Date:



### SUBJECT: UNITED STATES ENVIRONMENTAL PROTECTION AGENC Y WASHINGTON

, D

. C

. 20460

D ecember 4

, 20 1 5 OFF I CE OF C H EM I CAL SAFE TY AND POLLUT I ON PREVENTION

Penoxs u lam. Human Health New Use Risk Assessment to Support the Re g istration of Proposed Use o n P o m e Fruit

, Sto n e Fruit, Olive

, P omegranate. and Fruit

, Small

, Vine Climbing (S ubgroup l 3 -07F, Except Fuzzy Kiwifru i t); and Crop Group Conversion for Tree Nuts

.

PC Code: 119031 De c i s i on No.: 497353 Pet i tio n No.: 4E8330 DP Barcode: 0424710 Regi s trat i on No.: 62719-6 11 Reg ul atory Act i on: Section 3 C ase No.: 7265 Ri s k A ssess m e n t T y pe: S ingl e C hemical Aggregate TXR No.: NA CAS No.: 219714-96-2 40 CF R : 180

. 60 5 MRID No

. : NA



### F R OM: Eliza b eth H o lman

, Ph ys ical Scientist/Risk Assessor**~ ~**  Gerad Thornton

, Environmenta l Protection SRecialist**~** Linnea J. H a n sen, Ph.D., B i ologist

### ~ 

# cfv-

Ri sk Assessment Bran c h II (RA Bii ) 1
Health Effec t s Di v isi on (7509P) 

# oU- A-- T H ROUG H : Christina Swartz

, Branch C hief Ri sk Assessment Bran c h lJ (RAB ii ) H ea lth Effects Di vis i o n (7509P)



### T O : Sidney J ackson/Barbara M adden Minor Use and Emergency R esponse Br anc h Registration Division ( 7505P)

A human health risk a ssess ment was completed in s upp ort of the proposed Section 3 uses of penoxsulam o n pome frui t , sto n e fruit, olive

, pomegranate , and fruit , s mall

, vine climbin g (S ub g roup 1 3 -07F

, except fuzzy kiwifruit)

, plu s crop g r o up co nv e rsion for tree nut s

.

Pa ge I of61Table of Contents 1.0 Exec utive Summary

.......................................................................................................... 4 2.0 H E D R eco mmendation s

........................ ...... .. ... ...... .. ...... .. ...... ... ...................... . ............... . 5 2.1 Data Deficiencie s/Co ndition s of Registration

..................................................... 6 2.2 Tolerance Co n s ideration s

........... . ......................................... .. ..... .. ............... . ...... . 6 2.2.1 E nforcement Analytical Method

. ...... .. ...... .. ...... .. .. . .. ... ..... ....................... 6 2.2.2 International Harmonization

................................................................... 6 2.2.3 Recomm e nd e d Tolerances

....... .. ...... .. ...... .. ..... ... ..... .. . ... . ...... . ...... .. . ........... 7 2.2.4 Revi s ion s to Petitioned-For Tolerances

.. .. ..... .. ... . .. . ................................ 7 2.3 Label Recomm e nd at ion s

..................... .. ...... .. ...... .. ..... .. ...... .. ..... . .. .. ...................... 7 3.1 C hemical Identity

. ...... ... . ........ .. .. . ... .. ...... ... .. .................. . ...... .. .... ...... .. ..... ..... . ........ 8 3.2 Physical/Chemical C h a racteri s tic s

..................... . ....... . ........ .. ..... .. ...... . ................ 8 3.3 Summary of Propo sed Uses

................ . ....... .. . ....... . ... . ... . .. .. . ...... . ............. . ...... .... .. . 8 3.4 Anticipated Exposure Pathway s

. ....... . ........................................................ .. ...... . 9 3.5 Co n s ideration of Environmental Ju st ice

................... .. ..... ... . .. . ...... .. ..... .. ..... ..... .. 9 4.0 Hazard C haracterization and Do se-Respo n se Asses s ment

......................................... 1 0 4.1 Toxicology Studies Available for Analysis

........................................................ I 0 4.2 Absorption, Di st ribution

, Metabolism

, & E limination (ADME)

.................... 10 4.2.1 Dermal A b sor ption

................................................................................. l I 4.3 Toxicological Effec t s

.... ... .. ....... . ... . ... . .... . .. .. ... ...... . ............................................... 11 4.4 Safety Factor for Infant s and C hildren (FQPA Safety Factor)

...................... 12 4.4.1 Completeness of the Toxicology Database

.. .... ... ..... .......................... .. .. 13 4.4 .2 Evidence of Neurotoxicity

.. .. ... ...... ..... ... .. ................ . .............................. 1 3 4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

......... .. .. . ... ... . . ... ... ..... .... ...... .. ... . .. ... .. .. . ... .. ..... ...... . ...... .. ...... .. ....... . .............. 13 4.4.4 Re s idu a l U ncertainty in the E xpo s ure Databa se

. ..... ..... .. ..... .. ..... . ........ 1 3 4.5 Toxicity E ndpoint and Point of Departure Selections

.... .. ..... .... ...... .. .............. 13 4.5.1 Do se- R es pon se As s essment

.................................................................... 13 4.5.2 Recommendation for Co mbining Routes of Exposures for Ri s k Asses s ment

.. . ............................... .. ....... .. ...... .. ...... .. ...... . ...... . ........ ... ..... .... ..... . ...... 14 4.5.3 Cancer C la ss ification a nd Risk Assessment Recommendation

.... .... .. 14 5.1 Metabolite/Degradate R es idu e Profile

.............................................................. 17 5.1.1 Summary of Plant and Animal Metabolism Studies

.. ..... ..... .. ..... .. .... .. 17 5.1.2 Summary of Environmental D eg radation

............ . ............................... 18 5.1.3 Co mparison of Metabolic Pathways

. .. ... .. ................ .. ..... .. ...... . .. . ..... .. .... 18 5.1.4 Re s idue s of Co ncern Summary

. ... .. .. .. .. . ... .. .. .. .. ..... .. ........ .. .. .. . .. ..... .. ..... .. 18 5.2 Food Re s idue Profil e

........................................................................................... 19 5.3 Water Residue Profile

........................ . ............... .. ..... ...... . ...... .. . .. . ....................... 19 5.4 Dietary Ri s k Assessment

.................................................................................... 20 5.4.1 De sc ription of Re s idue Data Use d in Dietary Assessment

..... .. .. . .. ..... . 20 5.4.2 Percent C rop Treated Used in Dietary Assessment

.. . .......................... 20 5.4.3 Acute Dietary Ri s k As s essment

..... .. ...... .. ...... .. ...... . .. .. .. ..... .. . . ... .... ..... .. .. 20 5.4.4 Chronic Dietary Ri s k Assessment

.. . ... .. .. . ... . .. .. ...................................... 20 5.4.5 Cancer Dietar y Risk Asses s ment

... .. ...... .. ...... . ......... .. .... ... ..... . ...... . . ... .... 2 1 6.0 Re si dential (Non-Occupational) Exposure/Risk Characterization

.. . ......................... 21 6

. 1 Residential Handler Ex po s ur e

.................................................................... . ...... 21

Page 2 of61Page 3 of 61

6.2. Residential Post

- application Exposure

................................ ............................. 22 6.3 Other (Spray Drift, etc .)

................................ ................................ ..................... 23 7.0 Aggregate Risk Assessments and Risk Characterization

................................ ............ 24 7.1 Acute Aggregate Risk

................................ ................................ ......................... 24 7.2 Short

- Term Aggregate Risk

................................ ................................ ............... 24 7.3 Chronic Aggregate Risk

................................ ................................ ..................... 25 8.0 Cumulative Risk Characterization/Assessment

................................ ........................... 25 9.0 Occupational Exposure/Risk Characterizatio n

................................ ............................ 25 9.1 Post

- Application Risk

................................ ................................ ......................... 28 9.1.1 Post

- Application Dermal Exposure

................................ ....................... 28 9.1.2. Post

- Application Inhalation Exposure

................................ ................. 28 Appendix A. Toxicology Profile

................................ ................................ ................................ 30 A.1 Toxicology Data Requirements

................................ ................................ .......... 30 A.2 Toxicity Profiles

................................ ................................ ................................ .. 31 A.3 Hazard Identification and Endpoint Selection

................................ ................. 36 A.4 Executive Summaries

................................ ................................ .......................... 38 Appe ndix B. Physical/Chemical Properties of Penoxsulam

................................ ................... 58 Appendix C. Penoxsulam and Metabolites

................................ ................................ .............. 59 Appendix D. Summary of Residues from Penoxsulam Crop Field Trials

............................ 61 Appendix E. Review of Human Research

................................ ................................ ................ 61Page 4 of 61

1.0 Executive Summary

The Health Effects Division (HED) of OPP has completed an aggregate human health risk assessment for penoxsulam. This assessment includes all currently registered uses as we ll as the requested new uses on pome fruit, stone fruit, olive, pomegranate, and f ruit, small, vine climbing (Subgroup 13

- 07F, except fuzzy kiwifruit), plus crop group conversion for tree nuts

. Penoxsulam, 2

- (2,2

- difluoroethoxy)

- N

- (5,8

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

- c] pyrimidin

- 2

- yl)

- 6

- (trifluoromethyl) benzenesulfonamide, is a sulfonam ide herbicide used for the selective control of gras ses, broadleaf, and sedge weeds in several crops and on turf , as well as for control of vegetation in lakes, ponds, canals, and reservoirs. Tolerances are established in 40CFR §180.605 for residues in or on grapes, almond hulls, pistachios, tree nuts, rice (grain and straw), fish, crustaceans, and mollusks

. The petitioner has requested that permanent tolerances be established at 0.01 ppm for all proposed new uses and crop group conversions.

The toxico logical database is complete and considered adequate to assess the human health risk resulting from current registered and proposed new uses. An acceptable immunotoxicity study, required under current 40 CFR Part 158 toxicology guidelines, has been submit ted since the last risk assessment. There are no subchronic inhalation toxicity data on penoxsulam; however, the HED Hazard and Science Policy Council (HASPOC) concluded that an inhalation toxicity study is not needed based on the lack of evidence of port al of entry toxicity, low volatility, and high MOEs for both occupational and residential handler inhalation exposures. An oral toxicity study

was therefore selected for assessment of inhalation exposure risk.

In subchronic and chronic feeding studies in rats and dogs, the kidney was the most sensitive target organ. Hyperplasia of the renal pelvic epithelium was observed in both species, and in the rat, effects on renal function and increased severity of chroni c glomerulonephropathy were also observed following chronic exposure. Effects on the liver, hematological parameters and body weight were observed sporadically in some studies. In subchronic and chronic feeding studies in mice, no effects of toxicologica l significance were observed. There was no evidence of increased quantitative or qualitative susceptibility of fetuses or offspring, as compared to adults. In developmental toxicity studies in rats and rabbits, no developmental toxicity was observed at

m aternally toxic dose levels. In a 2

- generation reproduction study in rats, delays in preputial separation were noted in the presence of parental toxicity. No treatment

- related neurotoxicity or immunotoxicity were observed in any of the available studies on penoxsulam. The FQPA 10x safety factor has therefore been reduced to 1x. No systemic or dermal toxicity was noted in a 28

- day dermal toxicity study in rats. Technical grade penoxsulam exhibited minimal acute toxicity in the available studies (Toxicit y Category IV for all categories).

HED has classified penoxsulam as having suggestive evidence of car cinogen icity based on an increased incidence of mo nonuclear cell leukemia (MNCL) in Fisher 344 rats

, but recommended against quantitative assessment of cancer risk

, due to lack of a dose

- response , and questionable relevance to humans , sinc e there is no similar tumor occurring in humans . Additionally,
p enoxsulam is negativ e for mutagenicity, and MNCL is not associated with exposure to other triazolopyrimi dines

.Page 5 of 61

The toxicological database for penoxsulam shows no effects attributable to a single oral dose and, as noted above, indicates that a quantification of cancer risk, per se , is not appropriate for this chemical (i.e., the chronic Reference Dose or cRf D is protective for potential carcinogenicity) . An endpoint for toxicity from dermal exposure was not identified. Therefore, doses and endpoints have been selected to assess chronic dietary exposure, as well as non

occupational short

- term incidental oral and short

- and intermediate

- term inhalation exposures. For occupational exposures, doses and endpoints have been selected to assess short

- and intermediate

- term exposure by the inhalation route.

The residue chemistry database supporting the registered a nd proposed uses is complete. The nature of the residue in plants is understood for purposes of this petition. The residue of concern for tolerance expression and risk assessment is the parent, penoxsulam. This conclusion is based, in part, on the propo sed use pattern and HED notes that should the use pattern for the proposed new uses (i.e., from soil to foliar applications) change in the future , additio nal nature of the residue data may be needed

. Acceptable field trial, storage stability, and process ing studies have been completed to support the requested new uses and crop group changes

. Adequate

a nalytical methods are available for tolerance

- enforcement purposes.

HED has estimated dietary, residential, and aggregate risks from exposure to penoxsu lam. Dietary risk estimates are well below HED’s level of concern for all population subgroups, with the maximum risk estimate being 6 % of the chronic population

- adjusted dose (cPAD) for infants. The MOEs for residentia l exposure are 4,600 or more, indic ating risk estimates below HED’s level of concern. Likewise, MOEs for aggregate risk range from 1,500 to 5,400 and indicate risk estimates below HED’s level of concern.

HED has also estimated exposures to penoxsulam associated with occupational activitie s. For workers handling and/or applying penoxsulam, MOEs range from 53,000 to 5,200,000 and are not of concern. Based on the toxicological and chemical properties of penoxsulam, post

application exposures are not of risk concern.

The risk assessment is based, in part, on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These studies are compliant with applicable ethical requirements (refer to Appendix E ).

Potential areas of environmental justi ce concerns, to the extent possible, were considered in this human health risk assessment (see Section 3.5).

2.0 HED Recommendations

HED has examined the residue chemistry database for penoxsulam

. Pending submission of a revised Section F (to propose commodity definitions recommended by HED), there are no residue chemistry issues that would preclude establishing the recommended tolerances . The recommended tolerances are listed in Table 2.2. 3 , below.Page 6 of 61

40CFR §180.605 currently reads, “ Tolerances are e stablished 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 ...” According 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 metabolites 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) benzenesulfonami de

, in or on the commodity. ”

Note s to RD: Upon establishment of the proposed tolerance in t ree nut group 14

- 12 , the existing tolerance in tree nut group 14 and pistachio should be removed (40CFR §180. 605[a] ).

Upon establishment of the proposed tolerance in fruit, small, vine climbing (Subgroup 13

- 07F, except fuzzy kiwifruit) , the existing tolerance on grape should be removed (40CFR §180.605[a] ).

2.1 Data Deficiencies/Conditions of Registration

None

.

2.2 Tolerance Considerations

2.2.1 Enfor cement Analytical Method Residue Chemistry Summary D3 55914 ; M. Doherty ; 29 January 2009

High performance liquid chromatographic methods with positive

- ion electro spray interface (ESI) and tandem mass spectrometric detection (LC/MS/MS) were previously reviewed and found to be acceptable for tolerance enforcement of penoxsulam. Method GRM 01.2 5 was developed for rice commodities, and Method GRM 05.08 was developed for animal commodities. Successful validation of both methods was reported by the registrant, and by an independent laboratory validation (ILV). No radiovalidation was required for either of these methods. The limit of quantitation (LOQ), determined as the lowest level of method validation (LLMV), is 0.010 ppm for penoxsulam in all matrices.

Testing results of penoxsulam analyzed according to the FDA Multi

- Residue Method Test
g uidelines in PAM Vol. I, Appendix II (1/94) were previously submitted in conjunction with the rice petition (PP# 3F6542; DP# 288152, 8/11/04, W. Cutchin ). The multiresidue method data indicate that penoxsulam is not adequately recovered using any of the m ultiresidue methods.

2.2.2 International HarmonizationPage 7 of 61

There are no Codex, Canadian or Mexican MRLs established for residues of penoxsulam on any crops, including those under review for this petition. Therefore, there are no harmonization issues with respect to the proposed agricultural uses.

2.2.3 Recommended Tolerances

TABLE 2.2. 3

. Tolerance Summary for Penoxsulam (40CFR §180.605 ). Propose d or Existing * Commodity Proposed or Existing *

Tolerance (ppm) Recommended

Tolerance (ppm) Correct Commodity Definition ; Comments Fruit, Pome, group 11

- 10 0.01 0.01 Fruit, pome, group 11

- 10 Fruit, Stone, group 12

- 12 0.01 0.01 Fruit, stone, group 12

- 12 Fruit, small, vine climbing, subgroup 13

- 07F, except fuzzy kiwifruit 0.01 0. 01 Based on available data on grape.

Nut, Tree group 14

- 12 0.01 0.01 Nut, tree, group 14

- 12 ; Conversion from tree nut group 14. Olive 0.01 0.01 Based on submitted stone fruit and pome fruit field trial data. Pomegranate 0.01 0.01 Nut, tree, group 14 0.01* Remove Conversion to tree nut group 14

- 12. Grape 0.01* Remove Replace with tolerance on Fruit, small, vine climbing, subgroup 13

- 07F, except fuzzy kiwifruit. Pistachio 0.01* Remove Replace with the tolerance on tree nut group 14

- 12. * Proposed revisions to existing tolerances.

