

OPP Incident Data System (IDS) and the Centers for Disease Control and Prevention/National 

Institute for Occupational Safety and Health (CDC/NIOSH) Sentinel Event Notification System 

for Occupational Risk-Pesticides (SENSOR), there does not appear to be a concern at this time 

that would warrant further investigation. For the Main IDS, from January 1, 2010 to February 4, 

2015, there were zero incidents reported for the single chemical only in the database. In 

Aggregate IDS, from January 1, 2010 to February 4, 2015, there were three incidents reported 

involving topramezone. These incidents were classified as minor severity. Overall, there are 

few incidents involving topramezone reported to IDS. 

A query of the Sentinel Event Notification System for Occupational Risk (SENSOR)-Pesticides 

database for 1998-2011 identified zero cases involving topramezone. 

The Agricultural Health Study (AHS) is a high quality, prospective epidemiology study 

evaluating the link between pesticide use and various health outcomes including cancer. The 

AHS includes private and commercial pesticide applicators and their spouses. If there are AHS 

findings relevant to a particular pesticide going through registration review, the Agency will 

ensure they are considered in the problem formulation/scoping phase of the process and, if 

appropriate, fully reviewed in the risk assessment phase of the process. The AHS includes 

information on use of 50 different pesticide active ingredients commonly used in agriculture. 

Topramezone is not included in the AHS, and therefore, this study does not provide information 

for this report.

The Agency will continue to monitor the incident information and if a concern is triggered, 

additional analysis will be included in the risk assessment.

Conclusions: Based on the low frequency and low severity of incident cases reported for 

topramezone in both IDS and SENSOR-Pesticides databases, there does not appear to be a 

concern at this time that would warrant further investigation. The Agency will continue to 

monitor the incident information and if a concern is triggered, additional analysis will be 

included in the risk assessment.

8.0 Tolerance Assessment and International Harmonization

U.S. permanent tolerances (listed in 40 CFR §180.612) and Canadian, Codex, and Mexican 

maximum residue limits (MRLs) are summarized in Attachment 3.

Conclusions: Residue definitions and MRLs for topramezone have not been established by 

Codex or Mexican maximum residue limits (MRLs) (see Attachment 3). Canada has established 

MRLs for residues of topramezone per se in/on the following: corn, liver (cattle, goat, horses, 

and sheep) - 0.15 ppm; meat byproducts (except liver; cattle, goat, horses, and sheep) - 0.05 

ppm; and hog meat byproducts - 0.05 ppm. Harmonization of tolerances/MRLs for residues of 

topramezone in/on livestock commodities was not considered previously because the Canadian 

MRLs are too low to permit harmonization. As part of Registration Review, the international 

MRLs will be revaluated and tolerances harmonized when possible. 

9.0 Environmental Justice
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Potential areas of environmental justice concerns, to the extent possible, will be considered in the 

registration review, in accordance with US 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). 

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 

under the NHANES/WWEIA and are used in pesticide risk assessments for all registered food 

uses of a pesticide. These data are analyzed and categorized by subgroups based on age and

ethnic group. 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.

10.0 Cumulative

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 

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 
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cross species extrapolation methods. Therefore, EPA has not conducted cumulative risk 

assessment with other HPPD inhibitors. 

11.0 Human Studies

The risk assessments which have been previously conducted for topramezone relied in part on 

data from studies in which adult human subjects were intentionally exposed to a pesticide to 

determine their dermal and inhalation exposure. Many such studies, involving exposure to many 

different pesticides, comprise generic pesticide exposure databases such as the Pesticide 

Handlers Exposure Database (PHED), the Outdoor Residential Exposure Task Force (ORETF), 

and the ARTF Database. EPA has reviewed all the studies supporting these multi-pesticide 

generic exposure databases, and has found no clear and convincing evidence that the conduct of 

any of them was either fundamentally unethical or significantly deficient relative to the ethical 

standards prevailing at the time the research was conducted. All applicable requirements of 

EPA’s Rule for the Protection of Human Subjects of Research (40 CFR Part 26) have been 

satisfied, and there is no regulatory barrier to continued reliance on these studies.

12.0 Data Deficiencies

No toxicological data, residue chemistry, or occupational and residential exposure data are 

needed to support the registered uses of topramezone at this time. HED notes the following risk 

assessment updates may be needed during Registration Review: 

 Toxicology: Endpoints, doses, and safety factors used in the most recent risk 

assessment will be re-evaluated according to current HED policy

 Residue Chemistry/Dietary Exposure: A revised dietary-exposure analysis may be 

required to reflect significant changes to the drinking water exposure estimates and/or 

updates to the toxicity endpoints or safety factors. 

 Occupational/Residential Exposure: Residential handler and post-application 

residential exposure and risk assessment may be updated to reflect changes in toxicity 

endpoints or safety factors. Updated occupational handler assessments will be 

required using current ORE policies as well as any changes to the toxicity endpoints 

or safety factors. Additionally, the need for spray drift and volatilization risk 

assessments will be examined during Registration Review. 

 Aggregate Exposure: An updated aggregate assessment may be needed if there are 

changes in uses, procedures, drinking water exposure estimates, toxicity endpoints 

and/or safety factors.

