Flu azifop- P-but y l Human Health Ri sk Assessment 

### DP No. 0 420423

UNITED STATES ENVIRONMENTAL PROTECT ION A GENCY

WASH INGTON

, D.C. 20460

MEMORAND U M

Date : 2 1-J UL-20 15 OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION

SUBJECT: Fluazifop-P-Butyl. Hum an -H ea l th Ri s k Assessme nt for Swee t Potato Lab e l Amend m e nt and Resulting T olerance In c r ease.

PC Code: 1 22809 D ec i s ion No.: 489431 Petition No.: 4F8262 DP Barcodc: D4 20423 Regi s tration No

. : 100-100 1

, 100-1070 Regulatory Act ion: Label A mendment Case No. : NA Ri s k Assessme nt T y pe: Sing l e chemical
aggre g at e TXR No.: NA CAS No.: 7924 1 -46-6 40 CF R : §180.41 1 M RID No .: NA

FROM:

THROUGH:

TO: WilliamH.Donovan

, C hemi s t

# LJ~**~** Ronnie J. Bever Jr.
, Toxicolo g i s t

## ~ 

# 1 · 'f}-&v-eA/'TI · A l exandra Gavelek, Biolo gis t

### ~ 

### I

- , , '- t, t 

# G C

L/
Ri s k Assessment Branch V & V II f l ea l th Effec t s Division (7509P)

Michael S. Metzger
, Branch C hi ef

# ~I 

# nJ)

. Risk Assessment Branch V & VII

## ~ Health Effects Division (7509 P )

Banza Djapao

, Environmental P ro te ction Speciali s t Fungicide Herbicide Branch Registration Division

Pa g e I of38Fl uazi fop -P-but yl Human H ea lth Ri sk Assessme nt DP No

. D4 20423

Tab l e of Con tent s 1.0 E xecu ti ve Su n1n1 a r y

.. . .................. .. .. .. . ....... ... . ....... . ........... ................ .. ............ .. . .. . ... . .. ......... 4 2 .0 1-I E D R eco mrn e nd a tion s

...... . ... . ... . .. .. ... .. .. .............. .. .. ...... .. .. . ... .. . .. .. . ... . .. . .. . ...... . ...... .. .. ..... . .. . 6 2 .1 Data Defici e n c i es

........ . . .. .. .. .. .. .. .. ....................... .. . ... . ... . ... . ...... .. . .. . ..... ... . ...... ............ .. .. . ... 6 2.2 Tolerance Co n s id era ti ons

............ .. .. ........... .. .. .. . ... . ... . ... ..................................... .. . .. . .. .. .. .. . 6 2.2.1 E n forceme n t Analytica l Method

........................... .. .. .. .. .. . ... ................... .. . .. . . ............... 6 2.2.2 R ecommended Tolerances

............................................................................................ 6 2.2.3 Revisions to P et iti oned -F o r Tolerances

........... .......... .................................. . . ...... ......... 7 2.2.4 Int ernational H

. a rm onizat i o n .

. ... .. .. ............... .. . ... . ... .. .. ................................. ......... . .. ...... 7 2.3 Label R eco n1m enda tion s

... . ... . .. .. .. ....................... .. . ... . ... . .. .. . .......... . ................... .. .. .. ......... 7 3

. 0 Introdu ct i o n

. .................................................................... . .. .. .. . .. .. ................... .. . .. ................. 7 3

. I Ch e mical Id e ntit y

... .. .. .. . .......... .. .. .. .. ... . .. .. .. ... . ... . ... . ... . ... . .. .. .. . .. .. .. . .. .. .. . ......... ... . .. . .. ..... . ... . .. 7 3

. 2 Ph ysica l /C hemi ca l C h aracte ri st i cs

............................ .. . .......... .. .. . .. .. . ... . .. .. . .. . ... . .. .............. 8 3.3 P est i c id e Use P a tt ern

. .. . ... . ... . .. ............................... .. . ... . ... .................................... .. .. ..... .... 8 3.4 Anticipated Exposure P at hw ays

....................................................................................... 8 3.5 Cons id eration of E n viro nm ental Justice

...................................................... ............ ........ 9 4.0 H azard C h a r acterizatio n and D ose-Response Assessment

.................................................. 9 4.1 Summary of T ox i cologica l Effects

.. .. .............. ... . ... . ... ..................................................... 9 4.2 Safe t y Facto r for In fants a nd Children (FQ PA Safety Factor)

......................... . .. .. .. . ...... 1 1 4.2 .1 Co mpl e t eness of the Toxicol ogy D a t abase

.. .. .. .. .. .. .. .. .. .. .. . .. .. . .. .. .. .. . .. .. . .. .. .. . ...... . . ....... 1 2 4.2.2 Evide n ce of Ne u rotox i c ity

. . ... . ... . ... .. .. .. .. ...... ... . ........... . ...... . .. .. .. . ...... . .. .. .. . .. .. ..... .......... 1 2 4.2.3 Evidence of Se n s i t i v it y/S u sce ptibilit y in th e Deve l op in g or Young A nim a l

............. 1 2 4.2.4 R esidual Uncerta int y in th e Exposure D atabase

. ... . .. .................................................. 1 4 4.3 Tox i c it y Endpo int and P o int of Departure Se l ect i ons

.. .................................................. 14 5.0 Dietary Exposure a nd Risk Assessment

................ .......... ......................... . ........................ 1 8 5.1 Residues of Concern Su mm ary and Rationa l e

............................................................... 18 5.2 Food Residue Profile

...... .. .. . ... .. .. . ... .. ................................................................. .. . ... . .. .... 18 5.3 Water Res i due Pr ofi l e

. .. . .. .. .. .. .. . ....... .. .. .. . ... . ... .. .. .. .. ...... .. .. . .. .. ...... ............ ..... . ......... .. .. .... 18 5.4 Diet ary Ri sk Assess m e nt

.. . ... . ...... ................... .. . .................. .. .. . .. .. .. .. . .. .................... . . ..... 1 9 5.4 .1 D escr ipti o n o f R es idue D ata Used in Dietar y Assess ment..

.......................... . .. .. .. . .. . .. 1 9 5.4

. 2 P e r cent Crop T r eated Used i n Di e t a r y Assess ment..

.................................................. 1 9 5.4.3 Acute Di e t ary Ri sk Assessme nt

....................................................................... . .. .. . .. .. 19 5.4.4 Ch r on i c Dietary Risk Assessment

........ . ... ... .. .. .. ... . ... ......................... .. ...... . ................ 20 5.4.5 Cancer Dietary Risk Assessment..

.......................................................................... .. .. 20 5.4.6 Summary Table

........... .. .................................................................................. . ........... 20 6.0 Residential (No n- Occu p a ti onal) Exposu r e / R i sk C haract e ri zat i o n

............ .. .. .. . ...... . ... . .. .... 20 6.1 Re s id e nti a l H a ndl er Expos ur e

........................................................................................ 2 1 6.2 R es id e nti a l Post-app li cat i o n Exposu r e / Risk Es timate s

... . .. .. .. .. . ................... .. .. ...... . .. . .. .. 23 6.3 Re s i den ti al Ri s k Es timates for U se in Agg r egate Assessment

...................................... 23 6.4 Spray Dri f t

............. . ...... . .. .. ... . ... . ... . ... . ... .. . ... . ... .. ... . .. .. ... . .. .. .. . ... . .. .. .. . .. .. .. .. . . ... . .................. 24 6.5 R es id entia l Bystander Post-Application Inh a l at i o n Exposure

.......... .. ... . .... ... . .. ............. 24 7.0 Agg re gate Exposure / Risk Characterization

....................................................................... 25 7. l Acute Agg r egate Risk

.................................................................................................... 25 7.2 Short-Te r m Aggregate R isk

.................. . ........ . .. .. . ........... ........................... ........ .. .. ........ 25 7.3 Intermediate-Term Agg r egate Risk

................................................................................ 26

P a g e 2 of 38Fluazifop

- P

- butyl Human Health Risk Assessment DP No. D420423

Page 3 of 38 7.4 Chronic Aggregate Risk

................................ ................................ ................................ . 26 8. 0 Cumulative Exposure/Risk Characterization

................................ ................................ ..... 26 9.0 Occupational Exposure/Risk Characterization

................................ ................................ .. 26 10.0 References

................................ ................................ ................................ .......................... 27 Appendix A. Toxicology Profile and Executive Summaries

................................ ....................... 28 A.1 Toxicology Data Requirements

................................ ................................ ...................... 28 A.2 Toxicity Profiles

................................ ................................ ................................ ............. 29 Append ix B. Physical/Chemical Properties

................................ ................................ ................. 37 Appendix C. Review of Human Research

................................ ................................ ................... 38Fluazifop

- P

- butyl Human Health Risk Assessment DP No. D420423

Page 4 of 38 1.0 Executive Summary

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 poste mergence control of perennial and annual grass weeds. Fluazifop

- P

- butyl is the R enantiomer of fluazifop

- butyl [( R,S )

- 2

- (4

- ((5

- (trifluoromethyl)

- 2

- pyridinyl)oxy)phenoxy)propanoic acid, butyl ester]. Fluazifop

- butyl (PC Code 122805) r egistrations have bee n cancelled and only fluazifop

- P

- butyl registrations are currently supported. Fluazifop

- P

- butyl is currently registered for food/feed use on many agricultural crops. Fluazifop

- P

- butyl products are typically applied as postemergence foliar or soil applica tions using ground or aerial equipment.

