### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON

, D.C. 20460



### MEMORANDUM

DATE: 30 -M AY-2013 OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION



### SUBJECT: Topramezone: Human-Health Ri s k Assessment for (1) 

### New Uses in Non-Crop Aquatic Sites and (2) Increased Maximum Application Rate for Currently Registered Terrestrial Uses in the Maintenance of Bare Grounds (Roadsides, Utility and Railroad Righ ts-of-Ways, Industrial Sites, and Tank Farms).

PC Code: 123009 DP Barcode: D4 0031 0, D4040 14 Registration No.: 7969-GET

, 7969-XXX Regulatory Action: Section 

### 3 Decision No. : 462026, 465325 Petition No.: 2 F7997 Risk Assessment Type: Single Chemical/Aggregate 

### TXRNo.: NA 

### Case No.: 7268 CAS No.: 210631-68-8 40 

### CFR: §180.612 MRIDNo.: NA



### FROM: Chester E. Rodriguez, Ph.Q.,**To~xic** 

### 1 g· Sarah J

. Levy,

## Che~m·st Thoma s Bloem, Chemis Risk Assessme nt Branch (RAB 1) Health Effect s Di visio n (HED; 7509P)



### THROUGH: DanaM. Vogel,DeputyDirector

# '.~~~--- George F. Kramer

, Ph.D.

, Branch Senior

# Chemis**~~.:::~".!SC:~-<~=---­** RAB 1/HED (7509P)



### TO: Kathryn Montague, RM 23 Regi s tration Division (RD; 7505P)

The H ealth Effects Divi s i on (HE D ) of th e Office of Pesticide Pro grams (O PP ) i s charge d with esti mating the risk t o human h eal th from exposure to pesticides. The Regi s tration Division (RD) of OPP has requested that HED evaluate hazard and exposure data and cond u ct dietary, occupational, residential, and aggregate exposure assessments, as ne eded, to estima te the risk to human health that will result from all regist ered and proposed uses of topramezone ([3-(4,5- dihydro-isoxazol-3

- yl)

- 4

- methylsulfonyl-2-methylphenyl](5-hydroxy-1

- methyl-1H-pyrazol-4- yl)methanone). A summary of the findings and an assessment of human ri s k resulting from the registered and proposed uses for topramezone are pr ovided in 

### this document. The risk

assessment and ha za rd cha ra cter ization were provided by Chester Rodrigue z, the residue chemistry review and occupat i onal/resi d e nti a l exposure assessme nt by Thomas Bloem (RABl)

, the dietary risk asse ss ment by Sarah Le vy (RABl), an d the drinking water assess ment by Jame s Wolf of the Environmental Fate and Effects Division (EFED).

Page I of 

### 41Topramezone Human

- Health Risk Assessment DP#s 400310,404014 

### Table of Contents 2.0 HED Recommendations

...................................................................................................... ?
2.1 Data Deficiencies

............................................................................................. . ... . ............ 7 2.2 Tolerance Considerations

. ................................................................................... . ............. 8 

### 2.2.1 Enforcement Ana l ytica l Method

................................................................ . ............... 8 

### 2.2.2 Recomme n ded Tolerances

......................................................................... . ............... 8 

### 2.2.3 Revisions to Pet i tioned

- For Tolerances

..................................................................... 9 

### 2.2.4 International Harmonization

...................................................................................... 9 

### 2.3 Label Recommendations

.. .. .. .. .. ............................................................ . ... . ....... .. ............... 9 

### 2.3.1 Recommendations from Residue Reviews

...................................... . ... .. .. .. .. .. .. .. .. .. .. . . 9 

### 2.3.2 Recommendations from Occupationa l Assessment..

............................. . ................. lO 

### 3.0 Introduction

. .. . .. .. .. . ...... . ... .. . .. .. ... .. . ... . .. .. .. . ................................. . ... .. .. . ... . ......... . . . ................ 10 3.1 Chemica l Iden t i t y

.... . ...... . ... . ................................................................ . ........... . ... . .. . ... . ... . 

### 10 3.2 Physical/Chemica l Cha r ac t eristics

................................ . ....... . ... . ..................................... ! 

### 0 

### 3.3 Pesticide Use Pattern

... . ... . ... . ... . ... . ... . .. .. .. . ... . .................................. . .. .. .. .. ... . ....... . ... . ......... 

### 10 3.4 Anticipated Exposure Pathways

.................................................................... . ....... . ... . ... . . 

### l4 4.0 Hazard Characterization/Assessment

............................................................................. 14 4.1 Toxico l ogy Stud i es Available for Analysis

............................................ . ....................... 

### 14 4.2 Absorption, Distribution, Metabolism, and Excretion (ADME)

................. . ... . ... . ... . ...... 

### 14 4.3 Dermal Absorption

.............................................................................................. . ........... 

### l4 4.4 Tox i cological Effects

. ..................................................................................................... 

### 15 4.5 Safety Factor for Infants and Chi ld ren [FQPA SF )

........................................................ 

### l6 4.5.1 Completeness of the Toxicology Database

.............................................................. 

### l 6 4.5.2 Evidence of Neurotoxicity

....................................................................................... 

### 1 6 4.5.3 Evidence of Sensitivity/Susceptibility in 

### the Developing or Young Animal

.......... 

### l7 4.5.4 Residual Uncertainty i n the Exposure Database

...................................................... 

### l7 4.6 Toxicity Endpoints and Points of Departure Se l ections

..................... . ... .. .. . ... .. ... . .......... 

### 17 4.6.1 Dose-Response Assessment..

. . ... . ............................................................. . .... . .. .. .. .. .. !? 

### 4.6.2 Recommendat i on for Combining Routes of Exposure for Risk Assessment..

..... . .. 19 

### 4.6.3 Cancer Classif i cation and Risk Assessment Recommendat i o n

.. . . . .. .. ... . ........ . .... . ..... 

### 20 4.6.4 Summary of Tox i c i ty En d point and POD Se l ection

.................... . . . .... ... . ... . .. .. .. .. .. ... 

### 20 5.0 Dietary Exposure and Risk Assessment..

.. ............................. . ................................ . ... . .. . 21 5.1 Residues of Concern Summary and Rat i ona l e

....................... . ...................... . ................. 

### 21 5.2 Food Residue Profile

. . ... . .. . .. . .................................................................. .. .. .. .. .. .. . ............ 

### 22 5.3 Summary of Environmenta l Degradation

........................................................... . ... . ... . ... 

### 23 5.4 Water Residue Profile

.. . ... . ......................................................................... . ... . ................ 

### 23 5.5 Dietary Risk Assessment

..... . ... . ................................................................. . ... .. ... . .. . ........ 

### 23 5.5. 1 Description of Residue Data Used i n Dietary Assessment..

.................................... 

### 23 5.5.2 Percent Crop Treated Used in 

### Dietary Assessment..

............................................... 

### 24 5.5.3 Acute Dietary Risk Assessment..

....................................................... . ..................... 

### 24 5.5.4 Chronic Dietary Risk Assessment

................................................................. . ......... 

### 24 5.5.5 Cancer Dietary Risk Assessment

............................................................................. 

### 24 6.0 Residential (Non-Occupational) Exposure/Risk Characterization

........ . ...................... 25 6.1 Residential Handle r Exposure

. ............................................................. . ... . ... . ... . ............. . 

### 25
6.2 Post-Application Exposure···

·· ·· ·· ··················
. ······································
. . ... . ... .. .. . ....... . ...... 

### 25 6.3 Residential Risk Estimates for Use in Aggregate Assessment

................. . ...... . ... . ... . ... . .. 

### 27 6.4 Residentia l Bysta n der Pos t -a p p l ication Inha l ation Exposure

. . ... . ................................... 

### 27 6

. 5 Spray Dr i ft.

.......... . .. .. .. . ... .. . .. . . .................................................. . .. .. ... .. .. .. .. .. .. . ................... 

### 28

Page 2 of 41Topramezone Human

- Health Risk Assessment DP# s 400310 , 404014

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### 7.0 Aggregate Exposure/Risk Characterization

................................ ................................ .. 28 7.1 Acute Aggregate Risk

................................ ................................ ................................ .... 28 7.2 Short

- Term Aggregate Risk

................................ ................................ ........................... 29 7.3 Intermediate

- Term Aggregate Risk

................................ ................................ ................ 29 7.4 Long

- Term Aggregate Risk

................................ ................................ ........................... 29 7.5 Cancer Risk

................................ ................................ ................................ .................... 30 8.0 Cumulative Exposure/Risk Characterization

................................ ................................ 30 9.0 Occupational Exposure/Risk Characterization

................................ ............................. 31 9.1 Short

- /Intermediate

- Term Handler Risk

................................ ................................ ........ 31 9.2 Post

- Application Risk

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

................................ ................................ ................................ ......................... 34 Appendix A. Tox icology Profile and Executive Summaries

................................ .................. 36 A.1 Toxicology Data Requirements

................................ ................................ ...................... 36 A.2 Toxicity Profiles

................................ ................................ ................................ ............. 37 Appendix B. Physical/Chemical Properties of Topramezone

................................ ................ 41Topramezone Human

- Health Risk Assessment DP# s 400310 , 404014

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### 1.0 Executive Summary

BASF has submitted to the Agency a tolerance petition for topramezone in/on fish and shellfish in support of a new non

- crop aquatic use (DP# 400310). Also petiti oned by BASF and addressed in this document is an increase in the maximum application rate from 4 to 8 fl oz/A for currently registered non

- crop terrestrial uses in areas where bare grounds must be maintained such as roadsides, utility and railroad right

- o f

- ways, industrial sites, and tank farms (DP #404014). Topramezone ([3

- (4,5

- dihydro

- 3

- isoxazolyl)

- 2

- methyl

- 4

- (methylsulfonyl)phenyl](5

- hydroxy

- 1

- methyl

- 1 H

- pyrazol

- 4

- yl)methanone) is a broad

- spectrum, post

- emergent herbicide used to control grassy and broadleaf weeds and is currently registered for use on residential turfgrass, golf courses, sod farms, non

- crop ornamentals, rights

- of

- way, tree plantations, and other non

- crop areas, as well as for application to corn (field, pop, seed, and sweet) with tolerances ranging from 0.01 to 0.15 ppm (40 CFR §180.612). The end

- use product for the two proposed uses has the same composition : a soluble concentrate liquid formulation containing 2.8

- pound (lb) active ingredient (ai)/gallon. The proposed label for the aquatic use allows ground

, aerial

, and direct water application. The maximum single application rate proposed for the non

- crop aquatic use is 0.35 lbs ai/acre for foliar application or sequential in

- water applications to maintain a water concentration of 50 ppb for a recommended duration of 60 days.

Based on the proposed (aquatic and terrestrial) and registered uses, the U.S. population may be exposed to topramezone via food (corn, fish, and shellfish) and drinking water. In addition, there may be incidental oral, dermal, and inhalation exposure from the registered turf use (homeowner use allowed) and the proposed aquatic use. Post

- application residential exposures resulting from

r ecreational swimming in treated water can be expected for adults and children in the absence of label restrictions. In the occupational setting, applicators may be exposed via the dermal and inhalation routes while handling the pesticide for and during app lication. Dermal exposure is also anticipated for workers re

- entering treated areas.

Topramezone is a member of the class of herbicides known as 4

- hydroxyphenylpyruvate dioxygenase (HPPD) inhibitors

. Inhibition of the enzyme HPPD results in decreased carotenoid synthesis and ultimately bleaching of target plants . 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 toxicitie s resulting from tyrosinemia in laboratory animals include ocular, developmental, liver, and kidney effects. Topramezone exhibits a mammalian toxicity profile that is consistent with HPPD inhibition.

The primary target organs affected following oral admi nistration of topramezone in animal toxicity studies were the eyes, thyroid, pancreas, and liver. The most sensitive species was the

rat
, and in rats and dogs, males were more sensitive than females. The effects on the eyes in chronic toxicity studies co nsisted of pannus (vascularization) and keratitis (cloudiness) of the cornea in 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

r eported 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 inc reased susceptibility following in utero exposures to rats and rabbits. In rabbits, fetal abnormalities including supernumerary thoracic vertebrae and supernumeraryTopramezone Human

- Health Risk Assessment DP# s 400310 , 404014

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### 13th rib were observed in the presence of maternal toxicity in six of eight developmental toxicity studies conducted in two different strains. In rats, developmental effects consisting of skeletal variations occurred in the presence of maternal toxicity. Increase d maternal serum levels of tyrosine were reported in several developmental toxicity studies (several in rabbits and one in mice), consistent with the proposed mode of action for topramezone involving HPPD inhibition. In the rat two

- 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 F 2 

### (both sexes) and (2) increased time to preputial separation (F 1 

### males)

. Maternal effects were consistent with HPPD inhibition (decreased body weights and body

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

Topramezone did not show any evidence of neurotoxicity in the acute (ACN) or subchronic (SCN) neurotoxicity studies, but in a rat developmental neurotoxicity (DNT) study, where dosing with topramezone took place du ring the prenatal as well as postnatal time periods, there was evidence for increased qualitative susceptibility. In the maternal animals, toxicity was limited to corneal opacity, whereas effects in the offspring included neurobehavioral and neuropatholog ical 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 ne uropathological effects involving decreased brain morphometric measurements (e.g., hippocampus, and parietal cortex).

