UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

OFFICE OF CHEMICAL SAFETY 

AND POLLUTION PREVENTION 

MEMORANDUM 

DAT E: 4/16/2015 

SUBJ ECT: Penoxsulam. Human Health Assessment Scoping Document in Support of 

Registration Review 

FROM: 

THROUGH: 

PC Code: I 1903 I 

Decision No.: 499239 

Petition No.: NA 

Risk Assessment Type: NA 

TXR No.: NA 

MRID No.: NA 

DP Barcode: 0425160 

Registr·ation No.: 62 719-611 

Regula tory Action: Registration Review 

Case No.: 7265 

CAS No.: 219714-96-2 

40 CFR: § 180.605 

Douglas Dotson, Ph.D., Chemist . ~~ ;{ , _ .1..J' 

Linnea Hansen, Ph.D., Toxicologist ~~~U".1 

Zaida Figueroa, M.S., Industrial Hygienist v!J> t 

Risk Assessment Branch JI /----

Health Effects Division (7509P) 

Office of Pesticide Programs 

Christina Swaitz, Branch Chief~ Risk Assessment Branch II 

Jess Rowland, Associate Direct~-4r-E~.:c:: Dana Vogel, Acting Director 

Health Effects Division (7509P) 

Office of Pesticide Programs 

TO: Bonnie Adler, Chemical Review Manager 

Pesticide Re-Evaluation Division (7508P) 

Office of Pesticide Programs 

Attached is the Jlcalth Effects Division's (HED) human health risk assessment scoping document 

for penoxsulam Lo support registration review. 
Penoxsulam Registration Review Scoping Document 

Executive Summary 

The Health Effects Division Penoxsulam Registration Review Team has evaluated the database 

and the most recent human health risk assessment for penoxsulam. HED performed this 

evaluation in order to determine the scope of work necessary to support the established 

tolerances and existing registrations during registration review. The primary source of 

information for this evaluation was the most recent human health risk assessment for the 

chemical (D363910, C. Swartz, 4/9/2009). 

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

(trifluoromethyl) benzenesulfonamide, is a sulfonamide herbicide used for the selective control 

of grasses, broad leaf, and sedge weeds, 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 molluscs. 

The toxicological database is complete and considered adequate to assess the human health risk 

resulting from current registered uses, and HED does not recommend that any additional studies 

be required during registration review. An acceptable immunotoxicity study, required under 

current 40 CFR Part 158 toxicology guidelines, has been submitted. There are no subchronic 

inhalation toxicity data on penoxsulam; however, the HED Hazard and Science Policy Council 

(HASPOC) recommended that the inhalation toxicity study requirement be waived, based on the 

lack of evidence of po1ial of entry toxicity, low volatility, and high MO Es for both occupational 

and residential handler inhalation exposures. An oral toxicity study was selected for assessment 

of inhalation exposure risk. 

The primary target organs of penoxsulam toxicity are the kidney and liver. Effects on red blood 

cell (RBC) parameters have been reported in the rat. There is no evidence of increased 

qualitative or quantitative pre- and/or post-natal susceptibility, neurotoxicity, or immunotoxicity. 

In addition, exposure assessments are not likely to underestimate risk assoc iated with the 

registered uses. The FQPA Safety Factor for penoxsulam has, therefore, been reduced to Ix. 

Penoxsulam is classified as having "suggestive evidence" of carcinogenicity based on an 

increased incidence of mononuclear cell leukemia in male rats. A separate cancer risk 

assessment was not conducted. All current points of departure (PODs) and endpoints for noncancer risk, as selected in the most recent (2009) risk assessment for penoxsulam, are based on 

kidney histopathology seen in the dog chronic (chronic dietary exposure) and subchronic (all 

non-dietary residential and occupational exposure) toxicity studies. 

Although the PODs and endpoints are not expected to change during registration review, 1-IED 

recommends a review of the PODs and endpoints selected for risk assessment at the time of 

registration review to ensure that they are consistent with the current science and risk assessment 

policies. In addition, the following changes to exposure scenarios are noted: (1) intermediateterm incidental oral exposure will no longer be assessed, and onl y short-term exposure will be 

evaluated, and (2) the need for an intermediate-term dermal POD and endpoint should be 

reevaluated (based on lack of effects for short-term dermal exposure or lowering of 

NOAELs/LOAELs for the critical effect with increased exposure duration). 

Page 2 of24 
Penoxsulam Registration Review Scoping Document

Page 3 of 24

The residue chemistry database is adequate to support current registration review requirements. 

Adequate metabolism (crops, livestock, and rotational crops), storage stability, magnitude of the 

residue, and processing data are available to support the registered uses. Adequate methods are 

available for enforcement of the currently established tolerances. The tolerance expression needs 

to be updated to include both coverage and compliance statements. The dietary exposure 

database, including the potential for residues in food and drinking water, is adequate to support 

current registration requirements. The last risk assessment provided chronic dietary exposure 

estimates that are not of concern for all population subgroups.

Penoxsulam products are registered for use in residential areas. HED conducted residential postapplication assessments for the turf and aquatic uses (i.e., recreational fish and backyard ponds). 

The risk estimates were not of concern. During registration review, HED will update these 

assessments based on revised inputs, assumptions, and procedures (e.g., Aquatic Use SOP and 

HED’s 2012 Residential Turf SOP). In addition, HED will conduct a residential handler 

assessment for the aquatic use; however, no risks of concern are anticipated. In addition, the 

Agency will consider the potential for exposure through spray drift and volatilization.

