UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

OFFICE OF CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

MEMORANDUM 

Date: 

Subject: 

From: 

T hru : 

To: 

02-Sep-2015 

Pinoxadcn. Human Health Assessment Scoping Document in Support of 

Registration Review. 

PC Code: 147500 

Decision No.: 5txJzC?'IDP Bar code: 0425809 

Registration Nos.: NIA 

Petition No.: NIA Regulatory Action: Registration Review Scoping Document 

Risk Assessment Type: Scoping Document Case No.: 7266 

TXR No.: NIA CAS No.: 243973-20-8 

MRID No.: None 40 CFR: §180.611 

William D. Wassell, Chemist !Yl#J 

Anwar Y. Dunbar, Ph.D., Pharmacologist ~ James S. Miller, Environmental Health Scientist 

Risk Assessment Branch l (RAB I) 

Health Effects Division (HED; 7509P) 

George 

Thurston 

F. 

Morton

Kramer, 

, Acting 

Ph.D., 

Branch 

Senior Chemist 

Chief ~~ 

RAB l/HED (7509P) 

Linsey Walsh, Chemical Review Manager 

Kelly Sherman, Branch Chief 

Risk Management and Implementation Branch 3 

Pesticide Re-Evaluation Division (PRD) (7508P) 

Attached is BED human health risk assessment scoping document for pinoxaden submitted in 

support of Registration Review. To evaluate the scope of work necessary to support Registration 

Review, HED has considered recent risk assessments for pinoxaden, updates to its toxicity, 

exposure and usage databases, and the latest Agency science policy and risk assessment 

methodologies. The most recent HED human health risk assessment for pinoxaden was 

conducted in 2005 (Memo, 7/13/2005, M. Clock-Rust, el al., D3 I 0864). 

Page I of26 
Pinoxaden Human-Health Assessment Scoping Document 0425809 

Executive Summa ry 

Background: Pinoxaden (8-(2,6-diethyl-4-methylphenyl)-1 ,2,4,5-tetrahydro-7-oxo-7 Hpyrazolo[ 1,2-dJ( l ,4,5]oxadiazepin-9-yl 2,2-dimethylpropanoate) is a phenylpyrazole herbicide 

(Group 1 ). The active ingredient (ai) is rapidly absorbed by weed foliage and translocated to the 

growing points of leaves and stems where it inhibits the acetyl CoA carboxylase enzyme. 

Susceptible weed species generally stop growing within 48 hours of treatment, tum yellow 

within three weeks, and are completely controlled within three to five weeks. The registered 

products are fomrnlated as a suspension concentrate (SC), an emulsifiable concentrate (EC), and 

a flowable concentrate (FIC). The maximum seasonal application rate is 0.054 lbs ai/A. The 

most recent HED human health risk assessment was conducted in 2005 (Memo, 7/13/2005, M. 

Clock-Rust, et al., D310864). 

HED evaluated the most recent pinoxaden human health risk assessment to determine whether 

sufficient data are available and whether any updates are needed to support Registration Review. 

HED has considered all registered uses for pinoxaden with respect to its toxicity, exposure, and 

usage databases, and the most updated Agency science policy and risk assessment methodologies 

to detem1ine the scope of work necessary to support Registration Review. The current document 

pertains only to the Registration Review data requirements for pinoxaden. 

Hazard lde11tijicatio11ff oxicology: The primary effects in the hazard database for pinoxaden are 

kidney toxicity, clinical signs and decreased body weights. The toxicity database for pinoxaden 

is complete and adequate to support Registration Review requirements, and no new data are 

required. Jn the previous risk assessment for pinoxaden, the prenatal developmental rat study 

was used for all exposure scenarios. For future actions, the critical studies in pinoxaden's hazard 

database, in addition to the previous endpoints and safety factors will need to be re-evaluated and 

updated based upon current policies. 

Residue Chemistry am! Dietary Exposure: Adequate metabolism (crops, livestock, and 

rotational crops) and magnitude of the residue data are available to support the registered uses. 

Adequate methods are available for enforcement of the currently established tolerances. No 

additional residue chemistry data are needed to support the currently registered uses. As part of 

Registration Review, a revised dietary risk assessment may be necessary to reflect potential 

revised estimated drinking water concentrations (EDWCs), revised tolerances, the most recent 

dietary exposure models, and/or revised toxicological points of departure (PODs). 

Residential Exposure: Pinoxaden is not registered for residential uses. The Agency will 

examine the need for spray drift and volatilization assessments during Registration Review for 

pinoxaden based on the potential for exposure to bystanders from agricultural applications. 

Aggregate Risk Assessment: As part of Registration Review, updated aggregate risk 

assessments may be necessary to reflect revised dietary exposure estimates, and/or toxicological 

PODs. 

Occ11patio11al Exposure: The occupational exposure database is adequate to support the 

Registration Review for pinoxaden. The most recent occupational handler and post-application 

exposure assessment (Memo, 07/ 13/2005, M. Clock-Rust et al., D3 l 0864) did not identify risks 

of concern; however, the handler assessment is not reflective of all current exposure policies. 

Therefore, during Registration Review, updated occupational handler assessments will be 

Page 2 of26 
Pinoxaden Human-Health Assessment Scoping Document D425809

Page 3 of 26

conducted to reflect all currently registered uses, using current occupational/residential exposure 

(ORE) policies.

Summary - Risk Assessment Updates, Data Deficiencies, and Label Revisions: The risk 

assessment updates that may be required under Registration Review. Based on the current use 

patterns, there are no data deficiencies.

Risk Assessment Updates: 

 The current PODs will be reevaluated along with evaluation of the toxicological and 

exposure databases in terms of assigning a FQPA safety factor (SF). 

 Harmonization of the residues of concern with Canadian maximum residue limits 

(MRLs) will be evaluated.

 The need for livestock commodity tolerances should be reevaluated based on revisions to 

Table 1 of 860.1000 OCSPP Test Guidelines.

 Revised dietary risk assessment may be necessary to reflect the most recent EDWCs, 

dietary exposure models, and/or toxicological PODs.

 Revised aggregate risk assessment may be necessary to reflect revised dietary exposure 

estimates, and/or toxicological PODs. 

 Revised occupational risk assessment may be necessary to reflect the most recent HED 

policies and/or toxicological PODs.

 The need for spray drift and volatilization risk assessment for pinoxaden will be 

examined during Registration Review.

HED notes that based on the assumptions and resulting risks associated with the currently 

registered uses, it is highly unlikely that revised risk assessments conducted in support of 

Registration Review will yield exposures greater than HED’s level of concern. 

DETAILED CONSIDERATIONS

Registered Use Patterns

Pinoxaden is formulated as a SC, an EC, and an FlC and registered for control of annual grass 

weeds in wheat and barley. There are five registered end-use products. The maximum 

application rate is 0.054 lbs ai/A for applications to wheat and barley. Applications can be made 

using ground and aerial equipment. Applications to spring wheat, winter wheat, and barley may 

be made from the 2-leaf stage to pre-boot stage of growth. See Attachment E for a summary of 

the registered end-use products and application scenarios. 

Hazard Identification/Toxicology

The effects in the pinoxaden hazard database are indicative of kidney toxicity in rodents (alterations 

in urinalysis parameters and renal tubular basophilia). In all species tested, there were clinical 

signs, decreased absolute body weights, and food consumption. There was no evidence of 

neurotoxicity or dermal toxicity.

There was no increased qualitative or quantitative susceptibility for pinoxaden pre- or post-natally 

in rats or rabbits. In rats, fetal effects consisting of delays in skeletal ossification were seen in the 

presence of body-weight decrements in maternal animals. In rabbits, early resorptions, 
Pinoxaden Human-Health Assessment Scoping Document D425809

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postimplantation loss, and abortions were seen at doses also causing body-weight decrements and 

decreased food consumption in maternal animals. One death was also noted following a morbid 

condition. In the multigenerational reproductive study, parental effects were consistent with the 

kidney effects seen in the other rodent studies. Offspring effects occurred at the same dose and 

consisted of decreased body weights.

Carcinogenicity was not observed in the rat chronic/carcinogenicity study. The two carcinogenicity 

studies in mice (1 via gavage; 1 dietary) were considered to be inadequate for evaluating the 

carcinogenic potential of pinoxaden in mice. For the 2003 study, the increased mortality resulting 

from gavage error together with lung involvement confounded the results of the study. For the 

2004 study, the dosing was considered to be inadequate due to the lack of toxicity in animals at the 

highest dose tested. Despite these discrepancies, HED reviewed pinoxaden’s hazard database and 

determined that no new data were needed (Memo, 7/13/2005, M. Clock-Rust, et al., D310864).