In the current petition (PP# 4F8262), Syngenta has requested a label amendment to reduce the sweet potato pre harvest interval ( PHI ) from 55 to 14 days

, and requested an increase in the sweet potato root tolerance from 0.05 to 1.5 ppm

.

T he toxicology database for fluazifop

- P

- butyl consists of studies conducted using fluazifop

- butyl (racemic mixture) and its enriched R

- isomer, fluazifop

- P

- butyl. Comparison studies have shown similar toxicities from both compounds

. The toxicity database for fluazifop

- P

- butyl is complete and adequate for characterization of potential developmental, reproductive, carcinogenetic, mutagenic, immunotoxic

, and neurotoxic effects. The liver and kidney are the target organs

, and the toxi city is expressed as liver toxicity in the presence of peroxisome proliferation and exacerbation of age

- related kidney toxicity.

An acute dietary endpoint for the general U.S. population , including infants and children, was not identified. An acute diet ary endpoint for females 13

- 49 years of age was selected from a developmental toxicity study in rats based on diaphragmatic hernia ( N OAEL=50 mg/kg/day). The short

- term incidental oral endpoint was selected from the developmental toxicity studies in
rats an d is based on maternal body weight gain decrement (NOAEL=100 mg/kg/day). The chronic dietary (all populations), intermediate

- term dermal and inhalation, and intermediate term incidental oral endpoints were selected from the two

- generation reproduction stu dy in rats based on decreased spleen, testes and epididymal weights in males, and decreased uterine and pituitary weights in females (NOAEL = 0.74 mg/kg/day). The short

- term dermal for adults and inhalation endpoints used in the assessment were selected f rom the developmental toxicity studies in rats based on decreased fetal weights, hydroureter, and delayed ossification (NOAEL = 2 mg/kg/day). The short

- term dermal endpoint for children used in the assessment was selected from the developmental toxicity s tudies in rats based on maternal body weight gain decrement (NOAEL=100 mg/kg/day)

. Because oral NOAELs were selected for dermal and inhalation endpoints, dermal absorption factor s were used for oral

- dermal route

- to

- route extrapolation, and inhalation toxi city was assumed to be equivalent to oral toxicity

. Fluazifop

- P

- butyl is classified as “not likely to be carcinogenic to humans”, and no mutagenic potential was observed in adequate in vivo and in vitro studies with fluazifop

- P

- butyl.

HED recommends that the required 10X FQPA Safety Factor be reduced to 1X

, because n o increase in offspring sensitivity over parent was seen in the developmental or reproduction studies
, no evidenc e of neurotoxicity was observed

, and the exposure assessments are unlikely to underestimate exposure

.Fluazifop

- P

- butyl Human Health Risk Assessment DP No. D420423

Page 5 of 38 The fluazifop

- P

- butyl residue chemistry database support s the present petition , as adequate field trial data reflecting the amended use pattern for sweet potato were submitted

. Using the Organization for Economic Cooperation a nd Development (OECD) Maximum Residue Limit (MRL) calculation procedures with residues reflecting the proposed shorter PHI of 14 days, the recommended tolerance level for sweet potato roots is 1.5 ppm.

A cute and chronic risk assessment s were conducted fo r dietary exposure (food and water)

, including all registered crops and the new residue data for sweet potatoes

. The acute dietary analysis was unrefined ( i.e ., 100% crop treated and tolerance level residues). The resulting acute dietary exposure estimate for females 13

- 49 years old, the only relevant population subgroup, was 14% aPAD. The chronic dietary analyses were partially refined making use of average residues from the supervised field trials, percent cr op treated estimates and empirical processing factors, where available. The resulting chronic exposure estimates were less than HED’s level of concern (≤100% chronic PAD) for general U.S. population ( 17 % cPAD) and all population sub

groups. The most high ly exposed population subgroup was Children 1

- 2 years old with an estimated risk of 64 % cPAD.

E xisting residential uses of fluazifop

- P

- butyl were reassessed to reflect the updates in HED’s 2012 Residential SOPs 1 along with policy change s for body weigh t assumptions. All residential handler margins of exposure ( MOEs ) are greater than the level of concern ( LOC ) and are not of

concern. Further, a ll residential post

- application MOEs are greater than the LOC and not of

concern. An updated occupational ass essment is not required for the current label amendment.

An updated short

- term aggregate (food, drinking water and residential exposures) risk assessment gave risk estimates below HED’s LOC for children and adults. Based on current and proposed uses of fluazifop

- P

- butyl, neither intermediate

- nor long

- term aggregate exposures are expected.

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Ord er 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income Populations," ( http://epa.gov/compliance/ej/resources/policy/exec_order_12 898.pdf ).

This risk assessment relies

, in part

, on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical (Appendix C)

. These studies are subject to ethics review pursuant to 40 CFR 26, have received that review, and are compliant with applicable ethics requirements.

2.0 HED Recommendations

HED has no objections to the proposed sweet potato label amendment specifying a PHI of 14 da ys and the resulting tolerance increase to 1.5 ppm for sweet potato roots.

1 Available: http://www.epa.gov/pesticides/science/residential

- exposure

- sop.htmlFluazifop

- P

- butyl Human Health Risk Assessment DP No. D420423

Page 6 of 38 2.1 Data Deficiencies

Turf Transferable Residue (TTR): In accordance with 40 CFR 158, turf transferable residue (TTR) data are required for all occupational (e.g., sod farms, gol f courses, parks, and recreational areas) or residential 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 2

, as described below.

Since t he estimated residential turf postapplication exposure 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 40 C FR TTR data to facilitate any necessary exposure assessment refinements and to further EPA’s general understanding of the availability of turf transferable pesticide residues.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Adequate enforcement methodology (High Performance Liquid Chromatography/Ultra

- Violet Spectrometry (HPLC/UV)) is available to enforce the tolerance expression. The method is available in Pesticide Analytical Methods (PAM), Volume II : Method I for animal tissues an d milk and Method II for crops. The stated detection limits are 0.02

- 0.05 ppm for crops, 0.01 ppm for milk, and 0.02 ppm for animal tissues. Improved enforcement methods based on liquid chromatography and tandem mass spectroscopy, LC/MS/MS , are available as Method GRM044.01A and Method GRM044.02 A . Both of these methods have been validated at 0.01 ppm on a wide variety of crop matrices.

2.2. 2 Recommended Tolerances

Tolerances are currently established under 40 CFR §180.411 for residues of fluazifop

- P

- b utyl 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

- (triflu oromethyl)

- 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 measuring only those fluazifop

- P

- butyl residues con vertible to fluazifop, 2

- [4

- [[5

- (trifluoromethyl)

- 2

- pyridinyl]oxy]phenoxy]propanoic acid

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

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

. 10/23/2014 , Exposure Science Advisory CouncilFluazifop

- P

- butyl Human Health Risk Assessment DP No. D420423

Page 7 of 38 Table 2.2.3

. Tolerance Summary for Fluazifop

- P

- Butyl.
Commodity Proposed Tolerance (ppm) Recommended

Tolerance (ppm) Comments

Correct Commodity Definition Sweet potato, roots 1.5 1.5

2.2. 3 Revisions to Petitioned

- For Tolerances

None.

2.2. 4 International Harmonization

Codex has not established fluazifop

- P

- butyl Maximum Residue Limits (MRLs) in/on any commodity. Most of the Canadian MRLs are harmonized with the U

. S

. tolerances. However, the Canadian MRL for sweet potato is 0.5 ppm, while the recommended U.S. tolerance is 1.5 ppm. Harmonization of the U.S. tole rance with the Canadian MRL is not possible since the results of field trials reflecting a 14

- day PHI show that residue levels in sweet potato roots may exceed 0.5 ppm.

2.3 Label Recommendations

None.

3.0 In troduction

3.1 Chemical Identity

Table 3

. 1. Fluazifop

- P

- butyl Nomenclature. Compound

Empirical Formula C 19 H 20 F 3 NO 4 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) Chemical Class PhenoxyFluazifop

- P

- butyl Human Health Risk Assessment DP No. D420423

Page 8 of 38 Table 3

. 1. Fluazifop

- P

- butyl Nomenclature. Compound

Common name Fluazifop

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

- 2

- (4

- [5

- (trifluoromethyl

- 2

- pyridinyl)oxy]phenoxy)propionic acid

3.2 Physical/Chemical Characteristics

The physical/chemical properties of fluazifop

- P

- butyl are summarized in Appendix B. T he compound is not particularly volatile (vapor pressure = 3 x 10

- 8 k Pa) , and the log K OW (4.5) suggest s a potential to partition into fatty tissue s or bioaccumulate

.

3.3 Pesticide Use Pattern

The label directions are clear and complete

. Table 3.3 provides a summary of the proposed use directions on sweet potato, which include a reduced PHI of 14 days as compared to the 55 day PHI on the existing label

. T he submitted field trials reflect the maximum application rates and follow the proposed label directions.