In the 2009 risk assessment, no risks of concern were identified for the general U.S. population 

or any population subgroup. At the time of registration review, HED will conduct a new 

aggregate risk assessment that will be based on any policy changes, potential updates to points of 

departure, or exposure estimates from food and drinking water.

The occupational exposure database is adequate to support the registration review of

penoxsulam. The most recent occupational handler and post-application exposure assessments 

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

registration review, updated occupational handler assessments will be conducted to reflect all the 

registered uses and current occupational exposure policies.

The Interregional Research Project Number 4 (IR-4) proposed new uses for penoxsulam on 

pome fruit, stone fruit, olives, and pomegranate. IR-4 also requested that the tolerance for grapes 

be expanded to the crop subgroup 13-07F (Small fruit vine climbing subgroup except fuzzy 

kiwifruit) and that the tree nut crop group be updated to the new crop group, 14-12. The use

patterns for the proposed commodities are similar to the use patterns of the registered 

commodities. As a result, the new uses are not likely to have significantly different exposure and 

risk estimates. HED has not assessed the new uses, however. HED’s human health risk 

assessment in support of the new uses will be incorporated into the registration review risk 

assessment for penoxsulam.

Introduction

HED evaluated the most recent human health risk assessment for penoxsulam in association with 

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

and if further updates are needed to support registration review. In the 2009 risk assessment, 

HED evaluated proposed new uses on grapes and tree nuts (D363910, C. Swartz, 4/9/2009).
Penoxsulam Registration Review Scoping Document

Page 4 of 24

Penoxsulam is used for the selective control of grasses, broadleaf, and sedge weeds, as well as 

for control of vegetation in lakes, ponds, canals, and reservoirs. It is registered for use on grapes, 

tree nuts, and rice. Tolerances are established for residues in these commodities as well as for 

residues in fish, crustaceans, and molluscs. It is also registered for use on turfgrass, aquatic 

weeds, non-cropland, non-bearing cropland, and non-bearing fruit trees (including citrus), 

conifers, and eucalyptus. There are granular, flowable concentrate, emulsifiable concentrate, and 

suspension concentrate formulations of penoxsulam on the market at a maximum single 

application rate of 0.06 lb ai/A (treated turf). For the aquatic uses, the maximum single 

application rate is 0.175 lb ai/A in residential settings (i.e., recreational fish and backyard ponds). 

Tolerances for residues of penoxsulam are established in 40 CFR §180.605. Tolerances are 

established in terms of parent penoxsulam on the commodities listed above. The structure and

chemical names, as well as the chemical and physical properties can be found in the tables in 

Attachment 1.

Hazard Identification/Toxicology

The toxicology database for penoxsulam is considered to be complete, and HED does not 

recommend that any additional toxicology data be required at this time (see Toxicity Profile, 

Attachment 2, for complete summary of the toxicology database). Since the previous risk 

assessment was conducted (2009), the registrant submitted an acceptable rat immunotoxicity 

study. This study is required under the current 40 CFR Part 158 guidelines, and HED requested 

it in the 2009 risk assessment. A rat subchronic (28- or 90-day) inhalation study is not available, 

but the HED HASPOC recommended that the guideline requirement be waived (TXR No. 

0051714, J. Leshin, 3/17/2015). This determination was based upon low inhalation MOEs 

(≥5800) for all residential and occupational exposure scenarios of penoxsulam (calculated using 

current exposure SOPs and body weight assumptions), along with its low vapor pressure and 

lack of portal of entry effects in oral and dermal studies. 

Penoxsulam is rapidly and nearly completely absorbed in the rat following oral dosing at a low 

dose (5 mg/kg/day, 81-88% of the administered dose, or AD), but absorption appeared to be 

saturated at a high dose (250 mg/kg). At the low dose, the major route of excretion was via the 

feces for males and via the urine for females. At the high dose, however, excretion was mainly 

via the feces for both sexes. Significant enterohepatic circulation was observed in the males 

(55% AD) and to a lesser extent in females (14% AD). Most radioactivity was excreted by 48 

hours, and tissue retention was negligible. Penoxsulam was extensively metabolized, but most 

metabolites were present at less than 1% of the AD. Parent and a 2-hydroxyphenyl derivative 

were the major moieties observed in feces and urine, with parent representing a larger fraction in 

the high dose animals.

In the rat and dog, the kidney was the major target organ. Penoxsulam formed crystals and 

calculi in the urine, which were observed in the renal pelvis of both species and resulted in 

histopathological effects to the urothelium, including multifocal urothelial hyperplasia and 

subacute to chronic inflammation in the renal pelvis/collecting ducts. These effects were 

observed following subchronic and chronic exposure in both species. Dogs were more sensitive 

than rats to renal effects. Toxicity did not occur at significantly lower dose levels with longer 
Penoxsulam Registration Review Scoping Document

Page 5 of 24

exposure times, although in the rat there were additional findings related to kidney effects 

(changes in urinalysis parameters, increased BUN, increased severity of glomerulonephropathy 

in males) in the chronic study that were not observed at higher dose levels in the subchronic 

study. At high doses in the 4-week dog study, liver histopathology and increases in liver-related 

clinical enzymes (Alk, SGPT, SGOT) and liver weight were observed. In the rat, decreased 

RBC parameters and decreases in body weight/weight gain and food consumption were also 

observed in all studies. 