Pinoxaden is categorized as having low levels of acute toxicity by the oral, dermal and inhalation 

routes (Toxicity Categories III or IV). Pinoxaden is irritating to the eye, but is not a skin irritant or 

sensitizer. 

The endpoints presented in Attachment D are from the most recent risk assessment for pinoxaden 

(Memo, 07/13/2005, M. Clock-Rust, et al., D310864). Using weight-of-evidence approach, HED’s 

Hazard Science and Policy Council determined that subchronic inhalation and immunotoxicity 

studies and a new carcinogenicity study in mice for pinoxaden are not required at this time (J. 

Bever, et al., TXR #0057273, upholding the Division’s previous decision. The hazard profile table 

containing all of the currently reviewed data is presented in Attachment C. 

Conclusions: The toxicity database for pinoxaden is complete and adequate to support Registration 

Review requirements. For future actions, the critical studies in pinoxaden’s hazard database, in 

addition to previous endpoints and SFs will need to be re-evaluated and updated based upon current 

policies. 

Residue Chemistry and Tolerance Assessment

Pinoxaden is registered for use on wheat and barley. There are five registered end-use products. 

The maximum application rate is 0.054 lbs ai/A for applications to wheat and barley. 

Applications can be made using ground and aerial equipment. Applications to spring wheat, 

winter wheat, and barley may be made from the 2-leaf stage to pre-boot stage of growth.

Tolerances are currently established under 40 CFR §180.611(a)(1) for the combined residues of 

pinoxaden and its metabolites 8-(2,6-diethyl-4-methyl-phenyl)-tetrahydro-pyrazolo[1,2-

d][1,4,5]oxadiazepine-7,9-dione (also known as M2), and free and conjugated forms of 8-(2,6-

diethyl-4-hydroxymethyl-phenyl)-tetrahydro-pyrazolo[1,2-d][1,4,5]oxadiazepine-7,9-dione (also 

known as M4), and 4-(7,9-dioxo-hexahydro-pyrazolo[1,2-d][1,4,5]oxadiazepin-8-yl)-3,5-diethylbenzoic acid (also known as M6), calculated as pinoxaden. Tolerances for commodities range 

from 0.06 ppm (eggs and poultry commodities) to 3.5 ppm (wheat forage). Additionally, 

tolerances are established under 40 CFR §180.611(a)(2) for the combined residues pinoxaden 

and its metabolites M2 and free and conjugated forms of M4, calculated as pinoxaden. 

Tolerances for commodities range from 0.02 ppm (milk) to 0.04 ppm (cattle fat, meat, and meat 

byproduct).
Pinoxaden Human-Health Assessment Scoping Document D425809

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Adequate wheat (pyrazol, phenyl, and oxadiazepine ring-labeled pinoxaden), lactating goat 

(phenyl ring-labeled pinoxaden), laying hen (phenyl ring-labeled pinoxaden), metabolism 

studies, as well as adequate confined rotational crop studies (phenyl or oxadiazepine ring-labeled

pinoxaden) are available to support the registered agricultural uses. Based upon these studies, 

HED concluded the residues of concern for the tolerance expression and risk assessment in 

plants and poultry are pinoxaden, M2, M4 (free and conjugated forms), and M6. Additionally, 

HED concluded the residues of concern for the tolerance expression and risk assessment in 

ruminants are pinoxaden, and its metabolites M2 and M4 (free and conjugated forms). The 

residues of concern for the tolerance expression and risk assessment in rotational crops are 

pinoxaden, M2, M3 (free and conjugated forms), M10, and M11. The metabolism data were not 

presented to the HED Metabolism Assessment Review Committee. 

Adequate crop field trial and processing data are available for all registered crops. There are no 

outstanding issues related to the use directions; however, there are outstanding issues related to 

the established tolerances. Adequate methods are available for enforcement of the currently 

established tolerances for residues in wheat, barley, poultry, and ruminants. In addition, data

have been submitted which indicate that pinoxaden and its metabolites M2, M4, M6, and M10 

are not recoverable through the FDA Multiresidue Method (MRM) protocols. Additionally, 

pinoxaden and its metabolites are not recoverable by the multiresidue method QuEChERS. 

Conclusions: The current residue chemistry database is sufficient to support the registered uses; 

no additional residue chemistry data are required.

Estimated Drinking Water Concentrations (EDWCs)

Hydrolysis of pinoxaden is pH dependent and occurs faster under basic conditions. Acceptable

laboratory studies showed that pinoxaden degrades rapidly under aerobic soil metabolism 

conditions with half-lives ranging from 2 to 3 days, forming the major degradate M2, which 

degrades further to form the degradate M3. Under aerobic aquatic conditions, pinoxaden 

degrades rapidly to M2 (half-life < 1 day) the major transformation product, M2, with 

maximums of 96.6%, 16.7% and 103.5% of the applied in water layer, sediment and total 

system, respectively. M2 was the major product detected in the treated water-sediment systems 

under both anaerobic and aerobic conditions. The minor transformation product M3 was 

identified with maximums of 0.3%, 0.1%, and 0.4% in water, sediment and total system, 

respectively. Under aerobic aquatic conditions, more than 86% of applied activity remains (in 

total system) in form of the major degradate M2. The major degradates of pinoxaden (M2 and 

M3) are considered to be mobile based on Freundlich Kads values ranging from 0.06-128 mL/g, 

and 0856-0.28 mL/g, respectively, in three test soils (loamy sand, loam, silty clay loam textures).

The residues of concern in drinking water were determined to be pinoxaden, M2, and M3. 

EFED has provided surface water and groundwater EDWCs for pinoxaden and its metabolites 

resulting from the registered uses (Memo, 01/28/2005, I. Abdel-Saheb, D299583). EFED 

conducted a Tier II drinking water assessment using the Pesticide Root Zone Model-Exposure 

Analysis Modeling System (PRZM-EXAMS) and Screening Concentration In GROund Water 

(SCI-GROW) models to estimate residues in surface and ground water, respectively. Since the 

concentration estimates from PRZM-EXAMS were higher than those from SCI-GROW, the 

PRZM-EXAMS estimates were used in the dietary assessment. The acute and chronic EDWCs 
Pinoxaden Human-Health Assessment Scoping Document D425809

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were 0.00076 ppm and 0.000473 ppm, respectively. These estimates were incorporated into the 

most recent dietary exposure analyses. 

Conclusions: As part of Registration Review, EFED anticipates generating revised EDWCs to 

reflect current practices/models. 

Dietary Exposure

HED has conducted acute and chronic dietary exposure analyses which considered all currently 

registered uses (Memo, 07/07/2005, M. Sahafeyan, D313800). The analyses were conducted 

using the Dietary Exposure Evaluation Model – Food Consumption Intake Database (DEEMFCIDTM, ver. 2.03) which incorporates the food consumption data from the United States 

Department of Agriculture (USDA) Continuing Surveys of Food Intakes by Individuals (CSFII; 

1994-1996 and 1998) and assumed tolerance level residues and 100% crop-treated. The 

resulting acute (<1.5% acute population-adjusted dose or aPAD) and chronic (<2.1% chronic 

population-adjusted dose or cPAD) exposure estimates were less than HED’s level of concern

(LOC, 100% of aPAD or cPAD). 

Conclusions: As part of Registration Review, revised acute and chronic dietary exposure 

analyses may be required to reflect the most recent dietary exposure models, revised EDWCs, 

and/or changes to the toxicological PODs.

Residential Exposure

Pinoxaden is not currently registered for use in/on residential settings; therefore, a residential 

exposure assessment will not be conducted for Registration Review.

Spray Drift and Volatilization: Residential bystander exposures resulting from off-site transport 

(e.g., spray drift or volatilization) may occur as a result of applications of pinoxaden. The 

potential for spray drift may be quantitatively evaluated for each pesticide during the 

Registration Review process that ensures that all uses for that pesticide may be considered 

concurrently. The approach is outlined in the revised (2012) standard operating procedures 

(SOPs) for Residential Risk Assessment – Residential Exposure Assessment Standard Operating 

Procedures Addenda 1: Consideration of Spray Drift. This document outlines the quantification 

of indirect non-occupational exposure to drift.

In terms of volatilization, the agency has developed a Volatilization Screening Tool and a 

subsequent Volatilization Screening Analysis 

(http://www.regulations.gov/#!docketDetail;D=EPA-HQ-OPP-2014-0219). During 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 specific chemicals.

Conclusions: An updated post application exposure assessment will be needed for pinoxaden 

during Registration Review. In addition, the need for spray drift and volatilization risk 

assessment for pinoxaden will be examined during Registration Review.
Pinoxaden Human-Health Assessment Scoping Document D425809

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Aggregate Risk Assessment

As part of the most recent pinoxaden human health risk assessment, HED conducted aggregate 

exposure assessment which considered all registered pinoxaden uses (Memo, 07/07/2005, M. 

