T opramezone Hum an -H ealth Assessment Scoping Document 0425613



### UNITED STATES ENVIRONMENT AL PROTECTION AGENCY WASHINGTON, D .C. 20460

OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION



### MEMORANDUM

Dat e :

Subject: July IO, 20 1 5



### Top r amezone. Human-H ea lth Assess ment Scop ing Document in Support of R eg istrati o n R ev i ew

.



### PC Code : 1 23009 

### Deci s ion No.: 49992 1 

### Petition No

. : NA DP Barcode: D425613 

### R eg istration No.: NA 

### Regulatory Action: Registr a tion Review 

### Case No.: NA Risk A ssess m e nt T y pe: NA
TXR No.: NA CAS No.: 2 1 063 1-68-8 40 

### CFR: § 180 .6 12 

### MRID No.: NA

From:

Thru:



### To: Cass i L. Walls

, Ph.D.

, Senio r Biolog i st {l /i>v<

..

# Z~ Sa rah J. Levy

, C h e mi s t

### ~ Monique M. P e rron , Sc. D.

,**ox co** **o¥1f~** 

### Josh God s h a ll

, B i ologist 

# 5

Risk Assessment Branch 1 ( R AB 1 )
H ea lth Effec t s Divis i on ( H ED

, 7509 P ) /

------

Thurston G. Morton, Acting Br a n c h Ch i ef

# #J-~**~** George F. K r a m e r , Ph.D.

, Se ni or C h e mi s t RAB l /HED (7509 P )

J ose G ayoso, C h e mical R eview Manager R M IB 2/Pesticidc R e

- Evaluat i on D ivision ( PRO ) (7508 P ) Office of P es ti c id e P rograms

Attached i s H E D 's hum a n-h ea lth ri s k assessme nt sco pin g d oc um e nt fo r topram ez one ([3-(4

, 5- dihydro-3-isoxazo l yl)

- 2 -m et h y l-4- ( meth yls ul fo n y l ) phenyl] (S -h ydroxy -1-m et h y l- l H-p y razol-4- yl)met h anone) sub mitt ed in suppo rt of R eg i s tr a ti o n Re v i ew. To eva l uate th e scope of wo r k
necessary t o s upport R eg i s tr a ti on Re v ie w , H E D has cons i dered r ece nt risk assessments for topramezone, update s t o it s t ox i city, exposure a nd usage dat abases, an d t h e l a t es t Age nc y s ci e n ce policy and ri s k assess m e nt m et hod o lo g i es. T h e mo s t r ecent ri s k assess m e nt for topr a mezon e

was conducted in 2 013 for a new use on non- c r o p a qu atic s it es ( 0400310 and D404014

, C. Rodrigue z

. 05 / 30 / 20 1 3).

Pa g t: I of25Topramezone Hum a n-H ea lth Assessment Scoping Document 0425613



### Exec utiv e S umm ary

Topramezone is a pr e

- an d po s t-emergence herbicide u sed to control broad leaf weeds and
grasses b y inhibition of the e n zy me 4-hydroxyphenylpyruvate dioxygena se (HPPD) and b l ocks th e pathway of phenylquinone biosynthesis in p l ants. 

### lt i s current l y re g i ste red for u se on residential turf grass , golf cour ses, sod farms

, non-crop ornamenta l s , ri ghts-of

- way , tree pl a nt a tion s, aq uatic vege tati o n , a nd o th e r non- cro p areas , as we ll as for appl ic at i on t o corn (field

, pop , see d

, a nd sweet) w ith tolerances r ang in g fr o m 0

. 01 to 0.80 ppm ( 40 CF R 

### § 1 80.612).

The t ox icit y database for topr amezo n e is complete as r equi r ed by the 2007 re v i sed 40 CFR T ox i co lo gy Data R eq uir e m e nt s. No ad ditional t ox i co l og i ca l s tudie s are c urr e ntl y r equired. As part of Regi s tration Review, the e nd points, do ses

. a n d safe t y factors used in the most r ecent risk
assessment will be re-evaluated acco rding t o c urr e nt I-I ED policy.

The re s idue che mi stry databa se i s suffic i e nt to s upport the current r egistrations of lopramczone. The n at ur e of the r es idu e in th e re gis t e r ed prim ary crops a nd li vestock h as been adeq u a t e l y d efined

. Adeq uat e field trial / processing data

, s t orage s tabilit y data, rotat i onal c r o p data

, an d enfo r ceme nt method s are available.

New dietary expos ur e and aggregate ri sk assessme nt s a r e not a nticipat ed durin g R eg istr a ti o n Review

, unl ess the r e are significa nt increases t o the d rinkin g water exposure estimates that need

to be incorp ora t e d and / o r th e r e a re updat es to th e to x i c it y endpoints or safety facto r s

.

New residential handler and pos t- app li cat i on re s idential exposure an d ri sk assessme nt s arc not anticipated t o be ne eded durin g Re g i s tration R ev i ew unless the r e are 

### updates t o th e t ox i c it y

e ndp oints o r safety fac t ors

. Occupational handl e r and post

- application expos ur e an d ri s k

assessme nt s are 

### needed durin g Registration R eview l o account for recent ch an ges in exposu r e assessment ass umpti o n s, in cluding body weight

, a m ou nt treat ed, an d tran sfe r coefficients. as well as any updates t o th e t ox i c it y e ndp o int s or safe t y facto r s

.
Aggregate expos ur e t o topr a m ezo n e i s currently not of co nc e rn t o H E D. New agg re gate

assessme nt s a r e n ot an ticip a t ed to b e n eede d during R eg i strat i o n Re v i ew , unl ess th e re a r c changes in u ses

. procedures, d rinkin g wate r exposure e s timates

, toxicit y e ndpoint s, and/or safet y factors.

The Agency w i ll examine the need for sp ray drift and vo l at ili za ti on assessments during Regi stra tion Revi ew fo r topr a m ezo n e based o n the pot e ntial fo r ex po su r e to bystanders from
agr i cu ltur a l app lic at i o n s.

No d a ta d e fi c iencie s were id e ntified fo r topram ezo ne. H E D n o t es the fo ll ow in g ri sk assessment updat es may be ne eded during R eg i s tr a ti o n R ev i ew:

• Tox icolo gy: Endpoints, d oses, and safe ty factors u sed in th e m os t recent ri sk

assess m ent wi ll be re-evaluated accord in g t o cun-e nt I ! E D policy

• Residue Chemis t ry/Dietary Exposure: A r evised dietary-expo su re analys i s m ay be

r e quired t o r e flect s i g nificant changes to th e drinking water exposure es tim a t es , a n d/or updates to th e toxicity e ndp o int s o r safety fac t ors.

