UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

DATE: 9/5/2014 

OFFICE OF CHEMICAL SAFETY 

AND POLLUTION PREVENTION 

SUBJECT: Cyhalofop-butyl. Human Health 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: Registration Review 

Case No.: 7255 

CAS No.: 122008-85-9 

40 CFR: §180.576 

FROM: Douglas Dotson, Ph.D., Chemist $ ~;;J;;ih,; Margarita 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 

Risk Assessmen

Swartz, 

t Branch 

Branch 

II 

Chief ~ ~ 

Jess Rowland, Associate Director 

Dana Vogel, Acting Director 

Health Effects Division (7509P) 

Office of Pesticide Programs 

TO: Jolene Trujillo, Chemical Review Manager 

Pesticide Re-Evaluation Division (7508P) 

Office of Pesticide Programs 

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

for cyhalofop-butyl to support registration review. 
Cyhalofop-butyl Registration Review Scoping Document 

Executive Summary 

The Health Effects Division Cyhalofop-butyl Registration Review Team has evaluated the 

database and the most recent human health risk assessment for the herbicide. HED performed 

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

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

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

chemical (D387444, E. Holman, 11/3/201 1). 

Cyhalofop-butyl, butyl [R-( + )-n-butyl-2-( 4( 4-cyano-2-.fluorophenoxy)phenoxy)propionate ], is a 

highly selective aryloxyphenoxy-propionate post-emergence herbicide registered for use on rice. 

It is used to control many annual and seedling perennial grasses, including barnyard grass and 

sprangletop in drill-seeded and water-seeded rice. Cyhalofop-butyl acts through inhibition of the 

plant's acetyl coenzyme-A carboxylase, a pivotal enzyme in plant fatty acid biosynthesis. It can 

be applied as a broadcast treatment by ground and aerial equipment. 

The toxicology database for cyhalofop-butyl is complete except for a subchronic inhalation 

toxicity study. A 1 OX database uncertainty factor for the lack of an acceptable inhalation study 

will be applied to inhalation exposure; an alternative would be for the registrant to provide 

additional information regarding the fraction of respirable and inhalable particles in the granular 

formulation. 

The kidney is the target organ in rats, mice, and rabbits. Additional effects seen in the 

toxicology database include effects on the stomach, thymus, and liver. 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, or rat 2-generation 

toxicity studies. No systemic or neurotoxic effects were observed in either the acute or the 

subchronic neurotoxicity studies. In addition, there is no evidence that cyhalofop-butyl directly 

targets the immune system. 

There were no positive effects in a battery of mutagenic studies. HED concluded that cyhalofopbutyl is "Not Likely to be Carcinogenic to Humans." The FQPA Safety Factor fonnerly was 

reduced to 1 X based on the completeness of the toxicology database, the absence of 

neurotoxicity or susceptibility, the lack of potential for residential exposure, and the conservative 

nature of the exposure assessment. 

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

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

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

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

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

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

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

estimates that are not of concern for all population subgroups (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, 

aggregate risk is not of concern for cyhalofop-butyl.

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

updated 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 new policies or procedures are put into place, the Agency might revisit the 

need for a quantitative occupational post-application inhalation exposure assessment.

Although exposure and risk have 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 

identified potential risks of concern for handlers using the granular formulation of cyhalofopbutyl. The screening estimates should be captured in the draft risk assessment to support 

registration review, and should include the most recent recommendations with 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 recent 

human health risk assessment was conducted in 2012 when HED evaluated a label amendment to 

increase the single application rate for use of the herbicide on rice (D396698, W. Drew, et al., 

7/25/2012). Prior 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 in 40 CFR §180.576. For plant 

commodities, the tolerance is established in terms of parent cyhalofop-butyl as well as the acid 

and diacid metabolites. Tolerances 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 livestock commodities.

The structure and chemical names, as well as the chemical and physical properties can be found 

in the tables in Attachment 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, diclofopmethyl, 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 catalyzes 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 48180501). 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 characterization, including doses and endpoints 

selected (along with traditional uncertainty factors) for risk assessment.

The kidney is the target organ in rats, mice, and rabbits. Kidney effects were observed in

subchronic and chronic studies, as well as 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 relative 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 pathological 

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 addition, 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 weights 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 effects were observed in either the 

acute or the subchronic neurotoxicity studies. Acceptable dog and rat metabolism studies for 

cyhalofop-butyl are available.

The chronic toxicity/carcinogenicity study in the rat and the carcinogenicity study in mice 

showed 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 indicate that the liver was the 

target organ, and hepatotoxicity manifested as necrosis, increased liver weight, and moderate 

hypertrophy. Activation of PPARα was the primary 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, there were no positive effects in a battery of 

mutagenic studies. Therefore, in accordance with the EPA Final Guidelines for Carcinogen Risk 

Assessment (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 (Toxicity 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). It is not a dermal sensitizer.

