### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON , D

. C

. 20460

OFFICE OF CHEMICA L SAFETY AND POLLUTION PR E V E NTION



### MEMORAN D UM

D A T E : 4/ 1 6/2 015

SUB J ECT: 

### P e n oxs ul a m

. Huma n Health Assessment Scopi n g Document in Support of Registration Review

FROM :

T HR OUGH: PC Co d e: I 1903 I
Dec i s i o n No

. : 499239 P e t i ti o n No.: NA R i s k Assess m e nt T y p e : NA T X R No.: NA MRID No.: NA DP Ba r co d e: 0425160
R eg i s tr ·a ti o n No.: 62 719-611 Reg u la t o r y Act i o n : R eg i st ration R eview Case No.: 7265 CAS No.: 219714-96-2 40 CF R: 

### § 180.605



### Douglas Dot son, 

### Ph.D., Chemist

## .**~~** ;{

, _ 

### .1..J' Linnea Hansen, Ph.D.

, Toxicologi st

### ~~~U".1 Z aida Figueroa, M.S., Indu stria l Hy g i enis t 

# v!J >

t Ri sk Assessment Branch JI /---- 

### Health Effects Division (7509P) Office of Pesticide Programs

C hristina Swaitz, Branch

# Chief~ Ri s k Assessment Branch II

J ess R owla nd

, Associate

# Dir**ect~-4r-E~.:c::** Dana Vogel

, Acting Director H

ea lth Effects Division (7509P) Office of Pe stic id e Programs

TO: 

### Bonnie Adler, Chem ical R eview Manager Pesticide R e-Evaluat ion D i vision (7508 P ) Office of Pesticide Program s

Attached i s the Jlcalth Effects Division 's ( HED ) human h ea lth ri sk assessme nt scoping document for penox s ul am L o s upport registration review.Penox s ulam Registration R eview Scop in g Docum en t



### Execut i ve S u mmary

The Health Effects Division P e noxsulam Registration Review Team h as eva lu a t e d the databa se and the most r ecent hum a n h ea lth risk assessment for p e noxsu l am. H ED p erfor m e d this

eva luation in order to determine the scope of wo rk n ecessa r y to s upp ort th e es t ab li s hed tolerances and ex i st in g registrations during r eg i s tr a ti o n review. The pr im a ry sou rce of information fo r this evaluation was the most r ece nt human health ri sk assessment for t h e chemica l ( D363910

, C. Swartz

, 4 / 9 / 2009).

Penoxsulam

, 2-(2

, 2-difluoroethoxy)

- N

- (5,8 -dimcthoxy[ l

, 2,4]triazolo( 1 ,5 -c] p y rimidin-2- y l ) -6- (t riflu oro m ethy l ) ben ze ne s ul fonam id e, is a su l fonamide herbicide u sed fo r the se lective contro l of grasses, broad l eaf, a nd sedge weeds

, as w e ll as for control of vegetation in l akes

, ponds

, canals

, and r ese rvoir s. To l era nces are established in 40CFR 

### § 180.60 5 fo r r es idue s i n or on grapes , almond hull s, pi s t ac hio s, tree nut s, ri ce (grain and straw), fish

, crus t aceans , and mollu scs.

T h e t oxicological database is complete and con s idered adeq ua te to assess the human health ri s k

res ul ting from curre n t r eg i ste r e d uses , and H E D does not recommend that a n y a dditional studies be r eq uired during regi s t ratio n re v iew. An acceptab l e immun otoxicit y s tud y, r e quired und e r current 40 CFR Part 1 58 toxicology gu id elines, h as been s ubmitted. There are no subchronic inh a l a ti on toxicity da t a on penoxsulam ; h owever , th e H ED Hazard a nd Scie n ce Policy Council ( H AS POC) r eco mm e n de d that th e inhalati on toxicity s tud y r e qu i r emen t be waived, based on th e lack of evidence of po1i a l of e ntr y to x icity

, l ow vo l at ilit y , and hi g h MO Es fo r both occupational

a nd residential h a nd l e r inh ala ti o n exposures. A n ora l toxicity st ud y was se l ec ted fo r assessment of inhalation exposu r e ri sk.

The primar y targ e t o r gans of penoxsulam t oxic ity a re the kidney a n d li ver. E ffects on red blood

ce ll ( RBC ) paramet e r s h ave been reported in the r at. The r e is no evide n ce o f i ncreased qualitative or quantitativ e pre

- and/o r post-natal s u scep tibility

, n eurotoxici t y, or immunot ox icit y

. In addition

, ex p os ur e assess m en t s are n ot lik e l y to underestimate risk assoc i ated with the

r eg i ste r e d us es

. T h e FQPA Safety F acto r fo r p e noxsu l am has

, th erefo r e , b ee n r educed to Ix. P e nox s ulam i s classified as h aving "s u gges tiv e ev id e nce " of ca r cinogenicity based o n an in c r eased in ci d e n ce of m ono nucle a r cell l e uk e mia in mal e rats. A se p a r ate ca nc e r ri s k

assess m e nt was n o t co ndu cted

. A ll current point s of departure ( PODs) a nd endpo int s for noncancer risk

, as se le c t ed in the most r ecent (2009) ri sk assessment fo r penoxsulam

, are ba se d o n kidn ey histopath o l ogy s een i n the dog chronic (c hr o nic dietary exposure ) a nd subc hronic ( all

n o n- d i etary r es i den ti al and occupational exposure ) tox i city stud i es.

Although the POD s a nd e ndp o int s are not expec t ed t o change durin g registration review

, 1-I E D

r eco mm e nd s a r ev i ew of th e PODs a nd endpo int s se l ec t ed for ri s k assess m e nt at the t i m e of

re g i st ration rev i ew to e n s ure that they are co n sis tent with the current scie n ce and r i sk assessment policies. In a dditi o n , the following changes t o expos ur e s cenario s are n ot e d: ( 1 ) int ermed i ateterm in c id e ntal ora l expos ure w ill no longer b e assessed

, and o nl y s h o rt-t e rm ex posure w ill b e

eva luated

, and (2) th e ne e d for an intermediat e -t e rm dermal POD and endpoint s hould be

reeva l uate d ( ba se d on l ack o f effects for sho rt- term d e rm a l exposure or l owe rin g of N OAELs /L OAEL s for th e cr i t i cal effec t wi th incr ease d ex p osure duration ).

Pa ge 2 of24

### Penoxsulam Registration Review Scoping Document

Page 3 of 24 The residue chemistry database is adequate to support current r egistration r eview requirements. Adequate metabolism (crops, livestock, and rotational crops), storage stability, magnitude of the residue

, and processing data are available to support the registered uses. Adequate methods are available for enforcement of the currently established tolerances. T he tolerance expression needs to be updated to include both coverage and compliance statements. The dietary exposure database , including the potential for residues in food and drinking water, is adequate to support current registration requirements. The last risk assessment provided chronic dietary exposure estimates that are not of concern for all population subgroups

.

P enoxsulam products are registered for use in residential areas. HED co nducted r esidential post

application assessment s for the turf and aquatic uses (i.e., recreational fish and backyard ponds)

. The risk estimates were not of concern. During re gistration r eview

, HED will update these
assessments based on revised inputs, as sumptions

, and procedures (e.g., Aquatic Use SOP and HED’s 2012 Residential Turf SOP ). In addition, HED will conduct a residential handler
assessment f

or the aquatic use ; however

, no risks of concern are anticipated

. In addition, t he Agency will consider the potential for exposure through spray drift and volatilization.

In the 2009 risk assessment, no risks of concern were identified for the general U.S. population or any population subgroup. At the time of registration review, HED will conduct a new
ag gregate risk assessment that will be based on any policy changes, potential updates to points of departure, or exposure estimates from food and drinking water.

