### UNITED STA TE S ENV IRO NM EN TA L PROT EC T IO N AGENCY

WASHINGTON

, D

. C. 204 60



### MEMORANDUM

Date: December 5

, 2014 OFFICE OF CIJE M ICAL SA F E TY ANI> I)OLLl i TION PREVE N TION



### SUBJECT: F l uazifop-P-butyl. Human Health Risk Assessment Scoping Document in Support of Registra t ion Re v iew

PC Code : 122809 Decision No.: 492472 Petition No.: Not Applicabl e Risk Assessment Type : Single Chemical TXR No.: Not Applic a ble MRIO No.: Non e DP Barcode: D42ll07 Regis t ration No

. : N o t Applicable Regulatory Action: R e gistra t ion Review Scoping Case No.: 2285 CAS No.: 79241-46-6 40 CFR: §1 80.411



### FROM: Alexandra LaMay
, Ri s k Assessor (/

# cit-~ ltVVJ,/

William Donovan
, PhD.

, Chemist : 

# (1'· {'**~**

THRU:

TO: Steve D a p son, PhD

. , Toxicologist**;~ V~** **~** 

### Risk Assessment Branches V and VII ' · He alth Effects Division (7509P) Offic e of Pesticide Programs

Seyed Tadayon, Chemist Michael Me tzg er , Branch Chief Risk Assessment Branches V 

### and Health Effec ts Division (7509P) Office of Pesticide Programs

Matthew Manupella 

## r

Pesticide Re-eval uation Division (7508P) Office of Pesticide Programs

Attached i s the Hea lt h Effects D ivision's (HED) hum a n health scoping document for fluazifo p-P butyl to sup port the reg i stration review process.

Page 1 

### of27

### Executive Summary



### The Health Effects Division (HED) has eva lu ated the status of th e hum a n health risk assessment for fluazifop-P-butyl to det e rmine the scope of work n ecessa ry to s uppor t reg i s trat i on rev i ew. The most recen t hum a n health risk assessm ent ( D 385 178

, P

. Savoi a, 1 /4/ 11 ) was considered as part of this seeping exercise. As noted in the previous assessment, the toxicology da tab as e f or fluazifop-P-butyl consists of s tudies conducted using fluazifo p-b utyl (racem i c mixture) and its enriche d R-isomer

, fluazifop-P-butyl. Comparison s tudies have shown si mi l ar toxicities from both compounds.

Flua zifo p

- P

- bu ty l and fluazifop -bu ty l have l ow acute toxici ty by the oral, dermal a nd inh a l at i on

rou tes , are mi l dly irritating to the eye and skin

, and a re not skin sensitizers. S ubchronic and chron i c toxicity studies with fluaz i fop-P-but yl o r fl u azi fop-buty l show th at th e ra t is mor e

se n s iti v e to tox i c effects t h a n the dog, rabbi t or ham ster, possibly due t o lon ger retention time of the major metabolite (fluazifop acid) in the rat. The liver and kidney are the target o rgans and the toxicity i s expressed as liver toxicity in the pre se nce of pe r oxisome proliferation and

exace rba t i on of age related kidney toxicity. A subchronic inhalat i on study and a 90

- day dermal
tox i c i ty study were i d e n tifie d as d ata gaps.

The res idue chemistry database for fluazif op-P-butyl is complete with th e exception of a field

r o tational crop s tudy. The confined rotational c rop study showed that m etabo lit e TF P is taken up by rotational crops. Thu s, a field r otational crop st udy is requi r ed to determine if rotationa l crop tole rances are n eeded

.

Codex has not estab li s hed fluazifop-P-butyl Maximum Residue Limits (MRLs) inion any commodity. Mexico gener ally adopts US tolerances and/or Codex MRL s for export purposes. Most of the Canadia n MRLs are harmonized wi th the US tolerru:tces. Howe ver, highe r residues in U .S. trials preclude harmonization for the following commod i ties: dry bean

, cotton, and soybea n. E valuation of an amended us e petition for sweet potato, c ur rent l y i n progress, m ay result in harmonization of th e U. S to l erance and t h e Cana dian MRL f or this commod i ty

. F or g rape, an increa se in th e US t o l erance from 0.01 to 0.03 ppm would achieve harmonization and is recommended during registration review. HED is not cu rrentl y involved in any joint internatio nal review projects t hat in vo l ve the act i ve i ngredien t , fluazifop-P-butyl.

Cu rr ently there are no acute or chronic dietar y (f ood and drinking wa ter ) risk estimates which are of concern for flu azifop-P

- buty l and its metabolite s. H owever, updated dietary exposure assessments may be necessary under registration review i f there are significant changes to the
est im ate d drinkin g wa t er concen trat ions (EDWCs) that will be updated by EFED, or if there are changes to the points of departure (PoDs) or uncertainty f actors /safe ty factors (UFs/SF s).

In residentia l settings

, fluazifop-P-butyl is u sed on turf and ornamentals. R eside nti a l adult handler scenarios were previously assessed and are not of concern; combined dermal and inhalation M OE s ran ge fro m 240 to 4300. Resid en tial post-application exposure scena ri os include dermal and non-dietary ingest i on (hand-to-mouth, objec t- to-mouth

, ingestion) exposure to childre n o n tr eated lawns

, de r mal exposure to yo uths on treated go l f courses, and dermal
exposure to adults on t r eated lawns and on treated golf courses. A ll residential post

- ap pli cation
Page 2 of 27

### Page 3 of 27

MOEs were not of concern (MOEs > 100) for all populations. TTR data are r equired for fluazifop

- P

- butyl. An updated residential assessment may be required under registration review to incorporate updated exposure assessment methodology for residential exposure scenarios

. Residential bystander exposures resulting from off

- site t ransport (i.e., spray drift or volatilization) may occur as a result of occupational applications of fluazifop

- P

- butyl . The potential for bystander exposure of fluazifop

- P

- butyl will be assessed during registration review.

In the most recent risk assessment, HED provided aggregate exposure and risk estimates for dietary and residential exposures. The expo sure scenarios aggregated are: average dietary with short

- term dermal and incidental oral exposure in infants and childre n; and average dietary with short

- term dermal and inhalation exposure of adult s

. The combined MOE’s for the scenarios examined were below HED’s level of concern (i.e. MOE > 100). Aggregate exposures of fluazifop

- P

- butyl may be revised during registration review to consider new dietary and residential exposures estimates.

Based on the previous occupational exposure assessment, all of the handler (dermal and inhalation) exposure risk estimates were not of concern with some level of PPE (i.e., engineering controls for mixer/loaders)

. There are no post

- application worker exposure risk estimates of

concern

. DFR data are available for fluazifop

- P

- butyl; TTR data are required

. The Worker Protection Standard ( WPS ) restricted entry interval ( REI ) for fluazifop

- P

- butyl is 12 hours. An updated occupational exposure and risk assessment is likely required during registration review to include all registered uses as well as to include any changes to policy or toxicological points of departure.

Introduction

Fluazifop

- P

- butyl [( R )

- 2

- (4

- ((5

- (trifluoromethyl)

- 2

- pyridinyl)oxy)phenoxy)propanoic acid, butyl ester] is a selective herbicide registered for use to provide postemergence control of perennial and annual grass weeds. Fluazifop

- P

- butyl is currently registered for food/feed use on a variety of crops , as well as registered for use on lawns/turf, ornamentals, non

- bearing trees and non

- crop areas. Fluazifop

- P

- butyl is typically applied as a broadcast, banded, directed or spot treatment with ha ndheld, ground

, or aerial equipment. Applications are made as pre

- plant, at

- plant, post

emergence applications.

HE D has evaluated the most recent human health risk assessment for fluazifop

- P

- butyl to determine if sufficient data are available and if updates are needed to support registration review. HED has also considered updates to its toxicity, exposure and usage databases, and the latest Agency science policy and risk assessment methodologies.

The chemical structure, nomenclature, and the physical/chemical properties of fluazifop

- P

- butyl are presented in Attachment 1

. 