In the most recent risk assessment, the required 10X FQPA Safety Factor 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 exposure 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 for inhalation toxicity data, these 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 assessment 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, developmental, 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 

methodologies; however, no significant changes are expected during registration review.

Dietary Exposure

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

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

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

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

previous risk assessment.

For the 2012 risk assessment, HED conducted a chronic dietary exposure assessment for 

drinking water, rice, and wild rice (D403441, W. Drew, 7/25/2012). 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 the crop 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; D397211, R. Shamblen, 4/9/2012). It was 

generated by the Tier 1 Rice Model. The EDWC includes all residues of concern: cyhalofopbutyl, 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 registration 

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. If an assessment is needed, HED will use

the most current dietary exposure model and food consumption survey.

Conclusions for Dietary Exposure

The dietary exposure 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.

Bystander exposures resulting from off-site transport (e.g., spray drift or volatilization) might

occur as a result of applications of cyhalofop-butyl. The potential for spray drift will be 

quantitatively evaluated for cyhalofop-butyl during the registration review 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 

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

indirect non-occupational exposure to drift. In terms of volatilization, the Agency has developed 

a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis 

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

review, the Agency will utilize this analysis to determine if data (i.e., flux studies, route-specific 

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

Conclusions for Residential Exposure

During registration review, 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 2012 human 

health risk assessment. Aggregate risk assessments traditionally combine exposure estimates 

resulting from food, drinking water, and residential uses. As no acute endpoint was identified 

and cancer risk is not a concern for cyhalofop-butyl, acute and cancer aggregate risk assessments 

were not performed. There are no residential uses for cyhalofop-butyl. As a result, the shortterm aggregate exposure estimates are equivalent to the chronic dietary (food + water) aggregate 

estimates. 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.

 

Conclusions for Aggregate Exposure and Risk

An acute endpoint was not identified, cancer risk is not a concern, and there are no residential 

uses for cyhalofop-butyl. In the 2012 risk assessment, the chronic aggregate risk estimates were 

not of concern for the general U.S. population or any population subgroup. At the time of 

registration review, HED will conduct a new aggregate risk assessment that will be based on any 

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 EC formulated end-use-product, Clincher® CA, (Reg No. 

62719-356) contains 29.6% cyhalofop-butyl as the active ingredient (ai), which is equivalent 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 postflood, post-emergent herbicide for the selective control of emerged grass weeds in drill-seeded

rice and water-seeded rice. This formulation may only be applied aerially. 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 to estimate 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 Database Version 1.1 (PHED 1.1), and the Agricultural 

Handler Exposure Task Force (AHETF) Database, or other registrant-submitted occupational 

exposure studies. Some of these data are proprietary (e.g., AHETF data) and subject to the data 

protection provisions of 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. However, there 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 interspecies and intraspecies differences. 

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

concern. In the most recent risk assessments, occupational exposure for both formulations 

resulted in no risk estimates of concern. 

In conjunction with determining data needs during registration review, cyhalofop-butyl was 

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

previous assessments were conducted using data from an oral study. 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. In 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, the 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 additional 10X database uncertainty factor for inhalation exposure. Two 

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 highest inhalation 

exposure 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 an 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 required for the agricultural uses of cyhalofop-butyl. Although HED would 

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

requirement based on the existing use pattern, a DFR study 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 registered 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 Agency sought expert advice and input on issues related to volatilization of 

pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel 

(SAP) in December 2009, and received the SAP’s final report on March 2, 2010 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The Agency has 

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

Volatilization Screening Analysis (http://www.regulations.gov/#!docketDetail;D=EPA-HQOPP-2014-0219). During registration review, the Agency will utilize this analysis to determine 

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

required for 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 Agency’s risk assessments.

Although a quantitative occupational post-application 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 22

representative crop scenarios, based on the new10X 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 assessment 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 Institute 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

(D418578, S. Recore, 6/15/2014). The purpose of the database search was 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,

that study does not provide information for this document.

For the Main IDS, from January 1, 2009 to March 5, 2014, three incidents were reported in the 

database for the single chemical alone. Four additional incidents were reported involving more 

than one chemical. These incidents were classified as moderate severity. In the Aggregate IDS, 

from January 1, 2009 to March 5, 2014, two incidents involving cyhalofop-butyl were reported. 

These incidents were classified as minor severity. Overall, few incidents involving cyhalofopbutyl 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 local 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 SENSORPesticides from 1998 to 2010 revealed that no cases involving cyhalofop-butyl were reported.

Based on the low frequency and severity of incident cases reported in both IDS and SENSORPesticides, 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

Tolerances for residues of cyhalofop-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 or 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-fluorophenoxy)-

phenoxy)propionic acid], and the di-acid metabolite [(2R)-4-(4-(1-carboxyethoxy)phenoxy)-3-

fluorobenzoic acid].”