2.2.4 Revisions to Petitioned

- For Tolerances

The current tolerance expression for penoxsulam ( 40CFR §180.605 ) needs to be updated to include both coverage and compliance statements for enforcement purposes. Specifically, 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 metabolites and degradates, in or on the commodities listed in the table bel ow. 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 petitioner should submit a revised Section F using the correct commodity definitions provided in Table 2.2. 3 . All proposed tolerance values for these commodities are correct as listed and are identical to those recommended by HED.

2.3 Label Recommendations

None.

3.0 IntroductionPage 8 of 61

3.1 Chemical Identity

Penoxsulam is a sulfonamide herbicide 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. The herbicide’s mode of action at the cellular level involves the inhibition of acetolactate synthase (ALS). T he nomenclature of penoxsulam is summarized in Table 3. 1

Table 3. 1. Penoxsulam Nomenclature. Compound

Common name Penoxsulam Company experimental name XDE

- 638
IUPAC name 3

- (2,2

- difluoroethoxy)

- N

- (5,8

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

- c]pyrimidin

- 2

- yl)

- α,α,α

- trifluorotoluene

- 2

- sulfonamide
CAS name 2

- (2,2

- difluoroeth oxy)

- 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 (EP) Pindar GT Herbicide (EPA Reg. No. 62719

- 611 )

3.2 Physical/Chemical Characteristics

The information regarding physical / chemical characteristics of penoxsulam does not indicate that there are any special concerns in terms of bioaccumulation, exposure or other risk assessment considerations. A table of physical and chemica l properties for penoxsulam is included in Appendix B.

3.3 Summary of Proposed Uses

Penoxsulam is proposed for new use on pome fruit group 11

- 10, stone fruit 12

- 12, olive, and pomegranate. Penoxsulam is also requested for an extension of the tolerances from grapes to the crop subgroup 13

- 07F and a crop group update to the new tree nut croup group 14

- 12. The proposed formulated end

- use product is Pindar® GT, an emu l sifiable concentrate conta ining 0.85% penoxsulam (EPA Reg. #62719

- 611). Based on the proposed use pattern, the potential exposure scenarios include short

- and intermediate

- term occupational inhalation exposures for handlers. A summary of the proposed new use directions is include d in Table 3.3 below.

The personal protective equipment (PPE) specified on the l ab el indicates the baseline clothing scenario for handlers, i.e., long sleeved shirt, long pants, shoes plus socks, no gloves and noPage 9 of 61

respirator. Additional PPE including cove ralls, chemical

- resistant footwear plus socks, chemical

- resistant gloves, safety glasses, chemical

- resistant headgear when exposed overhead, and chemical

- resistant apron when exposed to the concentrate , are required for certain handler scenarios based on t he toxicity of the co

- formulant oxyfluorfen

. While a restricted entry interval (REI) of 12 hours would be considered adequate for penoxsulam , the Pindar GT label is 2 4 hours based on the toxicity of oxyfluorfen

.

Table 3

. 3 . Summary of Proposed Uses for Penoxsulam

. Applic. Timing, Type, and Equip. Formulation

(EPA Reg. No.) Applic. Rate

(lb ai/A) Max. Seasonal

Applic. Rate (lb ai/A) PHI (days) Use Directions and Limitations
Pome Fruit Group 11

- 10, Stone Fruit 12

- 12, Olive, and Pomegranate Crop Group extension from Grapes to Subgroup 13

- 07F Crop Group update to the new Tree Nut Group 14

- 12

Groundboom

, Backpack Sprayer

, Mechanically

Pressurized Handgun Emulsifiable

Concentrate (62719

- 611) 0.02 to 0.03 lb

ai/A 0.05 lb ai/A 60 Apply pre

- or post

- emergence of weeds in the dormant period before bud swell. Not to be applied via chemigation.

Penoxsulam is also currently registered for occupational use on grapes, tree nuts , rice, turfgrass, aquatic vegetation , non

- cropland, non

- bearing cropland, non

- bearing fruit trees (including citrus), conifers, and eucalyptus. It is also registered for residential use on turfgrass and aquatic vegetation for weed control.

3.4 Anticipated Exposure Pathways

As a result of the registered and proposed uses of the he rbicide penoxsulam, humans may be exposed through food and drinking water, since the chemical may be applied directly to growing crops and may reach surface and ground water sources of drinking water. Furthermore, this chemical is registered for a direct aquatic use to control vegetation in lakes, ponds, canals, and reservoirs. In an occupational setting, there is potential for dermal and inhalation exposure for applicators while handling the pesticide prior to application (i.e., mixing/loading), as well as during application. There is also potential for post

- application exposure for workers re

- entering treated fields.

Since penoxsulam is also registered for use on residential turf areas (e.g., lawns and golf courses) and aquatic sites (e.g., ponds and lakes), there is likely to be exposure in residential and non

occupational settings as well. There is potential for dermal and inhalation exposure in residential and non

- residential settings, as well as the potential for post

- applic ation oral exposure to children. Finally, there is also the potential for indirect exposure to adults and children from spray drift following agricultural applications. This risk assessment considers all of the relevant exposure pathways, combining them as appropriate, to est imate overall exposure and risk.

3.5 Consideration of Environmental JusticePage 10 of 61

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, “ Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income Populations, ” ( http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf

. As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well

- established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on pat terns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the U.S. Department of Agriculture under the Nation al Health and Nutrition Examination Survey, What We E at in America, (NHANES/WWEIA). These food consumption patterns are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups b ased on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever
app ropriate, non

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

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

4.0 Hazard Characterization and Dose

- Response Assessment

4.1 Toxicology Studies Available for Analysis

The toxicology database for penoxsulam is complete and is sufficient for characterizing the hazard to human health. No additional studies are required. T he HED HASPOC has determined that the required subchronic inhalation toxicity study is not needed (TXR No. 0051714, memorandum from J. Leshin dated March 17, 2015), based on MOEs that exceeded 10x the level of concern (LOC) (i.e., MOEs >1000)

, the low vapo r pressure and lack of evidence for portal of entry toxicity . The studies available for consideration in risk assessment are:

 rat, mouse and dog subchronic oral toxicity

 rat 28

- day dermal toxicity

 dog chronic, rat chronic/oncogenicity, mouse oncogenicity

 rat and rabbit developmental toxicity

 rat two

- generation reproductive toxicity

 genotoxicity battery

 rat general metabolism

 rat acute and subchronic neurotoxicity

 rat immunotoxicity

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

In the rat

, penoxsulam wa s rapidly absorbed, distributed and excreted following oral administration. At a low dose (5 mg/kg), absorption was largely complete (81

- 88% administeredPage 11 of 61

dose, or AD). Significant biliary excretion was observed, with males excreting a larg er percent of the dose in bile (55.8%) than females (14.1%). At a high dose (250 mg/kg), absorption appeared to reach saturation, based on nonlinearity of the are a under the curve ( AUC ) when compared to the low dose, and increased fecal excretion of the unmetabolized parent compound observed in both sexes. The time to maximum plasma concentration (T max ) was 0.5 hr at the low dose and 2 hr at the high dose. The p lasma half

- life (t 1/2 ) at the low dose was 2.6 to 2.9 hrs (males and females, respectively). At the high dose, t 1/2 was 2.9 to 5.6 hrs (males and females

, respectively ).

Radioactivity was widely distributed among tissues

, but bioaccumulation or sequestration was not observed. The main radioactive component excreted in urine and feces was unmetab olized parent compound (urine 7.53 to 65.97% AD; feces 3.45 to 80.08% AD and bile, 4.8 to 9.35% AD). Numerous metabolites were identified in urine (17), feces (37) and bile (19), but most represented less than 1% AD. The primary metabolic pathways were P hase I O

- dealkylation and hydroxylation and Phase II conjugation (with glucuronide, glutathione or sulfate). Only minor ring cleavage was observed. Minor quantitative and qualitative differences in the metabolite profile were observed between males and f emales. Excretion was essentially complete by 72 hrs after dosing in all groups. At a single low dose, excretion was primarily via the urine in females (69% AD

, vs. 36% in the feces but was primarily via the feces in males (55%

, vs. 20% in urine. Simila r results were obtained following the 15

- day repeated low dose. At the high dose, excretion was primarily in the feces for both males (87%) and females (70%), due largely to saturation of absorption at that dose.

4.2.1 Dermal Absorption

No dermal absorp tion data are available f or penoxsulam. However, a 28

- day dermal toxicity study in rats was submitted. N o systemic toxicity occurred at the limit dose (1000 mg/kg/day)

, and the primary toxic effects of concern were adequately assessed in the study. Ther efore, it is concluded that penoxsulam is not absorbed

, or is poorly absorbed

, through the skin.

4.3 Toxicological Effects

Penoxsulam is an acetolactase (ALS) inhibitor in plants and is a member of the triazolopyrimidine class of herbicides. Other members of this class include flumetsulam, asulam and chloransulam. This enzyme is present in humans but does not have any known function. The kidney was the major target organ for penoxsulam in the rat and dog following subc hronic and chronic dietary exposure. There are no mechanistic studies characterizing the mode of action for renal toxicity of penoxsulam or other triazolopyrimidine herbicides, but the presence of crystals in the urinary tract and lack of tissue bioaccumu lation suggests that one possibility is via cellular inflammation and damage secondary to their presence in the urine. In both the rat and dog, hyperplasia of the renal pelvic epithelium, and in the rat, inflammation of the renal pelvic epithelium, were o bserved by 4 weeks in dietary dose range

- finding studies. The dog was the more sensitive species in studies of all durations. The rat, but not the dog, showed progression of the severity of kidney toxicity with prolonged exposure. In dogs, renal toxicity in the subchronic and chronic studies occurred at comparable dose levels and measurable effects on renal function were not observed. In the rat, effects on renal function, as indicated by changes inPage 12 of 61

urinalysis parameters (increased BUN and in males, urin ary bladder mucosal hyperplasia and increased severity of chronic glomerulonephropathy), were observed only following chronic exposure. However, despite this increased severity of effects in the rat, the doses at which kidney toxicity occurred were compar able to the subchronic study. Although individual studies showed differences in the sensitivity of males and females to kidney effects, there was not a pattern that identified a consistent greater sensitivity of either sex.

Other effects in the rat inclu ded decreased red blood cell parameters and d ecreased body weight and/or weight gain . Liver effects (increased weight, increased serum ALT, ALK, AST, histopathological changes) were observed at the higher dose levels in the dog 4

- week feeding study but no t in other studies in the database. The findings of liver and/or kidney effects are consistent with effects observed for other triazolopyrimidine herbicides.

No effects of toxicological significance were observed in the mouse, although the 18

- month fee ding study did not test up to the limit dose (1000 mg/kg/day). Penoxsulam showed no evidence of neurotoxicity or immunotoxicity in the rodent, and no effects were seen in rats following dermal exposure. Inhalation data are not available for penoxsulam, b ut the HED HASPOC has determined this study is not needed based on high inhalation MOEs using an oral endpoint, lack of observed irritation effects and low vapor pressure.

There was no evidence of increased pre

- and/or post

- natal susceptibility. No devel opmental effects were observed in the rat or rabbit

. Maternal effects in the rat included decreased body weight gain and food consumption and increased kidney weights. In the rabbit, maternal effects included mortality, clinical signs of toxicity and dec reased body weight gain and food consumption. In the rat two

- generation reproductive toxicity study, delayed preputial separation and lactation body weights were observed in F1 offspring at a dose that caused kidney lesions in parental females.

T he acute lethality of penoxsulam is categorized as very low (Category IV) by all routes of administration. Dermal and eye irritation were minimal (Category IV) and no dermal sensitization potential was observed in guinea pigs.

4.4 Safety F actor for Infants and Children (FQPA Safety Factor)

A fter having evaluat ed the toxicological and exposure data for penoxsulam, HED recommends that the FQPA SF be reduced to 1x

. This recommendation is based on the following:

 The toxicology database is complete and no ad ditional studies are required.

 No evidence of quantitative or qualitative susceptibility was observed in developmental toxicity studies in rats or rabbits or a reproduction study in rats.

 There is no concern for neurotoxicity

.

 The dietary food exposu re assessment is based on the assumptions of tolerance

- level residues and 100% crop treated for all commodities . These assumptions result in veryPage 13 of 61

high

- end estimates of dietary exposure. Actual exposures and risks from penoxsulam are expected to be much l ower. Residential exposure estimates were derived using standard
upper

- bound assumptions, and the corresponding risk estimates were not of concern.

 The dietary drinking water assessment is based on values generated by a model whose associated modeling parameters are designed to provide conservative, high

- end estimates of drinking water concentrations.

4.4.1 Completeness of the Toxicology Database

The database for penoxsulam is complete. Acceptable/guideline studies for developmental toxicity in rats and rabbits, a two

- generation reproduction study in rats, neurotoxicity (acute and chronic) and immunotoxicity studies are available for FQPA assessment. The HED ToxSAC has determined that th e 28

- or 90

- day inhalation toxicity study is not needed (see Section 4.1).

4.4.2 Evidence of Neurotoxicity

N o evidence of neurotoxicity was observed in acute or chronic neurotoxicity studies or in other studies in the toxicology database

.

4.4.3 Evide nce of Sensitivity/Susceptibility in the Developing or Young Animal

No evidence of quantitative or qualitative increased susceptibility, as compared to adults, of rat fetuses to in utero or postnatal exposure was observed in developmental toxicity studies in rats or rabbits or a reproduction study in rats. Developmental toxicity was not observed in the rat or rabbit up to doses resulting in maternal toxicity. In the rat reproductive toxicity study, slightly increased time to preputial separation in F1 males and decreased pup weight gain were observed in the presence of parental toxicity (kidney lesions in females, decreased F1 body weight in males).

4.4.4 Residual Uncertainty in the Exposure Datab ase
There are no residual uncertainties in the exposure database. There are no data gaps that would affect the FQPA factor. Exposure is not likely to be underestimated for penoxsulam.

4.5 Toxicity Endpoint and Point of D eparture Selections

4.5.1 Dose

- Response Assessment

HED has determined that there is not an appropriate (single dose) endpoint to support an acute dietary exposure and risk assessment for the general population or any subpopulation. No toxicity was observed in the rat acute neurotoxic ity study and developmental toxicity was not observed at maternally toxic doses. A POD was therefore not selected.

For chronic dietary exposure, the one

- year chronic toxicity study in dogs was used to select the dose and endpoint for establishing the c hronic reference dose (cRfD). The POD of 14.7Page 14 of 61

mg/kg/day and combined UF of 100 (10x each for interspecies and intraspecies differences, 1x FQPA factor) were used to establish the cRfD of 0.147 mg/kg/day. The LOAEL is 46.2 mg/kg/day (HDT), based on multif ocal hyperplasia of the renal pelvic epithelium. This finding was only observed at the highest dose tested, but was also seen in the 13

- week oral dog study, as well as at higher dose levels in the rat following subchronic and chronic oral exposure, and is therefore a consistent toxicological finding. The selected POD is the most protective dose identified in the available studies.

For short

- term incidental oral exposure, the POD of 17.8 mg/kg/day from the dog 13

- week oral study was selected, based on multifocal hyperplasia of the renal pelvic epithelium at the LOAEL of 49.4 mg/kg/day. A combined UF of 100 (10x each for interspecies and intraspecies differences, 1x FQPA factor) was used. As with the chronic dog study, the endpoint was only seen at the HDT, but it was also observed in the rat at higher dose levels. The selected dose and endpoint are protective of offspring effects ( slightly increased time to preputial separation and decreased pup weight gain during lactation; NOAEL/LOAEL = 30/100 mg/kg/day) that were observed in the rat reproductive toxicity study, in the presence of parental toxicity.

Dermal exposure (short

- and in termediate

- term) was not assessed because an appropriate endpoint was not identified. No toxicity was observed in a rat 28

- day dermal toxicity study. No concerns for developmental toxicity or increased pre

- and/or post

- natal susceptibility were observed in the rat or rabbit.

A subchronic inhalation toxicity is not available for penoxsulam. For short

- and intermediate

term inhalation exposure, the POD of 17.8 mg/kg/day from the dog 13

- week oral study was selected, based on multifocal hyperplasia of the renal pelvic epithelium at the LOAEL of 49.4 mg/kg/day. The selected dose and endpoint are the most sensitive identified for this exposure duration and are protective for developmental toxicity, which was n ot observed in the rat or rabbit at ≥75 mg/kg/day. A combined UF of 100 (10x each for interspecies and intraspecies differences, 1x FQPA factor) was used.

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

As per FQPA, 1996, when there are potential residential exposures to a pesticide, aggregate risk assessment must consider exposures from three major r oute s: oral, dermal and inhalation. HED consider s the potential for concurrent exposure via different routes that produce the sa me toxicological effects. In the event that the same toxicological effect is produced upon exposure through different routes, HED aggregates those exposures. Based on the available toxicological information for penoxsulam , dermal exposures do not result in any adverse systemic effect; therefore, dermal exposures do not need to be included in the estimation of aggregate risk. Chronic dietary, incidental oral and inhalation exposures are being regulated based on renal pelvic hyperplasia seen in the dog sub chronic and chronic oral studies. The use of a common endpoint to evaluate multiple routes of exposure implicitly assumes that different routes of exposures will result in the same toxicological effects and should, therefore, be aggregated.