Studies in the mouse did not show adverse effects regardless of exposure duration, but adaptive 

liver changes (increased liver weight, hepatocellular hypertrophy, observations indicating 

increased microsomal enzyme activity) were observed. No systemic toxicity was observed in a 

28-day dermal toxicity study in the rat tested up to the limit dose. A dermal absorption study has 

not been provided, but comparison of rat oral and dermal 4-week studies indicates an upper 

bound absorption of 50%. There was no evidence of neurotoxicity in the acute and chronic 

neurotoxicity studies in the rat, and no evidence of immunotoxicity in the rat. 

HED reduced the 10x FQPA Safety Factory (FQPA SF) to 1x. There was no evidence of 

increased qualitative or quantitative pre- or post-natal susceptibility. No developmental toxicity 

was observed in the rat or rabbit developmental toxicity studies. Slight delays in preputial 

separation in male F1 offspring were observed in the rat two-generation reproductive toxicity 

study, and pup weight gains were reduced during lactation. However this finding was observed 

in the presence of parental toxicity (decreased adult F1 body weight in males and kidney 

histopathology in females). In addition, exposure assessments are not likely to underestimate 

risk associated with the registered uses. 

Penoxsulam is of low acute toxicity by all exposure routes and is not a dermal irritant or 

sensitizer, nor an eye irritant. Although the rat acute inhalation toxicity study was classified as 

unacceptable based on inconsistencies with the test chamber atmosphere concentrations during 

the study, the overall findings support its low toxicity via that route.

The non-cancer doses and endpoints for dietary, residential, and occupational exposure 

assessment used in the most recent risk assessment (see Attachment 3) are based on kidney 

toxicity in the dog 90-day study (all non-dietary exposures) and 1-year dietary study (chronic 

dietary exposure). These doses and endpoints are the most sensitive found in the available 

studies, and are protective of other effects. Acute dietary and short-term dermal exposures were 

not assessed because toxicological endpoints were not identified. No changes to the previously 

selected studies and doses/endpoints are anticipated during registration review. However, under 

current HED policy, intermediate-term incidental oral exposure is no longer assessed and,

therefore, an intermediate-term endpoint is not needed. HED should re-evaluate the need for an 

intermediate-term dermal endpoint given the lack of toxicity in the rat 28-day dermal study and 

lack of clear evidence of increased toxicity in the 13-week vs. 4-week oral studies in the dog and 

rat. 

Penoxsulam was classified by the HED Cancer Assessment Review Committee (CARC) as 

having “Suggestive Evidence of Carcinogenicity but Not Sufficient to Assess Human 

Carcinogenic Potential” (TXR No. 0050702, J. Kidwell, 3/24/2004) based on treatment-related 
Penoxsulam Registration Review Scoping Document

Page 6 of 24

(but not clearly dose-related) increases in the incidence and severity of large granular 

lymphocyte leukemia (also known as mononuclear cell leukemia, or MNCL) in male Fischer 344 

rats at levels exceeding in-lab historical control values for all treated groups. MNCL is 

recognized as a common neoplasm in Fischer rats, but the significance of MNCL and its 

biological relevance for human cancer risk remains uncertain. There were no tumor increases 

seen in female rats. Mice showed no increase in tumors, although a maximum tolerated dose 

was not achieved in males. There was no evidence of genotoxicity. Based on a weight-of-theevidence consideration for penoxsulam, concern for carcinogenicity was low, and quantification 

of cancer risk was, therefore, not required. 

Conclusions for Hazard Identification/Toxicology

The toxicology database for penoxsulam is adequate to support registration review, and HED 

does not recommend that any additional toxicology studies be required. The requirement for an 

immunotoxicity study has been satisfied. The rat subchronic inhalation toxicity study 

requirement was waived.

The PODs, endpoints, and safety factors selected in the most recent penoxsulam risk assessment 

are not expected to change during registration review, but should be reevaluated at that time to 

ensure that they are consistent with current science and regulatory policies for assessment of 

hazard. The intermediate-term incidental oral POD and endpoint are no longer required since 

only short-term incidental oral exposure is currently assessed. Additionally, the need for an 

intermediate-term dermal exposure assessment should be reconsidered.

Dietary Exposure

The residue chemistry database is adequate to support registration review. Adequate metabolism 

(crops and livestock), storage stability, magnitude of the residue, and processing data are 

available to support the registered uses. Adequate methods are available for enforcement of the 

currently established tolerances. No residue chemistry data deficiencies were cited in the 

previous risk assessment.

For the 2009 risk assessment, HED conducted a chronic dietary exposure assessment that 

included all commodities with established tolerances: drinking water, tree nuts, rice, grapes, 

fish, crustaceans, and molluscs (D360419, M. Doherty, 3/24/2009). The assessment was 

unrefined, including use of tolerance level residues of penoxsulam in all commodities, and an 

assumption of 100% crop treated (CT) for all crops. It was also based on conservative default 

processing factors that overestimate concentration in processed commodities. An estimated 

drinking water concentration was provided by the Environmental Fate and Effects Division 

(EFED, D355676, J. Wolf, 12/2/2008) and was incorporated directly into the dietary assessment. 

Penoxsulam is registered for control of aquatic weeds. For that use pattern, the maximum 

permitted water concentration in the water column is 0.15 ppm. For the dietary assessment, 

HED used a drinking water concentration of 0.15 ppm as a high-end estimate of penoxsulam 

residues in drinking water. The 0.15 ppm value is likely to be an overestimate of actual residues 
Penoxsulam Registration Review Scoping Document

Page 7 of 24

in drinking water. No new studies that are relevant to the dietary risk assessment have been 

submitted since penoxsulam was last assessed. The chronic dietary risk estimates were not of 

concern for the general U.S. population and all population subgroups. All subgroups use less 

than or equal to 7.1% of the cPAD. HED anticipates that the most recent drinking water 

assessment will be adequate for registration review, but if there are significant changes in the 

drinking water estimates during registration review, HED will likely conduct a new dietary 

exposure and risk assessment. If a new assessment is needed, HED will use the most current

dietary exposure model and food consumption survey data.

