UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460



### MEMORAND UM

DATE: 9/5/20 1 4 OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION



### SUBJECT : Cyhalofop -butyl. Human Heal th Assessment Scoping Document in Support of Registration Review

PC Code: 082583 Decision No.: 488117

Petition No.: NA Risk Assessment Type: NA TXRNo.: NA MRIDNo.: NA DP Barcode: 0418274 Registration No.: 62719-356,62719-613
, 62719-647 Regulatory Action: R eg i stration Revi e w Case No.: 7255 CAS No.: 122008-85-9 40 CFR: §180.576



### FROM: Douglas Dotson
, Ph.D., Chemist 

# $**~;;J;;ih,;** Ma rgarita Collantes, M.S., Biologist 

## ?ntf:7tar 

## tr/&-**(kRft:f'~** Jaime D ' Agostino, Ph.D.

, Toxicologist 

# d,::;;::s;y;J

Risk Assessment Branch II pHealth Effects Division (7509P) Office of Pesticide Programs 

### n

. (\

. __,/(

_ THROUGH : Christina Swartz, Branch Chief

## ~**~** Risk Assessmen t Branch II

Jess Rowland

, Associate Director Dana Vogel, Acting Direc t or Heal t h Effects Division (7509P) Office of Pesticide Programs



### TO: Jolene Trujillo, Chemical Re view Manager Pesticide Re-Evaluation Div i sion (7508P) Office of Pesticide Programs

Attached is the Health Ef fects Di v ision 's (HED) human health risk assessment scoping document for cyhalofop-butyl to supp ort registration review.Cyhalofop-butyl Reg i stration Review Scoping Document

Executive Summary

The Hea l th Effects Division Cyhalofop

- bu t yl Registra t ion Review Team has evaluated the database and the mos t recent human health risk assessme n t for the herb i c i de. HED performed this eva l uation in orde r to determ i ne the scope of work necessary to support the es t ablished tolerances and existing registra t ions dur i ng r egistration review. The p r imary source of i nfo r mat i on for th i s evaluation was the most recent human health risk assessment for the chemical (D387444, E. Holman, 11/3/201 1 )

. Cy h a l ofop

- buty l

, butyl [R

- ( 

### + )

- n

- buty l- 2

- ( 4( 4

- cyano

- 2

- .fluorophenoxy)phenoxy)propiona t e ], is a highly selective ary l oxyphenoxy-propionate post-emergence herbicide registered for use on rice

. It i s used to control many annual and seed li ng perennial grasses, i n clud i ng barnya r d grass and sprangletop i n d r ill-seeded and wate r -seeded rice. Cyhalofo p- butyl acts through inhibition of the plant's ace t yl coenzyme-A carboxylase, a pivo t al enzyme in plant fa tt y acid biosynthesis

. I t can be appl i ed as a broadcas t treatment by ground and ae r ia l eq ui pment.

The toxicology da t abase for cyhalofop-butyl is complete except for a subchronic inha l ation
tox i city study. A 1 OX database uncertainty fac t or fo r the l ack of an acceptable inhalation s t udy will be applied t o inhalat i on exposure; an alternative wou l d be fo r the registra n t to prov i de add i t i o n al i n format i o n r egarding the fraction of respirable and inhalable particles in the granular formu l at i on

.

T he kidney is the target orga n i n r ats, mice, a n d rabbi t s

. Addi t ional effects seen i n the toxicology database include effects on the stomach, thymus, a n d liver

. No adverse effec t s were observed i n a 2 1 -day derma l toxicity study in rats. No effec t s in the developing fetus or offspring were o b served in the rat deve l opmental, rabbit deve l opme n ta l

, or rat 2-genera t ion toxici t y s t udies. No systemic or neurotoxic effects were obse r ved i n e i ther the acute or the subchronic neuro t oxicity s t udies. In addition, there is no ev i dence that cy h alofop-b u tyl d i rectly targets the i mmune sys t em.

T h ere were n o pos i t i ve effects in a battery of mutagenic studies. H ED conc l uded t h at cyha l ofopbu t yl is "Not Like l y to be Carc i nogenic to Humans." The FQPA Safety Factor fonnerly was reduced t o 1 X based on t he completeness of the toxico l ogy database, the abse n ce of

neu r otoxicity or susceptibili t y, the l ack of po t en t ial for residen t ial exposure, and the conservative
nature of the exposure assessme n t.

T he r esidue c h emistry database is adequate to s u pport c u rrent registration rev i ew requi r ements. Ade q uate metabolism (crops, li vestock, and r o t a t ional crops), s t orage stabi l ity, mag n itude of the residue, and processing data are availa bl e to support the regis t ered uses. Adequa t e methods a r e

ava i lable for enforcemen t of the current l y esta bli shed to l erances. The t o l erance expression has been u p dated to i n c l ude bo t h coverage and compliance stateme n ts. T he dietary exposure database, including the potential for residues in foo d and dr i nking wa t er, is adequate to support current reg i strat i on r equ i rements. The las t risk assessment provided c h ro n ic dieta r y expos u re estimates t hat are not of concern fo r a ll population subgroups (0396698, W. Drew, et al., 7/25/2012)

.

Page 2 of22

### Cyhalofop

- butyl Registration Review Scoping Document

Page 3 of 22 There are no proposed or registered cyhalofop

- butyl products for use in residential areas. Therefore, a residential exposure assessment is not required during registration review; however, the Agency will consider the potential for exposure through spray drift and volatilization

. An acute dietary endpoint was not selected, there are no residential uses for cyhalofop

- butyl, the chemical is not likely to be a carcinogen, and chronic dietary risk is not of concern. As a result,

a ggregate risk is not of concern for cyhalofop

- butyl.

After receipt and review of the subchronic inhalation study recommended for registration review

, u pdated occupational handler inhalation exposure assessments might be needed during registration review

. Based on the Agency ’ s current practices, a quantitative non

- cancer occupational post

- application inhalation exposure assessment has not been performed for cyhalofop

- butyl . If ne w policies or procedures are put into place, the Agency m ight revisit the need for a quantitative occupational post

- application inhalation exposure assessment

. Although exposure and risk h ave been formally assessed in past risk assessments, HED has completed screening estimates of the risk associated with representative crop scenarios, the 10X database uncertainty factor, and application rates and equipment . These screening estimates ident ified potential risks of concern for handlers using the granular formulation of cyhalofop

butyl . The screening estimates should be captured in the draft risk assessment to support registration review, and should include the most recent recommendations wit h respect to unit exposures , PPE, and risk assessment methodology.

Introduction

HED evaluated the most recent human health risk assessment for cyhalofop

- butyl in association with updates to its toxicity

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

, and if further updates are needed to support registration review. The most r ecent human health risk assessment was conducted in 20 12 when HED evaluated a label amendment to increase the single application rate for use of the herbicide on rice ( D3 96698
, W. D rew, et al

. , 7 / 2 5 /20 12 )

. Pr ior to that assessment , HED evaluated a request for an increase in the rice tolerance (D387444, E. Holman, 11/3/2011). The increase was needed because the registrant proposed a new granular formulation and submitted field trial data to support the registration

.

Tolerances for residues of cyhalofop

- butyl are established i n 40 CFR §180. 576

. For plant commodities, the tolerance is established in terms of parent cyhalofop

- butyl as well as the a cid and diacid metabolites. T olerance s are established for both rice and wild rice at 0.40 ppm. Although there is a tolerance for residues in or on wild rice, cyhalofop

- butyl is not registered for use on wild rice. There are no tolerances for residues in l ivestock commodit ies.