Topramezone is classified as “ not likely to be carcinogenic to humans at doses that do not alter rat thyroid hormone homeostasis.” The Cancer Assessment Review Committee (CARC) has determined that the thyroid tumors arise through a non

- linear mode of action

, and the chronic reference dose (cRfD) is expected to be protective of alterations in hormone homeostasis or that may result in thyro id tumor formation. Mutagenicity studies conducted on technical topramezone and its major metabolites did not demonstrate any mutagenic potential.

Dose

- Response Assessment: The acute population

- adjusted dose (aPAD) for the general U.S. population includ ing infants and children was estimated at 0.008 mg/kg/day based on the lowest

observed adverse

- effect level ( LOAEL ) of 8 mg/kg/day for offspring effects in a rat DNT study. A different aPAD for females (13

- 49 years old) was estimated at 0.005 mg/kg/day ba sed on the

no

- observed adverse

- effect level (NOAEL) of 0.5 mg/kg/day for developmental effects in a rabbit prenatal developmental toxicity study. The chronic population

- adjusted dose (cPAD) estimated at 0.004 mg/kg/day was based on the NOAEL of 0.4 mg/kg/ day from a rat chronic toxicity study. The point of departure (POD) for short

- and intermediate

- term dermal, inhalation and incidental oral risk assessments was 0.4 mg/kg/day based on the NOAEL in a rat two

generation reproductive toxicity study. Since an oral study was used, a dermal

- absorption factor (DAF) of 2.6% estimated from a rat dermal

- penetration study was used for the dermal risk assessment and 100% absorption was assumed for inhalatio n exposures. The level of concern (LOC) for occupational/ residential dermal and inhalation exposures and residential incidental oral exposures are for margins of exposure (MOEs) <100.

Food Quality Protection Act (FQPA) Decision: Based on the evaluati on of the topramezone toxicity and exposure database s , it is recommended that the 10X FQPA Safety Factor (SF) be retained in the form of a database uncertainty factor for the acute dietary scenario for the generalTopramezone Human

- Health Risk Assessment DP# s 400310 , 404014

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Page 6 of 41 

### U.S. population including infants and chil dren ( for lack of a NOAEL), and be reduced to 1X for all other scenarios. This recommendation is based on the toxicity database with a DNT study being adequate for assessing the potential for increased pre

- and postnatal susceptibility

. Although there wa s qualitative evidence for suscepti bility, clear NOAELs and LOAELs were established for developmental effects and the e ndpoints of concern (developmental and target organ toxicity) were used for assessing risks for appropriate populations of concern

. Additionally, the dietary and residential exposure analyses are conservative in nature designed to provide conservative, health

- protective estimates

.
Dietary Risk Estimates (Food + Drinking Water ): Acute and chronic aggregate dietary (food + drinking w ater) exposure and risk assessments were conducted using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM

- FCID) Version 3.16, which uses food consumption data from the U.S. Department of Agriculture’s National He alth and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA). The acute and chronic dietary assessments assumed tolerance

- level residues, 100% crop treated, default processing factors (DEEM ver. 7.81), and modeled drinking water estimates

. The majority of the acute and chronic dietary exposure estimates were based on drinking water residues from the proposed non

- crop aquatic use

. The resulting acute and chronic dietary exposure and risk estimates (food + drinking water) did not exceed th e respective PAD for the general U.S. population or any subgroups and thus are below HED’s LOC.

Residential (Non

- Occupational) Exposure and Risk Assessment: Residential applicator (handler) scenarios were not assessed for the proposed uses due to the sp ecific label directions for the proposed aquatic use (ponds, lakes, and reservoirs) and the specific use sites for the terrestrial use (roadsides, utility and railroads rights

- of

- ways, industrial sites, and tank farms). Post

- application residential exposure s from recreational swimming activities were assessed for short

- term only because such recreational activity is expe cted to be episodic. Moreover, short

term risk assessment would be protective of intermediate

- term exposure s since both durations are based on the identical toxicity endpoint. The resulting MOE estimates are >100 and thus below HED’s LOC.

Aggregate

- Risk Estimates: Acute and chronic aggregate risks are based only on dietary exposure from food and drinking water sources. Therefore, acute and chronic aggregate risks to topramezone are not of concern to HED (see dietary assessment above). A cancer aggrega te

- risk assessment was not performed because topramezone is classified as “not likely to be carcinogenic to humans at doses that do not alter rat thyroid hormone homeostasis” and doses at or below the cRfD are not expected to alter thyroid hormone homeosta sis.

Short

- term aggregate risk assessment was performed that include s exposure via food, water, and the residential use (proposed or currently registered) that resulted in the highest estimated exposure. For adults and children, activities associated wit h the currently registered residential turf use resulted in the highest residential exposure estimate. When all exposures were aggregated and compared to an appropriate estimate of hazard, all resulting MOE estimates were >100 and thus below HED’s LOC.

O ccupational Exposure and Risk Assessment: Occupational handlers may be potentially exposed to topramezone during mixing/loading and applying activities associated with the proposed aquatic and terrestrial use. Estimated occupational handler dermal and in halation riskTopramezone Human

- Health Risk Assessment DP# s 400310 , 404014

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Page 7 of 41 

### estimates are below HED’s LOC provided handlers use (1) baseline personal

- protective equipment (PPE) including long

- sleeved shirts and chemical

- resistant gloves; and (2) engineering controls (closed system) are used for mixing/loading in supp ort of aerial application for the aquatic use

.
Occupational post

- application exposure associated with the aquatic use is likely limited to persons who come in contact with treated water

. A quantitative risk assessment was deemed unnecessary given the large MOE estimates for residential post

- application recreational swimming activities. In the case of the terrestrial use, the post

- application MOEs are not of

concern ; therefore, the restricted

- entry interval (REI) for topramezone is based on the acute

t oxicity categories. Topramezone has been classified as having low acute toxicity (Toxicity Category III or IV) via the oral, dermal, and inhalation routes of exposure. It is a slight eye and dermal irritant (Toxicity Category III and IV), but is not a de rmal sensitizer. Therefore, the Worker Protection Standard (WPS) interim REI of 12 hours is adequate to protect workers from post

- application exposures to topramezone.

Potential areas of environmental justice concerns, to the extent possible, were consid ered 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

. ” 1



### This risk assessment relies in part on data from studies in which adult h uman 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 48379401, are subject to ethics review pursuant to 40 CFR 26, have received that review, and are compliant with applicable ethics r equirements. 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

Pro vided the petitioner submits revised Sections B and F (see below), HED concludes that the toxicity, residue chemistry, and occupational/residential exposure databases support registration of the proposed non

- crop aquatic use, the maximum application rate i ncrease for the non

- crop terrestrial use , and the establishment of the tolerances listed in Section 2.2.

2.1 Data Deficiencies

Prior to Registration: Revised Section F

- see Section 2.2.2; Revised Section B

- see Section 2.3.

1 ( http://www.hss.energy.gov/nuclearsafety/env/guidance/justice/eo12898.pdf ).Topramezone Human

- Health Risk Assessment DP# s 400310 , 404014

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### Data that may be Necessary to Support Future Uses

R esidue Chemistry: If

, in the future

, the petitioner alters the aquatic application scenario such that concentrations in water are >50 ppb, then fish/shellfish metabolism and/or magnitude of the residue studies may be required. In addition, HED notes that a poultry feeding study has not been submitted

, and these data may be required to support future uses (residues of parent and the metabolite M670H02 should be monitored).

Occupa tional Residential Exposure: A dislodgeable foliar residues (DFR) study has not been submitted and is unnecessary for the proposed uses; however, future proposed uses may require the submission of these data.

Toxicology: For this action, the Hazard and Science Policy Council (HASPOC) waived the requirement for a 28

- day rat inhalation toxicity study. However, this study may be required for future actions that significantly increase occupational or residential inhalation exposures.

2.2 Tolerance Consid erations

2.2.1 Enforcement Analytical Method

HED concludes that the BASF method D0104 is appropriate for enforcement of the HED

recommended topramezone livestock meat byproduct and fish/shellfish tolerances. In brief, homogenized samples are extracted i n water, acidified with HCl, and partitioned with dichloromethane. The organic phase is collected and partitioned with ammonium formate (pH 10) with the aqueous phase collected and analyzed by liquid chromatography with tandem mass spectroscopy (LC/MS/MS)

.

2.2.2 Recommended Tolerances

Table 2.2.2 is a summary of the proposed and HED

- recommended tolerances for residues of topramezone per se (revised Section F is requested). In accordance with the most recent guidance concerning tolerance expressions, HED recommends that the tolerance expression for 180.612(a )( 1) be changed as indicated below. A revised Section F should be submitted which

s pecifies the new tolerance expression and the HED recommended commodity definitions and tolerance levels. With the establishment of the tolerances indicated in Table 2.2.2, the currently established kidney (cattle, goat, horse, and sheep) and liver (cattl e, goat, horse, and sheep) tolerances should be deleted.

180.612(a ) ( 1) Tolerances are established for residues of the herbicide topramezone, including its metabolites and degradates, in or on the commodities listed below. Compliance with the following tolerance levels is to be determined by measuring only topramezone ([3

- (4,5

- dihydro

- 3

- isoxazolyl)

- 2

- methyl

- 4

- (methylsulfonyl)phenyl](5

- hydroxy

- 1

- methyl

- 1 H

- pyrazol

- 4

- yl)methanone) in or on the following commodities:Topramezone Human

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Page 9 of 41 Table 2.2.2

. Tolerance Summary.

Commo dity Proposed Tolerance (ppm) HED

- Recommended

Tolerance (ppm) Comments

fish 0.05

--

Revised commodity definition is requested. fish

- freshwater finfish

-- 0.05
fish

- saltwater finfish

-- 0.05

shellfish 0.05

--
fish

- shellfish, crustacean

-- 0.05

fish

- shellfish, mollusk

-- 0.05
cattle, meat byproducts

-- 0.80

These tolerances are recommended as a result of the increased livestock dietary burdens associated with the proposed use. goat, meat byproducts

-- 0.80
horse, meat byproducts

-- 0.80
sheep, meat byproducts

-- 0.80
hog, meat byproducts

-- 0.40
poultry, meat byproducts

-- 0.02



### 2.2.3 Revisions to Petitioned

- For Tolerances

Based on the livestock dietary burdens resulting from all proposed/registered uses, HED determined that the meat byproduct tolerances listed in Table 2.2.2 are appropriate. With the establishment of these tolerances, the currently established kidney (cattle, goat, horse, and sheep) and liver (cattle, goat, horse, and sh eep) tolerances should be deleted as it is now general policy to establish meat byproduct tolerances rather than separate liver and kidney tolerances ( Chemistry Science Advisory Council (ChemSAC); min_494.12

- Jan

- 2011).

2.2.4 International Harmonization

There are no Codex or Mexican maximum res idue limits (MRLs) in/on fish/shellfish. Canada has established MRLs for residues of topramezone per se in/on the following: liver (cattle, goat, horses, and sheep)

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

- 0.05 ppm; a nd hog meat byproducts

- 0.05 ppm. Considering the proposed/registered topramezone uses, HED concludes that the Canadian MRLs are too low to permit harmonization at this time

.

2.3 Label Recommendations

HED concludes that the proposed labels are adequa te provided the revisions indicated in Sections 2.3.1 and 2.3.2 are incorporated (revised Section B is requested). HED notes that all revisions are for the aquatic label Oasis ® 

### (EPA Reg. No. 7969

- xxx ).

2.3.1 Recommendations from Residue Reviews

HED requ ests the proposed Oasis ® 

### 7969

- xxx label (aquatic label) be revised as follows (revised Section B is requested): (1) text in the label relating to restrictions concerning the use of treated water for irrigation purposes sho uld be changed from “food crop” t o “food/feed crops” and from “non

- food

- crop” to “non

- food/feed

- crop”; (2) the text specifying that an irrigation intake may be turned back on if the concentration “at the intake” has dropped to ≤1 ppb should be changed to indicate that the irrigation intak e may be turned back on provided the concentration “in theTopramezone Human

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Page 10 of 41 

### treated area” has dropped to ≤1 ppb; (3) the section concerning application to flowing water “including moving water canals” should be changed to indicate “including non

- irrigation moving

water can als”; (4) the section concerning application to dewatered irrigation canals should indicate that residues must drop to ≤1 ppb at the most downstream end of the treated area prior to the use of the water for irrigation purposes; and (5) addition of a statem ent noting that potable use of treated water is not permitted until the concentration h as dropped to ≤45 ppb.

2.3.2 Recommendations from Occupational Assessment

HED requests the proposed Oasis ® 

### 7969

- xxx label (aquatic label) be revised as follows (revise d Section B is requested): (1) for in

- water applications, the label should be changed to indicate that applicators must wear long

- sleeved shirt; long pants; chemical

- resistant gloves (Category A) and shoes plus socks ; and (2) for in

- water applications, mi xer loaders in support of aerial application must use engineering controls (i.e.

, closed system).

3.0 Introduction

T opramezone is a broad

- spectrum post

- emergence herbicide (triketone class; group 27 herbicide ). Topramezone inhibits carotenoid biosynthesis in susceptible plants (HPPD inhibitor). In the absence of carotene, chlorophyll is rapidly degraded in sunlight. The chemical structure and nomenclature of technical grade topramezone are pres ented in Tabl es 3.1

.

3.1 Chemical Identity

Table 3.1. Topramezone Nomenclature.

