### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON
, D

. C

. 20460

OF F IC E O F C HEMI CA L SA FET Y A ND PO LL U T IO N PR E VE N T I O N



### MEMORAN D UM



### D ate:

S ubj ect:

F r om:



### T hru :



### To : 02-Sep-2015

P in o x a d c n

. Human Health Assessment Scoping Document in Support of Registration R eview.

PC Code: 147500
Dec i sion No.: 

### 5txJzC? 'IDP Ba r code: 0425809 Regi s trat i o n Nos.: N I A
P et i tion No.: N I A Reg u latory Act i o n : Regi s tration Review Scoping Document R i sk Assess m ent Type: Scoping Document Case No.: 7266
TXR No. : N I A CAS No.: 243973-20-8
M R ID No.: None 40 CFR: §180.611



### William D. Wassell
, Chemist 

# !Yl #J

Anwar Y. Dunbar, Ph.D.
, Pharm acolog i s t

# ~ James S. Miller, Environmental He a lth Scientist Risk Assessment Branch l (RAB I ) Health Effects Division (HE D ; 7509P)

Thurston Morton
, Acting Branch Chief

# ~~ George F. Kramer, Ph.D.
, Senior Chemist RAB l/ H ED (7509 P )

Linsey Walsh
, Chemical Review Manager Kelly S h erman, Branch Chief Risk Mana geme nt and Impl ementation Branch 3 Pesticide Re-Evaluation Division (PRD) (7508P)

Attached i s B ED human h ealt h risk assessment scoping document for pinoxaden submitted in support of Registration Review. To evaluate the scope of work nece ssa ry to s upport Re g i st r ation Review
, H ED has considered recent risk assessments for pinoxaden
, updates to its toxicity
, exposure and usage databases, and the late st Agency sc i e n ce policy and risk assessment methodologies. The most recent HED human h ea lth risk assessment for pinoxaden was conducted in 2005 (Memo, 7/13 / 2005, M. C l ock-Rust, el 

### al.
, D 3 I 0864).

Page I of26

### Pinoxaden Human-Health Assessment Scoping Document 0425809



### E x ec u t i ve S umm a ry



### Bac k gro un d: Pinoxaden (8

- (2
, 6

- diethyl-4-methylphenyl)-1 ,2,4,5 -tetrahydro-7-oxo-7 H

### pyrazolo[ 1 ,2 -dJ( l ,4
, 5]oxadiazepin-9-y l 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 contro ll ed within three to five weeks. The registered products are fomrnlated as a suspension concentrate (SC)
, an emulsifiab l e concentrate (EC), and

a flowable concentrate (FIC). The maximum seasonal application rate is 0.054 lbs ai / A. The
most recent H ED human health risk assessment was conducted in 2005 (Memo, 7/13 / 2005, M. Clock- R ust , 

### et al., D310864).

HED evaluated the most recent pinoxaden human health risk assessment to determine whether sufficient data are ava i lable and whether any updates are needed to support R eg istration Review. HED ha s considered all registered uses for pinoxaden with respect to its toxicity
, exp os ure , and usage databases, and the mo st updated Agency science policy and risk assessment methodologies
to detem1ine the scope of work nece ssa ry to support Registration R eview. The current document pertains only to the Registration Re v iew data r equi r e ments for pinoxaden.



### Ha z ard ld e 11tiji c atio11 ff ox i c ol ogy : The primary effects in the hazard database for pinoxaden are kidney toxicity
, cl i n i ca l signs and decreased body weights. The toxicity database for pinoxaden i s complete and adequate to support Registration Review requirements
, and no new data are

r equ ired. Jn the previous risk assessment for pinoxaden, the prenatal developmental rat study

was u sed for all exposure s cenarios. For future actions
, the critical studies i n pinoxaden's hazard database
, in addition to the previous endpoints and safety factors will need to be re-e va luated and updated based upon current policies.



### R es idu e C h e mi s tr y am! D ie t ary Ex p os ur e : Adequate metabo l ism (crops, livestock, and
rotat i o n al 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 additiona l residue c h emistry data are needed to support the currently regist e red uses. As part of Registration Review
, a revised d i etary risk assessment may be necessary to reflect potential

rev i sed estimated drinking water concentrations (EDWCs), revised tolerances
, the most recent dietary exposure models
, and/or revised toxicologica l points of departure (PODs).



### R es id e ntial Ex p os ur e : P i noxaden is not registered for residential uses. The Agency will examine the need for spray drift and volatilization assessments du r ing Registration Review for pinoxaden based on the potent i al for exposure to by s tanders from agricultural applications.