Pa ge 2 of25Topramezone Human

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Page 3 of 25 

###  Occupational/Residential Exposure: Residential handler and post

- application residential exposure and risk assessment may be updated to reflect changes in toxicity endpoints or safety factors. Updated occupational handler assessments will be required using current ORE policies as well as any changes to the toxicity endpoin ts or safety factors. Additiona lly, the need for spray drift and volatilization risk assessments will be examined during Registration Review.

 Aggregate Exposure: An updated aggregate assessment may be needed if there are changes in uses, procedures, drinking water exposure estimates, toxicity endpoints and/or safety factors.

1.0 Introduct ion

Topramezone is currently registered for weed post

- emergence application to aquatic areas/water, Christmas tree plantations, corn (field, pop, sweet, and seed)

, nonagricultural uncultivated areas/soil, nursery stock, and turf (sod farms, ornamental, go lf course, recreational, residential) ; for application to agricultural fallow/idle

- land/conservation reserve; and for post

- transplant application to forest trees (hardwood and broadleaf trees)

. Topramezone end use products are formulated as suspended c onc entrate s (SC)

. Applications can be made with ground, aerial, and hand held spray equipment. The most recent risk assessment for topramezone was conducted in 2013 for a new use on non

- crop aquatic sites (D 400310 and D404014

, C. Rodriguez, 05/30/2013 ). Refer to Attachment 1 for the chemical identity of topramezone. A summary of the use pattern s is provided in Attachment 6.

2.0 Hazard Identification/Toxicology

Topramezone is an i nhibitor of the enzyme HPPD and blo cks the pathway of ph enylquinone biosy nthesis in plants

. Topramezone has a structural and toxicological profile that is similar to mesotrione. For mesotrione, a wealth of mechanistic data are available both experimentally and in the literature which thoroughly characterize its molecular init iating event and adverse outcome pathway. In mammals, the amino acid tyrosine is catabolized by the tyrosine aminotransferase (TAT) enzyme to form the substrate 4

- hydroxyphenylpyruvic acid (HPPA), which is then further catabolized by the HPPD enzyme for e xcretion. Inhibition of HPPD leads to the build

- up of HPPA and this build

- up results in elevated levels of tyrosine in the blood (tyrosinemia). Tyrosinemia in laboratory animals results in ocular, developmental, liver, and kidney effects. TAT activity c an vary depending on the species; therefore, the degree of tyrosine accumulation differs among species. Alt hough extensive mechanistic data are not available for topramezone , there is strong evidence of tyrosinemia in its database including dose

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

Similar to other HPPD inhibiting chemicals, t he rat was the most sensitive species and males were found to be more sensitive than females ( in rats and d ogs )

. In rat subchronic and c hronic oral studies

, topramezone produced ocular (corneal vascularization, opacity, and keratitis) and kidney ( microscopic findings and increased organ weights) effects, which are consistent with the mammalian toxicity profile for HPPD inhibitors caused by high tyrosine levels in the blood. Histopathological findings in the thyroid were frequently observed in rats and dogs following topramezone exposure. T h yroid tumors via a non

- linear mode of action involving thyroid hormone disruption were seen in the rat ; however, topramezone is classified as “not likely to be carcinogenic to humans at doses that do not alter rat thyroid hormone homeostasis.” AdditionalTopramezone Human

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Page 4 of 25 

### histopathological findings were seen in the pancreas of rats and the u rinary bladder in dogs. Body weight decrements were also noted in all species , including the mouse

, which did not exhibit any other adverse effects in the database

.

There is evidence of increased prenatal susceptibility following in utero exposures to rats and rabbits. In rats and rabbits, fetal skeletal variations and abnormalities were observed in all developmental toxicity studies and are consistent with those reported in the toxicological databases for other HPPD inhibiting chemicals. No increased susceptibility was observed in the rat reproduction toxicity study. A developmental neurotoxicity study (DNT) in rats is also available for topramezone. Offspring effects included neurobehavioral and neuropathological changes while toxicity in maternal animals was limited to corneal opacity. Although these offspring effects are indicators of potential neurotoxicity, there were no effects seen in the acute neurotoxicity study (ACN) up to the limit dose and effects in the subchronic neurotoxicity study (S CN) were consistent with the rest of the database (ocular effects and histopathological findings in the pancreas and thyroid). In the mouse, elevated tyrosine blood levels were noted in maternal animals; however, there were no developmental effects observ ed.

Topramezone is classified as having low acute toxicity ( Toxicity Category II I or IV) via the oral, dermal, and inhalation routes). It was found to be a slight eye and dermal irritant, but it was not found to be a dermal sensitizer.

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

- health risk assessment for topramezone ( C. Rodriguez; 30

- MAY

- 2013; D400310 and D404014) can be found in Attachment 4. Since the last assessment, an acceptable immunotoxicity study in mice ha s been submitted and reviewed for topramezone with no effects seen up to the highest dose tested (1615 mg/kg/day). A subchronic inhalation toxicity study is not available for topramezone, as required in accordance with the current 40 CFR Part 158 Toxicolo gy Data Requirements; however, the Hazard and Science Policy Council (HASPOC) concluded, using a weight

- of

- evidence approach, that this study is not required for topramezone at this time ( K. Rury; 01/30/13 ; TXR 0056531 ).

Conclusions: The toxicity database for topramezone is complete as required by the 2007 revised 40 CFR Toxicology Data Requirements. No additional toxicological studies are c urrently required. As part of R egistration R eview, the endpoints, PODs

, and safety factors u sed in the most recent risk assessment will be re

- evaluated according to current HED policy.

3.0 Residue Chemistry/ Dietary Exposure

Tolerances are currently established under 40 CFR §180.612 for residues of topramezone, including its metabolites and degr adates. Compliance with the tolerance levels are to be determined by measuring only topramezone. Tolerances for corn commodities range from 0.01

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

- 0.80 ppm.

The qualitative nature of topramezon e residues in corn and ruminants is adequately understood based on acceptable corn and goat metabolism studies; an adequate confined rotational crop study has also been submitted . HED previously concluded that topramezone per se is the residue of concern, for purposes of tolerance enforcement and risk assessment, in corn, rotational crops, and ruminants. An adequate poultry metabolism study has also been submitted. Based on theseTopramezone Human

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Page 5 of 25 

### data and the current dietary burden, residues in poultry are expected to be negligible. HED indicated that if a future proposed use significantly increase s the poultry dietary burden, then a poultry feeding study, which monitors for residues of parent and metabolite M670H02, may be required. Adequate analytical enforcement meth ods are available. Additionally, adequate field trial, processing, and storage stability data are available.