Table 3

. 3 . Summary of Directions for Use of Fluazifop

- P

- Butyl.
Applic. Timing, Type, and Equip. Formulation

[EPA Reg. No.] Applic.

Rate (lb ai/A) Max. No.

Applic. per Season Max.

Seasonal Applic. Rate (lb ai/A) RT I

(days) PHI

(days) Use Directions and

Limitations

Sweet Potato

Foliar broadcast Fusilade DX

[100

- 1070] 0.1875 4 0.75 14 14 Use crop oil concentrate or

non

- ionic surfactant

3.4 Anticipated Exposure Pathways

The Registration Division has requested an assessment of human health risk to support the label amendment request to reduce the PHI for use of fluazifop

- P

- butyl on sweet potatoes. Humans may be exposed to fluazifop

- P

- butyl residues in food and drinking wa ter, since fluazifop

- P

- butyl may be applied directly to growing crops and application may result in fluazifop

- P

- butyl reaching surface and ground water sources of drinking water. There are residential uses of fluazifop

- P

- butyl , so an assessment of exposur e in residential settings is provided . In an occupational setting, applicators may be exposed while handling the pesticide prior to application, as well as during application. There is a potential for post

- application exposure for workers re

- entering tre ated fields.Fluazifop

- P

- butyl Human Health Risk Assessment DP No. D420423

Page 9 of 38 This risk assessment considers all of the aforementioned exposure pathways based on the amended and existing use s of fluazifop

- P

- butyl

,

3.5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income Populations," ( http://epa.gov/compliance/ej/resources/policy/exec_order_12898.pdf )

. As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well

- established procedure s. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential

se tting. Extensive data on food consumption patterns are compiled by the USDA under the National Health and Nutrition Survey/What We Eat in America (NHANES/WWEIA) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when c onditions or circumstances warrant. Whenever appropriate, non

- dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas postapplication ar e evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0 Hazard Characterization and Dose

- Response Assessment

The 2005 risk assessment contained a thorough description of the toxicology profile for fluazifop

- P

- butyl (Locke, 2005, D316891). The database is adequate for FQPA assessment, endpoint selection, and do se

- response evaluation for fluazifop

- P

- butyl and the fluazifop mixed isomers. The acute neurotoxicity, subchronic neurotoxicity, and immunotoxicity studies have been screened, and effects observed in these st udies are not expected to result in risk concern s

. Consequently, the conclusions for the hazard characterization from the 2005 risk assessment are unchanged. A full update of the hazard characterization will be conducted in support of petition for new crop uses

.

4.1 Summary of Toxicological Effects

Fluazifop

- butyl is a n herbicide with mixed isomeric [RS] content, while fluazifop

- P

- butyl is the purified [R] enantiomer and is the only herbicide currently registered

. Fluazifop

- P

- butyl acts in plants by inhibiting ace tyl CoA carboxylase, a key enzyme in plant fatty acid synthesis and required for maintaining membranes in functioning condition. Peroxi some proliferation was shown in rat and mouse, and to a lesser extent in the hamster, in vivo, and human li ver cells, in vitro

.Fluazifop

- P

- butyl Human Health Risk Assessment DP No. D420423

Page 10 of 38 The toxicological database on fluazifop

- butyl is complete with sufficient data available showing equivalence of f

luazifop

- butyl ( FB, PC code 122805) with fluazifop

- P

- butyl (FPB, PC code 122809) in animal toxicity. The toxicity databa se is adequate to carry out FQPA assessment, endpoint selection, and dose

- response evaluation for both chemicals.

Metabolism studies have been conducted in the rat with fluazifop

- butyl, and absorption, excretion

, and confirmatory metabol ism studies in the dog with fluazifop

- butyl, and hamster with fluazifop

- P

- butyl. Comparative metabolism studies in the rat show that both fluazifop

- P

- butyl and fluazifop

- butyl mixed isomers are rapidly hydrolyzed to fluazifop acid and the [S] enantiomer is rapidly converte d to the [R] enantiomer in the blood, yielding similar toxicities i n vivo . A 50:50 mixture of the two isomers quickly converts to 97% R

- isomer in vivo

. Oral dog and female rat studies show similar results

, while male rats show greater toxicity

. Fluazifop

- butyl is rapidly absorbed through the gut after oral dosing

, and the ester linkage is hydrolyzed to produce the fluazifop acid in the blood. No parent fluazifop

- ester was detected in plasma at any time. Male rats show similar fluazifop acid excre tion to the female, but excretion is slower

, because fluazifop is excreted in t he bile and results in a higher percentage in the feces. The greater toxicity in male rats may be due to the longer retention time.

In a metabolism study (MRID 00131464 ), f luazifop

- butyl (99.6% a.i.) was administered to 3 male humans in a single dose in corn oil on a sugar cube at a dose level of 0.07 mg/kg. The results from the study were consistent with the studies in rats and dogs. That fluazifop

- butyl is rapidly absorb ed, hydrolyzed to the free acid and excreted mostly in the urine as the free acid, with minor amounts of conjugates of the free acid (conjugates unidentified in humans). The one

half life in the men studied was closer to that found in female rats, which l acked the delayed excretion characteristic of male rats

, possibly being due to bi liary recycling in male rats. If the toxicity of fluazifop

- butyl is related to delayed excretion time seen in male rats, then the rapid excretion in men in the current study may suggest that the toxicity in men is more closely related to the dog and female rats where the excretion time is also short. The ethics of this human study was cleared in the memo “Ethics Review of Fluazifop

- Butyl Absorption, Distribution and Metabolis m Study” (Sherman, 2010).

The liver and kidney are its target organs
, expressed for the most part as liver toxicity in the presence of peroxisome proliferation and exacerbation of age

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

- butyl and fluazifop

- P

- butyl, dog with fluazifop

- butyl, and hamster with fluazifop

- P

- butyl. Fluazifop

- P

- butyl show s similar toxicity by both the inhalation and oral routes

. Although the liver and kidney were the organs most consistentl y affected, other findings were used as endpoints for selection of the points of departure. 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 , while n eurotoxic effects were used for an endpoint for the general U.S. population , including infants and children . The short

- term incidental oral and children’s dermal endpoint s were selected based upon a maternal body weight gain decrement exhibited in the dev elopmental toxicity studies performed on rats. The chronic dietary (all populations), intermediate

- term dermal and inhalation, as well as the intermediate

- term incidental oralFluazifop

- P

- butyl Human Health Risk Assessment DP No. D420423

Page 11 of 38 endpoints, were selected from the 2

- generation reproduction study in rats. Thi s study was significant in exhibiting decreased testes and epididymal weights in males
, along with decreased uterine and pituitary weights in females. In regard to the short

- term dermal endpoint for adults and inhalation endpoints used in this assessment, the developmental toxicity studies performed on rats were used as the basis for endpoint selection. These studies were notable in exhibiting decreased fetal weights, as well as hydroureter and delayed ossification effects

. An additional endpoint was chos en that was specific for short

- term dermal exposure to children, as a developmental effect is generally protective of pregnant women and fetuses. In this case, the maternal toxicity (body weight gain decrement) was chosen to be protective of children. In summarizing the available toxicity data on fluazifop

- P

- butyl, the established toxicity endpoints for risk assessment are presented in Section 4.3, and the toxicity profile tables are provided in Appendix A.

Indications of possible neurotoxicity were o bserved in the acute neurotoxicity study, including clinical signs indicative of toxicity (reduced activity, decreased rearing, hunched posture and/or piloerection), decreased body temperature, and decreased motor activity (total distance and number of rea rings). No signs of neurotoxicity were observed in the subchronic neurotoxicity test at doses up to 70 mg/kg/day in males and 328 mg/kg/day in females. There was no observed immunotoxicity resulting from fluazifop

- P

- butyl exposure in the submitted study

. T here w as no carcinogenicity observed in acceptable studies in the rat with fluazifop

- butyl or in the hamster for fluazifop

- P

- butyl. The hamster was selected for cancer study
, because liver peroxisome prolif eration more closely resembled what was found fo r human liver cells. There w as no mutagenicity observed for fluazifop

- butyl or fluazifop

- P

- butyl.

In a dermal absorption and pharma cokinetic study in humans (MRID 46 082918, ethics of study cleared

- see Lowe, 2006), m ost of the applied dose appeared to be in the stratum corneum and easily removed (the unrecovered test material was speculated to be in the outer layers of the skin). Peak plasma levels were shown to occur 24 to 31 hours after application in these men. The one half

- life for excretion was ab out 18 hours. In the 2005 risk assessment, HED ( Locke, 2005, D316891) modified the study author’s percentage absorption estimates by scaling the
amount of recovered material to 100%, yielding absorption factors of 9 % and 2 % at the 2 mg dose and 200 mg dose , respectively.

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. Only low acute toxicity was observed: toxicity category IV for eye and dermal irritation and toxicity ca tegory III for acute oral, dermal, and inhalation toxicity.

