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7.4 Long-Term Aggregate Risk ........................................................................................................28

7.5 Cancer Risk.................................................................................................................................28

8.0 Cumulative Exposure/Risk Characterization...................................................................................28

9.0 Occupational Exposure/Risk Characterization................................................................................29

9.1 Short- and Intermediate-Term Handler Risk...............................................................................29

9.2 Short- and Intermediate-Term Post-Application Risk ................................................................32

9.2.1 Dermal Post-Application Risk ............................................................................................32

9.2.2 Inhalation Post-Application Risk ........................................................................................33

10.0 References.......................................................................................................................................33

Appendix A. Toxicology Profile and Executive Summaries.....................................................................34

A.1 Toxicology Data Requirements ..................................................................................................34

A.2 Toxicity Profiles..........................................................................................................................35

Appendix B. Physical/Chemical Properties of Topramezone....................................................................39
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1.0 Executive Summary

Topramezone ([3-(4,5-dihydro-isoxazol-3-yl)-4-methylsulfonyl-2-methylphenyl](5-hydroxy-1-

methyl-1H-pyrazol-4-yl)methanone) is a broad-spectrum, post-emergent herbicide used to 

control grassy and broadleaf weeds. It is currently registered for use on non-crop ornamentals, 

rights-of-way, tree plantations, and other non-crop areas, as well as field, pop, seed, and sweet 

corn with tolerances ranging from 0.01 to 0.15 ppm (40 CFR§180.612). There are currently no 

registered residential uses.

BASF has proposed a Section 3 Registration for application of topramezone to golf courses, sod 

farms, and residential turfgrass. The end-use product is Topramezone 2.8 Suspension 

Concentration (SC; EPA Reg # 7969-GET), a 2.8-pound (lb) active ingredient (ai)/gallon liquid 

formulation. The maximum single application rate proposed is 2 fl oz/A (0.044 lb ai/A) or 0.001 

lb ai/1000 ft2(with a spray volume of 1 gallon per 1000 ft2). 

Hazard Assessment: Topramezone is an inhibitor of the enzyme 4-hydroxyphenylpyruvate 

dioxygenase (HPPD) which results in impairment of chlorophyll biosynthesis. In mammals, 

HPPD is involved in the catabolism of the amino acid tyrosine, and its inhibition causes blood 

levels of tyrosine to rise, a condition known as tyrosinemia. Some of the toxicities resulting 

from tyrosinemia in laboratory animals include ocular, developmental, liver, and kidney effects.

Based on radiolabel disposition studies in rats, topramezone was rapidly absorbed via the oral 

route with peak plasma levels measured at 1 hr. However, the estimated absorbed fraction was 

only about 47%. Plasma elimination was biphasic, with the initial (primary) clearance half-life 

estimate being about 5 hours and the terminal elimination half-life estimate being about 30 

hours. The majority of the dose was eliminated within 48 hours in feces (73-91%) and urine (8-

29%). The highest levels of topramezone were found in the liver followed by the kidneys and, to 

some extent, in the thyroid. The parent chemical was the predominant compound identified in 

excreta. There were no apparent sex-dependent differences in metabolic profile.

The primary target organs affected following topramezone administration were the eyes, thyroid, 

pancreas, and liver. The most sensitive species was the rat and, in rats and dogs, males were 

more sensitive than females. The effects on the eyes in chronic toxicity studies consisted of 

pannus (vascularization) and keratitis (cloudiness) of the cornea of both sexes. Hypertrophy and 

hyperplasia of the thyroid, hypertrophy, and focal necrosis of the liver, and degeneration of the 

pancreas were among the histopathology findings reported across different subchronic and 

chronic studies in rats and dogs. Results of chronic toxicity studies in dogs, mice, and rats also 

suggest decrements in body weights, body-weight gains, and food utilization (dogs only).

There was evidence for increased susceptibility following in utero exposures to rats and rabbits. 

In rabbits, fetal abnormalities including supernumerary thoracic vertebrae and supernumerary 

13th rib were observed in the presence of maternal toxicity in six of the eight developmental 

toxicity studies conducted in two different strains. In rats, developmental effects consisting of 

skeletal variations occurred in the presence of maternal toxicity. Increased maternal serum levels 

of tyrosine were reported in several developmental toxicity studies (several in rabbits and one in 

mice), consistent with the proposed mode of action for topramezone involving HPPD inhibition. 

In the rat 2-generation reproductive toxicity study, there was no evidence of increased pre- or 

post-natal susceptibility; offspring effects occurred in the presence of maternal effects. The 

offspring effects consisted of (1) decreased pup body weight/body-weight gain in F2 (both sexes) 
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and (2) increased time to preputial separation (F1 males). Maternal effects were consistent with 

HPPD inhibition (decreased body weights and body-weight gains, increased thyroid and kidney 

weights, and microscopic findings in the eyes, kidneys, and thyroid). No reproductive effects 

were reported.

Topramezone did not show any evidence of neurotoxicity in the acute (ACN) or subchronic

(SCN) neurotoxicity studies, but in a rat developmental neurotoxicity (DNT) study, where dosing 

with topramezone took place during the prenatal as well as postnatal time periods, there was 

evidence for increased qualitative susceptibility. In the maternal animals, toxicity was limited to 

corneal opacity, whereas effects in the offspring included neurobehavioral and neuropathological 

changes. Offspring neurobehavioral effects consisted of a decreased auditory startle reflex at 

postnatal day 24 in both sexes (20-30%) and at postnatal day 60 for males (55%). There were 

also mild decreases in offspring absolute brain weights and neuropathological effects involving 

decreased brain morphometric measurements (e.g., hippocampus, and parietal cortex). 

Topramezone is classified as “Not likely to be carcinogenic to humans at doses that do not alter 

rat thyroid hormone homeostasis.” The Cancer Assessment Review Committee (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 chronic reference dose (cRfD) is not expected to 

alter thyroid hormone homeostasis nor result in thyroid tumor formation. Mutagenicity studies 

conducted on technical topramezone and its major metabolites did not demonstrate any 

mutagenic potential.

Topramezone exhibited relatively low dermal absorption. A dermal-absorption factor (DAF) of 

2.6% was the highest dermal penetration observed in a dermal penetration study, and has been 

selected to assess potential risk associated with dermal exposures to topramezone.

Dose-Response Assessment and Food Quality Protection Act (FQPA) Decision: HED’s RAB1 

toxicology team has evaluated the toxicology database for topramezone in order to select 

endpoints for risk assessment and to evaluate the potential for increased susceptibility of infants 

and children. Based on this evaluation, the team recommends that the 10X FQPA Safety Factor 

(SF) be retained in the form of a database uncertainty factor (UF) for the acute dietary scenario 

for the general population including infants and children [for lack of a no-observed adverseeffect level (NOAEL)], and be reduced to 1X for all other scenarios. This recommendation is 

based on the following rationale: 

(1) With the exception of an immunotoxicity study, the toxicology database for topramezone 

is complete. 

(2) Neurobehavioral, as well as neuropathological, effects were noted in the DNT study. In 

addition, there was evidence of increased qualitative susceptibility in the developing or 

young animal. However, there are no residual uncertainties for pre-and post-natal 

susceptibility for infants and children based on the following weight of evidence 

considerations: 

a. The toxicology database with a DNT is complete; 

b. Although there was qualitative evidence for susceptibility, clear NOAELs and lowestobserved-adverse-effect-levels (LOAELs) were established for developmental effects; 

c. Fetal findings were limited to visceral and skeletal variations; 

d. Endpoints of concern (developmental and target organ toxicity) were used for 

assessing risks for appropriate populations of concern; and

e. The concern for topramezone-induced toxicity is for HPPD inhibition that causes 
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increases in serum tyrosine levels, resulting in corneal clouding, histopathological 

lesions of the eyes and thyroid glands.

(3) The dietary and residential exposure analyses are conservative in nature. The dietary food 

and drinking water exposure assessments will not underestimate the potential exposures for 

infants and children. The dietary exposure assessment uses tolerance-level residues and 

assumes 100% crop-treated. The dietary drinking water assessment utilizes modelgenerated water concentration values 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 exposure assessment uses chemical-specific 

turf-transferable residue (TTR) data and the 2012 Residential SOPs and is considered

health-protective.

The acute population-adjusted dose (aPAD) for the general population is 0.008 mg/kg/day. The 

aPAD for females (13-49 years old) and the chronic population-adjusted dose (cPAD) are 0.005 

and 0.004 mg/kg/day, respectively. The point of departure (POD) for short- and intermediateterm dermal, inhalation and incidental oral risk assessments is 0.4 mg/kg/day. Since an oral 

study was used, the dermal absorption factor of 2.6% was used for the dermal risk assessment. 

Inhalation toxicity has been assumed to be equivalent to oral toxicity. The level of concern 

(LOC) for occupational/ residential dermal and inhalation exposures and for residential 

incidental oral exposures are for margins of exposure (MOEs) <100. 

Dietary Risk Estimates (Food + Drinking Water): Acute and chronic aggregate dietary (food +

drinking water) exposure and risk assessments were conducted using the Dietary Exposure 

Evaluation Model - Food Consumption Intake Database (DEEM-FCIDTM, ver. 2.03) which 

incorporates the food consumption data from the United States Department of Agriculture 

(USDA) Continuing Surveys of Food Intakes by Individuals (CSFII; 1994-1996 and 1998). The 

acute and chronic analyses assumed tolerance-level residues, 100% crop treated, and modeled 

drinking water estimates. The default DEEMTM (ver. 7.81) processing factors were retained for 

all commodities. The acute and chronic dietary exposure and risk estimates (food + drinking 

water) were all below HED’s LOC (<100% aPAD and <100% cPAD). 

Residential (Non-Occupational) Exposure and Risk Assessment: Topramezone is being 

proposed for use on residential turfgrass and athletic fields; therefore, there is the potential for 

exposure for both residential handlers and for exposure after treatment for adults and children. 