Unrefined acute and c hronic aggregate dietary (food and drinking water) exposure and risk
assessments were conducted for topramezone using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM

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

- level residues, DEEM 7.81 default processing factors, and 100% crop treated (%CT) for all registered commodities (S. Levy, 05/15/13 ; D400947). The drinking water residues used in the dietary risk assessment were provided by the Environmental Fate and Effects Division (E FED) (J. Wolf, 01/29/13 ; D 408687) and incorporated directly into the acute and chronic dietary assessments. The highest topramezone estimated drin king water concentrations ( EDWC ) is expected to result from the direct aquatic applications. The EDWCs were based on the registered use for water bodies with functional potable water intakes , which cannot exceed 45 ppb

. The acute and chronic dietary as sessments show that the acute and chronic dietary risk estimates are below HED’s level of concern (i.e., <100% of the acute or chronic population adjusted doses (aPAD or cPAD). The acute dietary risk estimate for females 13

- 49 years old at the 95 th


### percen tile of exposure was 50 % of the aPAD. For the general US population and the most high ly exposed population subgroup ( all infants <1 year old) , the risk for food and drinking water utilized 32% and 98% of the aPAD, respectively. For the general US populat ion, the risk for foo d and drinking water utilized 25 % of the cPAD. The chronic dietary risk estimate for the highest reported exposed population subgroup, all infants <1 year old , utilized 62 % of the cPAD.

Conclusions: The residue chemistry and dietary

- exposure database is adequate to support current registration requirements. No additional data are required at this time. In the most recent risk assessment, acute and chronic dietary exposures were not of concern to HED. Therefore, a new dietar y exposure assessment is not anticipated to be needed during Registration Review unless there are significant increases to the drinking water exposure estimates and/or there are updates to the toxicity endpoints or safety factors

.

4.0 Residential Exposure

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

course s , recreational, residential ) and aquatic areas/water (ponds, lakes, reservoirs, and shoreline)

. There is potential for short

- term re sidential exposure t o topramezone during handling (mixing, loading, and applying) and post

- application activities.

Residential Handlers Since topramezone is not a restricted

- use pesticide (RUP) a residential handler exposure
assessment was previously performed ( D388367

, K. Lowe, 02/02/12 ). Spot or broadcast

a pplications can be made using ha ndheld spray equipment to turf

. The residential handlerTopramezone Human

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Page 6 of 25 

### assessment was only conducted resulting in total (dermal + inhalation) margins of exposure (MOEs) ranging from 1,800 to 3,9 00 a nd are not of concern (MOE > 100)

.

Residential Post

- Application Short

- term dermal and incidental oral exposure and risk estimates wer e assessed using the 2012 Residen tial Standard Operating Procedures ( SOPs ) in the latest topramezone occupational and residential exposure ( ORE ) assessments ( D388367

, K. Lowe, 02 /02/1 2 and D400310/D404014, C. Rodriguez, 05/30/13 )

. These assessments considered post

- application exposures to treated turf and aquatic environments. A turf transferrable residue (TTR) study ha s been submitted, reviewed, and found to be acceptable for risk assessment (MRID 48379401). These data were incorporated into the most

- recent post

- application exposure assessment to treated turf in place of default assumptions for residue transfer.

Post

- application MOEs were not of concern ( MOEs >100) for any of the registere d residential uses of topramezone . The short

- term adult dermal pos t

- application MOEs range from 48 0 to 9,100 ,000. The short

- term combined incidental oral and dermal MOE for chi ldren 1 to <2 years old is 210

. Spray Drift or Volatilization Residential bystander exposures resulting from off

- site transport (e.g., spray drift or volatilization) may occur as a result of applications of topramezone . The potential for spray drift wi ll be evaluated for each pesticide during the Registration Review process which ensures that all uses for that pesticide will be considered concurrently. The approach is outlined in the revised (2012) Standard Operating Procedures for Residential Risk Ass essment (SOPs)

– Residential Exposure Assessment Standard Operating Procedures Addenda 1: Consideration of Spray Drift. This document outlines the quantification of indirect non

- occupational exposure to drift. In terms of volatilization, the agency has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis ( http://www.regulations.gov/#!docketDetail;D=EPA

- HQ

- OPP

- 2014

- 0219 ). During R egistration Review, the agency will utilize this analysis to determine if data (i.e., flux studies, route

- specific inhalation toxicological studies) or further analysis is required for topramezone

.

Conclusions : The registere d residential uses of topramezone have been assessed using the maximum application rates and revised 2012 Residential SOPs. New residential handler and post

- application residential exposure and risk assessments are not anticipated to be needed during Registration Review unless there are updates to the toxicity endpoints or safety factors. Further , the Agency will examine the need for a volatilization assessment, as well as evaluate the potential topramezone exposure from spray drift during Registration Review.

5.0 Aggregate R isk Assessment

Aggregate assessments consider exposures from food, drinking water, and residential uses. Since there are residential uses of topramezone , aggregate risk consi der s residential handler and post

- application exposures, food

, and drinking wate r

.

In the most recent human health risk assessment (D 400310 and D40414

, C. Rodr i guez , 0 5 / 30 /20 13 ), an acute aggregate risk assessment, which is equivalent to the acute dietary risk assessment, was not of concern to HED. Chronic exposure from the resident ial pathway is notTopramezone Human

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Page 7 of 25 

### anticipated based on the current topramezone use pattern. Therefore, the chronic aggregate risk (food and drinking water) is equivalent to the chronic dietary (food and drinking water) exposure estimate , which was not of concern to HED. An aggregate cancer risk assessment was not performed since topramezone is classified as “ not likely to be carcinogenic to humans at doses that do not alter rat thyroid hormone homeostasis”.

A short

- term aggregate risk assessment was conducted for adults and children. For adults, the pathways assessed for aggregate exposure include oral dietary (background), and post

application dermal (primary) routes. For children, the pathways assessed for aggregate exposure include oral die tary (background), incidental oral, and dermal (primary) routes from post

application exposure . The adult and children short

- term aggregate dietary and residential MOEs are 220 and 12 0, respectively (LOC = 100).