4. 2 Safety F actor for Infants and Children (FQPA Safety Factor)

No increased offspring sensitivity over parent was seen in the rabbit pre

- natal developmental studies or the rat post

- natal reproduction study
, and no evidence of neurotoxicity was observed. Although malformed fetuses were seen at high dose levels in the absence of maternal toxicity in the rat developmental toxicity studies, the definitive developmental endpoint s in five devel opmental studies were selected based on delayed ossification and fetal weight dec rement at much lower doses (100

- fold lower).Fluazifop

- P

- butyl Human Health Risk Assessment DP No. D420423

Page 12 of 38 T here is an adequate toxicity database for fluazifop

- P

- butyl and exposure data are complete. There are no r esidual uncertaintie s pertaining to pre

- and post

- natal toxicity

, and no developmental neurotoxicity or immunotoxicity was observed . The dietary (food and drinking water) exposure assessments are conservative. The dietary and residential assessments are based on reliable da ta and will not underestimate exposure/risk. Based on these data and conclusions, the FQPA Safety Factor can be reduced to 1X

. Although EPA has required additional data on transferable residues from treated turf for fluazifop

- P

- butyl , EPA is confident t hat it has not underestimated turf exposure
, due to the conservativeness of the default turf transfer value and conservative assumptions in the short

- term turf assessment procedures (e.g., assuming residues do not degrade over the thirty day assessment per iod and assuming high

- end activities on turf for every day of the assessment period). The additional data on transferable turf residues have been required in case refinement of exposure assessments is needed in the future and to fu r ther EPA’s general unde rstanding of the availability of turf transferable pesticide residues.

4.2.1 Completeness o f the Toxicology Database

The toxicology database for fluazifop

- butyl and fluazifop

- P

- butyl is currently considered complete

. The selected points of departure are protective for any immunotoxic or neurotoxic effect. Acceptable developmental toxicity studies in rats and rabbits on fluazifop

- butyl and fluazifop

- P

- butyl are available
, in addition to an acceptable 2

- generation repro duction study in rats. Studies on fluazifop

- butyl may be used to support fluazifop

- P

- butyl
, due to equivalency in toxicity. A comprehensive overview of the fluazifop

- butyl/ fluazifop

- P

- butyl toxicology database is provided in Appendix A

.

4.2.2 Evidence of N eurotoxicity

The assessment team concluded that there was not a concern for neurotoxicity resulting from exposure to fluazifop

- P

- butyl at relevant exposure levels. There was no evidence of clinical signs indicative of neurotoxicity or neuropathology in the available studies (excluding the 500 mg/kg gavage dose in the acute neurotoxicity study) . Marginal increases in brain weights at termination were seen in a subchronic toxicity study in rats and a carcinogenicity study in hamsters, but only at high do ses. A developmental neurotoxicity study is not required at this time.

4.2.3 Evidence o f Sensitivity/Su sceptibility in the Developing o r Young Animal

While t here was quantitative evidence of increased susceptibility in the fetuses of rats exposed in utero to fluazifop

- butyl and fluazifop

- P

- butyl , t he degree of concern is low based on the following considerations: the endpoint of concern (delayed ossifications) is considered to be a developmental delay as opposed to a malformation or variation
, which i s considered to be more serious in nature; there were considerable variations in the incidences among the five studies; the NOAELs/L OAELs for this effect were well

- defined and consistent across these studies; and a developmental endpoint of concern (diaphr agmatic hernia) is used for assessing acute dietary risk. Also, in a two

- generation reproduction toxicity study in rats, t here was no evidenceFluazifop

- P

- butyl Human Health Risk Assessment DP No. D420423

Page 13 of 38 (quantitative or qualitative) of increased susceptibility following in utero exposures to rabbi ts or following pr e

- and/or post natal toxicity

. Therefore, there is no residual uncertainty for pre and/or post natal toxicity.

A s there is limited indication of developmental neurotoxicity resulting from exposure to fluazifop

- P

- butyl with the current data sets, there is no need for a developmental neurotoxicity study. T here w ere no developmental or central nervous system malformations seen in any of the developmental toxicity studies with rats or rabbits and no evidence of neurotoxicity or neuropathology in adult animals in the available studies. The toxicological significance of the marginal increases in brain weights at high doses is unknown in the absence of corroborative histopathological lesions. The assessment team concluded that there is not a concern for developmenta l neurotoxicity resulting from exposure to fluazifop

- butyl or fluazifop

- P

- butyl.

The database included 7 developmental toxicity studies: 2 with fluazifop

- butyl in Sprague

Dawley rats
, 3 with fluazifop

- P

- butyl in Wistar rats
, 1 with fluazifop

- butyl in Ne w Zealand rabbits
, and 1 with fluazifop

- P

- butyl in New Zealand rabbits. The toxicology database is adequate for hazard characterization and endpoint selection. Therefore, no database uncertainty factors are needed for any database deficiencies. These studi es are summarized below:

The NOAEL/LOAEL in the five rat developmental toxicity studies was determined by a weight of evidence criteria mainly around consistency of delayed ossification, delayed development of the urinary tract, and diaphragmatic hernias. Although, delayed ossification was seen in some studies at lower doses, they were inconsistent (i.e., low incidence of delayed ossification in controls compared to historical controls, large variation in historical controls, the delayed ossification was not clearly dose

- related, and litter incidence was not statistically significant).

The LOAEL is 5.0 mg/kg/day based on decreased fetal weight and increased incidence of hydroureter in fetuses and litters, and delayed ossification in a 160 litter/group de v elopmental toxicity study (MRID 00088858). This LOAEL is also supported by a dose

- related increased fetal incidence in partially ossified sternebrae and sternebrae bipartite, 5th (MRID s 46082913 and 46082903), and statistically significant increased inci dence of fetuses and litters with interparietals, occipitals
, and parietals partially ossified, calcaneum not ossified
, and increased manus and pe s scores at 5.0 mg/kg/day (MRIDs 46082903 and 46158401). The NOAEL of 1.0 mg/kg/day in the 160 litter per gro up study was not selected
, and a NOAEL of 2.0 mg/kg/day from the Wistar rat studies was selected. Since apparent effects noted at 0.05 and 1.0 mg/kg/day were either not dose

- related, concurrent controls were low, the effects were lower than the historical control range, or were not statistically significant in litters, and 2 developmental studies that included a 2 mg/kg/day dos e group failed to elicit a dose

- dependent response, a NOAEL of 2.0 mg/kg/day was selected.

The overall rat studies showed a NOAEL/ LOAEL of 2.0/5.0 mg/kg/day. The NOAEL/ LOAEL was chosen from among MRID s 0008858, 46082903, 46082913
, and 46518401. For a single dose effect, the NOAEL/LOAELs are 50/200 mg/kg/day based on the diaphragmatic hernia malformations.Fluazifop

- P

- butyl Human Health Risk Assessment DP No. D420423

Page 14 of 38 The maternal toxicity NO AEL/LOAEL of 100/300 mg/kg/day was based on a combination of factors. There was a clear effect on maternal body weight gain decrement at 300 mg/kg/day in the Wistar rat studies and a clear NOAEL at 100 mg/kg/day in the Wistar rat studies. Although, the m aternal weight decrement in the Sprague Dawley rat was shown to be due to gravid uterine weight decrement, it was not completely clear that maternal toxicity was not expressed at 200 mg/kg/day. Therefore
, the maternal NOAEL was chosen among the three Wist ar rat developmental toxicity studies to remove this ambiguity in maternal toxicity.

4.2.4 Residual Uncertainty in the Exposure Datab ase
There are no residual uncertainties in the exposure database. Since the dietary and non

- dietary exposure estimates were based on several conservative assumptions, HED is confident that the exposure estimates are not underestimated.

Although EPA has requi red additional data on transferable residues from treated turf for fluazifop

- P

- butyl , EPA is confident that it has not underestimated turf exposure
, due to the conservativeness of the default turf transfer value and conservative assumptions in the short

- te rm turf assessment procedures (e.g., assuming residues do not degrade over the thirty day assessment period and assuming high

- end activities on turf for every day of the assessment period). The additional data on transferable turf residues have been requi red in case refinement of exposure assessments is needed in the future and to fu r ther EPA’s general understanding of the availability of turf transferable pesticide residues.

The acute and chronic dietary assessments are conservative evaluations. The acu te assessment utilized tolerance level residues for all crops. In addition, default processing factors were assumed for all commodities. One hundred percent crop treated was assumed for all commodities. A partially refined an a lysis was performed for the chronic assessment, using percent crop treated, average field trial residue levels and empirical or default processing factors
, as appropriate . Both the acute and chronic food plus water analyses were performed with the DEEM

- FCIDTM model, which assumes that all drinking water will contain fluazifop

- P

- butyl at the highest estimated drinking water concentration (EDWC) levels modeled by EFED for ground water or surface water. For these reasons
, it can be concluded that the dietary analysis does not underes timate risk from exposure to fluazifop

- P

- butyl.