Sahafeyan, D313800). The resulting acute (food and water; <1.5% aPAD) and chronic (food and 

water; <2.1% cPAD) exposure estimates were less than HED’s LOC. 

Conclusions: As part of Registration Review, revised aggregate exposure assessments may be 

necessary to reflect revised dietary exposure estimates and/or changes to the toxicological PODs. 

Occupational Exposure

Pinoxaden is registered for use on wheat and barley; and, based on these registered use patterns, 

there is potential for occupational handler and post-application exposures to pinoxaden. The 

most recent occupational exposure assessment for pinoxaden was conducted in 2005 (Memo, 

07/13/2005, M. Clock-Rust et al., D310864). Short- and intermediate-term handler risks were 

estimated for handlers and post-application workers. Handler exposure scenarios are based on 

information provided on registered labels (e.g., one application/season with a pre-grazing 

interval of 30 days, rotational crop restrictions of 0 days for wheat and barley and 30 days for 

leafy vegetables and root crops, and 90 days for other cereal grains and all other crops). The 

proposed pre-harvest interval (PHI) is 60 days. The restricted-entry interval (REI) specified on 

the registered labels is 48 hours. Pinoxaden registered labels require mixers, loaders, and other 

handlers to wear long-sleeved shirt, long pants, chemical-resistant gloves, and shoes plus socks. 

The labels also require applicators to wear long-sleeved shirt, long pants, chemical-resistant 

gloves, and shoes plus socks. 

Occupational Handlers: There is the potential for dermal and inhalation exposure to 

occupational handlers from the currently registered use patterns of pinoxaden. In the most recent 

exposure assessment for pinoxaden contained in the previous risk assessment, dermal and 

inhalation assessments were conducted for mixers/loaders, applicators for aerial and 

groundboom, applications of an EC formulation. Furthermore, no chemical-specific data were 

available with which to assess potential exposure to pesticide handlers. The maximum 

application rate range is 0.054 lbs ai/A. Short- and intermediate-term handler risks were 

estimated for handlers and post-application workers. A dermal-absorption factor of 40% was 

used to calculate occupational risks. HED assumed 100% inhalation absorption. Dermal and 

inhalation risk estimates were not of concern (i.e., MOEs ≥ 100) with label specific personalprotective equipment (PPE). Therefore, risks do not exceed HED’s LOC. 

Conclusions: The occupational exposure database is adequate to support the Registration 

Review process. Based on a review of the registered labels and the most recent risk assessment,

HED previously conducted occupational handler assessments for the occupational handler 

scenarios anticipated for the registered uses of pinoxaden. However, the scenarios were not 

assessed based on current ORE SOPs and policies; therefore, an updated assessment may be 

required during Registration Review. 
Pinoxaden Human-Health Assessment Scoping Document D425809

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Occupational Post-Application

HED expects that post-application exposure will occur since pinoxaden is applied postemergence as a foliar spray. Post-application exposure is expected to be short- and intermediateterm based on information provided on proposed labels (e.g., maximum of one sprays per season 

at a rate of 0.054 lbs ai/A). The point of departure for the dermal route of exposure is the same 

for short- and intermediate-term exposure durations, so the risk estimate is protective of both 

durations of exposure. 

Chemical-specific dislodgeable-foliar residue (DFR) data for apples and chrysanthemums were 

used as surrogates for all crops in the occupational post-application assessments. All agricultural 

crop scenarios resulted in MOEs greater than 100 on day zero and are not of concern.

Conclusions: The occupational exposure database is adequate to support the Registration 

Review for pinoxaden. The most recent occupational handler and post-application exposure 

assessments did not identify risks of concern; however, the occupational handler assessment is 

not reflective of current exposure policies. Therefore, during Registration Review, updated 

occupational assessments will be conducted to reflect all currently registered uses, using current 

ORE policies. 

Public Health, Pesticide Epidemiology, and Human Incidence Data

Reference:

Memo, 09/02/2015, E. Evans, et al., D428933

For this evaluation, 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) databases were 

consulted for pesticide incident data on the active ingredient pinoxaden (pc code: 147500). The 

purpose of the database search is to identify potential patterns in the frequency and severity of 

the health effects attributed to pinoxaden exposure. Pinoxaden is not included in the AHS, and 

therefore this study does not provide information for this report.

For the Main IDS, from January 1, 2010 to February 4, 2015, there were no incidents reported 

involving pinoxaden. 

In Aggregate IDS, from January 1, 2010 to February 4, 2015, there were 3 incidents reported 

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

incidents reported to IDS involving pinoxaden. 

A review of SENSOR-Pesticides 1998-2011 identifies two cases, stemming from one event, 

involving pinoxaden (pc code 147500). Both of these cases involve a single active ingredient. 

The cases were both low in severity. In 2010, the cases were exposed to spray drift from an 

aerial pesticide application taking place in an adjacent field about 900 feet away. After the two 

cases developed respiratory symptoms including cough, the family left their home to avoid 

further exposure. The Inspector from the Texas Department of Agriculture (TDA) took clothing 

and vegetation samples, the results of the TDA inspection were not included in SENSOR. 

Based on the low frequency and severity of cases reported for pinoxaden in both IDS and 

SENSOR-Pesticides, there does not appear to be a concern at this time that would warrant further 
Pinoxaden Human-Health Assessment Scoping Document D425809

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investigation. The Agency will continue to monitor the incident information and if a concern is 

triggered, additional analysis will be included in the risk assessment.

International Harmonization

There are no Codex or Mexican MRLs in/on the registered crops (see Attachment F). However, 

there are Canadian MRLs for residues of pinoxaden and its metabolites in/on barley bran, barley 

grain, wheat bran, wheat grain, egg, fat, meat and meat byproduct of poultry and cattle. These 

tolerances are harmonized with the U.S. established tolerances. Canada has additional MRLs for 

residues in/on fat, meat, and meat byproduct of goats, hogs, horses, and sheep. HED concluded 

that tolerances for residues of pinoxden and its metabolites should be established for fat, meat 

and meat byproduct of goats, hogs, horses, and sheep; however, these tolerances were not 

established. This discrepancy will be addressed in Registration Review. Therefore, 

harmonization of tolerance/MRL levels is an issue at this time. U.S. tolerances are established 

for residues of pinoxaden and its metabolites M2 and M4 whereas Canadian MRLs for ruminant 

tissues are established for residues of pinoxaden and its metabolites M2, M4, and M6. 

Therefore, harmonization of the residues of concern with Canada are an issue. Harmonization 

with Canadian established MRLs will be considered during Registration Review.

In accordance with the most recent guidance concerning tolerance expressions, HED 

recommends that the tolerance expression for 40 CFR §180.611(a) (1) and (2) be changed as 

follows: 

40 CFR §180.611(a) General. (1) Tolerances are established for residues of the herbicide 

pinoxaden (8-(2,6-diethyl-4-methylphenyl)-1,2,4,5-tetrahydro-7-oxo-7H-pyrazolo[1,2-

d][1,4,5]oxadiazepin-9-yl 2,2-dimethylpropanoate) including its metabolites and degradates, in 

or on the commodities listed below. Compliance with the following tolerance levels is to be 

determined by measuring only the sum of 8-(2,6-diethyl-4-methyl-phenyl)-tetrahydropyrazolo[1,2-d][1,4,5]oxadiazepine-7,9-dione (M2), free and conjugated 8-(2,6-diethyl-4-

hydroxymethyl-phenyl)-tetrahydro-pyrazolo[1,2-d][1,4,5]oxadiazepine-7,9-dione (M4), and 4-

(7,9-dioxo-hexahydro-pyrazolo[1,2-d][1,4,5]oxadiazepin-8-yl)-3,5-diethyl-benzoic acid (M6), 

calculated as the stoichiometric equivalent of pinoxaden, in or on the following commodities:

40 CFR §180.611(a) General. (2) Tolerances are established for residues of the herbicide 

pinoxaden (8-(2,6-diethyl-4-methylphenyl)-1,2,4,5-tetrahydro-7-oxo-7H-pyrazolo[1,2-

d][1,4,5]oxadiazepin-9-yl 2,2-dimethylpropanoate) including its metabolites and degradates, in 

or on the commodities listed below. Compliance with the following tolerance levels is to be 

determined by measuring only the sum of 8-(2,6-diethyl-4-methyl-phenyl)-tetrahydropyrazolo[1,2-d][1,4,5]oxadiazepine-7,9-dione (M2), and free and conjugated 8-(2,6-diethyl-4-

hydroxymethyl-phenyl)-tetrahydro-pyrazolo[1,2-d][1,4,5] oxadiazepine-7,9-dione (M4), 

calculated as the stoichiometric equivalent of pinoxaden, in or on the following commodities:

Endocrine Disruption

As required by the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and the Federal 

Food, Drug, and Cosmetic Act (FFDCA), EPA reviews numerous studies to assess potential 

adverse outcomes from exposure to chemicals. Collectively, these studies include acute, 
Pinoxaden Human-Health Assessment Scoping Document D425809

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subchronic, and chronic toxicity, including assessments of carcinogenicity, neurotoxicity, 

developmental, reproductive, and general or systemic toxicity. These studies include endpoints 

which may be susceptible to endocrine influence, including effects on endocrine target organ 

histopathology, organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, 

reproductive loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates 

acute tests and chronic studies that assess growth, developmental and reproductive effects in 

different taxonomic groups. As part of the most recent registration decision for pinoxaden, EPA 

reviewed these data and selected the most sensitive endpoints for relevant risk assessment 

scenarios from the existing hazard database. However, as required by FFDCA section 408(p), 

pinoxaden is subject to the endocrine screening part of the Endocrine Disruptor Screening 

Program (EDSP). 

