Date: 

SUBJECT: 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

December 4, 2015 

OFFICE OF C HEM ICAL SAFETY AND 

POLLUTION PREVENTION 

Penoxsulam. Human Health New Use Risk Assessment to Support the 

Registration of Proposed Use on Pome Fruit, Stone Fruit, Olive, Pomegranate. 

and Fruit, Small, Vine Climbing (Subgroup l 3-07F, Except Fuzzy Kiwifruit); and 

Crop Group Conversion for Tree Nuts. 

PC Code: 119031 

Decision No.: 497353 

Petition No.: 4E8330 

DP Barcode: 0424710 

Registration No.: 62719-6 11 

Regulatory Action: Section 3 

Risk Assessment Type: Single Chemical Aggregate Case No.: 7265 

TXR No.: NA CAS No.: 219714-96-2 

MRID No.: NA 40 CFR: 180.605 

FROM: Elizabeth Holman, Physical Scientist/Risk Assessor ~ ~ 

Gerad 

Linnea 

Thornton

J. Hansen, 

, Environmenta

Ph.D., Biologist 

l Protection 

~ 

SRecialist cfv-~ 

Risk Assessment Branch II (RABii) 1 

Health Effects Division (7509P) 

THROUGH: Christina Swartz, Branch Chief oU- A--

Risk Assessment Branch lJ (RABii) 

Health Effects Division (7509P) 

TO: Sidney Jackson/Barbara Madden 

Minor Use and Emergency Response Branch 

Registration Division (7505P) 

A human health risk assessment was completed in support of the proposed Section 3 uses of 

penoxsulam on pome fruit, stone fruit, olive, pomegranate, and fruit, small, vine climbing 

(Subgroup 13-07F, except fuzzy kiwifruit), plus crop group conversion for tree nuts. 

Page I of61 
Table of Contents 

1.0 Executive Summary .......................................................................................................... 4 

2.0 HED Recommendations ........................................... ........................................................ 5 

2.1 Data Deficiencies/Conditions of Registration ..................................................... 6 

2.2 Tolerance Considerations ....................................................... .............................. 6 

2.2.1 Enforcement Analytical Method ............... ........ ....... ............................... 6 

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

2.2.3 Recommended Tolerances ........................................ .... ....... ..................... 7 

2.2.4 Revisions to Petitioned-For Tolerances .... ....... ... .................................... 7 

2.3 Label Recommendations ...................................................... ................................ 7 

3.1 Chemical Identity .......... ......... .... .... ........ ..... ..................................... ..................... 8 

3.2 Physical/Chemical Characteristics ...................................................................... 8 

3.3 Summary of Proposed Uses .......................... ............ ....... ..................................... 8 

3.4 Anticipated Exposure Pathways .......................................................................... 9 

3.5 Consideration of Environmental Justice ................................ ....... ....... .............. 9 

4.0 Hazard Characterization and Dose-Response Assessment ......................................... 10 

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

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME) .................... 10 

4.2.1 Dermal Absorption ................................................................................. l I 

4.3 Toxicological Effects ....... ............. .... ........ ........................................................... 11 

4.4 Safety Factor for Infants and Children (FQPA Safety Factor) ...................... 12 

4.4.1 Completeness of the Toxicology Database .......................................... .. 13 

4.4.2 Evidence of Neurotoxicity .. .................................................................... 13 

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young 

Animal ........... .................................. ................. .................................................... 13 

4.4.4 Residual Uncertainty in the Exposure Database .................................. 13 

4.5 Toxicity Endpoint and Point of Departure Selections ...... ................. .............. 13 

4.5.1 Dose-Response Assessment .................................................................... 13 

4.5.2 Recommendation for Combining Routes of Exposures for Risk 

Assessment .. ................................................... ................................. ..................... 14 

4.5.3 Cancer Classification and Risk Assessment Recommendation .......... 14 

5.1 Metabolite/Degradate Residue Profile .............................................................. 17 

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

5.1.2 Summary of Environmental Degradation ............................................ 18 

5.1.3 Comparison of Metabolic Pathways ...................................................... 18 

5.1.4 Residues of Concern Summary .... .... .... .... .... .... ....... .......... .... ... ....... ....... 18 

5.2 Food Residue Profile ........................................................................................... 19 

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

5.4 Dietary Risk Assessment .................................................................................... 20 

5.4.1 Description of Residue Data Used in Dietary Assessment ..... .... ......... 20 

5.4.2 Percent Crop Treated Used in Dietary Assessment .. ........................... 20 

5.4.3 Acute Dietary Risk Assessment ............................................................. 20 

5.4.4 Chronic Dietary Risk Assessment ........ ........... ...................................... 20 

5.4.5 Cancer Dietary Risk Assessment ..... ................................. ..................... 2 1 

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ............................ 21 