Structure

Common name topramezone Company experimental name BAS 670 H

IUPAC name [3

- (4,5

- dihydro

- 1,2

- oxazol

- 3

- yl)

- 4

- mesyl

- o

- tolyl](5

- hydroxy

- 1

- methyl

- 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 emulsifiable concentrate



### 3.2 Physical/Chemical Characteristics

The physical/chemical properties of topramezone are summarized in Appendix B

. Based on its low vapor pressure of 7.5 x 10 - 13 

### mmHg, topramezone is not expected to be particularly volatile

, and based on its low octanol: water partition coefficient (Log Kow) of

- 1.52 at pH 7.0, it is not expected to significantly partition into fatty tissue while being relatively water soluble.

3.3 Pesticide Use Pattern

Registered Uses: Topramezone is currently registered for application to golf courses, sod farms,Topramezone Human

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Page 11 of 41 

### residen tial turfgrass, field corn, popcorn, sweet corn, and corn grown for seed. Topramezone is also registered for application to numerous non

- crop terrestrial sites.

Proposed Uses: The petitioner is proposing an increased application rate for the currently registered non

- crop terrestrial

- application scenario (this use does not concern application to turf) and is proposing non

- crop aquatic

- application. Table 3.3. 1 is a summary of the proposed uses

. The proposed labels include the following general informat ion, restrictions, and information concerning PPE /REI:

General Information Concerning the Non

- crop Aquatic

- Application (Oasis ® 

### label): The proposed label specifies the following general information: (1) consult the appropriate state or local pesticide and/or water authorities before applying this product in or around public waters. Permits and postings of treatment notification may be required by state or local public agencies; (2) for aerial application

, apply in a minimum spray volume of 2 gallons p er acre (GPA)

. For application by boat or with ground equipment to submerged, floating, or shoreline vegetation, use boom

- type, backpack, or hydraulic handgun equipment; apply in a sufficient spray volume (up to 100 GPA) to provide uniform distribution of the spray particles over the treated vegetation while minimizing runoff; (3) do not apply through irrigation equipment; (4) a surfactant or methylated seed oil should be added to the spray solution for post

- emergent foliar application and application to e xposed sediment where some weed growth is present; (5) Oasis ® 

### may be applied to exposed sediments of dewatered areas of aquatic sites. Upon inundation, all label restrictions apply to the use of water from these treated areas; and (6) there are no restric tions on use of the treated water for potable use (human or livestock) or for recreational purposes including swimming and fishing.

Restrictions Concerning the use of Water Treated with Topramezone for Purposes of Irrigation (Oasis ® 

### label): The label includes the following restrictions concerning the use of treated water for purposes of irrigation: (1) do not apply to waters used for food

- crop irrigation (except corn), unless the irrigation intakes can be shut off until c oncentrations are ≤1 ppb at the intake (concentrations may be determined using FasTEST or other analytical techniques); (2) corn

- do not irrigate corn if concentrations in treated water exceeds 25 ppb; (3) non

- food

- crop irrigation

- consult BASF Corporation before irrigati on if concentrations in treated water exceed 1 ppb; (4) do not use treated water for hydroponic farming until the concentrations are ≤1 ppb; (5) do not use treated water to irrigate greenhouse or nursery plants until concentrations are ≤1 ppb; and (6)

rota tional crops

- areas previously irrigated with treated water may be planted with corn. For other food crops and in areas irrigated with treated water containing concentrations exceeding 1 ppb, consult BASF Corporation for site

- specific risk evaluations be fore planting rotational crops or other plants.

PPE and REI for Non

- crop Aquatic

- Application (Oasis ® 

### label) and Non

- crop Terrestrial

Application ( Frequency ® 

### label): Excluding in

- water application, the proposed topramezone product labels direct handlers to wear long

- sleeved shirt; long pants; chemical

- resistant gloves (Category A); shoes plus socks; and goggles, face shield, or safety glasses. For in

- water application, the proposed labels direct handlers to wear short

- sleeved shirt, long pants; shoes pl us socks; and chemical

- resistant gloves [Category A].

The non

- crop terrestrial label indicates a 12

- hour REI for agricultural uses and, for nonagricultural uses, indicates that reentry is permitted once the spray solution has dried. TheTopramezone Human

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### non

- crop aquati c label does not specify a REI.

Conclusions: HED concludes that the proposed use directions are adequate provide the labels are revised as indicated in Section 2.3 (a revised Section B is requested).Topramezone Human

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Page 13 of 41 Table 3.3.1. Summary of Proposed Oasis ® (7969

- xxx) Use Directions. 1

End

- use Product App.

Timing App. Rate Max. No. App. per Season Max. Seasonal

App. Rate Use Directions and Limitations

Non

- crop Terrestrial

- Application

Frequency ® ; SC; 2.8 lb ai/gal; EPA Reg. No. 7969

- 281 pre

- /post

emergent 0.09

- 0.35 lb

ai/acre not specified 0.35 lb ai/acre - Application using ground (≥10 GPA) and aerial (≥2 GPA) equipment is permitted.

- Spot application is also permitted using a spray solution containing 0.25

- 0.5% o f the formulated product.

- Only soil

- directed applications are described for Christmas tree, conifer, and hardwood plantations and field

- grown ornamentals.

- Application to greenhouses and shadehouses is prohibited; do not apply to areas that may be gra zed or cut for hay. Non

- crop Aquatic

- Application

- in

- water application (including submersed or floating weeds); flowing water application (including canals (slow moving)) 1

Oasis ® SC; 2.8 lb ai/gal; EPA Reg. No. 7969

- xxx pre

- /post

emergent in

- water

concentration at application of 20

- 50 ppb not specified in

- water concentration at application of 20

- 50 ppb - Can be applied undiluted or diluted with water.

- The max. conc. that can be applied initially, and maintained through sequential application, is 50 ppb (application rate in lb ai/acre is based on calculation using the treated area and average depth). To maintain the desired conc., samples are collected/analyzed and additional product is added to raise the conc. to the desired level.

- Retreat the wate r to maintain the desired conc. for a min. of 60 days or until satisfactory weed control is achieved.

- Boat and aerial application is permitted; application via a metering system is also describe for application to flowing water. Non

- crop Aquatic

- Application

- shoreline and riparian areas within or adjacent to aquatic sites
Oasis ® SC; 2.8 lb ai/gal; EPA Reg. No. 7969

- xxx pre

- /post

emergent 0.09

- 0.35 lb

ai/acre not specified 0.35 lb ai/acre/year - Dilute with water to achieve proper coverage of treated plants (include an adjuvant).

- Sequential applications can be made throughout the growing seasons.

- Boat, ground, and aerial application is permitted Non

- crop Aquatic

- Application

- foliar spot treatment Oasis ® SC; 2.8 lb ai/gal; EPA Reg. No. 7969

- xxx pre

- /post

emergent spray solution

-

0.25

- 0.50% Oasis® not specified 0.35 lb ai/acre/year - To prepare the spray solution, thoroughly mix in water 0.25

- 0.50% Oasis ® (adjuvant should be included).

Spray coverage should be sufficient to moisten the leaves of the target vegetation but not to runoff. Ground and boat application is permitted Non

- crop Aquatic

- Application

- exposed sediment (including exposed sediment of dewatered irrigation canals)

Oasis ® SC; 2.8 lb ai/gal; EPA Reg. No. 7969

- xxx pre

- /post

emergent 0.09

- 0.35 lb

ai/acre not specified 0.35 lb ai/acre/year - Dilute with water to achieve proper coverage of treated plants (include an adjuvant).

- Sequential applications can be made throughout the growing seasons.

- Ground application is permitted

- The proposed label indicates the following restrictions concer ning the app. to dewatered irrigation canals: (1) only for use by Irrigation Districts in the western U.S. in canals that are seasonally filled and where the Irrigation District is aware of potential down

- stream use of water and can ensure water is not us ed for irrigation purposes during the recharge or refill process; (2) app. by only Irrigation Districts, Irrigation Water Suppliers, or those applicators who are licensed or certified as aquatic pest control applicators and are authorized by the Irrigation District; (3) app. must be conducted a minimum of 14 days prior to reflooding. The initial flush of water during recharge or refill must not be used for irrigation purposes unless the conc. has been determined to be ≤1 ppb; and (4) after canals have been refilled with a continuous flow for a min. of 24 hours, canal water may then be used for irrigation purposes.

1 The application rate to flowing water is identical to that for other bodies of water

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### 3.4 Anticipated Exposure Pathways

Based on the proposed and registered uses, the U.S. population may be exposed to topramezone in food (corn, fish, and shellfish) and water; in addition, the U.S. population may experience incidental oral, dermal, and/or inhalation exposure resulting from registered turf (homeowner applica tion is permitted), golf course uses, and/or the proposed aquatic use (proposed label has no restrictions concerning the recreat ional use of treated water). In the occupational setting, applicators may be exposed while handling the pesticide prior to application as well as during application (dermal and inhalation). There is also potential for post

- application exposure for worker s re

- entering treated areas (dermal; inhalation is anticipated to be negligible).

4.0 Hazard Characterization/Assessment

Topramezone belongs to a class of herbicides that includes pyrasulfotole, mesotrione, and isoxaflutole. The herbicidal mode of act ion of these agents involves inhibition of HPPD, which eventually results in impairment of chlorophyll biosynthesis. In mammals, the HPPD

- equivalent enzyme, tyrosine aminotransferase, is involved in the catabolism of the amino acid tyrosine, and its inhib ition causes blood levels of tyrosine to rise ; a condition known as tyrosinemia. Some of the toxicities resulting from tyrosinemia in laboratory animals include ocular, developmental, liver, and kidney effects.

4.1 Toxicology Studies Available for Analys is

The toxicological database for topramezone is adequate for hazard characterization, toxicity endpoint selection, and FQPA safety factor evaluation. In the last risk assessment (M emo , K. Lowe et al

., D3 88367 ; 02/ 12 /20 12 ), the only database deficiency noted was an immunotoxicity study (OPPTS 870.7800) as specified in 40 CFR Part 158 requirements

. This study has yet to be submitted to the Agency and represents a pending data requirement for topramezone.

4.2 Absorption, Distribution, Metabolism, and Exc retion (ADME)

Following oral administration, radiolabeled topramezone was rapidly absorbed into the systemic circulation, with the hi ghest plasma concentrations observed after 1 h ou r (the first time point measured) . The estimated absorbed fraction, howev er, 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 ar ea under the plasma concentration curve (AUC) scaled more linearly with dose than it did with peak plasma levels. The majority of the dose was recovered within 48 hours in feces (73

- 91%) and urine (8

- 29%). Bile collected up to 48 hours post

- dose

accounte d for 19

- 32% of the administered dose

. Concentrations of radioactivity were consistently highest in liver followed by kidneys and, to some extent, in the thyroid. The parent chemical was the predominant compound identified in both urine (4.0

- 21.3% dose) and feces (66.3

- 91.7% dose). There were no apparent sex

- dependent differences in ADME behavior noted.

4. 3 Dermal Absorption

A DAF of 2.6% was used in the last risk assessment (memo, K. Lowe et al ., 02/02/ 20 12; D388367) based on the highest degree of skin penetration observed in a rat dermal p enetration study

. A DAF of 2.6% will be used to assess the potential risk associated with dermal exposuresTopramezone Human

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Page 15 of 41 

### to topramezone associated with the proposed uses.

4. 4 Toxicological Effects

The effects observed following repeated oral exposures to topramezone are consistent with those expected from HPPD inhibition in mammals. In prenatal developmental toxicity studies (mouse and rabbit), where selected measured clinical parameters included serum measurements of tyrosine, orally administered topramezone resulte d 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 att empt to associate elevated levels of tyrosine to detrimental effects following topramezone administration.

T he primary target organs affected following topramezone administration were the eyes, thyroid, and pancreas. The most sensitive species was the ra t and, at least in rats and dogs, males were

more sensitive than females. The effects on the eyes in chronic toxicity studies consisted of pannus (vascularization) and keratitis (cloudiness) of the cornea of both sexes. Hypertrophy and hyperplasia of the thyroid, hypertrophy and focal necrosis of the liver, and degeneration of the pancreas were among the histopathology findings reported across different subchronic and chronic studies in rats and dogs. Results of chronic toxicity studies in dogs, mice, an d rats also suggest decrements in body weights, body

- weight gains, and food utilization (dogs only). Inflammation of the urinary bladder was also noted in a dog subchronic

- toxicity study.

There was evidence for increased prenatal susceptibility following in utero exposures to rats and rabbits. In six of eight developmental toxicity studies conducted in two different strains of rabbits, fetal abnormalities including supernumerary thoracic vertebrae and supernumerary 13th rib were observed in the presence of only increased maternal tyrosine blood level or body weight decrements toxicity. In the other two rabbit developmental studies, similar developmental effects were reported in the absence of any maternal toxicity. In rats, developmental effects consist ing of skeletal variations occurred in the presence of maternal toxicity. Increased maternal serum levels of tyrosine were reported in several developmental toxicity studies (several in rabbits and one in mice), consistent with the proposed mode of action for topramezone involving HPPD inhibition. It should be noted that the fetal skeletal variations observed following exposure to topramezone have also been reported with other HPPD

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

In the rat two

- generation reproductive toxicity study, there was no evidence of increased qualitative or quantitative pre

- or postnatal susceptibility; offspring effects occurred in the presence of maternal effects. The offspring effects consisted of (1) decreased pup body weight/body

- weight gain in F 2 

### (both sexes) and (2) increased time to preputial separation (F 1 

### males)

. Maternal effects were consistent with HPPD inhibition: decreased body weights and body

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

In a rat DNT study

, where dietary dosing was performed during gestation and lactation, there was evidence of increased qualitative pre

- /postnatal susceptibility. I n the maternal animals, toxicity was limited to corneal opacity, whereas effects in the offspring included neurobehavioral and neuropathological changes. Offspring neurobehavioral effects consisted of a decreased auditory startle reflex at postnatal day 2 4 in both sexes (20

- 30%) and at postnatal day 60 for males (55%). There were also mild decreases in offspring absolute brain weights andTopramezone Human

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Page 16 of 41 

### neuropathological effects involving decreased brain morphometric measurements (e.g., hippocampus, and parietal cortex)

.
Topramezone did not show any evidence of neurotoxicity in the ACN or SCN studies. In the case of the ACN study, there was no toxicity reported up to the limit dose, while the effects in the SCN study were not neurotoxic in nature, but more consistent with those involving HPPD inhibition (e.g., corneal clouding, diffuse degeneration of the pancreas, and histopathological findings in the thyroid).