### Hazard Identification/Toxicology

### Page 4 of 27

A subchronic inhalation study and a 90

- day dermal toxicity study were identified as data gaps in the 2011 risk assessment for fluazifop

- P

- butyl. These studies are still required. Therefore, t he toxicology database for fluazifop

- P

- butyl and fluazifop

- butyl is in complete

. Fluazifop

- P

- butyl has low volatility, is not an eye or skin irritant in acute or 21

- day dermal studies, and is not a skin sensitizer.

Fluazifop

- P

- butyl herbicidal specificity is by inhibiting acetyl CoA carboxylase (a key enzyme in plant fatty acid synthesis and required for maintaining membrane s in functioning condition). Fluazifop

- P

- butyl is not an eye or skin irritant in acute or 21

- day dermal studies, and is not a skin sensitizer. The liver and kidney are the target organs expressed for the most part as liver toxicity in the presence of pero xisome proliferation and exacerbation of age

- related kidney toxicity. These data are reasonably consistent among the rat with fluazifop

- butyl and fluazifop

- P

- butyl, dog with fluazifop

- butyl, and hamster with fluazifop

- P

- butyl. T here was no evidence of

c arcinogenicity in the rat with fluazifop

- butyl or in the hamster for fluazifop

- P

- butyl. The hamster , instead of the mouse, was selected for the second carcinogenicity study because liver peroxisome proliferation more closely resembled what was found for h uman liver cells. There were no mutagenicity concerns for fluazifop

- butyl or fluazifop

- P

- butyl.

A rat developmental study exhibiting diaphragmatic hernia effects was used as the basis to select the acute dietary endpoint for females 13

- 49 years of age. In contrast, there was no appropriate endpoint which correlated to a single dose identifiable for the general U.S. population. The short

- term incidental oral endpoint was maternal body weight gain decrement exhibited in the developmental toxicity studies performed on rats. The chronic dietary (all populations), intermediate

- term dermal and inhalation, as well as the intermediate

- term incidental oral endpoints, were selected from the 2

- generation reproduction study in rats. This study exhibit ed decreased testes, and epididymal weights in males along with decreased uterine and pituitary weights in females. In regard to the short

- term dermal and inhalation endpoints used in this assessment, the developmental toxicity studies performed on rats wer e used as the basis for endpoint selection. These studies exhibit ed decreased fetal weights, as well as hydroureter and delayed ossification effects. Because oral NOAELs were selected for dermal and inhalation endpoints, dermal absorption factors, calcula ted from a dermal absorption and pharmacokinetic study in humans, of 2% for high exposures and 9% for low exposures were used for oral

- dermal
route

- to route extrapolation, and inhalation hazard is assumed to be equivalent to oral hazard

.

The toxi city database includes m ultiple developmental toxicity studies in rats and rabbits on fluazifop

- butyl and

/or fluazifop

- P

- butyl and a two

- generation reproduction study in rats with fluazifop

- butyl. T here was no evidence of increased susceptibity following i n utero exposure in rabbits or following pre and post

- natal exposure in the reproduction study with rats . In the developmental toxicity study with rats, while t here was quantitative evidence of increased susceptibility , t he degree of concern is low based o n the following considerations: the endpoint of concern (delayed ossifications) is considered to be a developmental delay as opposed to a malformation or variation which is considered to be more serious in nature; there were considerable variations in the incidences among the five studies; the NOAELs/LOAELs for this effect were well defined and consistent across these studies; and a developmental endpoint of concern (diaphragmatic hernia) is used for assessing acute dietary risk

### Page 5 of 27

The chronic dietary (food and drinking water) exposure assessments and residential exposure risk assessments are based on conservative models and/or reliable data and therefore, the agency is confident that it will not underestimate risk from exposure to these compounds

.

The FQPA Safety Factor was reduced to 1X since the toxicology and exposure databases are completed and there is no residual uncertainty for pre and or post

- natal toxicity.

The ACN and SCN studies along with an immunotoxicity study are presently under review.

See Attachment 2 for Toxicity Profile Tables and Attachment 3 for Toxicity Doses and Endpoints Selection Table.

Conclusions : The toxicology database is complete with the exception of the subchronic inhalation study and a 90

- day dermal toxicity study

, which are required

. Dietary Exposure

The residue chemistry database for fluazifop

- P

- butyl is complete with the exception of a field rotational crop study. The residues of concern for tolerance expression and risk assessment for fluazifop

- P

- butyl in plants, livestock and water were determined by the HED Metabolism Assessment Review Committee (MARC) (See Attachment 5).

No decision was reached regarding the residue of concern in rotational crops due to the lack of rotational crop studies at the tim e of the 2004 MARC meeting. A confined rotational crop (CRC) study was recently submitted and reviewed (D374519, D. Soderberg, 8/19/2010). This study showed that detectable levels of 5

- trifluoromethyl

- 2

- pyridone (TFP) were taken up by rotational crops. B ecause TFP was identified as a residue of concern in plants for risk assessment purposes based on the results of the CRC study , a field rotational crop study is now needed.

A number of residue chemistry data deficiencies were identified in the fluazifop

- P

- butyl TRED (D319907, S.L. Kinard, 8/17/2005) and in more recent new use petitions. Syngenta has addressed these deficiencies with several data submissions that were evaluated by HED in abbreviated chemistry reviews (see References). Review of residue c hemistry data submitted to address co nditions of registration or DCI requests was recently completed (D415419, W. Donov an, 18

- JUN

- 2014). This review indicated the need for an increased tolerance level for soybean seed and decreased tolerance levels for p rocessed citrus commodities. While sweet potato already is a registered crop, the registrant submitted a label amendment request to reduce the PHI from 55 days to 14 days, and provided new sweet potato residue data. Adequate analytical methods are availa ble for data collection and tolerance enforcement. Other than the field rotational crop study, no other residue chemistry data deficiencies have been identified for fluazifop

- P

- butyl.

The most recent acute and chronic dietary (food) exposure assessment s were conducted in support of a January 2011 fluazifop

- P

- butyl new use risk assessment ( D379452, S. Tadayon, 08/09/2010)

.

### Page 6 of 27

The Dietary Exposure Evaluation Model (DEEM) analysis was performed using tolerance level residues and assuming 100% crop treated. T he acute and chronic dietary (food) risk estimates were not of concern. The only population subgroup requiring acute dietary exposure assessment, Females 13

- 49 years old, occupied 13% aPAD at the 95 th 

### percentile of exposure. The most highly exposed popula tion subgroup for chronic exposures was Children 1

- 2 years old , which occupied 40 % of the cPAD

. EFED (Environmental Fate and Effects Division) provided peak and average estimated drinking water concentrations (EDWCs) ; t hese EDWCs were incorporated directl y into the DEEM analysis ( D379452, S. Tadayon, 08/09/2010) . EFED may update the drinking water assessment under registration review; if estimated EDWCs increase substantially, then a new dietary exposure assessment for food and water may be needed.

Conclusions: A field accumulation in rotation al crop s study is required in registration review.

A new dietary assessment may be required if 1) there are any significant changes to toxicological PODs or uncertainty factors, or 2) EFED recommends higher EDWCs than the current values.

Residential (Non

- Occupational) Exposure

There are currently registered residential uses for f luazifop

- P

- butyl ; it is registered for use on turf and ornamentals

. T here is a potential for non

- occupational exposure to adults applying the chemical and to adults and children entering treated areas

. Residential Handler Exposure

E xposure to residential handlers is possible during the resid ential use of fluazifop

- P

- butyl. All resid ential handler scenarios were previously assessed (D316891, 8/29/05 and D 316892

, 4/22/05 ). The results indicate that all of the residential handler risks are no t of concern [i.e., MOEs are all greater than the LOC of 100]. Combined dermal and inhalation MOEs range from 240 to 4300 for residentia l handlers.

Since the previous assessment, the Health Effects Division’s 2012 Standard Operating Procedures for Residential Pesticide Exposure Assessment has updated exposure assessment methodology for residential exposure scenarios

. An updated residenti al handler assessment will likely be needed under registration review as a result of these revisions.

Residential Post

- application Exposure

Fluazifop

- P

- butyl can be used in many areas that can be frequented by the general population including residential areas (e.g., home lawns). As a result, adults and children can be exposed by entering these areas if they have been previously treated.