The structure and chemical names

, a s well as the chemical and physical properties can be found in the tables in A ttachment 1

.

### Cyhalofop

- butyl Registration Review Scoping Document

Page 4 of 22 Hazard Identification/Toxicology

Cyhalofop

- butyl is a diphenyl ether (aka oxyphenoxy acid ester) herbicide. Other members of this class of herbicides include fluazifop

- butyl, fenoxaprop

- ethyl, haloxyfop

- methyl, diclofop

methyl, quizalofop

- ethyl, fomesafen sodium, oxyfluorfen, acifluorfen sodium, nitrofen

, and lactofen. The herbicidal mode of action for cyhalofop

- butyl involves inhibition of acetyl coenzyme A carboxylase

, which cataly z es an essential step in plant fatty acid biosynthesis. The mammalian mode of action is unknown.

The toxicology database for cyhalofop

- butyl is complete except for a subchronic inhalation toxicity study. HED’s Hazard and Science Policy Council (HASPOC) recommended that an inhalation study be required (Leshin, J. 21 May 2014, TXR#0056956) for registration review. In the absence of these or other relevant data, a 10X database uncertainty factor will be applied to the occupational inhalation risk assessment

. An immunotoxicity study was submitted and reviewed by HED (MRID 4 8180501 ). The study is acceptable

, and the results show no evidence of immunotoxicity. These results are consistent with the existing toxicological database

, which does not indicate that the chemical targets the immune system. Given the above information, HED concludes that this new immunotoxicity study has no impact on the overall hazard c haracterization, including doses and endpoints selected (along with traditional uncertainty factors) for risk assessment

. The kidney i s the target organ in rats, mice

, and rabbits. Kidney effects were observed in subchronic and chronic studies, as well a s in the rabbit developmental and rat reproduction studies. In the 90

- day rat study, lipofuscin pigment deposition in proximal tubule kidney cells was noted in both sexes. In the 90

- day mouse study (females only), there was an increase in absolute and re lative kidney weights as well as swelling of the proximal tubule cells. In the rabbit developmental study, 1/18 dams in the mid

- dose group and 9/18 dams in the high

- dose group died or were sacrificed in extremis after exhibiting hematuria (gross pathologi cal examinations revealed cloudy or dark colored kidneys). Slight kidney tubular cell swelling was observed only in adult males in the reproductive toxicity study. In the 18

- month mouse carcinogenicity study, kidney findings included tubular dilatation, chronic glomerulonephritis, and hyaline casts in females (not males). In both sexes in the chronic/carcinogenicity rat study

, early and increased deposition of the pigments lipofuscin and hemosiderin in the renal proximal tubular cells was observed. In a ddition, renal mineralization was observed in females only

. Additional effects seen in the toxicology database included effects on the stomach, thymus, and liver. In the 18

- month mouse carcinogenicity study, hyperplasia of the stomach mucosal epithelium was reported in males only. Brown and/or atrophied thymuses as well as decreased thymus weight was observed in the 90

- day dog study (no effects were observed in the chronic dog study at the doses tested). Hepatocellular hypertrophy and increased liver we ights were observed in multiple studies ; however

, these effects were not considered to be adverse in the absence of corresponding changes in clinical chemistry parameters or histopathological findings.

No adverse effects were observed in a 21

- day dermal toxicity study in rats. No effects in the developing fetus or offspring were observed in the rat developmental, rabbit developmental, and

### Cyhalofop

- butyl Registration Review Scoping Document

Page 5 of 22 rat 2

- generation toxicity studies. No systemic or neurotoxic eff ects were observed in either the acute or the subchronic neurotoxicity studies. Acceptable dog and rat metabolism stud ies for cyhalofop

- butyl are available.

The chronic toxicity/carcinogenicity study in the rat and the carcinogenicity study in mice showe d no evidence of carcinogenicity in either species. Results of these studies indicated that higher doses could have been employed in both species (i.e., the animals could have tolerated higher doses). However, the available mechanistic studies in mice in dicate that the liver was the target organ , and hep ato toxicity manifested as necrosis, increased liver weight, and moderate hypertrophy. Act ivation of PPARα was t he p rimary mode of action. The doses employed in the mechanistic studies indicate that the highest dose tested in the carcinogenicity studies approached an adequate dose

, and repeating these studies at higher doses would not provide data that would impact risk assessment. Additionally, t here were no positive effects in a battery of mutagenic st udies. Therefore, i n accordance with the EPA Final Guidelines for Carcinogen Risk A ssessment (March 29, 2005), cyhalofop

- butyl is classified as “Not Likely to be Carcinogenic to Humans

. ”

Cyhalofop

- butyl has low or minimal acute toxicity via the oral (Tox icity Category IV), dermal (Toxicity Category IV) and inhalation routes of exposure (Toxicity Category IV). It is minimally irritating to the eye (Toxicity Category IV) and non

- irritating to the skin (Toxicity Category IV) . I t is not a dermal sensitizer.

In the most recent risk assessment, the required 10X FQPA S afety F actor was reduced to 1X based on the completeness of the database as well as : 1) the lack of increased pre

- and post

- natal susceptibility of rats and rabbits to in utero and/or postnatal e xposure in the developmental and reproductive toxicity studies ; 2) there is no evidence of neurotoxicity in the database and a developmental neurotoxicity (DNT) study is not required; 3) there are no registered residential

uses ; and 4) the risk assessment does not underestimate exposure because the dietary assessment is based on conservative assumptions such as tolerance

- level residues in foods and upper

- bound modeled estimates of residues in drinking water.

Aside from the 10X database uncertainty factor f or inhalation toxicity data, t hese conclusions are not expected to change during registration review. The toxicity profile of cyhalofop

- butyl is summarized in Attachment 2

. The toxicological endpoints and doses used in the most recent human health risk a ssessment are summarized in Attachment 3

. Conclusions for Hazard Identification/Toxicology

The toxicity database is nearly complete for the purpose of registration review and is appropriate for assessment of potential carcinogenic, mutagenic, development al, and reproductive effects

. A subchronic inhalation study is recommended ; alternatively

, the registrant may provide particle size distribution data for the granular product so that the Agency can determine the fraction of active ingredient respirable and inhalable

. In the absence of the inhalation study or particle size data, a 10X database uncertainty factor will be applied to inhalation exposure to account for the lack of an acceptable inhalation study

. HED will consider the appropriateness of the existing

### Cyhalofop

- butyl Registration Review Scoping Document

Page 6 of 22 endpoints and doses selected for risk assessment based on current policies and risk assessment methodol ogies ; however, no significant changes are expected during registration review

. Dietary Exposure

The residue chemistry database is adequate to support r egistration r eview. Adequate metabolism (crops and livestock), storage stability, magnitude of the re sidue

, and processing data are available to support the registered uses. Adequate methods are available for enforcement of the currently established tolerances. No residue chemistry data deficiencies were cited in the previous risk assessment.