The occupational exposure database is adequate to support the r egistration r eview of penoxsulam . The most recent occupational handler and post

- application exposure assessments are not reflective of current exposure policies, but did not identify risks of concern. During

r egistration r eview, updated occupational handler assessments will be con ducte d to reflect all the registered uses and current occupational exposure policies

.

The Interregional Research Project Number 4 (IR

- 4) proposed new uses for penoxsulam on pome fruit

, stone fruit , olives, and pomegranate

. IR

- 4 also requested that the toleran ce for grapes be expanded to the crop subgroup 13

- 07F (Small fruit vine climbing subgroup except fuzzy kiwifruit) and that the tree nut crop group be updated to the new crop group, 14

- 12. The use pattern s for the proposed commodities are similar to the us e patterns of the registered

c ommodities. As a result, the new uses are not likely to have significantly different exposure and risk estimates . HED ha s not assessed the new uses, however

. HED’ s human health risk assessment in support of the new uses wil l be incorporated into the registration review risk assessment for penoxsulam

.

Introduction

HED evaluated the most recent human health risk assessment for penoxsulam in association with updates to its toxicity

, exposure , and usage databases to determine if sufficient data are available

, and if further updates are needed to support registration review. In the 2009 risk assessment, HED evaluated proposed new uses on grapes and tree nuts ( D 363910 

### , C. Swartz, 4 / 9 /20 09)

.

### Penoxsulam Registration Review Scoping Document

Page 4 of 24 Penoxsulam is used for the selective control of gras ses, broadleaf, and sedge weeds, as well as for control of vegetation in lakes, ponds, canals, and reservoirs. It is registered for use on grapes, tree nuts, and rice. Tolerances are established for residues in these commodities as well a s for residues in fish, crustaceans, and molluscs. It is also registered for use on turfgrass, aquatic weeds, non

- cropland, non

- bearing cropland, and non

- bearing fruit trees (including citrus), conifers, and eucalyptus. There are granular

, flowable concentrate, emulsifiable concentrate, and

s uspension concentrate formulations of penoxsulam on the market at a maximum single application rate of 0.06 lb ai/A (treated turf). For the aquatic uses, the maximum single application rate is 0.175 lb ai/A in residential settings (i.e., recreational fish and backyard ponds)

. Tolerances for residues of penoxsulam are established i n 40 CFR §180. 6 05

. T olerance s are

e stablished in terms of parent penoxsulam on the commodities listed above

. The structure and chemical name s , a s well as the chemical and physical properties can be found in the tables in A ttachment 1

.

Hazard Identification/Toxicology

The toxicology database for penoxsulam is considered to be complete

, and HED does not recommend that any additional toxicology data be required at this time ( s ee Toxicity Profile, Attachment 2, for complete summary of the toxicology database). Since the previous risk assessment was conducted (2009)

, the registrant submitted an acceptable rat immunotoxicity

s tudy . This study is required under the current 40 CFR Part 158 guidelines

, and HED requ est ed it in the 2009 risk assessment

. A rat subchronic (28

- or 90

- day) inhalation study is not available, but the HED HASPOC recommended that the guideline requirement be waived (TXR No. 0051 714

, J. Leshin

, 3/17/2015 ). This determination was based upon low inhalation MOEs (≥5800) for all residential and occupational exposure scenarios of penoxsulam ( calculated using current exposure SOPs and body weight assumptions ) , a long with its low vapor pressure and lack of portal of entry effects in oral and dermal studies.

Penoxsulam is rapidly and nearly completely absorbed in the rat following oral dosing at a low dose (5 mg/kg/day

, 81

- 88% of the administered dose, or AD), bu t absorption appeared to be saturated at a high dose (250 mg/kg). At the low dose, t he major route of excretion was via the feces for males and via the urine for females . A t the high dose, however, excretion was mainly via the feces for both sexes. Sign ificant enterohepatic circulation was observed in the males (55% AD) and to a lesser extent in females (14% AD). Most radioactivity was excreted by 48 h ou rs , and tissue retention was negligible. Penoxsulam was extensively metabolized, but most metabolite s were present at less than 1% of the AD. Parent and a 2

- hydroxyphenyl derivative were the major moieties observed in feces and urine, with parent representing a larger fraction in the high dose animals.

In the rat and dog, the kidney was the major targe t organ. Penoxsulam formed crystals and calculi in the urine, which were observed in the renal pelvis of both species and resulted in histopathological effects to the urothelium, including multifocal urothelial hyperplasia and subacute to chronic inflamma tion in the renal pelvis/collecting ducts. These effects were observed following subchronic and chronic exposure in both species. Dogs were more sensitive than rats to renal effects. Toxicity did not occur at significantly lower dose levels with longer

### Penoxsulam Registration Review Scoping Document

Page 5 of 24 exposure time s , although in the rat there were additional findings related to kidney effects (changes in urinalysis parameters, increased BUN, increased severity of glomerulonephropathy in males) in the chronic study that were not observed at higher dose levels in the subchronic study . At high doses in the 4

- week dog study, liver histopathology and increases in liver

- related clinical enzymes (Alk, SGPT, SGOT) and liver weight were observed. In the rat, decreased RBC parameters and decreases in body weight/weight gain and food consumption were also observed in all studies.

Studies in the mouse did not show adverse effects regardless of exposure duration, but adaptive liver changes (increased liver weight, hepatocel lular hypertrophy, observations indicating increased microsomal enzyme activity) were observed. No systemic toxicity was observed in a 28

- day dermal toxicity study in the rat tested up to the limit dose. A dermal absorption study has not been provided

, b ut comparison of rat oral and dermal 4

- week studies indicates an upper bound absorption of 50%. There was no evidence of neurotoxicity in the acute and chronic neurotoxicity studies in the rat, and no evidence of immunotoxicity in the rat.

HED reduced t he 10x FQPA Safety Factory (FQPA SF) t o 1x. There was no evidence of increased qualitative or quantitative pre

- or post

- natal susceptibility. No developmental toxicity was observed in the rat or rabbit developmental toxicity studies. Slight delays in p reputial separation in male F1 offspring were observed in the rat two

- generation reproductive toxicity study, and pup weight gains were reduced during lactation. However this finding was observed in the presence of parental toxicity (decreased adult F1 bo dy weight in males and kidney histopathology in females). In addition, exposure assessments are not likely to underestimate risk associated with the registered uses.

Penoxsulam is of low acute toxicity by all exposure routes and is not a dermal irritan t or sensitizer, nor an eye irritant. Although the rat acute inhalation toxicity study was classified as unacceptable based on inconsistencies with the test chamber atmosphere concentrations during the study, the overall findings support its low toxicity via that route.

The non

- cancer doses and endpoints for dietary, residential

, and occupational exposure
assessment used in the most recent risk assessment (see Attachment 3) are based on kidney toxicity in the dog 90

- day study (all non

- dietary exposures) a nd 1

- year dietary study (chronic dietary exposure) . These doses and endpoints are the most sensitive found in the available studies, and are protective of other effects. Acute dietary and short

- term dermal exposures were not assessed because toxicologica l endpoints were not identified. No changes to the previously selected studies and doses/endpoints are anticipated during registration review. However, under current HED policy, intermediate

- term incidental oral exposure is no longer assessed and

, theref ore , an intermediate

- term endpoint is not needed. HED should re

- evaluate the need for an intermediate

- term dermal endpoint given the lack of toxicity in the rat 28

- day dermal study and lack of clear evidence of increased toxicity in the 13

- week vs. 4

- week oral studies in the dog and
rat.