Conclusions : Aggregate exposure to topra mezone is currently not of concern to HED. N ew aggregate assessments are not anticipated to be needed during Registration Review, unless there

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

.

6.0 Occupational Exposure

Topramezone is registered for weed control in post

- emergence application to aquatic areas/water, Christmas tree plantations, corn (field, pop, sweet, and seed), nonagricultural uncultivated areas/soil, nursery stock, and turf (sod farms, ornamental, golf course, recreational, residential) ; for fallow application to agricultural fallow/idle

- land/conservation reserve; and for post

transplant application to forest trees (hardwood and broadleaf trees). There is potential for short

and intermediate

- term occupational exposure to topramezone during handling (mixing, loading, and applying) and post

- application activities.

Occupational Handlers The registered topramezone labels require occupational handlers to wear long sleeved shirt s , long pants, shoes, socks, chemical resistant gloves , and in some cases goggles, face shield, or safety glasses . Applications can be made using ground, aerial, and handheld spray equipment. Mixer/loaders supporting aerial applications to aquatic areas a re required to employ closed systems. T he updated occupational exposure assessment policies and body weight assumptions were incor porated into the non

- crop terrestrial, aquatic, and turf topramezone exposure assessments, however updated assessments will be needed for occ upational handlers of topramezone for the treatment of corn and all exposure scenarios if there are changes in the toxicity endpoints or safety factors

. All current occupational handler MOEs are not of concern (MOE > 100).

Occupational P ost

- Application Occupational post

- application short

- and intermediate

- term dermal exposures are possible for workers contacting treated crops. Although the MOEs in the most recent occupational post

application exposure assessment for corn are not of conce rn (MOE > 100), it did not incorporate updated exposure assessment policies utilizing changes in transfer coefficients and body weight assumptions ( M. Dow, D317065, 05/09/05 ) . Therefore, an updated occupational post

application exposure assessment will be required during Registration Review for the topramezone use on corn and all exposure scenarios if there are changes in the toxicity endpointsTopramezone Human

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Page 8 of 25 

### or safety factors

. Dislodgeable Foliar Residue (DFR): In accordance with 40CFR § 158, DFR data are required for all occupational (e.g., crop, nursery, greenhouse use sites) or residential (e.g., ornamental and vegetable gardens, pick your own farms, retail tree farms) uses that could result in post

application exposure to foliage. In the absence of chemical

- sp ecific DFR data, EPA uses default values. The 2012 Standard Operating Procedures for Residential Pesticide Exposure Assessment includes an analysis of a number of DFR studies, which resulted in the selection of a revised default values for the fraction of the application rate available for transfer after a foliar application (F AR 

### ). These values are based on an analysis of 19 DFR studies. Since that time, the Agricultural Re

- entry Task Force (ARTF) has submitted information (MRID 49299201) that
corrects an application rate error made in the original submission of “ARF039

– Determination of Dermal and Inhalation Exposure to Reentry Workers During Chrysanthemum Pinching in a Greenhouse” (EPA MRID 45344501). As a result, the range of F AR 

### values was revised from 2%

- 89% to 2%

- 47%. In the data, a large range of transferability is observed and this variability can potentially be attributable to many factors such as active ingredient; formulation; field conditions in the studies; weather conditions (e.g., hu midity); or many other difficult to quantify factors. Although witnessed across multiple chemicals, this range in F AR 

### values is not expected when considering DFR data for a single chemical. At this time, the ARTF submission did not alter the selection of 25% as the reasonable, high

- end default value. Because DFR data are not available for topramezone EPA is using the default value of 25%. Although there may be a small degree of uncertainty in the use of the default DFR value for topramezone (i.e., there is a small chance that the F AR 

### value may exceed the applicable default value ), it is likely that the health

- protective aspects of EPA’s occupational post

- application assessment methodology will more than compensate for this potential uncertainty. For exa mple, when assessing residential and occupational post

- application exposure to gardens and ornamentals, EPA assumes the following: exposures occur to zero

- day (i.e., day of application ) residues every day of the assessed exposure duration (i.e., EPA as sumes that no dissipation or degradation occurs, it doesn’t rain, etc); individuals perform the same post

- application activities performed in the transfer coefficient study day after day (e.g., weeding, harvesting, pruning, etc.); and individuals engage in these post

- application activities for a high

- end amount of time every day (represented by data reflecting time spent gardening based on survey data).

Given the conservatisms discussed above and the potential compounding nature of these conservatisms, EPA is able to rely upon the calculated exposure estimates with confidence that exposure is not being underestimated. Therefore, DFR studies are not anticipated to be needed at this time.

Conclusions : There is sufficient information available to assess occupational handler and post

application exposures. There is an acceptable TTR study available to evaluate the post

application exposure to topramezone on turf

. Updated occupational handler and post

- a ppl ication exposure assessments will be conducted during Registration Review for topramezone use on

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

. Based on existing and anticipated occupational post

- appli cation risk estimates and the current toxicological PODs, DFR studies are not anticipated to be needed at this time

.

7.0 Public Health and Pesticide Epidemiology DataTopramezone Human

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### Based on the low frequency and severity of incident cases reported for t op r amezone in both the OPP Incident Data System (IDS) and the Centers for Disease Control and Prevention/National Institute for Occupational Safety and Health (CDC/NIOSH) Sentinel Event Notification System for Occupational Risk

- Pesticides (SENSOR), there does not ap pear to be a concern at this time that would warrant further investigation

. For the Main IDS, from January 1, 2010 to February 4, 2015, there were zero incidents reported for the single chemical only in the database. In Aggregate IDS, fr om January 1, 2010 t o February 4, 2015, there were three inciden ts reported involving t op r amezone . These incidents were classified as minor severity. Overall, there are few incidents involving t op r amezone reported to IDS.

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

- Pesticides database for 1998

- 2011 identified zero cases involving t op r amezone

.

The Agricultural Health Study (AHS) is a high quality

, prospective epidemiology study evaluating the link between pesticide use and vari ous health outcomes including cancer. The AHS includes private and commercial pesticide applicators and their spouses

. If there are AHS findings relevant to a particular pesticide going through registration review, the Agency will ensure they are considered in the problem formulation/scoping phase of the process and, if appropriate, fully reviewed in the risk assessment phase of the process

. The AHS includes information on use of 50 different pesticide active ingredients commonly used in agricultu re. T op r amezone is not included in the AHS, and therefore, this study does not provide information for this report.

The Agency will continue to monitor the incident information and if a concern is triggered, additional analysis will be included in the ri sk assessment.