### Agg r eg at e Ri s k Asses sm e nt: As part of Registration Review
, updated aggregate risk
assessments may be necessa r y to reflect revised dietary exposure est i mates , and / or toxicological PODs.



### O cc 11p a ti o 11 a l Ex p os ur e: The occupationa l 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 ri sks of concern; however
, the handler assessment is not reflective of all current exposure po l icies. Therefore
, during Registration Review
, updated occupational handler assessments will be

Page 2 of26Pinoxaden Human

- Health Assessment Scoping Document D 425809

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 POD s 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 O CSPP Test Guidelines.

 Revised dietary risk assessment may be necessary to reflect the most recent EDWCs, dietary exposure models, and/or toxicological PODs.

 Rev ised 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 re vised risk assessments conducted in support of Registration Review will yield exposure s greater than HED’s level of concern.

DETAILED CONSIDERATIONS
Registered U se Pattern s

P i noxaden 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 scenario s

. Hazard Identi fication/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 w eights
, 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 D 425809

Page 4 of 26 

### 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 multigene rational 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 potent ial 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 toxici ty 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 o f 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 fo r 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 pinoxad en are not required at this time (J. Bever, et al ., TXR #0057273, upholding the Division’s p revious 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 n eed to be re

- evaluated and u pdated based upon current policies.
Residue Chemistry and Tolerance Assessment

P i noxaden 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 a nd 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

- pyraz olo[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

- diethyl

benzoic acid (also known as M6), calculated as pinoxaden. Tolerances for commodities range from 0.06 ppm (eggs and p oultry 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 co mmodities range from 0.02 ppm (milk) to 0.04 ppm (cattle fat, meat, and meat byproduct).Pinoxaden Human

- Health Assessment Scoping Document D 425809

Page 5 of 26 

### Adequate wheat (pyrazol, phenyl, and oxadiazepine ring

- labeled pinoxaden ), lactating goat (phenyl ring

- labeled pinoxaden ), laying hen (phen yl 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 di rections ; however, there are outstanding issues related to the e stablished tolerances. Adequate method s 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 M 2, M4, M6
, and M10

are not recoverable t hrough the FDA Multiresidue Method (MRM) protocols

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

Conclusions: The current residue che mistry database is sufficient to support the registered uses ;
n o additional residue chemistry data are required.
Estimated Drinking Water Concentrations ( E DWCs )
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) t he 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 K ads 

### values ranging from 0.06

- 128 m L /g, and 0856

- 0.28 m L

/g, respectively, in t hree 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. A bdel

- 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 Wat er (SCI

- GROW) models to estimate residues in surface and ground water , respectively

. Since t he concentration estimates from PRZM

- EXAMS were higher than those from SCI

- GROW
, t he PRZM

- EXAMS estimates were used in the dietary assessment. The acute and chron ic EDWCsPinoxaden Human

- Health Assessment Scoping Document D 425809

Page 6 of 26 

### were 0.00076 ppm and 0.000473 ppm , respectively

. These estimates were incorporated in to the most recent dietary exposure analyses.

Conclusions: As part of Registration Review
, EFED anticipates generat ing revised EDWCs to reflect current pract ices/models.
Dietary Exposure

HE D has conducted a cute and chronic dietary exposure analyses which considered all currently registered uses ( Memo, 07/07/2005, M. Sahafeyan, D313800 ). T he analyses were conducted using the Dietary Exposure Evaluation Model

– Food Consumption Intake Database (DEEM

FCIDTM, 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 % a cute population

- adjusted dose or a PAD) and chronic (< 2 .1% chronic population

- adjusted dose or cPAD) exposure estimates were less than HED’s level of co ncern (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 Registr ation 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 Standa rd 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 subsequ ent 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 an alyses 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 D 425809

Page 7 of 26 

### Aggregate Risk Assessment
As part of the most recent pinoxaden human health risk assessment, HED c onducted 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 HE D’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 th ese registered use pattern s , there is potential for occupational handler and post

- application exposure s to pinoxaden. The most recent occupational exposure assessment for pinoxaden was conducted in 2005 (Memo, 07/1 3/20 0 5, 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 w ith a pre

- grazing interval of 30 days, rotational crop restrictions of 0 day s 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 label s is 48 hours. Pinoxaden registered labels require mixers, loaders, and other handlers to wear long

- sleeved shirt
, long pants, ch emical

- 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 exposur e to occupational handlers from the currently registered use pattern s 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, applic ators for aerial and groundboom, applications of an EC formulation. Furthermore, n o chemical