Penoxsulam was classified by the HED Cancer Assessment Review Committee (CARC) as having “Suggestive Evidence of Carcinogenicity but Not Sufficient to Assess Human Carcinogenic Potential” (TXR No. 0050702, J. Kidwell, 3/ 24 / 2004) based on treatment

- related

### Penoxsulam Registration Review Scoping Document

Page 6 of 24 (but not clearly dose

- related) increases in the incidence and severity of large granular lymphocyte leukemia (also known as mononuclear cell leukemia, or MNCL) in male Fischer 344 rats at levels exceeding in

- lab histor ical control values for all treated groups. MNCL is recognized as a common neoplasm in Fischer rats, but the significance of MNCL and its biological relevance for human cancer risk remains uncertain. There were no tumor increases seen in female rats. Mi ce showed no increase in tumors, although a maximum tolerated dose was not achieved in males. There was no evidence of genotoxicity. Based on a weight

- of

- the

evidence consideration for penoxsulam, concern for carcinogenicity was low

, and q uantification

o f cancer risk was

, therefore

, not required.

Conclusions for Hazard Identification/Toxicology

The toxicology database for penoxsulam is adequate to support registration review

, and HED does not recommend that any additional toxicology studies b e requir ed. The requirement for an immunotoxicity study has been satisfied. The rat subchronic inhalation toxicity study requirement was waived.

The P O Ds
, endpoints

, and safety factors selected in the most recent penoxsulam risk assessment are not expected to change during registration review, but should be reevaluated at that time to ensure that they are consistent with current science and regulatory policies for assessment of hazard. The intermediate

- term incidental oral P O D and endpoint are no longer required since only short

- term incidental oral exposure is currently assessed

. Additionally, the need for an intermediate

- term dermal exposure assessment should be reconsidered

.

Dietary Exposure

The residue chemistry database is adequate to support r egistration r eview. Adequate metabolism (crops and livestock), storage stability, magnitude of the residue

, and processing data are available to support the registered uses. Adequate methods are available for enforcement of the currently esta blished tolerances. No residue chemistry data deficiencies were cited in the previous risk assessment.

For the 20 09 risk assessment , HED conducted a chronic dietary exposure a ssessment that included all commodities with established tolerances: drinking water, tree nuts, rice, grapes, fish, crustaceans, and molluscs ( D 360419

, M. D oherty

, 3 / 2 4 /20 09 ). The assessment was unrefined , including use of tolerance level residues of penoxsulam in all commodities , and an assumption of 100% c rop treated (CT) for all crops

. It was also based on conservative default processing factors that overestimate concentration in processed commodities. An estimated d rinking water concentration was provided by the Environmental Fate and Effects Division (EFED, D3556 76, J. Wolf, 12/2/2008) and was incorporated directly into the dietary assessment

. Penoxsulam is registered for control of aquatic weeds. For that use pattern, the maximum permitted water concentration in the water column is 0.15 ppm . For the dietary as sessment, HED used a drinking water concentration of 0.15 ppm as a high

- end estimate of penoxsulam residues in drinking water. The 0.15 ppm value is likely to be an overestimate of actual residues

### Penoxsulam Registration Review Scoping Document

Page 7 of 24 in drinking water. No new studies that are relevant to th e dietary risk assessment have been submitted since penoxsulam was last assessed

. The chronic dietary risk estimates were not of concern for the general U.S. population and all population subgroups. All subgroups use less than or equal to 7.1 % of the cPAD. HED anticipates that the most recent drinking water assessment will be adequate for registration review , but if there are significant changes in the drinking water estimates d uring registration review, HED will likely conduct a new dietary exposure and risk assessment . I f a n ew assessment is needed, HED will us e the most current dietary exposure model and food consumption survey data

. According to HED’s Interim Guidance on Tolerance Expressions (S. Knizner; 27 May 2009), the tolerance expr ession for penoxsulam cited in 40 CFR §180. 605 should be revised to state:

Tolerances are established for residues of penoxsulam , including its metabolites and degradates, in or on the commodities listed in the table below. Compliance with the toleranc e levels specified below is to be determined by measuring only penoxsulam 2

- (2,2

- difluoroethoxy)

- N

- (5,8

- dimethoxy[1,2,4]triazolo[1,5

- c] pyrimidin

- 2

- yl)

- 6

- (trifluoromethyl) benzenesulfonamide

, in or on the commodity.

Conclusions for Dietary Exposure

The dietary exposure database is adequate to support the existing registrations. There are no anticipated changes to previous dietary exposure estimates, which are not of concern. The tolerance expression will be revised during registration review to reflect both coverage and compliance, in accordance with current guidance.

Residential Exposure

There are several end

- use product (EP) formulations of penoxsulam registered for weed control on residential and commercial turf areas (lawns and golf courses) and aquatic sites. Use of these formulations in residential settings results in potential expos ure to homeowners who apply the products on lawns

, and to adults and children who come into contact with treated areas while doing lawn maintenance or playing on treated turf. There are granular and s uspension concentrate formulations on the market at a m aximum single application rate of 0.06 lb ai/A (treated turf). For the aquatic uses, the maximum single application rate is 0.175 lb ai/A in residential settings (i.e., recreational fish and backyard ponds) . Penoxsulam may be applied as broadcast and per imeter (directed spray ) treatment through a variety of hand

- held equipment. Residential exposure is expected to be short

- term in duration.

Residential Handler Exposure

Homeowners m ight be exposed to penoxsulam when they handle granule and suspension
concentrate products for the control of weeds on residential and commercial lawns. Since a short

- term dermal POD was not selected, a quantitative dermal residential handler exposure
assessment has not been performed. Residential inhalation handler exposures were previously assessed, and are not of concern (D339488, M. Collantes, 5/23/2007)

.

### Penoxsulam Registration Review Scoping Document

Page 8 of 24 A residential handler assessment was not conducted for the aquatic use ; h owever, an exposure assessment w as conducted for commercial handlers applying penoxsulam directly into the water or as a foliar application to emergent aquatic vegetation . R isk estimates for commercial handlers

are not of concern ( D339488, M. Collantes, 5/23/2007 ). Since the current aq uatic use product label does not restrict penox s ulam from being applied by homeowners

, HED will complete a residential handler assessment for the aquatic use during r egistration r eview.

In conjunction with determining data needs during registration revi ew, penoxsulam was reviewed by the HED HASPOC to evaluate the need for a route

- specific inhalation study, as previous assessments were conducted using data from an oral study. As noted above, the HASPOC recommended that an inhalation toxicity study be waived

. In preparation for the HASPOC meeting, inhalation risk estimates were calculated using current SOPs and exposure assumptions. Residential handler and post

- application margin s of exposure (MOEs) ranged from 5,800 to 8.0 x 10 17 

### and are not of conce rn when compared to the target MOE of 100

.

Residential Post

- application Exposure

Uses of penoxsulam on lawn and turf areas and in aquatic sites around residential settings result in potential post

- appl ication exposures to adults and children.

Adults and children can be exposed to post

- application residues of penoxsulam on turf through dermal contact. No s hort

- term dermal endpoint has been identified. The short

- term post

application incidental oral exposures to children from treated turf (hand

- to

- mouth, objects

- to

mouth, and ingestion of contaminated soil) were previously assessed using chemical

- specific turf transferable residue (TTR) data. Th is most recent residential post

- application exposure
assessment does not reflect the policies of the HED’s 2012 Residential Standard Operating Procedures (SOPs), but did not identify risks of concern (D339488, M. Collantes, 5/23/2007). For r egistration r eview, H ED anticipate s that the post

- application exposure assessment for turf

use will need to be updated to reflect current exposure assumptions and procedures for residential assessment (e.g., HED’s 2012 Residential SOPs for Treated Turf)

. However, no risks of concern are expected

.
The penoxsulam aquatic uses in residential settings m ight result in post

- application dermal and oral exposure to adults and children while swimming in treated waters. The exposures to adults and children fr om the aquatic uses were previously assessed (D339488, M. Collantes, 5/23/2007), and are not of concern. For r egistration r eview, HED anticipate s that the post

application exposure assessment for the aquatic use will need to be updated to reflect current exposure assumptions and science methodology for aquatic assessments (e.g., Aquatic Use SOP)

. These risks are not expected to be of concern.