Conclusion s : Based on the low frequency and low severity of incident cases reported for
t op r amezone in both IDS and SENSOR

- Pesticides databases , there does not appear to be a concern at this time that would warrant further investigation. T he Agency will continue to monitor the incident information and if a concern is triggered, additional analysis will be included in the risk assessment.

8.0 Tolerance Assessment and International Harmonization

U.S. permanent tolerances (listed in 40 CFR § 180. 612 ) and Canadian, Codex, and Mexican maximum residue limits (MRLs) are summarized in Attachment 3

.

Conclusions : Residue definitions and MRLs for topramezone have not been established by Codex o r Mexican maximum residue limits (MRLs) (see Attachment 3)

. Canada has established MRLs for residues of topramezone per se in/on the following: corn, liver (cattle, goat, horses, and sheep)

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

- 0.05 ppm; and hog meat byproducts

- 0.05 pp m. Harmonization of tolerances/MRLs for residues of topramezone in/on livestock commodities was not considered previously because the Canadian MRLs are too low to permit harmonization. As part of Registration Review, the international MRLs will be revalu ated and tolerances harmonized when possible.

9.0 Environmental JusticeTopramezone Human

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Page 10 of 25 

### Potential areas of environmental justice concerns, to the extent possible , w ill be considered in th e registration review , in accordance with US Executive Order 12898 , "Federal Acti ons to Address Environmental Justice in Minority Populations and Low

- Income Populations," ( http://www.epa.gov/compliance/environmentaljustice/resources/policy/exec_order_12898.pdf ). As a part of every pesticide risk assessment, OPP considers a large varie ty of consumer subgroups according to well

- established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in an d around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled under the NHANES/WWEIA and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based on age and ethnic group. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropri ate, non

- dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas post

- application are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups

.

10.0 Cumulative

There are marked differences among species in the ocular toxicity associated with inhibition of HPPD. Ocular effects following treatment with HPPD inhibitor herbicides are seen in the rat but not in the mouse. Monkeys also seem to be recalcitrant to the ocular toxicity induced by HPPD inhibition. One explanation for this species

- specific response in ocular opacity may be related to species differences in the clearance of tyrosine. A metabolic pathway exists to remove tyrosine from the blood that involve s the liver enzyme TAT. In contrast to rats where ocular toxicity is observed following exposure to HPPD

- inhibiting herbicides, mice and humans are unlikely to achieve the levels of plasma tyrosine necessary to produce ocular opacities because the activit y of TAT in these species is much greater compared to rats.

HPPD inhibitors (e.g., nitisinone) are used as an effective therapeutic agent to treat patients suffering from rare genetic diseases of tyrosine catabolism. Treatment starts in childhood but is often sustained throughout patient’s lifetime. The human experience indicates that a therapeutic dose (1 mg/kg/day dose) of nitisinone has an excellent safety record in infants, children, and adults and that serious adverse health outcomes have not been observed in a population followed for approximately a decade. Rarely, ocular effects are seen in patients with high plasma tyrosine levels; however, these effects are transient and can be readily reversed upon adherence to a restricted protein diet. This observation indicates that an HPPD inhibitor in it and of itself cannot easily overwhelm the tyrosine

- clearance mechanism in humans.

Therefore, exposures to environmental residues of HPPD

- inhibiting herbicides are unlikely to result in the high blood le vels of tyrosine and ocular toxicity in humans due to an efficient metabolic process to handle excess tyrosine. The Agency continues to study the complex relationships between elevated tyrosine levels and biological effects in various species. In the fut ure, assessments of HPPD

- inhibiting herbicides may consider more appropriate models andTopramezone Human

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Page 11 of 25 

### cross species extrapolation methods. Therefore, EPA has not conducted cumulative risk assessment with other HPPD inhibitors.

11.0 Human Studies

The risk assessments which have been previously conducted for topramezone rel ied in part on data from studies in which adult human subjects were intentionally exposed to a pesticide to determine their dermal and inhalation exposure. Many such studies, involving exposure to m any different pesticides, comprise generic pesticide exposure databases such as the Pesticide Ha ndlers Exposure Database (PHED), the Outdoor Residential Exposure Task Force (ORETF), and the ARTF Database

. EPA has reviewed all the studies supporting these multi

- pesticide generic exposure databases, and has found no clear and convincing evidence that the conduct of any of them was either fundamentally unethical or significantly deficient relative to the ethical standards prevailing at the time the research w as conducted. A ll applicable requirements of EPA’s Rule for the Protection of Human Subjects of Research (40 CFR Part 26) have been satisfied , and t here is no regulatory barrier to continued reliance on these studies

.

12.0 Data Deficiencies

No toxicologi cal data, residue chemistry, or occupational and residential exposure data are needed to support the registered uses of topramezone at this time. HED notes the following risk assessment updates may be needed during Registration Review:

 Toxicology: E ndpo ints, doses

, and safety factors used in the most recent risk assessment will be re

- evaluated according to current HED policy

 Residue Chemistry/Dietary Exposure: A revised dietary

- exposure analysis may be required to reflect significant changes to the drin king water exposure estimates and/or updates to the toxicity endpoints or safety factors.

 Occupational/Residential Exposure: Residential handler and post

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

e ndpoints or safety factors. Updated occupational handler assessments will be required using current ORE policies as well as any changes to the toxicity endpoints or safety factors. Add itiona lly, the need for spray drift and volatilization risk
assessment s will be examined during Registration Review.

 Aggregate Exposure: An updated aggregate assessment may be needed if there are changes in uses, procedures, drinking water exposure estimates, toxicity endpoints and/or safety factors.