For the 2 0 12 risk assessment , HED conducted a chronic dietary exposure a ssessment for drinking water, rice, and wild rice ( D 403441
, W. D rew , 7 / 2 5 /20 12 ). The assessment was unrefined and, therefore, conservative . It was based on the assumption that cyhalofop

- butyl residues are present at tolerance levels in rice and wild rice , and that 100% of th e c rop is treated. A rice processing study demonstrated that residues do not concentrate in processed commodities (with the exception of very slight concentration in rice hulls (1.1

- 1.2x)). As a result, processing factors were not used in the dietary exposure assessment. Drinking water was incorporated directly into the dietary assessment using the estimated drinking water concentration (EDWC) for surface water. The EDWC is a modeled surface water residue estimate provided by the Environmental Fate and Effects Division (EFED; D 3 97211
, R. Shamblen, 4/9/2012 ) . It was generated by the Tier 1 Rice Model. The EDWC includes all residues of concern: cyhalofop

butyl, cyhalofop

- acid, and cyhalofop

- diacid

. The Rice Model generates conservative EDWCs. No refinements were incorporated. No new studies have been submitted. As a result, HED anticipates that the most recent drinking water assessment will be adequate for registratio n review. The chronic dietary risk estimates were not of concern for the general U.S. population and all population subgroups. All subgroups use less than or equal to 55 % of the cPAD. During registration review, HED will likely conduct a new dietary exposure and risk assessment if there are significant changes in the drinking water estimates . I f an assessment is needed, HED will us e the most current dietary exposure model and food consumption survey

. Conclusions for Dietary Exposure

The dietary exp osure database is adequate to support the existing registrations. There are no anticipated and significant changes to dietary exposure. Dietary exposure estimates are not of

concern.
Residential Exposure

There are no proposed or registered cyhalofop

- butyl products for use in residential areas at this time. Therefore, a residential exposure assessment is not required.

B ystander exposures resulting from off

- site transport (e.g., spray drift or volatilization) m ight occur as a result of applications o f cyhalofop

- butyl. The potential for spray drift will be quantitatively evaluated for cyhalofop

- butyl during the r egistration r eview process. The approach is outlined in the revised (2012) Standard Operating Procedures for Residential Risk

### Cyhalofop

- butyl Registration Review Scoping Document

Page 7 of 22 Assessment (SOPs)

– Residential Exposure Assessment Standard Operating Procedures Addend um 1: Consideration of Spray Drift. This document outlines the quantification of indirect non

- occupational exposure to drift. In terms of volatilization, the A gency has develop ed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis ( http://www.regulations.gov/#!docketDetail;D=EPA

- HQ

- OPP

- 2014

- 0219 ). During r egistra tion

r eview, the A gency will utilize this analysis to determine if data (i.e., flux studies, route

- specific inhalation toxicological studies) or further analysis is required for cyhalofop

- butyl.

Conclusions for Residential Exposure

During registration re view, HED will consider the potential for exposure through spray drift and volatilization in accordance with any new policies in place.

Aggregate Risk Assessment

The most recent aggregate risk assessment was performed in conjunction with the 20 12 human health risk assessment

. A ggregate risk assessment s traditionally combine exposure estimates resulting from food, drinking water, and residential uses. As n o acute endpoint was identified and cancer risk is not a concern for cyhalofop

- butyl , acute a nd cancer aggregate risk assessments were not performed. There are no residential uses for cyhalofop

- butyl. As a result, the short

term aggregate exposure estimates are equivalent to the chronic dietary (food + water) aggregate estimates. T he chronic d ietary risk estimates were not of concern for the general U.S. population and all population subgroups. All subgroups use less than or equal to 55 % of the cPAD.

Conclusions for Aggregate Exposure and Risk

An a cute endpoint was not identified, cancer risk is not a concern, and there are no residential uses for cyhalofop

- butyl. In the 2012 risk assessment, t he chronic aggregate risk estimates we re not of concern for the general U.S. population or any population subg roup . At the time of registration review, HED will conduct a new aggregate risk assessment that will be based on any potential updates to points of departure or exposure estimates from food and drinking water.

Occupational Exposure

Cyhalofop

- butyl is formulated as an emulsifiable concentrate (EC) , soluble concentrate, granule (G)
, and ready

- to

- use solution

. The E C formulated e nd

- use

- product , Clincher ® 

### CA , (Reg No. 62719

- 356) contains 29.6% cyhalofop

- butyl as the active ingredient (ai) , which is equ ivalent to 2.38 lb ai/gal of product

. It is registered as a post

- emergence herbicide for the selective control of emerged grass weeds in drill

- seeded and water

- seeded rice. It may be applied by either aerial or ground equipment. The personal protective equipment (PPE) statement for EC formulations requires applicators and other handlers to wear coveralls over long

- sleeved shirt and long pants, chemical resistant gloves, and protective eyewear. The granular formulation end

- use product, Clincher ® 

### GR, contains 1.7% by weight of cyhalofop

- butyl as the ai. It is registered as a post

flood

, post

- emergent herbicide for the selective control of emerged grass weeds in drill

- seeded rice and water

- seeded rice . Th is f ormulation may only be applied a erially . The PPE statement requires use of baseline clothing (i.e., long sleeved shirt, long pants, shoes

, and socks).

### Cyhalofop

- butyl Registration Review Scoping Document

Page 8 of 22 Occupational Handler Exposure

The registrant has not submitted chemical

- specific exposure data t o estim ate handler exposures for cyhalofop

- butyl . In the absence of chemical

- specific data, it is HED policy to use the best available data to assess handler exposures. Sources of such generic (surrogate) handler data include Pesticide Handlers Exposure Databas e Version 1.1 (PHED 1.1), and the Agricultural Handler Exposure Task Force (AHETF) D atabase, or other registrant

- submitted occupational exposure studies. Some of these data are proprietary (e.g., AHETF data) and subject to the data protection provisions o f the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA).

The use patterns associated with occupational exposure scenarios for cyhalofop

- butyl on rice remain unchanged since the previous occupational exposure assessment for Clincher ® 

### CA (M. Collantes, D354880, 12/30/2008) and the human health risk assessment for Clincher ® 

### GR (E. Holman, D387444, 11/3/2011). As a dermal point of departure (POD) was not selected, a quantitative dermal handler exposure assessment has not been performed. Howeve r, ther e is potential for occupational handlers to be exposed to the pesticide via the inhalation route prior to and during application of the pesticide

. Previously, the level of concern ( LOC ) for handlers was 100 , based on the combined 10X factors for in terspecies and intraspecies differences

. Occupational exposure scenarios resulting in margins of exposure ( MOEs ) below 100 were of

concern. In the most recent risk assessments, o ccupational exposure for both formulations resulted in no risk estimates of concern.
In conjunction with determining data needs during registration review, c yhalofop

- butyl was reviewed by the HED HASPOC to evaluate the need for a route

- specific inhalation study, a s previous assessments were conducted using data from an oral stu dy. The HASPOC recommended that an inhalation study be required based on weight

- of

- evidence considerations; alternatively

, the registrant may provide particle size distributions for the granular product such that the Agency can evaluate the respirable and inhalable fraction . I n the absence of the inhalation study or the particle size distribution, HED will retain a database uncertainty factor of 10X for inhalation exposure. With this additional factor

, t he revised inhalation LOC is 1000. Scenarios resulting in MOEs below 1000 are of concern

.