In a rat dermal toxicity study with topramezone, toxicity was manifested as thyroid follicular cell hypert rophy with male rats being more sensitive than females.

Topramezone is classified as “ not likely to be carcinogenic to humans at doses that do not alter rat thyroid hormone homeostasis.” The CARC determined that the thyroid tumors arise through

a non

- linear mode of action and the NOAEL (0.4 mg/kg/day) established for deriving the cRfD is not expected to alter thyroid hormone homeostasis nor result in thyroid tumor formation. Mutagenicity studies conducted with technical topramezone and its major m etabolites did not demonstrate any mutagenic/genotoxic potential.

4. 5 Safety Factor for Infants and Children [FQPA SF]

The 10X FQPA SF is retained for the acute dietary risk assessment for the U.S. general population including infants and children while being reduced to 1X for (1) the acute dietary risk assessment for females of child

- bearing age (i.e., 13

- 49 years old), (2) the chronic dietary risk assessment for the U.S. g eneral population, and (3) all non

- dietary exposure scenarios. The rationale for these decisions is described below.

4.5.1 Completeness of the Toxicology Database

The existing toxicology database for topramezone is adequate for FQPA SF evaluation. The following acceptable studies are available for FQPA consideration: developmental toxicity studies in mice, rats

, and rabbits; a two

- generation reproduction study in rats; ACN and SCN studies in rats; and a rat DNT study. A 10X FQPA safety factor (in the form of a database uncertainty factor) is not required for the lack of an immunot oxicity study since the PODs used for overall risk assessments are based on effects seen in target organs (e.g., eyes, thyroid, and liver) consistent with the actions of this chemical as an HPPD inhibitor. An immunotoxicity study is not likely to yield a lower POD and the preliminary results of the retrospective analyses provide strong support for not retaining the 10X FQPA SF as no immunotoxicity study available thus far has provided sensitive endpoints for use in deriving points of departure.

4.5.2 Evid ence of Neurotox icity

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 th e SCN study.

In the DNT study , maternal effects were limited to corneal opacity and there was no evidence of neurotoxicity or neuropathology in the maternal animals. The effects in the offspring were neurobehavioral as well as neuropathological, consisti ng of a decreased auditory startle reflex at postnatal day 24 in both sexes (20

- 30%) and at postnatal day 60 for males (55%), mild decreasesTopramezone Human

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Page 17 of 41 

### in absolute brain weights, and decreased brain morphometric measurements (e.g., hippocampus, and parietal cortex).

4. 5 .3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

In the prenatal developmental toxicity study with rats, there was evidence for increased qualitative, but not quantitative

, susceptibility in the fetuses. Qualitative suscep tibility 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.

In six of eight rabbit studies, there was evidence for increa sed 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 was ma nifested as increased incidences of visceral findings (i.e., absent kidney and ureter) and/or multiple skeletal variations (i.e., delayed ossification, supernumerary 13 th 

### rib and/or 27 th 

### presacral vertebrae). In two studies, skeletal variations were obser ved at high doses in the absence of any maternal toxicity.

In the two

- generation reproduction study with rats, there was no evidence of increased susceptibility. Offspring toxicity was characterized as decreased pup weight and weight gain in F 2 

### male and female pups and increased time to preputial separation in the F 1 

### males. These effects were observed in the presence of parental/systemic toxicity that included (1) decreased body weight, (2) decreased body

- weight gain in males, (3) increased th yroid and k idney weights of both sexes, and (4) microscopic findings in the eyes, kidney, and thyroid of both sexes.

In the DNT study, there was evidence for qualitative susceptibility. In the maternal animals, toxicity was limited to corneal opacity whereas effects in the offspring manifested as (1) neurobehavioral changes (decreased auditory startle reflex), (2) decre ases in absolute brain weight, and (3) decreases in brain morphometric measurements (e.g., hippocampus, and parietal cortex).

4.5.4 Residual Uncertainty in the Exposure Database

There are no residual uncertainties in the exposure database. The dietary and residential exposure analyses are conservative in nature. The dietary exposure assessment uses tolerance

level residues and assumes 100% crop treated. The residential exposure assessment uses chemical

- specific turf transferable residue data and the 2 012 Residential Standard Operating Procedures (SOPs) and is considered health

- protective.

4. 6 Toxicity Endpoints and Points of Departure Selections

4. 6 .1 Dose

- Response Assessment

Acute dietary for the general population including infants and children

HED 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 paramet ers 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 manifestTopramezone Human

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Page 18 of 41 

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

- and 10X intra species factors), the 10X FQPA SF was ret ained 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 childbearing age (13

- 49 years old)

HED has selected the developmental NOAEL of 0.5 mg/kg/day from the developmental toxicity study in rabbits as the endpoint of concern for this exposure scenario and population. This NOAEL is based on increased skeletal variations observed in the fetuses foll owing 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 th e 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 ar e used as the endpoint of concern for this scenario. Thus, the aRfD and aPAD for females of childbearing age are equivalent at 0.005 mg/kg body weight.

Chronic dietary (all populations)

HED has selected the NOAEL of 0.4 mg/kg/day from the chronic toxic ity/carcinogenicity study with rats for this exposure scenario. This NOAEL is based on increased incidences of corneal opacity, decreased body weight and body

- weight gains in males, and histopathological evaluations in the thyroid, pancreas, and eyes of b oth sexes observed at 3.6 mg/kg/day (LOAEL). This endpoint/study is appropriate for this exposure scenario since the effects were observed in the most sensitive species following chronic exposure. The conventional 100

- fold factor (10X inter

- and 10X intr a

- species) was applied to the NOAEL (0.4 mg/kg/day). The FQPA SF was not retained for this exposure scenario since the toxicology database is complete and there were no residual uncertainties for pre

- and or post natal susceptibility. Thus, the cRfD and cP AD are equivalent at 0.004 mg/kg bw/day.

Short

- and intermediate

- term incidental oral

HED has selected the NOAEL of 0.4 mg/kg/day from the two

- generation reproduction study for this exposure scenario

. Th e NOAEL of 0.4 mg/kg/day is based on decreases in b ody weights and body

- weight gains in the F 2 

### generation offspring and increased time to preputial separation in the F 1 

### male offspring seen at 4.2 mg/kg/day (LOAEL). These effects were observed in the offspring following approxima tely 13 weeks of treatment. Therefore, they are appropriate for the population subgroup (infants and children) and exposure duration (short

- and intermediate

term) of concern. This POD addresses concern for (1) the fetal effects observed in the developme ntal toxicity study in rabbits (LOAEL = 5 mg/kg/day), (2) the offspring effects observed in the DNT study (LOAEL = 8 mg/kg/day), and (3) the effects observed in the SCN study (LOAEL = 4.2 mg/kg/day)

A MOE of 100, which includes the 10X inter

- and 10X intr a

- species factors is adequate for this exposure scenario. The FQPA SF is reduced to 1X 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.Topramezone Human

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Page 19 of 41 

### Short

- and intermediate

- term dermal

HED 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 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)

, a nd (3) the effects observed in the SCN study (LOAEL = 4.2 mg/kg/day).

The available 28

- day dermal toxicity study in rats was not selected since this study did not evaluate the developmental potential following dermal exposures to topramezone.

Since an oral study was selected for the dermal endpoint, the DAF of 2.6% should be used to estimate a dermal

- equivalent dose. Based on a DAF of 2.6%, the equivalent dermal NOAEL would be 15.4 mg/kg/day (0.4 mg/kg/day 0.026).

A MOE of 100, which include s the 10X inter

- and 10X intra

- species factors is adequate for this exposure scenario. The FQPA SF is reduced to 1X since (1) the toxicology database is complete, (2) there are no residual uncertainties fo r pre

- and or postnatal susceptibility, and (3) the toxicity seen in the target organs is the endpoint of concern for this scenario.

Short

- and intermediate

- term inhalation

HED 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 (incr eased thyroid weights in males and flaky colloid in both sexes) at 4.2 mg/kg/day. This POD addresses concern for (1) the fetal effects observed in the developmental toxicity study in rabbits (LOAEL = 5 mg/kg/day), (2) the offspring effects observed in the DNT study (LOAEL = 8 mg/kg/day)

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

Since an oral dose was selected, 100% absorption was assumed via the inhalation route. T opramezone was placed in Toxicity Category IV for acute inha lation toxicity and has a low vapor pressure (7.5 x 10 - 13 

### mmHg)

. The HASPOC met on December 19 th 

### , 2012 (TXR #0056531) to decide on the need for a 28

- day rat inhalation toxicity study. The committee’s decision does not require a 28

- day inhalation toxicity study at this time.

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

4.6.2 Recommendation for Combining Routes of Exposure for Risk Assessment

The Agency must consider risks from individual rou tes 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, andTopramezone Human

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Page 20 of 41 

### incidental oral endpoints are based on the same toxicity endpoint, exposures via these routes may be aggregated.

4.6.3 Cancer Classification and Risk Assessment Recommendation

Topramezone is classified as “ not likely to be carcinogenic to humans at doses that do not alter rat thy roid hormone homeostasis.” The CARC has 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.

4.6.4 Summary of Toxicity Endpoint and POD Selection

The PODs, UFs, and toxicity endpoints are presented in Table 4.5. 1 (dietary and non

occupational assessments) and Table 4.5. 2 (occupational assessments).

Table 4.5. 1a

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

Exposure Scenario POD Uncertainty/ FQPA Safety Factors or LOC for Risk Assessment Study and Toxicological Effects

Acute Dietary (General population including infants and children) LOAEL = 8 mg/kg bw UF = 100X (for inter

- and 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

- 49 years old) NOAEL = 0.5 mg/kg/day UF = 100X (for inter

- and intra

- species extrapolation)

FQPA SF = 1X

aRfD = 0.005 mg/kg/day aPAD = 0.005 mg/kg/day Developmental Toxicity Study in Rabbits

Developmental LOAEL = 5 mg/kg/day based on alterations in skeletal ossification sites and increased number of pairs of ribs.

Chronic Dietary (All populations) NOAEL = 0.4 mg/kg/day UF = 100X (for inter

- and 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, decr eased 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 F 2 generation offspring and increased time to preputial separation in the F 1 male offspring

. Short

- and Intermediate

- Term, Dermal Oral NOAEL = 0.4

mg/kg/day

( DAF = 2.6%) Residential LOC for MOE = 100 Two

- Generation Reproduction Study in Rats

Parental LOAEL = 4.2 mg/kg/day based on decreased body weight, body

- weight gain in males, increased thyroid and kidney weights of both sexes , and microscopic findings in eyes, kidney and thyroid of both sexes.Topramezone Human

- Health Risk Assessment DP# s 400310, 404014

Page 21 of 41 Table 4.5. 1a

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

Exposure Scenario POD Uncertainty/ FQPA Safety Factors or LOC for Risk Assessment Study and Toxicological Effects

Short

- and Intermediate

- Term Inhalation Oral NOAEL = 0.4

mg/kg/day

(inhalation absorption = 100%) Residential LOC for MOE = 100 Two Generation Reproduction Study in Rats

Parental LOAEL = 4.2 mg/kg/day based on decreased body weight, body

- weight gain in males, increased thyroid and kidney weights of both sexes, and microscopic findings in eyes, kidney and thyroid of both sexes.