Residential handler dermal and inhalation risk estimates were calculated. For residential 

handlers, dermal and inhalation MOEs above 100 do not exceed HED’s LOC. The combined 

dermal and inhalation estimated risks are not of concern (i.e., MOEs >100) at baseline for all 

scenarios. Residential dermal and incidental oral post-application risk estimates were also 

calculated. The combined MOEs are greater than 100 and are not of concern.

Aggregate-Risk Estimates: Acute and chronic aggregate risks are assessed based on dietary 

exposure from food and drinking water sources only. They are the same as reported for acute 

and chronic dietary exposure. Therefore, acute and chronic aggregate risks to topramezone are 

not of concern to HED. A cancer aggregate-risk assessment was not performed because 

topramezone is classified as “not likely to be carcinogenic to humans.”

Aggregate risk assessments were performed for short- and intermediate-term aggregate 

exposures (food + drinking water + residential exposure) because there are residential uses. 

Short- and intermediate-term aggregate exposures and risk estimates for the general U.S. 
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population and for adults, children, and infants are >100 and are, therefore, not of concern to 

HED. 

Occupational Exposure and Risk Assessment: Based on the proposed uses, occupational 

handlers may be potentially exposed to topramezone during mixing/loading and applying 

activities associated with groundboom and handheld equipment applications. Occupational 

handler dermal and inhalation risk estimates were calculated. For occupational handlers, dermal 

and inhalation MOEs above 100 do not exceed HED’s LOC. The combined dermal and 

inhalation estimated risks are not of concern (i.e., MOEs >100) at baseline for all scenarios. 

Occupational dermal post-application risk estimates were calculated. The resulting MOEs are 

greater than 100 on day 0 (12 hours after application) for all activities. Since the postapplication MOEs are not of concern, the restricted-entry interval (REI) for topramezone is based 

on the acute toxicity categories. Topramezone has been classified as having low acute toxicity

(Toxicity Category III or IV) via the oral, dermal, and inhalation routes of exposure. It is a slight 

eye and dermal irritant (Toxicity Category III and IV), but is not a dermal sensitizer. Therefore, 

the Worker Protection Standard (WPS) interim REI of 12 hours is adequate to protect 

agricultural workers from post-application exposures to topramezone.

Environmental Justice Considerations: 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.hss.energy.gov/nuclearsafety/env/guidance/justice/eo12898.pdf).

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 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 Re-entry Task Force (ARTF) 

database; and MRID 483794-01, are subject to ethics review pursuant to 40 CFR 26, have 

received that review, and are compliant with applicable ethics requirements. For certain studies 

that 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 

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

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

2.0 HED Recommendations

HED has evaluated the toxicity and exposure databases for the active ingredient, topramezone, 

and has conducted a human health risk assessment in support of the proposed uses. Based on 

this assessment, HED has determined that there are no potential risk estimates of concern for the 

proposed uses of topramezone. HED recommends that the requested uses be granted.

2.1 Data Deficiencies

Toxicology

Immunotoxicity study

A 28-day inhalation study is not required to assess the proposed uses and the risk estimates 
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for occupational handlers are sufficiently protective (see Section 9.0).

Residue Chemistry

None

Occupational and Residential Exposure

None

2.2 Tolerance Considerations

No new tolerances have been proposed or recommended by HED to support the proposed uses. 

There are no residue chemistry issues that would preclude granting the topramezone turf uses as 

non-food uses (40 CFR Part 158).

2.3 Label Recommendations

No label revisions are needed and no recommendations are being made by HED.

3.0 Ingredient Profile

3.1 Chemical Identity

Table 3.1.1. Topramezone Nomenclature.

Chemical 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-methyl1H-pyrazol-4-yl)methanone

CAS # 210631-68-8

End-use product/EP Suspension Concentrate (SC)

Known Impurities of Concern None

3.2 Physical/Chemical Characteristics

The solubility of topramezone in water is high (15,000 mg/L at pH 7 and 20 C) and it is pHdependent. Topramezone is a weak acid (pKa 4.06) and, as the pH increases, the concentration 

of the anionic form increases. The higher the concentration of the anionic form, the higher the 

mobility of topramezone in soils. The vapor pressure and Henry’s Law Constant of topramezone 

are low and, therefore, topramezone has a low potential to volatilize from soil or water. It has a 

very low Log Kow, suggesting that it has a low potential to bioaccumulate in aquatic organisms. 

A detailed description of the physicochemical properties of topramezone is provided in 

Appendix B. 

S

N

O

N

N

O

O

OH

O
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3.3 Proposed Use Pattern

The petitioner submitted a draft label for the 2.8 lb ai/gal SC formulation [Topramezone 2.8 SC, 

EPA File Symbol No. 7969-GET]. Table 3.3.1 is a summary of the proposed use pattern. 

Table 3.3.1. Summary of Proposed 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

Golf Course Turf and Sod Farms

Post-emergence

Broadcast 

application

Groundboom 

and handheld 

equipment

SC

(7969-GET)

0.044 lb ai/A

0.001 lb ai/1000 ft2

(spray volume: 1 

gallon/1000 ft2)

2 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.

Residential Turfgrass and Athletic fields

Post-emergence

Spot application

Handheld 

equipment

SC

(7969-GET)

0.044 lb ai/A

0.001 lb ai/1000 ft2

(spray volume: 1 

gallon/1000 ft2)

2 0.089

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.

3.4 Anticipated Exposure Pathways

RD has requested an assessment of human health risk to support the proposed new uses of 

topramezone on golf courses, sod farms, and residential turfgrass. As a result of the 

proposed/registered uses, humans may be exposed to topramezone in food and drinking water. 

Topramezone can also be used in residential settings, so adults and children may be exposed to 

topramezone while handling the pesticide during application (adults only) and/or through 

exposure to treated areas after application. In an occupational setting, applicators may be 

exposed while handling the pesticide prior to application, as well as during application. There is 

also a potential for post-application exposure for workers re-entering treated fields. 

Risk assessments have been previously prepared for the existing uses of topramezone. This risk 

assessment considers all of the aforementioned exposure pathways based on the proposed new 

uses of topramezone, but also considers the existing 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://www.hss.energy.gov/nuclearsafety/env/guidance/justice/eo12898.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 USDA under the 

CSFII and are used in pesticide risk assessments for all registered food uses of a pesticide. These 
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data are analyzed and categorized 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/Assessment

Topramezone belongs to a class of herbicides that includes pyrasulfotole, mesotrione, and 

isoxaflutole. The herbicidal mode of action of these agents involves inhibition of HPPD, which 

eventually results in impairment of chlorophyll biosynthesis. In mammals, HPPD is involved in 

the catabolism of the amino acid tyrosine, and its inhibition causes blood levels of tyrosine to 

rise, a condition known as tyrosinemia. Some of the toxicities resulting from tyrosinemia in 

laboratory animals include ocular, developmental, liver, and kidney effects.

4.1 Toxicology Studies Available for Analysis 

The toxicological database for topramezone is adequate for evaluation. In the last risk 

assessment (M. Clock-Rust et al., D352696, 02/20/2009), the only database deficiency noted was 

an immunotoxicity study, as specified in 40 CFR Part 158 requirements. The immunotoxicity 

test (OPPTS 870.7800) is designed to evaluate the potential of repeated exposures to a chemical 

on the function of the immune system. This study has yet to be submitted to the Agency and 

represents a pending data requirement for topramezone.

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)

Following oral administration, radiolabeled topramezone was rapidly absorbed into the systemic 

circulation, with the highest plasma concentrations (Cmax) observed after 1 hr (the first time point 

measured). The estimated absorbed fraction, however, was only about 47% at the low dose 

tested of 10 mg/kg bw. Plasma elimination of radioactivity was biphasic, with the initial 

(primary) half-life estimate being about 5 hours and the terminal elimination half-life estimate 

being about 30 hours. The area under the plasma concentration curve (AUC) scaled more 

linearly with dose than it did with peak plasma levels. The majority of the dose was recovered 

within 48 hours in feces (73-91%) and urine (8-29%). Bile collected up to 48 hours post-dose 

accounted for 19-32% of the administered dose. Concentrations of radioactivity were 

consistently highest in liver followed by kidneys and, to some extent, in the thyroid. The parent 

chemical was the predominant compound identified in both urine (4.0-21.3% dose) and feces 

(66.3-91.7% dose). There were no apparent sex-dependent differences in ADME behavior 

noted.

 

4.2.1 Dermal Absorption

An adjusted DAF of 13% was previously used for topramezone (M. Clock-Rust, et al., D319704, 

7/14/2005) based on (1) its low oral absorption at the highest dose tested of 300 mg/kg bw in a 

rat oral metabolism study and (2) the results of a rat dermal penetration study. The DAF has 
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been revised in this document to be consistent with current guidelines. In the oral metabolism 

study, oral absorption is closer to 47% at the low dose tested of 10 mg/kg bw, which is a more 

relevant dose than 300 mg/kg bw for human health risk assessment. Because of this, more 

emphasis is placed on the DAF estimated from the dermal penetration study. A DAF of 2.6% 

was the highest dermal penetration observed in the dermal penetration study in rats, and is being 

selected to assess potential risk associated with dermal exposures to topramezone.

4.3 Toxicological Effects

The effects observed following repeated oral exposures to topramezone are consistent with those 

expected from HPPD inhibition in mammals. In prenatal developmental toxicity studies (mouse 

and rabbit), where selected measured clinical parameters included serum measurements of 

tyrosine, orally administered topramezone resulted in dose-dependent increases in serum 

tyrosine, consistent with the induction of tyrosinemia. The elevated levels of tyrosine that may 

result in detrimental (adverse) effects have not been delineated. Therefore, this hazard 

characterization does not attempt to associate observed adverse effects following topramezone 

administration to increased tyrosine levels.