EPA has developed the EDSP to determine whether certain substances (including pesticide 

active and other ingredients) may have an effect in humans or wildlife similar to an effect 

produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator 

may designate.” The EDSP employs a two-tiered approach to making the statutorily required 

determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a 

chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal 

systems. Chemicals that go through Tier 1 screening and are found to have the potential to 

interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA 

will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 

testing is designed to identify any adverse endocrine-related effects caused by the substance, and 

establish a dose-response relationship between the dose and the E, A, or T effect. Under FFDCA 

section 408(p), the Agency must screen all pesticide chemicals. Between October 2009 and 

February 2010, EPA issued test orders/data call-ins for the first group of 67 chemicals, which 

contains 58 pesticide active ingredients and 9 inert ingredients. Pinoxaden is not among the 

group of 58 pesticide active ingredients on the initial list screened under the EDSP. 

Accordingly, as part of Registration Review, EPA will issue future EDSP orders/data call-ins, 

requiring the submission of EDSP screening assays for pinoxaden. For further information on 

the status of the EDSP, the policies and procedures, the list of 67 chemicals, future lists, the test 

guidelines and the Tier 1 screening battery, please visit our website: http://www.epa.gov/endo/.

Cumulative 

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 for 

pinoxaden and any other substances. Therefore, EPA has assumed that pinoxaden does not have 

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/.

Human Studies 

Past pinoxaden risk assessments relied in part on data from studies in which adult human 

subjects were intentionally exposed to a pesticide to determine their dermal and inhalation 
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exposure. Many such studies, involving exposure to many different pesticides, comprise generic 

pesticide exposure databases such as the Pesticide Handlers Exposure Database (PHED), the 

Agricultural Reentry Task Force (ARTF) Database, and the Outdoor Residential Exposure Task 

Force (ORETF) Database. EPA has reviewed all the studies supporting these multi-pesticide 

generic exposure databases, and has found no clear and convincing evidence that the conduct of 

any of them was either fundamentally unethical or significantly deficient relative to the ethical 

standards prevailing at the time the research was conducted. All applicable requirements of 

EPA’s Rule for the Protection of Human Subjects of Research (40 CFR §26) have been satisfied, 

and there is no regulatory barrier to continued reliance on these studies.

Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in the 

most recent pinoxaden human health risk assessment, in accordance with U.S. Executive Order 

12898, “Federal Actions to Address Environmental Justice in Minority Populations and LowIncome Populations,” 

(http://www.epa.gov/compliance/environmentaljustice/resources/policy/exec_order_12898.pdf). 

The OPP typically considers the highest potential exposures from the legal use of a pesticide 

when conducting human health risk assessments, including, but not limited to, people who obtain 

drinking water from sources near agricultural areas, the variability of diets within the U.S., and 

people who may be exposed when harvesting crops. Should these highest exposures indicate 

potential risks of concern, OPP further refines the risk assessments to ensure that the risk 

estimates are based on the best available information.

Risk Assessment Updates and Data Deficiencies

The risk assessment updates that may be required under Registration Review are summarized 

below. Based on the current use patterns, there are no data deficiencies.

Risk Assessment Updates: 

 The current PODs will be reevaluated along with evaluation of the toxicological and 

exposure databases in terms of assigning a FQPA SF. 

 Harmonization of the residues of concern with Canadian MRLs will be evaluated.

 The need for livestock commodity tolerances should be reevaluated based on revisions to 

Table 1 of 860.1000 OCSPP Test Guidelines.

 Revised dietary risk assessment may be necessary to reflect the most recent EDWCs, 

dietary exposure models, and/or toxicological PODs.

 Revised aggregate risk assessment may be necessary to reflect revised dietary exposure 

estimates, and/or toxicological PODs. 

 Revised occupational risk assessment may be necessary to reflect the most recent HED 

policies and/or toxicological PODs.

 The need for spray drift and volatilization risk assessment for pinoxaden will be 

examined during Registration Review.

HED notes that based on the assumptions and resulting risks associated with the currently 

registered uses, it is highly unlikely that revised risk assessments conducted in support of 

Registration Review will yield exposures greater than HED’s level of concern. 
Pinoxaden Human-Health Assessment Scoping Document D425809

Page 12 of 26

Attachment A.: References

Attachment B.: Chemical Identity and Physicochemical Properties

Attachment C.: Hazard Profile Tables

Attachment D.: Toxicological Endpoint Selection Table 

Attachment E.: Registered Application Scenarios and Rates

Attachment F.: International Residue Limits

RDI: RAB1 (07/16/2015) and J. Rowland/D. Vogel (07/20/2015); PRD (09/02/2015)
Pinoxaden Human-Health Assessment Scoping Document D425809

Page 13 of 26

Attachment A: References

Table A. Memoranda Relevant to Registration Review.

Author Barcode Date Title

J. Carroll, et al. D305669 09/15/04 New Chemical Screen for Pinoxaden. 

M. Sahafeyan D313799 03/10/05 Pinoxaden on Plants Commodities. Request for Petition 

Method Validation (PMV).

M. Sahafeyan D299651 07/07/05 Pinoxaden in/on Wheat and Barley. PP# 4F6817. Summary 

of Analytical Chemistry and Residue Data.

M. Sahafeyan D313800 07/07/05 Pinoxaden- Dietary Exposure Assessment for the Section 3 

registration Action.

M. Clock-Rust, et al. D310864 07/13/05 Pinoxaden: Human Health Risk Assessment for New Active 

Ingredient; First Uses Proposed on Wheat and Barley. 

M. Sahafeyan D347343 07/31/05

Pinoxaden in/on Wheat and Barley. Response to 

Deficiencies Cited in Memorandum (DP#299651) of 

7/7/2005.

M. Sahafeyan D354427 07/31/08 Pinoxaden in/on Livestock Tissues. Request for Petition 

Method Validation (PMV).

J. Langsdale D354009 11/18/08

Review of Label Amendment for Pinoxaden (Axial® 

Herbicide, EPA Reg. No. 100-1199 and Axial® XL 

Herbicide, EPA Reg. No. 100-1256) to Reduce Rotational 

Crop Plantback Intervals (PBIs). 

J. Langsdale D362409 04/22/09

Pinoxaden. Review of Label Amendment for Pinoxaden 

(Axial® Herbicide, EPA Reg. No. 100-1199 and Axial® XL 

Herbicide, EPA Reg. No. 100-1256) to Reduce Rotational 

Crop Plantback Intervals (PBIs). Response to Health Effects 

Division (HED) Review of 18-NOV-2008. 
Pinoxaden Human-Health Assessment Scoping Document D425809

Page 14 of 26

Attachment B: Chemical Identity and Physicochemical Properties

Table B.1. Test Compound Nomenclature

Compound

N

N

O

O

O

O

Common name Pinoxaden

Company experimental 

name NOA 407855 or M1

IUPAC name 8-(2,6-diethyl-p-tolyl)-1,2,4,5-tetrahydro-7-oxo-7H-pyrazolo[1,2-

d][1,4,5]oxadiazepin-9-yl 2,2-dimethylpropionate

CAS name 8-(2,6-diethyl-4-methylphenyl)-1,2,4,5-tetrahydro-7-oxo-7H-pyrazolo[1,2-

d][1,4,5]oxadiazepin-9-yl 2,2-dimethylpropanoate

CAS # 243973-20-8

Table B.2. Physicochemical Properties of Pinoxaden

Parameter Value 

Melting point/range 120.5 - 121.6 °C

pH 4.9 at 25 °C

Density 1.16 x 103 kg/m3at 24 °C

Water solubility (at 25°C) 200 mg/L

Solvent solubility (g/L at 25°C)

acetone 250

dichloromethane >500

ethyl acetate 130

hexane 1.0

methanol 260

octanol 140

toluene 130

Vapor pressure 2.0 x 10-7 Pa at 20°C

4.6 x 10-7 Pa at 25°C

Octanol/water partition coefficient 

Log(KOW) 3.2 at 25°C

UV/visible absorption spectrum

Conditions

neutral solution 210, 258

acidic solution 210, 254

basic solution 220, 252

No absorption maximum between 350 and 750 was observed in any 

of the three solutions.
Pinoxaden Human-Health Assessment Scoping Document D425809