Spray Drift and Volatilization

Residential bystander exposures resulting from off

- site transport (e.g., spray drift or volatilization) can occur as a result of applications of penoxsulam . The potential for spray drift will be quantitatively evaluated for each pesticide during the r egistration r eview process that ensures that all uses for that pesticide will be co nsidered concurrently. The approach is outlined in the revised 2012 Standard Operating Procedures for Residential Risk Assessment

– Residential

### Penoxsulam Registration Review Scoping Document

Page 9 of 24 Exposure Assessment Standard Operating Procedures Addenda 1: Consideration of Spray Drift.

T he A gency has de veloped a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis

. During r egistration r eview, the A gency will utilize this analysis to determine if data (i.e., flux studies, route

- specific inhalation toxicological studies) or further analyses are required for penoxsulam

.

Conclusions for Residential Exposure

The residential exposure database is adequat e to support the existing penoxsulam registrations. HED previously conducted r esidential post

- application assessment s for the turf and aquatic uses

. The risk estimates were not of concern. H owever, during registration review

, HED will update these asses sment s as needed b ased on revised inputs

, assumptions

, and SOPs

. In addition, HED will complete a residential handler assessment for the aquatic use. The need for spray drift and volatilization risk assessment for penoxsulam will be examined during r egis tration r eview.

Aggregate Risk Assessment

The most recent aggregate risk assessment was performed as part of the 20 09 human health risk
assessment

. A ggregate risk assessment s traditionally combine exposure estimates resulting from food, drinking water, and residential uses. As n o acute toxicity endpoint was identified

, an acute aggregate risk assessment w as not performed. Penoxsulam was classified as having “suggestive evidence of carcinogenic potential

, but not sufficient to assess human carcinogenic p otential .” Because of the minimal concerns for human carcinogenicity of penoxsulam (see above), cancer risk was not quantified

, and t he chronic assessment is considered to be protective of potential carcino genic effects

. For the short

- term aggregate risk assessment, residential use exposures are aggregated with exposure from dietary sources. The short

- term aggregate risk estimates are not of concern. There are no intermediate

- term exposure scenarios for w hich quantitative aggregate risk estimates are appropriate. Long

- term aggregate risk estimates are considered to be protective for intermediate

- term exposures. The long term

- aggregate risk estimates are equivalent to the chronic dietary exposure estimate s and are not of concern.

Conclusions for Aggregate Exposure and Risk

In the 20 09 risk assessment, no risks of concern were identified for the general U.S. population or any population subgroup . At the time of registration review, HED will conduct a new aggregate risk assessment that will be based on any policy changes, potential updates to points of departure

, or updated exposure estimates from food

, drinking water

, and residential sources of
exposure

.

### Penoxsulam Registration Review Scoping Document

Page 10 of 24 Occupational Exposure

Penoxsulam is cur

rently registered for control of grasses, broadleaf weeds , and sedges in several agricultural crops (including rice, tree nuts

, and grapes), turf/sod (including residential lawns, golf courses, recreational / athletic fields) , forestry applications, and also to control vegetation in lakes, ponds, canals

, and reservoirs.

Occupational handler and post

- application exposures are expected based on the registered agricultural and commercial uses. Maximum single application rates range from 0.016

- 0.06 l b ai/A for agricultural crops and turf with 1

- 2 applications/season. For the aquatic uses, the maximum permitted water concentration is 0.15 ppm . Penoxsulam may be applied as broadcast (directed spray, foliar, in

- water) treatments through a variety of me thods, including aerial, ground, and hand

- held equipment. Handler e xposure is expected to be short

- and intermediate

term in duration.

Occupational Handler Exposure

There is the potential for dermal and inhalation exposure to occupational handlers fro m the currently registered use pattern of penoxsulam

. HED p revious ly conducted ORE assessments for the uses on rice ( D 301888 ), multiple crops ( D 355915 ; D373438), turf /golf course ( D339488 )

, and aquatic areas ( D 322533 ; D339488 ). HED based t he assessments on exposure data from the Pesticide Handlers Exposure Database (PHED), assumptions for area treated from the Science Advisory Council for Exposure (ExpoSAC) Policy #9, and maximum application rates. Handler exposure and risk were calculated at the baselin e level of personal protection ( i.e., long pants, a long

- sleeved shirt, no chemical

- resistant gloves, and no respirator) and with the use of additional personal

- protective equipment (PPE) when necessary (e.g., chemical

- resistant gloves, respirators, and engineering controls). Since a short

- term dermal POD was not selected, a quantitative short

- term dermal handler exposure assessment has not been conducted . However, quantitative intermediate

- term dermal exposure s were previously assessed for occupational handlers and are not of concern (i.e., MOEs ≥ 100; LOC=100) for all registered uses. The need for an intermediate

- term dermal assessment will be reconsidered during registration review.

In addition, HED previously assessed short

- and i ntermediate

- term inhalation exposures for occupational handlers . The risk estimates were not of concern for all registered uses. In conjunction with determining data needs for registration review

, penoxsulam was reviewed by HED ’s HASPOC to evaluate the n eed for a route

- specific inhalation study because previous assessments were conducted using data from an oral study. R evised inhalation risk estimates were calculated for occupational handlers using current policies and exposure assumptions. S hort

- and i ntermediate

- term o ccupational handler inhalation MOEs ranged from 12,000 to 14,000,000 and are not of concern

. Since the previous reviews, there have been several updates to HED’s exposure policies, including updated exposure data for occupational handl er assessments and updates to body

weight assumptions. These assessments m ight be revised during r egistration r eview to reflect current Agency polic ies, data

, and assumptions

.

### Penoxsulam Registration Review Scoping Document

Page 11 of 24 Occupational Post

- application Exposure

In the absence of toxicity via the dermal route, no quantitative short

- term dermal post

- application risk assessment was required for t he registered uses. Although HED would typically require dislodgeable foliar residue (DFR) data in accordance with the 40 CFR DFR data requirement based on the existing use pattern, a DFR study wa s not required because of the lack of toxicity via the dermal route. The restricted entry interval (REI) of 12 hours currently on th e registered labels is appropriate based on the acute toxicity of the technical ing redient.

There are multiple potential sources of 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 parti culates that contain pesticides. The A gency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SA P’s final report on March 2, 2010

. The A gency has evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis. During r egistration r eview, the A gency will utilize this analysis to determin e if data (i.e., flux studies, route

- specific inhalation toxicological studies) or further analysis are required for penoxsulam

.
In addition, the Agency is continuing to evaluate the available post

- application inhalation exposure data generated by the Agr icultural Reentry Task Force. Given these two efforts, the Agency will continue to identify the need for and, subsequently, the way to incorporate occupational post

- application inhalation exposure into the A gency ’ s risk assessments.

Although a quantitati ve occupational post

- application inhalation exposure assessment was not previously performed, an inhalation exposure assessment was performed for occupational handlers

. Handler exposure resulting from application of pesticides outdoors is likely to result in higher 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.

Conclusion for Occupational Exposure

The occupational exposure database is adequate to support the r egistration r eview process for penoxsulam . Based on a review of the registered labels for penoxsulam

, it appears that the previous assessments cover the occupational handler scenarios anticipated for all registered uses

. Updated assessments m ight be necessary during r egistration r eview if HED updates its exposure policies

.