The residential post

- application exposure scenarios include dermal and non

- dietary ingestion (hand

- to

- mouth , object

- to

- mouth, ingestion) exposure to children on treated lawns, dermal

### Page 7 of 27

exposure to youths on treated golf courses, and dermal exposure to adults on treated lawns and on treated golf courses.

The fluazifop

- P

- butyl postapplication MOE values were calculated for adults after applications to golf courses and lawns . All MOEs are >100 o n the day of application; MOEs range from 380 for d ermal exposure via high contact activities on lawns to 26,000 for dermal exposure while mowing turf. The postapplicat ion MOE values were calculated for youth following golf course applications of f

luazifop

- P

- butyl; MOEs for youths were >100. Exposure to children was calculated for postapplication risks following the application of fluazifop

- P

- butyl to lawn s . All MOEs ar e greater than HED’s LO C of 100 on day 0; MOEs range from 260 for dermal exposure during high contact activities on turf to 26,000,000 for oral exposure via incidental soil ingestion.

Since the previous assessment, the Health Effects Division’s 2012 Stand ard Operating Procedures for Residential Pesticide Exposure Assessment has updated exposure assessment methodology for residential exposure scenarios, including adult and children exposure to treated turf

. An updated residential postapplication assessment may be needed under registration review as a result of these revisions.

In accordance with 40CFR158, turf transferable residue ( TTR ) data are required for all occupational (e.g., sod farms, golf courses, parks, and recreational areas) or resi dential turf uses that could result in post

- application exposure to turf. TTR data are required for fluazifop

- P

- butyl based on HED’s guidance on requiring/waiving TTR/DFR data 1 

### , as described below

. Since the estimated residential turf postappl ication exp osure for residential turf using default TTR values for fluazifop

- P

- butyl is not minimal in comparison to the level of concern (i.e., the calculated MOE is not greater than 10 times higher than the level of concern , MOE < 1000 compared to the LOC of 100 ), future refinements of this postapplication exposure for fluazifop

P

- butyl may be necessary due to increased use of fluazifop

- P

- butyl or advances in EPA risk
assessments. Therefore, EPA is requiring the 40CFR TTR data to facilitate any neces sary exposure a ssessment refinements and to further EPA’s general understanding of the availability of turf transferable pesticide residues.

Residential Bystander Exposures

Residential bystander exposures resulting from off

- site transport (e.g., spray drift or volatili zation) may occur as a result of agricultural applications of fluazifop

- P

- butyl . The potential for spray drift will be quantitatively evaluated for each pesticide during the Registration Review process which ensures that all uses for that pesticide will b e considered concurrently. The approach is outlined in the revised (2012) Standard Operating Procedures for Residential Risk Assessment (SOPs)

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

non

- occupational exposure to drift. In terms of volatilization, the agency has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis

1 Guidance for Requiring/Waiving Turf Transferrable Residue (TTR) and Dislodgeable Foliar Residue (DFR) Studies

. 10/23/2014, , Exposure Science Advisory Council

### Page 8 of 27

( 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 studi es, route

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

- P

- butyl

.

Conclusions : TTR data are required for fluazifop

- P

- butyl. An updated residential handler and postapplication assessment are likely needed under r egistration review to include updated exposure assessment methodology for residential exposure scenarios

. The potential for spray drift will be assessed during registration review. Also, the volatilization screening analysis will be used during registrat ion review to determine if data or further analysis are required for fluazifop

- P

- butyl.

Aggregate Risk Assessment

In accordance with the Food Quality Protection Act (FQPA), HED must consider and aggregate pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. The acute and chronic aggregate risk assessments included f ood and drinking water. The short

- term aggregate risk assessment included food , drinking water, and residential
exposures

. No intermediate

- term aggregate risk assessment was conducted since a ll residential/recreational exposures are anticipated to be sho rt

- term in duration

.

Acute and Chronic

The 2011 acute and chronic aggregate risk assessment s included exposure to fluazifop

- P

- butyl residues in food and water. Acute and chronic dietary risk estimates for food and drinking water
exposure are below HED’s level of concern ( <1 00 % of the aPAD and cPAD)

.

Short

- term

In 2011, a short

- term aggregate risk assessment was completed for fluazifop

- P

- butyl

. For adults, the short

- term aggregate assessment combined the average food and drinking water exposures with handler (dermal and inhalation) and postapplication exposures on treated turf (dermal). For children, the short

- term aggregate assessment combined the average food and drinking water exposures with postapplication dermal and incidental oral (hand

- to

- mouth, object

- to

- mouth, soil ingestion) from contact with treated turf. The assessments resulted in risk estimates that are below the HED’s level of con cern (MOE < 100)

. The short

- term aggregate MOE for adults was 150 and for children was 250.

Conclusions : During registration review, updated aggregate assessments will likely be conducted as required to include any significant change that might occur fo r toxicological PODs, FQPA and other uncertainty factors, dietary exposure estimates

, or residential exposure estimates

. Occupational Exposure

Several occupational exposure scenarios were previously assessed (D385178, 1/4/11, P. Savoia; D347515, 9/18/0 8, P. Savoia). The uses assessed include dry beans, peanuts, soybeans, bananas,

### Page 9 of 27

citrus, grapes, sugar beets, and imported potatoes. Although the occupational assessments described did not include all registered crops, the major crop groups were assessed and generally cover the registered uses.

Occupational handler and post

- application scenarios were assessed as workers can become exposed to fluazifop

- P

- butyl at short

- or intermediate

- term durations through its use.

Occupational Handler Exposure

Occupational handler scenarios include exposure too fluazifop

- P

- butyl during mixing, loading, and application activities. Estimated risks for occupational handlers determined for short

- /intermediate

- term exposures yielded total MOEs greater than 100, with some scenarios requiring additional personal protection above baseline (e.g., engineering controls for mixer/loaders). In reaching or exceeding the LOC of 100, the resulting MOEs indicate these risks are not of concern.

Recommended unit exposures for occ upational handler assessments have generally been derived only from the Pesticide Handlers Exposure Database (PHED). However, recently both the Outdoor Residential Exposure Task Force (ORETF) and the Agricultural Handler Exposure Task Force (AHETF) have p roduced pesticide handler exposure monitoring data that the Agency is using in place of PHED (http://www.epa.gov/pesticides/science/handler

- exposure

- data.html) . As more reliable data become available, the Agency will continue to replace existing data. Rev iewers should incorporate new exposure monitoring data, as necessary, during registration review.

Conclusions : An updated occupational handler assessment is likely required under registration review to include all registered uses as well as to include any significant changes in exposure assessment methodology, toxicological PODs or uncertainty factors.

Occupational Post

- application Exposure

Some uses are ground directed applications where no crop foliage is being treated. As a result, this post

- applicati on exposure and risk to occupational workers was not quantitatively assessed. However, certain applications made to crops where workers can come in contact with foliage

were previously assessed; these risks are not of concern since the resulting MOEs wer e greater than or equal to 100.

DFR data are available on cotton (MRID 45243801, D279616). These data have been reviewed and found to be acceptable for risk assessment purposes. These data will be incorporated into an updated occupational post

- application assessment during registration review as necessary.

Recommended transfer coefficients for occupational post

- application assessments are derived from Agricultural Reentry Task Force (ARTF) expo sure monitoring studies ( http://www.epa.gov/pesticides/science/post

- app

- exposure

- data.html ). These transfer coefficients have been updated in 2012 based on a reanalysis and submission of new monitoring

### Page 10 of 27

data. Reviewers should incorporate new exposure moni toring data, as necessary, during registration review.

The Worker Protection Standard (WPS) Restricted Entry Interval (REI) for fluazifop

- P

- butyl is 12 hours.