Page 15 of 26

Attachment C: Toxicity Profiles

Table C.1. Acute Toxicity Profile - Test Substance

Guideline No. Study Type MRID(s) Results Toxicity 

Category

870.1100 Acute oral 46203214 LD50 >5000 mg/kg IV

870.1200 Acute dermal 46203219 LD50 > 2,000 mg/kg

(limit dose) III

870.1300 Acute inhalation 46203221 LC50 = 5.22 mg/L IV

870.2400 Acute eye irritation 46203223 Severe eye irritant I

870.2500 Acute dermal irritation 46203225 Non-irritating IV

870.2600 Skin sensitization 46203227 Non sensitizer n/a

Table C.2. Subchronic, Chronic, and Other Toxicity Profile for Pinoxaden. 

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.3100 90-Day oral 

toxicity (mouse)

46203241 (2002)

Acceptable/Guideline

0, 10, 100, 400, 700 or 

1000 mg/kg/day (limit 

dose)

NOAEL = 700 mg/kg/day. 

LOAEL = 1000 mg/kg/day based on 

increased incidence of piloerection and 

decreased body-weight gain in both sexes, 

and increased incidence of renal tubular 

basophilia in males.

870.3100 90-Day oral 

toxicity (mouse)

46203236, 46224805 

(2003) 

Acceptable/Guideline

0, 1000, 2500, 5000 or 

7000 ppm (0/0, 

140.9/165.9, 365.0/436.7, 

708.2/900.6, or 

992.3/1311.7 mg/kg/day 

in males/females)

NOAEL was not observed in females, but 

was 365.0 mg/kg bw/day in males.

LOAEL =165.9 mg/kg bw/day in females, 

based on decreased body weight and bodyweight gain and 708.2 mg/kg bw/day in 

males, based on decreased food efficiency.

870.3100 90-Day oral 

toxicity (rat)

46203239 (2003)

Acceptable/Guideline

0, 3, 10, 30, 100, or 300 

mg/kg/day

NOAEL = 300/100 mg/kg/day (M/F).

LOAEL was not observed in males; = 300 

mg/kg/day in females, based on increased 

water consumption and urinary volume.

870.3100 90-Day oral 

toxicity (rat)

46203235, 46203237 (2003) 

Acceptable/Guideline

0, 150, 1000, 5000, or 

10000 ppm (0/0, 15/16, 

98/110, 466/527, or 900/965

mg/kg/day in 

males/females)

NOAEL = 466/537 mg/kg/day (M/F).

LOAEL = 900/965 mg/kg/day based on 

decreased body weight and body-weight 

gain and increased incidence of renal 

lesions in both sexes; decreased food 

consumption and increased water 

consumption in males; and increased urine

volume in females.

870.3150 90-Day oral 

toxicity (dog)

46203242 (2003)

Acceptable/Guideline

0, 25, 100, 250, or 

500 mg/kg/day

NOAEL = 100 mg/kg/day. 

LOAEL = 250 mg/kg/day based on clinical 

signs of toxicity, fluid feces, vomit, pale 

and thin appearance, decreased activity, 

dehydration, cold to touch, and 

regurgitation in both sexes, and mucus in 

feces in the males) and decreased body 

weights, body-weight gains, and food 

consumption in both sexes.

870.3200 28-Day dermal 

toxicity (rat)

46203243 (2001)

Acceptable/Guideline

0, 10, 100, or 1000 

mg/kg/day

LOAEL was not observed.

NOAEL = 1000 mg/kg bw/day (the limit 

dose).
Pinoxaden Human-Health Assessment Scoping Document D425809

Page 16 of 26

Table C.2. Subchronic, Chronic, and Other Toxicity Profile for Pinoxaden. 

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.3465 90-Day 

inhalation 

toxicity (rat)

NA NA

870.3700a Prenatal 

developmental in 

(rat)

46203305 (2003)

Acceptable/Guideline

0, 3, 30, 30, 300, or 

800 mg/kg/day

Maternal NOAEL = 30 mg/kg/day.

Maternal LOAEL = 300 mg/kg bw/day, 

based on decreased body-weight gains and 

food consumption.

Developmental NOAEL = 30 mg/kg/day. 

Developmental LOAEL = 300 mg/kg/day, 

based on delays in skeletal ossification in 

the skull and hind digits.

870.3700b Prenatal 

developmental in 

(rabbit)

46203303 (2003)

Acceptable/Guideline

0, 3, 10, 30, or 100 

mg/kg/day

Maternal NOAEL = 30 mg/kg/day.

Maternal LOAEL = 100 mg/kg/day, based 

on increased mortality, abortion, and 

decreased body weights, body-weight gains 

and food consumption.

Developmental NOAEL = 30 mg/kg/day.

Developmental LOAEL = 100 mg/kg day, 

based on increased incidence of complete 

early litter resorption.

870.3800 Reproduction 

and fertility 

effects

(rat)

46203308 (2003)

Acceptable/Guideline

0, 10, 50, 250, and 

500 mg/kg/day

Parental NOAEL = 250 mg/kg/day.

Parental LOAEL = 500 mg/kg/day, based 

on increased water consumption, renal 

tubular atrophy, and chronic nephropathy in 

both sexes, and increased incidence of renal 

pelvic dilatation in the males.

Offspring NOAEL = 250 mg/kg/day.

Offspring LOAEL = 500 mg/kg bw/day, 

based on decreased body weights and bodyweight gains in the F1 pups, and decreased 

body weights in the F2 males.

Reproductive NOAEL = 500 mg/kg/day.

Reproductive LOAEL was not observed.

870.4100b Chronic toxicity 

(dog)

46203309 (2003)

Acceptable/Guideline

0, 5, 25, or 125 mg/kg/day

NOAEL = 125 mg/kg/day. 

LOAEL was not observed.

870.4200 Carcinogenicity

(mouse)

46224808 (2003)

Unacceptable/Guideline

0, 5, 40, 300, or 750 mg/kg

NOAEL/LOAEL could not be determined. 

The study could not be interpreted due to 

gavage errors and lung involvement.

870.4200 Carcinogenicity

(mouse)

46448801 (2004)

Unacceptable/Guideline

0, 10, 150, 500, 1500, or 

4000 ppm (0/0, 16.3/20.2, 

60.7/75.7, 181.2/216.5, and 

573.7/706.4 mg/kg/day in 

males/females)

[4000 ppm dose discontinued 

at Week 40]

NOAEL = 216.5/181.2 mg/kg/day (M/F).

LOAEL was not determined.
Pinoxaden Human-Health Assessment Scoping Document D425809

Page 17 of 26

Table C.2. Subchronic, Chronic, and Other Toxicity Profile for Pinoxaden. 

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.4200 Carcinogenicity

(rat)

46448801 (2004)

Unacceptable/Guideline

0, 10, 150, 500, 1500 or 

4000 ppm (0/0, 16.3/20.2, 

60.7/75.7, 181.2/216.5, and 

573.7/706.4 mg/kg/day in 

males/females)

[4000 ppm dose discontinued 

at Week 40]

NOAEL = 216.5/181.2 mg/kg/day (M/F).

LOAEL was not determined.

870.4300 Carcinogenicity

(rat)

46224809 (2003)

Acceptable/Guideline

0, 1, 10, 100 250, or 

500 mg/kg/day

NOAEL = 100 mg/kg/day.

LOAEL = 250 mg/kg/day, based on 

mortality, clinical signs, and increased

serum urea and creatinine in males, and 

decreased body weights and body-weight 

gains, increased water consumption and 

incidence of urinalysis findings, kidney 

surface granulation, and microscopic renal 

lesions in both sexes.

870.5100 In Vitro 

bacterial gene 

mutation S.

typhimurium/E.

coli

46203314 (2001)

Acceptable/Guideline

33, 100, 333, 1000, 2500, or

5000 μg/plate w/wo 

activation

(cytotoxicity was observed at 

≥1000 μg/plate) 

No marked increases in the number of 

revertants were observed at any 

concentration in any strain in either trial. 