Public Health and Pesticide E pidemiology Data

For this evaluation, HED consulted 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 Occupa tional Risk

- Pesticides (SENSOR)

### Penoxsulam Registration Review Scoping Document

Page 12 of 24 databases for pesticide incident data on the active ingredient penoxsulam (D 425276, S. Recore, 1/28/2015) . The purpose of the database search is to identify potential patterns in the frequency and severity of the health eff ects attributed to penoxsulam exposure. Penoxsulam is not included in the Agricultural Health Study (AHS) and, therefore, this study does not provide information for this report.

T he M ain IDS reported no incidents between January 1, 2010 and December 17, 2014 i nvolving only the single chemical penoxsulam. One incident was reported involving more than one chemical. This incident was classified as moderate severity. In Aggregate IDS, from January 1, 2010 to December 17, 2014, there were 18 incidents repo rted involving penoxsulam

. These incidents were classified as minor severity. Overall, there are few incidents involving penoxsulam reported to IDS.

The SENSOR

- Pesticides database covers 12 states from 1998

- 2011, although reporting varies from st ate to state. A revie w of SENSOR

- Pesticides 1998

- 2011 identifies no cases involving penoxsulam

. Based on the low frequency and low severity of incident cases reported for penoxsulam in both IDS and SENSOR

- Pesticides, there does not appear to be a concern at this time that would warrant further investigation. The Agency will continue to monitor the incident information and

, if a concern is triggered, the Agency will include additional analysis in the risk assessment.

Tolerance Assessment and International Harmonization

Tolerances for residues of p enoxsulam are established in 40CFR §180. 605

. The tolerances are established as follows: p enoxsulam, 2

- (2,2

- difluoroethoxy)

- N

- (5,8

- dimethoxy[1,2,4]triazolo [1,5

- c] pyrimidin

- 2

- yl)

- 6

- (trifluoromethyl ) benzenesulfonamide . A tolerance of 0.01 ppm is established for tree nuts, almond hulls, grapes, fish, and crustaceans ; a tolerance of 0.02 ppm is established for molluscs and rice grain ; and a tolerance of 0.50 ppm is established for rice straw.

40CFR §180.605 currently reads, “ Tolerances are established for the herbicide, penoxsulam (2

- (2,2

- difluoroethoxy)

- N

- (5,8

- dimethoxy[1,2,4] triazolo[1,5

- c]pyrimidin

- 2

- yl)

- 6

- (trifluoromethyl)benzenesulfonamide in/on the following raw agricultural commodities ...” Ac cording to HED’s Interim Guidance on Tolerance Expressions (S. Knizner; 27 May 2009), the tolerance expression for penoxsulam cited in 40 CFR §180. 605 should be revised to state:

“ Tolerances are established for residues of penoxsulam , including its metabo lites and degradates, in or on the commodities listed in the table below. Compliance with the tolerance levels specified below is to be determined by measuring only penoxsulam 2

- (2,2

- difluoroethoxy)

- N

- (5,8

- dimethoxy[1,2,4]triazolo[1,5

- c] pyrimidin

- 2

- yl)

- 6

- (trifluoromethyl) benzenesulfonamide

, in or on the commodity. ”

The re are no Codex Alimentarius Commission (Codex) or Canadian maximum residue limits ( MRLs ) for penoxsulam . As a result, there are no harmonization issues at the present time

. The international residue limit status sheet can be found in Attachment 4

.

### Penoxsulam Registration Review Scoping Document

Page 13 of 24 International or Intergovernmental Work Sharing

The European Food Safety Authority prepared a draft assessment report for penoxsulam (publication date 8/4/2010

, http://dar.efsa.europa.eu/dar

- web/provision ). The Authority came to the following conclusion: “The use of penoxsulam for the control of Echinochloa crus

- galli (all sub

- species and biotypes),, Alisma plantago

- aquatica and Ammania, Cyperus and Scirpus spp. i n rice in accordance with Good Agricultural Practice will not have any harmful effects on human or animal health or result in any unacceptable effects on the environment.” The Food and Agriculture Organization of th e United Nations (FAO/JMPR) has not evaluated penoxsulam . In Canada, the chemical is not registered for use on any commodities. The California Department of Pesticide Regulation has not initiated a human health risk assessment for penoxsulam, it has
not re

- evaluated it, and it is not currently re

- evaluating it.

In the U.S., tolerances are only established for residues in or o n tree nuts, rice , grapes, fish, crustaceans, and molluscs. IR

- 4 recently submitted a tolerance petition for pome fruit, stone fr uit, pomegranates, and olives. HED is not evaluating these commodities as a work share with any other country.

Cumulative Risk Assessments

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of tox icity, EPA has not made a common mechanism of toxicity finding as
to penoxsulam and any other substances

, and penoxsulam does not appear to produce a toxic metabolite produced by other substances. For the purposes of this action, therefore, EPA has not

as sumed that penoxsulam has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the poli cy statements released by EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/

.

HED’s Data Recommend ations

None

### Penoxsulam Registration Review Scoping Document

Page 14 of 24 R eferences

Memoranda Relevant to Registration Review Author DP

Number Date Title

C. Swartz D 3 63 9 10 4 / 9 /20 09 Penoxsulam: Revised Human Health Risk Assessment for Proposed Uses on Grapes and Tree Nuts S. Oonnithan D3 80179 8 / 10 /201 0 Penoxsulam: Human Health Risk Assessment Summary for the Proposed Use of Amore DF Herbicide on Non

- bearing Tree Nuts and Non

- bearing Grape Vines E. Budd TXR#

0052273 12/16/2003 Penoxsulam

– 1 st Report of the Hazard Identification Assessment Review Committee. EPA Memorandum J. Kidwell TXR#

0050702 3/24/2004 Penoxsulam: Report of the Cancer Assessment Review Committee. EPA Memorandum Y. Yang TXR#

0056076 6/24/2012 Penoxsulam, Immunotoxicity Study in Rats. EPA Memorandum

J

. Leshin TXR No.

00 51714 3 / 17 /201 5 Penoxsulam: Summary of Hazard and Science Policy Council (HASPOC) Meeting of February 19, 2015: Recommendation on the need for subchronic inhalation study in the rat M. Doherty D 355914 1/ 29 /200 9 Penoxsulam. Section 3 Registration Application For Use of GF

- 443 T&V on Grape and Tree Nuts Including Pistachio. Summary of Analytical Chemistry and Residue Data M. Doherty D 360419 3 /2 4 /20 09 Penoxsulam: Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessment to Evaluate the Requested New Uses on Grapes and Tree Nuts S. Oonnithan D 3 73438 8 / 9 / 20 10 Penoxsulam: Occupational and Residential Exposure Assessment for Adding Non

- bearing Trees, Conifers, Eucalyptus, and Non

cropland to the Registered Uses M. Collantes D339488 5/23/2007 Occupational and Residential Exposure Assessment for Use of Penoxsulam to Control Aquatic Weeds In and Around Slow

- moving and Quiescent Bodies of Water and Broadleaf Weeds in Turfgrass, Residential Lawns, Golf Courses, Sport Fields and Sod Farms L. Shanaman D 3 25468 11 / 8 /20 06 Tier 1 Drinking Water Assessment for the New Use Registration on Turf and Aquatic Vegetation of Penoxsulam, and Six Degradation Products Identified to be of Toxicological Concern J. Wolf D373443 4/7/2010 Penoxsulam (New Use) Tier 1 Drinking water exposure concentrations for the proposed new uses on non

- bearing trees, conifers, eucalyptus, and non

- cropland S. Recore D 4 2 5 276 1 / 2 8 /201 5 Penoxsulam : Tier I Review of Human Incidents



### Attachment s

Attachment 1

. Chemical Identity and Physical and Chemical Properties Attachment 2. Toxicology Profile Tables Attachment 3