6.1 Residential Handler Exposure ........................................................................... 21 

Page 2 of61 
Page 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 Characterization............................................................ 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

Appendix 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................................................................................ 61
Page 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 well as the 

requested new uses on pome fruit, stone fruit, olive, pomegranate, and fruit, 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 sulfonamide herbicide used for the selective control 

of grasses, 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 toxicological 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 submitted 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 portal 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 chronic 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 toxicological 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 

maternally 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 (Toxicity Category IV for all categories). 

HED has classified penoxsulam as having suggestive evidence of carcinogenicity based on an 

increased incidence of mononuclear 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, since there is no similar tumor occurring in humans. Additionally, 

penoxsulam is negative for mutagenicity, and MNCL is not associated with exposure to other 

triazolopyrimidines.
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 cRfD 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 nonoccupational 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 and 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 proposed 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, additional nature of 

the residue data may be needed. Acceptable field trial, storage stability, and processing studies 

have been completed to support the requested new uses and crop group changes. Adequate 

analytical methods are available for tolerance-enforcement purposes. 

HED has estimated dietary, residential, and aggregate risks from exposure to penoxsulam. 

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 residential exposure are 4,600 or more, indicating 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 activities. 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, postapplication 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 justice 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 established for the herbicide, penoxsulam (2-

(2,2-difluoroethoxy)-N-(5,8-dimethoxy[1,2,4] triazolo[1,5-c]pyrimidin-2-yl)-6-

(trifluoromethyl)benzenesulfonamide in/on the following raw agricultural commodities...” 

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) benzenesulfonamide, in 

or on the commodity.”

Notes to RD: Upon establishment of the proposed tolerance in tree 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 Enforcement Analytical Method

Residue Chemistry Summary D355914; 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 01.25 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 

guidelines 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 multiresidue methods. 

2.2.2 International Harmonization
Page 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). 

Proposed 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 

Pomegranate 0.01 0.01 pome fruit field trial data.

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 below. Compliance 

with the tolerance levels specified below is to be determined by measuring only 

penoxsulam 2-(2,2-difluoroethoxy)-N-(5,8-dimethoxy[1,2,4]triazolo[1,5-c] 

pyrimidin-2-yl)-6-(trifluoromethyl) benzenesulfonamide, in or on the commodity.

The 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 Introduction
Page 8 of 61

3.1 Chemical Identity

Penoxsulam is a sulfonamide herbicide used for the selective control of grasses, 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). The 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-difluoroethoxy)-N-(5,8-dimethoxy[1,2,4]triazolo[1,5-c] pyrimidin-2-yl)-6-

(trifluoromethyl) benzenesulfonamide

CAS registry number 219714-96-2

End-use product (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 chemical 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 emulsifiable concentrate containing 

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 included in Table 3.3 below.

The personal protective equipment (PPE) specified on the label indicates the baseline clothing 

scenario for handlers, i.e., long sleeved shirt, long pants, shoes plus socks, no gloves and no 

O

F F

S

N

H

O

N

N

N N

O

O

CH3

CH3

O

CF3
Page 9 of 61

respirator. 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. While a restricted entry interval 

(REI) of 12 hours would be considered adequate for penoxsulam, the Pindar GT label is 24 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, 

MechanicallyPressurized 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 herbicide 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 nonoccupational settings as well. There is potential for dermal and inhalation exposure in residential 

and non-residential settings, as well as the potential for post-application 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 estimate overall exposure and risk. 

3.5 Consideration of Environmental Justice
Page 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 patterns 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 National Health and Nutrition Examination Survey, What We Eat 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 based on age, season of the year, ethnic group, and region of the country. 

Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and 

exposure assessments are performed when conditions or circumstances warrant. Whenever 

appropriate, 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 currently in development as OPP has 

committed resources and expertise to the development of specialized software and models that 

consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary 

patterns among specific subgroups.