References

Recent Memoranda Relevant to Registration Review of Topramezone

Author DP/TXR # Date Title

Risk Assessment C . Rodriguez D400310,

D404014 05/30/13 Topramezone: Human

- Health Risk Assessment for (1) New Uses in Non

- Crop Aquatic Sites and (2) Increased Maximum Application Rate for Currently Registered Terrestrial Uses in the Maintenance of Bare Grounds (Roadsides, Utility and Railroad Rights

- of

- Ways, Industrial Sit es, and Tank Farms).Topramezone Human

- Health Assessment Scoping Document D425613

Page 12 of 25 Recent Memoranda Relevant to Registration Review of Topramezone

Author DP/TXR # Date Title

K. Lowe D388367 02/02/12 Topramezone: Human

- Health Risk Assessment for Proposed Uses on Golf Courses, Sod Farms, and Residential Turfgrass. Residue Chemistry T. Bloem D400949 02/26/13 Topramezone. Section 3 Registration Concerning Noncrop Aquatic

- Application. Summary of Analytical Chemistry and Residue Data G. Kramer D310772 05/11/05 Topramezone (BAS 670 H) Acute and Chronic Dietary Exposure Assessments for a Petition for Tolerances on Corn Dietary Exposure Assessment S. Levy D400947 05/15/13 Topramezone. Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments for the Section 3 Registration Action Concerning Non

- crop Aquatic Application. S. Levy D388806 06/06/12 Topramezone. Acute and Chronic Aggregate Dietary (Food + Drinking Water) Exposure and Risk Assessment for the Section 3 Registration Action Uses on Golf Courses, Sod Farms, and Residential Turfgrass. G. Kramer D314719 05/09/02 Topramezone (BAS 670 H) Acute and Chronic Dietary Exposure Assessments for a Petition for Tolerances on Corn Occupational and Residential Exposure Assessment T. Bloem D4 00948 02/26/13 Topramezone. Section 3 Registration Concerning Application to Noncrop Aquatic and Noncrop Terrestrial Areas. Occupational and Residential Exposure and Risk Assessment. K. Lowe D388807 02/02/12 Topramezone: Occupational and Residential Exposure/Risk Assessment for Proposed Uses on Golf Courses, Sod Farms, and Residential Turf grass. M. Dow D317065 05/09/05 TOPRAMEZONE (BAS 670 H )

- Exposure/Ris k Assessment for the Proposed Use of Topramezone On Corn (Field, Pop, Seed and Sweet) Incident Report E. Evans 03/01/15 Topramezone : Tier I Review of Human Incidents Toxicology K. Rury TXR 0056531 01/30/13 Topramezone : Summary of Hazard and Science Policy Council (HASPOC) Meetings of December 6, 2012 and December 19, 2012: Reconsideration on the Need for a 28

- day Inhalation StudyTopramezone Human

- Health Assessment Scoping Document D425613

Page 13 of 25 

### Attachments 1. Chemical Identity Table 2. Physicochemical Properties of Technical Grade Topramezone Table 3. Tolerance/MRL Summary Table 4 . Endpoint Selection Table s 5 . Toxicity Profile Tables 6. Summary of Use ProfileTopramezone Human

- Health Assessment Scoping Document D425613

Page 14 of 25 

### Attachment 1

Chemical Identity Table

Topramezone Nomenclature.

Structure

Common name topramezone Company experimental name BAS 670 H

IUPAC name [3

- (4,5

- dihydro

- 1,2

- oxazol

- 3

- yl)

- 4

- mesyl

- o

- tolyl](5

- hydroxy

- 1

- methyl

- 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 concentrateTopramezone Human

- Health Assessment Scoping Document D425613

Page 15 of 25 

### Attachment 2

Physicochemical Properti es of Technical Grade Topramezone Table

Physicochemical Properties of Physicochemical Properties of Topramezone

. Melting point/range 220.9°C

- 222.2°C

http://toxnet.nlm.nih.gov/cgi

bin/sis/search/a?dbs+hsdb:@term+ @DOCNO+7500 pH 2.9 (1% de

- ionized water) Density (20°C) 1.425 g/cm 3 Water solubility (20°C) 510 mg/L at pH 3.1; >100 g/L at pH >9

Solvent solubility (g/100 ml at 20°C) Acetone <1.0; Acetonitrile <1.0; Dichloromethane 2.5

- 2.9; N,N

- dimethylformamide 11.4

- 13.3; Ethyl acetate < 1.0; N

- Heptane <1.0; Methanol <1.0; 1

- Octanol <1.0; Olive oil <1.0; 2

- Propanol <1.0; Toluene <1.0 Vapor pressure ( 20°C) 7.5 x 10

- 13 mm Hg Dissociation constant (pK a ; 20°C) 4.06 Octanol/water partition coefficient (Log K OW; 20°C ) pH 4:

- 0.81; pH 7:

- 1.52; pH 9:

- 2.34 UV/visible absorption spectrum ( ξ, mol

- 1 cm - 1 ) alphamax = 207 nmTopramezone Human

- Health Assessment Scoping Document D425613

Page 16 of 25 

### Attachment 3 Tolerance/MRL Tabl es

Summary of U.S. To lerances and International MRLs U.S. Canada Mexico 1 Codex Residue Definition: 40 CFR § 180.612 (a) General. Tolerances are established for residues of the herbicide topramezone, including its metabolites and degradates, in or on the following commodities. Compliance with the following tolerance levels is to be determined by measuring only topramezone ([3

- (4,5

- dihydro

- 3

- isoxazolyl)

- 2

- methyl

- 4

- (methylsulfonyl)phenyl](5

- hydroxy

- 1

- meth yl

1 H

- pyrazol

- 4

- yl)methanone) [3

- (4,5

- dihydro

- 3

- isoxazolyl)

- 2

- methyl

- 4

- (methylsulfonyl)phenyl](5

- hydroxy

- 1

- methyl

- 1 H

pyrazol

- 4

- yl)methanone None

Commodity Tolerance (ppm)/Maximum Residue Limit (mg/kg) Commodity U.S. Canada Mexico 1 Codex Cattle, meat byproducts 0.80 0.05 (except liver) 0.15 liver of cattle Corn, field, forage 0.05 Corn, field, grain 0.01 0.01 Corn, field, stover 0.05 Corn, pop, grain 0.01 Corn, pop, stover 0.05 Corn, sweet, forage 0.05 Corn, sweet, kernel plus cob with husks removed 0.01 0.01 Corn, sweet, stover 0.05 Fish

- freshwater finfish 0.05 Fish

- saltwater finfish 0.05 Fish

- shellfish, crustacean 0.05 Fish, shellfish, mollusk 0.05 Goat, meat byproducts 0.80 0.05 (except liver) 0.15 liver of goats Hog, meat byproducts 0.40 0.05 Horse, meat byproducts 0.80 0.05 (except liver) 0.15 liver of horses Poultry, meat byproducts 0.02 Sheep, meat byproducts 0.80 0.05 (except liver) 0.15 liver of sheep

Fat of cattle 0.05 Fat of goats 0.05 Fat of hogs 0.05 Fat of horses 0.05 Fat of sheep 0.05 Meat of cattle 0.01 Meat of goats 0.01 Meat of hogs 0.01 Meat of horses 0.01 Meat of sheep 0.01 Milk 0.01 Completed by: M. Negussie; 06/22/15