Cancer (Oral, dermal, inhalation) In accordance with the 2005 EPA Guidelines for Carcinogen Risk assessment, topramezone was classified as

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

. ” The CARC determined that the thyroid tumors arise through a non

- lin ear 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

- obs erved 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. 2 . Summary of Toxicology Endpoints and PODs for Topramezone in Occupational Risk Assessment. Exposure Scenario Dose Used in Risk Assessment, UF FQPA SF and LOC for Risk Assessment Study and Toxicological Effects

Short

- and Intermediate

Term, Dermal Oral NOAEL = 0.4 mg/kg/day

( DAF = 2.6%) Occupational LOC for MOE = 100 Two

- Generation Reproduction Study in Rats

Parental LOAEL = 4.2 mg/kg/day based on decreased body weight, body weight gain in males, increased thyroid and kidney weights of both sexes, and microscopic findings in eyes, kidney and thyroid of both sexes. Short

- and Intermediate

Term Inhalation Oral NOAEL = 0.4 mg/kg/day

(inhalation absorption = 100%) Occupational LOC for MOE = 100 Two

- Generation Reproduction Study in Rats

Parental LOAEL = 4.2 mg/kg/day based on decreased body weight, body weight gain in males, increased thyroid and kidney weights of both sexes, and microscopic findings in eyes, kidney and thyroid of both sexes. Cancer (Oral, dermal, inhalation) In accordance with the 2005 EPA Guidelines for Carcinogen Risk assessment, t opramezone was classified as “ n ot 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

- 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

5.1 Residues of Concern Summary and Rationale

Toprame zone metabolism studies in corn, ruminant, and poultry were previously submitted and reviewed (D310772, G. Kramer, 05/ 112005). These studies yielded similar results in that the parent compound was not extensively metabolized. However, significant differe nces were observed in the metabolic pathways. In corn , topramezone underwent hydrolytic cleavage to form the acid metabolite s M670H05 and M670H08, while desmethylation formed M670H03. After cleavage, the pyrazole ring appeared to undergo complete catabol ism and reincorporation within the carbon backbone of natural products such as starch, soluble polysaccharides, and fatty acids. The phenyl ring portion of the molecule also underwent degradation, resulting in theTopramezone Human

- Health Risk Assessment DP# s 400310, 404014

Page 22 of 41 

### incorporation of radioactivity into natur al products. In ruminants , the proposed metabolic pathway involved hydroxylation of the parent compound at the 4

- position of the isoxazole ring to form M670H02. The isoxazole ring was then cleaved to form the cyano metabolite (M670H01). The linkage betw een the phenyl and pyrazole rings remained intact in all of the metabolites identified. In poultry , the proposed metabolic pathway also involved hydroxylation of the parent compound at the 4

- position of the isoxazole ring to form M670H02. Further N

- demet hylation of M670H02 occurred and formed the desmethyl hydroxy metabolite M670H04. M670H04 was only detected in the phenyl

- labeled liver. The pyrazole ring of topramezone could also be cleaved to form the acid metabolite M670H05. Similar metabolic pathwa ys were also observed in rotational crops , with M670H05 and M670H02 being the only metabolites identified.

HED concluded that topramezone per se is the residue of concern, for purposes of tolerance enforcement and risk assessment, in corn, rotational crops, and ruminants (D310772, G. Kramer, 11

- May

- 2005). Conclusions concerning the residues of concern in poultry were not determined with the D3107 72 memorandum indicating that if future proposed uses significantly increase the poultry dietary burden, then a poultry feeding study, which monitors for residues of parent and metabolite M670H02, may be required. Table 5.1 is a summ ary of the residues of concern for purposes of tolerance enforcement and risk assessment.

Table 5.1. Residues of Concern for Risk Assessment and Tolerance Expression Purposes.

Matrix Residues included in Risk Assessment Residues included in Tolerance Expression

Plants Corn topramezone topramezone Rotational Crop topramezone topramezone

Livestock Ruminant topramezone topramezone Poultry

-- 1

-- 1 Drinking Water topramezone Not Applicable

1 Conclusions concerning the residues of concern in poultry were not determined with the D310772 memorandum indicating that if future proposed uses significantly increase the poultry dietary burden, then a poultry feeding study, which monitors for residues of parent and metabolite M670H02, may be required.



### 5.2 Food Residue Profile

Topramezone is currently registered for application to field corn, popcorn, sweet corn, and corn grown for seed corn with tolerances established at the LOQ. The fiel d corn processing studies also resulted in residues of <LOQ following treatments at rates up to 20 X the registered rate. No additional residue chemistry data are required to support the corn use. Based on the corn application rate and the results of the confined/field rotational crop studies, residues in rotational crops were anticipated to be negligible at the labeled 28

- day plant

- back interval (PBI). The corn use is the only registered use which results in residues in/on food/feed commodities (D310772, G. Kramer, 11

- May

- 2005).

Of the proposed uses, HED concludes that only the aquatic application scenario could potentially result in residues in/on food/feed commodities. The proposed aquatic label includes instruction for the direct application to wat er, near

- shore foliar application, spot application (near

- shore and aquatic), and application to exposed sediment. The proposed label does not include any restrictions concerning the use of the treated water for potable use or by livestock.

Based on th e proposed use and since the residue of concern in water is only topramezone, HED concludes that the aquatic application scenario will result in a maximum concentration in water of 50 ppb. Provided the petitioner submits a revised Section B, HED concludes the proposed aquatic use will not result in residues in/on irrigated food/feed crops or rotational crops.Topramezone Human

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Page 23 of 41 

### Based on fish/shellfish metabolism studies, the bioconcentration factor (BCF) for both catfish and clam calculated from these studies (<1), and th e low the octanol

- water partition coefficient for topramezone (LogK OW 

### =
- 1.52 at pH 7), HED is recommending for fish/shellfish tolerances for residues of only topramezone at the same concentration as the maximum water concentration (0.05 ppm). HED is also recommending for meat byproduct tolerances for ruminant (0.80 ppm), hog (0.40 ppm), and poultry (0.02 ppm) as a result of the consumption of treated water by livestock (bulk of livestock dietary burden is f rom consumption of treated water). For more info rmation concerning these conclusions see D400949 (T. Bloem, 2/ 26 / 2013 ).

5.3 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), M670H01 (>15% of applied), and M670H 10 (> 16% of applied). The degradation product M670H05 is mobile and persistent (half

- life >350 days). Topramezone applications can lead to surface water contamination through spray drift and runoff. In addition, because it is persistent and mobile in soil, t opramezone is expected to leach into ground water.

In aerobic aquatic environments, topramezone degraded with total system half

- lives ranging from 19 to 277 days

. Topramezone degraded in aerobic aquatic environments to form M670H01 (<10.3% of applied) degradation product

. In anaerobic environments, topramezone degraded with total system half

- lives ranging from 13 to 24 days

. The major degradation products identified in anaerobic aq uatic environments were M670H10 (41% to 48% of applied) minor degradat ion products and M670H01 (≤5.3% of applied)

. Based upon soil organic carbon coefficient, K oc 

### , topramezone would fall into the mobile to moderately mobility class.

5. 4 Water Residue Profile

The drinking water residues used in the dietary risk assessment were provided by EFED (J. Wolf, 01/29/ 2013; DP# 408687) and incorporated directly into the acute and chronic dietary assessments. Estimated drinking water concentrations (EDWCs) were incorporated directly into DEEM

- FCID under the food categories “water, d irect, all sources” and “water, indirect, all sources.”

To date, no monitoring data are available for parent topramezone. The highest topramezone EDWC is expected to result from the direct aquatic applications. Although the highest proposed

concentrat ion in water is 50 ppb, the proposed use for water bodies with functional potable water intakes cannot exceed 45 ppb; therefore, this is the highest potential concentration recommended for drinking water.

5. 5 Dietary Risk Assessment

5. 5 .1 Description o f Residue Data Used in Dietary Assessment

The acute and chronic analyses assumed tolerance

- level residues, 100 percent crop treated (%CT) , DEEM default processing factors, and modeled water values. Therefore, these analyses were considered highly conservative and could be further refined if needed through the use of anticipated residues (ARs) for all commodities, % market share data for the proposed commodities, %CT data for registered commodities, empirical processing factors, and/or monitoring da ta for drinking water. However, as there are no risk estimates of concern,Topramezone Human

- Health Risk Assessment DP# s 400310, 404014

Page 24 of 41 

### refinements are not necessary at this time.

5. 5 .2 Percent Crop Treated Used in Dietary Assessment

100% CT was assumed in the acute and chronic dietary assessments.

5. 5 .3 Acute Dietary Risk Assessment

Two separate acute analyses were conducted as there were two different PODs identified: one for the general U.S. population (including infants and children) and one for females 13

- 49 years of age. Both Tier 1 acute analyses assum ed 100% CT , DEEM 7.81 default processing factors

, and tolerance

- level residues. Drinking water was incorporated directly in the dietary

assessments . The proposed use for water bodies with functional potable water intakes cannot exceed 45 ppb; therefore, this is the highest potential concentration recommended for drinking

water.

The acute dietary exposure and risk estimates (food + drinking water) were estimated at 0.002544 mg/kg/day for the general U.S. population (32% of the aPAD) and 0.007840 mg/kg/da y (98% of the aPAD) for the most highly exposed population subgroup (all infants <1 year old) and are thus below HED’s LOC. These results are shown for the 95 th 

### percentile of exposure, as all inputs were unrefined.

The resulting acute dietary exposure an d risk estimate using the DEEM

- FCID model at the 95 th 

### percentile for females 13

- 49 years of age was 0.002508 mg/kg/day (50% of the aPAD) and is below HED’s LOC.

Acute dietary exposure to topramezone is not of concern to HED for any population subgroup

.

5. 5 .4 Chronic Dietary Risk Assessment

The resulting chronic (food + drinking water) risk estimates were less than HED’s LOC for the U.S. general population (25% of the cPAD) and all population sub

- groups; the most highly exposed population subgroup was all infants (<1 year old), which utilized 62% of the cPAD. Therefore, the chronic dietary exposure to topramezone is not of concern to HED.

5. 5 .5 Cancer Dietary Risk Assessment

A chronic cancer dietary assessment was not conducted since topramezone was classified as “not likely to be carcinogen at doses that do not alter rat thyroid homeostasis.” The cRfD is expected to be protective of thyroid alterations and tumor formation.Topramezone Human

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Page 25 of 41 

### 5.4.6 Summary Table

Table 5.4.6. Summary of Dietary (Food and Drinki ng Water) Exposure and Risk for Topramezone.

Population Subgroup* Acute Dietary 1 (95th Percentile) Chronic Dietary 2 Cancer
Dietary Exposure (mg/kg/day) % aPAD Dietary Exposure (mg/kg/day) % cPAD Dietary Exposure (mg/kg/day) Risk

General U.S. Population 0.002541 32 0.000998 25

N/A N/A All Infants (<1 year old) 0.007829 98 0.002487 62 Children 1

- 2 years old 0.004041 51 0.001487 37 Children 3

- 5 years old 0.003230 40 0.001263 32 Children 6

- 12 years old 0.002467 31 0.000913 23 Youth 13

- 19 years old 0.002098 26 0.000738 19 Adults 20

- 49 years old 0.002469 31 0.000989 25 Adults 50+ years old 0.002205 28 0.000971 24 Females 13

- 49 years old 0.002508 50 0.000978 25

* The highest dietary exposure estimate for each type of risk assessment is bolded.

1 Acute dietary POD of 0.008 mg/kg/day applies to the general U.S. population, including infants and children. Acute dietary endpoint of 0.005 mg/kg/day applies to the females 13

- 49 years old population subgroup o nly.

2 Chronic dietary POD of 0.004 mg/kg/day applies to the general U.S. population and all population subgroups.



### 6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

The following are summaries of the residential exposures associated with the proposed uses. Residential exposures resulting from the registered golf course and turfgrass uses have been previously assessed and yielded exposures which do not exceed HED’s LOC ( D388367

, K. Lowe, 2

- Feb

- 201 2); it is noted that this previous assessment considered the 2012 residential SOPs.

6.1 Residential Handler Exposure

HED uses the term “handlers” to describe those individuals who are involved in the pesticide application process.

Non

- crop Terrestri

al

- Application: The application sites specified in the proposed non

- crop terrestrial

- application scenario are not associated with residential settings; therefore, a residential handler exposure assessment is unnecessary.

Non

- crop Aquatic

-

Application: Residential handler assessments were not conducted because the proposed use sites are not residential in nature and homeowner applications are unlikely. It is noted that the label includes the following statements which also imply commercial/professional applications: (1) state and/or local authorities are to be consulted prior to applying this product in or around public waters and (2) prior to retreatment, samples should be collected and analyzed for parent concentration to establish the amount of produ ct to apply so as to not exceed the labeled maximum water concentration of 50 ppb.

6.2 Post

- Application Exposure

Non

- crop Terrestrial

- Application: The application sites specified in the proposed non

- crop terrestrial

- application scenario are not associated with residential/recreational setting s ; therefore, a residential post

- application exposure assessment is unnecessary.Topramezone Human

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Page 26 of 41 

### Non

- crop Aquatic

-

Application: Since there are no restrictions concerning the recr eational use of treated water, post

- application residential exposures resulting from swimming in treated water were calculated. HED notes that although only short

- term exposures are anticipated, the short

term assessments are protective of intermediate

- te rm exposures as the short

- and intermediate

- term oral, inhalation, and dermal PODs are identical.

The lifestages selected for each post

- application scenario are based on an analysis provided as an Appendix in the 2012 Residential SOPs ( http://www.epa.gov/pesticides/science/residential

exposure

- sop.html ). These lifestages are not the only lifestages that could be potentially exposed for these post

- application scenarios; however, the assessment of these lifestages is protective for the exposures and risk estimates for any other potentially exposed lifestages. The following paragraphs are summaries of the anticipated inhalation, oral, and dermal exposures/risks

.

Inhalation: B ased on the Henry’s law constant for topramezone (7.03 x 10 - 16 

### atm m 3 

### /mole), there is a low potential for volatilization from water and post

- application inhalation exposures are anticipated to be negligible.

Dermal and Oral: The foll owing scenarios were assessed: ingestion of water while swimming and dermal exposure from water while swimming. Risks were calculated using the MOE approach, which is a ratio of the estimated exposure to the toxicological POD. The dermal and oral exposu res were combined as the PODs for these routes are identical. Tables 6 .2.1 and 6 .2.2 are summaries of the oral and dermal exposures, respectively. Table 5.2.3 is a summary of the combined oral and dermal post

- application expo sures. The combined oral and dermal MOEs for adult and child swimmers are >100 (MOEs ≥1000). Therefore, residential post

- application exposure does n ot exceed HED’s LOC.

HED did not combine swimmer exposures from th e proposed non

- crop aquatic use with the exposures from the registered turf and/or golfer e xposure due to the conservative nature of each of these individual assessments.