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. The 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 vapor 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 was rapidly absorbed, distributed and excreted following oral 

administration. At a low dose (5 mg/kg), absorption was largely complete (81-88% administered 
Page 11 of 61

dose, or AD). Significant biliary excretion was observed, with males excreting a larger 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 area 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 (Tmax) was 0.5 hr at the low 

dose and 2 hr at the high dose. The plasma half-life (t1/2) at the low dose was 2.6 to 2.9 hrs 

(males and females, respectively). At the high dose, t1/2 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 unmetabolized 

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 Phase 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 females. 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. 

Similar 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 absorption data are available for penoxsulam. However, a 28-day dermal toxicity 

study in rats was submitted. No systemic toxicity occurred at the limit dose (1000 mg/kg/day),

and the primary toxic effects of concern were adequately assessed in the study. Therefore, 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 subchronic 

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 bioaccumulation 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 observed 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 in 
Page 12 of 61

urinalysis parameters (increased BUN and in males, urinary 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 comparable 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 included decreased red blood cell parameters and decreased 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 not 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 

feeding 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, but 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 developmental 

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 decreased 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. 

The 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 Factor for Infants and Children (FQPA Safety Factor)

After having evaluated 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 additional 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 exposure assessment is based on the assumptions of tolerance-level 

residues and 100% crop treated for all commodities. These assumptions result in very 
Page 13 of 61

high-end estimates of dietary exposure. Actual exposures and risks from penoxsulam are 

expected to be much lower. 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 the 28- or 90-day inhalation toxicity study is not needed (see Section 4.1).

4.4.2 Evidence of Neurotoxicity

No evidence of neurotoxicity was observed in acute or chronic neurotoxicity studies or in other 

studies in the toxicology database. 

4.4.3 Evidence 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 Database

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 Departure 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 neurotoxicity 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 chronic reference dose (cRfD). The POD of 14.7 
Page 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 multifocal 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 intermediate-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 intermediateterm 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 not 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 routes: oral, dermal and inhalation. HED 

considers the potential for concurrent exposure via different routes that produce the same 

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 subchronic 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 Cancer Classification and Risk Assessment Recommendation
Page 15 of 61

Penoxsulam is classified as having “Suggestive Evidence of Carcinogenicity, but Not Sufficient 

to Assess Human Carcinogenic Potential.” The classification was based on an increased 

incidence of mononuclear 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 relevance 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 herbicides generally do not show evidence of carcinogenicity. Based on these 

weight-of-the-evidence considerations, human cancer risk was considered to be minimal, and 

quantification of human cancer 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

UFA= 10x

UFH=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 ShortTerm (1-30 

days)

NOAEL= 

17.8

mg/kg/day

UFA= 10x

UFH=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 

Short- Term 

(1-30 days) 

and 

IntermediateTerm (1-6 

months)

NOAEL= 

17.8 

mg/kg/day

UFA= 10x

UFH= 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 = uncertainty factor. UFA = extrapolation 

from animal to human (interspecies). UFH = potential variation in sensitivity among members of the human population 

(intraspecies). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference 

dose.

Table 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 

exposure scenario was not assessed for human health risk.

Inhalation 

Short-Term 

(1-30 days) 

and 

Intermediateterm (1-6 

months)

NOAEL= 

17.8 mg/kg/day

UFA=10x

UFH=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. UFA = 

extrapolation from animal to human (interspecies). UFH = potential variation in 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 Animal 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 has 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 vines was observed. HED notes 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 penoxsulam 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 study 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 pertaining 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 residues 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 (t1/2 = 1.5-14 days). 

Penoxsulam is slightly more persistent in aerobic aquatic (t1/2 = 12-38 days) and anaerobic 

environments (t1/2 = 5-11 days), and even more persistent in aerobic soil environments (t1/2 = 34-

118 days). Penoxsulam is also very mobile (Kd = 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 volatilize from soil and water. 

Eleven major degradation products have been identified for penoxsulam (BSTCA, 2-aminoTCA, 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 these 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-OHpenoxsulam, SFA, sulfonamide, and 5,8-di OH.