- specific data were available with which to assess potential exposure to pesticide handlers. The maximum application rate range is 0.0 54 lb s ai/A. Short

- and int ermediate

- 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 i nhalation risk estimates were not of c oncern (i.e., MOEs ≥ 100) with label specific personal

protective equipment (PPE). T herefore , 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 scen arios 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 D 425809

Page 8 of 26 

### Occupational Post

- Application
HED expects that post

- application exposure will occur since pinoxaden is applied post

emergence as a foliar spray. Post

- application exposure is expected to be short

- and intermediate

term based on information provided on proposed labels (e.g., maximum of one sprays per season at a rate of 0. 054 lb s 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 an d 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. , D 428933


### 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 se verity. 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 ingred ient. 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 furtherPinoxaden Human

- Health Assessment Scoping Document D 425809

Page 9 of 26 

### investigation. The Agency will continue to monitor the incident information and if a concern is triggered, ad ditional 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 MRL s for residues of pinoxaden and its metabolites in/o n 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 byprodu ct 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. Thi s 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

- 7 H

- 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)

- tetrahydro

pyrazolo[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) Gene ral. (2) Tolerances are established for residues of the herbicide pinoxaden (8

- (2,6

- diethyl

- 4

- methylphenyl)

- 1,2,4,5

- tetrahydro

- 7

- oxo

- 7 H

- pyrazolo[1,2

- d][1,4,5]oxadiazepin

- 9

- yl 2,2

- dimethylpropanoate) including its metabolites and degradates, in or on the co mmodities 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)

- tetrahydro

pyrazolo[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 D 425809

Page 10 of 26 

### subchronic, and chronic toxicity, inclu ding 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 reprodu ctive 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 es trogen, 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 chem ical 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 relationsh ip 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 a ctive ingredients on the initial list screened under the EDSP. Accordingly, as part of Registration Review , EPA will issue future EDSP orders/data ca ll

- 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 v isit 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 a nd 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 statement s 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 inhalationPinoxaden Human

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Page 11 of 26 

### exposure. Man y 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 Exposur e 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 1 2898, “Federal Actions to Address Environmental Justice in Minority Populations and Low

Income Populations,” ( http://www.epa.gov/compliance/environmentaljustice/resources/policy/exec_order_12898.pdf ). The OPP typically considers the highest potential expo sures 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 tolera nces 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 assess ment 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 volatili zation 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 exposure s greater than HED’s level of conc ern.Pinoxaden Human

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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 At tachment F

. : International Residue Limits

RDI: RAB1 ( 07 / 16 /2015) and J. Rowland/D

. Vogel ( 07 / 20 /2015 ); PRD ( 09 / 02 /2015 )Pinoxaden Human

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Page 13 of 26 

### Attachment A: References

Table A. Memoranda Relevant to R egistration 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

- 125 6) 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

- 2 008.Pinoxaden Human

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### Attachment B : Chemical Identity and Physicochemical Properties

Table B .1. Test Compound Nomenclature Compound

Common name P inoxaden Company experimental

name NOA 407855 or M1
IUPAC name 8

- (2,6

- diethyl

- p

- tolyl)

- 1,2,4,5

- tetrahydro

- 7

- oxo

- 7 H

- 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

- 7 H

- 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 10 3 kg/m 3 at 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(K OW ) 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

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### 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 LD 50 >5000 mg/kg IV
870.1200 Acute dermal 46203219 LD 50 > 2,000 mg/kg (limit dose) III
870.1300 Acute inhalation 46203221 LC 50 = 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 body

weight 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

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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/Guideli n e 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

. Dev elopmental NOAEL = 30 mg/kg/day. Developmental L OAEL = 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/d a y

. Offspring LOAEL = 500 mg/kg bw/day, based on decreased body weights and body

weight gains in the F 1 pups, and decreased body weights in the F 2 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 n ot determined

.Pinoxaden Human

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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 = 216.5/18 1.2 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 μ g/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 μ g/mL (

- S9) and 3.1, 6.3, 12.5, 25, 50, 100
, or 150 μ g/mL (+S9) No reproducible substantial ( ≥ 2x solven t controls) and/or concentration

- dependent increases in mutant colonies per 10 6 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 μ g/mL (

- S9); 10, 12.5, 20, 25, 30, 40, 50, 60, 70, 75, 80, 100 or 120 μ g/mL (+S9) Although there was not a clear dose

response 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 o f 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 μ g/mL (+S9) There was an increase in the percent aberrant cells that exceeded the histo rical 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

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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 C ells 46203329 (2001)