The primary target organs affected following topramezone administration were the eyes, thyroid, 

and pancreas. The most sensitive species was the rat and, at least in rats and dogs, males were 

more sensitive than females. The effects on the eyes in chronic toxicity studies consisted of 

pannus (vascularization) and keratitis (cloudiness) of the cornea of both sexes. Hypertrophy and 

hyperplasia of the thyroid, hypertrophy and focal necrosis of the liver, and degeneration of the 

pancreas were among the histopathology findings reported across different subchronic and 

chronic studies in rats and dogs. Results of chronic toxicity studies in dogs, mice, and rats also 

suggest decrements in body weights, body-weight gains, and food utilization (dogs only). 

Inflammation of the urinary bladder was also noted in a dog subchronic toxicity study.

There was evidence for increased susceptibility following in utero exposures to rats and rabbits. 

In rabbits, fetal abnormalities including supernumerary thoracic vertebrae and supernumerary 

13th rib were observed in the presence of maternal toxicity in six of the eight developmental 

toxicity studies conducted in two different strains. In the other two rabbit developmental studies, 

developmental effects were seen in the absence of maternal toxicity only at high doses. In rats, 

developmental effects consisting of skeletal variations occurred in the presence of maternal 

toxicity. Increased maternal serum levels of tyrosine were reported in several developmental

toxicity studies (several in rabbits and one in mice), consistent with the proposed mode of action 

for topramezone involving HPPD inhibition. It should be noted that the fetal skeletal variations 

observed following exposure to topramezone have also been reported with other HPPD-inhibitor 

herbicides (e.g., mesotrione and isoxaflutole). 

In the rat 2-generation reproductive toxicity study, there was no evidence of increased pre- or 

post-natal susceptibility; offspring effects occurred in the presence of maternal effects. The 

offspring effects consisted of (1) decreased pup body weight/body-weight gain in F2 (both sexes) 

and (2) increased time to preputial separation (F1 males). Maternal effects were consistent with 

HPPD inhibition: decreased body weights and body-weight gains, increased thyroid and kidney 

weights, and microscopic findings in the eyes, kidneys, and thyroid. No reproductive effects 

were reported.
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In a rat DNT study, there was evidence for qualitative susceptibility. In the maternal animals, 

toxicity was limited to corneal opacity, whereas effects in the offspring included neurobehavioral 

and neuropathological changes. Offspring neurobehavioral effects consisted of a decreased 

auditory startle reflex at postnatal day 24 in both sexes (20-30%) and at postnatal day 60 for 

males (55%). There were also mild decreases in offspring absolute brain weights and 

neuropathological effects involving decreased brain morphometric measurements (e.g., 

hippocampus, and parietal cortex). 

Topramezone did not show any evidence of neurotoxicity in the ACN or SCN studies. In the 

case of the ACN study, there was no toxicity reported up to the limit dose, while the effects in 

the SCN study were not neurotoxic in nature, but more consistent with those involving HPPD 

inhibition (e.g., corneal clouding, diffuse degeneration of the pancreas, and histopathological 

findings in the thyroid). 

In a rat dermal toxicity study with topramezone, the effects reported consisted of thyroid cell 

hypertrophy, with males being more sensitive than females.

Topramezone is 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. 

Mutagenicity studies conducted on technical topramezone and its major metabolites did not 

demonstrate any mutagenic potential.

4.4 Safety Factor for Infants and Children [FQPA SF]

The FQPA SF is retained only for the acute dietary risk assessment for the U.S. general 

population including infants and children. The FQPA SF is reduced to 1X for (1) the acute 

dietary risk assessment for females of child-bearing age (i.e., 13-49 years old), (2) the chronic 

dietary risk assessment for the U.S. general population, and (3) all non-dietary exposure 

scenarios. The rationale for these decisions is described below. 

4.4.1 Completeness of the Toxicology Database

The existing toxicology database for topramezone is adequate for FQPA evaluation. The 

following acceptable studies are available for FQPA consideration:

Developmental toxicity studies in mice, rats and rabbits;

Two-generation reproduction study in rats; 

ACN and SCN studies; and

DNT study.

4.4.2 Evidence of Neurotoxicity

There was no evidence of neurotoxicity or neuropathology to the adult nervous system either 

following a single oral administration to rats at the Limit Dose in the ACN study or following 

repeated dietary administration to rats in the SCN study.

In the DNT, maternal effects were limited to corneal opacity and there was no evidence of 
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neurotoxicity or neuropathology in the maternal animals. The effects in the offspring were 

neurobehavioral as well as neuropathological, consisting of a decreased auditory startle reflex at 

postnatal day 24 in both sexes (20-30%) and at postnatal day 60 for males (55%), mild decreases 

in absolute brain weights, and decreased brain morphometric measurements (e.g., hippocampus, 

and parietal cortex). 

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

The database contained a prenatal developmental toxicity study in mice and rats and eight

prenatal developmental toxicity studies in two strains (New Zealand and Himalayan) of rabbits.

In the prenatal developmental toxicity study with mice, no developmental toxicity was observed 

at the limit dose, whereas increased serum tyrosine levels were observed in maternal animals at 

the lowest dose tested.

In the prenatal developmental toxicity study with rats, there was evidence for increased 

qualitative, but not quantitative susceptibility in the fetuses. Qualitative susceptibility was 

demonstrated by the occurrence of decreased fetal body weight and increased incidences of 

skeletal variations in the presence of decreased body weight gain in the maternal animals.

The database contained multiple pre-natal developmental toxicity studies in two strains (New 

Zealand and Himalayan) of rabbits. In six of the eight studies, there was evidence for increased 

qualitative susceptibility. In the does, maternal toxicity was characterized as decreases in body 

weight, body weight gain and food consumption, all in the presence of increased serum levels of 

tyrosine. In the fetuses, developmental toxicity manifested as increased incidences of visceral 

findings (i.e., absent kidney and ureter) and/or multiple skeletal variations (i.e., delayed 

ossification, supernumerary 13th rib and/or 27th presacral vertebrae). In a two studies, skeletal 

variations were observed at high doses in the absence of any maternal toxicity.

In the two-generation reproduction study with rats, there was no evidence of increased 

susceptibility. Offspring toxicity was characterized as decreased pup weight and weight gain in 

F2 male and female pups and increased time to preputial separation in the F1 males. These 

effects were observed in the presence of parental/systemic toxicity that included (1) decreased 

body weight, (2) decreased body-weight gain in males, (3) increased thyroid and kidney weights 

of both sexes, and (4) microscopic findings in the eyes, kidney, and thyroid of both sexes.

In the DNT study, there was evidence for qualitative susceptibility. In the maternal animals, 

toxicity was limited to corneal opacity whereas effects in the offspring manifested as (1) 

neurobehavioral changes (decreased auditory startle reflex), (2) decreases in absolute brain 

weight, and (3) decreases in brain morphometric measurements (e.g., hippocampus, and parietal 

cortex). 

There are no residual uncertainties for pre- and post-natal susceptibility for infants and children 

based on the following weight of evidence considerations: 

1) The toxicology database with a DNT is considered complete; 

2) Although there was qualitative evidence for susceptibility, clear NOAELs and LOAELs 

were established for developmental effects; 

3) Fetal findings were limited to visceral and skeletal variations; 
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4) Endpoints of concern (developmental and target organ toxicity) were used for assessing 

risks for appropriate populations of concern; and

5) The concern for topramezone-induced toxicity is for HPPD inhibition that causes 

increases in serum tyrosine levels, resulting in corneal clouding, histopathological lesions 

of the eyes and thyroid glands. 

4.4.4 Residual Uncertainty in the Exposure Database

There are no residual uncertainties in the exposure database. The dietary and residential 

exposure analyses are conservative in nature. The dietary exposure assessment uses tolerancelevel residues and assumes 100% crop treated. The residential exposure assessment uses 

chemical-specific turf-transferable residue data and the 2012 Residential SOPs and is considered 

health-protective.

4.5 Toxicity Endpoints and Points of Departure Selections

4.5.1 Dose-Response Assessment

Acute dietary for the general population including infants and children

The Agency has selected the offspring LOAEL of 8 mg/kg/day from the DNT study as the 

endpoint of concern for this exposure scenario and population. The LOAEL is based on 

decreased auditory startle reflex, decreases in brain weight, and brain morphometric parameters 

at the lowest dose tested. In this study, the offspring were exposed to the chemical in utero and 

during the lactation period (i.e., postnatally). Consequently, it is presumed that the effects of 

concern could manifest after a single exposure anytime during the dosing regimen (i.e., either 

pre- or postnatal exposure). A 1000-fold factor was used for deriving the acute reference dose 

(aRfD) for this exposure scenario. In addition to the conventional 100X UF (10X inter-and 10X 

intra species factors), the 10X FQPA SF was retained in the form of a UFL (i.e., LOAEL-toNOAEL extrapolation) because a LOAEL was selected for risk assessment. Thus, the aRfD and 

aPAD are equivalent at 0.008 mg/kg body weight.

Acute dietary for females of child-bearing age (13-49 years old)

The Agency has selected the developmental NOAEL of 0.5 mg/kg/day from the developmental 

toxicity study in rabbits as the endpoint of concern for this exposure scenario and population. 

This NOAEL is based on increased skeletal variations observed in the fetuses following in utero

exposures to rabbits at 5 mg/kg/day (LOAEL). The in utero effects are the most sensitive 

endpoint for this sub-population (potentially pregnant females). The conventional 100-fold 

factor (10X inter- and 10X intra-species) was applied to the NOAEL. The FQPA SF of 10X was 

not retained for this exposure scenario for the following reasons: (1) the toxicology database is 

complete, (2) there were no residual uncertainties for pre-and or post-natal susceptibility, and (3) 

developmental effects are used as the endpoint of concern for this scenario. Thus, the aRfD and

aPAD for females of child-bearing age are equivalent at 0.005 mg/kg body weight.