4.5.3 Cance r Classification and Risk Assessment RecommendationPage 15 of 6 1

Penoxsulam is classified as having “Suggestive Evidence of Carcinogenicity, but Not Sufficient to Assess Human Carcinogenic Potential.” The classific ation wa s based on an increased incidence of mononucl ear cell leukemia (MNCL) in male Fischer 344 rats. Although the tumor incidence was increased in association with treatment, a clear dose

- response relationship was not observed. There were no increases in tumors in treated female rats or in mice. The re levance of MNCL to human cancer risk is not known since this tumor type is specific to the rat, and is also often observed at an increased incidence in older animals. In addition, there was no evidence of genotoxicity in in vitro and in vivo mutagenicity and chromosomal aberration assays. Other triazolopyrimidine her bicides generally do not show evidence of carcinogenicity. Based on these weight

- of

- the

- evidence considerations, human cancer risk was considered to be minimal, and
q uantification of human ca ncer risk was therefore not performed.

There was no evidence of carcinogenicity in cancer studies with mice. Therefore, in accordance with EPA’s Final Guidelines for Carcinogen Risk Assessment (March, 2005), penoxsulam is classified as having “ suggestive evidence of carcinogenicity, but not sufficient to asses human carcinogenic potential

. ” Quantification of human cancer risk was not performed.

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

Table 4.5.4 .1. Summary of Toxicological Doses 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 (All Populations, 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 = 10x

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

UF H =10x 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.

Dermal (all durations) An endpoint for systemic toxicity was not identified in the rat 28

- day dermal study and there

were no neurotoxic, developmental or immunotoxic effects observed for penoxsulam. This exposure scenario was not assessed for human health risk.Page 16 of 61

Table 4.5.4 .1. Summary of Toxicological Doses 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

Inhalation Shor t

- Term (1

- 30 days) and Intermediate

Term (1

- 6 months) NOAEL=

17.8 mg/kg/day UF A = 10x

UF H = 10x 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.

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

Assess Human Carcinogenic Potential 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 = 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 human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chro nic). RfD = reference dose.

Table 4.5.4 .2. Summary of Toxicological Doses and 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 (all durations) An endpoint for systemic toxicity was not identified in the rat 28

- day dermal study and there

were no neurotoxic, developmental or immunotoxic effects observed for penoxsulam. This
exposur e scenario was not assessed for human health risk. Inhalation Short

- Term (1

- 30 days) and 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 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 = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation i n sensitivity among members of the human population (intraspecies). MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

5.0 Dietary Exposure/Risk Characterization

For the purposes of this new use assessment, adequate residue data are available, including metabolism, field and rotational crops, storage stability, and analytical method studies.Page 17 of 61

5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant and An imal Metabolism Studies

Acceptable studies are available depicting the metabolic fate of penoxsulam in target crops, rotational crops and livestock. The nature of the residue in plants is understood for purposes of this petition. The residue of concern for tolerance expression and risk assessment is parent, penoxsulam. An acceptable rice metabolism study reflecting foliar application was previously submitted. Under the current petition, an acceptable grape metabolism study reflecting soil application h as been submitted. Both the rice and grape metabolism studies demonstrate that penoxsulam primarily degrades to its 5

- OH metabolite (5

- OH XDE

- 638); little translocation of penoxsulam or its metabolites into rice grain or grape vine s was observed. HED not es that, should the use pattern for the proposed uses change (i.e., from soil to foliar applications), additional nature of the residue data will be needed.

The HED review of an acceptable rotational crop study concluded that no quantifiable residues of p enoxsulam or 5

- OH XDE

- 638 are expected to be present in the raw agricultural commodities of small grains, leafy vegetables, and root crops planted 90 days following treatment with penoxsulam at 0.045 or 0.090 lb ai/A (1x or 2x the rate for rice). The data also indicate that residues of the metabolite penoxsulam BSTCA could be present at ≥0.01 ppm in the foliage of root crops planted 90 days following treatment at 0.090 lb ai/A (2x). However, HED determined that penoxsulam BSTCA is not a residue of concern for penoxsulam in rotated crops , given that there would be no expectation of finite BSTCA residues at the 1x maximum seasonal rate

. Therefore, HED concluded that parent penoxsulam was adequate as the sole residue of concern.

It was noted that the submitted confined rotational crop study only included one plantback interval, 90 days. If in the future plantback intervals other than 90 days are proposed, an additional confined rotational crop s tudy reflecting the proposed plantback interval would be required. Based on data from the confined rotational crop study, no quantifiable residues of penoxsulam, its 5

- OH metabolite, or BSTCA are expected to be present in the raw agricultural commodities of small grains, leafy vegetables, and root crops planted 90 days following treatment with penoxsulam at 1x the maximum seasonal rate.

With regard to the current petition, the proposed uses are all orchard crops and are not rotated. Therefore, no data pe rtaining to rotational crops and no rotational crop restrictions are required to support the proposed uses.

The nature of the residue in livestock is understood based on adequate goat and poultry metabolism studies. The studies indicated that penoxsulam is primarily excreted and not significantly metabolized in either ruminants or poultry. The sulfonanilide bridge in penoxsulam does not appear to be cleaved. The residue of concern for penoxsulam in livestock is parent only. The fish and shell fish resi dues of concern for risk assessment purposes is penoxsulam and its metabolite 5

- OH penoxsulam, whereas for tolerance enforcement the residue of concern is parent only.Page 18 of 61

5.1.2 Summary of Environmental Degradation D428419, J. Wolf, 28 Aug 2015

Penoxsulam is stable to hydrolysis, and is expected to be somewhat persistent in non

- aquatic environments. The major route of dissipation for penoxsulam in clear and shallow surface water under favorable light conditions is through direct aqueous photolysis ( t 1/2 = 1.5

- 14 days ). Penoxsulam is slightly more persistent in aerobic aquatic ( t 1/2 = 12

- 38 days ) and anaerobic environments ( t 1/2 = 5

- 11 days ), and even more persistent in aerobic soil environments ( t 1/2 = 34

- 118 days ). Penoxsulam is also very mobile (K d = 0.13

- 1.96) , and does have the potential to leach to ground water. The low vapor pressure and Henry’s Law constant limits the potential of penoxsulam to volatiliz e from soil and water.

Eleven major degradation products have been identified for penoxsul am (BSTCA, 2

- amino

TCA, 5

- OH

- penoxsulam, SFA, sulfonamide, 5,8

- di

- OH

- penoxsulam, BSA, 2

- amino

- TP, TPSA, BSTCA methyl, and 5

- OH 2 amino TP). Data are not available to fully characterize these degradates and their respective degradation pathways. Six of th ese degradation products have been identified by HED as being of toxicological concern and are included as residues of concern in drinking water estimates. These residues are: BSTCA, 2

- amino TCA, 5

- OH

penoxsulam, SFA, sulfonamide, and 5,8

- di OH.

5.1.3 Co mparison of Metabolic Pathways

Penoxsulam appears to undergo significant metabolism in rats, crops, and the environment. The 5

- hydroxy metabolite was common to many of these. However, i n the goat and hen metabolism studies, penoxsulam was excreted and n ot significantly metabolized.

5.1.4 Residues of Concern Summary MARC Decision Memo TXR No. 0052740 (DP Barcode D305542, 7/19/04, W. Cutchin)

The toxicological and residue chemistry databases for penoxsulam have been examined to determine residue defi nitions for the purposes of setting tolerances and risk assessments. The residue definitions are summarized in Table 5.1.4

.

Table 5.1.4 Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expression

Matrix Residues included in Risk Assessment Residues included in Tolerance Expression Plants Primary Crop Parent only Parent only

Rotational Crop Parent only Parent only Livestock Ruminant Parent only Parent only

Poultry Parent only Parent only Fish and Shellfish Parent plus 5

- OH penoxsulam Parent only Drinking Water Parent; BSTCA; 2

- amino TCA; 5

- OH

penoxsulam; SFA; sulfonamide; 5,8

- diOH * N/A

* See Appendix C for chemical structures of these compounds.

Residues of concern were determined by HED in 2004 (DP Barco de D305542, 7/19/04, W. Cutchin). Data submitted since that time do not alter those determinations.Page 19 of 61

5.2 Food Residue Profile D425013, 12/04/2015 , E. Holman Residue Chemistry Summary ; D3 55914 ; M. Doherty ; 29 January 2009

The residue chemistry database supporting the registered uses is complete. Acceptable studies are available depicting the metabolic fate of penoxsulam in target crops, rotational crops, and livestock. Acceptable analytical methods are available to enforc e the established tolerances. The tolerance expression for penoxsulam listed in 40CFR §180.605 needs to be updated to include both coverage and compliance statements for enforcement purposes (see Section 2.2.4)

. The data submitted in support of the cur rent action (PP# 4 E8330) along with previously reviewed data, are adequate for purposes of risk assessment and tolerance assessment for the proposed uses under review. HED previously concluded that as long as all field trial residues were below the LOQ of 0.01 ppm, the reduced submitted data set on pome fruit and stone fruit would be adequate to support the proposed uses on pome fruit, stone fruit, olive, and pomegranate (HED ChemSAC minutes, 09/01/2010). Residues were all below the LOQ (0.01 ppm) in submitted pome fruit and stone fruit field trials

. Further details on these field trials, including application rates, preharvest intervals, and number of samples, are provided in Appendix D. The results from these field trials are summarized in Table 5. 2. These data are adequate to support the proposed tolerances at 0.01 ppm in pome fruit, stone fruit, olive, and pomegranate. In addition, based on previously submitted data, the proposed crop group conversion on tree nuts (from
group 14 to group 14

- 12) is appropriate and the data on grape are adequate to support a crop group tolerance at 0.01 ppm for fruit , small, vine climbing, subgroup 13

- 07F. Due to the lack of quantifiable residues in the available field trial data, residue decline could not be asse ssed over time.

Quantifiable residues are not anticipated in livestock commodities, and livestock tolerances have not been established and are not required based on the proposed uses. Quantifiable residues of penoxsulam are not expected in rotational crops, given that all of the existing and registered crops are orchard crops.

5.3 Water Residue Profile D428419, J. Wolf, 28 Aug 2015

The Environmental Fate and Effects Division (EFED) has provided HED with Tier 1 modeled estimates of penoxsulam residues of concern in drinking water based on the proposed new uses, as well as the existing use pattern ( D428419, J. Wolf, 28 Aug 2015 ). The proposed new uses result in lower drinking water estimates than those from the existing use pattern. Based on t he existing turf grass use pattern (0.09 lb a.i./A), residues of penoxsulam are not expected to be greater than 0.0463 ppm (Table 5.3). Penoxsulam is registered for control of aquatic weeds. For that use pattern, the maximum application rate is 150 ppb ( 0.15 ppm) in the water column. For this assessment, HED has used 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 in drinking
water. R esidues were incorporate d in the DEEM

- FCID dietary model into the food categories “water, direct, all sources” and “water, indirect, all sources.”Page 20 of 61

Table 5.3 . Summary of Residue Estimates for Penoxsulam in Drinking Water.

Duration Aquatic Use, ppm Turf Use Surface Water, ppm Ground Water, ppm Acute 0.15 0.00 154 0.0 463 Chronic 0.15 0.00011 0.0313

5.4 Dietary Risk Assessment Memo, E. Holman, 12/04/2015 , D429010

5.4.1 Description of Residue Data Used in Dietary Assessment

For this analysis existing and recommended tolerance levels were used, as well as 100% CT assumptions for all commodities. DEEM (Version 7.81) default processing factors were used for all processed commodities

. Drinking water was incorporated directly in to the dietary assessment using the m aximum chronic concentration associated with the aquatic use at 150 ppb

.

5.4.2 Percent Crop Treated Used in Dietary Assessment

The chronic dietary exposure assessment

, based on food and drinking water

, includes the

as sumption of 100% CT for all existing and proposed uses.

5.4.3 Acute Dietary Risk Assessment

There was no appropriate endpoint identified for assessing acute dietary exposure; therefore, no acute dietary risk assessment was performed.

5.4.4 Chronic Dietary Risk Assessment

An unrefined chronic dietary analysis for penoxsulam was conducted using tolerance

- level residues and 100% CT for all existing and proposed primary crop uses, and additional residues of concern in fish and shellfish commodities

. P enoxsulam chronic dietary (food + drinking water) exposure estimates using the DEEM

- FCIDTM software are below HED’s LOC for the U.S. population and each of the population subgroups. Chronic dietary exposure was 2 % of the chronic population adjusted dose ( cPAD ) for the U.S. population. The chronic dietary exposure for the highest reported exposed population subgroup, children 1

- 2 years old, was 6 % of the cPAD. The results of the analysis indicate that chronic risk from the dietary (food + drinking water) exposure to penoxsulam will not exceed HED’s LOC for the general U.S. population, nor any other population subgroups. Based on the very conservative assumptions used, actual dietary exposure to penoxsulam from food and drinking water is expected to be sig nificantly lower than the exposures presented in Table 5.4.4.

Table 5.4.4

. Summary of Dietary (Food + Drinking Water) Exposure and Risk for Penoxsulam.

Population Subgroup Acute Dietary Chronic Dietary Cancer Dietary Exposure (mg/kg/day) % aPAD Dietary Exposure (mg/kg/day) % cPAD Dietary Exposure (mg/kg/day) Risk General U.S. Population N/A N/A 0.003173 2 N/A N/APage 21 of 61

Table 5.4.4

. Summary of Dietary (Food + Drinking Water) Exposure and Risk for Penoxsulam.

Population Subgroup Acute Dietary Chronic Dietary Cancer Dietary Exposure (mg/kg/day) % aPAD Dietary Exposure (mg/kg/day) % cPAD Dietary Exposure (mg/kg/day) Risk All Infants (< 1 year old) 0.008222 6 Children 1

- 2 years old 0.004725 3 Children 3

- 5 years old 0.003929 3 Children 6

- 12 years old 0.002798 2 Youth 13

- 19 years old 0.002308 2 Adults 20

- 49 years old 0.003153 2 Adults 50+ years old 0.003117 2 Females 13

- 49 years old 0.003140 2 The population subgroup with the highest exposure/risk estimate is bolded

.

5.4.5 Cancer Dietary Risk Assessment

Penoxsulam has been classified as having “suggestive evidence of carcinogenic potential ” for which a dose

- response assessment is not appropriate , and therefore HED has not conducted a quantitative dietary risk assessment for cancer

. T he tumors observed in Fis c her 344 rats did not show a dose

- response and are of questionable relevance to humans (see Section 4.5.3)

. The chronic dietary risk assessment is considered to be protective of all effects, including potential carcinogenicity, observed in the toxicit y database.

6.0 Residential (Non

- Occupational) Exposure/Risk Characterization D428906, 12/04/2015 , G. Thornton
There are no proposed residential uses at this time; however, there are existing residential uses that have been reassessed in this document to reflect updates to HED’s 2012 Residential SOPs 1 and the Aquatic Use SOP along with policy changes for body weight assumptions. Specifically,
t here 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 exposure to homeowners from applying the products on lawns and to adults and children from contacting treated areas while playing or doing lawn maintenance. Such exposures can be of short

- or intermediate

- term duration and can be through dermal, inhalation, or oral routes.

6.1 Residential Handler Exposure

Homeowners are exposed to penoxsulam when they handle granule and liquid products for the control of weeds on home lawns and other sites. The quantitative exposure/risk assessment developed for residential handlers is b ased on the application of penoxsulam to turfgrass through the use of hand held sprayers (e.g., hose

- end sprayer, manually

- pressurized handwand) for dilute liquid formulations and a variety of hand held, wearable, or pushable spreaders for gra nule formulations.

1 Available: http://www.epa.gov/pesticides/science/residential

- exposure

- sop.htmlPage 22 of 61

While there are registered uses for penoxsulam on aquatic vegetation, the label (EPA Reg. #62719

- 546) states under General Use Precautions and Restrictions that state or local authorities be consulted before use of this product. Accordi ng to Residential Aquatic Use SOP, it is assumed in this situation that penoxsulam will only be applied by professionals

. However, since aquatic vegetation in residential areas may be treated with penoxsulam, a residential post

- application
exposure assessm ent is still needed.

HED’s LOC is a MOE greater than or equal to 100 for residential exposure. A quantitative dermal ass essment for residential handlers was not conducted since there is no systemic toxicity associated with dermal exposure to penoxsulam

. Handler inhalation exposure scenarios resulted in MOEs greater than 100 , ranging from 170,000 to 780 million, and these risk estimates are not of concern . Although a point of departure from an oral study was used to assess the handler inhalation risks, t he calculated MOEs are all > 170,000 thus providing an ample margin of safety to account for any uncertainties in the route

- to

- route extrapolation. Handler exposure and risk estimates are summarized in Table 6 .1.

Table 6 .1. Residential Handler Non

- cancer Exposure a nd Risk Estimates for Penoxsulam

.

