Topramezone Human

- Health Risk Assessment DP#: 388367

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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

................................ ................................ .... 39Topramezone Human

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### 1.0 Executive Summary

Topramezone ([3

- (4,5

- dihydro

- isoxazol

- 3

- yl)

- 4

- methylsulfonyl

- 2

- methylphenyl](5

- hydroxy

- 1

- methyl

- 1 H

- 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 §18 0.612). 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 ft 2 

### (with a spray volume of 1 gallon per 1000 ft 2 

### ).

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 , topram ezone 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 ho urs 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 t he 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 (cloudine ss) 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), consi stent 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 mate rnal effects. The offspring effects consisted of (1) decreased pup body weight/body

- weight gain in F2 (both sexes)Topramezone Human

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### and (2) increased time to preputial separation (F1 males)

. Maternal effects were consistent with HPPD inhibition (decreased body weights an d 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 materna l 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 sex es (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).

Topramezo ne 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 NO AEL (0.4 mg/kg/day) established for deriving the chronic r eference d ose (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 di d 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 potenti al 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 asse ssment 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 dieta ry scenario for the general population including infants and children [for lack of a no

- observed adverse

effect level (NOAEL)], and be reduced to 1X for all other scenarios. This recommendation is based on the following rationale: (1) With the excep tion 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, t here 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 th ere was qualitative evidence for susceptibility, clear NOAELs and lowest

observed

- adverse

- effect

- levels (LOAELs) were established for developmental effects;

c. Fetal findings were limited to visceral and skeletal variations;
d. Endpoints of concern (developmen tal 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 causesTopramezone Human

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### increases in serum tyrosine levels, resulting in corneal clouding, hist opathological 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 c hildren. The dietary exposure assessment uses tolerance

- level residues and assumes 100% crop

- treated. The dietary drinking water assessment utilizes model

generated water concentration values and associated modeling parameters that are designed to provid e 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 intermediate

term 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 ha s 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 (Fo od + Drinking Water ): Acute and chr onic aggregate dietary (food + drinking water) exposure and risk assessments were conducted using the Dietary Exposure
Evaluation Model

- Food Consumption Intake Database (DEEM

- FCID TM 

### , 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
dr inking water estimates. The default DEEM TM 

### ( 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 conc ern (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 chroni c aggregate risks are assessed based on dietary exposure from food and drinking water sources only . They a re 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 “ n ot likely to be c arcinogenic to h umans .”

A ggregate risk assessment s w ere performed for short

- and intermediate

- term aggregate

exposur e s (food + drinking water + residential exposure) because there are residential uses.
Short

- and intermediate

- term aggregate exposures and risk estimates for the general U.S.Topramezone Human

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### population and for adults, children, and infants are >100 and are, therefore, no t 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 post

application 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 (Toxici ty C ategory 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 Considerati ons: 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 ar e 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 estimatesTopramezone Human

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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 an d 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

- 1 H

- pyrazol

- 4

- yl)

methanone

CAS name [3

- (4,5

- dihydro

- 3

- isoxazolyl)

- 2

- methyl

- 4

- (methylsulfonyl)phenyl](5

- hydroxy

- 1

- methyl

1 H

- pyrazol

- 4

- yl)methanone

CAS # 210631

- 68

- 8

End

- use product/EP Suspension Concentrate (SC) Known Impurities of Concern N one



### 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 pH

dependent

. Topramezone is a weak acid (pK
a 

### 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, t herefore, topramezone has a low potential to volatilize from soil or water

. It has a very low Log K
ow 

### , suggesting that it has a low potential to bioaccumulate in aquatic organisms. A detailed description of the physicochemical properties of topramezone i s provided in Appendix B.Topramezone Human

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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 ft 2

(spray volume: 1 gallon/1000 ft 2 ) 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 ft 2

(spray volume: 1 gallon/1000 ft 2 ) 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, h umans 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

exposur e 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 cons iders 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 Ac tions 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 s ubgroups 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 hom e 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. TheseTopramezone Human

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### data are analyzed an d 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
circumst ances 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. Furthe r 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 amo ng 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

eventu ally 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 result ing 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 toprame zone.

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

Following oral administration, radiolabeled topramezone was rapidly absorbed into the systemic circulation, with the highest plasma concentrations (C
max 

### ) 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 uri ne (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 pr edominant 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 penetr ation study. The DAF hasTopramezone Human

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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 hum an 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 developmenta l 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 we re 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 (d ogs 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 t horacic 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 wer e 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 developmen tal 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 be en 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 weig hts and body

- weight gains, increased thyroid and kidney weights, and microscopic findings in the eyes, kidneys, and thyroid. No reproductive effects were reported.Topramezone Human

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Page 12 of 39 

### In a rat DNT study, there was evidence for qualitative susceptibility. In the maternal an imals, 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 d id 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 involv ing 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 bei ng 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) establis hed 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 Safet y 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 fema les 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 Toxico logy 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 ofTopramezone Human

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Page 13 of 39 

### neurotoxicity or neuropathology in the maternal animals

. The effects in the offspring w ere 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 morphometr ic 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, supernume rary 13 th 