References

Recent Memoranda Relevant to Registration Review of Topramezone

Author DP/TXR # Date Title

Risk Assessment

C. Rodriguez D400310, 

D404014

05/30/13 Topramezone: Human-Health Risk Assessment for (1) New Uses 

in Non-Crop Aquatic Sites and (2) Increased Maximum 

Application Rate for Currently Registered Terrestrial Uses in the 

Maintenance of Bare Grounds (Roadsides, Utility and Railroad 

Rights-of-Ways, Industrial Sites, and Tank Farms).
Topramezone Human-Health Assessment Scoping Document D425613

Page 12 of 25

Recent Memoranda Relevant to Registration Review of Topramezone

Author DP/TXR # Date Title

K. Lowe D388367 02/02/12 Topramezone: Human-Health Risk Assessment for Proposed 

Uses on Golf Courses, Sod Farms, and Residential Turfgrass.

Residue Chemistry

T. Bloem D400949 02/26/13 Topramezone. Section 3 Registration Concerning Noncrop 

Aquatic-Application. Summary of Analytical Chemistry and 

Residue Data

G. Kramer D310772 05/11/05 Topramezone (BAS 670 H) Acute and Chronic Dietary Exposure 

Assessments for a Petition for Tolerances on Corn

Dietary Exposure Assessment

S. Levy D400947 05/15/13 Topramezone. Acute and Chronic Aggregate Dietary (Food and 

Drinking Water) Exposure and Risk Assessments for the Section 3 

Registration Action Concerning Non-crop Aquatic Application.

S. Levy D388806 06/06/12 Topramezone. Acute and Chronic Aggregate Dietary (Food + 

Drinking Water) Exposure and Risk Assessment for the Section 3 

Registration Action Uses on Golf Courses, Sod Farms, and 

Residential Turfgrass.

G. Kramer D314719 05/09/02 Topramezone (BAS 670 H) Acute and Chronic Dietary Exposure 

Assessments for a Petition for Tolerances on Corn

Occupational and Residential Exposure Assessment

T. Bloem D400948 02/26/13 Topramezone. Section 3 Registration Concerning Application to 

Noncrop Aquatic and Noncrop Terrestrial Areas. Occupational and 

Residential Exposure and Risk Assessment.

K. Lowe D388807 02/02/12 Topramezone: Occupational and Residential Exposure/Risk 

Assessment for Proposed Uses on Golf Courses, Sod Farms, and 

Residential Turf grass.

M. Dow D317065 05/09/05 TOPRAMEZONE (BAS 670 H) - Exposure/Risk Assessment for 

the Proposed Use of Topramezone On Corn (Field, Pop, Seed and 

Sweet)

Incident Report

E. Evans 03/01/15 Topramezone: Tier I Review of Human Incidents

Toxicology

K. Rury TXR 0056531 01/30/13 Topramezone: Summary of Hazard and Science Policy Council 

(HASPOC) Meetings of December 6, 2012 and December 19, 

2012: Reconsideration on the Need for a 28-day Inhalation Study
Topramezone Human-Health Assessment Scoping Document D425613

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Attachments

1. Chemical Identity Table

2. Physicochemical Properties of Technical Grade Topramezone Table

3. Tolerance/MRL Summary Table

4. Endpoint Selection Tables

5. Toxicity Profile Tables

6. Summary of Use Profile
Topramezone Human-Health Assessment Scoping Document D425613

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Attachment 1

Chemical Identity Table

Topramezone Nomenclature.

Structure

Common name topramezone

Company experimental name BAS 670 H

IUPAC name [3-(4,5-dihydro-1,2-oxazol-3-yl)-4-mesyl-o-tolyl](5-hydroxy-1-methyl-1H-pyrazol-4-

yl)methanone

CAS name [3-(4,5-dihydro-3-isoxazolyl)-2-methyl-4-(methylsulfonyl)phenyl](5-hydroxy-1-methyl-1Hpyrazol-4-yl)methanone

CAS # 210631-68-8

End-use product/EP emulsifiable concentrate

O

N

N

N

CH3

OH S

O CH3

O O

CH3
Topramezone Human-Health Assessment Scoping Document D425613

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Attachment 2

Physicochemical Properties of Technical Grade Topramezone Table

Physicochemical Properties of Physicochemical Properties of Topramezone.

Melting point/range 220.9°C - 222.2°C

http://toxnet.nlm.nih.gov/cgibin/sis/search/a?dbs+hsdb:@term+

@DOCNO+7500

pH 2.9 (1% de-ionized water)

Density (20°C) 1.425 g/cm3

Water solubility (20°C) 510 mg/L at pH 3.1; >100 g/L at pH >9

Solvent solubility (g/100 ml at 20°C)

Acetone <1.0; Acetonitrile <1.0; 

Dichloromethane 2.5-2.9; 

N,N-dimethylformamide 11.4-13.3; 

Ethyl acetate <1.0; N-Heptane <1.0; 

Methanol <1.0; 1-Octanol <1.0; 

Olive oil <1.0; 2-Propanol <1.0; 

Toluene <1.0

Vapor pressure (20°C) 7.5 x 10-13 mm Hg

Dissociation constant (pKa; 20°C) 4.06

Octanol/water partition coefficient (Log KOW; 20°C) pH 4: -0.81; pH 7: -1.52; pH 9: -2.34

UV/visible absorption spectrum (ξ, mol-1cm-1) alphamax = 207 nm
Topramezone Human-Health Assessment Scoping Document D425613

