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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF

CHEMICAL SAFETY AND

POLLUTION PREVENTION

MEMORANDUM

Date: January 4, 2011

SUBJECT: 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. 

PC Code: 122809 DP Barcode: 385178 

Decision No.: 423996 Registration No.: 100-1001

Petition No.: 9F7624 & 9E7651 Regulatory Action: New Use Registration

Risk Assessment Type: Human Health Case No.: 2285

TXR No.: NA CAS No.: 79241-46-6

MRID No.: 47874601-06 & 47920401-05 40 CFR: 180.411

FROM: Peter Savoia, Chemist

Seyed Tadayon, Chemist

William A. Irwin, PhD, Toxicologist

Danette Drew, Chemist

Risk Assessment Branch V

Health Effects Division (7509P)

THRU: Jack Arthur, Branch Chief

Risk Assessment Branch V

Health Effects Division (7509P)

TO: Kathryn Montague/Michael Walsh, RM

Herbicide Branch 

Registration Division (7505P)

This risk assessment revises the September 1, 2010 version (D371092) by providing a more complete 

characterization of uncertainties/data gaps. Syngenta Crop Protection, Inc. has submitted petition No. 

9F7624 requesting to allow for the use of fluazifop-P-butyl (PC Code 122809) on bananas, citrus, 

grapes, and sugar beets. In addition to these new crop uses, Syngenta has also submitted petition No. 

9E7651 which proposes that an import tolerance for fluazifop-P-butyl be established on potatoes. To 

address these proposed new uses, this document is HED’s amended human health risk assessment 

incorporating the Syngenta proposed new uses. It therefore contains updated sections of the HED 

Human Health Risk Assessment of September 2008 (DP No. D347515, P. Savoia, 09/18/2008). In 

doing so, the following sections which include residue chemistry, drinking water exposure, dietary

exposure, aggregate risk assessment, and occupational exposure have been updated to reflect the 
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proposed new uses. Information contained in the September 2008 risk assessment remains unchanged 

unless specifically noted in this memorandum. 

Table of Contents

1.0 Executive Summary............................................................................................................ 4

2.0 Background....................................................................................................................... 11

3.0 Summary of Proposed Uses.............................................................................................. 11

4.0 Hazard Characterization and FQPA Considerations......................................................... 12

4.1 Toxicology Studies Available for Analysis.......................................................... 13

4.2 Absorption, Distribution, Metabolism and Elimination (ADME)........................ 14

4.2.1 Dermal Absorption................................................................................................ 15

4.3 Toxicological Effects............................................................................................ 16

4.4 FQPA Safety Factor.............................................................................................. 17

4.4.1 Completeness of toxicology Database .................................................................. 18

4.4.2 Evidence of Neurotoxicity .................................................................................... 19

4.4.3 Evidence of Sensitivity/Suspectibility in the Developing or Young Animal ....... 19

4.4.4 Residual Uncertainty in Exposure Database......................................................... 20

4.4.4.1 HED’s Levels of Concern (LOC) ......................................................................... 21

4.5 Toxicity Endpoint and Point of Departure Selections.......................................... 21

4.5.1 Dose-Response Assessment.................................................................................. 23

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment...... 23

4.5.3 Cancer Classification and Risk Assessment Recommendation............................ 23

4.5.3.1 Carcenogenic Potential in Rats............................................................................. 24

4.5.3.2 Carcenogenicity Syudy in Hampsters................................................................... 26

4.5.3.3 Classification of Carcenogenic Potential.............................................................. 27

4.5.4 Summary of Points of Departure And Toxicity Endpoints Used In Human Risk 

Assessment............................................................................................................ 27

4.6 Endocrine Disruption............................................................................................ 28

5.0 Metabolism ....................................................................................................................... 29

5.1 Nature of the Residue - Plants .............................................................................. 29

5.2 Nature of the Residue - Animals........................................................................... 29

5.3 Meat, Milk, Poultry and Eggs................................................................................. 29

5.4 Analytical Methods................................................................................................. 30

5.5 Storage Stability Update ....................................................................................... 30

5.6 Magnitude of Residue in Food Update ................................................................. 31

5.7 Processing Factors ................................................................................................ 34