[negative]

870.5300 In Vitro

mammalian

gene mutation 

(L5178YTK+/-)

46203318 (2003)

Acceptable/Guideline

6.3, 12.5, 254200 μg/mL (-

S9) and 3.1, 6.3, 12.5, 25, 50, 

100, or 150 μg/mL (+S9) 

No reproducible substantial (≥2x solvent 

controls) and/or concentration-dependent 

increases in mutant colonies per 106 cells 

were observed at any dose level in the 

presence or absence of S9. 

[negative]

870.5375 In vitro

mammalian

cytogenetics in

V79 Chinese

Hamster Lung 

Fibroblasts

46203321(2001)

Acceptable/Guideline

6.3, 10, 12.5, 20, 25, 40, 50, 

60, 75, 80, or 100 μg/mL 10,

20, 40, 60, 80, or 100 μg/mL 

(-S9); 10, 12.5, 20, 25, 30,

40, 50, 60, 70, 75, 80, 100 or

120 μg/mL (+S9) 

Although there was not a clear doseresponse and several of the increases in 

percent aberrant cells were within the 

historical control range (0.0-4.0%), there 

was sufficient reproducible evidence of a 

positive mutagenic effect in the presence 

and absence of S9. 

[positive]

870.5375 In vitro

mammalian

cytogenetics in

V79 Chinese

Hamster Lung 

Fibroblasts

46203322 (2002)

Acceptable/Guideline

10, 15, 20, 30, 40, 45, 60, 75,

80, 90, and 100 μg/mL (-S9);

3.8, 7.5, 15, 30, 45, 60, and 

90 μg/mL (+S9)

There was an increase in the percent 

aberrant cells that exceeded the historical 

control range with/without S9 metabolic 

activation.

[positive]

870.5395 In Vivo 

mammalian

cytogenetics 

micronucleus 

mice

46203325 (2002)

Acceptable/Guideline

2000 mg/kg (bone 

marrow toxicity was not 

induced)

There were no marked increases observed 

in mean net nuclear grains (NNG) or 

percent cells in repair (NNG ≥5) at 2 or 16 

hours post-dosing compared to controls. 

[negative]
Pinoxaden Human-Health Assessment Scoping Document D425809

Page 18 of 26

Table C.2. Subchronic, Chronic, and Other Toxicity Profile for Pinoxaden. 

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.5550 UDS in 

mammalian

Cells

46203329 (2001)

Acceptable/Guideline

0, 1.17, 2.34, 4.69, 9.38,

18.75, 37.5, 75, 150, 300, or

600 μg/mL (cytotoxic levels

$300 μg/mL) 

There were no marked increases observed 

in the mean grains per nucleus or mean 

NNG in either trial. Negative for increased 

UDS up to limit dose. 

[negative]

870.5550 UDS in 

mammalian

Cells

46203325 (2002)

Acceptable/Guideline 

2000 mg/kg

There were no marked increases observed 

in mean net nuclear grains (NNG) or 

percent cells in repair (NNG ≥5) at 2 or 16 

hours post-dosing compared to controls.

[negative]

870.6200a Acute 

neurotoxicity 

screening battery

46203331, 46203330 (2003) 

Acceptable/Guideline

0, 100, 500, or 2000 mg/kg

NOAEL = 2000 mg/kg (for 

neurotoxicity).

LOAEL was not determined.

870.6200b Subchronic 

neurotoxicity 

screening battery

46203332 (2003)

Acceptable/Guideline

0, 10, 100, or 500 mg/kg/day

NOAEL = 500 mg/kg/day (for 

neurotoxicity).

LOAEL was not determined.

870.7485 Metabolism and 

pharmacokinetic

s

(rat)

46203333-46203336 (2001)

Acceptable/Guideline

0.5 or 300 mg/kg

Approximately 90% of the orally gavaged 

dose was absorbed from the gastrointestinal 

tract. Approximately, 90% of the absorbed 

dose was excreted in the urine and feces in 

72 hours and excretion was nearly complete 

in 7 days. Excretion in the urine ranged 

from 59-78% and in feces 20-25%. Tissue 

distribution data indicated no significant 

accumulation in the body. Biliary excretion 

study did not indicate enterohepatic 

circulation. No parent compound was 

detected in the urine, feces, or bile. Major 

metabolite in the urine and feces was the 

hydrolysis product M2. Major metabolites 

in the urine were M2 (65%-85%) and M4 

(5-13%) and in the feces 50%-70%) and M4 

(25%-35%) depending up on the dose. 

There were no sex related differences in the 

absorption, distribution, excretion, or 

qualitative profile of the metabolites.

870.7600 Dermal 

penetration (rat)

46203342 (2003)

Acceptable/Guideline

0.05, 0.25, or 4.0 mg/rat (EC

100 formulation)

Low dose= 4%, 14%, 18% at 

4, 10, 24 hours Mid dose= 1%, 

2%, 4% at 4, 10, 24 hours.

High dose = 17%, 30%, 36% at 4, 10, 24 

hours.

Table C.3. Subchronic, Chronic, and Other Toxicity Profile for Pinoxaden Metabolite M3.

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.3100 90-Day oral 

toxicity (rat)

46203240, 46203231, 

46203233 (2003)

Acceptable/Guideline

0/0, 15.0/15.2, 99.2/98.8, or 

600.6/645.4 mg/kg/day 

NOAEL = 99.2/98.8 mg/kg/day (M/F).

LOAEL = 600.6/645.4 mg/kg/day based on 

decreased body weight and body-weight gain 

and food efficiency in both sexes, and 

evidence of hepatotoxicity in both sexes and 

nephrotoxicity in males (M/F).
Pinoxaden Human-Health Assessment Scoping Document D425809

Page 19 of 26

Table C.3. Subchronic, Chronic, and Other Toxicity Profile for Pinoxaden Metabolite M3.

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.5100 In Vitro bacterial 

gene mutation 

S. typhimurium/

E.coli

46203315 (2003)

Acceptable/Guideline

100, 200, 500, 1000, 2500 or

5000 μg /plate (+/-

activation) 

No evidence of mutagenicity in Salmonella 

strains TA98, TA100, TA1535, and TA1537 

and Escherichia coli strain WP2uvrA.

[negative]

870.5300 In Vitro

Mammalian gene 

mutation 

(L5178YTK+/-)

46203319 (2003)

Acceptable/Guideline

0, 125, 250, 500, 1000, 1500 

or 2000 μg/mL (+/activation)

No reproducible significant (p≤0.05) and/or 

concentration dependent increases in mutant 

frequency were observed at any dose level in 

the presence or absence of S9. 

[negative]

870.5375 In vitro

Mammalian 

cytogenetics 

human 

lymphocytes

46203323 (2003)

Acceptable/Guideline

0, 50, 100, 250, 500, 750, 

1000, 1500, 2000, 2500, 

3000, and 3324 μg/mL 

(+/activation)

At 1500 μg/mL, NOA 447204 induced 

increased (p≤0.05) aberration frequencies 

(excluding gaps) in the presence of S9 in 

Trials 1 and 2 (4.5-8.67% treated vs 1.0% 

solvent control), and in the absence of S9 in 

Trial 1 (6.5% treated vs 2.0% solvent 

control) after a 3 hour treatment period and a 

17 hour recovery period. The significant 

increases observed equaled or exceeded the 

upper limit of the historical control ranges. 

[positive]

870.5395 In Vivo 

mammalian

cytogenetics 

micronucleus 

mice

46203328 (2003)

Acceptable/Guideline

0, 200, 400, or 800 mg/kg 

No significant increase in micronucleated 

polychromatic erythrocytes (MPCEs) was 

observed in any dose at either 24 or 48 hours 

post-dosing. The positive control induced 

the appropriate response.

[negative]

870.5550 UDS in 

mammalian

cells

46203326 (2003)

Acceptable/Guideline

0, 625, or 1250 mg/kg 

There were no marked increases observed in 

mean net nuclear grains (NNG) or percent 

cells in repair (NNG ≥5) at 2 or 16 hours 

post-dosing compared to controls. The 

positive control induced the appropriate 

response. 

[negative]

Table C.4. Subchronic, Chronic, and Other Toxicity Profile for Pinoxaden Metabolite M6.

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.3100 90-Day oral 

toxicity (rat)

46203238, 46203232 (2003)

Acceptable/Guideline

0/0, 23.9/26.8, 246.8/266.4,

or 977.5/1034.9 mg/kg/day

NOAEL = 977.5/1034.9 mg/kg/day (M/F).

LOAEL was not observed.