Exposure Scenario Application Equipment Inhalation Unit Exposure (mg/lb ai) Maximum Application

Rate 1 Area Treated

or Amount Handled Daily 2 Inhalation

Dose (mg/kg/day) 3 MOE 4

Lawns / Turf Hose

- end Sprayer 0.022 0.06 lb ai/acre 0.5 acres 0.0000083 2,200,000

Manually

- pressurized handwand 0.018 0.012 lb ai/gallon 5 gallons 0.000014 1,300,000

Sprinkler can 0.022 0.000001377 lb ai/ft 2 1000 ft 2 0.00000038 47,000,000 Backpack 0.14 0.012 lb ai/gallon 5 gallons 0.00011 170,000

Push

- type rotary spreader 0.0026 0.06 lb ai/acre 0.5 acres 0.00000098 18,000,000

Belly grinder 0.039 0.0000014 lb ai/ft 2 1200 ft 2 0.00000082 22,000,000 Spoon 0.087 0.0000014 lb ai/ft 2 100 ft 2 0.00000015 120,000,000 Cup 0.013 0.0000014 lb ai/ft 2 100 ft 2 0.000000023 780,000,000 Hand dispersal 0.38 0.0000014 lb ai/ft 2 100 ft 2 0.00000067 27,000,000
Shaker can 0.013 0.0000014 lb ai/ft 2 100 ft 2 0.000000023 780,000,000
1 Based on currently registered label s. 2 Based on HED’s 2012 Residential SOPs ( http://www.epa.gov/pesticides/science/residential

- exposure

- sop.html ). 3 Inhalation Dose = Inhalation Unit Exposure (mg/lb ai) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A

/day or gallons/day) ÷ BW (kg). 4 Inhalation MOE = Inhalation NOAEL (mg/kg/day) ÷ Inhalation Dose (mg/kg/day).

6.2. Residential Post

- application Exposure

There is the potential for post

- application exposure for individuals as a result of being in an environment that has been previously treated with penoxsulam. The quantitative ex posure/risk
assessment for residential post

- application exposures considers inhalation and incidental oral exposures following application to turf grass and aquatic areas in residential settings. Although exposure may result from the dermal route and from potential episodic ingestion of the granules, no endpoints were identified for these scenarios, and therefore, risks were not quantified. OnlyPage 23 of 61

incidental oral exposure for children (1 to < 2 years old) has been assessed for post

- application lawn/turf scenarios. For post

- application scenarios involving aquatic application of penoxsulam, exposure and risk estimates have been assessed for inhalation and ingestion for adults and children (3 to < 6 years old).

There are no risk estimates of concern for residential post

- application scenarios. The lowest MOE s do not result in risks of concern (MOEs > 4,600). Table 6.2 only contains the MOEs calculated for liquid formulations as they represent the w orst case scenario and are protective of exposure and risk associated with application of solid formulations (e.g., granules )

.

Table 6.2. Residential Post

- application Non

- cancer Exposure and Risk Estimates for Penoxsulam

.

Use/Target Formulation Applicat ion Rate 1 Lifestage Post

- application Exposure Scenario Dose/Exposure 2
MOE 3,4 (mg/kg

- day )

Lawns/Turf Liquid 0.06 (lb ai/acre) Child 1 to < 2
years Hand to Mouth 5 0.0038 4,600

Object to Mouth 5 0.00012 150,000 Soil Ingestion 5 2.0E

- 6 8

, 800

, 000

Lawns/Turf Granule 0.06 (lb ai/acre) Child 1 to < 2
years Hand to Mouth 5 0.0001 200,000

Object to Mouth 5 0.00001 3,200,000 Soil Ingestion 5 2.0E

- 6 8,800,000

Aquatic Uses Liquid 0 .009 (lb ai/ 1000 ft 3 ) Child 3 to < 6
years Inhalation 8.3E

- 21 2.1 E+21

Ingestion 4.0E

- 5 450,000

Adult Inhalation 7.5E

- 21 2.4E+2 1

Ingestion 2.3E

- 5 760

, 000

1 Based on currently registered labels. 2 Dose (mg/kg/day) algorithms provided in 2012 Residential SOPs ( http://www.epa.gov/pesticides/science/residential

- exposure

- sop.html ). 3 MOE = POD (mg/kg/day) ÷ Dose (mg/kg/day). 4 The MOEs listed are based off of the liquid formulations of penoxsulam as they represent the worst case for each exposure scenario and

cons idered protective for solid formulations. 5 Hand to Mouth, Object to Mouth, and Soil Ingestion are all considered incidental oral.

6.3 Other (Spray Drift, etc .)

Spray drift is a potential source of exposure to those nearby pesticide applications. This is particularly the case with aerial application, but, to a lesser extent, spray drift can also be a potential source of exposure from the ground application method s (e.g., groundboom and airblast) employed for penoxsulam

. The agency has been working with the Spray Drift Task Force (a task force composed of various registrants which was developed as a result of a Data Call

- In issued by EPA), EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the agency’s Spray Drift website for more information). 2 The agency has also developed a policy on how to appropriately consider spr ay drift as a potential source of exposure in risk assessments for pesticides. The potential for spray drift will be quantitatively 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 Assessment (SOPs)

- Residential Exposure Assessment Standard Operating

2 Available: http://www.epa.gov/opp00001/factsheets/spraydrift.htmPage 24 of 61

Procedures Addenda 1: Consideration of Spray Drift. This doc ument outlines the quantification of indirect non

- occupational exposure to drift.

7.0 Aggregate Risk Assessments and Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e .g., a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposure and risk from various sources, HED considers both the route and duration of exposure

.
Table 7.0 reflects the residential risk estimates that are recommended for use in the aggregate assessment for penoxsulam:

 The recommended residential exposure for use in the adult aggregate assessment reflect s handlers’ inhalation exposure during applications to l awn/turf via backpack sprayer.

 The recommended residential exposure for use in the children 3 to <6 years old aggregate assessment reflects post

- application ingestion during aquatic activities.

 The recommended residential exposure for use in the children 1 to <2 years old aggregate assessment reflects hand

- to

- mouth exposure from post

- application exposure to lawn/turf applications.

Table 7.0 . Recommendations for the Resident ial Exposures for Penoxsulam Aggregate Assessment. 1, 2

Lifestage Handler Post

- application

Use Inhalation

Dose (mg/kg/day) Inhalation

MOE Use Dose (mg/kg/day) MOE

Oral Oral
Adult Lawn/Turf 0.00011 170 , 000 Aquatic 2.3E

- 5 760,000
Child 3 to <6
yrs N/A N/A 4.0E

- 5 450,000

Child 1 to <2
yrs N/A Lawn/Turf 0.0059 4,600

1. Bolded MOEs are the recommended risk estimates to be used in the aggregate assessment. 2. Inhalation MOEs for post

- application were not included as they were either not quantified (child 1 to <2 years on turf) or exposures were negligible (adult and child 3 to <6 years for aquatic uses).

7.1 Acute Aggregate Risk

No toxicological endpoint attributable to a single exposure was identified in the available toxicology studie s on penoxsulam. Acute aggregate exposure is not a concern for this compound.

7.2 Short

- Term Aggregate Risk

Short

- term residential exposures may occur during residential handling on lawns/turf, as well as following application of penoxsulam to turf and aquatic use sites (see Section 6.2)

. T herefore, the s hort

- term aggregate risk estimates ( Table 7.2 ) include dietary exposure and incidental oral exposure from activities on turf or from the aquatic use . The resultin g short

- term MOEs arePage 25 of 61

greater than the level of concern of 100 and, therefore, reflect risk estimates that are not of concern to HED.

Table 7.2. Aggregate Short

- Term MOEs for Penoxsulam

Population Subgroup MOE

Dietary 1 Residential

Handler 2 Incidental Oral 2 Aggregate 3 General U.S. Population 5600 170,000 N/A 5400 All Infants (< 1 year old) 2200 N/A 4,600 1500 Children 1

- 2 years old 3800 N/A 4,600 2100 Children 3

- 5 years old 4500 N/A 450,000 4500

1 Dietary MOE = Short

- term NOAEL (17.8 mg/kg/day)  Chronic dietary exposure estimate (Table 5. 4.4 )

2 Table 7.0 (worst

- case value)

3 Aggregate MOE = 1  [(1  Dietary MOE) + (1  Handler MOE) + (1  Incidental Oral MOE)]

7.3 Chronic Aggregate Risk

Chronic aggregate risk is equivalent to chronic dietary exposure and risk, which is not of concern. Refer to Section 5.4.4.

8.0 Cumulative Risk Characterization/Assessment

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as
to penoxsulam and any other substances and penoxsulam does not appear to produ ce a toxic metabolite produced by other substances. For the purposes of this action, therefore, EPA has not assumed that penoxsulam has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determine which chemica ls have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy 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/.

9.0 Occupational Exposure/Risk Characterization

Penoxsulam may be used either as a pre

- or post

- eme rgence weed control via ground or aerial applications. However, the new uses currently under review do not allow aerial application. Based on the proposed use pattern ( i.e., repeat applications are allowed up to the seasonal maximum with a retreatment in terval of 30 days ), the duration of exposure for the proposed uses is expected to be short

- term (1 to 30 days) and intermediate

- term (1 to 6 months). Long

- term exposures (greater than 6 months) are not anticipated.

No chemical

- specific handler exposure data were submitted in support of this assessment ; therefore, HED relied on surrogate data and default assumptions in accordance with standard poli cies. In the absence of a dermal toxicity endpoint , dermal handler and post

- application exposure assessment s were not conducted

. The occupational handler exposure and risk estimates show that the inhalation MOEs are not of concern (i.e., MOE ≥ 100) assuming baseline attire (i.e., no respirator). The range of MOE estimates for all scenarios is 53,000 to 5,200,000.Page 26 of 61

Additional PPE including coveralls, chemical

- resistant footwear plus socks, chemical

- resistant gloves, safety glasses, chemical

- resistant headgear when exposed overhead, and chemical

resistant apron when exposed to the concentrate , are required for certain handler scenarios based on the toxicity of the co

- formulant oxyfluorfen

. A summary of the short

- and intermediate

- term occupational handler expos ure and risk estimates is provided in Table 9 .1

.Page 27 of 61

Table 9 .1. Occupational Handler Non

- Cancer Exposure and Risk Estimates for Penoxsulam.

Exposure Scenario Crop or Target Level of Concern Inhalation Unit Exposure ( μ g/lb ai) 1 Maximum

Application Rate 2 Area Treated

or Amount Handled Daily 3 Inhalation

Baseline Dose (mg/kg/day) 4 MOE 5

Mixer/Loader

Groundboom Orchard/

Vineyard 100 0.219 0.03 40 acres 0.0000034 5,2 00

, 000

Applicator

Groundboom Orchard/

Vineyard 100 0.34 0.03 40 acres 0.00000528 3,400,000

Mixer/Loader/Applicator

Backpack Orchard/

Vineyard 100 2.58 0.003 (lb ai/gal) 40 gallons 0.000004 4,5 00

, 000

Mechanically

pressurized Handgun Orchard/

Vineyard 100 8.68 1000 gallons 0.000336 53, 000

1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” ( March 2013 ) ; Level of mitigation: Baseline Eng. Controls. 2 Based on proposed uses on label (Reg. No. 62719

- 611 ). 3 Exposure Science Advisory Council Policy #9.1. 4 Inhalation Dose = Inhalation Unit Exposure ( μ g/lb ai) × Conversion Factor (0.001 mg/ μ g) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A or gal/day) ÷ BW (kg). 5 Inhalation MOE = Inhalat ion NOAEL (mg/kg/day) ÷ Inhalation Dose (mg/kg/day).

– level of concern is already in table & abbreviation not used herePage 28 of 61

9.1 Post

- Application Risk

9.1.1 Post

- Application Dermal Exposure

Since an endpoint for dermal toxicity was not identified for penoxsulam, a dermal post

application exposure and risk assessment was not conducted.

9.1.2. Post

- Application Inhalation Exposure

There are multiple potential sources of post

- application inhalation exposure to individuals performing post

- application ac tivities in previously treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides. The agency sought expert advice and input on issues related to volatilization of
pes ticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ). The agency has

e valuated the SAP report and has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis ( http://www.regulations.gov/#!docketDetail;D= EPA

- HQ

OPP

- 2014

- 0219 ). During Registration 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 penoxsulam

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

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

- application inhalation exposure into the agency's risk assessments.

Although a quantitative occupational post

- application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commerci al 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.

Restricted Entry Interval

Penoxsulam is classified as Toxicity Category IV for toxicity via the dermal route and for skin irritation potential. It is not a skin sensitizer. No dermal toxicolo gical endpoint was selected, so post

- application dermal exposure risk estimates were not of concern. Under 40 CFR 156.208 (c) (2), ai’s classified as Acute III or IV for acute dermal, eye irritation and primary skin irritation are assigned a 12

- hour REI. Therefore, the [156 subpart K] Worker Protection Statement interim REI of 12 hours is adequate to protect agricultural workers from post

- application exposures to penoxsulam . Currently, the penoxsulam labels specify a REI of 24 hours, compliant with both the acute toxicity based requirements of the Worker Protection Standard and HED’s risk
assessment

.

ReferencesPage 29 of 61

M. Doherty, D355914, 01/29/2009. “ 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. ”

J. Leshin, TXR No. 0051714, March 17, 2015. 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.

G. Thornton

, D428906

, 12/04/2015 . “ PENOXSULAM: Occupa tional and Residential Exposure Assessment for a Proposed Use on pome fruit Group 11

- 10, stone fruit Group 12

- 12, olive, and pomegranate; a requested crop group extension for grapes to small fruit vine climbing subgroup 13

- 07F; and a crop group update requested for tree nut to the new crop group 14

- 12.”

E. Holman, D425013, 12/04/2015 . “ Penoxsulam. Petition to Establish Permanent Tolerances (with Section 3 Regis tration) for Residues Resulting from Use of the Herbicide on Pome Fruit, Stone Fruit, Olive, Pomegranate, and Fruit, Small, Vine Climbing (Subgroup 13

- 07F, Except Fuzzy Kiwifruit); and Crop Group Conversion for Tree Nuts. Summary of Analytical Chemistry and Residue Data. ”

E. Holman , D 429010

, 12/04/2015 . “ Penoxsulam. Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessment for the Section 3 Registration on Pome Fruit, Stone Fruit, Olive, Pomegranate, and Fruit, Small, Vine Clim bing (Subgroup 13

- 07F, Except Fuzzy Kiwifruit); and Crop Group Conversion for Tree Nuts. ”

Minutes from ChemSAC meeting ; Chemistry Science Advisory Council (ChemSAC), Health Effects Division (HED), Office of Pesticide Programs (OPP), Office of Chemical Safety and Pollution Prevention (OCSPP), USEPA; 1 September 2010.

Penoxsulam: Revised Human Health Risk Assessment for Proposed Uses on Grapes and Tree Nuts; D363910 ; C. Swartz ; 9 April 2009

Penoxsulam Drinking water exposure concentrations for the p roposed new uses on pome fruit group 11

- 10 (plus olive and pomegranate), stone fruit group (12

- 12), conversion of nut tree group 12 to tree nut group 14

- 12, and group expansion from grapes to include small fruit vine climbing subgroup (13

- 07F) and updated assessment for drinking water exposure for the other

uses. D428419; J. Wolf; 28 Aug 2015.Page 30 of 61

Appendix A

. Toxicology Profile

A.1 Toxicology Data Requirements
The requirements (40 CFR 158.340) for food use for penoxsulam are in Table A. 1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Table A.1 Test Technical

Required Satisfied

870.1100 Acute Oral Toxicity

................................ ........................ 870.1200 Acute Dermal Toxicity

................................ ................... 870.1300 Acute Inhalation Toxicity

................................ ............... 870.2400 Primary Eye Irritation

................................ ..................... 870.2500 Primary Dermal Irritation

................................ ............... 870.2600 Dermal Sensitization

................................ ....................... yes yes yes yes yes yes yes

yes yes yes yes yes

870.3100 Oral Subchronic (rodent)

................................ ................ 870.3150 Oral Subchronic (nonrodent)

................................ .......... 870.3200 21/28

- Day Dermal

................................ .......................... 870.3250 90

- Day Dermal

................................ ............................... 870.3465 28/ 90

- Day Inhalation

................................ ...................... yes yes yes

no

no * yes

yes yes

---

---

870.3700a Developmental Toxicity (rodent)

................................ .... 870.3700b Developmental Toxicity (nonrodent)

.............................. 870.3800 Reproduction

................................ ................................ .. yes yes yes yes

yes yes

870.4100a Chronic Toxicity (rodent)

................................ ............... 870.4100b Chronic Toxicity (nonrodent)

................................ ......... 870.4200a Oncogenicity (rat)

................................ ........................... 870.4200b Oncogenicity (mouse)

................................ ..................... 870.4300 Chronic/Oncogenicity

................................ ..................... yes yes yes yes yes yes

yes yes yes yes

870.5100 Mutagenicity

— Gene Mutation

- bacterial

...................... 870.5300 Mutagenicity

— Gene Mutation

- mammalian

................. 870.5375 Mutagenicity

— Structural Chromosomal Aberrations

.... 870.5395 Mutagenicity

— Mammalian Erythrocyte Micronucleus

. 870.5550 Mutagenicity

— Unscheduled DNA S ynthesis

................ 870.5915 Mutagenicity

— In Vivo Sister Chromatid Exchange yes yes yes yes

no

no yes

yes yes yes

--

--

870.6100a Acute Delayed Neurotox icity . (hen)

............................... 870.6100b 90

- Day Neurotoxicity (hen)

................................ ............ 870.6200a Acute Neurotoxicity Screening Battery (rat)

.................. 870.6200b 90 Day Neurotoxicity Screening Battery (rat)

................ 870.6300 Develop. Neuro toxicity

................................ ................... no

no yes yes

no ---

--- yes yes

---

870.7485 General Metabolism

................................ ....................... 870.7600 Dermal Penetration

................................ ......................... yes

no yes

--

870.7800 Immunotoxicity................................................ yes yes

* Requirement waived by HED HASPOC (TXR No. 0051714 , 3/17/15 )Page 31 of 61

A.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.