Conclusions : An updated occupational post

- application assessment is likely required under regis tration review to include all registered uses as well as to include any significant changes in exposure assessment methodology

, toxicological endpoints or points of departure , or uncertainty factors

. Public Health and Pesticide Epidemiology Data

HED has evaluated the available incident data 2 

### and concludes that b ased on the low frequency and low 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 investiga tion. 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 are currently established unde r 40 CFR §180.411 for residues of fluazifop

- P

- butyl in/on many commodities. HED recommends that the residue definition for the fluazifop

- P

butyl tolerance expression be revised to read as follows :

“ Tolerances are established for residues of the herbicide fluazifop

- P

- butyl, butyl (2 R )

- 2

- [4

- [[5

- (trifluoromethyl)

- 2

- pyridinyl]oxy]phenoxy]propanoate

, including its metabolites and degradates, in or on the commodities listed below. Compliance with the tolerance levels specified below is to be determined by meas uring only those fluazifop

- P

- butyl residues convertible to fluazifop, 2

- [4

- [[5

- (trifluoromethyl)

- 2

- pyridinyl]oxy]phenoxy]propanoic acid

, expressed as fluazifop, in or on the commodity”.

A summary of US tolerances for residues of fluazifop

- P

- butyl may be f ound in A ttachment 4

. Codex has not established fluazifop

- P

- butyl Maximum Residue Limits (MRLs) in/on any commodity. Mexico generally adopts US tolerances and/or Codex MRLs for export purposes. Most of the Canadian MRLs are harmonized with the US tolerances. However, differences are noted for the following commodities: dry bean, cotton, grape, soybean, and sweet potato. For dry bean, cotton, and soybean, the US tolerances are higher than the corresponding Canadian MRLs based on residue levels fou nd in the supporting field trial studies due to different use patterns and/or formulations . It will be determined during registration review if harmonization is possible. . Harmonization of the sweet potato MRL and tolerance may be possible as part of the sweet potato label amendment review currently in progress. For grape, an increase in the US tolerance from 0.01 to 0.03 ppm would achieve harmonization and is recommended during registration review.

2 Fluazifop

- p

- butyl: Tier I Review of Human Incidents. S. Recore, 8/5/14. D421768

.

### Page 11 of 27

International or Intergovernmental Work Sharing

HED is not currently involved in any joint international review projects that involve the active ingredient, fluazifop

- P

- butyl . Additionally, HED is unaware of any ongoing international assessments for fluazifop

- P

- butyl

.

Cumulative

Though OPP recogni zes that there are compounds that have some structural similarity with fluazifop

- P

- butyl; specifically diclofop

- methyl [DFM], fenoxaprop

- ethyl [FPE], haloxyfopmethyl [HFM] and quizalofop

- ethyl

. A fter careful analysis, OPP has concluded that fluazifop

- P

- bu tyl, DFM, FPE, HFM and/or QFE do not have a common mechanism of toxicity by a common pathway within the framework of the Guidelines (FR 63 42031). When one progresses through the framework for the five pesticides, the five pesticides pass Step 1 and 2, but fail Step 3, the crucial step showing a common mechanism of toxicity by a common pathway (see Table 1 in RESPONSE TO PUBLIC COMMENTS. The Health Effects Division’s Response to Comments on EPA’s HED Chapter of the Fluazifop

- P

- butyl Tolerance Reregistration Eligibility Decision Document (12/10/04) and Related Documents. PC Code: 122809. Case# 2285. DP Barcode D291902. Diana Locke. August 22, 2005). Therefore, risks for these five pesticides can not be cumulated. For information regarding EPA’s efforts to det ermine 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 cumu lating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/

.

Human Studies

There are no fluazifop

- specific human studies that require an ethics review at this time.

Data Requirements

The following data deficiencies were identified for fluazifop

- P

- butyl :

Toxicolog y : 870.3250 90

- Day Dermal Toxicity 870.3465 90

- Day/28

- Day Inhalation Toxicity

Res idue Chemistry : 860. 1900 Field Accumulation in Rotational Crops The confined rotational crop study showed that metabolite TFP is taken up by rotational crops. Thus, a field rotational crop study is required to determine if rotation al crop tolerances are needed.

Occupational and Residential Exposure :

### Page 12 of 27

875.2100 Turf Transferable Residue Data

References

Table 1 . Memoranda Relevant to Registration Review Author Barcode Date Title W. Donovan D415419 6/18/2014 Fluazifop

- P

- Butyl: Review of Residue Chemistry Data Submitted as a Condition of Registration. P. Savoia D405418 12/19/ 2 012 Fluazifop

- P

- Butyl. Coffee Processing Study Submitted in Response to the August 2005 Tolerance Reassessment Eligibility Document (TRED). P. Savoia D377906 6/23/2011 Fluazifop

- P

- Butyl. Required Data Provided to Support the August 2005 Tolerance Reassessment Eligibility Document. Summary of Analytical Chemistry and Residue Data. P. Savoia D385205 1/4/2011 Fluazifop

- P

- Butyl. Amended Section 3 Registration Request to Add New Uses on Bananas, Citrus, Grapes, and Sugar Beets. Summary of Analytical Chemistry and Residue Data. P. Savoia D372408 8/31/2010 Fluazifop

- P

- Butyl. Request for the Registration of a Reduced Pre

- Harvest Interval for Applica tion of the Venture L End

- Use Product on Imported Potatoes. Summary of Analytical Chemistry and Residue Data. D. Soderberg D374519 8/19/2010 Fluazifop

- P

- butyl. Syngenta’s Response to the Residue Data Requirements of Fluazifop

- P

- Butyl TRED and Fluazifop

- P

- Butyl Generic DCI. S. Tadayon D379452 8/9/2010 Fluazifop

- p

- Butyl Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessment for the Section 3 Registration Action to add uses on B anana, Plantains, Citrus, Grapes, Potato and Sugar beet

. S.L. Kinard D319907 8/17/2005 Fluazifop

- P

- butyl. REVISED TRED

- Report on FQPA Tolerance Reassessment Progress and Interim Risk Management Decisions. Residue Chemistry Considerations. D. Locke D316891 8/29/2005 Fluazifop

- P

- butyl: Revi sed HED Chapte r of the Tolerance Reassessment Eligibility Document (TRED). PC Code: 1 22809, Case # 2285, DP Barcode: D316891 S.L. Kinard, D. Anderson, and W.P. Eckel TXR No.

0052680 3/17/2004 Fluazifop

- P

- butyl. Report of the Metabolism Assessment Review Committee.

S. Recore and E. Evans D421768 8/5/14 Fluazifop

- butyl and Fluazifop

- p

- butyl : Tier I Review of Human Incidents

P. Savoia D385178 1/4/2011 Revised Fluazifop

- P

- Butyl. Amended Human Health Risk Assessment to Support Use on Bananas, Citrus, Grapes, Sugar Beets, and the Establishment of a Tolerance on Imported Potatoes. P. Savoia D347515 9/18/08 Fluazifop

- P

- Butyl. Amended Human Health Risk Assessment to Support Use on Dry Beans, Peanuts, and the Post

- Bloom Application to Soybeans. M. Collantes D316892 4/22 /2005 Fluazifop

- p

- butyl: Revised Residential Exposure Assessment and Recommendations for the Tolerance Reassessment Eligibility Decision (TRED) Document S. Recore D279616 6/10/ 2003 Fusilade® DX on Cotton: Dislodgeable Foliar Residue Study



### Attachments

Attachment 1. Chemical Identity Attachment 2. Toxicity Profile Tables Attachment 3. Endpoint Tables

### Page 13 of 27

Attachment 4. International Residue Limits Table Attachment 5. Residues of Concern Table.

### Page 14 of 27

Attachment 1. Fluazifop

- P

- butyl Chemical Identity

Table A 1. 1. Fluazifop

- P

- butyl Nomenclature. Compound

Common name Fluazifop

- P

- butyl Company experimental name Not available.
IUPAC name Butyl (2 R )

- 2

- (4

- {[5

- (trifluoromethyl)pyridin

- 2

- yl]oxy}phenoxy)propanoate
CAS name ( R )

- 2

- (4

- ((5

- (trifluoromethyl)

- 2

- pyridinyl)oxy)phenoxy)propanoic acid, butyl ester CAS registry number 79241

- 46

- 6
End

- use product (EP) Fusilade® DX Herbicide (2 lb ai/gal EC; EPA Reg. No. 100

- 1070) Compound

Common name Fluazifop

- P (free acid) Company experimental name R151672
Chemical name ( R )

- 2

- (4

- [5

- (trifluoromethyl

- 2

- pyridinyl)oxy]phenoxy)propionic acid

Table A. 1. 2. Physicochemical Properties of Fluazifop

- P

- butyl.