5.8 Rotational Crops................................................................................................... 37

5.9 Proposed and Recommended Tolerances ............................................................ 37

6.0 Exposure Characterization/Assessment Section Update .................................................. 39

6.1 Dietary Exposure/Pathway.................................................................................... 39

6.1.1 Acute and Chronic Dietary Exposure and Risk Update........................................ 39

7.0 Water Exposure Risk/Pathway ......................................................................................... 41

8.0 Residential Exposure Risk Characterization..................................................................... 42

9.0 Aggregate Risk Assessment and Risk Characterization Updates..................................... 45

10.0 Occupational Exposure/Pathway Updates........................................................................ 46

10.1 Handler Exposure and Risk .................................................................................. 46

10.2 Occupational Post-Application Exposure and Risks............................................ 51

11.0 Data Needs and Label Requirements................................................................................ 53

11.1 Toxicology ............................................................................................................ 53

11.2 Residue Chemistry................................................................................................ 53
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11.3 Occupational and Residential Exposure ............................................................... 53

12.0 References......................................................................................................................... 53

Appendix A Hazard Identification and Endpoint Selection ...................................................... 57

A.1 Toxicology Data Requirements ............................................................................ 57

A.2 Toxicity Profiles.................................................................................................... 59

A.3 Hazard Identification and Endpoint Selection ...................................................... 68

A.3.1 Acute Reference Dose (aRfD) – Females Age 13-49........................................... 68

A.3.2 Acute Reference Dose (aRfD) – General Population ........................................... 68

A.3.3 Chronic reference Dose (cRfD) ............................................................................ 69

A.3.4 Incidental Oral Exposure (Short- and Intermediate-Term)................................... 69

A.3.5 Dermal Exposure (Short-, Intermediate-, and Long-Term).................................. 70

A.3.6 Inhalation Exposure (Short-, Intermediate-, and Long-Term).............................. 72

A.4 Executive Summaries............................................................................................ 73

A.5 Toxicology Data Required as a Condition of Registration................................... 74
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1.0 Executive Summary

Fluazifop-P-butyl [(R)-2-(4-((5-(trifluoromethyl)-2-pyridinyl)oxy)phenoxy)propanoic acid, butyl

ester] is a selective herbicide used for the post-emergence control of perennial and annual weed 

grasses. It works by interfering with fatty acid synthesis by inhibiting the enzyme acetyl CoA 

carboxylase, an adenosine triphosphate (ATP) dependent enzyme. It accumulates in the meristems of 

roots and shoots, root rhizomes and stolons in susceptible plants. This active ingredient is the resolved 

isomer (R enantiomer) of fluazifop-butyl (PC code 122805) which has since been cancelled resulting 

in only fluazifop-P-butyl to be supported for re-registration. Fluazifop-P-butyl end-use products are 

registered in the United States to Syngenta Crop Protection, Inc. under the trade names Fusilade®, 

Fusion®, Oramec®, Tornado®, and Typhoon®. 

Fluazifop-butyl isomers are List B chemicals with parent and fluazifop-acid (free and conjugated) 

regulated for tolerance expression as the residues of concern used to determine misuse (DP No. 

D319907, S. L. Kinard, 08/17/2005). It is currently registered for use on asparagus, carrot, coffee, 

cotton, endive (escarole), garlic, macadamia nut, onion, pecan, pepper, rhubarb, soybeans, stone fruits, 

sweet potato, and yam. It is also currently registered for use on lawns as a weed control application. 

Tolerances are established under 40 CFR §180.411(a) for residues of the herbicide fluazifop-P-butyl 

which include both the free and conjugated forms of its resolved isomer expressed as fluazifop.

There are no Section 18 emergency exemptions in effect but fluazifop-P-butyl tolerances are likewise

established under 40 CFR §180.411(c) which carry regional restrictions expressed as fluazifop.