. Endpoint Selection Table Attachment 4

. Intern a tional Residue Limit Status

### Penoxsulam Registration Review Scoping Document

Page 15 of 24 Attachment 1

. Chemical Identity and Physical and Chemical Properties

Table A.1 .1. Penoxsulam Nomenclature. Compound

Common name Penoxsulam
IUPAC name 6

- (2,2

- difluoroethoxy)

- N

- (5,8

- dimethoxy

- s

- triazolo[1,5

- c]pyrimidin

- 2

- yl)

- α,α,α

trifluoro

- o

- toluenesulfonamide
CAS name 2

- (2,2

- difluoroethoxy)

- N

- (5,8

- dimethoxy[1,2,4]triazolo[1,5

- c] pyrimidin

- 2

- yl)

- 6

- (trifluoromethyl) benzenesulfonamide CAS registry number 219714

- 96

- 2
End

- use product s (EP) (partial list) Pindar (EPA Reg. No. 62719

- 6 03 ) Pindar GT Herb icide (EPA Reg. No. 62719

- 611 ) Grasp SC ( EPA Reg. No. 62719

- 500 ) Granite SC (EPA Reg. No. 62719

- 514 ) GF

- 443 SC (EPA Reg. No. 62719

- 546 )

Table A.1. 2. Physic al and Ch emical Properties of Penoxsulam.

Parameter Value Reference 1 Melting point/range Not available pH 5.2 MRID 45830707 Density 1.61 g/mL at 20°C MRID 45830707 Water solubility at 19 °C Unbuffered 4.91 mg/L pH 5 5.66 mg/L pH 7 408 mg/L pH 9 1460 mg/L MRID 45830720

Solvent solubility at 19 °C Xylene 0.017 g/L 1

- Octanol 0.035 g/L Methanol 1.48 g/L Ethyl acetate 3.23 g/L Acetonitrile 15.3 g/L Acetone 20.3 g/L Dimethylsulfoxide 78.4 g/L MRID 45830720

Vapor pressure 7.16 x 10

- 16 mm Hg at 25°C MRID 45830720 Dissociation constant, pK a 5.1 (ambient) MRID 45830720 Octanol/water partition coefficient, Log(K OW ) Unbuffered

- 0.354 pH 5 1.137 pH 7

- 0.602 pH 9

- 1.418 MRID 45830720

UV/visible absorption spectrum Not available

1 As referenced in DP# 326985, 1/30/07, D. Soderbe rg.

### Penoxsulam Registration Review Scoping Document

Page 16 of 24 Attachment 2 . Toxicity Profiles

Table A.2.1

. Penoxsulam (XDE

- 638) Acute Toxicity Profile

. Guideline No. Study Type MRID(s) Results Toxicity Category

870.1100 Acute oral [rat] 45830812 M: LD50 >5000 mg/kg F: LD50 >5000 mg/kg IV

870.1200 Acute dermal [rabbit] 45830815 M: LD50 >5000 mg/kg F: LD50 >5000 mg/kg IV

870.1300 Acute inhalation [rat] [Note: study

classified as unacceptable/guideline due to issues with gravimetric vs. nominal dose levels, but tested at exposures exceeding 2 mg/L] 45830818 LD50 > 2 mg/L IV

870.2400 Acute eye irritation [rabbit] 45830820 Minimal irritation IV

870.2500 Acute dermal irritation [rabbit] 45830823 Minimal irritation IV

870.2600 Skin sensitization [guinea pig] 45830826 Negative for dermal sensitization N/A



### Table A.2.2

. Penoxsulam (XDE

- 638) Subchronic, Chronic and Other Toxicity Profile

. Guideline No. Study Type MRID No. (year)/ Classification /Doses Results

870.3050 4

- week oral

toxicity, range

finding (rat) 45830903 (1998)

M and F: 0, 10, 100, 500, 1000 mg/kg/day Acceptable/nonguideline NOAEL = 100 mg/kg/day LOAEL = 500 mg/kg/day based on decreased body weight and weight gain, decreased food consumption, decreased RBC parameters and in fem ales only, increased kidney weights and histopathology of the renal pelvic urothelium (very slight or slight inflammation and hyperplasia, presence of crystals).

870.3050 4

- week oral

toxicity, range

finding (Beagle dog) 45830908 (1998)

M: 0, 29, 133, 192 mg/kg/day F: 0, 32, 163, 196 mg/kg/day Acceptable/nonguideline NOAEL = Males 29 mg/kg/day; females = not determined (<32 mg/kg/day, LDT); LOAEL = 133 mg/kg/day, M, based on liver effects (increased weight and ALT, AST, ALK, histopathology) and kidney hi stopathology. 32 mg/kg/day, F, based on kidney histopathology. Effects at 163 mg/kg/day were similar to those in males.

### Penoxsulam Registration Review Scoping Document

Page 17 of 24 Table A.2.2

. Penoxsulam (XDE

- 638) Subchronic, Chronic and Other Toxicity Profile

. Guideline No. Study Type MRID No. (year)/ Classification /Doses Results

870.3050 4

- week oral

toxicity, range

finding (mouse) 45830904 (1998)

M: 0, 10.5, 103, 530, 1018 mg/kg/day F: 0, 10.8, 110, 545, 1069 mg/kg/day Acceptable/nonguideline NOAEL = 1018/1069 mg/kg/day, M/F LOAEL = not determined (>1018/1069 mg/kg/day, M/F (HDT)

870.3100 90

- Day oral

toxicity (Fischer 344 rat) 45830906 (2000)

0, 5, 50, 250, 500 mg/kg/day Acceptable/guideline NOAEL = 50/250 mg/kg/day, M/F LOAEL = 250/500 mg/kg/day, M/F, based on decreased body weight/weight gain, food consumption and RBC parameters in males and increased mineralization and hyperplasia of the renal pelvic urothelium in females.

870.3100 90

- Day oral

toxicity (mouse) 45830905 (2001)

M: 0, 10.2, 102, 511, 1027 mg/kg/day F: 0, 10.4, 104, 524, 1029 mg/kg/day

Acceptable/guideline NOAEL = 1027/1029 mg/kg/day, M/F LOAEL = not determined (>1027/1029 mg/kg/day, M/F (HDT)

870.3150 90

- Day oral

toxicity (Beagle dog) 45830909 (2000)

M: 0, 5.9, 17.8, 49.4 mg/kg/day F: 0, 5.7, 19.9, 57.1 mg/kg/day Acceptable/guideline NOAEL = 17.8/19.9 mg/kg/day, M/F LOAEL = 49.4/57.1 mg/kg/day, M/F, based on the presence of crystals and very slight multifocal pelvi c epithelial hyperplasia of the renal pelvic and collecting duct urothelium.

870.3200 28

- Day dermal

toxicity (Fischer 344 rat) 45830911 (2002)

M and F: 0, 100, 500, 1000 mg/kg/day Acceptable/guideline Systemic toxicity NOAEL = 1000 mg/kg/day (HDT)
LOAEL = not determined (> 1000 mg/kg/day)

870.3465 28

- or 90

- Day

inhalation toxicity (rat) -- Study waived by HASPOC (TXR No. 0051714 )

870.3700a Prenatal

developmental (Sprague

- Dawley rats) 45830917 (2000)

0, 100, 500, 1000 mg/kg/day (gavage) Acceptable/guideline Maternal NOAEL = 500 mg/kg/day Maternal LOAEL = 1000 mg/kg/day, based on decreased body weight gain and food consumption, increased kidney weights Developmental NOAEL = 1000 mg/kg/day Developmental LOAEL = not determined (>1000 mg/kg/d ay)

### Penoxsulam Registration Review Scoping Document

Page 18 of 24 Table A.2.2

. Penoxsulam (XDE

- 638) Subchronic, Chronic and Other Toxicity Profile

. Guideline No. Study Type MRID No. (year)/ Classification /Doses Results

870.3700b Prenatal

developmental (New Zealand white rabbit) 45830918 (2001)