There 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 on 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 work 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 

common 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 action, 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 

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/.

Data Requirements

[870.3465] Subchronic Inhalation Toxicity Study

Note: 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 subchronic 

inhalation toxicity study be required; however, if the registrant can 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

References

Memoranda Relevant to Registration Review

Author DP 

Number

Date Title

E. Holman D387444 11/3/2011 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

5/21/2014 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 D267558 11/13/2001 PP#0F06089. New Chemical: Cyhalofop-Butyl in/on Rice. 

Review of Residue Chemistry

W. Drew D403441 7/25/2012 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 D354880 12/30/2008 Cyhalofop-butyl: Occupational Exposure and Risk 

Assessment for Proposed Use on Wild Rice and Proposed 

Amended Labeling for Clincher SF Herbicide

R. Shamblen D397211 4/9/2012 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 D418578 6/25/2014 Cyhalofop-butyl: Tier I Review of Human Incidents

Attachments

Attachment 1. Chemical Identity and Physical and Chemical Properties

Attachment 2. Toxicology Profile Tables

Attachment 3. Endpoint Selection Table

Attachment 4. International Residue Limit Status 
Cyhalofop-butyl Registration Review Scoping Document

Page 13 of 22

Attachment 1. Chemical Identity and Physical and Chemical Properties

Table A.1.1. Cyhalofop-butyl Nomenclature 

Compound

F

O

O

O(CH2)

3CH3

O

CH3 H

NC

Common name Cyhalofop-butyl

Molecular formula C20H20FNO4

Molecular weight 357.38

IUPAC name n-Butyl (R)-2-[4-(4-cyano-2-fluorophenoxy)phenoxy]propionate

CAS name n-Butyl (2R)-2-[4-(4-cyano-2-fluorophenoxy)phenoxy]propanoate

CAS registry number 122008-85-9

Table A.1.2. Physical and Chemical Properties of Cyhalofop-butyl

Parameter Value References

Melting point/range 45.5-49.5oC Memo, D277695

pH 9.0 D. Davis, 4/10/2002

Relative Density (20oC) 1.172 g/cm3

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(KOW) (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

Guideline 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 and 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/kg/day (HDT)
Cyhalofop-butyl Registration Review Scoping Document

Page 15 of 22

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline 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, respectively.

870.3150 Subchronic 

Feeding - Dog

45014707

(main)

45000410

(pilot, palatability)

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 study 

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 clinical 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 toxicity.

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)
Cyhalofop-butyl Registration Review Scoping Document

Page 16 of 22

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline 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)

Systemic 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 used 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 

hyperplasia 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 approximately 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 for 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 increased 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.
Cyhalofop-butyl Registration Review Scoping Document

Page 17 of 22

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline 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 neuropathologic 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 

behavioral 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 
Cyhalofop-butyl Registration Review Scoping Document

Page 18 of 22

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline No.Study Type MRID No. (year)/ 

Classification /Doses

Results

tone, and minor changes in autonomic functions such as slight 

hyperthermia, and slightly 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

LOAEL = 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/NonGuideline (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 blood 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 Pharmacokinetics

Rat

45000427

(main)

45000426 (prelim.)

45000528

(stability, homog.)

(1995)

Acceptable/Guideline

Absorption of gavaged test article was 93-100%, and urinary 

excretion was the major 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 the 

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) 
Cyhalofop-butyl Registration Review Scoping Document

Page 19 of 22

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline 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-fluorophenoxy)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 metabolites 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-day 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 nbutyl ester is normally 

formulated) and a spray 

solution–at 0.005, 1.0, or 1.8 

mg/cm2.

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 LOAEL = 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.
Cyhalofop-butyl Registration Review Scoping Document

Page 20 of 22

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

Guideline 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-Day 

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); necrosis 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); nonactivator (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.
Cyhalofop-butyl Registration Review Scoping Document

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

UFA = 10X

UFH = 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 Based 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. UFA = 

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

population (intraspecies). FQPA SF = Food Quality Protection Act Safety Factor. PAD = population adjusted dose (a = acute, c 

= chronic). RfD = reference dose. N/A = not applicable. 

Table 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 Intermediateterm (1-6 months)

N/A N/A N/A 21-Day Dermal - rats

No systemic or dermal effects at the 

Limit 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]

UFA = 10X

UFH = 10X

UFDB = 10X

Occupational 

LOC for MOE = 

1000

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 Based 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. UFA = 

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

population (intraspecies). . UFDB = 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-butyl (082583; 4-28-2014)

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

Residue Definition:

US Canada Mexico1 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] and 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 Mexico1 Codex

Rice, grain 0.40

Wild rice, grain2 0.40

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.