4. 3 Toxicity Endpoint and Point of D eparture Selections

T here have been no changes to the prior dose

- response assessment and/or cancer classification

. The current toxicity endpoints and points of departure for various exposure scenarios are presented in Tables 4.3.1 and 4.3.2 below

.Fluazifop

- P

- butyl Human Health Risk Assessment DP No. D420423

Page 15 of 38 Table 4. 3 .1. Summary of Toxicological Doses and Endpoints for Fluazifop

- Butyl for Use in Dietary and Non

- Occupational 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

Acut e Dietary ( General Population, I ncluding Infants and Children) - - - An appropriate endpoint attributable to a single dose was not identified in the available studies including the developmental toxicity studies.

Acut e Dietary ( Females 13

- 49 years of age) NOAEL=

50 mg/kg/day UF A =10 x

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

a PAD = 0.50 mg/kg 00008857, 92067047, 00088858,

92067048, 92967020, Rat developmental Developmental LOAEL = 200 mg/kg/day based on diaphragmatic hernia

Chronic Dietary (All Populations) NOAEL=

0.74 mg/kg/day UF A =10 x

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

= cPAD = 0.0074 mg/kg/day 00088859, 92067050, Rat reproduction

LOAEL = 5.8 mg/kg/day based on decreased testes and epididymal weights

Incidental Oral Short

Term (1

- 30 days) NOAEL=

100 mg/kg/day UF A =10 x

UF H =10 x FQPA SF= 1 x Residential

LOC for MOE = 100 46158401, Rat developmental

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

- 16

Incidental Oral Intermediate

Term (1

- 6 months) NOAEL=

0.74 mg/kg/day UF A =10 x

UF H =10 x FQPA SF= 1 x Residential

LOC for MOE = 100 00088859, 92067050, Rat reproduction

LOAEL = 5.8 mg/kg/day based on decreased testes and epididymal weights

Dermal Short

Term (1

- 30 days ; children) NOAEL=

100 mg/kg/day

DAF=9% (low exposure) or 2% (high

exposure) UF A =10 x

UF H =10 x FQPA SF= 1 x Residential

LOC for MOE = 100 46158401, Rat developmental

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

- 16Fluazifop

- P

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Page 16 of 38 Table 4. 3 .1. Summary of Toxicological Doses and Endpoints for Fluazifop

- Butyl for Use in Dietary and Non

- Occupational 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

Dermal Short

Term (1

- 30 days ; adults ) NOAEL=

2.0 mg/kg/day

DAF=9% (low exposure) or 2% (high

exposure) UF A =10 x

UF H =10 x FQPA SF= 1 x Residential

LOC for MOE = 100 00088858, 92067048, 92967020, Rat

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

Dermal Intermediate

and Long

Term (1

- 6 month s and >6 months ) NOAEL=

0.74 mg/kg/day

DAF=9% (low exposure) or 2% (high

exposure) UF A =10 x

UF H =10 x FQPA SF= 1 x Residential

LOC for MOE = 100 00088859, 92067050, Rat reproduction

LOAEL = 5.8 mg/kg/day based on decreased testes and epididymal weights

Inhalation Short

- Term (1

- 30 days) NOAEL=

2.0 mg/kg/day UF A =10 x

UF H =10 x FQPA SF= 1 x Residential

LOC for MOE = 100 00088858, 92067048, 92967020, Rat

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

Inhalation Intermediate

and Long

Term (1

- 6 months and >6 months ) NOAE L=

0.74 mg/kg/day UF A =10 x

UF H =10 x FQPA SF= 1 x Residential

LOC for MOE = 100 00088859, 92067050, Rat reproduction

LOAEL = 5.8 mg/kg/day based on decreased testes and epididymal weights

Cancer (oral, dermal, inhalation) 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 ob served 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 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). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable. DAF = dermal absorption factor.Fluazifop

- P

- butyl Human Health Risk Assessment DP No. D420423

Page 17 of 38 Table 4. 3 .2. Summary of Toxicological Doses and Endpoints for Fluazifop

- 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

DAF=9% (low exposure) or 2% (high

exposure) UF A =10 x

UF H =10 x Occupational

LOC for MOE = 100 00088858, 92067048, 92967020, Rat

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

Dermal Intermediate

and Long

Term (1

- 6 month s and >6 months ) NOAEL=

0.74 mg/kg/day

DAF=9% (low exposure) or 2% (high

exposure) UF A =10 x

UF H =10 x Occupational

LOC for MOE = 100 00088859, 92067050, Rat reproduction

LOAEL = 5.8 mg/kg/day based on decreased testes and epididymal weights

Inhalation Short

- Term (1

- 30 days) NOAEL=

2.0 mg/kg/day UF A =10 x

UF H =10 x Occupational

LOC for MOE = 100 00088858, 92067048, 92967020, Rat

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

Inhalation Intermediate

and Long

Term (1

- 6 month s and >6 months ) NOAEL=

0.74 mg/kg/ day UF A =10 x

UF H =10 x Occupational

LOC for MOE = 100 00088859, 92067050, Rat reproduction

LOAEL = 5.8 mg/kg/day based on decreased testes and epididymal weights

Cancer (oral, dermal, inhalation) 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 ob served 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 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 ap plicable.Fluazifop

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Page 18 of 38 5.0 Dietary Exposure and Risk Assessment

5.1 Residues of Concern Summary and Rationale

The residues of concern for dietary risk assessment and the tolerance expression are summarized in Table 5.1. The parent and fluazifop acid (free and conj ugated) were identified as the residues of concern for the tolerance expression for plant and livestock commodities. The metabolites 5

- trifluoromethyl

- 2

- pyridone, and 2

- (4

- hydroxyphenoxy)propionic acid (free and conjugated) were also identified as residue s of concern to include in the dietary risk assessment for plants. The se metabolites were assumed to have equal toxicity to the parent compound. Parent and fluazifop acid were the major degradates in the environmental fate studies and were included in the drinking water assessment. Further information on the metabolism and degradation may be found in the Metabolism Assessment Review Committee memo for fluazifop

- P

- butyl ( TXR No. 0052680, S. Kinard et al. , 17

- MAR

- 2004)

.

Table 5.1. Summary of Metabolites and Degradates to be included in th e Risk Assessment and Tolerance Expression Matrix Residues included in Tolerance Expression Residues included in 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 (free and conjugated) Drinking Water NA Parent and fluazifop acid

5 .2 Food Residue Profile

Crop field trial studies are available to support the label amendment request for sweet potato. Thus, eight sweet potato field trials were conducted with the proper geographical distribution in the United States following the label amendment use pattern. Residues ranged from 0.11

– 0.85 ppm, with half of the trials above 0.5 ppm , the current Canadian MRL for sweet potato

. Analysis of this residue data set using the OECD MRL calculation procedures results in a recommended level of 1.5 ppm. Samples were stored frozen for a maximum period of 794 days. In a concurrent storage stability study, fluazifop

- P

- butyl residues were d emonstrated to be stable in frozen sweet potato samples for at least 922 days. There are no processed commodities or livestock feedstuffs associated with sweet potatoes . N o rotational crop issues have been identified for fluazifop

- P

- butyl

.

5.3 Water R esidue Profile

The drinking water residues used in the dietary risk assessment were provided by the Environmental Fate and Effects Division (EFED) ( W

. Shaughnessy, D371093, 05/25/2010 )

. Estim ated drinking water concentrations (EDW Cs) in ground water were modeled us ing Tier I SCIGROW (version 2.3 ) and surface water E DW Cs were modeled using Tier II PRZM (Pesticide Root Zone Model ) and EXAMS (Ex posure Analysis Modeling System ). The highestFluazifop

- P

- butyl Human Health Risk Assessment DP No. D420423

Page 19 of 38 EDWCs from the ground and surface water modeling were used in th e dietary assessment and are summarized in Table 5.3.

Table 5. 3 Summary of Estimated Surface Water and Groundwater Concentrations

for Fluazifop

- P

- Butyl.

Scenario Surface Water Conc., ppb a Ground W ater Conc., ppb b

Acute 33.4 1.56
Chronic 6.6 1.56

a From the Tier II PRZM

- EXAMS

- Index Reservoir model. Acute EDWC based on banana use pattern; chronic EDWC based on grape use pattern.
b From the SCI

- GROW model.
W. J. Shaughnessy, D371093, 05/25/2010

.

5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

The unrefined acute dietary assessment was based on 100% crop treated assumptions and tolerance

- level residues, adjusted as appropriate using factors from the metabolism studies, to account for residues of concern n ot measured by the analytical method. Water residues were also included using point estimates.

The partially refined chronic dietary exposure analysi s was based on m ean residue level s from crop field trials with a ratio adjustment for additional metaboli tes of concern, average percent crop treated estimates, and experimentally determined processing factors ( where available; otherwise default processing factors were used).

5.4.2 Percent Crop Treated Used in Dietary Assessment

For the acute dietary anal ysis, 100% crop treated was assumed for all crops.

The following average percent crop treated estimates ( Memo, J. Alsadek, 27

- MAR

- 2015) were used in the chronic dietary risk assessments for the following crops that are currently registered for fluazifop

- P

- butyl : apricots, 2.5%; asparagus, 2.5%; carrots, 15%; cherries, 1 %; co tton, 1 %; dry beans/peas. 1%; garlic, 10%; grapefruit, 15%; grapes, 2.5 %; nectarines, 1%; onions, 1 0 %; oranges, 2.5%; peaches, 2.5%; peanuts, 1%; pecans, 1%; peppers, 2.5%; plums, 2.5% ; potatoes, 1%, prunes, 2.5%; soybeans, 2.5%; and sugar beets, 1%. 100% crop treated was assumed for sweet potatoes and all other registered crops not listed above.