Table 6.2.1. Short

- Term Post

- application Exposure

- Ingestion of Water by Swimmers. Exposure Scenario Cw 1 (mg/L) IgR 2 (L/hr) ET 3 (hr/day) BW 4 (kg) Oral Dose 5 (mg/kg/day) MOE 6

swimmer; adult 0.050 0.021 3.7 80 4.92 x 10 - 5 8,100 swimmer; child (3

- <6 years old) 0.049 3.0 19 3.83 x 10 - 4 1,000

1 Cw = concentration in water = 50 ppb; based on the label instructions.

2 IgR = ingestion rate of water; based on 2011 EFH (Table 3

- 5).
3 ET =exposure time; based on 2011 EFH (Table 16

- 20)

. 4 BW = body weight; based on the Residential Pesticide Exposure Assessment SOP (February

- 2012).
5 Oral dose = (Cw x IgR x ET) ÷ BW (80 kg for adults and 19 kg for child (3

- <6 years old).

6 MOE = NOAEL (0.4 mg/kg/day; adult and child) ÷ dose (mg/kg/day).

Table 6.2.2. Short

- Term Post

- application Exposure

- Dermal Exposure from Water to Swimmers.

Exposure Scenario Cw 1 (mg/L) SA 2

(cm 2 ) ET 3 (hr/day) Kp 4 CF 5

(L/cm 3 ) BW 6 (kg) Dermal Dose in Oral Equvalents 7 (mg/kg/day) MOE 8

swimmer; adult 0.050 19,500 3.7 9.6 x 10 - 7 0.001 80 4.40 x 10 - 8 9,100,000 swimmer; child (3

- <6 years old) 7,600 3.0 19 5.73 x 10 - 8 7,000,000

1 Cw = concentration in water = 50 ppb; based on the label instructions.

2 SA = surface area; values based on the Residential Pesticide Exposure Assessment SOP (February

- 2012).
3 ET =exposure time; based on 2011 EFH (Table 16

- 20)

. 4 Kp = permeability coefficient = 10 [

- 2.72 + (0.71 x log Kow)

- (0.0061 x MW)] = 9.6 x 10 - 7 ; EPA 1992 default equation for organic compounds.
5 CF = conversion factor = 0.001 L/cm 3

. 6 BW = body weight; based on the Residential Pesticide Exposure Assessment SOP (February

- 2012).

7 Dermal dose in oral equivalents = (Cw x SA x ET x Kp x CF) ÷ BW ( 80 kg for adults and 19 kg for child (3

- <6 years old).Topramezone Human

- Health Risk Assessment DP# s 400310, 404014

Page 27 of 41 8 MOE = NOAEL (0.4 mg/kg/day; adult and child) ÷ dose (mg/kg/day).

Table 6.2.3. Short

- Term Post

- application Combined Oral and Dermal Exposure for Adult and Child Swimmers.

Exposure Scenario Oral Dose from Ingestion of Water 1 (mg/kg/day) Dermal Dose from

Water 2 (oral equivalents; mg/kg/day) Total Dose 3 (mg/kg/day) MOE 4

swimmer; adult 4.92 x 10 - 5 4.40 x 10 - 8 4.92 x 10 - 5 8,100 swimmer; child (3

- <6 years old) 3.83 x 10 - 4 5.73 x 10 - 8 3.83 x 10 - 4 1,000

1 From Table 6 .2.1.
2 From Table 6 .2.2.
3 Total dose = oral dose + dermal dose in oral equivalents.

4 MOE = NOAEL (0.4 mg/kg/day; adult and child) ÷ total dose (mg/kg/day)

.



### 6.3 Residential Risk Estimates for Use in Aggregate Assessment

The residential exposure/risk resulting from the registered turf and golf course uses were previously calculated and are summarized in D388367 (K. Lowe, 2

- Feb

- 2012); it is noted that this assessment considered the 2012 residential SOPs. Based on the resid ential exposure estimates from all proposed and registered uses and under the criteria that the uses which result in the highest exposures should be used in aggregate assessment, HED concludes that aggregate risk calculations should employ the following re sidential exposure estimates (see Table 6.3 for a summary):

● For adults, short

- term aggregate assessments should consider the post

- application exposure resulting from the registered turf use (physical activities on turf). ● For children, short

- term a ggregate assessments should consider combined dermal and incidental oral (hand

- to

- mouth) post

- application exposures to children 1

- <2 years old resulting from the registered turf use. The post

- application incidental oral scenarios ( hand

- to

- mouth )

, object

- to

- mouth, and soil ingestion were not combined due to the conservative nature of each individual assessment. The incidental oral scenario which yielded the highest exposure (hand

- to

mouth) was combined with post

- application dermal. This combinat ion is considered a protective estimate of children’s exposure to pesticides used on turf. ● For children, intermediate

- term aggregate assessments should consider incidental soil ingestion exposure for children 1

- <2 years old resulting from the register ed turf use.

Table 6.3. Residential Exposures for use in Topramezone Aggregate Exposure Assessments.

Population Residential Handler Post

- application

Total Exposure (mg/kg/day) MOE Total Exposure (mg/kg/day) MOE

Short

- term

adult 1 Residential handler exposure should not be used for aggregate assessment as it is lower than the post

application exposure. 0.00083 480

child (1

- <2 years old) 1 not applicable 0.0019 210 Intermediate

- term (assessment was conducted to address potential soil ingestion ) child (1

- <2 years old) 1 not applicable 3.0 x 10 - 6 130,000

1 E xposure resulting from the registered turf use (see D388367

, K. Lowe, 2

- Feb

- 2012 ).



### 6.4 Residential Bystander Post

- application Inhalation Exposure

Based on the Agency's current practices, a quantitative post

- application inhalation exposure assessment was not performed for topramezone at this time primarily because of the low acute inhalation toxicity (Toxicity Category IV), low vapor pressure (7.5 x 10 - 13 

### mm Hg), low Henry’s law constant (7.03 x 10 - 16 

### atm m 3 

### /mole), and the low proposed use rate. However, volatilizationTopramezone Human

- Health Risk Assessment DP# s 400310, 404014

Page 28 of 41 

### of pesticides may be a source of post

- application inhalation exposure to individuals nearby pesticide applications. The Agency sought exp ert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report and may, as appropriate, develop policies and procedures to ident ify 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 exposure assessment for topramezone.

6.5 Spray Drift

Spray drift is always a potential source of exposure to residents nearby to spraying operations. This is particularly the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application method employed for topramezone. The Agency has been working with the Spray Drift Task Force, EPA Regional Offices, and State Lead Agencies for pesticide regulation and other parties to develop the best spray

- drift

management practices (see the Agency’s Spray Drift website for more information at http://www.epa.gov/opp00001/factsheets/spraydrift.htm ). On a chemical

- by

- chemical basis , the Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/labeling. The Agency has completed its evaluation of the new database submitted by the Spray Drift Task Force, a membership of U.S. pes ticide 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 A gency may impose further refinements in spray

- drift

management practices to reduce off

- target drift with specific products with significant risk estimates associated with drift.

Although a quantitative residential post

- application inhalation exposure asse ssment was not performed as a result of pesticide drift from neighboring treated agricultural fields, an inhalation exposure assessment was performed for flaggers (MOE = 3300 ; no PPE). This exposure scenario is representative of a worse case inhalation (d rift) exposure and may be considered protective of residential exposure resulting from spray 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 e xposures 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 exposu re analysis represent acute aggregate exposures

. The acute dietary assessment did not result in exposure estimates above HED ’ s LOC (see Table 5.4.6)

.Topramezone Human

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Page 29 of 41 

### 7.2 Short

- Term Aggregate Risk

Short

- term aggregate exposures were made up of average dietary exposures from food, drinking water (the main driver in the dietary assessment due to the aquatic use), and residential exposures from either the proposed or registered uses

. The sum of these exposures was compared to appropriate quantitative estimate of hazard, an d the resulting risk estimate was expressed as a MOE. HED’s LOC is an MOE <100.

For adults and children, the highest estimated residential exposure was associated with post

application physical activities from the currently registered turf use ( D388367

, K. Lowe, 0 2

- Feb

2012 )

. For adults, this is the sum of high

- end post

- application dermal and inhalation estimated
exposures ; whereas

, f

or children, the highest residential exposure estimate is from incidental oral and dermal exposure

. Although incidental o ral exposures are more likely with children 1<2 years old, the exposure estimates are high

- end and protective of older children more likely to engage in recreational swimming activities

. Children 1

- 2 years of age were also the subgroup predicted to have t he highest dietary burden at 98 and 62% of the aPAD and cPAD, respectively

. The resulting aggregate short

- term MOE are >100 and therefore not of concern to HED (Table 7.2.1)

.

Table 7.2.1. Short

- Term Aggregate Risk Calculations.

Population NOAEL

(mg/kg/day) LOC Average Food and Water Exposure (mg/kg/day) 1 Residential

Exposure (mg/kg/day) 2 Total Exposure

(mg/kg/day) 3 Aggregate MOE

(food, water, and residential) 4

General U.S. Population 0.4 100 0.000998 0.00083 0.00183 220

Children 1

- 2 years old 0.4 100 0.001487 0.0019 0.00339 120

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

2 Residential Exposure = [Incidental oral exposure (i.e., Hand

- to

- Mouth) + Dermal exposure + Inhalation Exposure] (Table 6.3.1).

3 Total Exposure = Average Food & Water Exposure + Residential Exposure.

4



### 7.3 Intermediate

- Term Aggregate Risk Intermediate

- term residential exposures are not expected based on the proposed aquatic and terrestrial u ses

. However, intermediate incidental oral exposures (soil ingestion) for children 1<2 years old have been previously assessed for the registered turf use

. The resulting aggregate short

- term MOE are >100 and therefore not of concern to HED.

Table 7.2.2. Intermediate

- Term Aggregate Risk Calculations.

Population NOAEL

(mg/kg/day) LOC Average Food and Water Exposure (mg/kg/day) 1 Residential

Exposure (mg/kg/day) 2 Total Exposure

(mg/kg/day) 3 Aggregate MOE

(food, water, and residential) 4

Children 1

- 2 years old 0.4 100 0.001487 3.0 x 10 - 6 0.00149 270

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

2 Residential Exposure = [Incidental oral exposure (i.e., Hand

- to

- Mouth) + Dermal exposure + Inhalation Exposure] (Table 6.3.1).

3 Total Exposure = Average Food & Water Exposure + Residential Exposure.

4



### 7.4 Long

- Term Aggregate Risk

Long

- term residential exposures are not expected from the registered or proposed uses

. Therefore, chronic (long

- term) aggregate risk is made up only of dietary sources and the chronicTopramezone Human

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Page 30 of 41 

### dietary exposure analysis represents chronic aggregate exposure

. The chronic dietary assessment did not result in exposure estimates that are of concern to HE D (see Table 5.4.6)

7.5 Cancer Risk

Aggregate cancer risk was not performed because topramezone is classified as “not likely to be carcinogenic to humans at doses that do not alter rat thyroid hormone homeostasis ,” and doses at or below the cRfD are not expected to alter thyroid hormone homeostasis

.

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 t oxicities in laboratory animal studies including ocular, developmental, liver

, and kidney effects. Of these toxicities, the ocular effect (corneal opacity) is highly correlated wit h the elevated blood tyrosine levels. In fact, rats dosed with tyrosine al one 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 to xicity associated with inhibition of HPPD. Ocular effects following treatment with HPPD inhibitor herbicides are seen in the rat but not in the mouse. Monkeys also seem to be recalcitrant to the ocular toxicity induced by HPPD inhibition. The explanatio n of this species

- specific response in ocular opacity is related to the species differences in the clearance of tyrosine. A metabolic pathway exists to remove tyrosine from the blood that involves a liver enzyme called tyrosine aminotransferase (TAT). In contrast to rats where ocular toxicity is observed following exposure to HPPD

- inhibiting herbicides, mice and humans are unlikely to achieve the levels of plasma tyrosine necessary to produce ocular opacities because the activity of TAT in these species i s 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 di seases of tyrosine catabolism. Treatment starts in childhood but is often sustained throughout patient’s lifetime. The human experience indicates that a therapeutic dose (1 mg/kg/day dose) of nitisinone has an excellent safety record in infants, children , and adults and that serious adverse health outcomes have not been observed in a population followed for approximately a decade. Rarely, ocular effects are seen in patients with high plasma tyrosine levels; however, these effects are transient and can be readily reversed upon adherence to a restricted protein diet. This indicates that an HPPD inhibitor in it of itself cannot easily overwhelm the tyrosine

- clearance mechanism in humans.

Therefore, exposure to environmental residues of HPPD

- inhibiting herbicides are unlikely to result in the high blood levels of tyrosine and ocular toxicity in humans due to an efficient metabolic process to handle excess tyrosine. In the future, assessments of HPPD

- inhibiting herbicides will consider more appropriate mode ls and cross species extrapolation methods

. Therefore, EPA has not conducted cumulative risk assessment with other HPPD inhibitors (D341612; dated 7/02/ 20 07).Topramezone Human

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Page 31 of 41 

### 9.0 Occupational Exposure/Risk Characterization

9.1 Short

- /Intermediate

- Term Handler Risk

HED uses the term handlers to describe those individuals who are involved in the pesticide application process. HED believes that there are distinct job functions or tasks related to applications and exposures can vary depending on the specifics of each t ask. Job requirements (amount of chemical used in each application), the kinds of equipment used, the target being treated, and the level of protection used by a handler can cause exposure levels to differ in a manner specific to each application event.