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Attachment 3

Tolerance/MRL Tables

Summary of U.S. Tolerances and International MRLs

U.S. Canada Mexico1 Codex

Residue Definition:

40 CFR§180.612

(a) General. Tolerances are established for residues of the 

herbicide topramezone, including its metabolites and 

degradates, in or on the following commodities. Compliance 

with the following tolerance levels is to be determined by 

measuring only topramezone ([3-(4,5-dihydro-3-isoxazolyl)-

2-methyl-4-(methylsulfonyl)phenyl](5-hydroxy-1-methyl1H-pyrazol-4-yl)methanone) 

[3-(4,5-dihydro-3-

isoxazolyl)-2-methyl-4-

(methylsulfonyl)phenyl](5-

hydroxy-1-methyl-1Hpyrazol-4-yl)methanone

None

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

Commodity U.S. Canada Mexico1 Codex

Cattle, meat byproducts 0.80 0.05 (except liver)

0.15 liver of cattle

Corn, field, forage 0.05

Corn, field, grain 0.01 0.01

Corn, field, stover 0.05

Corn, pop, grain 0.01

Corn, pop, stover 0.05

Corn, sweet, forage 0.05

Corn, sweet, kernel plus cob with husks removed 0.01 0.01

Corn, sweet, stover 0.05

Fish-freshwater finfish 0.05

Fish-saltwater finfish 0.05

Fish-shellfish, crustacean 0.05

Fish, shellfish, mollusk 0.05

Goat, meat byproducts 0.80 0.05 (except liver)

0.15 liver of goats

Hog, meat byproducts 0.40 0.05 

Horse, meat byproducts 0.80 0.05 (except liver)

0.15 liver of horses

Poultry, meat byproducts 0.02

Sheep, meat byproducts 0.80 0.05 (except liver)

0.15 liver of sheep

Fat of cattle 0.05

Fat of goats 0.05

Fat of hogs 0.05

Fat of horses 0.05

Fat of sheep 0.05

Meat of cattle 0.01

Meat of goats 0.01

Meat of hogs 0.01

Meat of horses 0.01

Meat of sheep 0.01

Milk 0.01

Completed by: M. Negussie; 06/22/15

1 Mexico defers to US tolerances and/or Codex MRLs for its export purposes. 
Topramezone Human-Health Assessment Scoping Document D425613

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Attachment 4

Endpoint Selection Tables

Summary of Toxicology Endpoints and PODs for Topramezone in Dietary and Non-Occupational Risk Assessment.

Exposure

Scenario POD

Uncertainty/ FQPA Safety 

Factors or LOC for Risk 

Assessment

Study and Toxicological Effects

Acute Dietary

(General 

population 

including infants 

and children)

LOAEL = 8 mg/kg bw

UF = 100X

(for inter- and intraspecies extrapolation)

FQPA SF = 10X

aRfD = 0.08 mg/kg bw

aPAD = 0.008 mg/kg bw

Developmental Neurotoxicity Study in 

Rats

Offspring LOAEL = 8 mg/kg bw based on 

decreased maximum auditory startle reflex 

response, decreased brain weights, and 

changes in brain morphology.

Acute Dietary 

(Females 13-49 

years old)

NOAEL = 0.5 mg/kg/day

UF = 100X

(for inter- and intraspecies extrapolation)

FQPA SF = 1X

aRfD = 0.005 mg/kg/day

aPAD = 0.005 mg/kg/day

Developmental Toxicity Study in Rabbits

Developmental LOAEL = 5 mg/kg/day 

based on alterations in skeletal ossification 

sites and increased number of pairs of ribs.

Chronic Dietary

(All populations) NOAEL = 0.4 mg/kg/day

UF = 100X

(for inter- and intraspecies extrapolation)

FQPA SF = 1X

cRfD = 0.004 mg/kg/day

cPAD = 0.004 mg/kg/day

Chronic toxicity/Carcinogenicity Study in 

Rats

LOAEL = 3.6 mg/kg/day based on 

increased incidences of corneal opacity, 

decreased body weight and body-weight 

gains in males and histopathological 

evaluations in the eyes, thyroid and 

pancreas of both sexes.

Incidental Oral

(Short- and 

IntermediateTerm)

NOAEL = 0.4 mg/kg/day Residential LOC for MOE 

= 100

Two-Generation Reproduction Study in 

Rats

Offspring LOAEL = 4.2 mg/kg/day based 

decreases in body weights and body-weight 

gains in the F2 generation offspring and 

increased time to preputial separation in 

the F1 male offspring.

Short- and 

IntermediateTerm, Dermal 

Oral NOAEL = 0.4 

mg/kg/day

(DAF = 2.6%)

Residential LOC for MOE 

= 100

Two-Generation Reproduction Study in 

Rats

Parental LOAEL = 4.2 mg/kg/day based on 

decreased body weight, body-weight gain 

in males, increased thyroid and kidney 

weights of both sexes, and microscopic 

findings in eyes, kidney and thyroid of 

both sexes.
Topramezone Human-Health Assessment Scoping Document D425613

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Summary of Toxicology Endpoints and PODs for Topramezone in Dietary and Non-Occupational Risk Assessment.