Chronic dietary (all populations)

The Agency has selected the NOAEL of 0.4 mg/kg/day from the chronic toxicity/carcinogenicity 

study with rats for this exposure scenario. This NOAEL is based on increased incidences of 
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corneal opacity, decreased body weight and body-weight gains in males, and histopathological 

evaluations in the thyroid, pancreas, and eyes of both sexes observed at 3.6 mg/kg/day (LOAEL). 

This endpoint/study is appropriate for this exposure scenario since the effects were observed in 

the most sensitive species following chronic exposure. The conventional 100-fold factor (10X 

inter- and 10X intra-species) was applied to the NOAEL (0.4 mg/kg/day). The FQPA SF was 

not retained for this exposure scenario since the toxicology database is complete and there were 

no residual uncertainties for pre-and or post-natal susceptibility. Thus, the cRfD and cPAD are 

equivalent at 0.004 mg/kg bw/day.

Short- and intermediate-term incidental oral

The Agency has selected the NOAEL of 0.4 mg/kg/day from the two-generation reproduction 

study for this exposure scenario. This NOAEL is based on decreases in body weights and bodyweight gains in the F2 generation offspring and increased time to preputial separation in the F1 

male offspring seen at 4.2 mg/kg/day (LOAEL). These effects were observed in the offspring 

following approximately 13 weeks of treatment. Therefore, they are appropriate for the 

population (infants and children) and exposure duration (short- and intermediate-term) of 

concern. 

In addition, this POD addresses concern for the effects observed in the DNT and the SCN 

studies. In the DNT study, the offspring LOAEL was 8 mg/kg/day based on decreased 

maximum auditory startle reflex response, decreased brain weight, and changes in brain 

morphology; an offspring NOAEL was not established. When the uncertainty factor for using a 

LOAEL instead of a NOAEL is taken into consideration, the POD for the DNT study is 0.8 

mg/kg/day (8 mg/kg/day ÷10 UFL = 0.8 mg/kg/day), which is 2-fold higher than the POD 

selected for this exposure scenario. In the SCN study, the LOAEL was 4.2 mg/kg/day in males 

and 5.0 mg/kg/day in females, and was based on the following effects: (1) elevated levels of 

granular casts and transitional epithelial cells in the urinary sediment of the males, (2) increased 

incidences of corneal clouding in females, (3) minimal diffuse degeneration of the pancreas (both 

sexes), and (4) slight to moderate flaky colloid in the thyroid of the males. In this study, a 

NOAEL was not established. When the uncertainty factor for using a LOAEL instead of a 

NOAEL is taken into consideration, the POD for the SCN study is 0.42 mg/kg/day (4.2 

mg/kg/day ÷ 10 UFL = 0.42 mg/kg/day), which is numerically similar to the selected POD for 

this exposure scenario. 

There is a concern regarding the two-generation reproduction study in that no histopathological 

evaluation was conducted of eyes, thyroid, and pancreas (the target organs) in the offspring. In 

the chronic toxicity/carcinogenicity study, corneal opacity and histopathological lesions in the 

eyes, thyroid, and pancreas were seen in both sexes at 3.6 mg/kg/day. The NOAEL from that 

study of 0.4 mg/kg/day is numerically similar to the selected POD for this exposure scenario. 

Although there is concern that histopathological evaluations in the offspring were not conducted 

in two-generation reproduction study, it should be noted that corneal opacity was observed on 

Days 267 (females) and 282 (males), and lesions of the eyes, thyroid and pancreas were observed 

only at the termination of the chronic toxicity/carcinogenicity study.

A MOE of 100, which includes the 10X inter- and 10X intra-species factors is adequate for this 

exposure scenario. The FQPA SF is not retained since (1) the toxicology database is complete, 

(2) there are no residual uncertainties for pre-and or post-natal susceptibility, and (3) the toxicity 

seen in the target organs is the endpoint of concern for this scenario.
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Short- and intermediate-term dermal

The Agency has selected the parental/systemic NOAEL of 0.4 mg/kg/day from the twogeneration reproduction study. This NOAEL is based on decreases in body weights and body 

weight gains in males; effects on the eyes (cornea opacity, cataracts, enlarged eye bulb, and 

chronic keratitis) and kidneys (increased kidney weights and pelvic dilatation) in both sexes; and 

effects on the thyroid (increased thyroid weights in males and flaky colloid in both sexes) at 4.2 

mg/kg/day. This POD addresses concern for (1) the fetal effects observed in the developmental 

toxicity study in rabbits (LOAEL = 5 mg/kg/day), (2) the offspring effects observed in the DNT 

study (LOAEL = 8 mg/kg/day) and (3) the effects observed in the SCN study (LOAEL = 4.2 

mg/kg/day). 

The available 28-day dermal toxicity study in rats was not selected since this study did not 

evaluate the developmental potential following dermal exposures to topramezone. 

Since an oral dose was selected, the DAF of 2.6% should be used to estimate a dermal equivalent 

dose. Based on a DAF of 2.6%, the equivalent dermal NOAEL would be 15.4 mg/kg/day (0.4 

mg/kg/day divided by 0.026).

A Margin of Exposure (MOE) of 100, which includes the 10X inter- and 10X intra-species 

factors is adequate for this exposure scenario. The FQPA SF is not retained since (1) the 

toxicology database is complete, (2) there are no residual uncertainties for pre-and or post-natal 

susceptibility, and (3) the toxicity seen in the target organs is the endpoint of concern for this 

scenario.

Short- and intermediate-term inhalation

The Agency has selected the parental/systemic NOAEL of 0.4 mg/kg/day from the twogeneration reproduction study. This NOAEL is based on decreases in body weights and body 

weight gains in males; effects on the eyes (cornea opacity, cataracts, enlarged eye bulb, and 

chronic keratitis) and kidneys (increased kidney weights and pelvic dilatation) in both sexes; and 

effects of the thyroid (increased thyroid weights in males and flaky colloid in both sexes) at 4.2 

mg/kg/day. This POD addresses concern for (1) the fetal effects observed in the developmental 

toxicity study in rabbits (LOAEL = 5 mg/kg/day), (2) the offspring effects observed in the DNT 

study (LOAEL = 8 mg/kg/day) and (3) the effects observed in the SCN study (LOAEL = 4.2 

mg/kg/day). 

Since an oral dose was selected, a 100% absorption factor will be assumed. For topramezone, 

the estimated orally absorbed fraction is only about 47% at the low dose tested of 10 mg/kg bw. 

Inhalation exposures are not expected to be significant based on the proposed residential outdoor 

turfgrass use. Additionally, topramezone is placed in Toxicity Category IV and has a low vapor 

pressure (7.5 x 10-13 mmHg). A 28-day inhalation study is not required to assess the proposed 

uses and the risk estimates for occupational handlers are sufficiently protective (see Section 9.0).

A Margin of Exposure (MOE) of 100, which includes the 10X inter- and 10X intra-species 

factors is adequate for this exposure scenario. The FQPA SF is not retained since (1) the 

toxicology database is complete, (2) there are no residual uncertainties for pre-and or post-natal 

susceptibility, and (3) the toxicity seen in the target organs is the endpoint of concern for this 

scenario.
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4.5.2 Recommendation for Combining Routes of Exposure for Risk Assessment

The Agency must consider risks from individual routes of exposure (oral, dermal, and inhalation) 

and perform an aggregate risk assessment if a common toxicity endpoint is established across 

different routes of exposure. Since short- and intermediate-term dermal, inhalation, and 

incidental oral endpoints are based on oral studies, dietary exposure will be aggregated with 

residential dermal, inhalation, and incidental oral exposures for all populations/durations, where 

appropriate. 

4.5.3 Cancer Classification and Risk Assessment Recommendation

Topramezone is 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 chronic 

Reference Dose (cRfD) is not expected to alter thyroid hormone homeostasis nor result in 

thyroid tumor formation. 

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

Assessment

The PODs, UFs, and toxicity endpoints are presented in Table 4.5.4a (dietary and nonoccupational assessments) and Table 4.5.4b (occupational assessments).

Table 4.5.4a. Summary of Toxicology Endpoints and Point of Departure Doses for Topramezone in Dietary 

and Residential Risk Assessment.

Exposure

Scenario Point of Departure Uncertainty/FQPA SFs 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 =0.008 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 13-50 

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 

Intermediate-Term)

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 
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Table 4.5.4a. Summary of Toxicology Endpoints and Point of Departure Doses for Topramezone in Dietary 

and Residential Risk Assessment.

Exposure

Scenario Point of Departure Uncertainty/FQPA SFs or LOC for Risk Assessment Study and Toxicological Effects

increased time to preputial separation in the F1 

male offspring.

Short- and 

Intermediate-Term, 

Dermal 

Oral NOAEL = 0.4 

mg/kg/day

(dermal-absorption

factor = 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.

Short- and 

Intermediate-Term 

Inhalation

Oral NOAEL = 0.4 

mg/kg/day

(inhalation absorption 

rate = 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 EPA Final Guidelines for Carcinogen Risk Assessment (March 29, 2005), the CARC classified 

topramezone 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.

Table 4.5.4b. Summary of Toxicology Endpoints and Point of Departure Doses 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 

Intermediate-Term, 

Dermal 

Oral NOAEL= 0.4 

mg/kg/day

(dermal-absorption

factor = 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 

Intermediate-Term 

Inhalation

Oral NOAEL= 0.4 

mg/kg/day

(inhalation absorption 

rate = 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 EPA Final Guidelines for Carcinogen Risk Assessment (March 29, 2005), the 

CARC classified topramezone 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.