HED has re

- evaluated handlers’ inhalation exposure estimates for two registered end

- use products using current assumptions for inhalation handler unit exposure values , body weight assumptions, and the additio nal 10 X database uncertainty factor for inhalation exposure

. T wo handler scenarios resulted in risk estimates of concern (target MOE 1000) . The handler loading and applying a granular formulation by aerial application resulted in the high est inhalation

e xposure estimate (lowest MOE), equal to an MOE of 470 assuming the use of baseline clothing (i.e. long sleeved shirt, long pants, socks and shoes). When additional PPE consisting of a protection factor (PF) 5 respirator was used

, the MOE increased to 2300 and was no longer of

concern. The second handler scenario of concern is aerial applicators applying granules , which resulted in a n MOE of 610 at the engineering controls level of mitigation. The current registered label for the granular formulation does not require use of a PF5 respirator or engineering controls. Both scenarios assume 1200 acres are treated. During registration review, HED will reevaluate these scenarios using the results of the recommended route

- specific inhalation study

### Cyhalofop

- butyl Registration Review Scoping Document

Page 9 of 22 (or will take into account any new information regarding the respirable and inhalable particle size distribution)

. Occupational Post

- application Exposure

In the absence of toxicity via the dermal route, no quantitative dermal post

- application risk assessment is requi red for the agricultural uses of cyhalofop

- butyl. Although HED would typically require dislodgeable foliar residue (DFR) data in accordance with the 40 CFR DF R data requirement based on the existing use pattern, a DFR study is not required because of the lack of toxicity via the dermal route. Furthermore, as there are no proposed or registered turf uses associated with cyhalofop

- butyl, a turf transferable residue (TTR) study is not required at this time. The restricted entry interval (REI) on both regist er e d labels currently stipulate a 12

- hour REI, which is considered appropriate based on the toxicity of the technical ingredient.

There are multiple potential sources of post

- application inhalation exposure to individuals performing post

- application activities in previously treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides. The A gency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received t he SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ). The A gency has evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis ( http://www.regulations.gov/#!docketDetail;D=EPA

- HQ

OPP

- 2014

- 0219 ). During r egistration r eview, the A gency will utilize this analysis to determine if data (i.e., flux studi es, route

- specific inhalation toxicological studies) or further analysis is required for cyhalofop

- butyl

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

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

- application inhalation exposure into the A gency ’ s risk assessments.

Although a quantitative occupational post

- ap plication inhalation exposure assessment was not previously performed, an inhalation exposure assessment recently was performed for occupational handlers , based on the additional database uncertainty factor for inhalation risks

. Handler exposure resulting from application of pesticides outdoors is likely to result in higher exposure than post

- application exposure. Therefore, it is expected that these handler inhalation exposure estimates would be protective of most occupational post

- application inhalation exposure scenarios.

Conclusion for Occupational Exposure

Updated occupational handler inhalation exposure assessments will be needed during registration review to incorporate the results of the recommended subchronic inhalation study , or to incorporate information regarding the particle size distribution and amount of active ingredient respirable and inhalable

. HED has completed screening estimates of the risk associated with

### Cyhalofop

- butyl Registration Review Scoping Document

Page 10 of 2 2 representative crop scenarios, based on the new 10X database uncertainty factor , and representative application rates and equipment . These estimates identified potential risks of concern for handlers using the granular formulation of cyhalofop

- butyl . The exposure and risk estimates should be captured in the preliminary risk assessm ent to support registration review, and should include the most recent recommendations with respect to unit exposures , PPE, and risk assessment methodology. As necessary, an inhalation post

- application risk assessment could be conducted in accordance with the development of relevant HED policies for risk
assessment.

Public Health and Pesticide Epidemiology Data

For this evaluation, the Agency consulted both the OPP Incident Data System (IDS) and the Centers for Disease Control and Prevention/National In stitute for Occupational Safety and Health (CDC/NIOSH) Sentinel Event Notification System for Occupational Risk

- Pesticides (SENSOR) databases for pesticide incident data on the active ingredient cyhalofop

- butyl ( D41 8 5 78 , S. Recore, 6/15 /201 4 ). The purpose of the database search wa s to identify potential patterns in the frequency and severity of the health effects attributed to cyhalofop

- butyl exposure. Cyhalofop

- butyl is not included in the Agricultural Health Study ( AHS ) ; therefore

, th at study does not p rovide information for this documen t.

For the M ain IDS, from January 1, 200 9 to March 5 , 201 4
, three incidents were reported in the database for the single chemical alone

. Four additional incidents were reported involving more than one chemical. The se incidents were classified as m oderate severity. In the A ggregate IDS
, from January 1, 200 9 to March 5 , 201 4
, two incidents involving cyhalofop

- butyl were reported

. These incidents were classified as minor severity. Overall, few incidents involving cyha lofop

butyl were reported to IDS.

The SENSOR

- Pesticides database covers 11 states from 1998

- 2009, although reporting varies from state to state. Cases of pesticide

- related illnesses are ascertained from a variety of sources including reports from lo cal Poison Control Centers, state Department of Labor workers’ compensation claims when reported by physicians, reports from State Departments of Agriculture, and physician reports to state Departments of Health. A query of SENSOR

Pesticides from 1998 to 20 10 revealed that n o cases involving cyhalofop

- butyl were reported

. Based on the low frequency and severity of incident cases reported in both IDS and SENSOR

Pesticides

, there does not appear to be a concern at this time that would warrant further investigation

. The Agency will continue to monitor the incident information and

, if a concern is triggered, additional analysis will be included in the risk assessment.

Tolerance Assessment and International Harmonization

T olerance s for residues of cyha lofop

- butyl in or on agricultural commodities are established in 40CFR §180. 576

. For plant commodities, the tolerances are established as follows : “ Tolerances are established for residues of cyhalofop

- butyl, including its metabolites and degradates, in o r on the commodities listed in the table below. Compliance with the tolerance levels specified below is to be determined by measuring cyhalofop butyl [R

- (+)

- n

- butyl

- 2

- (4(4

- cyano

- 2

-

### Cyhalofop

- butyl Registration Review Scoping Document

Page 11 of 22 fluorophenoxy)

- phenoxy)propionate], cyhalofop acid [R

- (+)

- 2

- (4(4

- cyano

- 2

- fl uorophenoxy)

- phenoxy)propionic acid], and the di

- acid metabolite [(2R)

- 4

- (4

- (1

- carboxyethoxy)phenoxy)

- 3

- fluorobenzoic acid]. ”

The re are no Codex Alimentarius Commission (Codex) or Canadian maximum residue limits ( MRLs ) for cyhalofop

- butyl. As a result, there are no harmonization issues at the present time

. The international residue limit status sheet can be found in Attachment 4

. International or Intergovernmental Work Sharing

The Food and Agriculture Organization of the United Nations (FAO/JMPR) has not evaluated cyhalofop

- butyl. In Canada, the chemical is not registered for use on any commodities. The California Department of Pesticide Regulation has not prioritized cyhalofop

- butyl for risk assessment yet, nor has it been subject to reevaluation in California.

In the U.S., tolerances are only established for residues in or o n rice and wild rice. In the event that the registrant proposes tolerances and MRLs on other commodities in the future, the global partners could evaluate the petition as a wo rk share or joint review. The partners could jointly evaluate toxicity data, metabolism data, residue data, and analytical methods.

Cumulative Risk Assessments

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

com mon mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as
to cyhalofop

- butyl and any other substances

, and cyhalofop

- butyl does not appear to produce a toxic metabolite produced by other substances. For the purposes of this act ion, therefore, EPA has not assumed that cyhalofop

- butyl has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s Office of Pesticide Programs concerning common

m echanism 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/

.