To further develop the use of fluazifop-P-butyl, Syngenta has submitted petition No. 9F7624 for 

establishing permanent tolerances in/on bananas, citrus, grapes, and sugar beets. The end-use product

relevant for this petition request is Fusilade® DX Herbicide (EPA Reg. No. 100-1070), an 

emulsifiable concentrate formulation containing 24.5% ai of fluazifop-P-butyl (equivalent to 2 lb 

ai/gal). It is proposed for use as multiple foliar or vineyard/orchard floor applications made at 

maximum seasonal rates of 1.125 lb ai/A for bananas, grapes, and citrus and 0.75 lb ai/A for sugar 

beets. Applications are to be made with an adjuvant using ground or aerial equipment at Pre-Harvest 

Intervals (PHIs) which range from 0 days on treatments made to bananas up to 90 days for sugar beets.

In addition, petition No. 9E7651 is also being put forward by Syngenta which requests that an import 

tolerance for fluazifop-P-butyl be established on potatoes. The end-use products relevant for this 

petition request are the VENTURE L and Fusilade® MAX(X) herbicide Emulsifiable Concentrate 

(EC) formulations. These end-use products are identical with both of them containing approximately

14.0% fluazifop-P-butyl active ingredient (ai) equivalent to 125 g ai/L. For this action, Syngenta has 

requested to amend the label of the VENTURE L product by adding this new use on potatoes in 

Canada. Treatments of these products are to be made as a single foliar spray application not to exceed 

the maximum labeled rate of 250 g ai/ha timed at PHIs of 45 or 90 days.

This HED document provides a summary of the findings from the data evaluation and subsequent 

assessment of human health risk resulting from these submissions. Prior actions made to develop the 

fluazifop-P-butyl herbicide active ingredient (ai) have identified a number of studies that are required 

for completing data gaps. In accordance, a number of Data Call-In (DCI) submissions have been 

provided by the registrant in order to satisfy these database requirements. These studies are as 

follows:
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• Carrot and endive nature of residue studies, test guideline 860.1300. 

• Ruminant and poultry nature of residue studies, test guideline 860.1300. 

• Radiovalidation study made for the tolerance enforcement method proposed for analyzing plants, 

test guideline 860.1340. 

• Method validation study made for the tolerance enforcement method proposed for analyzing 

poultry, eggs and livestock, test guideline 860.1340.

• Cattle and poultry feeding studies, test guideline 860.1480.

• Confined rotational crop study, test guideline 860.1850. 

An assessment of these studies is currently in progress and when completed, will be addressed in a 

separate memorandum. Should the results of the studies submitted in response to the registration DCI

impact the conclusions reached in this summation, appropriate changes will be made at that time. 

Hazard Assessment

Fluazifop-P-butyl has low acute toxicity by the oral, dermal and inhalation

routes, and mildly irritating to the eye and skin, and is not a skin sensitizer. Sub-chronic and

chronic toxicity studies with fluazifop-P-butyl show that the rat is more

sensitive to toxic effects than the dog, rabbit or hamster, possibly due to longer retention time of

the major metabolite (fluazifop acid) in the rat. The liver and kidney are the target organs and

the toxicity is expressed as liver toxicity in the presence of peroxisome proliferation and

exacerbation of age related kidney toxicity. An acute dietary endpoint for females 13-49 years of age 

was selected from a developmental toxicity study in rats, based on diaphragmatic hernia (LOAEL=50 

mg/kg/day). No appropriate endpoint attributable to a single dose was identified for the general U.S. 

population. The short-term incidental oral endpoint was selected from the developmental toxicity

studies in rats and 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 study 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). This endpoint was also utilized for the intermediate & longterm dermal and inhalation exposures (1 to >6 months). The short-term dermal and inhalation 

endpoints used in the assessment were selected from the developmental toxicity studies in rats based 

on decreased fetal weights, hydroureter and delayed ossification (NOAEL=2 mg/kg/day). Though this 

endpoint was selected by the Hazard Identification Risk Assessment Committee specifically for 

females 13-49 years of age, and a separate, higher, dose/endpoint was selected for all other population 

sub-groups from the developmental toxicity studies in rats, based on maternal weight gain decrement, 

HED chose to use the female-specific endpoint for all population sub-groups. By using the lower 

dose/endpoint approach for all population sub-groups, the risk assessment is protective of the toxic 

effects seen at higher doses. Because oral NOAELs were selected for dermal and inhalation endpoints, 

dermal absorption factors, calculated from a dermal absorption and pharmacokinetic study in

humans, of 2% for high exposures and 9% for low exposures were used for oral-dermal route-to route

extrapolation, and 100% absorption was used for inhalation exposure. 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.
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Though increased susceptibility of offspring was observed in rats, the degree of concern is low.