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)Page 32 of 61

Table A.2.2. Penoxsulam (XDE

- 638) Subchronic, Chronic and Other Toxicity Profile.

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

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)

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)Page 33 of 61

Table A.2.2. Penoxsulam (XDE

- 638) Subchronic, Chronic and Other Toxicity Profile.

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

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.

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)Page 34 of 61

Table A.2.2. Penoxsulam (XDE

- 638) Subchronic, Chronic and Other Toxicity Profile.

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

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 mutat ions 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.

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.Page 35 of 61

Table A.2.2. Penoxsulam (XDE

- 638) Subchronic, Chronic and Other Toxicity Profile.

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

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.

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)Page 36 of 61

A.3 Hazard Identification and Endpoint Selection

A.3.1 A cute Reference Dose (aRfD)

– All P opulation s Including Infants, Children and Females 13

- 49 Years of Age

An acute reference dose for the general population or any subpopulation has not been established because an appropriate endpoint was not identified

. There were no clinical signs observed in the available studies following single or repeated dosing. In an acute neurotoxicity study in rats (MRID 45830902), no toxicity was observed up to the limit dose of 2000 mg/kg. No developmental effects were observed in the rat (MRID 45830917) or rabbit (MRID 45830918).

A.3 .2 Chronic Reference Dose (cRfD )

Study Selected : One Year Chronic Dietary Toxic ity Study in Dog s MRID No: 45830914 Dose and Endpoint for Risk Assessment : NOAEL= 14.7 mg/kg/day Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability)

Chronic RfD = = 0. 147 mg/kg/day

Comments about Study/Endpoint/Uncertainty Factors: The dog chronic toxicity study was used to select the dose and endpoint for establishing the cRfD of 0.147 mg/kg/day. The NOAEL of 14.7 mg/kg/day an d the LOAEL of 46.2 mg/kg/day were based on hyperplasia of the renal pelvic epithelium in one male

. However, similar lesions were seen in male and female dogs in 4

- and 13

- week d ietary studies at similar dose levels. Furthermore, The route of exposure and duration of this study are appropriate for assessing risks from chronic dietary exposure. The selected dose and endpoint are protective of all other effects, including develop mental toxicity, which was not observed

A.3.3 Incidental Oral Exposure

Short

- Term (

1

- 30 days)

Study Selected: 13

- week dietary study in Dogs MRID No: 45830909 Dose and Endpoint for Risk Assessment: 17.8 mg/kg/day, based on hyperplasia of the renal pelvic epithelium in males and females at 49.4 mg/kg/day. Uncertainty Factor: 100x (10x for interspecies and 10x for intraspecies variation) Comments about Study/Endpoint/Uncertainty Factors : The 13

- week study is of the appropriate duration for this risk assessment. This effect was only observed at the highest dose tested, but it was seen in the 4

- week and the chronic dog study, as well as in rat subchronic and chronic studies at higher dos e levels, and is therefore a consistent effect of treatment, and an appropriate endpoint. For short

- term exposure the 13

- week study was selected, instead of the 4

- week study, because a NOAEL for renal pelvic hyperplasia was not observed in females after 4 weeks (LOAEL = 32 mg/kg/day, lowest dose tested). The study is the most sensitive availablePage 37 of 61

and is protective of all other observed effects, including offspring toxicity (slight delays in preputial separation and decreased pup weight during lactation in F1 males) in the rat reproductive toxicity study, which was observed in the presence of parental toxicity (NOAEL = 30 mg/kg/day). A combined UF of 100 (10x interspecies and 10x intraspecies UF) was selected.

A.3. 4 Dermal Absorption

Dermal absorption data are not available f or penoxsulam. However, a 28

- day dermal toxicity study in rats was submitted (MRID 45830911). N o systemic toxicity occurred at the limit dose (1000 mg/kg/day)

, and the primary toxic effects of con cern were adequately assessed in the study. Therefore, it is concluded that penoxsulam is not absorbed

, or is poorly absorbed

, through the skin.

A.3. 5 Residential and Occupational Dermal Exposure (Short

- and Intermediate

- Term )

A dermal risk assessment was not performed because an appropriate endpoint was not identified. In a 28

- day dermal toxicity study in rats, no systemic toxicity or local dermal irritation was observed up to t he limit dose tested of 1

, 000 mg/kg/day. No evidence of increased pre

- or postnatal susceptibility, or endpoints of concern for developmental toxicity, were observed. Therefore, a POD was not selected.

A.3. 6 Residential and Occupational Inhalation Expo sure

Short

- Term (1

- 30 days) and Intermediate

- Term (1

– 6 months)

Study Selected: 13

- week dietary toxicity study in dogs MRID No: 45830909 Dose and Endpoint for Risk Assessment: NOAEL= 1 7.8 mg /kg/day , based on hyperplasia in the renal pelvis in males at the LOAEL of 49.4 mg/kg/day. Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability) Comments about Study/Endpoint/Uncertainty Factors: A subchronic inhalation toxicity is not available for penoxsulam. The HED HASPOC determined that the study was not needed based on sufficiently high MOEs (>1000) for inhalation exposure using oral data. In the absence of data on toxicity via the inhalat ion route, an oral study was selected see Incidental Oral Exposure, above, for details). The study is the most sensitive and is protective of all other observed effects. Developmental toxicity was not observed in the available studies at doses resulting in maternal toxicity. The inhalation absorption is assumed to be 100%. A combined UF of 100 (10x interspecies and 10x intraspecies UF) was selected.Page 38 of 61

A.4 Executive Summaries

A.4.1 Subchronic Toxicity

870.3050 28

- Day Oral Toxicity

– Rat

In a 4

- week dietary toxicity study (MRID 45830903), XR

- 638 (penoxsulam technical, 99% a.i.

, lot number 597

- CO49

- 17C, TSN101644) was administered to 5 Fischer 344 rats/sex/dose in the diet at concentrations targeted to provide 0, 10, 100, 500 or 1000 mg/kg/day. Animal care, diet preparation, and gross necropsy were as described in the main study (MRID 45830906). Tissues from animals receiving the control and 1000 mg/kg/day diets, as well as the liver, kidneys, and relevant gross lesions from the remaining dose groups, were processed as in the main study and examined microscopically.

All animals survived until scheduled sacrifice. Perineal urine soiling, observed in one 500 mg/kg/day male, four 500 mg/kg/day females and three 1000 mg/kg/day females, was not considered t o be a toxicologically significant adverse effect. Ophthalmology was unremarkable. Body weights of both sexes receiving 1000 mg/kg/day were lower than those of controls throughout the study, and at day 29 were about 10% (males) and 6% (females) below those of controls. Body weight gains at day 29 were 25% (males and females) lower than those of controls. At 500 mg/kg/day, body weights of both sexes were also lower than those of controls throughout the study, and at day 29 were about 8% (males) and 4% (femal es) below those of controls. Body weight gains at day 29 were 20% (males and females) lower than those of controls. At 1000 and 500 mg/kg/day, overall food consumption by both sexes was about 5

- 11% lower than that of controls. Slight, statistically signifi cant decreases in red blood cell parameters (<10% at 1000 mg/kg/day) were present in males and females from all dose levels but were more pronounced at 1000 and 500 mg/kg/day. There were no toxicologically significant changes in clinical chemistry or urina lyses. Kidney weight was increased by about 10% in the 1000 and 500 mg/kg/day females. Slight multifocal hyperplasia of the renal pelvic epithelium, very slight subacute to chronic inflammation of the renal pelvic epithelium, and crystals in the urinary sp ace of the renal pelvis were found in females of the 500 and 1000 mg/kg/day groups (Table 1) . One 500 mg/kg/day male had a few crystals in the urinary space of the renal pelvis of one kidney. The LOAEL is 500 mg/kg/day based on decreased body weights (mal es and females), decreased body weight gains (males and females), decreased feed consumption (males and females), decreased RBC parameters (males and females), increased kidney weights (females), and histopathology in the kidneys of females (crystals in th e pelvis and inflammation and hyperplasia of the pelvic epithelium). The NOAEL is 100 mg/kg/day.

This 4

- week oral toxicity study in the rat is classified as Acceptable/Non

- Guideline as a range finding study. It was conducted for purposes of dose selection and does not satisfy the guideline requirement for a subchronic oral toxicity study (O CSPP 870.3100; OECD 408) in rats.

870.3050 28

- Day Oral Toxicity

– Mouse

In a 4

- week subacute oral toxicity study (MRID 45830904), XR

- 638 [ penoxsulam technical, 99.0% a.i. , Lot No. 597

- C049

- 17C/TSN101644) was administered to 5 CD

- 1 mice/sex/dose in the diet at concentrations targeted to pro vide 0, 10, 100, 500 or 1000 mg/kg bw/day (actual doses were 0, 10.5, 103.1, 529.8 a nd 1018.4 mg/kg bw/day and 0, 10.8, 110.0, 545.2 and 1068.8 mg /kg bw/day in males and females, respectively). The average concentration of XR

- 638 in the dietPage 39 of 61

ranged from 62 to 6026 ppm for males and 52 to 5108 ppm for females. The highest targeted dose selected was the limit dose and the lower targeted dose levels were expected to provide dose

- response data. The objective of this study was to evaluate the potential toxicity of XR

- 638 in mice by dietary administration over 4 weeks.

There were no mortali ties and no effects of treatment on clinical obser vations, body weight, food consumption, ophthalmoscopic examinations, hematology, clinical chemistry, or gross necropsy examinations. An increase in absolute and relative liver weights (7

- 27% and 6

- 27%, r espec

tively) was observed in mice of both sexes at doses  100 mg/kg/day. The increases correlated with the presence of centrilobular hepatocellular hypertrophy at 500 and 1000 mg/kg/day (5/5 and 5/5 in males and 3/5 and 5/5 in females, respectively). Th e hypertrophy was moderate in most males and slight in all females. One 1000 mg/kg/day female had a urinary bladder calculus (with hyperplasia and chronic inflammation of the urinary bladder epithelium) that may have been treatment

- related.

The study a uthors concluded that based on the increase in liver weights accompanied by hepatocellular hypertrophy, ingestion of XR

- 638 by mice in the diet for 4 weeks had an adverse effect at > 500 mg/kg/day in males and females. In contrast to the interpretation of the study authors, however, the increases in liver weight and hepato cellular hypertrophy observed in the male and female mice in this study are not considered adverse findings. Rather, they are considered adaptive responses indicating a stimulation of th e liver microsomal enzyme system by the test material. This conclusion is supported by the absence of any other toxicologically significant effects in this study, and particularly the lack of effects suggesting significant toxicity to the liver (e.g. incr eased ALT or AST, changes in other clinical chemistry parameters suggesting liver damage, and results of macroscopic and microscopic examination of liver tissue). This interpretation of the results in this study is consistent with the most recent and

curr ent guidance provided to HED reviewers in the following two documents: 1) “Hepatocellular Hypertrophy” (HED Guidance Document #G0201, dated October 21, 2002), and 2) “Rodent Carcinogenicity Studies: Dose Selection and Evaluation

- Interim Guidance” (HED Inte rim Guidance Document #G2003.02, dated July 1, 2003). The NOAEL for the male and female mice in this study is 1018 mg/kg/day for males and 1069 mg/kg/day for females (actual doses , HDT ). A LOAEL was not observed in this study (>1018 mg/kg/day for males a nd >1069 mg/kg/day for females). Dosing in this study is considered to be adequate since the limit dose in subchronic feeding studies is 1000 mg/kg/day.

This 4

- week oral toxicity study in mice is Acceptable/Non

- Guideline as a range

- finding study. It was conducted for dose selection purposes for the 90

- day mouse study and does not satisfy the guideline requirement for a 90

- day oral toxicity study (OCSPP 870.3100; OECD 408) in mice.

870.3050 28

- Day Oral Toxicity

– Dog

In a 4

- week oral toxicity study (MRID 45830908), XDE

- 638 (penoxsulam technical >99% a.i.; Lot No. 597

- C049

- 17C, TSN101644) was administered to two Beagle dogs/sex/dose in the diet at concentrations of 0, 0.09, 0.45 or 0.9% (equal to average daily doses of 0, 29, 133 or 192 mg/kg bw /day, respectively, in males and 0, 32, 163 or 196 mg/kg bw/day, respectively, in females).

At 0.9% XDE

- 638, males and females lost body weight (decreased 7 to 13% from the initial body weights) and decreased food consumption (reduced by 1/3, males and 1⁄2, females, relativePage 40 of 61

to controls). The primary target organs were the liver and kidney. Histopathological changes in the liver at 0.45% and 0.9% in both sexes were slight to moderate hepatocellular necrosis with very slight to moderate subacute to chronic inflammation. Additionally, hepatocellular atrophy, bile stasis and increased mitotic figures in hepatocytes were seen in one male at 0.45% and necrosis of individual hepatocytes was noted in one female. Other liver effects at 0.45% and 0.9% included inc reased absolute and relative liver weights and increased ALT, ALK and AST activities. One female at 0.09% had increased absolute and relative liver weights but no clinical chemistry or histopathological changes.

Histopathological changes in the kidneys at 0.45% and 0.9% consisted of hyperplasia and subacute to chronic inflammation of the pelvic epithelium, and crystals in the urinary space of the renal pelvis. Amorphous crystals observed in the urine of these ani mals were similar to those in the renal pelvis. Additionally, one female at 0.09% had inflammation and hyperplasia of the renal pelvic epithelium, and the other female had amorphous crystals in the urine, which were considered treatment

- related findings. The LOAEL for male dogs was 0.45% (133 mg/ kg bw/day), based on increased liver weights, increased ALT, ALK and AST, and on histopathological changes in the liver and kidneys. The LOAEL for female dogs was 0.09% (32 mg/kg bw/day), based on histopathologi cal changes in the kidneys. The NOAEL for males was 0.09% (129 mg/kg bw/day) and <0.09% (<32 mg/kg bw/day) for females.

This 4

- week oral toxicity study in the dog is classified Acceptable/Non

- guideline and does not satisfy the guideline requirement for a subchronic oral toxicity study in the dog (OPPTS 870.3150; OECD 409). The study was conducted for purposes of dose selection for the 90

- day dog study and not to satisfy a guideline requirement.

870.3100 90

- Day Oral Toxicity

- Rat

In a 90

- day oral toxicity study (MRID 45830906) XDE

- 638 (penoxsulam technical, 97.5% a.i.

, lot number ND05167938, TSN101773), was administered to 10 Fischer 344 rats/sex/dose in the diet at concentrations targeted to provide 0, 5, 50, 250 or 500 mg/kg/day. Recovery groups receiving 0 or 500 mg/kg/day during the study were maintained for an additional four weeks on the control diet. Dosing was based on 4

- week dietary range

- finding toxicity study (MRID 45830903), in which penoxsulam was administered to 5 Fischer 344 rats/se x/dose in the diet at concentrations targeted to provide 0, 10, 100, 500 or 1000 mg/kg/day (summarized in the Appendix to this DER)

. No animals died during the 90

- day study. The only treatment

- related clinical sign was perineal urine soiling (more preval ent in females than males) that was not considered to be a toxicologically significant adverse effect. Body weights were reduced in males at 500 and 250 mg/kg/day. At 500 mg/kg/day, body weights were decreased 4

- 5% from control values during the study an d were decreased 5% at termination of the study. At 250 mg/kg/day, body weights were decreased 3

- 8% from control values during the study and were decreased 7% at termination of the study. Body weight gains were also reduced in males at 500 and 250 mg/kg/ day. The overall body weight gains were decreased 9% at 500 mg/kg/day and 12% at 250 mg/kg/day compared to controls at termination of the study. Average daily feed consumption was reduced in males at 500 and 250 mg/kg/day throughout the duration of the s tudy. At 500 mg/kg/day, overall feed consumption (days 1

- 92) was decreased 6%. At 250 mg/kg/day, overall feed consumption was decreased 8%. The changes in body weights and food consumption were of a small magnitude (<10%) and therefore, were not biologica lly relevant.Page 41 of 61

In males at 500 mg/kg/day, statistically significant decreases in red blood cell counts (decreased 5%), hemoglobin (decreased 8%) and hematocrit (decreased 7%) were observed. Also, in males at 250 mg/kg/day, statistically significant decre ases in hemoglobin (decreased 4%) and hematocrit (decreased 4%) were observed. These changes in hematological parameters were marginal (<10%) and were not toxicologically significant. . Although possibly treatment

- related, increases in total protein, album in and serum cholesterol observed in the 500 and 250 mg/kg/day males are considered to be of equivocal toxicological significance.