5.0 Dietary Exposure and Risk Assessment

While there are no new food uses proposed in this action, dietary exposure was assessed based 

on estimated drinking water concentrations and existing tolerances on corn, and liver and kidney 

in beef cattle, goat, and sheep. 
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5.1 Summary of Environmental Degradation

Major routes of dissipation for topramezone are anaerobic microbial-mediated degradation, 

leaching, surface water runoff, and spray drift. Topramezone degrades to form M670H05 (15% 

of applied parent at 365 days), and M670H01 (>15% of applied), M670H 10 (>16% of applied). 

The degradation product M670H05 is mobile and persistent (half-life >350 days). Topramezone 

applications can lead to surface water contamination through spray drift and runoff. In addition, 

because it is persistent and mobile in soil, topramezone is expected to leach into ground water. 

5.2 Comparison of Metabolic Pathways

A detailed discussion of the metabolic pathways in corn, rat, ruminants and poultry was provided 

in a previous risk assessment (Memo, M. Clock-Rust et al., 7/14/05, DP# 290075). In summary, 

the results of the topramezone metabolism studies were similar in that the parent compound was 

not extensively metabolized; however, significant differences were observed in the metabolic 

pathways.

5.3 Residues of Concern Summary and Rationale

A detailed discussion of the residues of concern and rationale was provided in a previous 

risk assessment (Memo, M. Clock-Rust et al., 7/14/05, DP# 290075). Table 5.3.1 below 

provides a summary.

Table 5.3.1. Summary of Metabolites and Degradates of Concern for Risk Assessment and Tolerance 

Enforcement.

Matrix Residues of Concern

Risk Assessment Tolerance Enforcement

Plants Corn Topramezone Topramezone

Rotational Crops Topramezone Not required1

Livestock Ruminant Topramezone Topramezone

Poultry To be determined2 To be determined2

Drinking Water Topramezone Not applicable

1. As a result of the proposed plantback restrictions, residues in rotational crops are not expected to result from the proposed uses.

2. To be determined. Note: if future proposed uses significantly increase the dietary exposure to poultry, then the poultry feeding study should 

include analysis for metabolite M670H02.

5.4 Food Residue Profile

Magnitude of the residue data were submitted for field corn, sweet corn, limited field rotational 

crops and lactating dairy cows. A detailed discussion of the food residue profile was provided in 

a previous risk assessment (Memo, M. Clock-Rust et al., 7/14/05, DP# 290075). 

5.5 Water Residue Profile

There have been numerous drinking water assessments to support topramezone uses. These uses 

include corn (field, seed, popcorn, and sweet corn) and non-cropped areas. Non-cropped areas 

include Christmas tree, conifer, and hardwood plantations; field-grown ornamentals; railroad, 

utility, highway, and pipeline rights-of-way; highway guardrails, delineators, and sign posts; 

utility substations; petroleum tank farms; pumping installations; farmyards; fence rows; storage 

areas; airports; non-irrigation ditchbanks; wildlife openings; and areas grazed or cut for hay. 
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For the current action on turf, EFED provided modeled ground [SCI-GROW (Screening 

Concentration in Groundwater] and surface [PRZM (Pesticide Root Zone Model) and EXAMS 

(EXposure Analysis Modeling System)] estimated drinking water concentrations (EDWCs) for 

topramezone applications to turf (EFED memorandum; D388368, J. Hetrick, 11/14/11). Table 

5.5.1 provides a summary of the surface and ground water modeling for drinking water 

assessments for topramezone for all registered uses (bolded numbers were used in the 

assessment). 

These drinking water values were incorporated directly into this dietary assessment. For acute 

dietary risk, the highest acute surface water concentration was used (5.281 ug/L) and for chronic 

dietary risk assessment, the highest chronic (non-cancer) surface water concentration was used 

(1.998 ug/L). Water residues were incorporated in the DEEM-FCIDTM into the food categories 

“water, direct, all sources” and “water, indirect, all sources.” The water models and their 

description are available at the EPA internet site: http://www.epa.gov/oppefed1/models/water/. 

Table 5.5.1. Summary of Estimated Surface Water and Groundwater Concentrations for Topramezone.

Use Site Scenario Surface Water Conc., ppb a Groundwater Conc., ppb b

Turfc

FL 

Acute 0.536

0.271

Chronic (non-cancer) 0.367

Chronic (cancer) 0.216

PA

Acute 1.355

Chronic (non-cancer) 0.693

Chronic (cancer) 0.380

Cornd

Acute 0.77

Chronic (non-cancer) 0.14 0.0671

Chronic (cancer) 0.07

Non Crop Arease

Acute 5.281

Chronic (non-cancer) 1.998 0.006

Chronic (cancer) 1.016

a

From the Tier II PRZM-EXAMS - Index Reservoir model. 

b

From the SCI-GROW model.

c

Input parameters are based on the maximum application rate per season (0.089 lb ai/A).

d

Input parameters are based on the maximum application rate per season (0.22 lb ai/A).

e

Input parameters are based on the maximum application rate per season (0.089 lb ai/A).

5.6 Dietary (Food + Drinking Water) Risk Assessment

5.6.1 Description of Residue Data Used in Dietary Assessment

An acute and chronic dietary exposure analysis (food and drinking water) was performed to 

support the new use of topramezone. The analysis was performed using the Dietary Exposure 

Evaluation Model DEEM-FCIDTM, Version 2.03. This model uses food consumption data from 

the USDA’s CSFII from 1994-1996 along with a supplemental children’s survey from 1998. 

5.6.2 Percent Crop Treated Used in Dietary Assessment

Percent crop treated values were not estimated. A default of 100% was used. 

5.6.3 Acute Dietary Risk Assessment

The acute dietary exposure and risk estimates (food + drinking water) were 0.000309 mg/kg/day 

for the general U.S. population (3.9% of the aPAD) and 0.001097 mg/kg/day (14% of the cPAD) 

for the most highly exposed population subgroup (all infants <1 year old) and are, thus, below 
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HED’s LOC (<100% aPAD). The resulting acute dietary exposure and risk estimates for 

females 13-49 years of age were 0.000279 mg/kg/day (5.6% of the aPAD) and are below HED’s 

LOC (<100% aPAD). 

5.6.4 Chronic Dietary Risk Assessment

The chronic dietary exposure and risk estimates (food + drinking water) were 0.000064 

mg/kg/day for the general U.S. population (1.6% of the cPAD) and 0.000167 mg/kg/day (4.2% 

of the cPAD) for the most highly exposed population subgroup (all infants <1 year old) and are,

thus, below HED’s LOC (<100% cPAD).

5.6.5 Cancer Dietary Risk Assessment

No cancer dietary risk assessment was performed because topramezone is not considered to be a 

carcinogen.

5.6.6 Summary Table

Table 5.6.6.1 is a summary of the acute and chronic dietary (food and water) exposure and risk 

estimates. 

Table 5.6.6.1. Summary of Dietary (Food + Drinking Water) Exposure and Risk for Topramezone1.

Population Subgroup

Acute Dietary

(95th Percentile) Chronic Dietary

Dietary Exposure 

(mg/kg/day) % aPAD Dietary Exposure(mg/kg/day) % cPAD

General U.S. Population 0.000309 3.9 0.000064 1.6

All Infants (<1 year old) 0.001097 14 0.000167 4.2

Children 1-2 years old 0.000508 6.4 0.000106 2.6

Children 3-5 years old 0.000467 5.8 0.000109 2.7

Children 6-12 years old 0.000324 4.0 0.000079 2.0

Youth 13-19 years old 0.000259 3.2 0.000059 1.5

Adults 20-49 years old 0.000278 3.5 0.000057 1.4

Adults 50+ years old 0.000247 3.1 0.000052 1.3

Females 13-49 years old 0.000279 5.6 0.000057 1.4

1

 Acute dietary POD of 0.008 mg/kg/day applies to the general U.S. population, including infants and children. Acute dietary POD of 0.005 

mg/kg/day applies to the females 13-49 years old population subgroup only. Chronic dietary POD of 0.027 mg/kg/day applies to the general U.S. 

population and all population subgroups. The values for the highest exposed population are bolded.

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

Since the product can be applied to residential turf sites, exposure and risk estimates were 

calculated for both residential handlers and for post-application activities associated with 

residential turfgrass and golf courses. 

6.1 Residential Handler Exposure and Risk 

The residential handler exposure assessment estimates dermal and inhalation exposures for 

individuals using topramezone on residential turfgrass. The following are key differences 

between residential and occupational handler assessments: 

Residential handler exposure scenarios are considered to be short-term only, due to the 

infrequent use patterns associated with homeowner products.
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A tiered approach for personal protection using increasing levels of PPE is not used in 

residential handler risk assessments. Homeowner handler assessments are based on the 

assumption that individuals are wearing shorts, short-sleeved shirts, socks, and shoes.

Homeowner handlers are expected to complete all tasks associated with the use of a 

pesticide product including mixing/loading if needed as well as the application.

The quantitative exposure/risk assessment developed for residential handlers is based on the 

following scenarios: 

(1) Mixing/Loading/Applying Liquids with Backpack Sprayer, and 

(2) Mixing/Loading/Applying Liquids with Manually-Pressurized Handwand.

Unit exposure values and estimates for area treated were taken from HED’s 2012 SOPs for 

Residential Pesticide Exposure Assessment: Lawns/Turf. 

Short-term risks for residential handlers are presented in Table 6.1.1. Intermediate-term 

exposures are not likely because of the intermittent nature of applications by homeowners. 

Short-term combined dermal plus inhalation risk estimates to residential handlers do not exceed 

HED’s LOC for all scenarios. 

Table 6.1.1. Residential Handler Exposure and Risk Estimates for Topramezone Applications to Turfgrass.