5.1.3 Comparison 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, in the goat and hen metabolism 

studies, penoxsulam was excreted and not 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 definitions 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-OHpenoxsulam; 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 Barcode 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; D355914; 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 enforce 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 current action (PP#4E8330) 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 assessed 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 the 

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. Residues were incorporated 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 0.00154 0.0463

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 into the dietary assessment 

using the maximum 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 

assumption 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. Penoxsulam 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 significantly 

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/A
Page 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. The tumors observed in Fischer 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 toxicity 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 SOPs1

and the Aquatic Use SOP along with policy changes for body weight assumptions. Specifically, 

there are several end-use product (EP) formulations of penoxsulam registered for weed control 

on residential and commercial turf areas (lawns and golf courses) and aquatic sites. Use of these 

formulations in residential settings results in 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 based 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 granule 

formulations.

 

1 Available: http://www.epa.gov/pesticides/science/residential-exposure-sop.html
Page 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. According 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 assessment is still needed.

HED’s LOC is a MOE greater than or equal to 100 for residential exposure. A quantitative 

dermal assessment 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, the 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 and Risk Estimates for Penoxsulam.

Exposure 

Scenario Application Equipment

Inhalation Unit 

Exposure 

(mg/lb ai)

Maximum Application 

Rate1

Area Treated 

or Amount 

Handled 

Daily2

Inhalation

Dose (mg/kg/day)3 MOE4

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/ft2 1000 ft2 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/ft2 1200 ft2 0.00000082 22,000,000

Spoon 0.087 0.0000014 lb ai/ft2 100 ft2 0.00000015 120,000,000

Cup 0.013 0.0000014 lb ai/ft2 100 ft2 0.000000023 780,000,000

Hand dispersal 0.38 0.0000014 lb ai/ft2 100 ft2 0.00000067 27,000,000

Shaker can 0.013 0.0000014 lb ai/ft2 100 ft2 0.000000023 780,000,000

1 Based on currently registered labels.

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 exposure/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. Only 
Page 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 

MOEs 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 worst 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 Application Rate1 Lifestage Post-application 

Exposure Scenario

Dose/Exposure2

MOE3,4

(mg/kg-day)

Lawns/Turf Liquid 0.06 (lb ai/acre) Child 1 to < 2 

years

Hand to Mouth5 0.0038 4,600

Object to Mouth5 0.00012 150,000

Soil Ingestion5 2.0E-6 8,800,000

Lawns/Turf Granule 0.06 (lb ai/acre) Child 1 to < 2 

years

Hand to Mouth5 0.0001 200,000

Object to Mouth5 0.00001 3,200,000

Soil Ingestion5 2.0E-6 8,800,000

Aquatic 

Uses Liquid 0.009 (lb ai/1000ft3

)

Child 3 to < 6 

years

Inhalation 8.3E-21 2.1E+21

Ingestion 4.0E-5 450,000

Adult

Inhalation 7.5E-21 2.4E+21

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 

considered 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 methods (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 spray 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.htm 
Page 24 of 61

Procedures Addenda 1: Consideration of Spray Drift. This document 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 reflects

handlers’ inhalation exposure during applications to lawn/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 Residential 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 studies 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). Therefore, 

the short-term aggregate risk estimates (Table 7.2) include dietary exposure and incidental oral 

exposure from activities on turf or from the aquatic use. The resulting short-term MOEs are 
Page 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 2Incidental 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 produce 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 chemicals 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-emergence 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 interval 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 

policies. In the absence of a dermal toxicity endpoint, dermal handler and post-application 

exposure assessments 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 chemicalresistant 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 exposure 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 (μg/lb ai)1 Maximum 

Application 

Rate2

Area Treated 

or Amount 

Handled 

Daily3

Inhalation

Baseline Dose (mg/kg/day)4 MOE5

Mixer/Loader

Groundboom Orchard/

Vineyard 100 0.219 0.03 40 acres 0.0000034 5,200,000

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 4,500,000

Mechanicallypressurized 

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 (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A or gal/day) ÷ BW (kg).

5 Inhalation MOE = Inhalation NOAEL (mg/kg/day) ÷ Inhalation Dose (mg/kg/day). – level of concern is already in table & abbreviation not used here
Page 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 postapplication 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 activities in previously treated fields. These potential sources 

include volatilization of pesticides and resuspension of dusts and/or particulates that contain 

pesticides. The agency sought expert advice and input on issues related to volatilization of 

pesticides from its 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 

evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent 

Volatilization Screening Analysis (http://www.regulations.gov/#!docketDetail;D=EPA-HQOPP-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 

occupational 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/commercial 

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 toxicological 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.