Increased liver weights observed in males and females at 250 and 500 mg/kg/day are considered to be adaptive responses, ra ther than adverse effects, as there were no microscopic correlates except for slight hypertrophy in the 500 mg/kg/day males. Microscopic kidney changes were seen in the females at 500 mg/kg/day (mineralization and hyperplasia of the pelvic epithelium)

, ar e considered to be treatment

- related, and may be related to the sex

- related difference in metabolism in which elimination of XDE

- 638 was found to be primarily fecal in males and urinary in females.

In male rats, the NOAEL is 50 0 mg/kg/day. A LOAEL in mal e rats was not identified. In female rats, the LOAEL is 500 mg/kg/day based on increased incidences of mineralization and hyperplasia of the pelvic epithelium in the kidneys. In female rats, the NOAEL is 250 mg/kg/day.

This 90

- day oral toxicity study in the rat is classified as Acceptable/Guideline and satisfies the guideline requirement for a 90

- day oral toxicity study (OPPTS 870.3100; OECD 408) in rats.

870.3100 90

- Day Oral Toxicity

- Mouse

In a 90

- day subchronic oral toxicity study (MRID 45830905 ), XDE

- 638 ( penoxsulam technical, 97.5% a.i .; Lot No. ND05167938/TSN1017731) was administered to 10 CD

- 1 mice/sex/dose in the diet at concentrations targeted to provide 0, 10, 100, 500 or 1000 mg/kg/day (actual doses were 0, 10.2, 101.8, 511.3 and 1027 mg/kg bw/day, respectively for males and 0, 10 .4, 103.7, 524.1 and 1029 mg/kg bw/day, respectively for females).Page 42 of 61

There were no compound

- related effects on mortality, body weights, food consumption, clinical signs, ophthalmologic examinations, or hematology. A slight increase in alkaline phos phatase activity in males at 500 and 1000 mg/kg/day was considered to be of only minimal toxicologic al significance. Alanine aminotransferase and aspartate aminotransferase were not affected. There were increases in absolute (33

- 41%) and re lative (32

- 48%) liver weights at 500 and 1000 mg/kg/day in males. There were also increases in absolute (32%) liver weight at 1000 mg/kg/day and in relative (11

- 29%) liver weights at 500 and 1000 mg/kg/day in females. Histopathological findings revealed a dose

- related increase in the occurrence of hepatocellular hypertrophy in the livers of males at  100 mg/kg/day and in the livers of females at  500 mg/kg/day. Electron microscopic examination of liver samples from two males given 1000 mg/kg/day showed an increase in smooth endoplasmic reticulum. Although treatment

- related, the increases in liver weight, hepato cellular hypertrophy and smooth endoplasmic reticulum observed in the male and female mice in this study are not considered to be adverse findings

. Rather, they are considered to be adaptive responses indicating a stimulation of the liver microsomal enzyme system by the test material. Electron microscopic examination of the two male mice also revealed cytoplasmic inclusions consistent with lipid a ccumulation, but which were not considered to be of toxicologic al concern. The NOAEL for the male and female mice in this study is 1027 mg/kg/day for males and 1029 mg/kg/day for females (actual doses , HDT ). A LOAEL was not observed in this study (>1027 mg/kg/day for males and >1029 mg/kg/day for females). Dosing in this study is adequate since the limit dose for subchronic feeding studies is 1000 mg/kg/day.

This study is Acceptable/Guideline and satisfies the guideline requirement for a 90

- day or al toxicity study ( OCSPP 870.3100; OECD 408) in the mouse.

870.3150 90

- Day Oral Toxicity

- Dog

In a 90

- day oral toxicity study (MRID 45830909), XDE

- 638 (penoxsulam technical, 97.5% a.i.; Lot No. ND05167938, TSN101773) was administered to four Beagle dog s/sex/dose in the diet at concentrations of 0, 0.015, 0.045 or 0.15% (equal to average daily intakes of 0, 5.9, 17.8 or 49.4 mg/kg bw/day, respectively, in males and 0, 5.7, 19.9 or 57.1 mg/kg bw/day, respectively, in females) for 13 weeks.

There were no compound

- related effects on mortality, clinical signs, body weight, food consumption, ophthalmologic examinations, hematology, clinical chemistry, urinalyses, or gross pathology. Increased relative liver weight ratios in males and females at 0.15% were co nsidered
treatment

- related but not adverse in the absence of associated changes in clinical pathology or histopathology. At 0.15%, histopathological changes in kidneys in males and females consisted of very slight, multifocal pelvic epithelial hyperplasia and crystals in the renal pelvis and collecting ducts in 2/4 animals/sex. The LOAEL for male dogs is 49.4 mg/kg bw/day and for female dogs was 57.1 mg/kg bw/day, based on histopathological changes in the kidney. The NOAEL is 17.8 and 19.9 mg/kg bw/day f or males and females, respectively.

This subchronic feeding study is classified as Acceptable/Guideline and satisfies the guideline requirement for a 90

- day oral toxicity study in the dog (OPPTS 870.3150; OECD 409).Page 43 of 61

870.3200 21/28

- Day Dermal Toxicity

– Rat

In a 28

- day dermal toxicity study (MRID 45830910), XDE

- 638 ( technical, 97.5% a.i., Lot# ND05167938, TSN101773) was applied to the shaved skin of 10 Fisher 344 rats/sex/dose at do se levels of 0, 100, 500, or 1000 mg/kg bw/day, 6 hours/day for 7 days/week during a 28

- day period (main study). Additional groups of 10 rats/sex were similarly administered 0 or 1000 mg/kg and held for 2 weeks following the treatment period to assess recovery from any treatment

- related effects (recovery group). Doses w ere applied to a treated area equivalent to approximately 10% of the skin surface area in a dosing volume of 4 mL/kg using 0.5% aqueous methylcellulose solvent.

There were no dea ths reported during the study. There were no treatment

- related effects on cli nical observations, dermal observations, body weight, body weight gain, food consumption, urinalysis parameters, hematology, clinical chemistry, organ weights, or gross pathology or histopathology d uring the 4

- week dosing phase. The recovery group animals showed no treatment related effects in body weight, food consumption, or gross pathology (the only parameters assessed).

T he systemic and dermal NOAEL for XDE

- 638 in male and female rats is the limit dose of 1000 mg/kg/day, and the systemic and dermal LOAEL is not identified (>1000 mg/kg/day).

This 28

- day dermal toxicity study in the rat is classified as Acceptable/Guideline and satisfies the guideline requirement for a 28

- day dermal toxicity study ( OCSPP 870.3200; OECD 410) in
rats.

A.4.2 Prenatal D evelopmental Toxicity

870.3700a Prenatal Developmental Toxicity Study

- Rat

In a developmental toxicity study (MRID 45830917) XDE

- 638 (penoxsulam technical; 97.5% a.i., lot #ND05167938, TSN101773) was administered to 25 time

- mated female CD rats/dose by gavage in 0.5% aqueous METHOCELTM at dose levels of 0, 100, 500, or 1000 mg/kg bw/day on gestation days (GD) 6 through 20, inclusive. On GD 21, surviving females were sacrificed and necropsied. All fetuses were weighed, sexed, and examined for external alt erations. Approximately one

- half of the fetuses from each litter were subjected to visceral examination, and the remaining one

- half were subjected to skeletal examination.

Dose selection was based on the results from a range

- finding developmental toxici ty study with penoxsulam in rats (MRID 45830916), in which administration to groups of 8 time

- mated females by gavage at dose levels of 0, 250, 500, 750, or 1000 mg/kg bw/day on GD 6

- 20 resulted in decreased body weight gain by high

- dose dams during GD 15

- 18 (79% of controls), with no
treatment

- related effects on post

- implantation loss, live litter size, or resorptions per dam.Page 44 of 61

In the main study, there were no treatment

- related effects on survival, clinical signs, or absolute body weights. Maternal toxic ity was evident at 1000 mg/kg bw/day as decreased body weight gain (84% of control) and food consumption (91% of control) during GD 18

- 21 and increased absolute and relative (to body) kidney weights (118% and 121%, respectively; p<0.05). The maternal toxic ity LOAEL for penoxsulam is 1000 mg/kg bw/day, based on decreased food consumption and increased absolute and relative kidney weights. The maternal toxicity NOAEL is 500 mg/kg bw/day.

There were no treatment

- related increases in fetal deaths/resorptions, and there was no evidence of altered growth or an effect on developmental variations. Malformations were observed in 0, 2, 2 and 3 fetuses and in 0/24, 2/24, 1/25, and 2/22 litters from the control, low

- , mid

- , and high

dose groups, respectively. Incidences of individual variations were similar in the treated and control groups, and there were no significant increases in fetal or litter incidences of any individual structural abnormaliti es for any treated group. Observation of an apparently rare external malformation (cutis laxis) in 2 fetuses in single litters at both the 500 and 1000 mg/kg/day dose levels are considered noteworthy since a dose

- response could be masked by the rarity of t his condition. However, based on a weight

- of

- the

- evidence consideration of all the available information/data, including information from Dow Agrosciences LLC (received by the Agency on 11/18/03) it is concluded that the cutis laxis observed in this study is likely to have a genetic etiology and that there is insufficient information to conclude that it is a treatment

- related effect due to the test material. The developmental toxicity LOAEL for penoxsulam is not identified (>1000 mg/kg day), and the develop mental toxicity NOAEL is 1000 mg/kg/day.

This developmental toxicity study in the rat is classified Acceptable/Guideline and satisfies the guideline requirement for a developmental toxicity study [OCSPP 870.3700a; OECD 414] in the
rat.

870.3700b Prenat al Developmental Toxicity Study

– Rabbit

In a developmental toxicity study (MRID 45830918), XDE

- 638 ( penoxsulam technical, 97.5% a.i., Lot # ND05167938, TSN101773) was administered to 25 mated New Zealand white rabbits/dose daily by gavage (7 days per wee k) in 0.5% aqueous METHOCEL TM (dosing volume 4 mL/kg) at dose levels of 0, 5, 25, or 75 mg/kg bw/day on gestation days (GD) 7 through 27, inclusive. Dose selection was based on the results from a range

- finding prenatal developmental toxicity study with XDE

- 638 in New Zealand white rabbits (MRID 45830919). In the main study, on GD 28, all surviving do es were killed and necropsied. All fetuses were weighed, sexed, and examined for external, visceral, and skeletal alterations, and heads from approximately one

h alf the fetuses per litter were examined by serial sections.

One high

- dose doe died on GD 27 after exhibiting decreased defecation, soft mucoid feces, and/or hy poactivity beginning on GD 22. One high

- dose female aborted on GD 23 after exhibiting severely reduced food consumption beginning on GD 12 with decreased to absent defecation and/or b lack feces beginning on GD 15. An increased number of high

- dose animals exhibited gastrointestinal tract effects including decreased or absent feces or mucoid, soft, or abnormally colored feces (5, 5, 2, and 12 females from the control, low

- , mid

- , and hi gh

- dosePage 45 of 61

groups, respectively). High

- dose females had decreased body weight gains during GD 13

- 24 and decreased mean daily food consumption during GD 19

- 25 (74% and 81

- 90 % of controls, respectively), although cumulative body weight gain during dosing was unaffected due to increased body weigh t gain during GD 24

- 28 (252%). There were no treatment

- related effects on absolute body weights, corrected (for gravid uterus) body w eights and body weight gains , or liver and kidney weights. The maternal toxicity LOAEL for XDE

- 638 in New Zealand white rabbits is 75 mg/kg bw/day, based on death, abortion, clinical signs, and decreased food consumption. The maternal toxicity NOAEL is 25 mg/kg bw/day.

One high

- dose female aborted on GD 23. A single dead fetus was noted in the high

- dose group, and t here were no total litter resorptions. High

- dose females had slight increases in mean post

implantation loss (10.8% vs. 5.6% for controls) and percentage of resorbed implantations (12.1% vs. 5.6%) due to small increases in the mean numbers of resorptions per dam and late resorptions per dam (1.1 vs. 0.5 and 0.7 vs. 0.2 , respectively). There were no treatment

- related effects on fet al body weights or sex ratios. Malformations were observed in a total of 3/24, 3/22, 4/24, and 2/21 litters from the control, low

- , mid

- , and high

- dose groups, respectively, with no treatment

related increases in the fetal or litter incidences of any indiv idual malformation or variation and no evidence of altered ossification. The developmental toxicity LOAEL for XDE

- 638 in New Zealand white rabbits is 75 mg/kg bw /day , based on abortion, increased post

- implantation loss, and increased resorptions. T he devel opmental toxicity NOAEL is 25 mg/kg bw/day.

This developmental toxicity study in the rabbit is classified Acceptable/ Guideline and satisfies the guideline requirement for a developmental toxicity study (O CSPP 870.3700b; OECD 414) in the rabbit.

A.4.3 Reproductive Toxicity

870.3800 Reproduction and Fertility Effects

– Rat

In a two

- generation reproduction toxicity study (MRID 45830920), XDE

- 638 ( penoxsulam technical, 97.7% a.i., lot #B

- 765

- 44, TSN102058) was administered to 30 male and 30 female Crl:CD (SD) IGS BR rats/dose at dietary concentrations that provided 0, 30, 100, or 300 mg/kg/day. One litter wa s produced in each generation. F 0 and F 1 parental animals were administered test or control diet for 10 weeks prior to mating, throughout mating , gestation, and lactation, and until sacrifice. Doses were selected on the basis of a range

- finding study in non

mated CD rats (MRID 45830907).

Intercurrent deaths of several F 0 and F 1 animals were consi dered incidental to treatment. No
treatment

- relate d clinical signs of toxicity were observed i n any animal during the study. No
treatment

- related effects on body weights, body weight gains, or food consumption values were observed in males or females of the F 0 generation during the premating interval. Abs olute body weights of the high

- dose F 1 males were significantly (p  0.05; 88

- 94% of controls) less than those of the controls throughout the study. High

- dose F 1 females had significantly lower (p  0.05; 93% of controls) body weight than the controls only fo r the first week of premating. Body weight gains by the high

- dose F 1 animals were similar to the controls. Reduced body weights ofPage 46 of 61

the high

- dose F 1 parental animals during premating were considered a conti nuation of preweaning effects. Food consumption b y the high

- dose F 1 males was significantly less (p  0.05; 92

- 93% of controls) than that of the control group for the first two weeks of premating.

At necropsy, mid

- and high

- dose males of both generations had increased absolute and/or relative liver weig hts due to slight hepatocellular hypertrophy that was not considered to be adverse. High

- dose females of both generations had significantly increased (p  0.05; 109

- 115% of control) absolut e and relative kidney weights. Microscopic lesions of the kidney of high

- dose F 0 and F 1 females included epithelial hyperplasia, inflammation, and crystal formation in the
pe lvis and tubular degeneration. The incidences (severity) of kidney lesions in control and high

dose females were 1

- 2/30 (1.00) and 25

- 26/30 (1.58

- 2.0 4), respectively, for hyperplasia, 0/30 and 3

- 7 /30 (1.25

- 2.14), respectively, for inflammation, and 3/30 (1.00) and 20

- 21/30(1.62

- 1.85),
respe ctively, for degeneration. In addition, crystals were observed in 0, 0, 2, and 16 F 0 females and in 2, 1, 7, and 1 1 F 1 females in the control, low

- , mid

- , and high

- dose groups, respectively. Therefore, the parental systemic toxicity LOAEL for XDE

- 638 in rats is 100 mg/kg/day for females based on kidney lesions and 300 mg/kg/day for males based on reduced body weights of the F 1 males. The parental systemic toxicity NOAEL is 30 mg/kg/day for females and 100 mg/kg/day for males

. No differences in mating or fertility indices, precoital interval, or gestation length were seen between the treated and contro l groups of eithe r generation. Estrous cyclicity, follicle counts, and sperm parameters were not affected by tre atment.

Body weights of the high

- dose F 0 and F 1 dams were significantly lower (p  0.05; 87

- 94% of controls) than that of controls from GD 21 through lactation day 14. The most pronounced effect on body weight gains during gestation was for days 14

- 21 when the high

- dose F 0 and F 1 dams had weight gains 79% and 82%, respectively , of the control group levels. Weight changes by the high

- dose dams during the first we ek of lactation consisted of marked weight loss during days 1

- 4 and a lower weight gain t han the controls for days 4

- 7. Recovery was noted in the high

- do se dams after lactation day 7. During gestation, food consumption was similar between the treated and contr ol groups of both generations. Food consumption by the high

- dose F 0 dams was significantly less (p  0.05; 76

- 88% of controls) than that of the controls on lactation days 1

- 11. Food consumption by the high

- dose F 1 dams was significantly (p  0.05; 70

- 72% of controls) less than that of the c ontrols on lactation days 1

- 7. Compensation was noted in the high

- dose F 0 and F 1 dams with food consumption reaching 115% and 110%, respectively, of controls (both p
 0.05) during lactation days 17

- 19. The effects on maternal body weights, body weight gain and food consumption levels during late gestation and early lactation and the effect on pup weight gain during early lactation support an adverse effect on lactation. The reproductive toxicity LOAEL for XDE

- 638 in rats is 300 mg/kg/day for females based on adverse effects on lactation due to decreased maternal body weight gain during late gestation and early lactation and was not identified for males (>300 mg/kg/day). The r eproductive toxicity NOAEL is 100 mg/kg/da y for females and 300 mg/kg/day for males.