Exposure Scenario

Application 

Rate (lb 

ai/gallon)a

Area 

Treated 

Daily 

(gallons)b

Baseline Unit 

Exposuresb(mg/lb ai)

Baseline Dosed

(mg/kg/day) Baseline MOEe Combined MOEf

DermalcInhalationc Dermal Inhalation Dermal Inhalation Dermal + Inhalation 

Mixer/Loader/Applicator

Mixing/Loading/Applying 

Liquids with Manuallypressurized Handwand 0.001 5 63 0.018 0.0001 1.1 x 10-63,900 360,000 3,900

Mixing/Loading/Applying 

Liquids with Backpack 

Sprayer

0.001 5 130 0.14 0.00021 8.8 x 10-61,900 46,000 1,800

a. Application rates based on proposed label for topramezone (Topramezone 2.8 SC, EPA Reg#7969-GET).

b. Based on HED’s SOPs for Residential Pesticide Exposure Assessment; Lawns/Turf (January 2012).

c. Baseline Dermal: Long-sleeve shirt, long pants, and no gloves; Baseline Inhalation: no respirator. 

d. Dose (mg/kg/day) = daily unit exposure (mg/lb ai) x application rate (lb ai/gal) x gal treated * absorption factor (dermal = 2.6%) / body 

weight (80 kg).

e. MOE = NOAEL (0.4 mg/kg/day) / daily dose (mg/kg/day). LOC = 100.

f. Combined MOE = NOAEL (0.4 mg/kg/day) / combined dermal + inhalation dose (mg/kg/day).

6.2 Residential Post-application Exposure and Risk

Topramezone can be used in many areas that can be frequented by the general population 

including residential areas (e.g., home lawns). As a result, individuals can be exposed by 

entering these areas if they have been previously treated. 

6.2.1 Post-application Inhalation

Based on the Agency's current practices, a quantitative post-application inhalation exposure 

assessment was not performed for topramezone at this time. However, volatilization of 

pesticides may be a potential source of post-application inhalation exposure to individuals nearby 

to 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. The Agency received the SAP’s final report 

on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The
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Agency is in the process of evaluating the SAP report and may, as appropriate, developing 

policies and procedures, to identifying the need for and, subsequently, the way to incorporate 

post-application inhalation exposure into the Agency's risk assessments. If new policies or 

procedures are put into place, the Agency may revisit the need for a quantitative post-application 

inhalation exposure assessment for topramezone.

6.2.2 Post-application Dermal and Incidental Oral

Short-term dermal and incidental oral exposure and risk estimates have been assessed here and 

since the short- and intermediate-term PODs are the same, the short-term assessment is 

protective of longer-term exposures. However, in the case of incidental soil ingestion, HED has 

conducted a conservative assessment of potential intermediate-term oral risk from soil ingestion 

by using a yearly application rate of 0.089 lb ai/A, instead of the maximum single rate of 0.044 

lb ai/A, to address the persistence [half life of ≥ 240 days (J. Hetrick, D388368, 11/14/2011)] and 

likely potential build-up of topramezone in the soil. 

The scenarios, routes of exposure and lifestages assessed include:

Physical activities on turf: adults (dermal) and children 1 < 2 years old (dermal and 

incidental oral);

Mowing: adults (dermal) and children 11 < 16 years old (dermal); and

Golfing: adults (dermal), children 11 < 16 years old (dermal), and children 6 < 11 years 

old (dermal).

Table 6.2.2.1 presents the post-application dermal and incidental oral MOE values calculated for 

the appropriate lifestages after applications of topramezone to turf. Since the toxicological 

effects are similar for dermal versus incidental oral PODs, dermal risks were combined with 

incidental oral risks for children 1 < 2 years old. Post-application risk estimates do not exceed 

HED’s LOC for any of the scenarios assessed. 

Table 6.2.2.1. Short-Term Residential Post-application Exposure and Risk Estimates for Topramezone.

Lifestage Post-application Exposure Scenario Dose (mg/kg/day) MOEs

Adult

Turf -

sprays

Dermal 

Physical Activities on Turf 0.00083 480

Mowing 1.7 x 10-524,000

Golfing 6.6 x 10-56,100

Child 11 < 16 years old Dermal Mowing 2.0 x 10-5

21,000

Golfing 7.6 x 10-55,200

Child 6 < 11 years old Dermal Golfing 9.0 x 10-54,500

Child 1 < 2 year old

Dermal Physical Activities on Turf 0.0017 240

Hand to Mouth 0.00026 1,500

Object to Mouth 2.1 x 10-519,000

Short-term Incidental Soil Ingestion 1.5 x 10-6270,000

Intermediate-term Incidental Soil Ingestion 3.0 x 10-6130,000

6.3 Combined Exposure

HED combines risk estimates resulting from separate post-application exposure scenarios when 

it is likely they can occur simultaneously based on the use pattern and the behavior associated 

with the exposed population and when the toxicological effects are similar. For topramezone, 

the toxicological effects are similar for the dermal, inhalation and incidental oral routes; 

therefore, the exposures via these routes were combined where appropriate. For residential 
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handlers, dermal and inhalation exposures were combined. For post-application scenarios, 

dermal and incidental oral exposures were combined for children 1 < 2 years old. 

The incidental oral scenarios (i.e., hand-to-mouth, object-to-mouth, and soil ingestion) should be 

considered inter-related and it is likely that they occur interspersed amongst each other across 

time. Combining all three of these scenarios with the dermal exposure scenario would be overlyconservative because of the conservative nature of each individual assessment. Therefore, the 

post-application exposure scenarios that were combined for children 1 < 2 years old are the 

dermal and hand-to-mouth scenarios. This combination should be considered a protective 

estimate of children’s exposure to pesticides used on turf.
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Table 6.3.1. Short- and Intermediate-Term Residential Exposures for the Topramezone Combined Residential Risk Calculations.

Population

Handler Exposure 

(mg/kg/day)1 Residential 

Handler Total 

Exposure 

(mg/kg/day)3

Residential 

Handler 

Total MOE

Post-application Exposure (mg/kg/day)2 Residential 

Postapplication 

Total Exposure 

(mg/kg/day)3

Residential 

Postapplication 

Total MOE Dermal Inhalation Dermal Inhalation Oral

Short-Term

Adult Male 0.00021 8.8 x 10-60.00022 1,800 0.00083 N/A N/A 0.00083 480

Child 11 < 16 years old N/A 7.6 x 10-5 N/A N/A 7.6 x 10-55,200

Child 6 < 11 years old N/A 9.0 x 10-5 N/A N/A 9.0 x 10-54,500

Child 1 < 2 years old N/A 0.0017 N/A 0.00026 0.0019 210

Intermediate-Term

Child 1 < 2 years old N/A N/A N/A 3.0 x 10-63.0 x 10-6130,000

1. Handler exposure represents high-end inhalation handler exposure, where the exposure duration is appropriate to assess.

2. Postapplication exposure represents high-end incidental oral exposure for the relevant exposure duration.

3. For adults, residential total exposure combines the highest dermal and inhalation exposures (Table 4.2.2.1), where applicable. For young children, total residential exposure 

combines high-end post application incidental oral AND dermal exposure, where applicable (Table 5.2.2.1). 
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6.4 Residential Bystander Post-application Inhalation Language

Based on the Agency's current practices, a quantitative post-application inhalation exposure 

assessment was not performed for topramezone at this time. However, 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 FIFRA 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 is in the process of evaluating the SAP report and may, as appropriate, develop 

policies and procedures to identify the need for and, subsequently, the way to incorporate postapplication inhalation exposure into the Agency's risk assessments. If new policies or 

procedures are developed, the Agency may revisit the need for a quantitative post-application 

inhalation exposure assessment for topramezone.

6.5 Spray Drift

Spray drift is always a potential source of exposure to residents nearby to spraying operations. 

This is particularly the case with aerial application, but, to a lesser extent, could also be a 

potential source of exposure from the ground application method employed for topramezone. 

The Agency has been working with the Spray Drift Task Force, 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 at 

http://www.epa.gov/opp00001/factsheets/spraydrift.htm). On a chemical-by-chemical basis, the 

Agency is now requiring interim mitigation measures for aerial applications that must be placed 

on product labels/labeling. The Agency has completed its evaluation of the new database 

submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is 

developing a policy on how to appropriately apply the data and the AgDRIFT®computer model 

to its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic 

methods. After the policy is in place, the Agency may impose further refinements in spray-driftmanagement practices to reduce off-target drift with specific products with significant risks 

associated with drift.

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) 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.

7.1 Acute Aggregate Risk

Acute aggregate risk is made up only of dietary sources; therefore, the acute exposure estimates 

provided in the acute dietary exposure analysis represents acute aggregate exposure. 

 
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7.2 Short-Term Aggregate Risk

Short-term aggregate risk is made up of dietary and non-dietary sources of exposure. Since 

topramezone has a residential lawn use, adult residential handler exposure (dermal and 

inhalation) is expected, as well as adult and child post-application exposure (dermal and 

incidental oral). Short-term aggregate risk is made up of average dietary exposures from food 

and drinking water sources, and residential exposures. 

Dietary (food and drinking water) exposure is based on a Tier 1 (unrefined) chronic dietary 

exposure assessment (see Table 5.6.1). Residential exposure estimates are conservative 

estimates due to the standard assumptions that were built into the calculations. The short-term 

aggregate risk calculations for both the general U.S. population and children (1-2 years old) are 

shown below in Table 7.2.1 and are not of concern to HED.

Table 7.2.1. Short-Term Aggregate Risk Calculations.

Population NOAEL

(mg/kg/day) LOC

Average Food 

and Water 

Exposure 

(mg/kg/day)2

Residential 

Exposure 

(mg/kg/day)3

Total Exposure 

(mg/kg/day)4

Aggregate MOE 

(food, water, and 

residential)5

General U.S. 

Population 0.4 100

0.000064 0.00022 0.00028 1,400

Children 1-2 

years old1 0.000106 0.0019 0.0020 200

1 Children 1-2 were selected for the aggregate risk evaluation as the index lifestage; i.e., a subpopulation more likely to be exposed than infants 

<1 year old. Infants <1 year old did have a higher background (chronic dietary) exposure, and the MOE for that population subgroup is 190. 