According to HED’s Interim Guidance on Tolerance Expressions (S. Knizner; 27 May 2009), 

the tolerance 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.

Conclusions for Dietary Exposure

The dietary exposure database is adequate to support the existing registrations. There are no 

anticipated changes to previous dietary exposure estimates, which are not of concern. The 

tolerance expression will be revised during registration review to reflect both coverage and 

compliance, in accordance with current guidance.

Residential Exposure

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

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

formulations in residential settings results in potential exposure to homeowners who apply the 

products on lawns, and to adults and children who come into contact with treated areas while 

doing lawn maintenance or playing on treated turf. There are granular and suspension

concentrate formulations on the market at a maximum single application rate of 0.06 lb ai/A

(treated turf). For the aquatic uses, the maximum single application rate is 0.175 lb ai/A in 

residential settings (i.e., recreational fish and backyard ponds). Penoxsulam may be applied as 

broadcast and perimeter (directed spray) treatment through a variety of hand-held equipment. 

Residential exposure is expected to be short-term in duration.

Residential Handler Exposure

Homeowners might be exposed to penoxsulam when they handle granule and suspension

concentrate products for the control of weeds on residential and commercial lawns. Since a 

short-term dermal POD was not selected, a quantitative dermal residential handler exposure 

assessment has not been performed. Residential inhalation handler exposures were previously 

assessed, and are not of concern (D339488, M. Collantes, 5/23/2007).
Penoxsulam Registration Review Scoping Document

Page 8 of 24

A residential handler assessment was not conducted for the aquatic use; however, an exposure 

assessment was conducted for commercial handlers applying penoxsulam directly into the water 

or as a foliar application to emergent aquatic vegetation. Risk estimates for commercial handlers 

are not of concern (D339488, M. Collantes, 5/23/2007). Since the current aquatic use product 

label does not restrict penoxsulam from being applied by homeowners, HED will complete a 

residential handler assessment for the aquatic use during registration review. 

In conjunction with determining data needs during registration review, penoxsulam was 

reviewed by the HED HASPOC to evaluate the need for a route-specific inhalation study, as 

previous assessments were conducted using data from an oral study. As noted above, the 

HASPOC recommended that an inhalation toxicity study be waived. In preparation for the 

HASPOC meeting, inhalation risk estimates were calculated using current SOPs and exposure 

assumptions. Residential handler and post-application margins of exposure (MOEs) ranged from 

5,800 to 8.0 x 1017 and are not of concern when compared to the target MOE of 100. 

Residential Post-application Exposure

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

in potential post-application exposures to adults and children. 

Adults and children can be exposed to post-application residues of penoxsulam on turf through 

dermal contact. No short-term dermal endpoint has been identified. The short-term postapplication incidental oral exposures to children from treated turf (hand-to-mouth, objects-tomouth, and ingestion of contaminated soil) were previously assessed using chemical-specific turf 

transferable residue (TTR) data. This most recent residential post-application exposure 

assessment does not reflect the policies of the HED’s 2012 Residential Standard Operating 

Procedures (SOPs), but did not identify risks of concern (D339488, M. Collantes, 5/23/2007). 

For registration review, HED anticipates that the post-application exposure assessment for turf 

use will need to be updated to reflect current exposure assumptions and procedures for 

residential assessment (e.g., HED’s 2012 Residential SOPs for Treated Turf). However, no risks 

of concern are expected. 

The penoxsulam aquatic uses in residential settings might result in post-application dermal and 

oral exposure to adults and children while swimming in treated waters. The exposures to adults 

and children from the aquatic uses were previously assessed (D339488, M. Collantes, 

5/23/2007), and are not of concern. For registration review, HED anticipates that the postapplication exposure assessment for the aquatic use will need to be updated to reflect current 

exposure assumptions and science methodology for aquatic assessments (e.g., Aquatic Use 

SOP). These risks are not expected to be of concern.

Spray Drift and Volatilization

Residential bystander exposures resulting from off-site transport (e.g., spray drift or 

volatilization) can occur as a result of applications of penoxsulam. The potential for spray drift 

will be quantitatively evaluated for each pesticide during the registration review process that 

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– Residential 
Penoxsulam Registration Review Scoping Document

Page 9 of 24

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

The Agency has developed a Volatilization Screening Tool and a subsequent Volatilization 

Screening Analysis. During registration review, the Agency will utilize this analysis to 

determine if data (i.e., flux studies, route-specific inhalation toxicological studies) or further 

analyses are required for penoxsulam.

Conclusions for Residential Exposure

The residential exposure database is adequate to support the existing penoxsulam registrations. 

HED previously conducted residential post-application assessments for the turf and aquatic uses. 

The risk estimates were not of concern. However, during registration review, HED will update 

these assessments as needed based on revised inputs, assumptions, and SOPs. In addition, HED 

will complete a residential handler assessment for the aquatic use. The need for spray drift and 

volatilization risk assessment for penoxsulam will be examined during registration review.

Aggregate Risk Assessment

The most recent aggregate risk assessment was performed as part of the 2009 human health risk 

assessment. Aggregate risk assessments traditionally combine exposure estimates resulting from 

food, drinking water, and residential uses. As no acute toxicity endpoint was identified, an acute 

aggregate risk assessment was not performed. Penoxsulam was classified as having “suggestive 

evidence of carcinogenic potential, but not sufficient to assess human carcinogenic potential.” 