Data Re quirements

[ 870.3465 ] Subchronic Inhalation Toxicity Study

N ote : although the guideline is for a 90

- day study, a 28

- day study is considered to be adequate to satisfy the data requirement

HED’s HASPOC recommended

, based on weight

- of

- evidence considerations

, that a sub chronic inhalation toxicity study be required; however, if the registrant c an provide particle size distribution data for the granular product such that HED can determine what fraction of the product is both respirable and inhalable, the Agency could reconsider the need for the inhalation study.

### Cyhalofop

- butyl Registration Review Scoping Document

Page 12 of 22 R eferences

Memoranda Relevant to Registration Review Author DP

Number Date Title

E. Holman D 3 87444 1 1 / 3 /20 11 Cyhalofop

- butyl. Human Health Risk Assessment for Proposed Amended Tolerances on Rice and Wild Rice W. Drew D396698 7/25/2012 Cyhalofop

- butyl. Human Health Risk Assessment for Label Amendments Increasing the Single Application Rate for Use of the Herbicide on Rice J. Leshin TXR No.

0056956 5 / 21 /201 4 Cyhalofop

- butyl: Summary of Hazard and Science Policy Council (HASPOC) Meeting of April 24, 2014: Recommendation on the Requirement for a Subchronic Inhalation Study M. Nelson D 267558 1 1 / 13 /200 1 PP#0F06089. New Chemical: Cyhalofop

- Butyl in/on Rice. Review of Residue Chemistry W. Drew D 403441 7 / 2 5 /20 12 Cyhalofop

- Butyl. Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessment for Label Amendments Increasing the Single Application Rate for Use of the Herbicide on Rice M. Collantes D 3 54880 12 / 30 / 200 8 

### Cyhalofop

- butyl: Occupational Exposure and Risk Assessment for Proposed Use on Wild Rice and Proposed Amended Labeling for Clincher SF Herbicide R. Shamblen D 3 97211 4 /9 /20 12 Cyhalofop

- butyl: Drinking Water Exposure Assessment for Proposed Section 3 Label Amendments for Clincher ® GR and Clincher ® Granule Uses on Rice Grown in California S. Recore D 418578 6 / 25 /201 4 Cyhalofop

- butyl: Tier I Review of Human Incidents



### Attachment s

Attachment 1

. Chemical Identity and Physical and Chemical Properties Attachment 2. Toxicology Profile Tables Attachment 3

. Endpoint Selection Table Attachment 4

. Intern a tional Residue Limit Status

### Cyhalofop

- butyl Registration Review Scoping Document

Page 13 of 22 Attachment 1

. Chemical Identity and Physical and Chemical Properties

Table A.1 .1. Cyhalofop

- b utyl Nomenclature Compound

Common name Cyhalofop

- butyl Molecular formula C 20 H 20 FNO 4 Molecular weight 357.38 IUPAC name n

- Butyl ( R )

- 2

- [4

- (4

- cyano

- 2

- fluorophenoxy)phenoxy]propionate CAS name n

- Butyl (2 R )

- 2

- [4

- (4

- cyano

- 2

- fluorophenoxy)phenoxy]propanoate CAS registry number 122008

- 85

- 9

T able A.1.2. Physic a l and Chemical Properties of Cyhalofop

- butyl

Parameter Value References Melting point/range 45.5

- 49.5oC Memo, D277695 D. Davis, 4/10/2002 pH 9.0 Relative Density (20oC) 1.172 g/cm 3 Water solubility (20oC) 0.44 mg/L at pH 7 Solvent solubility (g/L) n

- heptane : 6.06

n

- octanol : 16.0 methanol : >250
acetone : >250 ethyl acetate : >250 acetonitrile : >250 Vapor pressure (25oC) 5.3 x 10

- 8 kPa (4.0 x 10

- 7 mmHg) Octanol/water partition coefficient, Log(K OW ) (25oC) 3.32

### Cyhalofop

- butyl Registration Review Scoping Document

Page 14 of 22 Attachment 2 . Toxicity Profiles

Table A

. 2 .1 Acute Toxicity Profile

– Cyhalofop

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

870.1100 Acute Oral

- Rat 45000237 LD50 >5000 mg/kg (limit test) Toxicity Category IV
870.1100 Acute Oral

- Mice 45000238 LD50 >5000 mg/kg (limit test) Toxicity Category IV 870.1200 Acute Dermal

-

Rat 45000240 LD50 >2000 mg/kg (limit test) Toxicity Category III

870.1200 Acute Dermal

-

Rat 45381901

45000241 LD50 >5000 mg/kg

(2.5 x the limit dose) Toxicity Category IV

870.1300 Acute Inhalation

-

Rat 45000401 LC50 >5.63 mg/L (2.8 x the limit concentration) Toxicity Category IV

870.2400 Primary Eye

Irritation

- Rabbit 45000403 Minimally irritating Toxicity Category IV

870.2500 Primary Skin

Irritation

- Rabbit 45000405 Essentially nonirritating Toxicity Category IV

870.2600 Dermal

Sensitization

- Guinea Pig 45000407 Not a dermal sensitizer N/A

Table A .2 .2 Subchronic, Chronic and Other Toxicity Profile Guide

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

870.3100 Subchronic (4

and 13 Week) Feeding

- Rat 45000413 (1991) Acceptable/Guideline Main

- 0, 3 (males), 10 (females), 25 (males), Satellite

- 0, 25, 400 (males), 800 (females), or 1600 mg/kg/day in the feed for 4 weeks. NOAEL (male)  400 mg/kg/day (HDT) NOAEL (female) 400 mg/kg/day LOAEL (female) = 800 mg/kg/day (HDT) based on perineal soiling and reduced body weights an d body weight gain.

The only short

- term effect was perineal staining. Onset was late except in 60% of the 800 mg/kg/day females which had involvement as early as day 16. The only functional observation battery (FOB) finding was perineal soiling at the high

- dose in 1/10 males and 6/10 females. In addition to the 13 week study, which included a FOB, a 4 week satellite was used to determine organ weight and microscopic changes in potential target tissues

. 870.3100 Subchronic

Feeding

- Rat 45014705 (1993 ) Acceptable/Guideline Levels tested: 0, 30, 300, 1000, or 3000 ppm in the feed (0, 1.719, 17.43, 60.5, or 189.5 mg/ kg/day in males; 0, 1.958, 19.64, 65.3, or 199.6 mg/kg/day in females) in Fischer strain. NOAEL = 60.5 / 65.3 mg/kg/day, M/F LOAEL = 189.5 / 199.6 mg/kg/day, M/F (HDT) based on kidney toxicity (lipofuscin pigment deposition in proximal tubule cells) in both sexes, and possible liver toxicity (hepatocyte eosinophilic granules) in males.