2 Average Food and Water Exposure = Dietary exposure (Table 5.6.1).

3Residential Exposure = [Incidental oral exposure (i.e., Hand-to-Mouth) + Dermal exposure + Inhalation Exposure] (Table 6.3.1).

4 Total Exposure = Average Food & Water Exposure + Residential Exposure).

5

.

7.3 Intermediate-Term Aggregate Risk

Intermediate-term residential exposures are not expected for adults. However, for children, an 

intermediate-term aggregate assessment was conducted by adding the incidental soil ingestion 

exposure and average food and water exposure (chronic dietary exposure). As seen in Table 

7.3.1, intermediate-term aggregate risk estimates for children (1-2 years old) are not of concern 

to HED. 

Table 7.3.1. Intermediate-Term Aggregate Risk Calculations.

Population NOAEL

(mg/kg/day) LOC

Average Food 

and Water 

Exposure 

(mg/kg/day)2

Residential 

Exposure 

(mg/kg/day)3

Total Exposure 

(mg/kg/day)4

Aggregate MOE 

(food, water, and 

residential)5

Children 1-2 

years old1 0.4 100 0.000106 3.0 x 10-6

0.00011 3,700

1 Children 1-2 were selected for the aggregate risk evaluation as the index lifestage, i.e., a subpopulation more likely to be exposed than infants 

<1 year old. Infants <1 year old did have a higher background (chronic dietary) exposure, and the MOE for that population subgroup is 2,400. 

2 Average Food and Water Exposure = Dietary exposure (Table 5.6.1).

3 Residential Exposure = [Incidental Soil Ingestion] (Table 6.3.1).

4 Total Exposure = Average Food & Water Exposure + Residential Exposure).

5

.
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7.4 Long-Term Aggregate Risk

Chronic (long-term) aggregate risk is made up only of dietary sources; therefore, the chronic 

exposure estimates provided in the chronic dietary exposure analysis represents chronic 

aggregate exposure. 

7.5 Cancer Risk

Aggregate cancer risk was not calculated because topramezone is not considered to be a 

carcinogen.

8.0 Cumulative Exposure/Risk Characterization

Pyrasulfotole, mesotrione, isoxaflutole, and topramezone belong to a class of herbicides that 

inhibit the liver enzyme HPPD, which is involved in the catabolism (metabolic breakdown) of 

tyrosine (an amino acid derived from proteins in the diet). Inhibition of HPPD can result in 

elevated tyrosine levels in the blood, a condition called tyrosinemia. HPPD-inhibiting herbicides 

have been found to cause a number of toxicities in laboratory animal studies including ocular, 

developmental, liver and kidney effects. Of these toxicities, the ocular effect (corneal opacity) is 

highly correlated with the elevated blood tyrosine levels. In fact, rats dosed with tyrosine alone 

show ocular opacities similar to those seen with HPPD inhibitors. Although the other toxicities 

may be associated with chemically induced tyrosinemia, other mechanisms may also be 

involved. 

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. The explanation of this species-specific response in ocular opacity is related to the 

species differences in the clearance of tyrosine. A metabolic pathway exists to remove tyrosine 

from the blood that involves a liver enzyme called tyrosine aminotransferase (TAT). In contrast 

to rats where ocular toxicity is observed following exposure to HPPD-inhibiting herbicides, mice 

and humans are unlikely to achieve the levels of plasma tyrosine necessary to produce ocular 

opacities because the activity of TAT in these species is much greater compared to rats. Thus, 

humans and mice have a highly effective metabolic process for handling excess tyrosine. 

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 indicates that an HPPD inhibitor in it of itself cannot easily 

overwhelm the tyrosine-clearance mechanism in humans. 

Therefore, exposure 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. In the future, assessments of HPPD-inhibiting 

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

Doc. D 341612; dated 7/02/07).

9.0 Occupational Exposure/Risk Characterization

9.1 Short- and Intermediate-Term Handler Risk

Based on the anticipated use patterns and current labeling, types of equipment and techniques 

that can potentially be used, occupational handler exposure is expected from the proposed uses. 

The quantitative exposure/risk assessment developed for occupational handlers is based on the 

following scenarios: 

(1) Open mixing/loading liquids for groundboom applications;

(2) Applying sprays via groundboom applications;

(3) Mixing/loading/applying with a manually-pressurized handwand; 

(4) Mixing/loading/applying with a mechanically-pressurized handwand; and

(5) Mixing/loading/applying with a backpack sprayer.

For pesticide handlers, HED presents estimates of dermal exposure for “baseline” (i.e., workers 

wearing a single layer of work clothing consisting of a long-sleeved shirt, long pants, shoes plus 

socks and no protective gloves), as well as for “baseline” and the use of protective gloves or 

other PPE, as might be necessary. The topramezone product labels direct mixers, loaders, 

applicators and other handlers to wear long-sleeved shirt and long pants, chemical-resistant 

gloves, shoes plus socks, goggles, face shield or safety glasses.

It is the policy of HED to use the best available data to assess handler exposure. Sources of 

generic handler data, used as surrogate data in the absence of chemical-specific data, include the 

PHED 1.1, the AHETF database, the ORETF database, or other registrant-submitted 

occupational exposure studies. Some of these data are proprietary, and subject to the data 

protection provisions of FIFRA. The standard values recommended for use in predicting handler 

exposure that are used in this assessment, known as “unit exposures,” are outlined in the 

“Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” 

(http://www.epa.gov/opp00001/science/handler-exposure-table.pdf), which, along with 

additional information on HED policy on use of surrogate data, including descriptions of the 

various sources, can be found at http://www.epa.gov/pesticides/science/handler-exposuredata.html.

 

Typically, HED completes short- and intermediate-term assessments for occupational scenarios 

in all cases because these kinds of exposures are likely and acceptable use/usage data are not 

available to justify deleting intermediate-term scenarios. Based on use data and label 

instructions, HED believes that occupational exposures may occur over a single day or up to 

weeks at a time for many of the use-patterns and that intermittent exposure over several weeks 

may also occur. Some applicators may apply these products over a period of weeks, because 

they are commercial applicators who are completing multiple pesticide applications for multiple 

clients. Long-term exposures are not expected; therefore, a long-term assessment was not 

conducted. 

The daily areas treated and amounts handled were defined for each handler scenario (in 

appropriate units) by determining the amount that can be reasonably treated by an individual in a 
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single day. When possible, the assumptions for daily areas treated and amounts handled are 

taken from the HED’s Science Advisory Council for Exposure (ExpoSAC) Policy #9: “Standard 

Values for Daily Acres Treated in Agriculture,”,” which was revised on July 5, 2000. Values 

used for area treated and amount handled in each scenario include: 80 acres for groundboom 

application, 1000 gallons for mechanically-pressurized handgun, and 40 gallons for backpack 

and manually-pressurized handwand equipment.

Since an oral study was selected for the short- and intermediate-term assessments, a 2.6% 

dermal-absorption factor was applied. In addition, an assumption of equivalent toxicity from the 

oral and inhalation routes of exposure was made. A body weight of 80 kg was used. 

Table 9.1.1 presents the exposure/risks for short and intermediate-term dermal and inhalation 

exposures at baseline. The combined dermal and inhalation exposure risk estimates are not of 

concern (i.e., MOEs >100) at baseline for all scenarios. 
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Table 9.1.1. Short-/Intermediate-Term Occupational Exposure and Risk Estimates for Topramezone. 

All estimates are at Baseline (i.e., no gloves/respirator).

Exposure Scenario Crop or 

Target

Dermal Unit

Exposure

(ug/lb ai)1

Inhalation 

Unit 

Exposure

(ug/lb ai)1

Application 

Rate2

Amount 

Treated 

Daily3

Dermal Inhalation Total

Baseline Baseline Dose

(mg/kg/day)4 MOE5 Dose(mg/kg/day)6 MOE7 MOE8

Mixer/Loader

Mixing/Loading Liquids 

for Groundboom 

Applications

Turf 220 0.219 0.044 lb 

ai/A 80 A 0.00025 1,600 9.6 x 10-6

42,000 1,500

Applicator

Applying Sprays via 

Groundboom Equipment Turf 78.6 0.34 0.044 lb ai/A 80 A 0.00009 4,400 1.5 x 10-5

27,000 3,800

Mixer/Loader/Applicator

Mixing/Loading/Applying 

Liquids via Manuallypressurized HandwandTurf 100,000 30 0.001 lb 

ai/gallon

40 

gallons 0.0013 310 1.5 x 10-5

27,000 300

Mixing/Loading/Applying 

Liquids via Backpack 

Sprayer

Turf 8,260 2.58 0.001 lb 

ai/gallon

40 

gallons 0.00011 3,700 1.3 x 10-6

310,000 3,700

Mixing/Loading/Applying 

Liquids via Mechicallypressurized HandgunTurf 1,140 1.9 0.001 lb 

ai/gallon

1000 

gallons 0.00037 1,100 2.4 x 10-5

17,000 1,000

1 Based on “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (September 26, 2011); includes data from PHED/ORETF/AHETF (level of mitigation: Baseline and PPE (gloves)).

2 Based on proposed label (Reg. No. #7969-GET).

3 ExpoSAC Policy #9.1.

4 Dermal Dose = Dermal Unit Exposure (mg/lb ai) x Application Rate (lb ai/acre or lb ai/gallon) x Area Treated or Amount Handled (A/day or Gallons/day) x DAF (2.6%)/BW (80 kg).

5 Dermal MOE = Dermal NOAEL (0.4 mg/kg/day)/Dermal Dose (mg/kg/day).

6 Inhalation Dose = Inhalation Unit Exposure (mg/kg) x Application Rate (lb ai/acre or lb ai/gallon) x Area Treated or Amount Handled (A/day or Gallons/day) /BW (80 kg).