Acceptable/Guideline 0, 1.17, 2.34, 4.69, 9.38, 18.75, 37.5, 75, 150, 300, or 600 μ g/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 C ells 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 compl ete 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 detecte d 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 . S ubchronic, 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

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Page 19 of 26 Table C .3 . S ubchronic, 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 WP2 uvr A. [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 μ g/mL (+/activation) At 1500 μ g/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 reco very 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 respo nse. [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 WP2 uvr A. [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

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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 WP2 uvr A. [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 WP2 uvr A. [negative]Pinoxaden Human

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Page 21 of 26 

### 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 Short

Term (1

- 30 days) NOAEL=

30 mg/kg/day Dermal

absorption rate=40% UF A = 10X

UF H = 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 Intermediate

Term (1

- 6 months) NOAEL=

30 mg/kg/day Dermal

absorption rate=40% UF A = 10X

UF H = 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 UF A = 10X

UF H = 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 Intermediate

term (1

- 6 months) NOAEL=

30 mg/kg/day UF A = 10X

UF H = 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 d eparture (POD) = A data point or an estimated point that is derived from observed dose

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no

- observed adverse

- effect level. LOAEL = lowest

- observed adverse

- effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human p opulation (intraspecies). MOE = margin of exposure. LOC = level of concern. N/A = not applicable.Pinoxaden Human

- Health Assessment Scoping Document D 425809

Page 22 of 26 Table D.2. Summary of Toxicological Doses and Endpoints for Pinoxaden for Use in Dietary and Non

Occupational 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 UF A = 10X

UF H = 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 UF A = 10X

UF H = 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 Short

Term (1

- 30 days) NOAEL =

30 mg/kg/day UF A = 10X

UF H = 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 Intermediate

Term (1

- 6 months) NOAEL =

30 mg/kg/day UF A = 10X

UF H = 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 gai ns and food consumption.

Dermal Short

Term (1

- 30 days) NOAEL =

30 mg/kg/day Dermal

absorption rate = 40% UF A = 10X

UF H = 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 Intermediate

Term (1

- 6 months) NOAEL=

30 mg/kg/day Dermal

absorption rate = 40% UF A = 10X

UF H = 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

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Page 23 of 26 Table D.2. Summary of Toxicological Doses and Endpoints for Pinoxaden for Use in Dietary and Non

Occupational 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 UF A = 10X

UF H = 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 Intermediate

Term (1

- 6 months) NOAEL =

30 mg/kg/day UF A = 10X

UF H = 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. Canc er (oral, dermal, inhalation) Classification: Data Are Inadequate for An Assessment of Human Carcinogenic Potential

.
Point of d eparture (POD) = A data point or an estimated point that is derived from observed dose

- response data and used to mark the beginning of ext rapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no

- observed adverse

- effect level. LOAEL = lowest

- observed adverse

- effect level. UF = uncertainty factor. UF A = extrapolation from anima l to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = population

- adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of expo sure. LOC = level of concern. N/A = not applicable.Pinoxaden Human

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Page 24 of 26 

### Attachment E : Registered End

- Use Products and Application Scenarios /R ates
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 pre

boot 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/A

100

- 1429 only 0.054 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 o r harvest forage for 30 days following application. Do not h arvest grain for 60 days following application (70 days for Wyoming). Straw may be fed to livestock 60 days after application.

REI 1 = 48 hours.
1 REI = restricted

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

100

- 1429: fenoxaprop

- p

- ethyl; 100

- 1389: fluroxyr 1

- methylheptyl ester; 100

- 1314: florasulam.Pinoxaden Human

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Page 25 of 26 

### 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 Mexico 1 Codex 40 CFR § 180.611: Plant & poultry commodities: Combined residues of pinoxaden (8

- (2,6

- diethyl

- 4

- met hylphenyl)

- 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 fo rms 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

- diethyl

- benzoic acid (also known as M6), calculated as pinoxa den. Ruminant commodities: 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 M2, 8

- (2,6

- diethyl

- 4

- methyl

- phenyl)

- tetrahydro

- pyrazolo[1,2

- d][1,4,5]ox adiazepine

- 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

- 7H

pyrazolo[1,2

- d][1,4,5]oxadiazepin

- 9

- yl 2,2

- dimethylpropanoate, including the metabolites 8

- (2,6

- diethyl

- 4

- methyl

phenyl)

- 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

- tetrahydro

pyrazolo[1,2

- d] [1,4,5]oxadiazepin

- 7

- o ne 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 Mexico 1 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 0.04Pinoxaden Human

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Page 26 of 26 Table F. Summary of US and International Tolerances and Maximum Residue Limits. Residue Definition : US Canada Mexico 1 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.