For litters of both generations, no treatment

- related effects were observed on live birth and viability indices, mean litter sizes, post

- implantation losses, numbers of s tillborn pups, and sexPage 47 of 61

ratios. No treatmen t

- related clinical signs of toxicity were observed in the pups during lactation and gr oss necropsy was unremarkable. At birth, body weight of the high

- dose pups was slightly ( 9%, n.s.) lower t han that of the control group. High

- dose male and female pups fr om both generations had significantly lower ( 8 to 17%, p  0.05) body weights on lactation days 4

- 21 compared with the controls. Lower body weights of the high

- dose pups were a result of weight gains 76

- 80% of the control group le vels from lactations days 1

- 7. Weight gains by the high

- dose pups were slightly lower than the controls from lactation days 7

- 14 and comparable to control levels from lactation days 14

- 21. The offspring toxicity LOAEL for XDE

- 638 in rats is 300 mg/kg/day based on reduced body weigh t gain during lactation days 1

- 7 in both generations. The offspring toxicity NOAEL is 100 mg/kg/day.

This study is classified as Acceptable/Guideline and satisfies the guideline requirement for a
two

- generation reproduction study ( OCSPP 870.3800; OECD 416 ) in rats.

A.4.4 Chronic Toxicity

870.4100a (870.4300) Chronic Toxicity

– Rat

In a combined chronic toxicity/carcinogenicity study (MRID 45830901, 45830913) penoxsulam (XDE

- 638 technical, Lot # B

- 765

- 44; TSN 102058; 97.7% a.i.) was administered to 50 Fischer 344 rats/sex/dose in the diet at dose levels of 0, 5, 50 or 250 mg/kg/day for two years. An additional ten rats/sex/group were treated at the same dosages and necropsied after one year of treatment. Another five rats/sex/group were treated at the s ame dosages and examined for neurological effects as part of a chronic (one

- year) neurotoxicity study (reported separately in MRID 45830912).Page 48 of 61

There was no treatment

- related increase in mortality. An increase in perineal urine soiling, particularly in females, at 50 and 250 mg/kg/day, while treatment

- related, was not considered to be a toxicological ly significant adverse effect. Statistically significant decreases in body weight and body weight gain in males and females at 250 mg/kg/day, although of relatively small magnitude, were considered to be toxicologically significant. Slight but statistically significant decreases in RBC parameters (RBC counts, HGB and HCT) in males at 250 mg/kg/day were also

c onsidered to be toxicologically significant. There were no ophthalmoscopic effects due to
treatment.

Blood urea nitrogen (BUN) was significantly increased (11

- 44%) at 18 and 24 months in males at 250 mg/kg/day. Urine volume was increased in males and females at 250 mg/kg/day (26

- 175% in males and 38

- 103% in females) throughout the study. Specific gravity was decreased in treated males with statistical significance achieved at 12, 18 and 24 month s for the 250 mg/kg/day group. The urinary system effects were not considered toxicologically significant in males or females at 5 and 50 mg/kg/day due to the small magnitude of the changes.

In the interim sacrifice animals , the only gross change considered treatment

- related was perineal urine soiling which was present in 9/10 males and 7/10 females at 250 mg/kg/day, as compared to 2/10 male and 1/10 female control rats. Four of ten female rats at 50 mg/kg/day also had perineal soiling. Male rats at 250 mg/kg/day had increased absolute and relative kidney weights, approximately 11% and 15%, respectively, and an increase in the severity of chronic progressive glomeru lonephropathy (CPGN).

In the main study groups , the incidences of the following gross pathology findings were increased: calculi in the pelvis and bilateral roughened surface of the kidney in males at 250 mg/kg/day; enlarged spleen (with probable lymphoid tumor) in all treated males (no dose response); and urinary bladder calculi in males and females at 250 mg/kg/day. Terminal body weight was significantly decreased (7%) in males at 250 mg/kg/day. There was a statistically significant increase (11

- 20%) in the absolute and relative kidney weights of males at 250 mg/kg/day.

Microscopic examination of the kidney showed an increase in the severity of CPGN at all dose levels in males; the increase in severity at 5 and 50 mg/kg/day was not dose related and there fore was considered an incidental finding. The incidence of crystals in the renal pelvis was significantly increased in males at 250 mg/kg/day. The increased incidence and severity of hyperplasia of the renal pelvic epithelium found in male rats at 250 mg/ kg/day was often associated with crystals; however, hyperplasia was a more common finding. In females, the only h istopathologic al finding in the kidney was a slight increase in incidence and severity of pelvic epithelium hyperplasia at 50 and 250 mg/kg/day ; none of the findings was significantly increased. In the urinary bladder, there was a significant increase in the incidence and/or severity of the following in males and females at 250 mg/kg/day: crystals in the lumen (incidence); multifocal mucosal hype rplasia (incidence and severity); and diffuse hyperplasia (inciden ce and severity, females only).Page 49 of 6 1

The LOAEL is 250 mg/kg/day based on decreased RBC parameters (decreased RBC count, HGB and HCT in males), clinical pathology changes (increased BUN in males, increased urine volume in males and females, and decreased specific gravity in males), increased absolute and relative kidney weights (males), increased incidence of renal pelvis crystals (males), increased incidence of bladder crystals and calculi (males and females), hyperplasia of the renal pelvis epithelium (males and females) and bladder mucosa (males and females), and increased severity of chronic progressive glomerulonephropathy (males). The NOAEL is 50 mg/kg/day.

In the main study groups , there w as a statistically significant increase in the overall incidence [24%, 60%, 58% and 60% at 0, 5, 50 and 250 mg/kg/day, respectively) and the incidence of Stage 3 large granular lymphocyte (LGL) leukemia in treated male rats. The histopathology slides were reviewed by an external Pathology Working Group (PWG) to establish consensus diagnoses which were included in the study report. The incidence in all groups of treated males exceeded the conducting laboratory’s historical control mean (28.5%) and range (16

- 40%). The study demonstrated that XDE

- 638 may produce an increase in the incidence and severity of LGL leukemia in male Fischer 344 rats. The dosages in the study were adequate in males and marginally adequate in females to assess the carcinogenicity of th e chemical based primarily on decreased body weight and body weight gain and the effects on the urinary system.

This combined chronic toxicity/carcinogenicity study in the rat is classified as Acceptable/Guideline and satisfies the guideline requirement f or a chronic toxicity/carcinogenicity study (O CSPP 870.4300; OECD 453) in rats.

870.4100b Chronic Toxicity

- Dog

In a chronic oral toxicity study (MRID 45830914), XDE

- 638 ( penoxsulam technical, 97.7% a.i. ; Lot No

. B

- 765

- 44) was administered to four Beagle dogs/sex/dose in the diet at concentrations of 0, 0.015, 0.045 or 0.15% (equivalent to 0, 5.3, 14.7, or 46.2 mg/kg/day, respectively, for males and 0, 4.4, 14.0, or 44.8 mg/kg/day, respectively, for females) for one year.

There were no toxicologically significant compound

- related effects on mortality, clinical signs, ophthalmologic examinations, hematology, clinical chemistry, urinalyses, orga n weights, or gross pathology. There appeared to be marginal inhibition of body weight gain and food consumption in males, but not fem ales, receiving 0.15% XDE

- 638. The only effect of toxicological significance was the occurrence of very slight, multifocal hyperplasia of the pelvic epithelium in both kidneys o f one male in the 0.15% group. Similar le sions were seen in male and female dogs in 4

- and 13

- week dietary studies with XDE

- 638. Exacerbation of the lesions observed in these shorter

- term studies was not o bserved in the one

- year study. The incidence of kidney lesions seen in the 13

- week study was actually greater (2/4 males and 2/4 females) than in the one

- year study (1/4 males and 0/4 females) at the same dietary level (0.15%) of XDE

- 638. In addition, crystals were seen in the renal pelvis and collecting ducts of both genders in the 13

- week stud y, but not in the one

- year study.Page 50 of 61

The LOAEL is 46.2 mg/kg/day for males based on slight multifocal hyperplasia in the renal epithelium; a LOAEL was not established for females (>44.8 mg/kg/day). The NOAEL for males is 14.7 mg/kg/day; the NOAEL for females is 44.8 mg/kg/day.

This chronic study in the dog is classified as Acceptable/Guideline and satisfies the guideline requirement for a chronic oral study [ OCSPP 870.4100, OECD 452] in dog.

A.4.5 Carcinogenicity

870.4200a Carcinogenicity Study

- Rat

See 870.4100a

870.4200b Carcinogenicity (feeding)

- Mouse

In a n oral carcinogenicity study (MRID 45830915), XDE

- 638 ( penoxsulam technical, 97.7% a.i., lot # B

- 765

- 44, TSN 102058) was administered to groups of 50 CD

- 1 mice/sex/dose in the diet at dose levels of 0, 10, 100, or 375 mg/kg/day (male mice) or 0, 10, 100, or 750 mg/kg/day (female mice) for 18 months.

There were no treatment

- related effects on mortality, clinical signs, body weight, body weight gain, food consumption, ophthalmol ogic examinations, hematology, or gross pathology. Treatment

- related effects were limited to the liver. Absolute and relative liver weights were increased by 12% in males administered 375 mg/kg/day and relative liver weight was increased by 11% in males ad ministered 100 mg/kg/day (all p<0.05). Absolute and relative liver weights were marginally increased in females at 750 mg/kg/day and 100 mg/kg/day (non

- significant). Microscopically, changes in the liver included hepatocellular hypertrophy in males adminis tered 375 or 100 mg/kg/day and in females administered 750 mg/kg/day. The hepatocellular hypertrophy in males and females was associated with increased eosinophilic staining properties, and along with the increased liver weights was considered to be an ada ptive change resulting from induction of the liver microsomal enzyme system by the test material. This change was not

con sidered to be an adverse effect.

The affected hepatocytes in male mice administered 375 and 100 mg/kg/day were said to contain clear c ytoplasmic vacuoles, but there was no quantitative description of the incidence or severity of these vacuoles. Based on the information presented in this study, the clear cytoplasmic vacuoles are not considered to be of toxicological significance. In addit ion, very slight (3 animals) to slight (1 animal) dil a tation of the sinusoidal spaces (cystic spaces) or peliosis of the liver was observed in 4/50 males in the 375 mg/kg/day group. Because of the severity of this lesion (very slight/slight) and its low fr equency (4/50), it also is not considered to be of toxicological significance. The NOAEL for male and female mice in this study is 375 mg/kg/day for males and 750 mg/kg/day for females (HDT) . A LOAEL was not observed in this study for the male or female m ice (>375 mg/kg/day for males and >750 mg/kg/day for females).Page 51 of 61

XDE

- 638 administered to male mice at up to 375 mg/kg/day and to female mice at up to 750 mg/kg/day did not induce an increased incidence of treatment

- related tumors of any kind in either mal es or females. However, an MTD was not achieved for either sex and in males, the highest dose tested (375 mg/kg/day) was inadequate for carcinogenicity testing because no adverse effect was observed at this dose.

Although dosing in male mice was not cons idered to be adequate, the HED CARC concluded that an additional mouse carcinogenicity study was not required. This was based on the following: 1) no treatment

- related effects were seen up to the limit dose of a 1000 mg/kg/day in the 90

- day mouse study; 2) no hyperplasia was seen in the mouse carcinogenicity study at 375 mg/kg/day in males and 750 mg/kg/day in females; 3) no structural alerts were seen with the SAR data; 4) rat data indicate saturation of absorption at 250 mg/kg/day; and 5) no mutagenic act ivity. Based on these data, the CARC determined that a new mouse cancer study would have no impact on the regulation of penoxsulam.

In females, the highest dose tested (750 mg/kg/day) was considered adequate for carcinogenicity testing, but only because it was sufficiently close to the limit dose of 1000 mg/kg/day. Additional support for this determination was provided in the 90

- day s ubchronic oral study in mice (MRID 45830905). In this study treatment

- related toxicologically significant adverse effects were not observed at the highest dose tested in males (1027 mg/kg/day) or in females (1029 mg/kg/day). All treatment

- related effects observed in the 90

- day subchronic study were essentially the same liver effects as in the 18

- month carcinogenicity study and were considered to be adaptive rather than adverse effects.

This study is classified as A cceptable / Nong uideline but does s atisfy the guideline requirement for a carcinogenicity study [O CSPP 870.4200b; OECD 451] in mice . A lthough a LOAEL was not identified for either males or females, the CARC determined that the high dose in females was close enough to t he limit dose of 1000 mg/kg/day. I n males the dosing did not achieve an MTD, but the CARC supported not requiring a new mouse study for the reasons outlined above

. For further information see the CARC memo (TXR No. 0050702, March 24, 2004)

.

A.4.6 Mutagenicity

Gene Mutation

Guideline 870.5100, Bacterial reverse gene mutation, S. typhimurium MRID 45830921 Acceptable/guideline Doses tested

- 0, 3.3, 10, 33.3, 100, 333.3, 1000 or 1500 ug/plate

- S9 Negative for increased frequency of reverse gene mutations in the presence or absence of rat S9 metabolic activation. Cytotoxicity observed at >333 ug/plate.
Guideline 870.5100, Bacterial reverse gene mutation, S. typhimurium MRID 45830922 Acceptable/guideline Formulation GR

- 443 , 21.9% penoxsulam

. Doses tested

– 0, 3.3, 10, 33.3, 100, 333 or 1000 ug/plate +/

- S9 and 5000 ug/plate +S9 Negative for increased frequency of reverse gene mutations in the presence or absence of rat S9 metabolic activation. Cytotoxicity observed at >333 ug/plate.Page 52 of 61

Guideli ne 870.5300, Mammalian cell forward gene mutation, CHO cells MRID 45830924 Acceptable/guideline Doses tested

– 0, 46.88, 93.75, 187.5, 375, 750 or 1500 μg/mL +/

- S9 Negative for forward gene mutation in the presence and absence of rat S9 metabolic activation. Limit of solubility observed at 750 to 1500 μg/mL. Guideline 870.5300, Mammalian cell forward gene mutation, rat primary lymphocyte cells MRID 45830925 Acceptable/guideline Doses tested

– Assay 1: 0, 3.3, 10, 33.3, 100, 333.3, 1000 or 15 00 μg/mL, +/

- S9 activation Assay 2: Same doses, 24 hr incubation without S9 and 4 hr with S9 Assay 3: 12 doses between 100

– 1500 μg/mL, 24 hr incubation without S9 Negative for forward gene mutation in the presence and absence of rat S9 metabolic activation.

Cytogenetics

Guideline 870.5395, In vivo mouse bone marrow micronucleus assay MRID 45830925 Acceptable/guideline Doses tested 0, 500, 1000 or 2000 mg/kg, dosed for two days and harvested at 24 hr after the second dose. Negative for induction of micronuclei formation.

Guideline 870.5395, In vivo mouse bone marrow micronucleus assay MRID 45830926 Acceptable/guideline Formulation GR

- 443 , 21.9% penoxsulam. Doses tested 0, 500, 1000 or 2000 mg/kg, dosed for two days and harvested at 24 hr after the second dose. Negative for induction of micronuclei formation.

A.4.7 Neurotoxicity

870.6200 Acute Neurotoxicity Screening Battery

In an acute neurotoxicity study (MRID 45830902 )

, four groups (10/sex/group) of fasted, 7 week old, Charles River Fischer 344 rats were given a single oral dose of XDE

- 638 ( penoxsulam technical, 97.5% a.i., Lot # ND05167938) in 0.5% aqueous methylcellulose (10 mL/kg dosing volume) at doses of 0, 500, 1000, or 2000 mg/kg bw and observed for 14 days. Neurobehavior al
assessment s (functional observational battery (FOB) and motor activity testing) w ere performed in 10 animals/sex/group before trea tment and at Day 1, 8, and 15. At Day 16, 5 animals/sex/group were euthanized and perfused in situ for neurop athological ex amination. Of the perfused animals, males and females in the control and high dose groups were subjected to histopathological evaluation of selected central and peripheral nervous system tissues.

There were no treatment

- related effects on mortality, clini cal signs, body weight, ophthalmaloscopic findings, or gross and histologi c pathology or neuropathology. FOB and motor activity testing revealed no treatment

- related effects.