1 Mexico defers to US tolerances and/or Codex MRLs for its export purposes.Topramezone Human

- Health Assessment Scoping Document D425613

Page 17 of 25 

### Attachment 4

Endpoint Selection Tables

Summary of Toxicology Endpoints and PODs for Topramezone in Dietary and Non

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

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

- and intra

species extrapolation)

FQPA SF = 10X

aRfD = 0.0 8 mg/kg bw aPAD = 0.00 8 mg/kg bw Developmental Neurotoxicity Study in Rats

Offspring LOAEL = 8 mg/kg bw based on decreased maximum au ditory 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, decreased body weight and body

- weig ht 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 Assessment Scoping Document D425613

Page 18 of 25 Summary of Toxicology Endpoints and PODs for Topramezone in Dietary and Non

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

Short

- and Intermediate

Term Inhalation Oral NOAEL = 0.4

mg/kg/day

(inhala tion absorption = 100%) Residential LOC for MOE = 100 Two Generation Reproduction Study in

Rats

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

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

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

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

- linear mode of action and the NOAEL (0.4 mg/kg/ day) established for deriving the cRfD is not expected to alter thyroid hormone homeostasis nor result in thyroid tumor formation. Point of departure (POD) = A data point or an estimated point that is derived from observed dose

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no

- observed adverse

- effect level. LOAEL = lowest

- observed adverse

- effect level. UF = uncertainty factor. FQPA SF = FQPA Safety Factor. PAD = population

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

Summary of Toxicology Endpoints and PODs for Topramezone in Occupational Risk Assessment.
Exposure Scenario Dose Used in Risk

Assessment, UF FQPA SF and LOC for Risk Assessment Study and Toxicological Effects

Short

- and 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 o f both sexes, and microscopic findings in eyes, kidney and thyroid of both

sexes.

Cancer (Oral, dermal, inhalation) In accordance with the 2005 EPA Guidelines for Carcinogen Risk assessment, topramezone was classified as “not likely to be carcinogenic to humans at doses that do not alter rat thyroid hormone homeostasis.” The CARC determined that the thyroid tumors arise through a non

- linear mode of action and the NOAEL (0.4 mg/kg/day) established for deriving the cRfD is not expected to alter thyroid hor mone homeostasis nor result in thyroid tumor formation. Point of departure (POD) = A data point or an estimated point that is derived from observed dose

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no

- observed adverse

- effect level. LOAEL = lowest

- observed adverse

- effect level. UF = uncertainty factor. FQPA SF = FQPA Safety Factor. MOE = margin of exposure. LOC = level of concern.Topramezone Human

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Page 19 of 25 

### Attachment 5

Toxicity Profile for Topramezone

Acute Toxicity Profile on Topramezone

. OPPTS Guideline Study Type Results Toxicity Category

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

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

870.1300 Acute inhalation toxicity /
rat LC50  5.05 mg/L (males and females) IV

870.2400 Primary eye irritation / rabbit Slight irritant III

870.2500 Primary dermal irritation / rabbit Slight irritant IV

870.2600 Dermal sensitization / guinea pig Non

- Sensitizer

--

Subchronic, Chronic, and Other Toxicity Profile for Topramezone

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

870.3100 Subchronic Oral

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

870.3100 Subchronic Oral

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

870.3150 Subchronic Oral

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

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

870.3200 28

- Day dermal toxicity

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

870.3700a Prenatal developmental

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

- weight gains. Developmental: NOAEL = not established, the LOAEL = 100 mg/kg/day based on decreased fetal body weight and increased incidences 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

- Health Assessment Scoping Document D425613

Page 20 of 25 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 establishe d. Developmental: NOAEL = not established, the LOAEL for N33 and N17/CFR 1

- 2 was 1.5 mg/kg/day based on increased presence of supernumerary thoracic vertebrae and supernumerary 13th rib. No effect was observed for N17/CFR 3 at 0.5 mg/kg/day (the only do se 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. Developmental: NOAEL = 0.5 mg/kg/day. LOAEL = 5 mg/kg/day based on increased presence of 27 pre

- sacral vertebrae and increased an incidence of full supernumerary 13th rib.

870.3700b Prenatal developmental

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

870.3700a Prenatal developmental

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

870.3800 Reproduction and fertility effects

- Rat 45902214 (2003) (0, 4, 40, 400, 4000 ppm) M: 0, 0.4, 4.2, 42.2, 426.8 mg/kg/day F: 0, 0.5, 4.6, 46.9, 471.9 mg/kg/day Acceptable/guideline Parental/system: NOAEL = 0.4/0.5 mg/kg/day (M/F)

. LOAEL = 4.2/4.6 mg/kg/day (M/F) based on decreased body weight, 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 Assessment Scoping Document D425613

Page 21 of 25 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 ef fects 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 his topathological 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.

870.5 100 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

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

– plate incorporation and  2500 μg/plate

– pre

- incubation). It was further concluded that the mutagenic effect was likely due to impurities in the test article because: 1) the response was seen at high concentrations including and exceeding the limit dose, 2) bacterial gene mutation assays conducted with other lots of the test material were negative up to the limit dose (see MRID Nos. 45902225 through 45902227, and 3) the ai used in the current study has the lowest percentage of purity (95.8% versus 97.7 to 99.3% ai for the other lots). 870.5100 Gene mutation Salmonella typhimurium 45902229 (2001) Acceptable/Guideline No indication of a mutagenic response in any strain up t o cytotoxic levels either with or without S9 activation.

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

- Health Assessment Scoping Document D425613

Page 22 of 25 Subchronic, Chronic, and Other Toxicity Profile for Topramezone

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

870.5375 In vitro Mammalian Chromosome Aberration 45902233 (2002) Acceptable/guideline Topramezone

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

870.5375 In vi tro Mammalian Chromosome Aberration 45902232 (1999) Acceptable/guideline Topramezone

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

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

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

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

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

870.6200 Subchronic neurotoxicity

- Rat 45902201 (2002) (0,60,600,6000 ppm) M: 0, 4.2, 43.8, 432.9 mg/kg/day F: 0, 5.0, 50.9, 510.1 mg/kg/day Acceptable/guideline No neurotoxicity observed. Systemic NOAEL = not established. LOAEL = 4.2/5/0 mg/kg/day (M/F) based on elevated levels of granular casts and transitional epithelial cells in the urinary sediment of the males, increased incidences of corneal clouding in females, minimal diffuse degeneration of the pancreas (both sexes), and slight to moderate flaky colloid in the thyroid of the males. 870.6300 Developmental Neurotoxicity

- Rat 45902304 (2003) 0, 8, 80, 800 mg/kg/day Acceptable/Non

- guideline Maternal: NOAEL = not established. LOAEL = 8 mg/kg/day based on corneal opacities. Offspring: NOAEL = not established. LOAEL = 8 mg/kg/day base d on decreased a uditory startle reflex
response.