5.4.3 Acute Dietary Risk Assessment

The food plus drinking water results of the acute dietary exposure and risk analysis at the 95 th percentile of exposure are reported in Table 5.4.6 , below. T he unrefined acute dietary risk estimate is below the Agency’s level of concern (<100 % aPAD) for the only relevant population subgroup, females 13

- 49 years of age (14 % aPAD)

, at the 95 th exposure percentile.Fluazifop

- P

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Page 20 of 38 5.4.4 Chronic Dietary Risk Assessment

The food plus drinking water results of the chronic dietary exposure and risk analysis are

r eported in T able 5.4.6, below. The analysis indicates that for all supported commodities and proposed uses, the chronic dietary risk estimates are below the Agency’s level of concern (<100 % cPAD) for the U.S. population ( 17 % cPAD) and all population subg roups. The most highly exposed population subgroup in the chronic dietary exposure analysis is C hildren 1

- 2 years of age ( 64 % cPAD).

5.4.5 Cancer Dietary Risk Assessment

As fluazifop

- P

- butyl has been classified as “ Not likely to be carcinogenic to hum ans ”, a cancer dietary risk assessment is not required.

5.4.6 Summary Table

Table 5.4.6 . Summary of Dietary (Food and Drinking Water) Exposure and Risk for Fluazifop

P

- Butyl.

Population Subgroup Acute Dietary ( 95th Percentile) Chronic Dietary Cancer
Dietary Exposure (mg/kg/day) % aPAD* Dietary Exposure (mg/kg/day) % cPAD* Dietary Exposure (mg/kg/day) Risk

General U.S. Population

NA NA 0.001244 17

NA NA All Infants (<1 year old) 0.001577 21
Children 1

- 2 years old * 0.004756 64
Children 3

- 5 years old 0.003705 50
Children 6

- 12 years old 0.001819 25
Youth 13

- 19 years old 0.001104 15
Adults 20

- 49 years old 0.000897 12
Adults 50

- 99 years old 0.000916 12
Females 13

- 49 years old * 0.067665 14 0.000893 12 *The subpopulation s with the highest risk estimates

.

6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

There are no proposed residential uses at this time; however, there are existing residential uses that have been reassessed in this document to reflect updates to HED’s 2012 Residential SOPs 3 along with policy changes for body weight assumptions. The revision of residential exposures will impact the human health aggregate risk assessment for fluazifop

- P

- butyl.

Registered non

- agricultural use si tes of fluazifop

- P

- butyl include: non

- agricultural outdoor buildings, building foundations, curbs, driveways, fencerows, non

- agricultural areas (wildlife refuge), non

- crop areas, ornamentals (lawns, flowering shrubs, flowering plants, gardens, ground

3 Available: http://www.epa.gov/pesticides/science/residential

- exposure

- sop.htmlFluazifop

- P

- butyl Human Health Risk Assessment DP No. D420423

Page 21 of 38 cover s, plants, trees, turf, and woody shrubs), patios, pathways, rights

- of

- way, sidewalks, and storage yards.

6.1 Residential Handler Exposure

Summary of Residential Handler Non

- Cancer Exposure and Risk Estimates

The combined (dermal and inhalation) residential handler exposure estimates ranged from 230 to 530; a 9% dermal absorption factor was used to assess dermal residential handler exposures because these are consi dered low exposure activities.Fluazifop

- P

- butyl Human Health Risk Assessment DP No. D420423

Page 22 of 38 Table 6 .1.1. Residential Handler Non

- cancer Exposure a nd Risk Estimates for Fluazifop

- P

- butyl

.

Exposure Scenario Level of Concern Dermal Unit

Exposure (mg/lb ai) Inhalation

Unit Exposure (mg/lb ai) Maximum

Application Rate 1 Area Treated or

Amount Handled Daily 2 Dermal Inhalation Total

Dose (mg/kg/day) 3 MOE 4 Dose (mg/kg/day) 5 MOE 6 MOE 7

Mixer/Loader/Applicator
Handwand 100 63 0.018 0.01 lb ai/gallon 5 gallons 0.0041 490 0.000013 150,000 490 Hose end sprayer 100 58 0.0014 0.01 lb ai/gallon 11 gallons 0.0083 240 0.0000022 900,000 240 Hose end sprayer 100 13.4 0.022 0.9 lb ai/acre 0.5 acres 0.0079 25 0 0.00014 1 4 ,000 250 Backpack 100 130 0.14 0.01 lb ai/gallon 5 gallons 0.0085 240 0.0001 20,000 230 Sprinkler Can 100 58 0.0014 0. 01 lb ai/gallon 5 gallons 0.0038 5 30 0.000001 2,00 0,000 530 RTU hose end sprayer 100 6.26 0.034 0.9 lb ai/acre 0.5 acres 0.0037 540 0.0002 9,000 510 RTU hose end sprayer 100 6.26 0.034 0.04 lb ai/gallon 11 gallons 0.0036 560 0.0002 9,200 530
1 Based on registered labels

. 2 Based on HED’s 2012 Residential SOPs ( http://www.epa.gov/pesticides/science/residential

- exposure

- sop.html ). 3 Dermal Dose = Dermal Unit Exposure (mg/lb ai) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A /day or gallons/day) × Dermal Absorption Factor (%) ÷ Body Weight (kg). 4 Dermal MOE = Dermal NOAEL ( 2 mg/kg/day) ÷ Dermal Dose (mg/kg/day). 5 Inhalation Dose = Inhalation Unit Exposure (mg/lb ai) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A /day or gallons/day) ÷ B ody W eight (kg). 6 Inhalation MOE = Inhalation NOAEL ( 2 mg/kg/day) ÷ Inhalation Dose (mg/kg/day). 7 Total MOE = NOAEL ( 2 mg/kg/day) ÷ (Dermal Dose + Inhalation Dose).Fluazifop

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Page 23 of 38 

### 6.2 Residential Post

- application Exposure/Risk Estimates

There is the potential fo r post

- application exposure for individuals exposed as a result of being in an environment that has been previously treated with fluazifop

- P

- butyl.

C onsistent with the previous assessment ( D316891, D. Locke et al. , 29

- AUG

- 2005 ), two separate dermal abso rption values are used : 9% is used for assessing dermal exposures while golfing or mowing a lawn, since these are representative of low exposure activities, whereas 2% is used for assessing dermal exposures from high contact lawn activities, since these are representative of high exposure activities.

Chemical

- specific dislodgeable foliar residue (DFR) data are available and were used for the residential postapplication exposure assessment for gardens. Since TTR data are not available for fluazifop

- P

- b utyl, default TTR values were used for the residential postapplication exposure assessment for turf. Given the conservatisms associated with default TTR values and the potential compounding nature of conservatisms in the turf assessment , EPA is able to re ly upon the calculated exposure estimates with confidence that exposure is not being underestimated. All residential post

- application MOEs are greater than the LOC and are therefore not of concern (Table 6.2.1)

. Summary of Residential Post

- application Non

- Cancer Exposure and Risk Estimates

Table 6.2.1. Residential Post

- application Non

- cancer Exposure and Risk Estimates for Fluazifop

P

- butyl.

Lifestage Post

- application Exposure Scenario Application Rate 1 Dose

(mg/kg/day) 2 MOEs 3 Combined MOE Use Site Route of

Exposure Adult Turf

– High

Contact Dermal

0.9 lb ai/acre 0.0078 260 NA

Child (1 to < 2 years) Dermal 0.0134 7,500 3,700 HtM 0.0137 7
, 300 OtM 0.00042 240,000 NA Adult Mowing Dermal 0.9 lb ai/acre 0.00072 2,800 NA Youth (11

– 16 years) Dermal 0.00071 140,000 NA Adult Golfing Dermal 0.4 lb ai/acre 0.0012 1,600 NA Youth (11

– 16 years) Dermal 0.0012 81,000 NA Child (6 to <11 years) Dermal 0.0014 69,000 NA Adult Garden Dermal 0.4 lb ai/acre 0.00 84 240 NA Child (6 to <11 years ) Dermal 0. 00 5 20,000 NA

1 Based on registered labels. 2 Dose (mg/kg/day) equations provided in 2012 Residential SOPs. 3 MOE = POD ( 2 mg/kg/day for adults, 100 mg/kg/day for children ) ÷ Dose (mg/kg/day).



### 6.3 Residential Risk Estimates for Use in Aggregate Assessment

Table 6 .3.1 reflects the residential risk estimates via dermal, inhalation, and oral routes that should be considered for use in the aggregate assessment for fluazifop

- P

- butyl

. For adults, noFluazifop

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- butyl Human Health Risk Assessment DP No. D420423

Page 24 of 38 incidental oral exposure is expected; for children, incidental oral exposure is possible from hand

to

- mouth or object

- to

- mouth exposure from turf activities.