870.3100 Subchronic

Feeding

- Mice 45000412 (1991) NOAEL (male)  30 mg/kg/day (HDT)

NOAEL (female)  100 mg/k g/day (HDT)

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Page 15 of 22 Table A .2 .2 Subchronic, Chronic and Other Toxicity Profile Guide

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

Acceptable/Guideline Levels tested (main): 0, 1 (males), 3, 10, 30, or 100 (females) mg/kg/day in the feed. Levels tested (pilot): 0, 10 (males), 30, 100, or 350 (females) mg/kg/day in the feed. 870.3100 Subchronic

Feeding

- Mice 45014706 (1993) Acceptable/Guideline Levels tested: 0, 3, 30, 100, or 300 ppm in the diet (0, 0.4, 3.6, 12.4, or 37.5 mg/kg/day in males; 0, 0.4, 4.3, 14.1, or 41.4 mg/kg/day in females) NOAEL (male)  37.5 mg/kg/day (HDT) NOAEL (female) = 4.3 mg/kg/day LOAEL (female) = 14.1 mg/kg/day based on enlarged kidneys (20% absolute and relative) accompanied by swelling of the proximal tubule cells (4/12 mice). Kidney weights and pathology were normal in males. Compared to controls, absolute and (relative) kidney weight increases in females were 1, 14, 20, and 23% (

- 1, 12, 20, and 18%); and proximal tubular cell swelling incidences were 0/12, 0/12, 0/12, 4/12, and 6/12 at doses of 0, 3, 30, 100, and 300 ppm, resp ectively. 870.3150 Subchronic

Feeding

- Dog 45014707 (main) 45000410 (pilot, palatab ility ) 1994 Acceptable/Guideline Levels tested: 0, 100, 500, or 2500 ppm (0, 2.91, 14.7, or 75.2 mg/kg/day in males; 0, 3.17, 15.6, or 79.4 mg/kg/day in females) NOAEL = 14.7 / 15.6 mg/kg/day, M/F LOAEL = 75.2 / 79.4 mg/kg/day, M/F (HDT) based on brown and/or atrophied thymuses , and decreased thymus weight.

MRID 45000410 was a combination 4

- week pilot toxicity and a 2 week palatability study. Doses in the palatability s tudy were 250, 500, or 1000 mg/kg/day. At 1000 mg/kg/day, food consumption was dramatically reduced, suggesting decreased palatability of the treated diet.

870.3200 21

- Day Dermal

- Rat 45000415 (1999) Acceptable/Guideline Levels tested: 0, 10, 100, 1000 mg/kg/day in aqueous 0.5% methylcellulose, 6 hours/day, 5 days/week for 4 weeks. A recovery group was held for a 2 week period. Systemic NOAEL  1000 mg/kg/day (limit dose) Dermal NOAEL  1000 mg/kg/day (limit dose) Increased liver weights and clinica l chemistry changes suggestive of liver adaptation were observed during the dosing interval. The reversibility of the clinical chemistry and liver weight effects in the recovery group demonstrates these changes are biological markers of exposure, not toxi city.

870.3700 Gavage

Developmental Toxicity

- Rat 45014709 (1992) Acceptable/Guideline Levels tested: 0, 25, 250, or 1000 mg/kg/day by gavage on gestation days 6

- 15 Maternal NOAEL =1000 mg/kg/day (limit dose) Developmental NOAEL  1000 mg/kg/day (limit dose)

870.3700 Gavage

Developmental Toxicity

- Rabbit 45014710 (1994) Acceptable/Guideline Levels tested: 0, 40, 200, or 1000 mg/kg/day by gavage on gestation days 6

- 18 Maternal NOAEL = 40 mg/kg/day Maternal LOAEL = 200 mg/kg/day based on maternal death (1/18 dams at 200 and 9/18 at 1000 mg/kg/day exhibited hematuria and died or were sacrificed in extremis with gross pathology showing cloudy or dark colored kidneys) Developmental NOAEL  1000 mg/kg/day (limit dose)

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Page 16 of 22 Table A .2 .2 Subchronic, Chronic and Other Toxicity Profile Guide

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

870.3800 Feeding

Reproductive Toxicity

- Rat 45000419 (1994) Acceptable/Guideline Levels tested: Dietary levels of 0, 10, 100, or 1000 ppm (F0 males

- 0, 0.495

- 1.049, 4.88

- 10.68, or 50.0

- 102.9 mg/kg/day; F1 males

- 0, 0.499

- 1.361, 4.85

- 13.75, or 51.1

- 138.7 mg/kg/day ; F0 females

- 0, 0.695

- 1.113, 6.75

- 11.13, or 69.2

- 113.1 mg/kg/day; F1 females

- 0, 0.750

- 1.430, 7.42

- 13.96, or 74.8

- 147.7 mg/kg/day) in Crj:CD (SD) strain. Systemic NOAEL (males) = 100 ppm (4.85

- 13.75 mg/kg/day) System ic LOAEL (males) = 1000 ppm (50.0

- 138.7 mg/kg/day) based on kidney lesions (slight tubular cell swelling) in F0 and F1 male rats. Systemic NOAEL (females)  1000 ppm (69.2

- 147.7 mg/kg/day, HDT) Reproductive NOAEL  1000 ppm (50.1

- 138.7 mg/kg/day for males; 69.2

- 147.7 mg/kg/day for females) Offspring NOAEL  1000 ppm (50

- 147.7 mg/kg/day) No short

- term effects were observed which could be used for a short

- term endpoint. Acceptable/Guideline

870.4100 Chronic

Feeding Toxicity

- Dog 45014708 (1994) Acceptable/Guideline Levels tested: 0, 50, 300, or 1800 ppm in the feed (males

- 0, 1.22, 7.59, and 46.7 mg/kg/day; females

- 0, 1.29, 7.63, and 45.9 mg/kg/day. NOAEL  46.7 / 45.9 mg/kg/day; M/F (HDT) No short

- term effects were observed which could be use d for a short

- term endpoint.

870.4200 Carcinogenicity

Feeding

– Mouse (18 months) 45000418 (1994) Unacceptable/Guideline Levels tested: 0, 3, 10, or 100 ppm (0, 0.31, 1.0, and 10.06 mg/kg/day in males; 0, 0.29, 1.0, or 10.28 mg/kg/day in females) in CD

- 1 strain. Satellite groups were sacrificed at 26 and 52 weeks NOAEL = 1.0 mg/kg/day LOAEL = 10.06 / 10.28 mg/kg/day, M/F (HDT) based on effects on the kidney including tubular dilatation, chronic glomerulonephritis, and hyaline casts in females, and h yperplasia of the stomach mucosal epithelium in males. There was no evidence of carcinogenic potential under the conditions of this study. Dosing was too low to elicit frank toxicity and inadequate to assess carcinogenic potential. The high dose of app roximately 10 mg/kg/day was based on the endpoint of liver hypertrophy which is an adaptive
response. No short

- term effects were observed which could be used for a short

- term endpoint. 870.4300 Chronic

Feeding Toxicity/ Carcinogenicity

- Rat 45000417 (1994) Acceptable/Guideline (chronic toxicity) Unacceptable/Guideline (carcinogenicity Levels tested: 0, 3, 6, 24, or 100 ppm (0, 0.1020, 0.2047, 0.823, or 3.44 mg/kg/day) in males; 0, 6, 60, or 600 ppm (0, 0.2451, 2.475, or 24.97 mg/kg/day) in females fo r 104 weeks in Fischer strain. Satellite groups were sacrificed at 13, 26, 52, and 78 weeks. NOAEL = 0.823 mg/kg/day in males and 2.475 mg/kg/day in females LOAEL = 3.44 mg/kg/day (HDT in males), 24.97 mg/kg/day (HDT in females) based on the early and inc reased deposition of the pigments lipofuscin and hemosiderin in the renal proximal tubular cells of both sexes, and renal mineralization in female rats. There were no treatment

- related increases in tumor incidence, compared to controls. Dosing was too low to elicit frank toxicity and inadequate to assess carcinogenic potential. No short

- term effects were observed which could be used for a short

- term endpoint.

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Page 17 of 22 Table A .2 .2 Subchronic, Chronic and Other Toxicity Profile Guide

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

870.5100 Bacterial

Reverse Gene Mutation Test (Ames Assay) 45000421 (1991) Acceptable/Guideline Negative in Salmonella TA strains and E. coli WP2 uvrA.