Exposure

Scenario POD

Uncertainty/ FQPA Safety 

Factors or LOC for Risk 

Assessment

Study and Toxicological Effects

Short- and 

IntermediateTerm Inhalation

Oral NOAEL = 0.4 

mg/kg/day

(inhalation absorption = 

100%)

Residential LOC for MOE 

= 100

Two Generation Reproduction Study in 

Rats

Parental LOAEL = 4.2 mg/kg/day based on 

decreased body weight, body-weight gain 

in males, increased thyroid and kidney 

weights of both sexes, and microscopic 

findings in eyes, kidney and thyroid of 

both sexes.

Cancer 

(Oral, dermal, 

inhalation)

In accordance with the 2005 EPA Guidelines for Carcinogen Risk assessment, topramezone was 

classified as “not likely to be carcinogenic to humans at doses that do not alter rat thyroid hormone 

homeostasis.” The CARC determined that the thyroid tumors arise through a non-linear mode of 

action and the NOAEL (0.4 mg/kg/day) established for deriving the cRfD is not expected to alter 

thyroid hormone homeostasis nor result in thyroid tumor formation.

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. FQPA SF = FQPA Safety Factor. PAD = population-adjusted dose (a 

= acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern.

Summary of Toxicology Endpoints and PODs for Topramezone in Occupational Risk Assessment.

Exposure

Scenario

Dose Used in Risk 

Assessment, UF

FQPA SF and LOC 

for Risk 

Assessment

Study and Toxicological Effects

Short- and IntermediateTerm, Dermal 

Oral NOAEL = 0.4 

mg/kg/day

(DAF = 2.6%)

Occupational LOC 

for MOE = 100

Two-Generation Reproduction Study in 

Rats

Parental LOAEL = 4.2 mg/kg/day based on 

decreased body weight, body weight gain 

in males, increased thyroid and kidney 

weights of both sexes, and microscopic 

findings in eyes, kidney and thyroid of both 

sexes.

Short- and IntermediateTerm Inhalation

Oral NOAEL = 0.4 

mg/kg/day

(inhalation absorption 

= 100%)

Occupational LOC 

for MOE = 100

Two-Generation Reproduction Study in 

Rats

Parental LOAEL = 4.2 mg/kg/day based on 

decreased body weight, body weight gain 

in males, increased thyroid and kidney 

weights of both sexes, and microscopic 

findings in eyes, kidney and thyroid of both 

sexes.

Cancer 

(Oral, dermal, 

inhalation)

In accordance with the 2005 EPA Guidelines for Carcinogen Risk assessment, topramezone 

was classified as “not likely to be carcinogenic to humans at doses that do not alter rat 

thyroid hormone homeostasis.” The CARC determined that the thyroid tumors arise 

through a non-linear mode of action and the NOAEL (0.4 mg/kg/day) established for 

deriving the cRfD is not expected to alter thyroid hormone homeostasis nor result in 

thyroid tumor formation.

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. FQPA SF = FQPA Safety Factor. MOE = margin of exposure. LOC = 

level of concern.
Topramezone Human-Health Assessment Scoping Document D425613

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Attachment 5

Toxicity Profile for Topramezone

Acute Toxicity Profile on Topramezone.

OPPTS Guideline Study Type Results Toxicity Category

870.1100 Acute oral toxicity / rat LD50 2000 mg/kg (males and females) III

870.1200 Acute dermal toxicity / rat LD50 2000 mg/kg (males and females) III

870.1300 Acute inhalation toxicity / 

rat LC50 5.05 mg/L (males and females) IV

870.2400 Primary eye irritation / 

rabbit Slight irritant III

870.2500 Primary dermal irritation / 

rabbit Slight irritant IV

870.2600 Dermal sensitization / 

guinea pig Non-Sensitizer --

Subchronic, Chronic, and Other Toxicity Profile for Topramezone.

Guideline No./ Study 

Type

MRID Nos.

Doses/Classification Results

870.3100

Subchronic Oral

- Rat

45902203, 45902204 (2001, 2003)

(0, 15, 30 ppm)

M:0, 1.1, 2.1 mg/kg/day

F:0, 1.3, 2.5 mg/kg/day

Acceptable/guideline

Males: NOAEL =1.1 mg/kg/day, LOAEL = 2.1 

mg/kg/day based on diffuse degeneration in the pancreas.

Females: NOAEL = 2.1 mg/kg/day, the LOAEL was not 

established.

870.3100

Subchronic Oral

- Mouse

45902202 (2000)

(0, 125, 1000, 8000 ppm)

M: 0, 3 7, 288, 2289 mg/kg/day 

F: 0, 51, 406, 3010 mg/kg/day 

Acceptable/guideline

NOAEL = 2289/3010 mg/kg/day (M/F).

LOAEL = not established.

870.3150

Subchronic Oral

- Dog

45902205 (2002)

(0, 3000, 9000, 25000 ppm)

0, 182, 535, 1511 mg/kg/day (M)

0, 205, 624, 1712 mg/kg/day(F)

Acceptable/guideline

Males: NOAEL = 535 mg/kg/day, and the LOAEL = 

1511 mg/kg/day based on decreased body-weight gain, 

impaired food efficiency, and inflammation of the urinary 

bladder. 

Females: NOAEL = 1712 mg/kg/day, the LOAEL for 

females is not established. 