Because of the minimal concerns for human carcinogenicity of penoxsulam (see above), cancer 

risk was not quantified, and the chronic assessment is considered to be protective of potential 

carcinogenic effects. For the short-term aggregate risk assessment, residential use exposures are

aggregated with exposure from dietary sources. The short-term aggregate risk estimates are not 

of concern. There are no intermediate-term exposure scenarios for which quantitative aggregate 

risk estimates are appropriate. Long-term aggregate risk estimates are considered to be 

protective for intermediate-term exposures. The long term-aggregate risk estimates are 

equivalent to the chronic dietary exposure estimates and are not of concern. 

 

Conclusions for Aggregate Exposure and Risk

In the 2009 risk assessment, no risks of concern were identified for the general U.S. population 

or any population subgroup. At the time of registration review, HED will conduct a new

aggregate risk assessment that will be based on any policy changes, potential updates to points of 

departure, or updated exposure estimates from food, drinking water, and residential sources of 

exposure.
Penoxsulam Registration Review Scoping Document

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Occupational Exposure 

Penoxsulam is currently registered for control of grasses, broadleaf weeds, and sedges in several 

agricultural crops (including rice, tree nuts, and grapes), turf/sod (including residential lawns, 

golf courses, recreational/athletic fields), forestry applications, and also to control vegetation in 

lakes, ponds, canals, and reservoirs. 

Occupational handler and post-application exposures are expected based on the registered 

agricultural and commercial uses. Maximum single application rates range from 0.016-0.06 lb 

ai/A for agricultural crops and turf with 1-2 applications/season. For the aquatic uses, the 

maximum permitted water concentration is 0.15 ppm. Penoxsulam may be applied as broadcast 

(directed spray, foliar, in-water) treatments through a variety of methods, including aerial, 

ground, and hand-held equipment. Handler exposure is expected to be short- and intermediateterm in duration. 

Occupational Handler Exposure

There is the potential for dermal and inhalation exposure to occupational handlers from the 

currently registered use pattern of penoxsulam. HED previously conducted ORE assessments for 

the uses on rice (D301888), multiple crops (D355915; D373438), turf/golf course (D339488),

and aquatic areas (D322533; D339488). HED based the assessments on exposure data from the 

Pesticide Handlers Exposure Database (PHED), assumptions for area treated from the Science 

Advisory Council for Exposure (ExpoSAC) Policy #9, and maximum application rates. Handler 

exposure and risk were calculated at the baseline level of personal protection (i.e., long pants, a 

long-sleeved shirt, no chemical-resistant gloves, and no respirator) and with the use of additional 

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

respirators, and engineering controls). Since a short-term dermal POD was not selected, a 

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

quantitative intermediate-term dermal exposures were previously assessed for occupational

handlers and are not of concern (i.e., MOEs ≥ 100; LOC=100) for all registered uses. The need 

for an intermediate-term dermal assessment will be reconsidered during registration review.

In addition, HED previously assessed short- and intermediate-term inhalation exposures for 

occupational handlers. The risk estimates were not of concern for all registered uses. In 

conjunction with determining data needs for registration review, penoxsulam was reviewed by 

HED’s HASPOC to evaluate the need for a route-specific inhalation study because previous 

assessments were conducted using data from an oral study. Revised inhalation risk estimates 

were calculated for occupational handlers using current policies and exposure assumptions. 

Short- and intermediate-term occupational handler inhalation MOEs ranged from 12,000 to 

14,000,000 and are not of concern. 

Since the previous reviews, there have been several updates to HED’s exposure policies, 

including updated exposure data for occupational handler assessments and updates to bodyweight assumptions. These assessments might be revised during registration review to reflect 

current Agency policies, data, and assumptions.
Penoxsulam Registration Review Scoping Document

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Occupational Post-application Exposure

In the absence of toxicity via the dermal route, no quantitative short-term dermal post-application 

risk assessment was required for the registered uses. Although HED would typically require 

dislodgeable foliar residue (DFR) data in accordance with the 40 CFR DFR data requirement 

based on the existing use pattern, a DFR study was not required because of the lack of toxicity 

via the dermal route. The restricted entry interval (REI) of 12 hours currently on the registered 

labels is appropriate based on the acute toxicity of the technical ingredient. 

There are multiple potential sources of inhalation exposure to individuals performing postapplication 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. The Agency has evaluated the SAP report 

and has developed a Volatilization Screening Tool and a subsequent Volatilization Screening 

Analysis. 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 are 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 

previously performed, an inhalation exposure assessment was performed for occupational 

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

higher exposure than post-application exposure. Therefore, it is expected that these handler 

inhalation exposure estimates would be protective of most occupational post-application 

inhalation exposure scenarios.

Conclusion for Occupational Exposure

The occupational exposure database is adequate to support the registration review process for 

penoxsulam. Based on a review of the registered labels for penoxsulam, it appears that the 

previous assessments cover the occupational handler scenarios anticipated for all registered uses. 

Updated assessments might be necessary during registration review if HED updates its exposure 

policies. 