The endpoint of concern (delayed ossifications) is a well defined endpoint based on five

developmental toxicity studies and the NOAEL/LOAEL(s) are much lower dose levels than

resulted in the malformations. A developmental endpoint of concern for a single-dose effect

(diaphragmatic hernia) is used for assessing acute dietary risk. However, the 2-generation reproduction 

study in rats did not reveal increased susceptibility of the offspring. No increased offspring sensitivity

over parent was seen the rabbit pre-natal developmental studies or the post-natal reproduction study 

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

neuropathology or immunotoxicity in the available studies. Marginal increases in brain weights at 

termination were seen in a sub-chronic toxicity study in rats and a carcinogenicity study in hamsters, 

but only at high doses. HED concluded that there is not a concern for developmental neurotoxicity

resulting from exposure to fluazifop-P-butyl. The Agency concluded that the toxicology database is 

complete for FQPA assessment and that outstanding studies are not likely to have an endpoint of less 

than 0.74 mg/kg/day. Therefore, the FQPA 10X uncertainty factor need not be retained for 

susceptibility or data base uncertainty concerns. 

Residue Chemistry

The Fluazifop-P-Butyl Residue Chapter of the TRED (DP No. 319907, S. L. Kinard, 08/17/2005) 

concluded that the nature of the residue in soybeans is adequately understood. No new plant 

metabolism studies for the proposed new use crops were submitted as part of the current petition. It

has been concluded that for tolerance expression, parent and fluazifop-acid (free and conjugated) are 

the residues of concern since they are adequate to determine misuse (DP No. D298939, S. L. Kinard, 

06/22/2004). For this action, there are no residue chemistry issues that would preclude the conditional 

registration of the requested uses of fluazifop in/on bananas, citrus, grapes and grape processed 

commodities, or sugar beet. An unconditional registration may be appropriate upon determination of 

the adequacy of a new citrus processing study. In regard to the establishment of a tolerance for 

fluazifop-P-butyl in/on imported potato commodities, registration can be granted for this requested 

use. There are adequate analytical methods available for carrying out data collection efforts and 

enforcing all recommended tolerances.

Residential Exposure and Risk Estimates

Short-term (1-30 days) residential exposure may occur from its use in post-emergent control of weed 

grasses on turf. For adults, exposure may occur from homeowner application of fluazifop-P-butyl 

products (dermal and inhalation routes) and from contact with treated turf (dermal) following 

application. For children, post-application exposures (dermal and incidental oral) can occur from

contact with treated turf. Adult applicator and post-application risks were combined in the assessment. 

Likewise, risks to children from dermal plus hand-to-mouth, object-to-mouth, and soil ingestion 

exposures were combined for scenarios involving post-application contact with treated turf. 

For fluazifop-P-butyl, residential risk estimates were determined using the Margins of Exposure 

(MOEs) approach made as a ratio of the toxicological point of departure to the body burden. By

means of this technique, aggregate risk estimates were made using the most conservative endpoints, 

high-end exposures, and worst-case scenarios. Estimated risks for residential handlers and short-term 

post-application exposures, as well as those involving children, all yielded MOEs above 100 which are 

not of concern to HED. 
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Based upon these proposed new uses for this action, the existing residential fluazifop-P-butyl use 

patterns will not be affected. As a result, HED’s most recent residential risk assessment will require 

no revision with its conclusions remaining relevant and appropriate (DP No. D291905, M. Collantes, 

11/29/2004). 

 

Dietary Exposure and Risk Estimates

Revised acute and chronic dietary exposure assessments using the version 2.03 Dietary Exposure 

Evaluation Model (DEEM-FCIDTM) were subsequently conducted for fluazifop-P-butyl (DP No. 

D379452, S. Tadayon, 08/09/2010). This modeling effort uses food consumption data from the U.S. 