0, 5, 25, 75 mg/kg/day (gavage) Acceptable/guideline Maternal NOAEL = 25 mg/kg/day Maternal LOAEL = 75 mg/kg/day, based on mortality, clinical signs of toxicity, decreased body weight and food consumption. Developmental NOAEL = 75 mg/kg/day Developmental LOAEL = not determined (> mg/kg/day, HDT)

870.3800 Reproduction and

fertility effects (Sprague Dawley rat) 45830920 (2002)

M and F: 0, 30, 100, 300 mg/kg/day Acceptable/guideline Parental NOAEL = 100/30 mg/kg/day M/F Parental LOAEL =300/100 mg/kg/day M/F, based on decreased F1 body weight in males and kidney lesions in females Reproductive/offspring NOAEL = 30 mg/kg/day Reproductive/offspring LOAEL = 100 mg/kg/ day) based slightly increased time to preputial separation in F1 males (at 300 mg/kg/day pup weight gain was also decreased during lactation)

870.4100a Chronic toxicity

(rat) See 870.4300, below

870.4100b Chronic toxicity

(Beagle dog) 45830914 (2002)

M: 0, 5.3, 14.7, 46.2 mg/kg/day in the diet F: 0, 4.4, 14.0, 44.8 mg/kg/day Acceptable/guideline NOAEL = 14.7/44.8 mg/kg/day, M/F LOAEL = 46.2 mg/kg/day, M, based on slight multifocal hyperplasia in the renal pelvic urothelium. Not determined in females ( >44.8, HDT)

870.4200 Combined

Chronic/ Carcinogenicity (Fischer 344 rat) 45830901,

- 13 (2002)

M and F: 0, 5, 50, 250 mg/kg/day in the diet Acceptable/guideline NOAEL = 50 mg/kg/day LOAEL = 250 mg/kg/day, based on decreased body weight/weight gain, increased urine volume, crystals and calculi in kidney, hyperplasia of the renal pelvic and urinary bladder urothelium in both sexes; decreased urine specific gravity, increased BUN, decrea sed RBC parameters and increased severity of chronic progressive glomerulonephropathy in males.

In males, possible treatment

- related increase in the incidence of large granular lymphocyte leukemia at all dose levels with increased severity at 250 mg/kg/da y. No evidence of carcinogenicity in females.

### Penoxsulam Registration Review Scoping Document

Page 19 of 24 Table A.2.2

. Penoxsulam (XDE

- 638) Subchronic, Chronic and Other Toxicity Profile

. Guideline No. Study Type MRID No. (year)/ Classification /Doses Results

870.4300 Carcinogenicity

(CD

- 1 mouse) 45830915 (2002)

M: 0, 10, 100, 375 mg/kg/day F: 0, 10, 100, 750 mg/kg/day Unacceptable/guideline (new study not required) NOAEL = 375/750 mg/kg/day, M/F
LOAEL = not determined (>375/750 mg/kg/day, M/F, highest doses tested)

No evidence of carcinogenicity (dosing inadequate in males)

Gene Mutation 870.5100 Salmonella

typhimurium TA98, TA100, TA1535, Ta1537, Ta1538 45830921 (1999)

With S9: 0, 3.3, 10.0, 33.3, 100, 333, 1000 μg/plate Without S9: 0, 3.3, 10.0, 33.3, 100, 333, 1000, 5000 μg/plate

Acceptable/guideline Negative for increased reverse gene mutations in the presence and absence of rat S9 metabolic activation. Cytotoxicity observed at >333 μg/plate.

Gene Mutation
870.5100 Salmonella

typhimurium TA98, TA100, TA1535, Ta1537, Ta1538 45830922 (2002)

Formulation GF

- 443 21.9% penoxsulam 0, 10.0, 33.3, 100, 333, 1000, 5000 μg/plate with and without S9 Acceptable/guideline Negative for increased reverse gene mutations in the presence and absence of rat S9 metabolic activation. Cytotoxicity observed at >333 μg/plate.

Mammalian cell forward
gene mutation
assay 870.5300 Chinese hamster

ovary (CHO) cells

(+/

- S9) 45830923 (1999)

0, 46.88, 93.75, 187.5, 375, 750, 1500 μg/mL Acceptable/guideline Negative for forward gene mutation in the presence and absence of rat S9 metabolic activation. Limit of solubility observed at 750

- 1500 μg/mL.

### Penoxsulam Registration Review Scoping Document

Page 20 of 24 Table A.2.2

. Penoxsulam (XDE

- 638) Subchronic, Chronic and Other Toxicity Profile

. Guideline No. Study Type MRID No. (year)/ Classification /Doses Results

In vitro chromosomal aberration
assay 870.5375 Primary rat

lymphocyte cultures 45830924 (1999)

First assay 0, 3.3, 10, 33.3, 100, 333.3, 1000, 1500 μg/mL with and without S9, 4 hr incubation Second assay same doses, without S9, 24 hr incubation and with S9, 4 hr incubation Third assay, 12 doses between 100

- 1500 μg/mL without S9, 24 h r incubation Acceptable/guideline Negative for forward gene mutation in the presence and absence of rat S9 metabolic activation.

In vivo

mouse micronucleus
assay 870.5395 CD

- 1 mouse, bone

marrow 45830925 (2002)

0, 500, 1000, 2000 mg/kg, dosed for two days and harvested at 24 hr post

dosing Acceptable/guideline Negative at oral doses (once per day on two consecutive days) of up to 2000 mg/kg.

In vivo

mouse micronucleus
assay 870.5395 CD

- 1 mouse, bone

marrow 45830926 (2002)

Formulation GF

- 443, 21.9% penoxsulam 0, 500, 1000, 2000 mg/kg, dosed for two days and harvested at 24 hr post

dosing Acceptable/guideline Negative at oral doses (once per day on two consecutive days) of up to 2000 mg/kg.

870.6200a Acute

neurotoxicity screening battery
rat 45830902 (2000)

M and F: 0, 500, 1000, 2000 mg/kg Acceptable/guideline NOAEL = 2000 mg/kg LOAEL = not determined (>2000 mg/kg/day, HDT)

870.6200b Chronic

neurotoxicity screening battery

rat 45830901,

- 12 (2002)

M and F: 0, 5, 50 or 250 mg/kg/day Acceptable/guideline Neurotoxicity NOAEL = 250 mg/kg/day Neurotoxicity LOAEL = not determined (>250 mg/kg/day), based on slight decreases in body weight and weight gain in the main chronic toxicity study.

870.6300 Developmental

neurotoxicity -- Study not required.

### Penoxsulam Registration Review Scoping Document

Page 21 of 24 Table A.2.2

. Penoxsulam (XDE

- 638) Subchronic, Chronic and Other Toxicity Profile

. Guideline No. Study Type MRID No. (year)/ Classification /Doses Results

870.7485 Metabolism and

pharmacokinetics (species) 45830927 (2002)

Acceptable/guideline Penoxsulam was rapidly and nearly completely absorbed (81

- 88% AD) at the low dose of 5.0 mg/kg but at the high dose of 250 mg/kg there was evidence that absorption was largely incomplete. At low dose the major route of excretion of radioactivity was via t he feces in males and via the urine in females. At high dose, excretion was predominantly in the feces for both sexes. A significant enterohepatic circulation was observed, especially in males. Most (>90%) of the AD was excreted by 36

- 48 hrs post

- dosing . There was negligible radioactivity found in tissues at 7 days post

dosing, and no evidence of accumulation in tissues or organs. Although numerous metabolites were found in the urine, feces and bile, nearly all were <1% of AD. Unmetabolized parent comp ound and a 2

- hydroxyphenyl derivative were the major compounds found in urine and feces.