870.3200

28-Day dermal toxicity

- Rat

45902206 (2002)

0, 100, 300, 1000 mg/kg/day

Acceptable/Guideline

Males: NOAEL = 100 mg/kg/day, the LOAEL = 300 

mg/kg/day based on thyroid follicular cell hypertrophy. 

Females: NOAEL = 300 mg/kg/day, the LOAEL = 1000 

mg/kg/day based on thyroid follicular cell hypertrophy.

870.3700a

Prenatal developmental 

- Rat 

45902207 (2003)

0, 100, 300, 1000 mg/kg/day

Acceptable/Guideline

Maternal: NOAEL = not established, the LOAEL = 100 

mg/kg/day based on decreased body-weight gains.

Developmental: NOAEL = not established, the LOAEL = 

100 mg/kg/day based on decreased fetal body weight and 

increased incidences of skeletal variation.

870.3700b

Prenatal developmental 

- NZW Rabbit

45902210 (2003)

0, 0.5, 5, 50, 450 mg/kg/day

Acceptable/Guideline

Maternal: NOAEL = not established, the LOAEL= 0.5 

mg/kg/day based on increased serum tyrosine level.

Developmental: NOAEL = 0.5 mg/kg/day, the LOAEL = 

5 mg/kg/day based on alterations in skeletal ossification 

sites and increased number of pairs of ribs.

870.3700b

Prenatal developmental 

- NZW Rabbit

45902211 (2003)

0, 5, 50, 500 mg/kg/day

Unacceptable/Guideline

Maternal: NOAEL = not established. LOAEL = 5 

mg/kg/day based on increased tyrosine level.

Developmental: Unable to established because fetal 

skeletons were not evaluated.
Topramezone Human-Health Assessment Scoping Document D425613

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Subchronic, Chronic, and Other Toxicity Profile for Topramezone.

Guideline No./ Study 

Type

MRID Nos.

Doses/Classification Results

870.3700b

Prenatal developmental 

- NZW Rabbit

45902212 (2003)

0, 1.5, 5.0 mg/kg/day

Acceptable/Non-guideline

Maternal: NOAEL = not established. LOAEL = 1.5 

mg/kg/day based on increased serum tyrosine level.

Developmental: NOAEL = not established, the LOAEL = 

1.5 mg/kg/day based on an increased incidence of absent 

kidney and ureter and increased incidences of 

supernumerary thoracic vertebrae and supernumerary 13th 

rib.

870.3700b

Prenatal developmental 

- NZW Rabbit

45902213 (2003)

0, 1.5, 5.0 mg/kg/day

Acceptable/Non-guideline

Maternal: NOAEL = 5.0 mg/kg/day. LOAEL was not 

established. Developmental: NOAEL = not established, 

the LOAEL for N33 and N17/CFR 1-2 was 1.5 mg/kg/day 

based on increased presence of supernumerary thoracic 

vertebrae and supernumerary 13th rib. No effect was 

observed for N17/CFR 3 at 0.5 mg/kg/day (the only dose 

tested). 

870.3700b

Prenatal developmental 

- NZW Rabbit

46020301 (2003)

0, 5, 50, 450 mg/kg/day

Acceptable/Guideline

Maternal: NOAEL = 450 mg/kg/day. LOAEL not 

established.

Developmental: NOAEL = not established. LOAEL = 5 

mg/kg/day based on visceral findings (fluid-filled 

abdomen, pale liver, and dark content of the stomach and 

intestines) and alterations in skeletal development (i.e., 

incomplete ossification of the vertebrae and talus, and 

supernumerary thoracic vertebrae and 13th rib).

870.3700b

Prenatal developmental 

- Himalayan Rabbit

46020302 (2003)

0, 50, 150, 450 mg/kg/day

Acceptable/Guideline

Maternal: NOAEL = 150 mg/kg/day. LOAEL = 450 

mg/kg/day based on decreased body weight body-weight 

gains, food consumption and increased incidences of 

abortion and lack of defecation. No serum tyrosine level 

was measured.

Developmental: NOAEL = not established. LOAEL = 50 

mg/kg/day based on decreased fetal weight and increased 

an incidence of visceral malformations, and skeletal 

malformations, variations, and unclassified abnormalities.

870.3700b

Prenatal developmental 

- NZW Rabbit

46020303 (2003)

0, 0.5, 5, 50, 450 mg/kg/day

Acceptable/Guideline

Maternal: NOAEL = 450 mg/kg/day. LOAEL = not 

established.

Developmental: NOAEL = 0.5 mg/kg/day. LOAEL = 5 

mg/kg/day based on increased presence of 27 pre-sacral 

vertebrae and increased an incidence of full 

supernumerary 13th rib.

870.3700b

Prenatal developmental 

- Himalayan Rabbit

46020304 (2003)

0, 50, 150, 450 mg/kg/day

Acceptable/Guideline

Maternal: NOAEL=450 mg/kg/day. LOAEL= not 

established.

Developmental: NOAEL = not established. LOAEL = 50 

mg/kg/day based on an increased incidence of extra 

sternebral ossification sites and supernumerary 13th rib. 

870.3700a

Prenatal developmental 

- Mouse

45902208, 45902209 (2003)

0, 30, 200, 1000 mg/kg/day

Acceptable/guideline

Maternal: NOAEL = not established. LOAEL = 30 

mg/kg/day based on increased serum tyrosine level. 

Developmental: NOAEL = 1000 mg/kg/day. LOAEL = 

not established.