Department of Agriculture’s Continuing Surveys of Food Intakes by Individuals (CSFII) from 1994-

1996 and 1998 to calculate dietary risk. These analyses were performed to support the Section 3 

registration of fluazifop-P-butyl on bananas, citrus, grapes and grape processed commodities, as well 

as sugar beets. Also included in this determination are all uses which would be relevant to the 

establishment of an import tolerance made for fluazifop-P-butyl on potatoes. The proposed new crop 

uses were added into the residue file for all previously registered commodities so that a current 

evaluation of dietary exposure could be made. 

The resulting acute and chronic risk assessments which include both food and water are conservative 

evaluations. Tolerance level residues with ratio adjustment to account for additional metabolites of 

concern were used with the assumption that 100% of all crops are treated to perform an unrefined 

acute analysis. DEEM 7.81 processing factors were utilized for any applicable commodities to reflect 

the possible altering of residue levels through the manufacture of other food forms such as meal and 

flour. For all other commodities, the default adjustment factor of 1.0 was used to weight the 

processing effects of alternate food forms. In conjunction, percent crop treated estimates determined 

by BEAD along with the average residue levels observed in the applicable field trial studies with ratio 

adjustment was used to carry out the refined chronic analysis. Default processing factors along with 

the measured peanut and soybean processing factors were used to weight the effects of alternate food 

forms for chronic assessment. For both determinations, drinking water considerations were 

incorporated directly into these analyses using the Estimated Environmental Concentrations (EECs) 

generated by EFED to complete the combined dietary exposure assessments.

The acute and chronic dietary risk analyses performed herein with the DEEM-FCIDTM model form a

careful evaluation of exposure for fluazifop-P-butyl. The acute dietary assessment was limited to the 

females 13-49 years of age population subgroup. This is the only population subgroup for which an 

appropriate toxic endpoint attributable to a single dose was identified. For females 13-49 years of age, 

acute dietary risk was estimated to be only 13 % of the aPAD with an exposure of 0.0641 mg/Kg/day.

In conjunction, the refined chronic analysis likewise yielded risk estimates well below the 100% of the 

cPAD threshold level of concern for each population subgroup. For the most highly exposed 

population subgroup, children 1-2 years of age, chronic dietary risk was estimated to be 40% of the 

cPAD with an exposure of 0.0030 mg/Kg/day. In all, the dietary risks for combined food and drinking 

water exposure from the proposed expanded uses of fluazifop-P-butyl are not of concern. 
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Drinking Water Exposure and Risk Estimates

The potential human exposure to fluazifop-P-butyl in drinking water was likewise re-evaluated by 

EFED to support the proposed new crop uses being requested by Syngenta for risk assessment 

purposes. For this assessment, EECs in both ground and surface water were estimated using the Tier I 

SCIGROW and Tier II PRZM/EXAMS models, respectively (DP Nos. D371093 & D371094, W. J 

Shaughnessy, 05/25/2010). These modeling efforts indicate that the most significant levels of 

fluazifop-P-butyl would likely be found in surface water resulting from applications made to bananas 

and plantains. Corresponding drinking water levels of fluazifop-P-butyl resulted in estimated 

concentrations of 33.4 μg/L and 6.6 μg/L for acute and chronic exposures respectively. As such, these 

concentration estimates provided by EFED indicate that the proposed new uses would result in greater 

water exposures relative to those which were previously determined. However, as stated above, when 

combined with exposures through food, combined drinking water and food exposures are not of 

concern.

 

Aggregate Exposure and Risk Estimates

To ensure risk characterization efforts are all inclusive, HED aggregated the exposures/risks from 

food, drinking water, and residential (oral, dermal & inhalation) sources. This evaluation is typically

made by adding together the exposures from each source for comparison to a quantitative estimate of 

hazard (NOAEL, PAD, etc.), or just by simply aggregating the risks themselves. When aggregating 

various sources of exposures and risks, HED gives consideration to both the route and duration of 

exposure. 