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 occupat ional handlers is based on the following scenarios:

● Mixing/loading soluble

- concentrate (SC) formulations for aerial application

● Mixing/loading SC formulations for groundboom application

● Applying sprays aerially (fixed

- wing aircraft; closed cab)

● Applying sprays by groundboom equipment

● Flagger in support of aerial application

● Mixing/ l oading/ a pplying using backpack sprayer (spot treatment)

● Mixing/ l oading/ a pplying using manually pressurized handwand sprayer (spot treatment)

● Mixing/ l oading/ a pp lying using mechanically pressurized handgun sprayer (spot treatment)

HED classifies exposures from 1 to 30 days as short

- term and exposures 30 days to six months as intermediate

- term. Exposure duration is determined by many things, including the exposed population, the use site, the pest pressure triggering the use of the pesticide, and the cultural practices surrounding that use site. For most agricultural uses, it is reasonable to believe that occupational handlers will not apply the same chemical eve ry day for more than a one

- month time frame; however, there may be a large agribusiness and/or commercial applicators who may apply a product over a period of weeks (e.g., completing multiple applications for multiple clients within a region). For the cur rent proposed topramezone uses, exposures are expected to be short

- term and intermediate

- term in duration. It is noted that the short

- term assessments are protective of intermediate

- term exposures as the short

- and intermediate

- term inhalation and dermal PODs are identical. Long

- term exposures are not expected.

Occupational handler exposure assessments are completed by HED using different levels of risk mitigation. Typically, HED uses a tiered approach. The lowest tier is designed as the baseline
exp osure scenario (i.e., long

- sleeve shirt, long pants, shoes, socks, no respirator). If risk estimates are of concern at baseline attire, then increasing levels of PPE (i.e., gloves, respirators) are evaluated. If risk estimates remain a concern with maxim um PPE, then engineering controls (i.e., enclosed cabs or cockpits, water

- soluble packaging, and closed mixing/loading systems) are evaluated. This approach is used to ensure that the lowest level of risk mitigation that provides adequate protection is se lected, since the addition of PPE and engineering controls involves an additional expense to the user and (in the case of PPE) also involves an additional burden to the user due to decreased comfort and dexterity and increased heat stress and respiratory s tress.

Conclusions: Table 9.1 summari z es the dermal, inhalation, and combined dermal/inhalation exposures and risk estimates (dermal and inhalation combined as identical POD) for topramezone

.Topramezone Human

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Page 32 of 41 

### MOEs were calculated assuming baseline PPE (long

- sleeved sh irt, long pants, shoes plus socks, and no protective gloves clothing) as well as baseline PPE plus protective gloves. The mixer/loader scenario in support of aerial application for the non

- crop aquatic scenario resulted in a risk estimate of concern assum ing baseline PPE plus protective gloves ; therefore this scenario was also assessed assuming DL (double layer/coveralls) and EC (engineering control).

Provided handlers wear protective gloves as specified on the proposed labels and the labels are revised as indicated below, the combined dermal and inhalation MOEs are >100 (MOEs ≥1 7 0). Therefore, occupational handler exposures do not exceed HED’s LOC.

A revised Section B specifying the following is requested: (1) for in

- water applications, applicators must wear long

- sleeved shirt, long pants, chemical

- resistant gloves, and shoes plus socks and (2) for in

- water applications, mixer loaders in support of aerial application must use engineering controls (i.e.

, closed system).

Table 9.1. Short

- /Intermediate

- Term Occupational Exposure and Risk Estimates for Topramezone.

Unit Exposure 1 (μg/lb ai handled) Application Rate 2 Units Treated Per Day 3 Daily Dose 4

(mg/kg/day) Short

- /Intermediate

- Term MOE 5

Dermal and Inhalation Combined

Mixer/Loader

- Liquid

- Aerial

- Typical Field Crop (aquatic) Dermal: NG: 220 WG: 37.6 DL: 29.1 EC: 8.6 Inhalation: NR: 0.219 EC: 0.083 1.36 lb ai/acre 350 acres Dermal: NG: 0.0341 WG: 0.00582 DL: 0.00452 EC: 0.00133 Inhal: NR: 0.0013 EC: 0.000494 Dermal:

NG: 12 WG: 69 DL: 88 EC: 300 Inhalation: NR: 310 EC: 810 NG/NR: 12

WG/NR: 56 DL/NR: 69 EC/EC: 220

Mixer/Loader

- Liquid

- Aerial

- Typical Field Crop (terrestrial) Dermal: NG: 220 WG: 37.6 Inhalation: NR: 0.219 0.35 lb ai/acre 350 acres Dermal: NG: 0.00878 WG: 0.0015 Inhal: NR: 0.000335 Dermal:

NG: 46 WG: 270 Inhalation: NR: 1200 NG/NR: 44

WG/NR: 220

Mixer/Loader

- Liquid

- Groundboom

- Typical Field Crop (aquatic) Dermal: NG: 220 WG: 37.6 Inhalation: NR: 0.219 1.36 lb ai/acre 80 acres Dermal: NG: 0.00777 WG: 0.00133 Inhal: NR: 0.000298 Dermal:

NG: 51 WG: 300 Inhalation: NR: 1300 NG/NR: 49

WG/NR: 240

Mixer/Loader

- Liquid

- Groundboom

- Typical Field Crop (terrestrial) Dermal: NG: 220 WG: 37.6 Inhalation: NR: 0.219 0.35 lb ai/acre 80 acres Dermal: NG: 0.002 WG: 0.000341 Inhal: NR: 0.0000766 Dermal:

NG: 200 WG: 1200 Inhalation: NR: 5200 NG/NR: 190

WG/NR: 980

Applicator

- Liquid

- Fixed

- wing Aircraft (closed cab)

- Typical Field Crop (aquatic) Dermal: EC: 5 Inhalation: NR: 0.068 1.36 lb ai/acre 350 acres Dermal: EC: 0.000774 Inhal: EC: 0.000405 Dermal:

EC: 520 Inhalation: EC: 990 EC/EC: 340

Applicator

- Liquid

- Fixed

- wing Aircraft (closed cab)

- Typical Field Crop (terrestrial) Dermal: EC: 5 Inhalation: NR: 0.068 0.35 lb ai/acre 350 acres Dermal: EC: 0.000199 Inhal: EC: 0.000104 Dermal:

EC: 2000 Inhalation: EC: 3800 EC/EC: 1300Topramezone Human

- Health Risk Assessment DP# s 400310, 404014

Page 33 of 41 Table 9.1. Short

- /Intermediate

- Term Occupational Exposure and Risk Estimates for Topramezone.

Unit Exposure 1 (μg/lb ai handled) Application Rate 2 Units Treated Per Day 3 Daily Dose 4

(mg/kg/day) Short

- /Intermediate

- Term MOE 5

Dermal and Inhalation Combined

Applicator

- Liquid

- Groundboom

- Open Cab

- Typical Field Crop (aquatic) Dermal: NG: 78.6 WG: 16.1 Inhalation: NR: 0.34 1.36 lb ai/acre 80 acres Dermal: NG: 0.00278 WG: 0.000569 Inhal: NR: 0.000463 Dermal:

NG: 140 WG: 700 Inhalation: NR: 860 NG/NR: 120

WG/NR: 390

Applicator

- Liquid

- Groundboom

- Open Cab

- Typical Field Crop (terrestrial) Dermal: NG: 78.6 WG: 16.1 Inhalation: NR: 0.34 0.35 lb ai/acre 80 acres Dermal: NG: 0.000715 WG: 0.000147 Inhal: NR: 0.000119 Dermal:

NG: 560 WG: 2700 Inhalation: NR: 3400 NG/NR: 480

WG/NR: 1500

Flagger (terrestrial) Dermal: NG: 11 WG: 12 Inhalation: NR: 0.3 4 0.35 lb ai/acre 80 acres Dermal: NG: 0.000100 WG: 0.000109 Inhal: NR: 0.000123 Dermal:

NG: 4000 WG: 3700 Inhalation: NR: 3300 NG/NR: 1800

WG/NR: 1700

Mixer/Loader/Applicator

- Liquid

- Backpack

- Broadcast

- Rights

- of

- way, Forestry, Aquatic Areas; Mixer/Loader/Applicator

- Liquid

- Backpack

- Soil

- Directed

- Christmas Tree Farm, Nursery Dermal: NG: 8260 WG: 8260 Inhalation: NR: 2.58 0.014 lb ai/gal 40 gall Dermal: NG: 0.0015 WG: 0.0015 Inhal: NR: 0.000018 Dermal:

NG: 270 WG: 270 Inhalation: NR: 22,000 NG/NR: 270

WG/NR: 270

Mixer/Loader/Applicator

- Liquid

- Backpack

- Broadcast

- Industrial/Commercial Dermal: NG: 2510 WG: 2500 Inhalation: NR: 30 0.014 lb ai/gal 40 gall Dermal: NG: 0.000458 WG: 0.000455 Inhal: NR: 0.00021 Dermal:

NG: 870 WG: 880 Inhalation: NR: 1900 NG/NR: 600

WG/NR: 600

Mixer/Loader/Applicator

- Liquid

- Manually Pressurized Handwand

- Broadcast

-

Industrial/Commercial, Aquatic Areas Dermal: NG: 100000 WG: 430 Inhalation: NR: 30 0.014 lb ai/gal 40 gal Dermal: NG: 0.0182 WG: 0.0000783 Inhal: NR: 0.00021 Dermal:

NG: 22 WG: 5100 Inhalation: NR: 1900 NG/NR: 22

WG/NR: 1400

Mixer/Loader/Applicator

- Liquid

- Mechanically Pressurized Handgun

- Broadcast

-

Industrial/Commercial, Aquatic Areas Dermal: NG: 1300 WG: 390 Inhalation: NR: 3.9 0.014 lb ai/gal 1000 gal Dermal: NG: 0.00592 WG: 0.00177 Inhal: NR: 0.000683 Dermal:

NG: 68 WG: 230 Inhalation: NR: 590 NG/NR: 61

WG/NR: 170

1 Unit Exposures are from the Occupational Pesticide Handler Unit Exposure Surrogate Reference Table (Revised March

- 2012); NG = no gloves; WG = with gloves; DL = double layer/coveralls; EC = eng ineering control; NR = no respirator.

2 Application rates based on the proposed label; 1.36 lb ai/ A is derived from the proposed non

- crop aquatic

- application label and assumes a water depth of 10 feet.
3 Values are taken from HED’s ExpoSAC Policy #9: “Standard Values for Daily Acres Treated in Agriculture,” which was revised on July 5, 2000.

4 Average Daily Dose (ADD) = Unit Exposure x Application Rate x Units Treated x Absorption Rate (2.6% dermal absorption; inhalation absorption is assumed to be 100% ) x (1 mg/1000 μg) ÷ Body Weight (80 kg).
5 MOE = margin of exposure = NOAEL ÷ ADD (dermal + inhalation). Short

- and i ntermediate

- term NOAEL = 0.4 mg/kg/day.



### 9.2 Post

- Application Risk

Occupational post

- application dermal exposure following aquatic application of topramezone is likely limited to persons who contact treated water to perform tests, such as testing theTopramezone Human

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Page 34 of 41 

### concentration of topramezone in water to determine if retreatment is nec essary. Since the post

application combined dermal and oral (ingestion of water) exposure to adult recreational swimmers resulted in a MOE of 8100 , HED concludes that post

- application occupational exposure is less than HED’s LOC and a quantitative assessm ent is unnecessary. Although the proposed non

- crop terrestrial label does include instructions for application to Christmas tree, conifer, and hardwood plantations and field

- grown ornamental production, the proposed use is for weed control and does not in volve foliar application to the desired plant (confirmed via email communication with the petitioner; Jeffry Britt BASF to Grant Rowland EPA RD). Therefore, post

- application dermal occupational exposures are anticipated to be negligible.

Based on the A gency's current practices, a quantitative post

- application inhalation exposure assessment was not performed for topramezone at this time primarily because of the low acute inhalation toxicity (Toxicity Category IV), low vapor pressure (7.5 x 10 - 13 

### mm Hg), low Henry’s law constant (7.03 x 10 - 16 

### atm m 3 

### /mole), and the low proposed use rate. However, there are multiple potential sources of post

- application inhalation exposure to individuals 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, 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 as well as available post

- application inhalation exposure data generated by the ARTF and may, as appropriate, develop policies and procedures, to identify the need for and, subsequently, the way to incorporate occupational post

- application inhalatio n exposure into the Agency's risk assessments. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post

- application inhalation exposure assessment for topramezone.

Although a quantitative occu pational post

- application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commercial handlers. Handler exposure resulting from application of pesticides outdoors is likely to result in hig her exposure than post

- application exposure. Therefore, it is expected that these handler inhalation exposure estimates would be protective of most occupational post

- application inhalation exposure scenarios.

10.0 References

Memo, M. Clock

- Rust et al.