870.3800

Reproduction and 

fertility effects

- Rat

45902214 (2003)

(0, 4, 40, 400, 4000 ppm)

M: 0, 0.4, 4.2, 42.2, 426.8 

mg/kg/day

F: 0, 0.5, 4.6, 46.9, 471.9 mg/kg/day

Acceptable/guideline

Parental/system:

NOAEL = 0.4/0.5 mg/kg/day (M/F). LOAEL = 4.2/4.6 

mg/kg/day (M/F) based on decreased body weight, bodyweight gain in males, increased thyroid and kidney 

weights of both sexes, and microscopic findings in eyes, 

kidney and thyroid of both sexes.

Reproductive:

NOAEL = 426.8/471.9 mg/kg/day (M/F). LOAEL = not 

established

Offspring:

NOAEL = 0.4/0.5 mg/kg/day (M/F). LOAEL = 4.2/4.6 

mg/kg/day (M/F) based on decreased pup weight and 

weight gain in F2 male and female pups and increased 

time to preputial separation in the F1 males. 
Topramezone Human-Health Assessment Scoping Document D425613

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Subchronic, Chronic, and Other Toxicity Profile for Topramezone.

Guideline No./ Study 

Type

MRID Nos.

Doses/Classification Results

870.4300

Chronic toxicity 

-Rat

45902217 (2002)

(0, 6, 60, 600, 6000 ppm)

M: 0, 0.4, 3.9, 42.0, 422.6 

mg/kg/day

F: 0, 0.5, 5.3, 53.2, 535.0 mg/kg/day

Acceptable/guideline

NOAEL = 0.4/0.5 mg/kg/day (M/F). LOAEL = 3.9/5.3 

mg/kg/day (M/F) based on effects on the eyes consisting 

of opacity, pannus, and chronic keratitis of the cornea in 

both sexes. In addition, thyroid hypertrophy was noted in 

males.

870.4200a

Carcinogenicity

-Rat

45902222 (2003)

(0, 6, 60, 600, or 6000 ppm)

M: 0, 0.4, 3.6, 36.4, 381.5 

mg/kg/day

F: 0, 0.5, 4.7, 50.8, 524.1 mg/kg/day

Acceptable/Guideline

NOAEL = 0.4/0.5 mg/kg/day (M/F). LOAEL = 3.6/4.7 

mg/kg/day (M/F) based on increased incidences of corneal 

opacity, decreased body weight and body-weight gains 

(males only) and histopathological evaluations in the 

thyroids, pancreas, and eyes of both sexes. Neoplastic 

pathology showed increased incidences of follicular cell 

adenomas in the thyroid glands of both sexes.

870.4100b

Chronic toxicity

- Dog

45902215, 45902216 (2002)

(0, 100, 500, 3000/2600, 9000/7800, 

25000/22000 ppm). 

M: 0, 2.9, 15.3, 81, 248, 688 

mg/kg/day

F: 0, 3.1, 15.4, 92, 287, 780 

mg/kg/day

Acceptable/guideline

For males, NOAEL = 2.9 mg/kg. LOAEL = 15.3 

mg/kg/day based on increased incidence of thyroid C-cell 

hyperplasia.

For females, NOAEL = 15.4 mg/kg/day. LOAEL = 92 

mg/kg/day based on decreased body weight, body-weight 

gain and food efficiency. 

870.4200b

Carcinogenicity 

- Mouse

45902221 (2002)

(0, 80, 800, 8000 ppm)

M: 0, 19, 194, 1903 mg/kg/day

F: 0, 26, 256, 2467 mg/kg/day

Acceptable/guideline

NOAEL = not established. LOAEL = 19/26 mg/kg/day 

(M/F) based on decreased body weight and body-weight 

gains in males. No serum tyrosine level was measured. 

No treatment-related tumors were demonstrated.

870.5100

Gene mutation

Salmonella 

typhimurium

45902225 (1999)

Acceptable/guideline

No indication of a mutagenic response in any strain at any 

level up to cytotoxic concentrations either with or without 

S9 activation.

870.5100

Gene mutation

Salmonella 

typhimurium

45902226 (2002)

Acceptable/Guideline

No indication of a mutagenic response in any strain at any 

level up to cytotoxic concentrations either with or without 

S9 activation. 

870.5100

Gene mutation

Salmonella 

typhimurium

45902227 (2002)

Acceptable/Guideline

No indication of a mutagenic response in any strain at any 

level up to cytotoxic concentrations either with or without 

S9 activation.

870.5100

Gene mutation

Salmonella 

typhimurium

45902228 (2003)

Acceptable/Guideline

Based on these considerations, it was concluded that there 

was confirmed evidence of a mutagenic response in S. 

typhimurium TA98 in the non-activated portion of both 

the plate incorporation and pre-incubation assays. The 

effect was, however, observed at high concentrations 

(3000 μg/plate– plate incorporation and 2500 μg/plate–

pre-incubation). It was further concluded that the 

mutagenic effect was likely due to impurities in the test 

article because: 1) the response was seen at high 

concentrations including and exceeding the limit dose, 2) 

bacterial gene mutation assays conducted with other lots 

of the test material were negative up to the limit dose (see 

MRID Nos. 45902225 through 45902227, and 3) the ai

used in the current study has the lowest percentage of 

purity (95.8% versus 97.7 to 99.3% ai for the other lots). 