 

For this action, the proposed new uses of fluazifop-P-butyl were found to slightly increase total 

exposures through food, and significantly increase exposures through drinking water. Based upon this 

outcome, the impact on dietary exposure is the only occurrence which would necessitate updating the 

current aggregate short-term risk assessment in place for this herbicide. To complete this evaluation, 

aggregate risk assessments were carried out for the most likely exposure scenarios resulting from the 

existing and expanded uses of fluazifop-P-butyl. These scenarios are for combined acute (1-day) 

exposures made through food and drinking water, as well as combined chronic exposures occurring 

through food and drinking water. In addition, the short-term aggregate exposures resulting from food, 

drinking water, and residential uses were considered. 

In making this characterization, estimates of aggregate risk from combined acute (1-day) fluazifop-Pbutyl exposures occurring in food and drinking water were determined with DEEM-FCIDTM modeling. 

DEEM-FCIDTM modeling was also used to determine estimates of aggregate risk from combined 

chronic fluazifop-P-butyl exposures in food and drinking water as well. A detailed discussion of these 

findings evaluating the expanded use of fluazifop-P-butyl is therefore provided in the Section 6.1.1 

Acute and Chronic Dietary Exposure and Risk Update of this memorandum. As for the short-term (1-

30 days in duration) aggregate risk assessment, it was made as an estimate of potential exposures from 

food, drinking water, and home lawns. High-end estimates of exposure resulting from treatment of 

lawns along with average exposures from food and drinking water were used to form this evaluation. 

For this short-term aggregate risk assessment, aggregate MOEs of 150 for adults and 250 for children 

(1 – 2 years of age) were obtained which are well above the level of concern of 100 indicating there 

are no concerns resulting from the proposed expanded uses of fluazifop-P-butyl. 
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Occupational Exposure Estimates

The new crop uses proposed with this petition are for the Fusilade® DX Herbicide (EPA Reg. No. 

100-1070), an EC formulation containing 24.5% ai of fluazifop-P-butyl (equivalent to 2 lb ai/gal). Its 

expanded use will employ multiple foliar or vineyard/orchard floor applications at maximum seasonal 

rates of 1.125 lb ai/A for bananas, grapes, and citrus and 0.75 lb ai/A for sugar beets. Applications are 

to be made using an adjuvant and applied with either ground or aerial equipment. Labeling 

instructions propose PHIs for the requested new uses which range from 0 days on treatments made to 

bananas up to 90 days for sugar beet applications. In accordance, occupational handlers and postapplication workers can become exposed to fluazifop-P-butyl at short- or intermediate-term durations 

through its use. 

For the new crop uses being proposed in this action, the expanded use of fluazifop-P-butyl will 

support commercial agricultural efforts in controlling grass weeds through limited foliar application. 

Occupational exposures/risks were addressed in the prior HED human health risk assessment made to 

support the new uses to dry beans and peanuts (DP No. D347515, P. Savoia, 09/18/2008). For this 

current action, a new evaluation of the occupational exposure/risk pathway was performed herein to 

ensure worker protection safeguards (DP No. D379451, S. Tadayon, 06/23/2008). This accounts for 

potential exposure to fluazifop-P-butyl during mixing, loading, and application activities pertinent to the 

existing and proposed new uses. 

Most occupational activities will involve worker contacts with the herbicide requiring the 

consideration of dermal and inhalation exposure when evaluating risk. Dermal absorption factors of 

2% and 9% were determined for fluazifop-P-butyl depending on high versus low levels of exposure 

respectively. Re-entry intervals have been assessed using both values. HED believes that prior 

dermal absorption studies demonstrate saturation of the skin if the mass per unit area exceeds a certain 

level. Given this, use of the 9% factor in combination with high levels of exposure would result in a 

conservative estimate of risk. 

No long-term exposures are expected for the general agricultural use-patterns of fluazifop-P-butyl, 

therefore, no long-term risks were assessed. Estimated risks for occupational handlers determined for 

short-/intermediate-term exposures yielded total MOEs greater than 100, with some scenarios 

requiring additional personal protection above baseline (e.g., engineering controls for mixer/loaders). 

In reaching or exceeding the LOC of 100, the resulting MOEs indicate these risks are not of concern. 

Most of the proposed new uses are ground directed applications where no crop foliage is being treated. 