870.5300 Gene Mutation

in Mouse Lymphoma L5178Y TK Cells 45014711 (1996) Acceptable/Guideline Negative

870.5375 In Vitro

Chromosomal Aberration in Chinese Hamster Lung 45000423 (1991) Acceptable/Guideline Polyploidy was induced when CHL (V79) cells were treated for 48 hours in the absence of S9, but there was no clastogenic effect on DNA.

870.5395 In Vivo

Mammalian Cytogenetics

- Micronucleus Assay in Mouse Bone Marrow Cells 45000422 (1991) Acceptable/Guideline Negative

870.5550 Unscheduled

DNA Synthesis in Rat Hepatocytes 45000420 (1991) Acceptable/Guideline Negative

870.6200 Gavage Acute

Neurotoxicity

- Rats 45000409 (1998) Acceptable/Guideline Doses: 0, 200, 600 or 2000 by gavage NOAEL  2000 mg/kg (limit dose) based on the absence of clinical signs, a lack of effects on FOB parameters and motor activity, and the absence of neuropathologic lesions.

870.6200 Feeding

Subchronic Neurotoxicity

- Rats 45000509 (1999) Acceptable/Guideline Levels tested: 0, 2, 20, or 75 (males) / 250 (females) mg/kg/day for 13 weeks. NOAEL  75/  250 mg/kg/day M/F (HDT) based on the absence of clinical signs, lack of effects on FOB parameters and motor activity, and absence of neuropath ologic lesions. NOTE: The doses tested were based on mild systemic effects (perineal soiling, reduced body weights, and lipofuscin pigment deposition in proximal tubule cells) at similar doses in two subchronic feeding studies in rats, and were too low to elicit toxicity in this study.

870.xxxx [special study] Pharmacology

-

Mice and Rabbits

- Special Study 45000424 (1992) Acceptable/Non

- Guideline Levels tested in mice: 0, 4.88, 19.5, 78.1, 313, 1250, or 5000 mg/kg as a single I.P. dose.

Levels tested in rabbits: 0, 313, 1250, 2500 or 5000 mg/kg as single gavage dose Mice: A single I.P. dose of 1250 or 5000 mg/kg was lethal to all male and female mice within 24 hours. Death occurred as early as three hours at 5000 mg/kg and was preceded by behaviora l and motor function abnormalities (e.g., alterations in alertness, visual placing, spontaneous activity, motor incoordination, decreased muscle tone, and compromised autonomic reflexes), some of which appeared as early as 30 minutes post dosing . Male and female mice responded similarly. NOAEL = 78.1 mg/kg LOAEL = 313 mg/kg (based on minimal effects including decreased spontaneous activity, minor alterations in muscle

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Page 18 of 22 Table A .2 .2 Subchronic, Chronic and Other Toxicity Profile Guide

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

tone, and minor changes in autonomic functions such as slight hyperthermia, and slightl y decreased respiratory rate). LD  1250 mg/kg Rabbits: One of three rabbits gavaged at 5000 mg/kg showed decreased spontaneous activity, prostration, decreased muscle tone, compromised autonomic reflexes, and decreased respiratory and heart rate at one day after dosing, and died on Day 4. There were no clinically significant findings in the remaining rabbits of the 5000 mg/kg dose group or any lower dose groups, and no significant effects on EKGs or blood pressure in any dosed rabbits. NOAEL = 2500 mg/kg L OAEL = 5000 mg/kg (based on the response of one of three test subjects including decreased spontaneous activity, prostration, decreased muscle tone, compromised autonomic reflexes, decreased respiratory and heart rate at one day after dosing, and death on day 4). 870.7485 Absorption,

Metabolism, and Excretion

- Dog 45000425

(1995 Acceptable/Non

Guideline (Two dogs were used instead of four; and tissue distribution was not measured.) Level tested: Two male beagles were gavaged with [ 

- 14C]XRD

- 537 BE and nonlabeled XRD

- 537 at a dose of 1 mg/kg. No treatment

- related adverse effects were reported. Approximately 50% of a single gavage dose was absorbed over several hours. Blood and plasma radioactivity peaked after 1

- 2 hours. Clearance from plasma and bl ood was not especially rapid but nearly complete at 48 hours. Over 168 hours, excretion was 42.5

- 43.9% in the urine, and 48.6

- 50.6% in the feces. Tissue distribution was not measured. The test article appears to be metabolized primarily by hydrolysis to R

- (+)

- 2

- [4

- cyano

- 2

- fluorophenoxy)phenoxy]propanoic acid which was found in both the urine and feces. Several other metabolites were also formed, each representing <5% of the administered dose. No parent compound was found in the urine, and only minimal amounts were detected in the feces. 870.7485 Metabolism

and Pharmaco

kinetics Rat 45000427 (main) 45000426 (prelim.) 45000528 (stability, homog.) (1995) Acceptable/Guideline Absorption of gavaged test article was 93

- 100%, and urinary excretion was the m ajor route of elimination regardless of dose, label position, or gender. Over 168

- hours, 84

- 100% of the radioactivity was eliminated in urine, with 86

- 90% eliminated within 24 hours. Fecal excretion was <5%. There was no elimination via expired air. Over a 24

- hour period, biliary elimination accounted for 1.7 % and 20.1% of the administered dose in males and females, respectively, in the low

- dose [α

- 14C]XRD

- 537 BE group, and 17.0% (males) and 11.6% (females) of the administered dose in the [β

- 14C]XRD

- 537 BE low

- dose group. The greatest radioactivity levels were found in liver, kidneys, plasma, whole blood, heart, lung, and stomach, with the highest tissue levels being found in the liver and kidney at 2 hours. Most tissue levels accounted for <1% of th e administered dose. Due to rapid excretion, tissue/organ levels declined to near detection limits by 24 hours in all dose groups. There was a biphasic pattern for both labels with no substantial differences in pharmacokinetic indices (Cmax, tcmax, t1/2, AUC). Time

- to

- maximum plasma concentration (tcmax of 0.5 to 4 hrs) and elimination half

- times (t1/2 of 1.4 to 7.9 hrs)

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Page 19 of 22 Table A .2 .2 Subchronic, Chronic and Other Toxicity Profile Guide

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

reflected the relatively rapid absorption. Females had somewhat shorter tcmax and lower Cmax values suggestive of saturated absorption processes. The acid metabolite (R

- (+)

- 2

- [4

- (4

- cyano

- 2

- fluoro phenoxy)phenoxy]propanoic acid) was the most prominent plasma fraction (~90

- 94% of the plasma activity for males and ~75

- 81% for females regardless of dose). No parent compound or other metab olites were detected. The acid metabolite was the most common product in urine and feces

– 71

- 87% (urine) and 46

- 75% (feces) of the activity in those matrices. Levels tested (main study): single low dose (1 mg/kg), single high dose (50 mg/kg), and a 14

- d ay repeated low dose (1 mg/kg/day) using non

- labeled XRD

- 537 BE, and [α

- 14C] XRD

- 537 BE or [β

- 14C] XRD

- 537 BE by gavage. 870.7600 Dermal

Penetration

- Rat 45000505 (1998) Acceptable/Non

- Guideline (Only one exposure duration (24 hours) was used instead of six.