Parameter Value Reference Melting point/range Decomposes at 210 oC 164 oC at 0.02 mm Hg 2002 Farm Chemicals Handbook RCB No. 1674, 2/3/87, L. Cheng pH Not dispersible in water RCB No. 1674, 2/3/87, L. Cheng Density 1.22 g/cc (PAI) and 1.20 g/cc (T) at 20 oC RCB No. 809, 6/3/86, L. Cheng

Water solubility 1 mg/L RCB No. 1674, 2/3/87, L. Cheng Solvent solubility Soluble in most organic solvents >500 g/L in acetone, dichloromethane, ethyl acetate, hexane, methanol, toluene, and xylene 2002 Farm Chemicals Handbook RCB No. 1674, 2/3/87, L. Cheng

Vapor pressure 3 x 10

- 8 KPa at 20 oC RCB No. 809, 6/3/86, L. Cheng Dissociation constant, pK a - 3.1 (by calculation) RCB No. 809, 6/3/86, L. Cheng Octanol/water partition coefficient, Log(K OW ) 4.5 at 20 oC RCB No. 809, 6/3/86, L. Cheng

### Page 15 of 27

Attachment 2. Toxicity Profile Tables

Table A2. 1 a . Fluazifop

- butyl Acute Toxicity Profile Guideline No. Study Type MRID(s) Results Toxicity Category 870.1100 Acute oral

– rat

(PP009; 97.2%) 00162439 (1983) LD 50 = 1940 mg/kg

(males) ± 1193

- 2758 mg/kg LD 50 = 2653 mg/kg (females) ± 1764

- 3625 mg/kg III

870.1200 Acute dermal

- rabbit

(PP009; 97.2%) 00162439 (1983) LD 50 > 2mL/kg (males

and females) or approximately 2000 mg/kg III

870.1300 Acute inhalation

- rat

(PP009; 97%) 79/ISK034/387 46082901,

same as 41563701 (1979) LC 50 > 2.3 mg/L for

43% with a particle size <5 μm LC 50 >4.37 mg/L for 83% with a particle size <10 μm III

870.2400 Acute eye irritation

- rabbit

(PP009; 93.3%) 79/ILK9/068 00088855 (1979) Non

- irritating IV

870.2500 Acute dermal irritation

– rabbit

(PP009; 93.3%) 79ILK8/056 00088853 (1979) Mild erythema at 72

hours IV

870.2600 Skin sensitization

– guinea pig

(PP009; 99.6%) 80/ILK026/349 00088854 (1980) Not a dermal

sensitizer Table A2. 1b. Fluazifop

- P

- butyl Acute Toxicity Profile Guideline No. Study Type MRID(s) Results Toxicity Category 870.1100 Acute oral

– rat

(PP005; 93.7% & 86.3% ) 00162440 (1984) LD 50 = 3680 mg/kg for

males LD 50 = 2451 mg/kg for female III

870.1200 Acute dermal

- rabbit

(PP005; 93.7% & 86.3%) 00162440 (1984) LD 50 > 2000 mg/kg or

>1.73 mL/kg III

870.1300 Acute inhalation

- rat

(PP005; 24.6%) CTL/P/3331 a 41917904 (1991) LC 50 > 1.7 mg/L III

870.2400 Acute eye irritation

- rabbit

(PP005; 86.3%) CTL/P/856 00162441 (1983) Mild irritation, cleared

within 3 days IV

870.2500 Acute dermal irritation

– rabbit

(PP005; 86.3%) CTL/P/856 00162441 (1983) Slight irritation,

cleared within 72 hours IV

870.2600 Skin sensitization

– guinea pig

(PP005; 99.6%) 80/ILK026/349 00162441 (1983) Not a dermal

sensitizer

a This study was conducted with a mixture of 24.6% fluazifop

- p

- butyl and 7.0% fenoxyprop

- p

- ethyl, however, the concentration fluazifop

- p

- butyl in the inhalation chamber was determined to be 1.7 mg/L. PPOO9 was used to indicate the technical grade of fluazifop

- butyl. PPOO5 was used to indicate the technical grade of fluazifop

- P

- butyl.

### Page 16 of 27

Table A .2. 2. Fluazifop

- butyl [FB] and Fluazifop

- P

- butyl [FPB] Subchronic, Chronic and Other Toxicity Profile Guideline No. Study Type MRID No. (year)/ Classification /Doses Results

870.3100 90

- Day oral

toxicity (rat) with FB 00093820 (1980)

Acceptable/guideline 0, 10, 100, 2000 ppm M: 0, 0.7, 7.1, 144.5 mg/kg/day F; 0, 0.8, 8.0, 161.9 mg/kg/day NOAEL= 0.7 mg/kg/day LOAEL=7.1 mg/kg/day based on liver and kidney histopathology.

870.3100 90

- Day oral

toxicity (rat) with FPB 46158402 (1985)

Acceptable/guideline 0, 10, 100, 2000 ppm

- F: 0, 0.5, 5, 100 mg/kg/day NOAEL= 0.5 mg/kg/day LOAEL=5 mg/kg/day based on decreased spleen weight and decreased hematological parameters in males. Dose related testicular weight decrement and cho lesterol depression. 870.3100 90

- Day oral

toxicity (mouse) No study available

870.3100 90

- Day oral

toxicity (hamster) with FPB 46082902 (2001)

Acceptable/guideline Males: 0, 19.5, 78.3 or 291.9 mg/kg/day Females: 0, 19.9, 79.0 or 319.6 mg/kg/day NOAEL = M/F: 78.3/79.0 mg/kg/day LOAEL = M/F: 291.9/319.6 mg/kg/day based on decreased body weight/body weight gain and food efficiency in males and evidence of liver toxicity; centrilobular eosinophilia/loss of glycogen in males and females. 870.3150 90

- Day o ral

toxicity (dog) with FB 00093821 (1980)

Acceptable/guideline 0, 5, 25, 125/250 mg/kg/day NOAEL = 25 mg/kg/day LOAEL = 125/250 mg/kg/day based on multiple pathologies in 3 dogs (2 males and 1 female) killed at 1 month dosed at 250 mg/kg/day. Also seen were body weight loss gut lesions, severe eye lesions and hepatotoxicity. In remaining surviving dogs dosed at 125 mg/kg/day, mild to equivocal liver lesions were seen. 870.3200 21/28

- Day dermal

toxicity (rabbit) with FB 00093819 (1980)

Acceptable/guideline 0, 100, 500, 2000 mg/kg/day NOAEL = 100 mg/kg/day LOAEL = 500 mg/kg/day based on death in 1 male and at 2000 mg/kg/day, death 4 males and 5 females, possibly due to kidney failure. 870.3465 90

- Day inhalation

toxicity (species) Data Waiver will be presented to HASPOC

.

870.3700 Prenatal

developmental toxicity in Sprague Dawley rats with FB 00008857, 92067047

(1981) Acceptable/guideline 0, 10, 50, 200 mg/kg/day Maternal NOAEL = 200 mg/kg/day; LOAEL = None based on maternal weight decrement due to gravid uterine weight decrement. Developmental NOAEL=none; LOAEL=10 mg/kg/day based on delayed ossification. At 200 mg/kg/day

- diaphragmatic hernia.