870.7485 Metabolism 45902305, 45902306 (2002) 1, 100, 200, 400, 500 mg/kg Acceptable/Guideline Absorption of [ 14 C]

- topramezone following a single oral dose was rapid but limited, with the highest plasma concentrations observed at 1 hour (first time point measured). Oral absorption is estimated to be approximately 20% of the administered dose. The majority of the d ose was recovered within 48 hours in the feces (73

- 91% dose) and urine (8

- 29% dose).

870.7600 Rodent In Vivo Dermal Penetration Study

- Rat 45902307 (2002)

Doses 0, 0.004, 0.068, or 3.36 mg ai/cm2. The majority of the applied dose for each group was no t absorbed (91.0

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

- absorbed material being recovered from the skin wash (90.8

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

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

870.7800

Immunotoxicity

- Mice 49365101 (2011) 0, 168, 523, or 1615 mg/kg/day Acceptable/guideline Systemic NOAEL = 1615 mg/kg/day. Systemic LOAEL = not established.

Immunotoxicity NOAEL = 1615 mg/kg/day. Immunotoxicity LOAEL = not established.Topramezone Human

- Health Assessment Scoping Document D425613

Page 23 of 25 

### Summary of Use Profile

Summary of Application Scenarios. App. Timing; Type; and Equip. Formulation

(EPA Reg. No.) App. Rate Max. #. App. per Season Max. Seasonal App.

Rate (lb ai/acre) Use Directions and Limitations

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

Post

- emergence

Broadcast application

Groundboom and handheld equipment Pylex ® SC;

2.8 lb ai/gal; EPA Reg. No. 7969

- 327

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

- 327 0.044 lb ai/A

0.001 lb ai/1000 ft 2

(spray volume: 1 gallon/1000 ft 2 ) 3 0.089  REI = 12 hrs.

 Do not apply to golf course collars or greens.

 Do not apply via chemigation or air.

 If single application of topramezone does not provide complete control, then a sequential application can be made 2 to 3 weeks lat er

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

Non

- crop Terrestrial

- Application
Pre

- /post

emergence

Broadcast application

Groundboom, and handheld equipment Frequency ® ;

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

- 281 0.09

- 0.35 lb

ai/acre 2 not

specified 0.35 lb ai/acre 

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



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

- 0.5% of the formulated product.



- Only soil

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

- grown ornamentals.



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

Non

- c rop Aquatic

- Application

- in

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

Pre

- /post

emergence

Broadcast, spot, and metering applications

Groundboom, handheld equipment, aircraft, and boat Oasis ® SC;

2.8 lb ai/gal; EPA Reg. No. 7969

- 339 in

- water

concentration at application of 20

- 50 ppb 3 not

specified 150 ppb/year

or 0.41 lb ai/acre

foot/year 

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

application, is 50 ppb (application rate in lb ai/acre is based on calculation using the treated area and average depth). To maintain the desired conc., samples are collected/analyzed and additional product is added to raise the conc. to the desired level

.



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

 Do not apply via chemigation.

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

Non

- crop Aquatic

- Application

- shoreline and riparian areas within or adjacent to aquatic sitesTopramezone Human

- Health Assessment Scoping Document D425613

Page 24 of 25 Summary of Application Scenarios. App. Timing; Type; and Equip. Formulation

(EPA Reg. No.) App. Rate Max. #. App. per Season Max. Seasonal App.

Rate (lb ai/acre) Use Directions and Limitations

Pre

- /post

emergence

Broadcast, spot, and metering applications

Groundboom, handheld equipment, aircraft, and boat Oasis ® SC;

2.8 lb ai/gal; EPA Reg. No. 796 9

- 339 0.09

- 0.35 lb

ai/acre 2 not

specified 0.35 lb ai/acre/year  Do not exceed 45 ppb for single in

- water applications with functional potable water intakes.

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



- Sequential applications can be made throughout the growing seasons.

Non

- crop Aquatic

- Application

- foliar spot treatment
Pre

- /post

emergence

Broadcast, spot, and metering applications

Groundboom, handheld equipment, and boat Oasis ® SC;

2.8 lb ai/gal; EPA Reg. No. 7969

- 339 0.09

- 0.35 lb

ai/acre 2 not

specified 0.35 lb ai/acre/year  Spray coverage should be sufficient to moisten the leaves of the target vegetation but not to runoff.

Non

- crop Aquatic

- Application

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

Pre

- /post

emergence

Broadcast, spot, and metering applications

Groundboom, handheld equipment, aircraft, and boat Oasis ® SC;

2.8 lb ai/gal; EPA Reg. No. 7969

- 339 0.09

- 0.35 lb

ai/acre 2 not

specified 0.35 lb ai/acre/year  (1) only for use by Irrigation Districts in the western U.S. in canals that are seasonally filled and where the Irrigation District is aware of potential down

- stream use of water and can ensure water is not used for irrigation purposes during the recharge or refill process;

 (2) app. by only Irrigation Districts, Irrigation Water Suppliers, or those applicators who are licensed or certified as aquatic pest control applicators and are authorized by the Irrigation District;

 (3) app. must be conducted a minim um 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. o f 24 hours, canal water may then be used for irrigation purposes.Topramezone Human

- Health Assessment Scoping Document D425613

Page 25 of 25 Summary of Application Scenarios. App. Timing; Type; and Equip. Formulation

(EPA Reg. No.) App. Rate Max. #. App. per Season Max. Seasonal App.

Rate (lb ai/acre) Use Directions and Limitations

Corn (field, sweet, pop) & Fallow

Post

- emergence Broadcast application

Groundboom and aircraft Armezon ® SC;

2.8 lb ai/gal; EPA Reg. No. 7969

- 262 Topramezone ® SC; 2.8 lb ai/gal; EPA Reg. No. 5481

- 524 0.011

- 0.022 lb

ai/A not

specified 0.022 lb ai/A  REI = 12 hrs

 PHI = 45 days

 PGI = 45 days

 Do not apply after V8 stage of growth

 Do not apply via chemigation