Public Health and Pesticide Epidemiology Data

For this evaluation, HED consulted both the OPP Incident Data System (IDS) and the Centers for 

Disease Control and Prevention/National Institute for Occupational Safety and Health 

(CDC/NIOSH) Sentinel Event Notification System for Occupational Risk-Pesticides (SENSOR) 
Penoxsulam Registration Review Scoping Document

Page 12 of 24

databases for pesticide incident data on the active ingredient penoxsulam (D425276, S. Recore, 

1/28/2015). The purpose of the database search is to identify potential patterns in the frequency 

and severity of the health effects attributed to penoxsulam exposure. Penoxsulam is not included 

in the Agricultural Health Study (AHS) and, therefore, this study does not provide information 

for this report.

The Main IDS reported no incidents between January 1, 2010 and December 17, 2014 involving 

only the single chemical penoxsulam. One incident was reported involving more than one 

chemical. This incident was classified as moderate severity. In Aggregate IDS, from January 1, 

2010 to December 17, 2014, there were 18 incidents reported involving penoxsulam. These 

incidents were classified as minor severity. Overall, there are few incidents involving 

penoxsulam reported to IDS. 

 

The SENSOR-Pesticides database covers 12 states from 1998-2011, although reporting varies 

from state to state. A review of SENSOR-Pesticides 1998-2011 identifies no cases involving 

penoxsulam.

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

IDS and SENSOR-Pesticides, there does not appear to be a concern at this time that would 

warrant further investigation. The Agency will continue to monitor the incident information and,

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

Tolerance Assessment and International Harmonization

Tolerances for residues of penoxsulam are established in 40CFR §180.605. The tolerances are 

established as follows: penoxsulam, 2-(2,2-difluoroethoxy)-N-(5,8-dimethoxy[1,2,4]triazolo

[1,5-c] pyrimidin-2-yl)-6-(trifluoromethyl) benzenesulfonamide. A tolerance of 0.01 ppm is 

established for tree nuts, almond hulls, grapes, fish, and crustaceans; a tolerance of 0.02 ppm is 

established for molluscs and rice grain; and a tolerance of 0.50 ppm is established for rice straw.

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

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

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

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.”

There are no Codex Alimentarius Commission (Codex) or Canadian maximum residue limits 

(MRLs) for penoxsulam. As a result, there are no harmonization issues at the present time. The 

international residue limit status sheet can be found in Attachment 4.
Penoxsulam Registration Review Scoping Document

Page 13 of 24

International or Intergovernmental Work Sharing

The European Food Safety Authority prepared a draft assessment report for penoxsulam 

(publication date 8/4/2010, http://dar.efsa.europa.eu/dar-web/provision). The Authority came to 

the following conclusion: “The use of penoxsulam for the control of Echinochloa crus-galli (all 

sub-species and biotypes),, Alisma plantago-aquatica and Ammania, Cyperus and Scirpus spp. 

in rice in accordance with Good Agricultural Practice will not have any harmful effects on 

human or animal health or result in any unacceptable effects on the environment.” The Food and 

Agriculture Organization of the United Nations (FAO/JMPR) has not evaluated penoxsulam. In 

Canada, the chemical is not registered for use on any commodities. The California Department 

of Pesticide Regulation has not initiated a human health risk assessment for penoxsulam, it has 

not re-evaluated it, and it is not currently re-evaluating it.

In the U.S., tolerances are only established for residues in or on tree nuts, rice, grapes, fish, 

crustaceans, and molluscs. IR-4 recently submitted a tolerance petition for pome fruit, stone 

fruit, pomegranates, and olives. HED is not evaluating these commodities as a work share with 

any other country.

Cumulative Risk Assessments 

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a 

common mechanism of 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/.

HED’s Data Recommendations

None
Penoxsulam Registration Review Scoping Document

Page 14 of 24

References

Memoranda Relevant to Registration Review

Author DP 

Number

Date Title

C. Swartz D363910 4/9/2009 Penoxsulam: Revised Human Health Risk Assessment for Proposed 

Uses on Grapes and Tree Nuts

S. Oonnithan D380179 8/10/2010 Penoxsulam: Human Health Risk Assessment Summary for the 

Proposed Use of Amore DF Herbicide on Non-bearing Tree Nuts 

and Non-bearing Grape Vines

E. Budd TXR# 

0052273

12/16/2003 Penoxsulam – 1

st Report of the Hazard Identification Assessment 

Review Committee. EPA Memorandum

J. Kidwell TXR# 

0050702

3/24/2004 Penoxsulam: Report of the Cancer Assessment Review Committee. 

EPA Memorandum

Y. Yang TXR# 

0056076

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

J. Leshin TXR No. 

0051714

3/17/2015 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

M. Doherty D355914 1/29/2009 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

M. Doherty D360419 3/24/2009 Penoxsulam: Chronic Aggregate Dietary (Food and Drinking 

Water) Exposure and Risk Assessment to Evaluate the Requested 

New Uses on Grapes and Tree Nuts

S. Oonnithan D373438 8/9/2010 Penoxsulam: Occupational and Residential Exposure Assessment 

for Adding Non-bearing Trees, Conifers, Eucalyptus, and Noncropland to the Registered Uses

M. Collantes D339488 5/23/2007 Occupational and Residential Exposure Assessment for Use of 

Penoxsulam to Control Aquatic Weeds In and Around Slow-moving 

and Quiescent Bodies of Water and Broadleaf Weeds in Turfgrass, 

Residential Lawns, Golf Courses, Sport Fields and Sod Farms

L. Shanaman D325468 11/8/2006 Tier 1 Drinking Water Assessment for the New Use Registration on 

Turf and Aquatic Vegetation of Penoxsulam, and Six Degradation 

Products Identified to be of Toxicological Concern

J. Wolf D373443 4/7/2010 Penoxsulam (New Use) Tier 1 Drinking water exposure 

concentrations for the proposed new uses on non-bearing trees, 

conifers, eucalyptus, and non-cropland

S. Recore D425276 1/28/2015 Penoxsulam: Tier I Review of Human Incidents

Attachments

Attachment 1. Chemical Identity and Physical and Chemical Properties

Attachment 2. Toxicology Profile Tables

Attachment 3. Endpoint Selection Table

Attachment 4. International Residue Limit Status 
Penoxsulam Registration Review Scoping Document

Page 15 of 24

Attachment 1. Chemical Identity and Physical and Chemical Properties

Table A.1.1. Penoxsulam Nomenclature.