Table 6

. 3 .1. Recommendations for the Residential Exposures for the Fluazifop

- P

- B utyl Aggregate Assessment.

Lifestage Ex posure

Scenario Dose (mg/kg/day) 1 MOE 2

Dermal Inhalation Oral Dermal Inhalation Oral

Adult Handler 0.0085 0.0001 N/A 240 20,000 N/A

Child Turf 0.0134 N/A 0.0137 7,5 00 N/A 7
, 300

1 Dose = the highest dose for each applicable lifestage of all residential scenarios assessed

. 2 MOE = the MOEs associated with the highest residential doses

.

6.4 Spray Drift

Spray drift is a potential source of exposure to those nearby pesticide applications. This is particularly the case with aerial application, but, to a lesser extent, spray drift can also be a potential source of exposure from the ground application methods (e.g., groundboom and airb last) employed for fluazifop

- P

- butyl

. The agency has been working with the Spray Drift Task Force (a task force composed of various registrants which was developed as a result of a Data Call

- In issued by EPA), EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the A gency’s Spray Drift website for more information). 4 The agency has also developed a policy on how to appropriately consider spray drift as a potential source of exposure in risk assessments for pesticides. The potential for spray drift will be quan titatively evaluated for each pesticide during the Registration Review process which ensures that all uses for that pesticide will be considered concurrently. The approach is outlined in the revised (2012) Standard Operating Procedures For Residential Ris k 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.

6.5 Residential Bystander Post

- Applic ation Inhalation Exposure

Volatilization of pesticides may be a source of post

- application inhalation exposure to individuals nearby pesticide applications. The agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fu ngicide, 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 develope d 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
st udies, route

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

- P

- butyl.

4 Available: http://www.epa.gov/opp00001/factsheets/spraydrift.htmFluazifop

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- butyl Human Health Risk Assessment DP No. D420423

Page 25 of 38 7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be a ggregated. When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure.

7.1 Acute Aggregate Risk

Acute aggregate risks are identical to the acute dietary risk s previously discussed, see section 5.4.4.

7.2 Short

- Term Aggregate Risk

Short

- term aggregate risk assessments consider exposures that may occur between 1 and 30 days. To aggregate across routes of exposure, toxicity endpoint s must be similar. The short

- t erm dermal and inhalation endpoints are the same for adults ; thus, these routes of exposure can be aggregated. The short

- term incidental oral and dermal endpoints are the same for children; thus these routes of exposure can be aggregated. For children, t he aggregate assessment consists of average food and drinking water exposures plus incidental oral exposures and dermal exposure

. For adults, the aggregate assessment consists of average food and drinking water exposures and dermal and inhalation exposure

. The results from this assessment are presented below in Table 7.2 , and indicate that short

- term aggregate risks are not of concern for fluazifop

- P

- butyl , since all short

- term aggregate MOEs exceed the LOC of 100

.

Table 7.2 Short

- Term Aggregate Risk Calculations

Population Short

- Term Scenario

NOAEL mg/kg/day LOC 1 Max

Allowable Exposure 2 mg/kg/day Average

Food and Water Exposure 3 mg/kg/day Residential

Exposure mg/kg/day 4 Tota l

Exposure mg/kg/day 5 Aggregate

MOE (food, water, and residential) 6

Adult 2 100 0.02 0.001104 0.0086 0.00 9704 210 Child 100 100 1 0.004756 0.0 271 0.0 31856 3,100

1 LOC = 100 (10X interspecies uncertainty factor, 10X intraspecies uncertainty factor, 1X FQPA safety factor)

2 Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC

3 Average Food and Water Exposure from Table 5.4.6 (chronic dietary)

4 Residential Exposure = [Oral & dermal exposure (children) ] (Table 6.3.1)

5 Total Exposure = Avg Food & Water Exposure + Residential Exposure

6 Aggregate MOE = [NOAEL / (Avg Food & Water Exposure + Residential Exposure)]Fluazifop

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Page 26 of 38 7.3 Intermediate

- Term Aggregate Risk

All residential exposures are anticipated to be short

- term in duration ; thus, an intermediate

- term aggregate risk assessment is not required.

7.4 Chronic Aggregate Risk

Chroni c aggregate risks are identical to the chronic dietary risk s previously discussed , see section 5.4.4

. N o long

- term residential exposures are anticipated for fluazifop

- P

- butyl.

8.0 Cumulative Exposure/Risk Characterization

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 fluazifop

- P

- butyl and any other substances and fluazifop

- P

- butyl does not a ppear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that fluazifop

- P

- butyl has a common mechanism of toxicity with other substances. For information regarding EPA’s eff orts 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 procedur es for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

9.0 Occupational Exposure/Risk Characterization

An updated occupational assessment is not required for this action.Fluazifop

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- butyl Human Health Risk Assessment DP No. D420423

Page 27 of 38 10.0 References

Table 1 0.0. Memoranda Relevant to Fluazifop

- P

- B utyl. Author Barcode Date Title W. Donovan D426930 5/1 3 /201 5 Fluazifop

- P

- Butyl: Residue Chemistry Review for Sweet Potato Label Amendment and Resulting Tolerance Increase. Abbreviated Review

. W. Donovan D426145 3/31 /201 5 Fluazifop

- P

- Butyl: Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments for the Sweet Potato Label Amendment and Resulting Increase in Tolerance Level. J. Alsadek

-- 3/27/2015 Usage Report in Support of Fluzifop (122809) A. LaMay, S. Dapson, and W. Donovan D421107 12/5/2014 Fluazifop

- P

- butyl. Human Health Risk Assessment Scoping Document in Support of Registration Review

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

- butyl and Fluazifop

- p

- butyl : Tier I Review of Human Incidents

W. Donovan D415419 6/18/2014 Fluazifop

- P

- Butyl: Review of Residue Chemistry Data Submitted as a Condition of Registration. P. Savoia D385205 1/4/2011 Fluazifop

- P

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

- P

- Butyl. Request for the Registration of a Reduced Pre

- Harvest Interval for Application of the Venture L End

- Use Product on Imported Pot atoes. Summary of Analytical Chemistry and Residue Data. D. Locke D316891 8/29/2005 Fluazifop

- P

- butyl: Revised HED Chapter of the Tolerance Reassessment Eligibility Document (TRED). PC Code: 122809, Case # 2285, DP Barcode: D316891 S.L. Kinard, D. Ander son, and W.P. Eckel TXR No.

0052680 3/17/2004 Fluazifop

- P

- butyl. Report of the Metabolism Assessment Review Committee.Fluazifop

- P

- butyl Human Health Risk Assessment DP No. D420423

Page 28 of 38 A ppendix A

. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements The requirements (40 CFR 158.500) for food

- use for fluazifop

- P

- butyl are in Table 1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Study Technical
Required Satisfied 870.1100 Acute Oral Toxicity

................................ ....................... 870.1200 Acute Dermal Toxicity

................................ .................. 870.1300 Acute Inhalation Toxicity

................................ .............. 870.2400 Primary Eye Irritation

................................ .................... 870.2500 Primary Dermal Irritation

................................ .............. 870.2600 Dermal Sensitization

................................ ..................... yes yes yes yes yes yes yes

yes yes yes yes yes 870.3100 Oral Subchronic (rodent)

................................ ............... 870.3150 Oral Subchronic (nonrodent)

................................ ......... 870.3200 28

- Day Dermal

................................ .............................. 870.3250 90

- Day Dermal

................................ .............................. 870.3465 90

- Day Inhalation

................................ .......................... yes yes yes

no

no yes

yes yes yes yes 870.3700a Developmental Toxicity (rodent)

................................ .. 870.3700b Developmental Toxicity (nonrodent)

............................ 870.3800 Reproduction

................................ ................................ . yes yes yes y es

yes yes 870.4100a Chronic Toxicity (rodent)

................................ .............. 870.4100b Chronic Toxicity (nonrodent)

................................ ........ 870.4200a Oncogenicity (rat)

................................ .......................... 870.4200b Oncogenicity (mouse)

................................ ................... yes yes yes yes y es a

yes
y es b
yes 870.5100 Mutagenicity

— Bacterial reverse mutation assay

.................... 870.5300 Mutagenicity

— In vitro mammalian cell gene mutation test

....... 870.5375 Mutagenicity

— In vitro mammalian chromosome aberration test 870.5395 Mutagenicity

— Mammalian erythrocyte micronucleus test

........ yes yes yes yes y es

yes yes yes 870.6100a Acute Delayed Neurotoxicity (hen)

............................... 870.6100b 90

- Day Neurotoxicity (hen)

................................ .......... 870.6200a Acute Neurotoxicity Screening Battery (rat)

................. 870.6200b 90

- Day Neurotoxicity Screening Battery (rat)

.............. 870.6300 Developmental Neurotoxicity

................................ ....... yes yes yes yes

no yes

yes yes yes yes
870.7485 General Metabolism

................................ ...................... 870.7600 Dermal Penetration

................................ ........................ 870.7800 Immunotoxicity

................................ ............................. yes

no yes y es

yes yes

a The combined chronic toxicity/carcinogenicity study in rats (OCSPP 870.4300) satisfies these requirements.
b An oncogenicity study in hamster satisfies the requirement for an oncogenicity study in a second species.Fluazifop

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- butyl Human Health Risk Assessment DP No. D420423

Page 29 of 38 A.2 Toxicity Profile s

Table A.2.1 .a Acute Toxicity Profile

– Fluazifop

- Butyl a

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

870.1100 Acute oral

- Rat 00162439 LD 50 = 1940 mg/kg ( ♂ ) ± 1193

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

- 3625 mg/kg III

870.1200 Acute dermal

- Rat 00162439 LD 50 > 2 mL/kg ( ♂♀ ) or approximately 2000 mg/kg III

870.1300 Acute inhalation

- Rat 46082901,

same as 41563701 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 00088855 Non

- irritating IV

870.2500 Acute dermal irritation

- Rabbit 00088853 Mild erythema at 72 hours IV

870.2600 Skin sensitization

- Guinea Pig 00088854 Not a dermal sensitizer -

a Purity of 93.3

- 99.6% a.i.