References
Page 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: Occupational 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 Registration) 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, D429010, 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 Climbing (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 proposed 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 Synthesis................

870.5915 Mutagenicity—In Vivo Sister Chromatid Exchange

yes

yes

yes

yes

no

no

yes

yes

yes

yes

--

--

870.6100a Acute Delayed Neurotoxicity. (hen)...............................

870.6100b 90-Day Neurotoxicity (hen)............................................

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

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

870.6300 Develop. Neurotoxicity...................................................

no

no

yes

yes

no

---

---

yes

yes

---

870.7485 General Metabolism .......................................................

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

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, rangefinding (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 

females 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, rangefinding (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 histopathology.

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, rangefinding (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 pelvic 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/day)

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, 

decreased 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/day.

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 mutations 

in the presence and absence of rat S9 metabolic 

activation. Cytotoxicity observed at >333 

μg/plate.

Mammalian 

cell forward 

gene 

mutation 

assay

870.5300

Chinese hamster 

ovary (CHO) cells 

(+/-S9)

45830923 (1999) 

0, 46.88, 93.75, 187.5, 

375, 750, 1500 μg/mL

Acceptable/guideline

Negative for forward gene mutation in the 

presence and absence of rat S9 metabolic 

activation. Limit of solubility observed at 750-

1500 μg/mL.

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 hr 

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 postdosing

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 postdosing

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 the 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 postdosing, 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 compound 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 Acute Reference Dose (aRfD) – All Populations 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 Toxicity Study in Dogs 

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 = 

100( )

14.7 / /

UF

mg kg day = 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 and 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 dietary 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 developmental 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 dose 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 available 
Page 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 for penoxsulam. However, a 28-day dermal toxicity 

study in rats was submitted (MRID 45830911). No systemic toxicity occurred at the limit dose 

(1000 mg/kg/day), and the primary toxic effects of concern 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 the 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 Exposure 

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= 17.8 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 inhalation 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 to 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% (females) 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 significant 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 urinalyses. 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 space 

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 (males 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 the 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 rangefinding study. It was conducted for purposes of dose selection and does not satisfy the guideline 

requirement for a subchronic oral toxicity study (OCSPP 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 provide 0, 10, 100, 500 or 1000 mg/kg bw/day (actual doses 

were 0, 10.5, 103.1, 529.8 and 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 diet 
Page 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 mortalities and no effects of treatment on clinical observations, 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%, respectively) 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). The 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 authors 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 hepatocellular 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 the 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. increased 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 

current 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 Interim 

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 and 

>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, relative 
Page 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 increased 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 animals 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 histopathological 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/sex/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 prevalent 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 and 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 study. 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 biologically 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 decreases 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, albumin 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, rather 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),

are 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 500 mg/kg/day. A LOAEL in male 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 phosphatase 

activity in males at 500 and 1000 mg/kg/day was considered to be of only minimal toxicological

significance. Alanine aminotransferase and aspartate aminotransferase were not affected. There 

were increases in absolute (33-41%) and relative (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, hepatocellular 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 accumulation, but which 

were not considered to be of toxicological 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 oral 

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 dogs/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 considered 

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 for 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 dose 

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 were 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 deaths reported during the study. There were no treatment-related effects on 

clinical observations, dermal observations, body weight, body weight gain, food consumption, 

urinalysis parameters, hematology, clinical chemistry, organ weights, or gross pathology or 

histopathology during 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).

The 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 Developmental 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 alterations. 

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 toxicity 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 toxicity 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 toxicity 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 highdose 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 abnormalities 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 this 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 developmental 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 Prenatal 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 week) in 0.5% aqueous METHOCELTM (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 does were killed and necropsied. All fetuses were weighed, sexed, 

and examined for external, visceral, and skeletal alterations, and heads from approximately onehalf 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 hypoactivity 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 black 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 high-dose 
Page 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 weight gain during GD 24-28 (252%). There were no treatment-related effects on 

absolute body weights, corrected (for gravid uterus) body weights 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 there were no total litter resorptions. High-dose females had slight increases in mean postimplantation 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 

fetal 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 treatmentrelated increases in the fetal or litter incidences of any individual 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. The developmental 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 (OCSPP 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 was produced in each generation. F0 and F1 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 nonmated CD rats (MRID 45830907).