870.5100 In Vitro bacterial 

gene mutation 

S. 

typhimurium/E.

coli

46203316 (2003)

Acceptable/Guideline

100, 200, 500, 1000, 2500, or

5000 μg /plate 

(-/+ activation) 

No evidence of mutagenicity in Salmonella 

strains TA98, TA100, TA1535, and TA1537 

and Escherichia coli strain WP2uvrA.

[negative]

870.5300 In Vitro

Mammalian gene 

mutation 

(L5178YTK+/-)

46203320 (2003)

Acceptable/Guideline

0, 125, 250, 500, 1000, 1500,

or 2000 μg/mL (-/+ 

activation)

No reproducible significant (p≤0.05) and/or 

concentration dependent increases in mutant 

frequency were observed at any dose level in 

the presence or absence of S9. 

[negative]
Pinoxaden Human-Health Assessment Scoping Document D425809

Page 20 of 26

Table C.4. Subchronic, Chronic, and Other Toxicity Profile for Pinoxaden Metabolite M6.

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.5375 In vitro

Mammalian 

cytogenetics 

human 

lymphocytes

46203324 (2003)

Acceptable/Guideline

50, 100, 200, 500, 1000, 1500 

or2000 μg/mL

(-/+ activation)

There was no evidence of chromosome 

aberrations induced over background in the 

presence or absence of S9-activation.

[negative]

Table C.5. Subchronic, Chronic, and Other Toxicity Profile for Pinoxaden Metabolite M10.

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.5100 In Vitro bacterial 

gene mutation 

S. 

typhimurium/E.

coli

46224810 (2003)

Acceptable/Guideline

100, 200, 500, 1000, 2500, or

5000 μg /plate 

(-/+ activation) 

No evidence of mutagenicity in Salmonella 

strains TA98, TA100, TA1535, and TA1537 

and Escherichia coli strain WP2uvrA.

[negative]

870.5300 In Vitro

Mammalian gene 

mutation 

(L5178YTK+/-)

46224811 (2003)

Acceptable/Guideline

0, 125, 250, 500, 1000, 2000,

or 3484 μg/mL (-/+ 

activation)

No reproducible significant (p≤0.05) 

increases in mutant frequency were observed 

at any dose level in the presence or absence 

of S9. 

[negative]

870.5375 In vitro

Mammalian 

cytogenetics 

human 

lymphocytes

46224812 (2003)

Acceptable/Guideline

10, 50, 100, 250, 500, 750,

1000, 1500, 2500, or 3484 

μg/mL

(-/+ activation)

There was no evidence of chromosome 

aberrations induced over background in the 

presence or absence of S9-activation.

[negative]

870.5395 In Vivo 

mammalian

cytogenetics 

micronucleus 

mice

46224813 (2004)

Acceptable/Guideline

0 or 2000 mg/kg

No significant increase in micronucleated 

polychromatic erythrocytes (MPCEs) was 

observed in any dose at either 24 or 48 hours 

post-dosing. The positive control induced 

the appropriate response.

[negative]

870.5550 UDS in 

mammalian

cells

46224814 (2004)

Acceptable/Guideline

2000 mg/kg

There were no marked increases observed in 

mean net nuclear grains (NNG) or percent 

cells in repair (NNG ≥5) at 2 or 16 hours 

post-dosing compared to controls. The 

positive control induced the appropriate 

response. 

[negative]

Table C.6. Subchronic, Chronic, and Other Toxicity Profile for Pinoxaden (Impurity SYN519312).

Guideline 

No. 

Study Type MRID No. (year)/ 

Classification /Doses

Results

870.5100 In Vitro bacterial 

gene mutation 

S. 

typhimurium/E.

coli

46203317 (2003)

Acceptable/Guideline

100, 200, 500, 1000, 2500, or

5000 μg /plate 

(-/+ activation) 

No evidence of mutagenicity in Salmonella 

strains TA98, TA100, TA1535, and TA1537 

and Escherichia coli strain WP2uvrA.

[negative]
Pinoxaden Human-Health Assessment Scoping Document D425809

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Attachment D: Endpoint Selection and Toxicity Profile Tables

Table D.1. Summary of Toxicological Doses and Endpoints for Pinoxaden 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)

NOAEL= 

30 

mg/kg/day

Dermalabsorption 

rate=40%

UFA= 10X

UFH= 10X

Residential LOC 

for MOE = 100

Developmental toxicity - rabbit

Maternal LOAEL = 100 mg/kg/day based 

on morbid condition in one rabbit

(mortality), clinical signs of toxicity in a 

morbid rabbit, abortion, decreased body 

weights, body-weight gains and food 

consumption.

Dermal 

IntermediateTerm (1-6 

months)

NOAEL= 

30 

mg/kg/day

Dermalabsorption 

rate=40%

UFA= 10X

UFH= 10X

Residential LOC 

for MOE = 100

Developmental toxicity - rabbit

Maternal LOAEL = 100 mg/kg/day based 

on morbid condition in one rabbit

(mortality), clinical signs of toxicity in a 

morbid rabbit, abortion, decreased body 

weights, body-weight gains and food 

consumption.

Inhalation 

Short-Term (1-

30 days)

NOAEL= 

30 

mg/kg/day

UFA= 10X

UFH= 10X

Residential LOC 

for MOE = 100

Developmental toxicity - rabbit

Maternal LOAEL = 100 mg/kg/day based 

on morbid condition in one rabbit

(mortality), clinical signs of toxicity in a 

morbid rabbit, abortion, decreased body 

weights, body-weight gains and food 

consumption.

Inhalation 

Intermediateterm (1-6 

months)

NOAEL= 

30 

mg/kg/day

UFA= 10X

UFH= 10X

Residential LOC 

for MOE = 100

Developmental toxicity - rabbit

Maternal LOAEL = 100 mg/kg/day based 

on morbid condition in one rabbit

(mortality), clinical signs of toxicity in a 

morbid rabbit, abortion, decreased body 

weights, body-weight gains and food 

consumption.

Cancer (oral, 

dermal, 

inhalation)

Classification: Data Are Inadequate for An Assessment of Human Carcinogenic Potential.

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.
Pinoxaden Human-Health Assessment Scoping Document D425809

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Table D.2. Summary of Toxicological Doses and Endpoints for Pinoxaden for Use in Dietary and NonOccupational Human Health Risk Assessments.

Exposure/

Scenario

Point of 

Departure

Uncertainty/FQP

A Safety Factors

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment

Study and Toxicological Effects

Acute Dietary 

(Females 13-

49 years of 

age)

NOAEL = 

30 

mg/kg/day

UFA = 10X

UFH = 10X

FQPA SF = 1X

Acute RfD = 

0.3 

mg/kg/day

aPAD = 0.3 

mg/kg/day

Developmental toxicity - rabbit

Developmental LOAEL = 100 

mg/kg/day based on increased incidence 

of complete early litter resorption.

Acute Dietary 

(General 

Population, 

including 

Infants and 

Children)

N/A N/A N/A

An endpoint of concern attributable to a 

single dose effect was not identified in 

the database. Quantification of acute risk 

to general population including infants 

and children is not required.

Chronic 

Dietary (All 

Populations)

NOAEL = 

30 

mg/kg/day

UFA = 10X

UFH = 10X

FQPA SF = 1X

Chronic RfD 

= 0.3 

mg/kg/day

cPAD = 0.3 

mg/kg/day

Developmental toxicity - rabbit

Maternal LOAEL = 100 mg/kg/day 

based on morbid condition in one rabbit

(mortality), clinical signs of toxicity in a 

morbid rabbit, abortion, decreased body 

weights, body-weight gains and food 

consumption.

Incidental 

Oral ShortTerm (1-30 

days)

NOAEL = 

30 

mg/kg/day

UFA = 10X

UFH = 10X

FQPA SF = 1X

Residential 

LOC for 

MOE = 100

Developmental toxicity - rabbit

Maternal LOAEL = 100 mg/kg/day 

based on morbid condition in one rabbit

(mortality), clinical signs of toxicity in a 

morbid rabbit, abortion, decreased body 

weights, body-weight gains and food 

consumption.

Incidental 

Oral 

IntermediateTerm (1-6 

months)

NOAEL = 

30 

mg/kg/day

UFA = 10X

UFH = 10X

FQPA SF = 1X

Residential 

LOC for 

MOE = 100

Developmental toxicity - rabbit

Maternal LOAEL = 100 mg/kg/day 

based on morbid condition in one rabbit

(mortality), clinical signs of toxicity in a 

morbid rabbit, abortion, decreased body 

weights, body-weight gains and food 

consumption.