Table A.2.1 .b Acute Toxicity Profile

– Fluazifop

- P

- Butyl a

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

870.1100 Acute oral

- Rat 00162440 LD 50 = 3680 mg/kg for males
LD 50 = 2451 mg/kg for female s III

870.1200 Acute dermal

- Rat 00162440 LD 50 > 2000 mg/kg or >1.73 mL/kg III

870.1300 Acute inhalation

- Rat 41917904 LC 50 > 1.7 mg/L III

870.2400 Acute eye irritation

- Rabbit 00162441 Mild irritation, cleared within 3 days IV

870.2500 Acute dermal irritation

- Rabbit 00162441 Slight irritation, cleared within 72 hours IVFluazifop

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- butyl Human Health Risk Assessment DP No. D420423

Page 30 of 38 870.2600 Skin sensitization

- Guinea Pig 00162441 Not a dermal sensitizer -

a Purity of 86.3

- 99.6% a.i., except acute inhalation. 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.

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

– Fluazifop

- butyl [FB] and Fluazifop

- P

- butyl [FPB]

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 cholesterol depression.

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 oral

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.Fluazifop

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- butyl Human Health Risk Assessment DP No. D420423

Page 31 of 38 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

– Fluazifop

- butyl [FB] and Fluazifop

- P

- butyl [FPB]

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

870.3700 a 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.

870.3700 a Prenatal

developmental toxicity in Sprague Dawley rats with FB 00088858, 92067048,

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 a Prenatal

developmental toxicity in Wistar rats with FPB 46158401 (19 91)

Acceptable, guideline 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 arch es and centrum in fetuses and litters and delayed ossification in the manus and pes.

870.3700 a Prenatal

developmental toxicity in Wistar rats with FPB 46082903 (1989)

Acceptable, guideline 0, 2, 5

, 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 a 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 b 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 controlsFluazifop

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Page 32 of 38 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

– Fluazifop

- butyl [FB] and Fluazifop

- P

- butyl [FPB]

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

870.3700 b 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.

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. 4100a Chronic toxicity

(rat) Not submitted. See

870.4300. -

870. 4100b 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 = 12.1 mg/kg/day LOAEL = 45.5 mg/kg/day based on based on increased incidence of males with reduced sperm, testicular degeneration, eye cataract changes, liver inflammation and gall stones and in females, increased incide nce of ovarian stroma cell/sex chord hyperplasia No evidence of carcinogenicityFluazifop

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Page 33 of 38 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

– Fluazifop

- butyl [FB] and Fluazifop

- P

- butyl [FPB]

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

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 = 0.51 mg/kg/day LOAEL = 4.15 mg/kg/da y based on increased mortality and nephropathy exacerbated by respiratory stress No evidence of carcinogenicity

Gene Mutation
870.5100 Ames/

Salmonella typhimurium, reverse mutation with FB (96.8% a.i .) 00162443, 92067023

Acceptable
H istidine 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.

Gene Mutation
870.5100 Ames/

Salmonella typhimurium,

revers e mutation with FPB (93.6% a.i. ) 00162442, 92067013

Acceptable
H istidine 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 (insoluble at 5000 μg/plate).

Mammalian cell gene mutation
assay 870.5300 Mouse lymphoma

cell test w ith FPB (99.6% a.i. ) at concentrations of 0, 0.25, 2.5, 25, 250 or 2500 μg/mL 00116678

Acceptable
H eterozygous 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.Fluazifop

- P

- butyl Human Health Risk Assessment DP No. D420423

Page 34 of 38 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

– Fluazifop

- butyl [FB] and Fluazifop

- P

- butyl [FPB]

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

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 0, 100, 200, 500, 700 or 1000 μg/mL 46082906

Acceptable
M ouse 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. N egative with and without S9 activation up to and including excessive precipitation.

In vitro chromosoma l aberrations in human blood lymphocytes 870.5375 Mammalian cell

cytogenetic assays (chromosome aberration) with FPB (R

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

L ymphocy te 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. Negative with no evidence of chromosome aberration induced over bac kground in the presence or absence of S9

- activation at toxic doses.

In vivo rat mammalian cytogenetics; bone

marrow chromosoma l 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 harveste d at 6 or 24 hours after treatment in the acute study, and at 6 hours after treatment in the sub

- acute study. Negative with no evidence of chromosome aberration induced over background at toxic doses.

In vivo

mouse micro

nucleus test 870.5395 in vivo

mammalian cell

mouse micronucleus 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. Negative with 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.Fluazifop

- P

- butyl Human Health Risk Assessment DP No. D420423

Page 35 of 38 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

– Fluazifop

- butyl [FB] and Fluazifop

- P

- butyl [FPB]

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

Other Effects
870.5900
sister chromatid exchange
assay Dominant lethal

assay [PP009, fluazifop

butyl (97.0% a.i., ) 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 the 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 sufficiently toxic. The investiga tors 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, 15000

m g/kg Fluazifop

- butyl exposed hens showed no evidence of delayed neurotoxicity.

870.6200 Acute

neurotoxicity screening battery

- rat 49188708 (2013)

Acceptable, guideline 0, 500, 1000, 2000 mg/kg NOAEL was not observed
LOAEL = 500 mg/kg based on clinical signs indicative of toxicity (reduced activity, decreased rearing, hunched posture and/or piloerection), decreased body temperature, and decreased motor activity (total distance and number of rearings) in both sexes

870.6200 Subchronic

neurotoxicity screening battery

- rat 49188705 (2013)

Acceptable, guideline ♂: 0, 100, 250, 1000 ppm ♂: 0, 6.7, 16.8, 69.5 mg/kg/day ♀: 0, 100, 250, or 4000
ppm ♀: 0, 7.9, 20.2, or 328.1 mg/kg/day NOAEL = 69.5 mg/kg/day
LOAEL was not observed in either sex

870.7485 Metabolism and

pharmaco kinetics in (rats) with FB 00093822 through

00093828 (1981) Acceptable, guideline 1, 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 proportions than in feces of the female. Excretion was complete in 7 days, with th e exception of small amounts in the fat in
some rats.Fluazifop

- P

- butyl Human Health Risk Assessment DP No. D420423

Page 36 of 38 Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

– Fluazifop

- butyl [FB] and Fluazifop

- P

- butyl [FPB]

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

870. 7600 Dermal

penetration (human) MRID 46082918 a human study/NG satisfies guideline 870.7600.

870. 7800 Immunotoxicity

(rat) 49188706 (2013)

Acceptable, guideline ♀: 0, 100, 500, 2000 ppm ♀: 0, 9, 44, 173 mg/kg/day Systemic and immunotoxic NOAEL = 173 mg/kg/day, the highest dose tested Systemic and immunotoxic LOAEL were not observedFluazifop

- P

- butyl Human Health Risk Assessment DP No. D420423

Page 37 of 38 Appendix B

. Physical/Chemical Properties

Table B

. 1. Physicochemical Properties of Fluazifop

- P

- butyl.

Parameter Value Reference Molecular Weight 383.37 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 Chemi cals 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. ChengFluazifop

- P

- butyl Human Health Risk Assessment DP No. D420423

Page 38 of 38 Appendix C

. Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These data, which include studies from the Residential SOPs, are (1) subject to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable ethics requirements. For certain studies, the ethics review may have included review by the Human Studies Review Board. Descriptions of data sources, as well as guidance on their use, can be found at the Agency website 5

. In a metabolism study (MRID 00131464 ), f luazifop

- butyl (99.6% a.i.) was administered to 3 male humans in a single dose in corn oil on a sugar cube at a dose level of 0.07 mg/kg. The ethics of this human study was cleared in the memo “Ethics Review of Flu azifop

- Butyl Absorption, Dist ribution and Metabolism Study” Sherman, 2010.

Human research was conducted as part of a dermal absorption study for fluazifop

- P

- butyl (MRID 46 082918). The ethics of this study was cleared in the memo “ Initial Ethics Review of a Human Study of Dermal Absorption and Pharmacokinetics of Fluazifop

- Butyl ” Lowe MF, Carley JM, June 10, 2006

.

5 http://www.epa.gov/pesticides/science/handler

- exp osure

- data.html and http://www.epa.gov/pesticides/science/post

- app

- exposure

- data.html