Postive control studies were provided. An FOB profi ci ency report demonstrated th e ability of the technician observer to dete ct major neurotoxic endpoints. Motor activity positive control data demonstrated the ability to detect both increases (amphetamine) and decreases (chlo rpromazine) in motor activity. Neuropathology positive contro l data, validated with trimethyltin and acrylamide, demonstrated the ability to detect central and peripheral nervous system histopathologic al changes. T he neurotoxic ity NOAEL for XDE

- 638 in male and female ra ts is 2000 mg/kg (limit dose). The LOAEL was no t identified (>2000 mg/kg).Page 53 of 61

This neurotoxicity study is classified as Acceptable/Guideline and does satisfy the guideline requirement for an acute neurotoxicity study in rats (870.6200; OECD 424).

870.6200 Chronic Neurotoxicity Screening Battery

In a chronic neurotoxicity study (MRID 45830912), penoxsulam (XDE

- 638 technical, Lot # B

765

- 44; TSN 102058; 97.7% a.i.) was administered to 10 Fischer 344 rats/sex/dose in the diet at dose levels of 0, 5, 50 or 250 mg/kg/day for one year. This study was i ncorporated in a combined chronic toxicity/carcinogenicity study (MRID 45830901). Neurobehavioral assessment (including functional observational battery (FOB), grip performance, landing foot splay, rectal temperature, and motor activity testing) was perfo rmed on 10 animals/sex/group pretreatment and at months 1, 3, 6, 9 and 12. At 12 months, five animals/sex from the control and 250 mg/kg/day group were euthanized and perfused in situ followed by gross examination and histopathological examination of sele cted tissues from the central and peripheral nervous systems. The remaining rats were sacrificed and examined according to standard procedures used in the combined chronic toxicity/carcinogenicity study.

There was no treatment

- related effect on mortality or ophthalmoloscopic examination. Although statistically significant decreases in body weights and body weight gains in males and females dosed at 250 mg/kg/day were not observed in the 10 rats/sex/dose assigned to the neurotoxicity study, statistically significant decreases in body weights and body weight gains were observed for the 65 rats/sex/dose assigned to the larger more comprehensive study. In the larger study, body weights were statistically significantly decreased in both males and females at 25 0 mg/kg/day beginning on day 8 and continued throughout the first year of the study (decreased 2

- 4% in both sexes). At 250 mg/kg/day, body weight gains were decreased during days 1

- 8 (11% and 17% in males and females, respectively) and days 1

- 92 (6% and 5% in males and females, respectively). Based on the above findings, the high dose was considered sufficient to test the chronic neurotoxicity of the chemical. An additional treatment

- related effect was an increased incidence of urine perineal soiling in mal es and females at 250 mg/kg/day and females at 50 mg/kg/day observed during the FOB testing; this was not considered to be a toxicologically significant adverse effect.

There was no toxicologically significant evidence of neurotoxicity observed in this study. There
was no treatment

- related effect on FOB findings, grip performance, landing foot splay, rectal temperature, motor activity or neuropathology. A FOB profi ci ency report and positive control data for motor activity and neuropathology examin ations were submitted. These studies produced the expected results and demonstrated the laboratory’s proficiency in conducting FOB testing, motor activity testing and neuropathology examinations.

The LOAEL for neurotoxicity for males and females was not established (> 250 mg/kg/day, HDT). The neurotoxicity NOAEL for males and females was 250 mg/kg/day. Despite the lack of a LOAEL, no further data on neurotoxicity are required because the metabolism study indicated that absorption appears to be saturated a t 250 mg/kg/day.Page 54 of 61

This chronic neurotoxicity study is classified as Acceptable/Guideline and does satisfy the guideline requirement for a chronic neurotoxicity study in rats (870.6200; OECD 424).

A.4.8 Metabolism

870.7485 Metabolism

- Rat

In a metabolism/disposition study (MRID 45830927), Fischer 344 rats (four/sex/group) were given single or 15 multiple oral low doses (5 mg/kg) or a single high dose (250 mg/kg) of 14 C

XDE

- 638 (Penoxsulam). Both a triazole ring label (Lot no. F

- 458

- 159, IN V 1456, 28.9 mCi/mmol, >99% radiochemical purity) and phenyl ring label (Lot no. F

- 458

- 183A, INV 1475, 24.6 mCi/mmol, >98.4% radiochemical purity) were utilized along with non

- labeled XDE

- 638 (Lot no. N D05167938, TSN101773, che mical purity 97.5%). An addi tional group of three male and three female rats were fitted with bile duct cannulae and biliary elimination monitored over 24 hours foll owing an oral dose of 5 mg/kg. Absorption, distribution, metabolism and kinetic parameters were evaluated for the singl e and multiple low dose and the high

- dose groups.

Overall recovery of administered radioactiv ity was an acceptable 91

- 107%. Dose confirmation revealed that dosing was within 13% of the target doses, and results of homogeneity and stability
assessments wer e acceptable.

Absorption of the test article was rapid. Urinary, fecal and biliary excretion data revealed that absorption of a single low dose was 81

- 88% and that much of the radioactivity in the feces was the result of biliary contributi ons of absorbe d radioactivity. Biliary excretion was greater for males (55.8% of dose) tha n for females (14.1% of dose). Data on plasma kinetics supported the contention that absorption was saturated at the 250 mg/kg dose. Both the C max and AUC values were indicative of substantially decreased absorption at the higher dose. Essentially identical elimination kinetics were observed at both dose levels. Maximum plasma concentration (C max ) and whole body clearance (Cl) data also supported observed gender

- related variability in disposition of the test article.

Urine and fece s were major excretory routes. Both gender and dose affected excretion pattern. Following a single low dose (5 mg/kg), excretion of radioactivity over 168 hours was primarily via the urine in females (69% vs 36% for males) and via the feces in m ales (55% vs 20% for females). Elimination patterns were similar for t he repeated (15

- day) low dose. Excretion in urine was more prominent following a single low dose (36% and 69% males and females, respecti vely) and in feces more prevalent at the high dose (70% and 87% for fem ales and males, respectively). The shift in excretory route was greater for males (3.8

- fold) than for females (2.5

- fold) and was consistent with saturated absorption. Most urinary excre tion (>90%) occurred within 36 hours for the low

- dose group and within 48 hours for the high

- dose group. Fecal excretion was essentially complete withi n 72 hours regardless of dose. Excretion profiles following the repeated low dose regimen were similar to that for the single low dose. Label position (triazole vs phenyl) did not significantly alter the di sposition of the test article. Tissue burdens assessed at various times after dosing revealed that at sampling times equivalent to C max (0.5 hrs) and 1⁄2 C ma x (3 hrs), most radioactivity was associated with the gastrointestinal tract andPage 55 of 61

organs/tissues associated with initial absorption, metabolism and elimination (e.g., liver). Assessment of tissue and carcass burdens at 7 days post dose showed that radioact ivity was negligible (~0.69% and <1.9% of the low and high doses, respectively) and, therefore, there was no evidence of sequestration.

Analysis of metabolite profiles revealed up to 17 urinary components, 37 fecal components, and 19 biliary fractions in pooled samples, but most represented <1% of the administered dose. Parent compound was the most prevalent urinary component in both the low

- and high

- dose
groups. Metabolite profiles of pooled fecal samples also revealed numerous components, most of which represented <1% of t he administered radioactivity. Saturated absorption was also reflected in that greater amounts of parent compound occurred in the feces of the high

- dose group (67

- 80% of administered dose) than in the low

- dose group (3

- 12%). A 2

- hydroxyphenyl derivative was detected in the urine and accounted for ~1.3

- 2.9% (low dose) and <1.0% (high dose) of administered radioactivity; in the feces it represented <1.05% of the administered dose. A glucuronide conjugate was also ide ntified primar ily in the bile. Unidentified components with retention times of 22.9 and 24.0 minutes represented 5.6 and 6.2%, respectively of the administered do se in feces of low

- dose males. The absence of radioactivity in expired air precluded the formation of volati le metabolites or carbon dioxide. Metabolite profiles of the pooled bile samples also revealed numerous metabolites. The presence of parent compound in the bile (~9.4% and 4.8% of the administered dose for males and females, respectively) in conjunction wi th reduced urinary excretion of radioactivity in bile

- cannulated rats were indicative of potent ial enterohepatic circulation. Only min or ring cleavage was observed. The investigators proposed a metabolism pathway specifying various Phase I (O

- dealkylation and hydroxylation products) and Phase II (conjugation products) metabolites.

The results of this study showed that 14 C

- XDE

- 638 (Penoxsulam) orally administered to male and female rats underwent fairly rapid but incomplete absorption which became do se

- limited at or below a dose of 250 mg/kg. Although widely distributed among tissues, there was no evidence of seq uestration or bioaccumulation. Excretion was primarily via the urine and feces, with unabsorbed test article accounting for much of the fecal radioactivity espec ially for the high

- dose
group. A large number of metabolites were detec ted in urine, feces, and bile. Minor qualitative, gender

- rela ted differences were observed. Most metabolites represented only a small portion ( <1%) of the administer ed dose. Minor qualitative and quantitative differences in metabolite profiles observed for the phenyl and triazole labels provided information on biotransformation supportive of the proposed metabolism scheme.

This metabolism study in the rat is classifi ed Acceptable/Guideline and satisfies the Guideline Requirement for a metabolism study [ OCSPP 870.7485, OECD 417] in rats. The studies provide data consistent with Tier 1 requirements as well as Tier 2 ancillary studies.

A.4.9 Immunotoxicity

870.7800 ImmunotoxicityPage 56 of 61

In an immunotoxicity study (MRID 48125301 )

, Penoxsulam (99.0% a.i., Lot WL12431401) was administered to female F344/DuCrl rats (10/dose) in the diet at dose levels of 0 , 50, 200, or 1000 mg/kg (the actual doses received were equivalent to 0, 54.4, 220, and 1058 mg/kg bw/day, respectively) for 2 8 consecutive days

. On Day 23, animals in all groups were immunized with a suspension of sheep red blood cells ( S RBC) by intravenous injection (2x10 8 SRBC/animal, 0.5 mL/animal dose volume). Animals in the positive control group received an intraperitoneal injection of cyclophosphamide on Days 24

- 28 at a dose of 20 mg/kg bw /day in sterile isotonic saline

. All animals were evaluated for mortality, clin ical signs, body weight changes, food consumption, hematology, and gross pathology. Immunotoxicity was assessed us ing an enzyme

linked immunosorbe nt assay (ELISA) approach that measured the concentration of serum anti

SRBC IgM. The organ weights of the spl een, thymus, and liver were determined at necropsy.

There were no test substance

- related effects on mortality, clinical signs, or humoral immune
response. Body weight was statistically lower for subjects in the 1000 mg/kg group on days 11 and 15 as compar ed to the control. When compared to the control, subjects in the 1000 mg/kg group had lower red blood cell counts, hemoglobin concentrations, and hematocrit levels and higher reticulocyte and platelet counts. The terminal body weights of female rats given 1000 mg/kg were lower than the controls. Treatment relat ed and statistically significant increases in relative liver weights of 6.8% and 10.7%, relative to the control occurred at 200 and 1000 mg/kg/day, respectively. Treatment relat ed and statistically si gnificant increases in relative kidney weights of 10.4 % relative to the control occurred at 1000 mg/kg/day. These findings were consistent with pri or repeated doses stud ies

.

The systemic toxicity NOAEL is 20 0 mg/kg; the LOAEL wa s 10 00 mg/kg/day based on increase s in l iver and kidney weight s and hematology parameters which were consistent with previous findings.

There were no statistically significant differences in the mean anti

- SRBC IgM concentrations between the test substance treatment groups and the vehicle control. A high inter

- individual variability of anti

- SRBC IgM level was noted in all the treatment groups as well as in the control group. Evaluation of individual animal data did not show any trend or distribution that would demonstrate significan t suppression of the anti

- SRBC antibody response. The group mean IgM result from rats dosed with the positive control, cyclophosphamide monohydrate, was 99 % lower than the vehicle control group. The positive control group confirmed the validity of the immu notoxicity assay.

The Natural Killer (NK) cells activity was not evaluated in this study. The toxicology database for penoxsulam does not reveal any evidence of treatment

- related effects on the immune system. The overall weight of evidence suggests that t his chemical does not dire ctly target the immune system. Under HED guidance, a NK cells activity assay is not required at this time.

The NOAEL for immunotoxicity is 1000 mg/kg; the LOAEL was not established, tested at the limit dose

.Page 57 of 61

This immunotoxici ty study is classified as acceptable/guideline and satisfies the guideline requirement for an immunotoxicity stud y (OPPTS 870.7800) in the rat.Page 58 of 61

Appendix B

. Physical/Chemical Properties of Penoxsulam

Table B.1

. Physicochemical 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.Page 59 of 61

Appendix C: Penoxsulam and Metabolites

Table C.1 Penoxsulam and Metabolite Structures.
Name Structure
Penoxsulam CAS. No.: 219714

- 96

- 2 CAS Name: 2

- (2,2

- difluoroethoxy)

- N

- (5,8

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

- c]pyrimidin

- 2

- yl)

- 6

- (trifluoromethyl) benzenesulfonamide IUPAC Name: 3

- (2,2

- Difluoroethoxy)

- N

- (5,8

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

- c]pyrimidin

- 2

- yl)

- α,α,α

- trifluorotoluene

- 2

- sulfonamide Synonyms: XDE

- 638

BSTCA CAS Name: 3

- [[[2

- (2,2

- difluoroethoxy)

- 6

- (trifluoromethyl)phenyl]

- sulfonyl]amino]

- 1H

- 1,2,4

- triazole

- 5

- carboxylic acid IUPAC Name: 3

- [6

- (2,2

- Difluoroethoxy)

- α,α,α

- (trifluoro

- o

- toluenesulfonamido]

- s

- triazole

- 5

- carboxylic acid Synonyms:

2

- amino TCA CAS name: 2

- amino

- 1,2,4

- triazole carboxylic acid Synonyms: Polars

5

- OH

- XDE

- 638 CAS name: 2

- (2,2

- difluoroethoxy)

- N

- (5,6

- dihydro

- 8

- methoxy

- 5

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

- c]pyrimidin

- 2

- yl)

- 6

- (trifluoromethyl)benzenesulfonamide IUPAC name: 6

- (2,2

- Difluoroethoxy)

- N

- (5,6

- dihydro

- 8

- methoxy

- 5

- oxo

- s

- triazolo[1,5

- c]pyrimidin

- 2

- yl)

- α,α,α

- trifluoro

- o

toluenesu lfonamidePage 60 of 61

Table C.1 Penoxsulam and Metabolite Structures.
Name Structure
SFA CAS name: 2

- (2,2

- difluoroethoxy)

- N

- (iminomethyl)

- 6

- (trifluoromethyl)

- benzenesulfonamide IUPAC name: 2

- (2,2

- difluoroethoxy)

- N

- [(E)iminomethyl

- 6

-

sulfonamide CAS name: 2

- (2,2

- difluoroethoxy)

- 6

- (trifluoromethyl)

- benzenesulfonamide IUPAC name: 2

- (2,2

- difluoroethoxy)

- 6

- (trifluoromethyl)

- benzenesulfonamide

5,8

- diOH CAS name: 2

- (2,2

- Difluoroethoxy)

- 6

- trifluoromethyl

- N

- (5,8

- dihydroxy

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

- c]pyrimidin

- 2

- yl)benzenesulfonamidePage 61 of 61

Appendix D

. Summary of Residues from Penoxsulam Crop Field Trials

Summary of Residues from Pome Fruit and Stone Fruit Field Trials with Penoxsulam

. Crop Matrix Analyte Total Application Rate (lb ai/A) PHI

(days) n 1 Residues (ppm)

Min. 2 Max. 2 LAFT 3 HAFT 3 Median 3 Mean 3 SD 3

Apple Penoxsulam 0.0624

- 0.0643 56

- 61 4 <0.01 <0.01 <0.01 <0.01 0.01 0.01 NA
0.3172 60 1 < 0.01 <0.01 <0.01 <0.01 0.01 0.01 NA
Pear 0.0611

- 0.0638 60 2 <0.01 <0.01 <0.01 <0.01 0.01 0.01 NA Cherry, sweet and

sour 0.0629

- 0.0752 51

- 61 4 <0.01 <0.01 <0.01 <0.01 0.01 0.01 NA

Peach 0.0639

- 0.0644 57 2 <0.01 <0.01 <0.01 <0.01 0.01 0.01 NA
Plum 0.0642

- 0.0672 52

- 63 3 <0.01 <0.01 <0.01 <0.01 0.01 0.01 NA

1 n = number of field trials.

2 Values based on total number of samples.
3 Values based on per

- trial averages. LAFT = lowest average field trial, HAFT = highest average field trial, SD = standard deviation. For computation of the LAFT, HAFT, median, mean, and standard deviation, values < LOQ are assumed to be at the LOQ ( 0.01 ppm ) . NA = Not applicable.

Appendix E . Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These data, which include [studies from PHED 1.1; the AHETF database; the Outdoor Residential Exposure Task Force (ORETF) database; Aquatic Use SOP, the Residential SOPs ; and MRID s 47947802, 48725101, 48326701, 48314201, 47947803, 44339801, 49478602

, are (1) subject to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable ethics requirements. For certain studies, the ethics review may have included review by the Human Studies Review Board. Descriptions of data sources, as well as guidance on their use, can be found at the Agency website 3

.

3 http://www.epa.gov/pesticides/science/handler

- exposure

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

- app

- exposure

- data.html