### Page 17 of 27

Table A .2. 2. Fluazifop

- butyl [FB] and Fluazifop

- P

- butyl [FPB] Subchronic, Chronic and Other Toxicity Profile Guideline No. Study Type MRID No. (year)/ Classification /Doses Results

870.3700 Prenatal

developmental toxicity in Sprague Dawley rats with FB 00088858, 9206 7048,

92967020 (1981) Acceptable/guideline 0, 1.0, 5.0, 10, 200 mg/kg/day Maternal NOAEL=200 mg/kg/day; LOAEL=None based on maternal weight decrement partially explained by gravid urine weight decrement. Developmental NOAEL=1 mg/kg/day; LOAEL=5 mg/kg/day based on fetal weight decrement and increased incidence of small fetuses and delayed ossification. At 200 mg/kg/day

- increased inc. of diaphragmatic hernia. 870.3700 Prenatal

developmental toxicity in Wistar rats with FPB 46158401 (1991)

Acceptable/guid eline 0, 0.5, 1.0, 20, 300 mg/kg/day Maternal NOAEL=20 mg/kg/day; LOAEL=300 mg/kg/day based on body weight gain decrement. Developmental NOAEL=1.0 mg/kg/day; LOAEL=20 mg/kg/day based on delayed ossification in skull bones, cervical arches and centrum in fetuses and litters and delayed ossification in the manus and pes. 870.3700 Prenatal

developmental toxicity in Wistar rats with FPB 46082903 (1989)

Acceptable/guideline 0, 2, 5 or 100 mg/kg/day Maternal NOAEL=100 mg/kg/day; LOAEL= None based no maternal toxicity. Developmental NOAEL=2.0 mg/kg/day; LOAEL=5.0 mg/kg/day based on based on dose related delayed ossification in skull bones [occipital and parietal] in fetuses and litters. 870.3700 Prenatal

developmental toxicity in Wistar rats with FPB 46082013 (1990)

Acceptable/guideline 0, 2.0, 5.0, 100 mg/kg/day Maternal NOAEL=100 mg/kg/day; LOAEL= None based on no toxic effects Developmental NOAEL=2.0 mg/kg/day; LOAEL=5.0 mg/kg/day based on delayed ossification in skull bones, sternebrae bipartite, sternebrae and calcenum unossified in fetuses and litters 870.3700 Prenatal

developmental toxicity in NZW rabbits with FB 00088856, 92067049,

92067021 (1981) Acceptable/guideline 0, 10, 30, 90 mg/kg/day Maternal NOAEL=30 mg/kg/day; LOAEL=90 mg/kg/day based on abortions. Developmental NOAEL=30 mg/kg/day; LOAEL=90 mg/kg/day based on nominal increases in delayed ossification, total litter loss, abortions, small fetuses, cloudy eyes all above mean or range of historical controls 870.3700 Prenatal

developmental toxicity in NZW rabbits with FPB 46082904 (1993)

Acceptable/guideline 0, 2, 10, 50 mg/kg/day Maternal NOAEL=10 mg/kg/day; LOAEL=50 mg/kg/day based death, abortions and body weight loss Developmental NOAEL=10 mg/kg/day; LOAEL=50 mg/kg/day based on increased incidence of 13 th rib and delayed ossification in sternebrae 2.

### Page 18 of 27

Table A .2. 2. Fluazifop

- butyl [FB] and Fluazifop

- P

- butyl [FPB] Subchronic, Chronic and Other Toxicity Profile Guideline No. Study Type MRID No. (year)/ Classification /Doses Results

870.3800 Reproduction and

fertility effects in
rats with FB 00088859, 92067050

(1981) Acceptable/guideline 0, 10, 80, 250 ppm M/F: 0/0, 0.74/0.88, 5.8/7.1, 21.7/17.5 mg/kg/day Parental/Systemic NOAEL = M/F 0.74/7.1 mg/kg/day; LOAEL = M/F 5.8/ 21.7 mg/kg/day based on decreased spleen wt. in males & increased absolute & relative liver & kidney wts. & geriatric nephropathy in females. Offspring NOAEL = 7.1 mg/kg /day; LOAEL = 21.7 mg/kg/day based on pup viability in f1 and f2 pups during lactational day 1, 4, 11, 18 & 25 and decreased f2 pup weight on lactational day 25. Reproductive NOAEL = M/F

- 0.74/0.88 mg/kg/day; LOAEL = M/F

- 5.8/7.1 mg/kg/day based on decre ased abs. & rel testes & epididymal weight and in females decreased pituitary & uterine weights. 870.4100 Chronic toxicity

-

rat 870.4300 satisfies the requirement

870.4100 Chronic toxicity

-

dog with FB 00131462, 00131463,

92067018 (1982) Acceptable/guideline 0, 5, 25, 125 mg/kg/day NOAEL = 5 mg/kg/day; LOAEL = 25 mg/kg/day based on marginally increased incidence adrenal fatty vacuolation & increased incidence of thymic involution and at 125 mg/kg/day death of 4/6 males and 2/6 females,
eye , gastrointestinal tract lesions, adrenal and bone marrow pathology & thymic involution 870.4200 Carcinogenicity

in hamsters with FPB 4534501, 46082905

(2001) Acceptable/guideline 0, 0, 200, 750, 3000 ppm M: 0, 0, 12.5, 47.4, 193.6 mg/kg/day F: 0, 0, 12. 1, 45.5, 181.4 mg/kg/day NOAEL =M/F 12.5/12.1 mg/kg/day LOAEL = 47.5/45.5 mg/kg/day based on based on increased incidence of males with reduced sperm, testicular degeneration, eye cataract changes, liver inflam m ation and gall stones and in females, increas ed incidence of ovarian stroma cell/sex chord hyperplasia. No evidence of carcinogenicity 870.4300 Combined

Chronic/ Carcinogenicity in rat with FB 41563703 (1985)

Acceptable/guideline 0, 2, 10, 80, 250 ppm M: 0, 0.10, 0.51, 4.15, 12.3 mg/kg/day F: 0, 0.13, 0.65, 5.2, 16.0 mg/kg/day NOAEL = M/F 0.51/5.2 mg/kg/day LOAEL = M/F 4.15/16.0 mg/kg/day based on increased mortality & nephropathy exacerbated by respiratory stress, and in females possible increased basal and/or follicular/luteal cysts. No evidence of carcinogenicity Gene Mutation 870.5100 Ames/

Salmonella typhimurium, reverse mutation with FB (96.8% a.i., batch/lot# P25 00162443, 92067023

Acceptable histidine deficient strains TA98, TA100, TA1535, TA1537, TA1538 of S. typhimurium were exposed in the presence and absence of mammalian metabolic activation by plate incorporation Negative with and without S9 up to the limit dose of 5000 μg/plate.

### Page 19 of 27

Table A .2. 2. Fluazifop

- butyl [FB] and Fluazifop

- P

- butyl [FPB] Subchronic, Chronic and Other Toxicity Profile Guideline No. Study Type MRID No. (year)/ Classification /Doses Results

Gene Mutation 870.5100 Ames/

Salmonella typhimurium, reverse mutation with FPB (93.6% a.i., batch/lot# P8) 00162442, 92067013

Acceptable histidine deficient strains TA98, TA100, TA1535, TA1537, TA1538 of S. typhimurium were exposed in the presence and absence of mammalian metabolic activation by plate incorporation Negative with and without S9 up to the lim it dose of 5000 μg/plate (insoluble at 5000 μg/plate).

Mammalian cell gene mutation
assay 870.5300 Mouse lymphoma

cell test with FPB (99.6% a.i., batch/lot # ADGM/1021/79) at concentrations of 0, 0.25, 2.5, 25, 250 or 2500 μg/mL 00116678

Acceptable heterozygous TK+/

- P 388 mouse lymphoma cells cultured in vitro were exposed in the presence and absence of mammalian metabolic activation, S9, for 30 minutes. Negative with and without S9 up to cytotoxic doses.

Mouse lymphoma L5178Y TK+
test 870.5300 Mammalian cell

gene mutation assay with FPB at 0, 100, 200, 500, 700, 1000 or 1500 μg/mL and to 0, 100, 200, 500, 700 or 1000 μg/mL 46082906

Acceptable mouse lymphoma L5178Y TK+ cells in vitro were exposed 4 hr with and without S9 activation. In second assay the cells were exposed with and without S9 activation. Test was negative with and without S9 activation up to and including excessive precipitation.