Levels tested: Four Fischer 344 rats were dermally dosed for 24 hours with 14C

- labeled DE

- 537

n

- butyl ester and nonlabeled DE

- 537 n

- butyl ester in two formulations

– 200 mg/mL test article in EF1218 (Clincher EDC with which DE

- 537 n

butyl ester is normally formulated) and a spray solution

– at 0.005, 1.0, or 1.8 mg/cm 2

. Dermal absorption was ~25

- 34% for the spray formulation and ~11

- 16% for the EF

- 1218 formulation following a 24 hour dermal dosing. Within 48 hours, excretion was >85% in the urine and <1% in the feces, which is consistent with metabolism to water soluble metabolites and subsequent urinary excretion.

870.7800 Immunotoxicity

Rat 48180501 (2010) Acceptable/Guideline

Levels tested: 0, 4, 12, or 41 mg/kg/day for 28 days in male rats in the diet. Systemic NOAEL = 4 mg/kg/day Systemic LOAEL = 12 mg/kg/day based on increased relative and absolute liver weights which were consistent with previous reported results.

Immunotoxicity NOAEL = 41 mg/kg/day (highest dose tested). Immunotoxicity LO AEL = not established 870.xxxx [special study] Hepatocellular

Proliferation Rat 45000414 (1991) Acceptable/Non

- Guideline In a subchronic oral toxicity study in rats (MRID 45000413), satellite rats dosed for 4 weeks had hepatocellular hypertrophy and focal necrosis at all dose levels. Although multiple necrotic foci accompanied by inflammatory cells were graded very slight, and were not considered dose

- related, this study was performed to explore these findings. An initial dramatic increase in DNA synthesis during the first week of treatment was followed by hepatocellular hypertrophy at subsequent observations. This was the reason for enlarged livers observed in XRD

- 537nBu

- treated rats.

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Page 20 of 22 Table A .2 .2 Subchronic, Chronic and Other Toxicity Profile Guide

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

Levels tested: 0, 3.0, 25, 100, or 400 mg/kg/day in the diet with sacrifices at 1, 2, 4, and 13 weeks. One week prior to sacrifice, 10 μL BrdU/hour was administered via an ALZET osmotic pump implanted subcutaneously. BrdU is a DNA stain used to quantify hepatocellular proliferation.

870.xxxx [special study] 28

- Da y

Mechanistic Study for Evaluation of Peroxisome Proliferation (Mouse) 46471101 (2004) Acceptable/Non

- Guideline

Doses: 0, 0.5, 5, 50 &150 mg/kg/day Increased liver weight and hepatocellular hypertrophy at ≥5 mg/kg/day (M&F); n ecrosis at ≥50 (M) & 150 (F) mg/kg/day.

Increased peroxisomal acyl

- CoA oxidase activity ≥5 mg/kg/day (M) and ≥50 mg/kg/day (F). Increases are reversible. Peroxisome volume density in hepatocytes increased ≥0.5 mg/kg/day (M) and ≥5 mg/kg/day (F). Increases are reversible. 870.xxxx [special study] Evaluation of

Activity in a Peroxisome Proliferator Receptor

- Alpha Reporter Assay (Mouse) 46471102 (2004) Acceptable/Non

- Guideline

Doses: 10

- 7 , 10

- 6 , 10

- 5 , 2x10

- 5

, 5x10

- 5 , 10

- 4 , 2x10

- 4 & 5x10

- 4 M; also: positive control activator (WY14643) ; PPAR

- γ specific activator (Ciglitazone); non

activator (TPA) Cyhalofop

- butyl binds to the PPAR

- ά receptor and activates a downstream reporter gene. Considered a weak PPAR

- ά agonist.

870.xxxx [special study] Discussion of

Mechanistic data in the

mouse. 46471103 (2005) Acceptable/Non

- Guideline Discussion of mechanistic data in the mouse in support of a waiver for repeating chronic studies.

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Page 21 of 22 Attachment 3. Summary of Toxicological Doses and Endpoints for Use in Human Risk

Assessments

Table A3.1 Toxicological Doses and Endpoints for Cyhalofop

- butyl for Use in Dietary Human

Health Risk Assessments Exposure/ Scenario Point of

Departure Uncertainty/

FQPA Safety Factors RfD, PAD, Level

of Concern for Risk Assessment Study and Toxicological Effects

Acute Dietary (General Population, including Infants and Children) N/A N/A N/A No appropriate endpoint identified

Acute Dietary (Females 13

- 49 years of age) N/A N/A N/A No appropriate endpoint identified

Chronic Dietary (All Populations) NOAEL =

1.0 mg/kg/day UF A = 10X

UF H = 10X FQPA SF = 1X Chronic RfD =

0.01 mg/kg/day

cPAD = 0.01 mg/kg/day Carcinogenicity

– mice

LOAEL = 10.0 mg/kg/day, based on effects on the kidney including tubular dilatation, chronic glomerulo

- nephritis and hyaline casts in females as well as hyperplasia of the stomach mucosal epithelium in males. Cancer B ased on the mechanistic studies submitted by the registrant and reviewed by HED, HED

has classified cyhalofop

- butyl as “Not Likely to be Carcinogenic to Humans.” NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapola tion from animal to human (inter species). UF H = potential variation in sensitivity among member s of the human population (intra species). FQPA SF = F ood Q uality P rotection A ct Safety Factor. PAD = population adjusted dose (a = acute, c = ch ronic). RfD = reference dose. N/A = not applicable.

Tab le A3.2 Summary of Toxicological Doses and Endpoints for Cyhalofop

- butyl 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 (1

- 30 days) and Intermediate

term (1

- 6 months) N/A N/A N/A 21

- Day Dermal

- rats No systemic or dermal effects at the L imit dose (1000 mg/kg/day)
Inhalation Short

- (1

- 30 days) and Intermediate

- term (1

- 6 months) NOAEL =

4.3 mg/kg/day [Inhalation toxicity assumed to be equivalent to oral toxicity] UF A = 10X

UF H = 10X UF DB = 10X Occupational

LOC for MOE = 100 0 90

- Day Oral

- mice

LOAEL = 14.1 mg/kg/day (M/F), based on enlarged kidneys in females with swelling of proximal tubular cells in 4/12 mice.

Cancer Base d on the mechanistic studies submitted by the registrant and reviewed by HED, HED

has classified cyhalofop

- butyl as “Not Likely to be Carcinogenic to Humans.” 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 population (in traspecies). . UF DB = database uncertainty factor. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

### Cyhalofop

- butyl Registration Review Scoping Document

Page 22 of 22 Attachment 4

. International Residue Limit Status



### Cyhalofop

- b utyl ( 082583 ; 4

- 28

- 2014 )

Table A.4. Summary of US and International Tolerances and Maximum Residue Limits. Residue Definition : US Canada Mexico 1 Codex
40 CFR 180. 576

Plants: cyhalofop butyl [R

- (+)

- n

- butyl

- 2

- (4(4

- cyano

- 2

- fluorophenoxy)

- phenoxy)propionate], cyhalofop acid [R

- (+)

- 2

- (4(4

- cyano

- 2

- fluorophenoxy)

- phenoxy)propionic acid] a nd the di

- acid metabolite [(2R)

- 4

- (4

- (1

- carboxyethoxy)phenoxy)

- 3

- fluorobenzoic acid]. None None

Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg) US Canada Mexico 1 Codex Rice, grain 0. 4 0 Wild rice, grain 2 0. 4 0

Completed: : M. Negussie ; 05/01/14

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

2 Although a tolerance of 0.40 ppm has been established for residues in or on wild rice, there are no U.S. registrations for wild rice.