Intercurrent deaths of several F0 and F1 animals were considered incidental to treatment. No 

treatment-related clinical signs of toxicity were observed in 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 F0 generation during the premating interval. Absolute body 

weights of the high-dose F1 males were significantly (p  0.05; 88-94% of controls) less than 

those of the controls throughout the study. High-dose F1 females had significantly lower (p0.05; 

93% of controls) body weight than the controls only for the first week of premating. Body 

weight gains by the high-dose F1 animals were similar to the controls. Reduced body weights of 
Page 46 of 61

the high-dose F1 parental animals during premating were considered a continuation of 

preweaning effects. Food consumption by the high-dose F1 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 weights 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) absolute and relative kidney weights. Microscopic lesions of the kidney of high-dose 

F0 and F1 females included epithelial hyperplasia, inflammation, and crystal formation in the 

pelvis and tubular degeneration. The incidences (severity) of kidney lesions in control and highdose females were 1-2/30 (1.00) and 25-26/30 (1.58-2.04), 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), 

respectively, for degeneration. In addition, crystals were observed in 0, 0, 2, and 16 F0 females 

and in 2, 1, 7, and 11 F1 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 F1 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 control groups of either generation. Estrous cyclicity, follicle counts, and 

sperm parameters were not affected by treatment. 

Body weights of the high-dose F0 and F1 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 F0 and F1 dams 

had weight gains 79% and 82%, respectively, of the control group levels. Weight changes by the 

high-dose dams during the first week of lactation consisted of marked weight loss during days 1-

4 and a lower weight gain than the controls for days 4-7. Recovery was noted in the high-dose 

dams after lactation day 7. During gestation, food consumption was similar between the treated 

and control groups of both generations. Food consumption by the high-dose F0 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 F1 dams was significantly (p  0.05; 70-72% of controls) 

less than that of the controls on lactation days 1-7. Compensation was noted in the high-dose F0

and F1 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 reproductive toxicity 

NOAEL is 100 mg/kg/day 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 stillborn pups, and sex 
Page 47 of 61

ratios. No treatment-related clinical signs of toxicity were observed in the pups during lactation 

and gross necropsy was unremarkable. At birth, body weight of the high-dose pups was slightly 

(9%, n.s.) lower than that of the control group. High-dose male and female pups from 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 levels 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 weight 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 same 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 toxicologically 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 

considered 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 months 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 

glomerulonephropathy (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 therefore 

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 

histopathological 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 hyperplasia (incidence and severity); and diffuse hyperplasia (incidence and 

severity, females only).
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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 was 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 the 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 for a chronic 

toxicity/carcinogenicity study (OCSPP 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, organ weights, or 

gross pathology. There appeared to be marginal inhibition of body weight gain and food 

consumption in males, but not females, 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 of one male in the 0.15% group. Similar lesions 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 observed 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 study, 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 an 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, ophthalmologic 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 administered 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 administered 

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 adaptive change resulting 

from induction of the liver microsomal enzyme system by the test material. This change was not 

considered to be an adverse effect.

The affected hepatocytes in male mice administered 375 and 100 mg/kg/day were said to contain 

clear cytoplasmic 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 addition, very slight (3 

animals) to slight (1 animal) dilatation 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 frequency (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 mice (>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 males 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 considered 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 activity. 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 subchronic 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 Acceptable/Nonguideline but does satisfy the guideline requirement 

for a carcinogenicity study [OCSPP 870.4200b; OECD 451] in mice. Although a LOAEL was 

not identified for either males or females, the CARC determined that the high dose in females 

was close enough to the limit dose of 1000 mg/kg/day. In 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

Guideline 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 1500 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. Neurobehavioral 

assessments (functional observational battery (FOB) and motor activity testing) were performed 

in 10 animals/sex/group before treatment and at Day 1, 8, and 15. At Day 16, 5 

animals/sex/group were euthanized and perfused in situ for neuropathological examination. 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, clinical signs, body weight, 

ophthalmaloscopic findings, or gross and histologic pathology or neuropathology. FOB and 

motor activity testing revealed no treatment-related effects.