Dermal ShortTerm (1-30 

days)

NOAEL = 

30 

mg/kg/day

Dermalabsorption 

rate = 40%

UFA = 10X

UFH = 10X

FQPA SF = 1X

Residential 

LOC for 

MOE = 100

Developmental toxicity - rabbit

Maternal LOAEL = 100 mg/kg/day 

based on morbid condition in one rabbit

(mortality), clinical signs of toxicity in a 

morbid rabbit, abortion, decreased body 

weights, body-weight gains and food 

consumption.

Dermal 

IntermediateTerm (1-6 

months)

NOAEL= 

30 

mg/kg/day

Dermalabsorption 

rate = 40%

UFA = 10X

UFH = 10X

FQPA SF = 1X

Residential 

LOC for 

MOE = 100

Developmental toxicity - rabbit

Maternal LOAEL = 100 mg/kg/day 

based on morbid condition in one rabbit

(mortality), clinical signs of toxicity in a 

morbid rabbit, abortion, decreased body 

weights, body-weight gains and food 

consumption.
Pinoxaden Human-Health Assessment Scoping Document D425809

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Table D.2. Summary of Toxicological Doses and Endpoints for Pinoxaden for Use in Dietary and NonOccupational Human Health Risk Assessments.

Exposure/

Scenario

Point of 

Departure

Uncertainty/FQP

A Safety Factors

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment

Study and Toxicological Effects

Inhalation 

Short- Term 

(1-30 days)

NOAEL = 

30 

mg/kg/day

UFA = 10X

UFH = 10X

FQPA SF = 1X

Residential 

LOC for 

MOE = 100

Developmental toxicity - rabbit

Maternal LOAEL = 100 mg/kg/day 

based on morbid condition in one rabbit

(mortality), clinical signs of toxicity in a 

morbid rabbit, abortion, decreased body 

weights, body-weight gains and food 

consumption.

Inhalation 

IntermediateTerm (1-6 

months)

NOAEL = 

30 

mg/kg/day

UFA = 10X

UFH = 10X

FQPA SF = 1X

Residential 

LOC for 

MOE = 100

Developmental toxicity - rabbit

Maternal LOAEL = 100 mg/kg/day 

based on morbid condition in one rabbit

(mortality), clinical signs of toxicity in a 

morbid rabbit, abortion, decreased body 

weights, body-weight gains and food 

consumption.

Cancer (oral, 

dermal, 

inhalation)

Classification: Data Are Inadequate for An Assessment of Human Carcinogenic Potential.

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. MOE = margin of exposure. LOC = level 

of concern. N/A = not applicable.
Pinoxaden Human-Health Assessment Scoping Document D425809

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Attachment E: Registered End-Use Products and Application Scenarios/Rates

The information in the following two tables is based on the LUIS reports. 

Table E.1. Summary of End-Use Products.

Product 

Type

Trade Names (EPA 

Reg. No.)

ai

Concentration

Application Type/

Equipment Use Sites REI Target Pests

WDG

Axial Herbicide

(100-1199) 9.71% Foliar application by ground/aerial Wheat and barley

48 hours

Annual/

perennial 

grass weeds

Axial TBC Herbicide

(100-1256) 9.0% Foliar application by ground/aerial Wheat and barley

Foxfire Herbicide

(100-1429) 5.01% Foliar application by ground/aerial Wheat and barley

FlC Axial Star Herbicide

(100-1389) 4.9% Foliar application by ground/aerial Wheat and barley

SC Axial XL Herbicide

(100-1256 5.05% Foliar application by ground/aerial Wheat and barley

Table 3.2.1. Summary of Registered Uses for Pinoxaden.

Applic. Timing, Type, and 

Equip.

Formulation 

[EPA Reg. No.]

Max 

Application 

Rate

Max Seasonal 

Application Rate

Use Directions and 

Limitations

Spring Wheat (excluding Durum), Winter Wheat, and Barley

Apply from 2-leaf stage to preboot stage of growth by ground 

or aerial equipment

EC

[100-1314]2

[100-1429]2

(wheat only)

[100-1199]

SC

[100-1256]

FlC

[100-1389]2

0.054 lbs ai/A

0.0269 lbs ai/A100-1429 only0.054 lbs ai/A/year

Apply in a minimum of 5 

gallons of water per acre. 

Use the full label rate of 

product. Do not apply 

through any type of 

irrigation system. Make 1 

application per crop season. 

Do not graze livestock or

harvest forage for 30 days 

following application. Do 

not harvest grain for 60 

days following application 

(70 days for Wyoming). 

Straw may be fed to 

livestock 60 days after 

application. 

REI1 = 48 hours.

1REI = restricted-entry interval.

2These products containing multiple ai’s. The other ai’s are:

100-1429: fenoxaprop-p-ethyl;

100-1389: fluroxyr 1-methylheptyl ester;

100-1314: florasulam.
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Attachment F: International Residue Limits

Pinoxaden (147500; 06/01/2015)

Table F. Summary of US and International Tolerances and Maximum Residue Limits. 

Residue Definition:

US Canada Mexico1 Codex

40 CFR §180.611:

Plant & poultry commodities: Combined residues 

of pinoxaden (8-(2,6-diethyl-4-methylphenyl)-1,2,4,5-

tetrahydro-7-oxo-7H-pyrazolo[1,2-d][1,4,5] 

oxadiazepin-9-yl 2,2-dimethylpropanoate)and its 

metabolites 8-(2,6-diethyl-4-methyl-phenyl)-

tetrahydro-pyrazolo[1,2-d][1,4,5]oxadiazepine-7,9-

dione (also known as M2), and free and conjugated 

forms of 8-(2,6-diethyl-4-hydroxymethyl-phenyl)-

tetrahydro-pyrazolo[1,2-d][1,4,5] oxadiazepine-7,9-

dione (also known as M4), and 4-(7,9-dioxohexahydro-pyrazolo[1,2-d] [1,4,5]oxadiazepin-8-yl)-

3,5-diethyl-benzoic acid (also known as M6), 

calculated as pinoxaden. 

Ruminant commodities: pinoxaden, 8-(2,6-diethyl4-methylphenyl)-1,2,4,5-tetrahydro-7-oxo-7Hpyrazolo[1,2-d][1,4,5] oxadiazepin-9-yl 2,2-

dimethylpropanoate), and its metabolites M2, 8-(2,6-

diethyl-4-methyl-phenyl)-tetrahydro-pyrazolo[1,2-

d][1,4,5]oxadiazepine-7,9-dione, and free and 

conjugated forms of M4, 8-(2,6-diethyl-4-

hydroxymethyl-phenyl)-tetrahydro-pyrazolo[1,2-

d][1,4,5] oxadiazepine-7,9-dione

8-(2,6-diethyl-4-

methylphenyl)-1,2,4,5-

tetrahydro-7-oxo-7Hpyrazolo[1,2-

d][1,4,5]oxadiazepin-9-yl 

2,2-dimethylpropanoate, 

including the metabolites 8-

(2,6-diethyl-4-methylphenyl)-9-hydroxy-1,2,4,5-

tetrahydro-pyrazolo [1,2-

d][1,4,5]oxadiazepin-7-one, 

8-(2,6-diethyl-4-

hydroxymethyl-phenyl)-9-

hydroxy-1,2,4,5-tetrahydropyrazolo[1,2-d] 

[1,4,5]oxadiazepin-7-one 

and 3,5-diethyl-4-(9-

hydroxy-7-oxo-1,2,4,5-

tetrahydro-7H-pyrazolo[1,2-

d] [1,4,5]oxadiazepin-8-

yl)benzoic acid

None

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

US Canada Mexico1 Codex

Barley, bran 1.6 1.6

Barley, grain 0.9 0.9

Barley, hay 1.5

Barley, straw 1.0

Egg 0.06 0.06

Poultry, fat 0.06 0.06

Poultry, meat 0.06 0.06

Poultry, meat byproduct 0.06 0.06

Wheat, bran 3.0 3.0

Wheat, forage 3.5

Wheat, grain 1.3 1.3

Wheat, hay 2.0

Wheat, straw 1.5

Cattle, fat 0.04 0.04

Cattle, meat 0.04 0.04

Cattle, meat byproduct 0.04 0.04

Milk 0.02 0.02

MRLs with NO US Equivalent

Fat of goats 0.04

Fat of hogs 0.04

Fat of horses 0.04

Fat of sheep 0.04

Meat byproducts of goats 0.04

Meat byproducts of hogs 0.04

Meat byproducts of horses 0.04

Meat byproducts of sheep 0.04

Meat of goats 0.04
Pinoxaden Human-Health Assessment Scoping Document D425809

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Table F. Summary of US and International Tolerances and Maximum Residue Limits. 

Residue Definition:

US Canada Mexico1 Codex

Meat of hogs 0.04

Meat of horses 0.04

Meat of sheep 0.04

Completed: M. Negussie; 06/03/2015

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