### rib and/or 27 th 

### 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 susceptibili ty. 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 include d (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 qualitativ e 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;Topramezone Human

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Page 14 of 39 

### 4) E ndpoints 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, resu lting 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 con servative in nature. The dietary exposure assessment uses tolerance

level 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
he alth

- 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 fac tors), the 10X FQPA SF was retained in the form of a UF L 

### (i.e., LOAEL

- to

NOAEL 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 varia tions 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 ofTopramezone Human

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Page 15 of 39 

### 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/stud y 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 S F 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 intermedi ate

- 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 b ody weights and body

weight gains in the F2 generation offspring and i ncreased 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 chil dren) 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 aud itory 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 UF L 

### = 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) ele vated 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 UF L 

### = 0.42 mg/k g/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 organ s) 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 simil ar 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 (fe males) 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 t his scenario.Topramezone Human

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Page 16 of 39 

### Short

- and intermediate

- term dermal

The Agency has selected the parental/systemic NOAEL of 0.4 mg/kg/day from the two

generation reproduction study. This NOAEL is based on decreases in body weights and body weight gains in males; effects o n 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 th e 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 o f 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

- spec ies 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 two

generation 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/da y) 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 m g/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 fo r 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 concer n for this
scenario.Topramezone Human

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Page 17 of 39 

### 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 Classificat ion 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 actio n 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 Hu man Risk
Assessment

The PODs, UFs, and toxicity endpoints are presented in Table 4.5.4a (dietary and non

occupational 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 S F s 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 intra

species 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 intra

species extrapolation)

FQPA SF = 1X

aRf D = 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 intra

species 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 b ody weights and body

- weight gains in the F2 generation offspring andTopramezone Human

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Page 18 of 39 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 S F s or LOC for Risk Assessment Study and Toxicological Effects

increased time to preputial separation in the F1 male offspring

. Short

- and

Intermediate

- Term,
Dermal Or al 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 dete rmined 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

- ob served 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 thyr oid 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 kidn ey in beef cattle, goat, and sheep.Topramezone Human

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Page 19 of 39 

### 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 throu gh 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, signific ant 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# 290 075 ). 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 required 1

Livestock Ruminant Topramezone Topramezone

Poultry To be determined 2 To be determined 2
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 fe eding study should include analy sis 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 pr evious 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; petroleu m tank farms; pumping installations; farmyards; fence rows; storage areas; airports; non

- irrigation ditchbanks; wildlife openings; and areas grazed or cut for hay.Topramezone Human

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Page 20 of 39 

### For the current action on turf, EFED provided modeled ground [SCI

- GROW ( S creening

C oncent ration i n Gro und w ater] and surface [PRZM ( P esticide R oot Z one M odel) and EXAMS ( EX posure A nalysis M odeling S ystem)] estimated drinking water concentrations (EDWCs) for
topramezone applications to turf (EFED memorandum; D388368, J. Hetrick, 11/ 14 /1 1). Tabl e 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 die tary 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

Turf c 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

Corn d Acute 0.77

0.0671

Chronic (non

- cancer) 0.14 Chronic (cancer) 0.07

Non Crop Areas e Acute 5.281

0.006

Chronic (non

- cancer) 1.998 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 Resid ue 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 consumptio n 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

, belowTopramezone Human

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Page 21 of 39 

### 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 Dieta ry 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 Topramezone 1

.

Population Subgroup Acute Dietary (95 th 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 Expo sure 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.Topramezone Human

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Page 22 of 39 

### A tiered approach for personal protection using increasing levels of PPE is not used in
residential handle r 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

- P ressurized Handwand.

Unit exposure values and estimates for area treated were taken from HED ’s 201 2 SOP s for Residential Pesticide Exposure Assessment: Lawns/Turf.

Short

- term risks for residential handler s 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

Exposures b (mg/lb ai) Baseline Dose d (mg/kg/day) Baseline MOE e Combined MOE f

Dermal c Inhalation c Dermal Inhalation Dermal Inhalation Dermal + Inhalation

Mixer/Loader/Applicator Mixing/Loading/Applying Liquids with Manually

pressurized Handwand 0.001 5 63 0.018 0.000 1 1.1 x 10

- 6 3,90 0 3 6 0,000 3,900

Mixing/Loading/Applying Liquids with Backpack Sprayer 0.001 5 130 0.14 0.00 021 8.8 x 10

- 6 1,900 4 6 ,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 SOP s 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). L OC = 100.
f. Combined MOE = NOAEL (0.4 mg/kg/day) / combined dermal + inhalation dose (mg/kg/day).