870.5100

Gene mutation

Salmonella 

typhimurium

45902229 (2001)

Acceptable/Guideline

No indication of a mutagenic response in any strain up to 

cytotoxic levels either with or without S9 activation.

870.5300

In vitro Mammalian 

Cell Gene Mutation

45902230

Acceptable/guideline

No indication that topramezone induced a mutagenic 

response, either in the presence of absence of S9 

activation. 
Topramezone Human-Health Assessment Scoping Document D425613

Page 22 of 25

Subchronic, Chronic, and Other Toxicity Profile for Topramezone.

Guideline No./ Study 

Type

MRID Nos.

Doses/Classification Results

870.5375

In vitro Mammalian 

Chromosome 

Aberration 

45902233 (2002)

Acceptable/guideline

Topramezone-induced a clastogenic response in the 

presence of S9 activation with significant effects recorded 

only at an insoluble limit concentration. 

870.5375

In vitro Mammalian 

Chromosome 

Aberration 

45902232 (1999)

Acceptable/guideline

Topramezone-induced a clastogenic response in the 

presence of S9 activation with significant effects recorded 

only at an insoluble limit concentration.

870.5395

In vivo Mouse Bone 

Morrow Micronucleus

45902234 (1999)

Acceptable/guideline

No evidence that topramezone was clastogenic or 

aneugenic. 

870.5550

UDS

45902302 (1999)

Acceptable/Guideline

No evidence that topramezone-induced UDS, as 

determined by radioactive tracer procedures [nuclear 

silver grain counts] at any concentration tested.

870.6200

Acute Neurotoxicity

- Rat

45902303 (2002)

0, 125, 500, 2000 mg/kg

Acceptable/guideline

NOAEL = 2000 mg/kg/day, no neurotoxicity observed.

870.6200

Subchronic 

neurotoxicity

- Rat 

45902201 (2002)

(0,60,600,6000 ppm)

M: 0, 4.2, 43.8, 432.9 mg/kg/day

F: 0, 5.0, 50.9, 510.1 mg/kg/day

Acceptable/guideline

No neurotoxicity observed.

Systemic NOAEL = not established. LOAEL = 4.2/5/0 

mg/kg/day (M/F) based on elevated levels of granular 

casts and transitional epithelial cells in the urinary 

sediment of the males, increased incidences of corneal 

clouding in females, minimal diffuse degeneration of the 

pancreas (both sexes), and slight to moderate flaky colloid 

in the thyroid of the males.

870.6300

Developmental 

Neurotoxicity

-Rat

45902304 (2003)

0, 8, 80, 800 mg/kg/day

Acceptable/Non-guideline

Maternal: NOAEL = not established. LOAEL = 8 

mg/kg/day based on corneal opacities.

Offspring: NOAEL = not established. LOAEL = 8 

mg/kg/day based on decreased auditory startle reflex 

response.

870.7485

Metabolism

45902305, 45902306 (2002)

1, 100, 200, 400, 500 mg/kg

Acceptable/Guideline

Absorption of [14C]-topramezone following a single oral 

dose was rapid but limited, with the highest plasma 

concentrations observed at 1 hour (first time point 

measured). Oral absorption is estimated to be 

approximately 20% of the administered dose. The 

majority of the dose was recovered within 48 hours in the 

feces (73-91% dose) and urine (8-29% dose). 

870.7600

Rodent In Vivo Dermal 

Penetration Study - Rat

45902307 (2002)

Doses 0, 0.004, 0.068, or 3.36 mg 

ai/cm2.

The majority of the applied dose for each group was not 

absorbed (91.0-98.3% dose), with the greatest amount of 

the non-absorbed material being recovered from the skin 

wash (90.8-96.0% dose). Absorbed radioactivity was low 

and accounted for 0.16-2.60% of the dose for all groups 

for all exposures. 

870.7800

Immunotoxicity - Mice

49365101 (2011)

0, 168, 523, or 1615 mg/kg/day

Acceptable/guideline

Systemic NOAEL = 1615 mg/kg/day.

Systemic LOAEL = not established.

Immunotoxicity NOAEL = 1615 mg/kg/day.

Immunotoxicity LOAEL = not established.
Topramezone Human-Health Assessment Scoping Document D425613

Page 23 of 25

Summary of Use Profile

Summary of Application Scenarios.

App. Timing; 

Type; and 

Equip.

Formulation 

(EPA Reg. 

No.)

App. Rate

Max. #. 

App. per 

Season

Max. Seasonal App. 

Rate (lb ai/acre) Use Directions and Limitations

Residential Turf, Athletic Fields, Golf Course Turf, and Sod Farms

Post-emergence

Broadcast 

application

Groundboom 

and handheld 

equipment

Pylex® SC;

2.8 lb ai/gal;

EPA Reg. No.

7969-327

Pylex® SC;

2.8 lb ai/gal;

EPA Reg. No.

7969-327

0.044 lb ai/A

0.001 lb ai/1000 ft2

(spray volume: 1 

gallon/1000 ft2)

3 0.089

 REI = 12 hrs.

 Do not apply to golf course collars or greens.

 Do not apply via chemigation or air.

 If single application of topramezone does not provide complete control, then a 

sequential application can be made 2 to 3 weeks later

 Do not apply for a period of 28 days after seeding tolerant turfgrass..