870.7600 Dermal penetration

(rat) -- Study not available

870.7800 Immunotoxicity,

28

- day oral ( female F344/DuCrl rats) 48125301 (2010)

M,F: 0, 50, 200, 1000 mg/kg/day Acceptable/guideline Systemic toxicity NOAEL = 200 mg/kg/day Systemic toxicity LOAEL = 1000 mg/kg/day, based on Immunotoxicity NOAEL = 1000 mg/kg/day Immunotoxicity LOAEL = not determined (>1000 mg/kg/day)

### Penoxsulam Registration Review Scoping Document

Page 22 of 24 Attachment 3. Penoxsulam Endpoints and Doses for Risk Assessment

Table A.3. 1

. Summary of Toxicological Do ses and Endpoints for Penoxsulam for Use in Dietary and Non

Occupational Human Health Risk Assessments

.

Exposure/ Scenario Point of

Departure Uncertainty/

FQPA Safety Factors RfD, PAD,

Level of Concern for Risk Assessment Study and Toxicological Effects

Acute Dietary (Al l Population s , including Infants and Children and Females 13

- 49 years of
age ) No toxicological endpoint attributable to a single exposure was identified in the available

toxicology studies on penoxsulam. This exposure scenario was therefore not assessed for human health risk.

Chronic Dietary (All Populations) NOAEL=

14.7 mg/kg/day UF A = 10 x

UF H =10 x FQPA SF= 1 x Chronic RfD

= 0.147 mg/kg/day

cPAD = 0.147 mg/kg/day 1 Year Chronic Feeding Study in Dogs

LOAEL = 46.2 mg/kg/day based on multifocal hyperplasia of the renal pelvic epithelium.

Incidental Oral Short

Term (1

- 30 days) NOAEL=

17.8 mg/kg/day UF A = 10 x

UF H =10 x FQPA SF= 1 x Residential

LOC for MOE = 100 13

- Week Feeding Study in Dogs

LOAEL = 49.4 mg/kg/day based on multifocal hyperplasia of the renal pelvic epithelium and crystals in the renal pelvis and collecting ducts. Incidental Oral Intermediate

Term (1

- 6 months) NOAEL=

17.8 mg/kg/day UF A = 10 x

UF H =10 x FQPA SF= 1 x Residential

LOC for MOE = 100 13

- Week Feeding Study in Dogs

LOAEL = 49.4 mg/kg/day based on multifocal hyperplasia of the renal pelvic epithelium and crystals in the renal pelvis and collecting ducts. Dermal Short

Term (1

- 30 days) An endp oint for systemic toxicity was not identified in the rat 28

- day dermal study and there

were no neurotoxic, developmental, immunotoxic effects observed for penoxsulam. This exposure scenario was not assessed for human health risk.

Dermal Intermediate

Term (1

- 6 months) NOAEL=

17.8 mg/kg/day UF A = 10 x

UF H =10 x FQPA SF= 1 x Residential

LOC for MOE = 100 13

- Week Feeding Study in Dogs

LOAEL = 49.4 mg/kg/day based on multifocal hyperplasia of the renal pelvic epithelium and crystals in the renal pelvis and collect ing ducts.

Inhalation Short

- Term (1

- 30 days) NOAEL=

17.8 mg/kg/day UF A = 10 x

UF H = 10 x FQPA SF= 1 x Residential

LOC for MOE = 100 13

- Week Feeding Study in Dogs

LOAEL = 49.4 mg/kg/day based on multifocal hyperplasia of the renal pelvic epithelium and crystals in the renal pelvis and collecting ducts.

Inhalation Intermediate

Term (1

- 6 months) NOAEL=

17.8 mg/kg/day UF A = 10 x

UF H = 10 x FQPA SF= 1x Residential

LOC for MOE = 100 13

- Week Feeding Study in Dogs

LOAEL = 49.4 mg/kg/day based on multifocal hyperplasia of the renal pelvic epithelium and crystals in the renal pelvis and collecting ducts.

### Penoxsulam Registration Review Scoping Document

Page 23 of 24 Table A.3. 1

. Summary of Toxicological Do ses and Endpoints for Penoxsulam for Use in Dietary and Non

Occupational Human Health Risk Assessments

.

Exposure/ Scenario Point of

Departure Uncertainty/

FQPA Safety Factors RfD, PAD,

Level of Concern for Risk Assessment Study and Toxicological Effects

Cancer (oral, dermal, inhalation) Classification: Classification : Suggestive Evidence of Carcinogenicity, but Not Sufficient to

Assess Human Carcinogenic P otential based on a possible treatment

- related increase in mononuclear cell leukemia in F344 rats, a tumor type of uncertain relevance to humans. The cRfD is considered protective of potential carcinogenic effects. 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 = l owest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose.

Table A.3 .2

. Summary of Toxicological Doses an d Endpoints for Penoxsulam for Use in Occupational

Human Health Risk Assessments

. Exposure/ Scenario Point of

Departure Uncertainty

Factors Level of Concern

for Risk Assessment Study and Toxicological Effects

Dermal Short

Term (1

- 30 days) An endpoint for systemic toxicity was not identified in the rat 28

- day dermal study and there

were no neurotoxic, developmental, immunotoxic effects observed for penoxsulam. This exposure scenario was not assessed for human health risk.

Dermal Intermediate

Term (1

- 6 months) NOAEL=

17.8 mg/kg/day UF A =10x

UF H =10x Occupational LOC

for MOE = 100 13

- Week Feeding Study in Dogs

LOAEL = 49.4 mg/kg/day based on multifocal hyperplasia of the renal pelvic epithelium and crystals in the renal pelvis and collecting ducts.

Inhalation Short

- Term (1

- 30 days) NOAEL=

17.8 mg/kg/day UF A =10x

UF H =10x Occupational LOC

for MOE = 100 13

- Week Feeding Study in Dogs

LOAEL = 49.4 mg/kg/day based on multifocal hyperplasia of the renal pelvic epithelium and crystals in the renal pelvis and collecting ducts.

Inhalation Intermediate

term (1

- 6 months) NOAEL=

17.8 mg/kg/day UF A =10x

UF H =10x Occupational LOC

for MOE = 100 13

- Week Feeding Study in Dogs

LOAEL = 49.4 mg/kg/day based on multifocal hyperplasia of the renal pelvic epithelium and crystals in the renal pelvis and collecting ducts.
Cancer (oral, dermal, inhalation) Classification : Suggestive Evidence of Carcinogenicity, but Not Sufficient to Assess Human

Carcinogenic Potential based on a possible treatment

- related i ncrease in mononuclear cell leukemia in F344 rats, a tumor type of uncertain relevance to humans. The cRfD is considered protective of potential carcinogenic effects. 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 = u ncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the hum an population (intraspecies). MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

### Penoxsulam Registration Review Scoping Document

Page 24 of 24 Attac hment 4

. International Residue Limit Status



## Penoxsulam ( 119031 ; 2

- 2

- 201 5 )

Table A.4. Summary of US and International Tolerances and Maximum Residue Limits. Residue Definition : US Canada Mexico 1 Codex 40 CFR 180. 605

Penoxsulam:

2

- (2,2

- difluoroethoxy)

- N

- (5,8

- dimethoxy[1,2,4]triazolo[1,5

- c] pyrimidin

- 2

- yl)

- 6

- (trifluoromethyl) benzenesulfonamide None None

Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg) US Canada Mexico 1 Codex

Almond, hulls 0.01

Fish 0.01 Fish, shellfish, crustacean 0.01 Fish, shellfish, mollusc 0.02 Grape 0.01 Nut, tree, group 14 0.01
Pistachio 0.01 Rice, grain 0.02 Rice, straw 0.50

Completed: : M. Negussie (2/2/2015)

1 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.