### 6 .2 Reside ntial 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 b een 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 pestic ides 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 ). TheTopramezone Human

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Page 23 of 39 

### 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 assessment s. 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 o ral 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 risk s 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 T opramezone. 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
- 5 24,000 Golfing 6.6 x 10
- 5 6,100

Child 11 < 16 years old Dermal Mowing 2.0 x 10
- 5 21,000 Golfing 7.6 x 10
- 5 5,200 Child 6 < 11 years old Dermal Golfing 9.0 x 10
- 5 4,500

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
- 5 19,000

Short

- term Incidental Soil Ingestion 1.5 x 10
- 6 270,000

Intermediate

- term Incidental Soil Ingestion 3.0 x 10
- 6 130,000



### 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 residentialTopramezone Human

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Page 24 of 39 

### handlers, dermal and inhalation exposures were combined. For post

- application scenarios, dermal and incidental oral exposures were combined for children 1 < 2 year s 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 overly

conservative because of the conservative nature of each individual assessment. Therefore, the
post

- appl ication 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.Topramezone Human

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Page 25 of 39 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

Post

application Total Exposure (mg/kg/day) 3 Residential

Post

application
Total MOE Dermal Inhalation Dermal Inhalation Oral

Short

- Term
Adult Male 0.00 021 8.8 x 10 - 6 0.00 022 1,800 0.0008 3 N/A N/A 0.0008 3 480
Child 11 < 16 years old N/A 7. 6 x 10 - 5 N/A N/A 7. 6 x 10 - 5 5,200 Child 6 < 11 years old N/A 9.0 x 10 - 5 N/A N/A 9.0 x 10 - 5 4, 5 00 Child 1 < 2 years old N/A 0.001 7 N/A 0.0002 6 0.001 9 2 1 0

Intermediate

- Term Child 1 < 2 years old N/A N/A N/A 3.0 x 10 - 6 3.0 x 10 - 6 1 3 0,000

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

. F or adults, r esidenti al 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).Topramezone Human

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Page 26 of 39 

### 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 2 009, 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 post

application 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 exposu re 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 sou rce 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 dr ift 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

- drift

management practices to reduc e 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 r epresents acute aggregate exposure.Topramezone Human

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Page 27 of 39 

### 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 dietar y 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 A ggregate 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 0.00006 4 0.00 022 0.00 028 1,400

Children 1

- 2 years old 1 0.000106 0.001 9 0.00 20 200

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 tha t population subgroup is 190

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

3 Residential 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, f or children, an

i ntermediate

- 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 old 1 0.4 100 0.000106 3.0 x 10 - 6 0.0001 1 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 su bgroup 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

.Topramezone Human

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Page 28 of 39 

### 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

Ag gregate 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 tyros ine 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 tox icity 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 e nzyme 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 opaciti es 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 ha s 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

- inhibiti ng herbicides will consider more appropriate models and cross species extrapolation methods.Topramezone Human

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Page 29 of 39 

### 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 Charact erization

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 occupatio nal 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/applyin g 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 lo ng

- 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 s urrogate 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 provi sions 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.ep a.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

- exposure

data.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 in termittent 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 aTopramezone Human

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Page 30 of 39 

### 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.

Sinc e 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.Topramezone Human

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Page 31 of 39 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

Rate 2 Amount

Treated Daily 3 Dermal Inhalation Total

Baseline Baseline Dose (mg/kg/day) 4 MOE 5 Dose (mg/kg/day) 6 MOE 7 MOE 8

Mix er/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 Manually

pressurized Handwand Turf 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 Mechically

pressurized Handgun Turf 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: Base line and PPE (gloves)).

2 Based on proposed label (Reg. No. #7969

- GET ).

3 ExpoSAC Policy #9.1.

4 Dermal Do se = 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 = I nhalation Unit Exposure (mg/kg) x Application Rate (lb ai/acre or lb ai/gallon) x Area Treated or Amount Handled (A/day or Ga llons/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

.Topramezone Human

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Page 32 of 39 

### 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 f

oliar 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 post

application data, used as surrogate data in the absence of chemical

- speci fic 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 post

application 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/post

app

- 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 (cm 2 /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 post

application 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 use s (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 estima tes 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 (cm 2 /hr) Application Rate

(lb ai /A) TTR 1

(ug/cm 2 ) Day 0

MOE 2 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/cm 2 ) x TC x 0.001 mg/μg x 8 hrs/day x 2.6 % dermal absorption] body weight ( 80 kg adult).Topramezone Human

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Page 33 of 39 

### Restricted Entry Interval

Short

- and intermediate

- term post

- ap plication 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 i ndividuals performing post

application 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 evaluati ng 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 o ccupational
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 topr amezone.

10.0 References

Memo, M. Clock

- Rust et al. , D 319704

, 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. , D 352696

, 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, D 388368, 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

T urfgrass .”Topramezone Human

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Page 34 of 39 

### 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 Accepta ble/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 v ariation.

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 (t he 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 r ib).

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

Pren atal 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, body

weight 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 = n ot
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 F 2 male and female pups and increased time to preputial separation in the F 1 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
Chron ic 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, o r 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 toxici ty

- 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 i ncreased 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

- rela ted 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.

870.510 0
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 respons e 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 viv o 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
neurotoxic ity

- 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 [ 14 C]

- 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 d ose 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 no t 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/cm 3

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 (pK

a ) 4.06

Octanol/water partition coefficient Log(K OW ) at 20 C Buffer pH Log K

ow 4

– 0.81

7

– 1.52

9

– 2.34

UV/visible absorption spectrum λ, nm ξ, mol

- 1 cm - 1

207 27 077
272 8601
300 5800

410 410