Postive control studies were provided. An FOB proficiency report demonstrated the ability of the 

technician observer to detect major neurotoxic endpoints. Motor activity positive control data 

demonstrated the ability to detect both increases (amphetamine) and decreases (chlorpromazine) 

in motor activity. Neuropathology positive control data, validated with trimethyltin and 

acrylamide, demonstrated the ability to detect central and peripheral nervous system 

histopathological changes. The neurotoxicity NOAEL for XDE-638 in male and female rats 

is 2000 mg/kg (limit dose). The LOAEL was not 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 # B765-44; 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 incorporated 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 performed 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 selected 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 250 

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 males 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 proficiency report and positive control 

data for motor activity and neuropathology examinations 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 at 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 14CXDE-638 (Penoxsulam). Both a triazole ring label (Lot no. F-458-159, INV 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, chemical purity 97.5%). An additional group of three male 

and three female rats were fitted with bile duct cannulae and biliary elimination monitored over 

24 hours following an oral dose of 5 mg/kg. Absorption, distribution, metabolism and kinetic 

parameters were evaluated for the single and multiple low dose and the high-dose groups.

Overall recovery of administered radioactivity was an acceptable 91-107%. Dose confirmation 

revealed that dosing was within 13% of the target doses, and results of homogeneity and stability 

assessments were 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 contributions of absorbed radioactivity. Biliary excretion was greater for 

males (55.8% of dose) than 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 Cmax 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 (Cmax) 

and whole body clearance (Cl) data also supported observed gender-related variability in 

disposition of the test article.

Urine and feces 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 males (55% vs 20% for 

females). Elimination patterns were similar for the repeated (15-day) low dose. Excretion in 

urine was more prominent following a single low dose (36% and 69% males and females, 

respectively) and in feces more prevalent at the high dose (70% and 87% for females 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 excretion (>90%) occurred 

within 36 hours for the low-dose group and within 48 hours for the high-dose group. Fecal 

excretion was essentially complete within 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 disposition of the test article. Tissue 

burdens assessed at various times after dosing revealed that at sampling times equivalent to Cmax

(0.5 hrs) and 1⁄2 Cmax (3 hrs), most radioactivity was associated with the gastrointestinal tract and 
Page 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 radioactivity 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 the 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 identified primarily 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 dose in feces of low-dose males. The absence of radioactivity in expired air 

precluded the formation of volatile 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 with reduced urinary excretion of radioactivity in bile-cannulated rats were 

indicative of potential enterohepatic circulation. Only minor 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 14C- XDE-638 (Penoxsulam) orally administered to male 

and female rats underwent fairly rapid but incomplete absorption which became dose-limited at

or below a dose of 250 mg/kg. Although widely distributed among tissues, there was no evidence

of sequestration or bioaccumulation. Excretion was primarily via the urine and feces, with 

unabsorbed test article accounting for much of the fecal radioactivity especially for the high-dose 

group. A large number of metabolites were detected in urine, feces, and bile. Minor qualitative, 

gender-related differences were observed. Most metabolites represented only a small portion 

(<1%) of the administered 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 classified 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 Immunotoxicity
Page 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 28 consecutive days. On Day 23, animals in all groups were immunized with a 

suspension of sheep red blood cells (SRBC) by intravenous injection (2x108 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, clinical signs, body weight changes, food 

consumption, hematology, and gross pathology. Immunotoxicity was assessed using an enzymelinked immunosorbent assay (ELISA) approach that measured the concentration of serum antiSRBC IgM. The organ weights of the spleen, 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 compared 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 related 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 related and statistically significant increases in relative 

kidney weights of 10.4% relative to the control occurred at 1000 mg/kg/day. These findings were 

consistent with prior repeated doses studies.

The systemic toxicity NOAEL is 200 mg/kg; the LOAEL was 1000 mg/kg/day based on 

increases in liver and kidney weights 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 significant 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 

immunotoxicity 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 this chemical does not directly 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 immunotoxicity study is classified as acceptable/guideline and satisfies the guideline 

requirement for an immunotoxicity study (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, pKa 5.1 (ambient) MRID 45830720

Octanol/water partition coefficient, 

Log(KOW)

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. Soderberg.
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-otoluenesulfonamide

 
Page 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)benzenesulfonamide
Page 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 LAFT3 HAFT3 Median3 Mean3 SD3

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 MRIDs 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 website3.

 

3 http://www.epa.gov/pesticides/science/handler-exposure-data.html and 

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