Non-crop Terrestrial-Application

Pre-/postemergence

Broadcast 

application

Groundboom, 

and handheld 

equipment

Frequency®; 

SC; 

2.8 lb ai/gal; 

EPA Reg. No. 

7969-281

0.09-0.35 lb 

ai/acre2

not 

specified 0.35 lb ai/acre

 -Application using ground (≥10 GPA) and aerial (≥2 GPA) equipment is permitted. 

 -Spot application is also permitted using a spray solution containing 0.25-0.5% of the 

formulated product. 

 -Only soil-directed applications are described for Christmas tree, conifer, and 

hardwood plantations and field-grown ornamentals. 

 -Application to greenhouses and shadehouses is prohibited; do not apply to areas that 

may be grazed or cut for hay. 

Non-crop Aquatic-Application - in-water application (including submersed or floating weeds); flowing water application (including canals (slow moving))1

Pre-/postemergence

Broadcast, spot, 

and metering 

applications

Groundboom, 

handheld 

equipment, 

aircraft, and boat

Oasis® SC;

2.8 lb ai/gal;

EPA Reg. No. 

7969-339

in-water 

concentration at 

application of 20-

50 ppb3

not 

specified

150 ppb/year

or

0.41 lb ai/acrefoot/year

 -The max. conc. that can be applied initially, and maintained through sequential 

application, is 50 ppb (application rate in lb ai/acre is based on calculation using the 

treated area and average depth). To maintain the desired conc., samples are 

collected/analyzed and additional product is added to raise the conc. to the desired 

level.

 -Retreat the water to maintain the desired conc. for a min. of 60 days or until 

satisfactory weed control is achieved. 

 Do not apply via chemigation.

 Do not use treated water with a concentration above 45 ppb for potable use/human 

consumption.

Non-crop Aquatic-Application - shoreline and riparian areas within or adjacent to aquatic sites
Topramezone Human-Health Assessment Scoping Document D425613

Page 24 of 25

Summary of Application Scenarios.

App. Timing; 

Type; and 

Equip.

Formulation 

(EPA Reg. 

No.)

App. Rate

Max. #. 

App. per 

Season

Max. Seasonal App. 

Rate (lb ai/acre) Use Directions and Limitations

Pre-/postemergence

Broadcast, spot, 

and metering 

applications

Groundboom, 

handheld 

equipment, 

aircraft, and boat

Oasis® SC;

2.8 lb ai/gal;

EPA Reg. No. 

7969-339

0.09-0.35 lb 

ai/acre2

not 

specified 0.35 lb ai/acre/year

 Do not exceed 45 ppb for single in-water applications with functional potable water 

intakes.

 Do not exceed 150 ppb/year (0.41 lb ai/acre foot/year)

 -Sequential applications can be made throughout the growing seasons. 

Non-crop Aquatic-Application - foliar spot treatment

Pre-/postemergence

Broadcast, spot, 

and metering 

applications

Groundboom, 

handheld 

equipment, and 

boat

Oasis® SC;

2.8 lb ai/gal;

EPA Reg. No. 

7969-339

0.09-0.35 lb 

ai/acre2

not 

specified 0.35 lb ai/acre/year

 Spray coverage should be sufficient to moisten the leaves of the target vegetation but 

not to runoff. 

Non-crop Aquatic-Application - exposed sediment (including exposed sediment of dewatered irrigation canals)

Pre-/postemergence

Broadcast, spot, 

and metering 

applications

Groundboom, 

handheld 

equipment, 

aircraft, and boat

Oasis® SC;

2.8 lb ai/gal;

EPA Reg. No. 

7969-339

0.09-0.35 lb 

ai/acre2

not 

specified 0.35 lb ai/acre/year

 (1) only for use by Irrigation Districts in the western U.S. in canals that are 

seasonally filled and where the Irrigation District is aware of potential down-stream 

use of water and can ensure water is not used for irrigation purposes during the 

recharge or refill process; 

 (2) app. by only Irrigation Districts, Irrigation Water Suppliers, or those applicators 

who are licensed or certified as aquatic pest control applicators and are authorized by 

the Irrigation District; 

 (3) app. must be conducted a minimum of 14 days prior to reflooding. The initial 

flush of water during recharge or refill must not be used for irrigation purposes 

unless the conc. has been determined to be ≤1 ppb; and (4) after canals have been 

refilled with a continuous flow for a min. of 24 hours, canal water may then be used 

for irrigation purposes. 
Topramezone Human-Health Assessment Scoping Document D425613

Page 25 of 25

Summary of Application Scenarios.

App. Timing; 

Type; and 

Equip.

Formulation 

(EPA Reg. 

No.)

App. Rate

Max. #. 

App. per 

Season

Max. Seasonal App. 

Rate (lb ai/acre) Use Directions and Limitations

Corn (field, sweet, pop) & Fallow

Post-emergence

Broadcast 

application

Groundboom 

and aircraft 

Armezon® SC;

2.8 lb ai/gal;

EPA Reg. No. 

7969-262

Topramezone®

SC;

2.8 lb ai/gal;

EPA Reg. No. 

5481-524

0.011-0.022 lb 

ai/A

not 

specified 0.022 lb ai/A

 REI = 12 hrs

 PHI = 45 days

 PGI = 45 days

 Do not apply after V8 stage of growth

 Do not apply via chemigation