In vitro chromosomal aberrations in human blood lymphocytes 870.5375 Mammalian cell

cytogenetic assays (chromosome aberration) with FPB (R

- enantiomer, 93.8% a.i.; CTL ref. # Y02746/001/008) in dimethyl sulfoxide at concentrations of 0, 1, 10, 100, 500, or 1000 μg/mL 41555202 (1985)

lymphocyte cultures prepared from human peripheral blood were exposed for 4 hours both in the presence and absence of S9

- activation. Cells were harvested at 27 hours after initiation of
treatment. There was no evidence of chromosome aberration induced over background in the presence or absence of S9

- activation a t toxic doses.

### Page 20 of 27

Table A .2. 2. Fluazifop

- butyl [FB] and Fluazifop

- P

- butyl [FPB] Subchronic, Chronic and Other Toxicity Profile Guideline No. Study Type MRID No. (year)/ Classification /Doses Results

In vivo rat mammalian cytogenetics; bone marrow chromosomal aberrations 870.5385 Bone marrow

chromosome aberration assays with FB (94.5% a.i.; Lot/Batch #: CTL Compound code: Y00083/001/006), in corn oil at doses of 0, 21.0, 67.2, or 210.0 mg/kg. 00088861 (1980)

Acceptable 10 male CD rats/dose were treated via oral gavage (10 mL/kg) either once (acute) or daily for 5 consecutive days (sub

acute). Bone marrow cells were harvested at 6 or 24 hours after treatment in the acute study, and at 6 hours after treatment in the sub

- acute study. There was no evidence of chromosome aberration induced over background at toxic doses.

In vivo

mouse micro

nucleus test 870.5395 in vivo mammalian

cell mouse micro nucleus assay with FB or FPB at doses of 250 or 400 mg/kg 00016244,92068014

(1983) C57BL/6J mice

- bone marrow removed after 24, 48 or 72 hours to determine the frequency of MPCEP. FB and FPB were tested up to 80% and 50% of the LD50 in mice. There was no adequate evidence of a positive response of increased micronuclei over background with either fluazifop

- butyl [FB] or fluazifop

- P

- butyl [FPB] at toxic doses.

Mouse Dominant lethal test 870.5450 DNA damage in

Bacillus subtilis

Other Effects 870.5900 sister chromatid exchange
assay Dominant lethal

assay [PP009, fluazifop

butyl (97.0% a.i., batch/lot # 310M)] at dose levels of 0, 28.7, 91.8 or 287 mg/kg/day in corn oil (10 mL /kg) 00088862 (1980)

Unacceptable 25 CD

- 1 male mice/group treated for 5 days for the first mating. Based on t he results of the first mating, subsequent matings were based on 15 of the 25 dosed males. These 15 males were mated with 30 females in 8 sets and the females examined for dominant lethal effects (resorptions) at day 15 of
pregnancy. Top dose not sufficien tly toxic. The investigators reported that fluazifop

- butyl does not cause dominant lethal effects in CD

- 1 mice up to and including 287 mg/kg/day for 5 days. No toxicity demonstrated.

870.6100 Acute

neurotoxicity in hens with FB 00093818 (1981)

Acceptable/guideline 0, 3750, 7500 or 15000 or 15000 mg/kg Fluazifop

- butyl exposed hens showed no evidence of delayed neurotoxicity.

870.6200 Acute

neurotoxicity screening battery

- rat 49188708 Under review

### Page 21 of 27

Table A .2. 2. Fluazifop

- butyl [FB] and Fluazifop

- P

- butyl [FPB] Subchronic, Chronic and Other Toxicity Profile Guideline No. Study Type MRID No. (year)/ Classification /Doses Results

870.6200 Subchronic

neurotoxicity screening battery

- rat 4918870 5 Under review

870.6300 Developmental

neurotoxicity Not required

870.7485 Metabolism and

pharmaco

- kinetics in (rats) with FB 00093822 through

00093828 (1981) Acceptable/guideline 1 mg/kg and 1000 mg/kg Fluazifop

- butyl is rapidly hydrolyzed to fluazifop acid by blood enzymes and excreted as the acid and its conjugates in the urine of males and females. Due to biliary excretion parent compound, fluazifop acid and its conjugates are excreted in the feces of males at much higher prop ortions than in feces of the female. Excretion was complete in 7 days, with the exception of small amounts in the fat in
some rats. 870.7600 Dermal penetration MRID# 46082918 a human study/NG satisfies guideline 870.7600. 870.7800 Immunotoxicity 4918870 6 Under review

### Page 22 of 27

Attachment 3

. Fluazifop

- P

- butyl Endpoints and Doses for Risk Assessment

Table A3 .1

. Summary of Toxicological Doses and Endpoints for Fluazifop

- P

- butyl for Use in Dietary and Non

- Occupational Human Health Risk Assessments

Exposure/ Scenario Point of

Departure Uncertainty/FQP

A Safety Factors RfD, PAD,

Level of Concern for Risk Assessment Study and Toxicological Effects

Acute Dietary (General Population, including Infants and Children) An appropriate endpoint attributable to a single dose was not identified in the available studies

including the developmental toxicity studies.

Acute Dietary (Females 13

- 49 years of age) NOAEL =

50 mg/kg/day UF A = 10x

UF H = 10x FQPA SF= 1x Acute RfD =

0.50 mg/kg/day Developmental Toxicity in rats

LOAEL = 200 mg/kg/day based on diaphragmatic hernia

Chronic Dietary (All Populations) NOAEL=

0.74 mg/kg/day UF A = 10x

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

= 0.008 mg/kg/day

cPAD = 0.0074 mg/kg/day Two

- Generation Reproduction in rats

LOAEL = 5.8 mg/kg/day in males and 7.1 in females based on decreased spleen, testes & epididymal weights in males and uterine & pituitary weights in females

Incidental Oral Short

Term (1

- 30 days) NOAEL=

100 mg/kg/day UF A = 10x

UF H = 10x FQPA SF= 1x Residential

LOC for MOE = 100 Developmental Toxicity Study in rats

LOAEL = 300 mg/kg/day based on maternal body weight decrement during GD 7

- 16.

Incidental Oral Intermediate

Term (1

- 6 months) NOAEL=

0.74 mg/kg/day UF A = 10x

UF H = 10x FQPA SF= 1x Residential

LOC for MOE = 100 Two

- Generation Reproduction in rats

LOAEL = 5.8 mg/kg/day in males and 7.1 in females based on decreased spleen, testes & epididymal weights in males and uterine & pituitary weights in females Dermal Short

- Term (1

- 30 days) a (Females 13

- 49) NOAE L=

2.0 mg/kg/day UF A = 10x

UF H = 10x FQPA SF= 1x Residential

LOC for MOE = 100 Developmental Toxicity Study in rats

LOAEL = 5.0 mg/kg/day based on fetal weight, hydroureter and delayed ossification Dermal Short

- Term (1

- 30 days) a ( General Population including Infants & children) NOAEL=

100 mg/kg/day UF A = 10x

UF H = 10x FQPA SF= 1x Residential

LOC for MOE = 100 Developmental Toxicity Study in rats

LOAEL = 300 mg/kg/day based on maternal body weight decrements during GD 7

- 16.

### Page 23 of 27

Table A3 .1

. Summary of Toxicological Doses and Endpoints for Fluazifop

- P

- butyl for Use in Dietary and Non

- Occupational Human Health Risk Assessments

Exposure/ Scenario Point of

Departure Uncertainty/FQP

A Safety Factors RfD, PAD,

Level of Concern for Risk Assessment Study and Toxicological Effects

Dermal Intermediate

Term (1

- 6 months) a NOAEL=

0.74 mg/kg/day UF A = 10x

UF H = 10x FQPA SF= 1x Residential

LOC for MOE = 100 Two

- Generation Reproduction in rats

LOAEL = 5.8 mg/kg/day in males and 7.1 in females based on decreased spleen, testes & epididymal weights in males and uterine & pituitary weights in females Inhalation Short

- Term (1

- 30 days) b (Females 13

- 49) NOAEL=

2.0 mg/kg/day UF A = 10x

UF H = 10x FQPA SF= 1x Residential

LOC for MOE = 100 Developmental Toxicity Study in rats

LOAEL = 5.0 mg/kg/day based on fetal weight, hydroureter and delayed ossification Inhalation Short

- Term (1

- 30 days) b General Population including Infants & children) NOAEL=

100 mg/kg/day UF A = 10x

UF H = 10x FQPA SF= 1x Residential

LOC for MOE = 100 Developmental Toxicity Study in rats

LOAEL = 300 mg/kg/day based on maternal body weight decrements during GD 7

- 16.