7 Inhalation MOE = Inhalation NOAEL (0.4 mg/kg/day)/ Inhalation Dose (mg/kg/day).

8 Total MOE = NOAEL (mg/kg/day)/Dermal Dose + Inhalation Dose.
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9.2 Short- and Intermediate-Term Post-Application Risk

9.2.1 Dermal Post-Application Risk

In the case of topramezone, there is a potential for post-application dermal exposure to workers 

following foliar applications of topramezone to golf courses and sod farms. It is the policy of 

HED to use the best available data to assess post-application exposure. Sources of generic postapplication data, used as surrogate data in the absence of chemical-specific data, are derived 

from ARTF exposure monitoring studies, and, as proprietary data, are subject to the data 

protection provisions of FIFRA. The standard values recommended for use in predicting postapplication exposure that are used in this assessment, known as “transfer coefficients,” are 

presented in the “ExpoSAC Policy 3” 

(http://www.epa.gov/pesticides/science/exposac_policy3.pdf), which, along with additional 

information about the ARTF data, can be found at http://www.epa.gov/pesticides/science/postapp-exposure-data.html. Table 9.2.1.1 provides a summary of the transfer coefficients and 

activities associated with golf course and sod farm turf.

Table 9.2.1.1. Post-application Activities and Dermal Transfer Coefficients.

Proposed Use Site Transfer Coefficients (cm2/hr) Activities

Turf

3,700 golf course maintenance

6,700 harvesting, maintenance, transplanting

In addition, the following assumptions and data were used in the topramezone dermal postapplication assessment:

• Application Rate = 0.044 lb ai/A 

• Exposure Duration = 8 hours per day

• Body Weight = 80 kg

• Dermal absorption = 2.6%

• Chemical-specific TTR data submitted in support of the proposed turf uses (MRID 

48379401).

Post-application dermal exposure and risk estimates for workers conducting activities on golf 

courses and sod farms resulted in MOEs greater than the LOC of 100 and, therefore, are not of 

concern. A summary of the post-application exposure and risk estimates from use of 

topramezone is provided in Table 9.2.1.2.

Table 9.2.1.2. Summary of Short-and Intermediate-term Occupational/Commercial Post-application Risks for 

Topramezone.

Crop/Site Activities

Transfer 

Coefficient 

(cm2/hr)

Application Rate 

(lb ai/A)

TTR1

(ug/cm2)

Day 0 

MOE2

Day X at 

which MOE 

≥ LOC

Turf

golf course 

maintenance 3,700

0.044 0.0019

23,000 0

harvesting, 

maintenance, 

transplanting

6,700 13,000 0

1. TTR value is from chemical-specific turf transferable residue study (MRID 48379401).

2. MOE = POD (NOAEL, 0.4 mg/kg/day) / Daily Dermal Dose. Daily Dermal Dose = [TTR (μg/cm2) x TC x 0.001 mg/μg x 8 hrs/day x 2.6% 

dermal absorption] body weight (80 kg adult). 
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Restricted Entry Interval

Short- and intermediate-term post-application risks were not a concern on day 0 (12 hours 

following application) for all post-application activities. Therefore, the REI is based on the acute 

toxicity of topramezone. Topramezone has been classified as having low acute toxicity 

(Category III or IV) via the oral, dermal and inhalation routes of exposure. It is a slight eye and 

dermal irritant (Toxicity category III and IV), but is not a dermal sensitizer. Therefore, the WPS 

interim REI of 12 hours is adequate to protect agricultural workers from post-application 

exposures to topramezone. 

9.2.2 Inhalation Post-Application Risk

Based on the Agency's current practices, a quantitative occupational post-application inhalation 

exposure assessment was not performed for topramezone at this time. However, there are 

multiple potential sources of post-application inhalation exposure to individuals performing postapplication activities in previously treated fields. These potential sources include volatilization 

of pesticides and resuspension of dusts and/or particulates that contain pesticides. The Agency 

sought expert advice and input on issues related to volatilization of pesticides from its FIFRA 

SAP in December 2009. The Agency received the SAP’s final report on March 2, 2010 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The Agency is in the 

process of evaluating the SAP report as well as available post-application inhalation exposure 

data generated by the Agricultural Reentry Task Force and may, as appropriate, develop policies 

and procedures, to identify the need for and, subsequently, the way to incorporate occupational 

post-application inhalation exposure into the Agency's risk assessments. If new policies or 

procedures are put into place, the Agency may revisit the need for a quantitative occupational 

post-application inhalation exposure assessment for topramezone. 

10.0 References

Memo, M. Clock-Rust et al., D319704, 7/14/05. “Topramezone/BAS670H: Amendment to the 

Human Health Risk Assessment for New Active Ingredient Dated May 11 For Uses Proposed on 

Field, Pop, Seed and Sweet Corn (DP290075).”

Memo, M. Clock-Rust et al., D352696, 2/20/09. “Topramezone: Human-Health Risk 

Assessment for Uses Proposed on Non-crop Ornamentals, Rights-of-Way, Tree Plantations, and 

Other Non-Crop Areas.”

Memo, J. Hetrick, D388368, 11/14/11, “Drinking Water Assessment to Support Topramezone 

Use on Golf Courses, Sod Farms, and Residential Lawns” 

Memo, S. Levy, D388806, Pending, “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.”

Memo, K. Lowe, D388807, 2/2/12. “Topramezone: Occupational and Residential 

Exposure/Risk Assessment for Proposed Uses on Golf Courses, Sod Farms, and Residential 

Turfgrass .”
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Appendix A. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.340) for food uses for topramezone are in Table A.1. Use of the 

new guideline numbers does not imply that the new (1998) guideline protocols were used.

Table A.1. Study Requirements for Food Uses for Topramezone.

Study Technical

Required Satisfied

870.1100 Acute Oral Toxicity

870.1200 Acute Dermal Toxicity

870.1300 Acute Inhalation Toxicity

870.2400 Primary Eye Irritation

870.2500 Primary Dermal Irritation

870.2600 Dermal Sensitization

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.3100 Oral Subchronic (rodent)

870.3150 Oral Subchronic (nonrodent)

870.3200 21-Day Dermal

870.3250 90-Day Dermal

870.3465 90-Day Inhalation

yes

yes

yes

no

no

yes

yes

yes

-

-

870.3700a Developmental Toxicity (rodent)

870.3700b Developmental Toxicity (nonrodent)

870.3800 Reproduction

yes

yes

yes

yes

yes

yes

870.4100a Chronic Toxicity (rodent)

870.4100b Chronic Toxicity (nonrodent)

870.4200a Oncogenicity (rat)

870.4200b Oncogenicity (mouse)

870.4300 Chronic/Oncogenicity

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.5100 Mutagenicity—Gene Mutation - bacterial

870.5300 Mutagenicity—Gene Mutation - mammalian

870.5xxx Mutagenicity—Structural Chromosomal Aberrations

870.5xxx Mutagenicity—Other Genotoxic Effects

yes

yes

yes

yes

yes

yes

yes

yes

870.6100a Acute Delayed Neurotoxicity (hen)

870.6100b 90-Day Neurotoxicity (hen)

870.6200a Acute Neurotoxicity Screening Battery (rat)

870.6200b 90-Day Neurotoxicity Screening Battery (rat)

870.6300 Develop. Neurotoxicity

no

no

yes

yes

no

-

-

yes

yes

-

870.7485 General Metabolism

870.7600 Dermal Penetration

870.7800 Immunotoxicity

yes

yes

yes

yes

yes

no

Special Studies for Ocular Effects

 Acute Oral (rat)

 Subchronic Oral (rat)

 Six-month Oral (dog)

no

no

no

-

-

-
Topramezone Human-Health Risk Assessment DP#: 388367

Page 35 of 39

A.2 Toxicity Profiles

Table A.2.1. 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 --

Table A.2.2. 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 Risk Assessment DP#: 388367

Page 36 of 39

Table A.2.2. 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, the 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 Risk Assessment DP#: 388367

Page 37 of 39

Table A.2.2. 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 (9M/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 nonactivated portion of both the 

plate incorporation and preincubation assays. The effect 

was, however, observed at high concentrations ( 3000 

μg/plate–plate incorporation and 2500 μg/plate–

preincubation). 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 

active ingredient (a.i.) used in the current study has the 

lowest percentage of purity (95.8% versus 97.7 to 99.3% 

a.i. 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 Risk Assessment DP#: 388367

Page 38 of 39

Table A.2.2. 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. 
Topramezone Human-Health Risk Assessment DP#: 388367

Page 39 of 39

Appendix B. Physical/Chemical Properties of Topramezone

Table B1. Physicochemical Properties of Topramezone.

Parameter Value

Melting point/range 220.9 C - 222.2 C

pH 2.9 (1% deionized water)

Density (20 C) 1.425 g/cm3

Water solubility (20 C)

 pH g/L

 3 0.06

 5 0.98

 7 15

 9 23.4

Solvent solubility (g/100 mL at 20 C)

 Solvent Solubility

 Acetone <1.0

 Acetonitrile <1.0

 Dichloromethane 2.5 - 2.9 

 Ethyl acetate <1.0

 Methanol <1.0

 n-heptane <1.0

 N,N-dimethylformamide 11.4-13.3

 1-octanol <1.0

 2-propanol <1.0

 Toluene <1.0

Vapor pressure at 20 C and 25 C < 1.0 x 10–12 hPa (7.5 x 10-13 mmHg)

Dissociation constant (pKa) 4.06

Octanol/water partition coefficient Log(KOW) at 20 C

 Buffer pH Log Kow

 4 – 0.81

 7 – 1.52

 9 – 2.34

UV/visible absorption spectrum

 λ, nm ξ, mol-1cm-1

 207 27 077

 272 8601

 300 5800

 410 410