Compound

Common name Penoxsulam

IUPAC name 6-(2,2-difluoroethoxy)-N-(5,8-dimethoxy-s-triazolo[1,5-c]pyrimidin-2-yl)-α,α,αtrifluoro-o-toluenesulfonamide

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

(trifluoromethyl) benzenesulfonamide

CAS registry number 219714-96-2

End-use products (EP)

(partial list)

Pindar (EPA Reg. No. 62719-603)

Pindar GT Herbicide (EPA Reg. No. 62719-611)

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

Granite SC (EPA Reg. No. 62719-514)

GF-443 SC (EPA Reg. No. 62719-546)

Table A.1.2. Physical and Chemical 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.

O

F F

S

N

H

O

N

N

N N

O

O

CH3

CH3

O

CF3
Penoxsulam Registration Review Scoping Document

Page 16 of 24

Attachment 2. Toxicity Profiles

Table A.2.1. Penoxsulam (XDE-638) Acute Toxicity Profile.

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

870.1100 Acute oral [rat] 45830812 M: LD50 >5000 

mg/kg

F: LD50 >5000 mg/kg

IV

870.1200 Acute dermal [rabbit] 45830815 M: LD50 >5000 

mg/kg

F: LD50 >5000 mg/kg

IV

870.1300 Acute inhalation [rat] [Note: study 

classified as 

unacceptable/guideline due to 

issues with gravimetric vs. nominal 

dose levels, but tested at exposures 

exceeding 2 mg/L]

45830818 LD50 > 2 mg/L IV

870.2400 Acute eye irritation [rabbit] 45830820 Minimal irritation IV

870.2500 Acute dermal irritation [rabbit] 45830823 Minimal irritation IV

870.2600 Skin sensitization [guinea pig] 45830826 Negative for dermal 

sensitization

N/A

Table A.2.2. Penoxsulam (XDE-638) Subchronic, Chronic and Other Toxicity Profile.

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.3050 4-week oral 

toxicity, 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.
Penoxsulam Registration Review Scoping Document

Page 17 of 24

Table A.2.2. Penoxsulam (XDE-638) Subchronic, Chronic and Other Toxicity Profile.

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.3050 4-week oral 

toxicity, 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)

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)
Penoxsulam Registration Review Scoping Document

Page 18 of 24

Table A.2.2. Penoxsulam (XDE-638) Subchronic, Chronic and Other Toxicity Profile.

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.3700b Prenatal 

developmental 

(New Zealand 

white rabbit)

45830918 (2001)

0, 5, 25, 75 mg/kg/day 

(gavage)

Acceptable/guideline

Maternal NOAEL = 25 mg/kg/day

Maternal LOAEL = 75 mg/kg/day, based on 

mortality, clinical signs of toxicity, decreased 

body weight and food consumption.

Developmental NOAEL = 75 mg/kg/day

Developmental LOAEL = not determined (> 

mg/kg/day, HDT)

870.3800 Reproduction and 

fertility effects

(Sprague 

Dawley rat)

45830920 (2002)

M and F: 0, 30, 100, 300 

mg/kg/day

Acceptable/guideline

Parental NOAEL = 100/30 mg/kg/day M/F

Parental LOAEL =300/100 mg/kg/day M/F, 

based on decreased F1 body weight in males 

and kidney lesions in females

Reproductive/offspring NOAEL = 30 

mg/kg/day

Reproductive/offspring LOAEL = 100 

mg/kg/day) based slightly increased time to 

preputial separation in F1 males (at 300 

mg/kg/day pup weight gain was also decreased 

during lactation)

870.4100a Chronic toxicity 

(rat)

See 870.4300, below

870.4100b Chronic toxicity 

(Beagle dog)

45830914 (2002)

M: 0, 5.3, 14.7, 46.2 

mg/kg/day in the diet

F: 0, 4.4, 14.0, 44.8 

mg/kg/day

Acceptable/guideline

NOAEL = 14.7/44.8 mg/kg/day, M/F

LOAEL = 46.2 mg/kg/day, M, based on slight 

multifocal hyperplasia in the renal pelvic 

urothelium. Not determined in females (>44.8, 

HDT)

870.4200 Combined 

Chronic/

Carcinogenicity

(Fischer 344 rat)

45830901, -13 (2002)

M and F: 0, 5, 50, 250 

mg/kg/day in the diet

Acceptable/guideline

NOAEL = 50 mg/kg/day

LOAEL = 250 mg/kg/day, based on decreased 

body weight/weight gain, increased urine 

volume, crystals and calculi in kidney, 

hyperplasia of the renal pelvic and urinary 

bladder urothelium in both sexes; decreased 

urine specific gravity, increased BUN, 

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.
Penoxsulam Registration Review Scoping Document

Page 19 of 24

Table A.2.2. Penoxsulam (XDE-638) Subchronic, Chronic and Other Toxicity Profile.