Inhalation Intermediate

Term (1

- 6 months) b NOAEL=

0.74 mg/kg/day UF A = 10x

UF H = 10x FQPA SF= 1x Residential

LOC for MOE = 100 Two

- Generation Reproduction in rats

LOAEL = 5.8 mg/kg/day in males and 7.1 in females based on decreased spleen, testes & epididymal weights in males and uterine & pituitary weights in females Cancer (oral, dermal, inhalation) Classification: “Not likel y to be carcinogenic to humans.”

a Use either 9% (low exposure scenario) or 2% (high exposure scenario) for route

- to

- route extrapolations
b Absorption via the inhalation route is presumed to be equivalent to oral absorption.

Point of Departure (PoD) = A data point or an estimated point that is derived from observed dose

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF L = use of a LOAEL to ext rapolate a NOAEL. FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose.

### Page 24 of 27

Table A3 .2

. Summary of Toxicological Doses and Endpoints for Fluazifop

- P

- 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 Short

Term (1

- 30 days) NOAEL=

2.0 mg/kg/day UF A =10x

UF H =10x Occupational LOC

for MOE = 100 Developmental Toxicity Study in rats

LOAEL = 5.0 mg/kg/day based on fetal weight, hydroureter and delayed ossification

Dermal Intermediate

Term (1

- 6 months) NOAEL=

0.74 mg/kg/day UF A =10x

UF H =10x Occupational LOC

for MOE = 100 Two

- Generation Reproduction in

rats

LOAEL = 5.8 mg/kg/day in males and 7.1 in females based on decreased spleen, testes & epididymal weights in males and uterine & pituitary weights in females

Inhalation Short

- Term (1

- 30 days) NOAEL=

2.0 mg/kg/day UF A =10x

UF H =10x Occupational LOC

for MOE = 100 Developmental Toxicity Study in rats

LOAEL = 5.0 mg/kg/day based on fetal weight, hydroureter and delayed ossification

Inhalation Intermediate

term (1

- 6 months) NOAEL=

0.74 mg/kg/day UF A =10x

UF H =10x Occupational LOC

for MOE = 100 Two

- Generation R eproduction in

rats

LOAEL = 5.8 mg/kg/day in males and 7.1 in females based on decreased spleen, testes & epididymal weights in males and uterine & pituitary weights in females Cancer (oral, dermal, inhalation) Classification: “Not likely to be carcinogenic to humans.”

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

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human p opulation (intraspecies). UF L = use of a LOAEL to extrapolate a NOAEL. UF S = use of a short

- term study for long

- term risk assessment. UF DB = to account for the absence of key data (i.e., lack of a critical study). MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

### Page 25 of 27

Attachment 4

. Fluazifop

- P

- butyl International Residue Limits Table

Table A4. Summary of US and International Tolerances and Maximum Residue Limits : Fluazifop

- P

- butyl (PC Code 122809) Residue Definition : US Canada Mexico 2 Codex 40 CFR 180.411: Plants and livestock: sum of fluazifop

- P

butyl, butyl(R)

- 2

- [4

- [[5

- (trifluoromethyl)

- 2

- pyridinyl]oxy]phenoxy]propanoate, and the free and conjugated forms of the resolved isomer of fluazifop, (R)

- 2

- [4

- [[5

- (trifluoromethyl)

- 2

- pyridinyl]oxy]phenoxy]propanoic acid, calculated as the stoichiometric equivalent of fluazifop butyl (RS)

- 2

- [4

- [[5

- (trifluoromethyl

- 2

- pyridinyl]oxy] phenoxy]propanoate (calculated as acid) None

Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg) US Canada Mexico 2 Codex Banana 0.01 Beans, dry, seed 50 0.15 Dry (adzuki beans, beans, blackeyed peas, broad beans, catjang seeds, chickpeas, cowpea seeds, guar seeds, kidney beans, lablab beans, lima beans, moth beans, mung beans, navy beans, pink beans, pinto beans, rice beans, southern peas, tepary beans, urd beans, grain lupin

1 dry soybeans Beet, sugar, dried pulp 1.0 Beet, sugar, molasses 3.5 Beet, sugar, roots 0.25 Carrot, roots 2.0 2 Cattle, fat 0.05 0.05 Cattle, meat 0.05 0.05 Cattle, meat byproducts 0.05 0.05 Citrus, dried pulp 0.40 Citrus, juice 0.06 Citrus, oil 30.0 Cotton, gin byproducts 1.5 Cotton, refined oil 1.3 0.2 Cotton, undelinted seed 1.0 0.1 Egg 0.05 0.05 Endive 6.0 Fruit, citrus, group 10 0.03 Fruit, stone 0.05 0.05 apricots, fresh prune plums, nectarines, peaches, plumcots, plums, sweet cherries, tart cherries Goat, fat 0.05 0.05 Goat, meat 0.05 0.05 Goat, meat byproducts 0.05 0.05 Grape 0.01 0.03 Hog, fat 0.05 0.05 Hog, meat 0.05 0.05

### Page 26 of 27

1 No US registration

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

(c) Tolerances with regional registrations. Tolerances with regional registrations are established for residues of the herbicide fluazifop

- P

- butyl, including its metabolites and degradates, in or on the following commodities in the table. Compliance with the tolerance levels specified in the table below is to be determined by measuring only the sum of fluazifop

- P

- butyl, butyl(R)

- 2

- [4

- [[5

- (trifluoromethyl)

- 2

- pyridinyl]oxy]phenoxy]propanoate, and the free and conjugated forms of the resolved isomer of fluazifop, (R)

- 2

- [4

- [[5

- (trifluoromethyl)

- 2

- pyridi nyl]oxy]phenoxy]propanoic acid, calculated as the stoichiometric equivalent of fluazifop, in or on the commodity.

Commodity Parts per million Canada
Asparagus 3.0 3
Coffee, bean 0.1 0.1 green coffee beans
Pepper, tabasco 1.0

Rhubarb 0.5 0.5 Hog, meat byproducts 0.05 0.05 Horse, fat 0.05 0.05 Horse, meat 0.05 0.05 Horse, meat byproducts 0.05 0.05 Milk 0.05 0.05 Nut, macadamia 0.10 0.1 Onion, bulb 0.50 0.5 Peanut 1.5 1.5 Peanut, meal 2.2 Pecans 0.05 0.05 Poultry, fat 0.05 0.05 Poultry, meat 0.05 0.05 Poultry, meat byproducts 0.05 0.05 Potato 1 1.0 1 Potato, chips 1 2.0 2 Potato, granules/flakes 1 4.0 4 Sheep, fat 0.05 0.05 Sheep, meat 0.05 0.05 Sheep, meat byproducts 0.05 0.05 Soybean, seed 2.5 1 dry soybeans Sweet potato, roots 0.05 0.5 MRLs with NO US Equivalent Blueberries 0.1 Flaxseeds 0.2 Mustard 0.3 Non

- bell peppers 1 Solin 0.2 Strawberries 1

Completed: M. Negussie; 07/22/14

### Page 27 of 27

Attachment 5

. Fluazifop

- P

- butyl Residues of Concern.

Table A5 . Fluazifop

- P

- Butyl Residues of Concern in Plants, Livestock, Rotational Crops and Water. Residues of Concern Matrix For Tolerance Expression For Risk Assessment Plants Parent and fluazifop acid (free and conjugated) Parent and fluazifop acid (free and conjugated), 5

- trifluoromethyl

- 2

- pyridone, and 2

- (4

- hydroxyphenoxy)propionic acid (free and conjugated) Livestock Parent and fluazifop acid (free and conjugated) Parent and fluazifop acid (fr ee and conjugated) Rotational Crops No decision 1 No decision 2 Water NA Parent and fluazifop acid

1 Parent and fluazifop acid (free and conjugated)

. 2 Parent and fluazifop acid (free and conjugated), and 5

- trifluoromethyl

- 2

- pyridone

.