, D 319704 , 7/ 14/ 20 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/ 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. Wolf

, D 408687

, D401166, 01 / 29 / 30 13 , “ Drinking Water Exposure Assessment for a Proposed Increase of the maximum u se rate of Topramezone Frequency Herbicide (EPA Reg. No. 7969

- 281) for non

- cropland 2 

### uses, and Proposed New Use for Direct Applications to

2 For preemergence and post

- emergence weed control in Christmas tree, conifer, and hardwood plantations; field grown ornamental production; and non

- cropland areas such as railroad, utility, highway, and pipeline rights

- of

- way; highwayTopramezone Human

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Page 35 of 41 

### Aquatic Environments (Oasis Aquatic Herbicide, EPA File Symbol No. 7969

- GGO) ”

Memo, S. Levy, D 400310 , “ Topramezone. Acute and Chronic Aggregate Dietary (Food + Drinking Water) Exposure and Risk Assessment for the Section 3 Registration Action Uses on Non

- Crop Aquatic Sites and Increased Maximum Application Rates for Currently Registered Terrestrial Uses

. ”

Memo, K. Lo we, D388367 , 2/2/ 20 12 . “Topramezone: Occupational and Residential Exposure/Risk Assessment for Proposed Uses on Golf Courses, Sod Farms, and Residential Turfgrass.”

Memo, K. Rury, D400310, D404014 , 01/30/2013. “ Topramezone : Summary of Hazard and Science Policy Council (HASPOC) Meetings of December 6, 2012 and December 19, 2012: Reconsideration on the Need for a 28

- day Inhalation study.

Memo, T. Bloem, D400949, 2/26/2013. Topramezone. Section 3 Registration Concerning N on crop Aquatic

- Application. Summary of Analytical Chemistry and Residue Data.

Memo, T. Bloem, D 400948 , 2/26/2013. Topramezone. Section 3 Registration Concerning Application to Noncrop Aquatic and Noncrop Terrestrial Areas. Occupational and Residenti al Exposure and Risk Assessment.

guardrails, delineators, and sign posts; utility substations, petroleum tank farms, pumping installations, farmya rds and around farm buildings; fence rows, storage areas, airports, and non

- irrigation ditches

.Topramezone Human

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Page 36 of 41 

### 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

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Page 37 of 41 

### A.2 Toxicity Profiles

Table A.2.1. Acute Toxicity Profile on Topramezone

. OPPTS Guideline Study Type Results Toxicity Category
870.1100 Acute oral toxicity / rat LD50 2000 mg/kg (males and females) III
870.1200 Acute dermal toxicity / rat LD50 2000 mg/kg (males and females) III

870.1300 Acute inhalation toxicity /

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

870.2400 Primary eye irritation / rabbit Slight irritant III

870.2500 Primary dermal irritation / rabbit Slight irritant IV

870.2600 Dermal sensitization / guinea pig Non

- Sensitizer

--

Table A.2.2. Subchronic, Chronic, and Other Toxicity Profile for Topramezone

. Guideline No/ Study Type/ MRID Nos. Doses/Classification Results

870.3100 Subchronic Oral

- Rat 45902203, 45902204 (2001, 2003) (0, 15, 30 ppm) M:0, 1.1, 2.1 mg/kg/day F:0, 1.3, 2.5 mg/kg/day Acceptable/guideline Males: NOAEL =1.1 mg/kg/day, LOAEL = 2.1 mg/kg/day based on diffuse degeneration in the pancreas. Females: NOAEL = 2.1 mg/kg/day, the LOAEL was not established.

870.3100 Subchronic Oral

- Mouse 45902202 (2000) (0, 125, 1000, 8000 ppm) M: 0, 3 7, 288, 2289 mg/kg/day F: 0, 51, 406, 3010 mg/kg/day Acceptable/guideline NOAEL = 2289/3010 mg/kg/day (M/F). LOAEL = not established.

870.3150 Subchronic Oral

- Dog 45902205 (2002) (0, 3000, 9000, 25000 ppm) 0, 182, 535, 1511 mg/kg/day (M) 0, 205, 624, 1712 mg/kg/day(F) Acceptable/guideline Males: NOAEL = 535 mg/kg/day, and the LOAEL = 1511 mg/kg/day based on decreased body

- weight gain, impaired food efficiency, and inflammation of the urinary bladder. Females: NOAEL = 1712 mg/kg/day, the LOAEL for females is not established. 870.3200 28

- Day dermal toxicity

- Rat 45902206 (2002) 0, 100, 300, 1000 mg/kg/day Acceptable/Guideline Males: NOAEL = 100 mg/kg/day, the LOAEL = 300 mg/kg/day based on thyroid follicular cell hypertrophy. Females: NOAEL = 300 mg/kg/day, the LOAEL = 1000 mg/kg/day based on thyroid follicular cell hypertrophy. 870.3700a Prenatal developmental

- Rat 45902207 (2003) 0, 100, 300, 1000 mg/kg /day Acceptable/Guideline Maternal: NOAEL = not established, the LOAEL = 100 mg/kg/day based on decreased body

- weight gains. Developmental: NOAEL = not established, the LOAEL = 100 mg/kg/day based on decreased fetal body weight and increased incidences o f skeletal variation. 870.3700b Prenatal developmental

- NZW Rabbit 45902210 (2003) 0, 0.5, 5, 50, 450 mg/kg/day Acceptable/Guideline Maternal: NOAEL = not established, the LOAEL= 0.5 mg/kg/day based on increased serum tyrosine level. Developmental: NOAEL = 0.5 mg/kg/day, the LOAEL = 5 mg/kg/day based on alterations in skeletal ossification sites and increased number of pairs of ribs. 870.3700b Prenatal developmental

- NZW Rabbit 45902211 (2003) 0, 5, 50, 500 mg/kg/day Unacceptable/Guideline Matern al: 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

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Page 38 of 41 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 effe ct was observed for N17/CFR 3 at 0.5 mg/kg/day (the only dose tested). 870.3700b Prenatal developmental

- NZW Rabbit 46020301 (2003) 0, 5, 50, 450 mg/kg/day Acceptable/Guideline Maternal: NOAEL = 450 mg/kg/day. LOAEL not established. Developmental: NOAEL = not established

. LOAEL = 5 mg/kg/day based on visceral findings (fluid

- filled abdomen, pale liver, and dark content of the stomach and intestines) and alterations in skeletal development (i.e., incomplete ossification of the vertebrae and talus, and supernumerary thoracic vertebrae and 13th rib). 870.3700b Prenatal developmental

- Himalayan Rabbit 46020302 (2003) 0, 50, 150, 450 mg/kg/day Acceptable/Guideline Maternal: NOAEL = 150 mg/kg/day. LOAEL = 450 mg/kg/day based on decreased body weight body

- weight gains, food consumption and increased incidences of abortion and lack of defecation. No serum tyrosine level was measured. Developmental: NOAEL = not established. LOAEL = 50 mg/kg/day based on decreased fetal weight and increased an incidence of visceral malformati ons, 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. Deve lopmental: NOAEL = 0.5 mg/kg/day. LOAEL = 5 mg/kg/day based on increased presence of 27 pre

- sacral vertebrae and increased an incidence of full supernumerary 13th rib. 870.3700b Prenatal developmental

- Himalayan Rabbit 46020304 (2003) 0, 50, 150, 450 mg/kg/day Acceptable/Guideline Maternal: NOAEL=450 mg/kg/day. LOAEL= not established. Developmental: NOAEL = not established. LOAEL = 50 mg/kg/day based on an increased incidence of extra sternebral ossification sites and supernumerary 13th rib.
870 .3700a Prenatal developmental

- Mouse 45902208, 45902209 (2003) 0, 30, 200, 1000 mg/kg/day Acceptable/guideline Maternal: NOAEL = not established. LOAEL = 30 mg/kg/day based on increased serum tyrosine level. Developmental: NOAEL = 1000 mg/kg/day. L OAEL = 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 = not established Offspring: NOAEL = 0.4/0.5 mg/kg/day (M/F )

. LOAEL = 4.2/4.6 mg/kg/day (M/F) based on decreased pup weight and weight gain in F 2 male and female pups and increased time to preputial separation in the F 1 male s.Topramezone Human

- Health Risk Assessment DP# s 400310, 404014

Page 39 of 41 Table A.2.2. Subchronic, Chronic, and Other Toxicity Profile for Topramezone

. Guideline No/ Study Type/ MRID Nos. Doses/Classification Results

870.4300 Chronic toxicity

- Rat 45902217 (2002) (0, 6, 60, 600, 6000 ppm) M: 0, 0.4, 3.9, 42.0, 422.6 mg/kg/day F: 0, 0.5, 5.3, 53.2, 535.0 mg/kg/day Acceptable/guideline NOAEL = 0.4/0.5 mg/kg/day (M/F )

. LOAEL = 3.9/5.3 mg/kg/day (M/F) based on effects on the eyes consisting of opacity, pannus, and chronic keratitis of the cornea in both sexes. In addition, thyroid hypertrophy was noted in males.

870.4200a Carcinogenicity

- Rat 45902222 (2003) (0, 6, 60, 600, or 6000 ppm) M: 0, 0.4, 3.6, 36.4, 381.5 mg/kg/day F: 0, 0.5, 4.7, 50.8, 524.1 mg/kg/day Acceptable/Guideline NOAEL = 0.4/0.5 mg/kg/day (M/F )

. LOAEL = 3.6/4.7 mg/kg/day (M/F) based on increased incidences of corneal opacity, decreased body weight and body

- weight gains (males only) and histopathological evaluations in the thyroids, pancreas, and eyes of both sexes. Neoplastic pathology showed increased incidences of follicular cell adenomas in the thyroid glands of both sexes. 870.4100b Chronic toxicity

- Dog 45902215, 45902216 (2002) (0, 100, 500, 3000/2600, 9000/7800, 25000/22000 ppm). M: 0, 2.9, 15.3, 81, 248, 688 mg/kg/day F: 0, 3.1, 15.4, 92, 287, 780 mg/kg/day Acceptable/guideline For males, NOAEL = 2.9 mg/kg

. LOAEL = 15.3 mg/kg/day based on increased incidence of thyroid C

- cell hyperplasia. For females, NOAEL = 15.4 mg/kg/day

. LOAEL = 92 mg/kg/day based on decreased body weight, body

- weight gain and food efficiency.

870.4200b Carcinogenicity

- Mouse 459022 21 (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 le vel was measured. No treatment

- related tumors were demonstrated.

870.5100 Gene mutation Salmonella typhimurium 45902225 (1999) Acceptable/guideline No indication of a mutagenic response in any strain at any level up to cytotoxic concentrations either with or without S9 activation.

870.5100 Gene mutation Salmonella typhimurium 45902226 (2002) Acceptable/Guideline No indication of a mutagenic response in any strain at any level up to cytotoxic concentrations either with or without S9 activation.

870.5100 Gene mutation Salmonella typhimurium 45902227 (2002) Acceptable/Guideline No indication of a mutagenic response in any strain at any level up to cytotoxic concentrations either with or without S9 activation.

870.5100 Gene mutation Salmonella typhimurium 45902228 (2003) Acceptable/Guideline Based on these considerations, it was concluded that there was confirmed evidence of a mutagenic response in S. typhimurium TA98 in the non

- activated portion of both the plate incorporation and pre

- incubation assays. The effect was, however, observed at high concentrations ( 3000 μg/plate

– pl ate incorporation and 2500 μg/plate

– pre

- incubation). It was further concluded that the mutagenic effect was likely due to impurities in the test article because: 1) the response was seen at high concentrations including and exceeding the limit dose, 2) bacterial gene mutation assays conducted with other lots of the test material were negative up to the limit dose (see MRID Nos. 45902225 through 45902227, and 3) the ai used in the current study has the lowest percentage of purity (95.8% versus 97.7 to 99 .3% ai for the other lots). 870.5100 Gene mutation Salmonella typhimurium 45902229 (2001) Acceptable/Guideline No indication of a mutagenic response in any strain up to cytotoxic levels either with or without S9 activation.

870.5300 In vitro Mammalian Cell Gene Mutation 45902230 Acceptable/guideline No indication that topramezone induced a mutagenic response, either in the presence of absence of S9 activation.Topramezone Human

- Health Risk Assessment DP# s 400310, 404014

Page 40 of 41 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

- in duced a clastogenic response in the presence of S9 activation with significant effects recorded only at an insoluble limit concentration.

870.5395 In vivo Mouse Bone Morrow Micronucleus 45902234 (1999) Acceptable/guideline No evidence that topramezone was clastogenic or aneugenic.

870.5550 UDS 45902302 (1999) Acceptable/Guideline No evidence that topramezone

- induced UDS, as determined by radioactive tracer procedures [nuclear silver grain counts] at any concentration tested.
870.6200 Acute Neurotoxicity

- Rat 45902303 (2002) 0, 125, 500, 2000 mg/kg Acceptable/guideline NOAEL = 2000 mg/kg/day, no neurotoxicity observed.

870.6200 Subchronic neurotoxicity

- Rat 45902201 (2002) (0,60,600,6000 ppm) M: 0, 4.2, 43.8, 432.9 mg/kg/day F: 0, 5.0, 50.9, 510.1 mg/kg/day Acceptable/guideline No neurotoxicity observed. Systemic NOAEL = not established. LOAEL = 4.2/5/0 mg/kg/day (M/F) based on elevated levels of granular casts and transitional epithelial cells in the urinary sediment of the males, increased incide nces 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 dose was recovered within 48 hours in the feces (73

- 91% dose) and urine (8

- 29% dose). 870.7600 Rodent In Vivo Dermal Penetration Study

- Rat 45902307 (2002)

Doses 0, 0.004, 0.068, or 3.36 mg ai/cm2. The majority of the applied dose for each group was not absorbed (91.0

- 98.3% dose), with the greatest amount of the non

- absorbed material being recovered from the skin wash (90.8

- 96.0% dose). Absorbed radioactivit y was low and accounted for 0.16

- 2.60% of the dose for all groups for all exposures.Topramezone Human

- Health Risk Assessment DP# s 400310, 404014

Page 41 of 41 

### 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