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.4300 Carcinogenicity

(CD-1 mouse)

45830915 (2002)

M: 0, 10, 100, 375 

mg/kg/day

F: 0, 10, 100, 750 

mg/kg/day

Unacceptable/guideline 

(new study not required)

NOAEL = 375/750 mg/kg/day, M/F

LOAEL = not determined (>375/750 

mg/kg/day, M/F, highest doses tested)

No evidence of carcinogenicity (dosing 

inadequate in males)

Gene 

Mutation

870.5100

Salmonella 

typhimurium

TA98, TA100, 

TA1535, Ta1537, 

Ta1538

45830921 (1999)

With S9: 0, 3.3, 10.0, 

33.3, 100, 333, 1000 

μg/plate

Without S9: 0, 3.3, 10.0, 

33.3, 100, 333, 1000, 

5000 μg/plate

Acceptable/guideline

Negative for increased reverse gene mutations 

in the presence and absence of rat S9 metabolic 

activation. Cytotoxicity observed at >333 

μg/plate.

Gene 

Mutation

870.5100

Salmonella 

typhimurium

TA98, TA100, 

TA1535, Ta1537, 

Ta1538

45830922 (2002)

Formulation GF-443 

21.9% penoxsulam

0, 10.0, 33.3, 100, 333, 

1000, 5000 μg/plate with 

and without S9

Acceptable/guideline

Negative for increased reverse gene mutations 

in the presence and absence of rat S9 metabolic 

activation. Cytotoxicity observed at >333 

μg/plate.

Mammalian 

cell forward 

gene 

mutation 

assay

870.5300

Chinese hamster 

ovary (CHO) cells 

(+/-S9)

45830923 (1999) 

0, 46.88, 93.75, 187.5, 

375, 750, 1500 μg/mL

Acceptable/guideline

Negative for forward gene mutation in the 

presence and absence of rat S9 metabolic 

activation. Limit of solubility observed at 750-

1500 μg/mL.
Penoxsulam Registration Review Scoping Document

Page 20 of 24

Table A.2.2. Penoxsulam (XDE-638) Subchronic, Chronic and Other Toxicity Profile.

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

In vitro

chromosomal 

aberration 

assay

870.5375

Primary rat 

lymphocyte 

cultures

45830924 (1999)

First assay 0, 3.3, 10, 

33.3, 100, 333.3, 1000, 

1500 μg/mL with and 

without S9, 4 hr 

incubation

Second assay same doses, 

without S9, 24 hr 

incubation and with S9, 4 

hr incubation

Third assay, 12 doses 

between 100-1500 μg/mL 

without S9, 24 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.

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.
Penoxsulam Registration Review Scoping Document

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Table A.2.2. Penoxsulam (XDE-638) Subchronic, Chronic and Other Toxicity Profile.

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.7485 Metabolism and 

pharmacokinetics

(species)

45830927 (2002)

Acceptable/guideline

Penoxsulam was rapidly and nearly completely 

absorbed (81-88% AD) at the low dose of 5.0 

mg/kg but at the high dose of 250 mg/kg there 

was evidence that absorption was largely 

incomplete. At low dose the major route of 

excretion of radioactivity was via 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)
Penoxsulam Registration Review Scoping Document

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Attachment 3. Penoxsulam Endpoints and Doses for Risk Assessment

Table A.3.1. Summary of Toxicological Doses and Endpoints for Penoxsulam for Use in Dietary and NonOccupational 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.

Incidental 

Oral 

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.

Dermal ShortTerm (1-30 

days)

An endpoint for systemic toxicity was not identified in the rat 28-day dermal study and there 

were no neurotoxic, developmental, immunotoxic effects observed for penoxsulam. This 

exposure scenario was not assessed for human health risk.

Dermal 

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.

Inhalation 

Short- Term 

(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.

Inhalation 

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.
Penoxsulam Registration Review Scoping Document

Page 23 of 24

Table A.3.1. Summary of Toxicological Doses and Endpoints for Penoxsulam for Use in Dietary and NonOccupational Human Health Risk Assessments.

Exposure/ 

Scenario

Point of 

Departure

Uncertainty/

FQPA Safety 

Factors

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment

Study and Toxicological Effects

Cancer (oral, 

dermal, 

inhalation)

Classification: Classification: Suggestive Evidence of Carcinogenicity, but Not Sufficient to 

Assess Human Carcinogenic 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 A.3.2. 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 ShortTerm (1-30 

days)

An endpoint for systemic toxicity was not identified in the rat 28-day dermal study and there 

were no neurotoxic, developmental, immunotoxic effects observed for penoxsulam. This 

exposure scenario was not assessed for human health risk.

Dermal 

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.

Inhalation 

Short-Term (1-

30 days)

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.

Inhalation 

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.
Penoxsulam Registration Review Scoping Document

Page 24 of 24

Attachment 4. International Residue Limit Status

Penoxsulam (119031; 2-2-2015)

Table A.4. Summary of US and International Tolerances and Maximum Residue Limits. 

Residue Definition:

US Canada Mexico1 Codex

40 CFR 180.605

Penoxsulam:

2-(2,2-difluoroethoxy)-N-(5,8-

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

pyrimidin-2-yl)-6-(trifluoromethyl) 

benzenesulfonamide

None None

Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico1 Codex

Almond, hulls 0.01

Fish 0.01

Fish, shellfish, crustacean 0.01

Fish, shellfish, mollusc 0.02

Grape 0.01

Nut, tree, group 14 0.01

Pistachio 0.01

Rice, grain 0.02

Rice, straw 0.50

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

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