Currently, HED has no Transfer Coefficients (TCs) or other data to assess post-application dermal 

exposures to soil by occupational workers. As a result, this post-application exposure and risk to 

occupational workers was not quantitatively assessed. However, in assessing the applications made to 

sugar beets and potatoes where workers can come in contact with foliage, these risks are not of 

concern since the resulting MOEs where found to exceed 100. 
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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://www.epa.gov/compliance/resources/policies/ej/exec_order_12898.pdf. The Office of Pesticide 

Programs (OPP) typically considers the highest potential exposures from the legal use of a pesticide 

when conducting human health risk assessments, including, but not limited to, people who obtain 

drinking water from sources near agricultural areas, the variability of diets within the U.S. (including 

different ages, regions, and ethnicities), and people who may be exposed when harvesting crops. 

Should these highest exposures indicate potential risks of concern, OPP further refines the risk 

assessments to ensure that the risk estimates are based on the best available information.

Cumulative

FQPA requires that EPA consider “available information” concerning the cumulative effects of a 

particular pesticide’s residues and “other substances that have a common mechanism of toxicity.” The 

Agency considers other substances because low-level exposures to multiple chemical substances that 

cause a common toxic effect by a common mechanism could lead to the same adverse health effect, as 

would a higher level of exposure to any of the substances individually. Risks summarized in this 

document are those that result only from the use of fluazifop. The Food Quality Protection Act 

(FQPA) requires that the Agency consider “available information” concerning the cumulative effects 

of a particular pesticide’s residues and “other substances that have a common mechanism of toxicity.” 

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

and any other substances. In addition, fluazifop does not appear to produce a toxic metabolite 

produced by other substances which have tolerances in the U.S. Therefore, for the purposes of 

tolerance reassessment, EPA has not assumed that fluazifop shares a common mechanism of toxicity

with other compounds.

Recommendations for Tolerances/Registration

Provided the petitioner submits revised Sections B and F (see Section 11.0), HED concludes that the 

toxicological, residue chemistry and occupational/residential databases support a conditional 

registration and establishment of permanent tolerances for the proposed new uses of fluazifop-P-butyl.

Tolerances are to be established for residues of the herbicide fluazifop-P-butyl, 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 the sum of fluazifop-P-butyl, butyl(R)-2-

[4-[[5-(trifluoromethyl)-2-pyridinyl]oxy]phenoxy]propanoate, and the free and conjugated forms of 

the resolved isomer of fluazifop, (R)-2-[4-[[5-(trifluoromethyl)-2-pyridinyl]oxy]phenoxy]propanoic 

acid, calculated as the stoichiometric equivalent of fluazifop, in or on the commodity.

Banana..................................................................................0.01 ppm

Fruit, citrus, group 10...........................................................0.03 ppm

Citrus, oil............................................................................30.0 ppm

Citrus, dried pulp .................................................................0.40 ppm

Citrus, juice..........................................................................0.06 ppm

Grape....................................................................................0.01 ppm

Beet, sugar, root ...................................................................0.25 ppm

Beet, sugar, dried pulp .........................................................1.0 ppm
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Beet, sugar, molasses...........................................................3.5 ppm

Potato ...................................................................................1.0 ppm

Potato, chips.........................................................................2.0 ppm

Potato, granules/flakes.........................................................4.0 ppm

Registration of these tolerances should be made conditionally until the remaining data deficiencies 

described in Section 11.0 are satisfied. An unconditional registration may be appropriate upon 

determination of the adequacy of a new citrus processing study (see requirements under Processed 

Food and Feed).

2.0 Background

In August of 2005, HED completed a human health risk assessment of the fluazifop-P-butyl herbicide 

active ingredient for Tolerance Reassessment Eligibility Decision (DP No. D316891, D. Locke, 

08/29/2005). Following this risk assessment, Syngenta Crop Protection, Inc. submitted petition No. 

7F7289 which requested to allow for the post-emergence use of fluazifop-P-butyl on dry beans and 

peanuts. Along with these two new crop uses, the registrant also proposed in this petition to allow 

fluazifop-P-butyl treatments made on soybeans to include post-bloom application. In response to this 

action, HED has conducted a subsequent risk assessment to support all existing uses as well as the new 

crop treatments which were requested (DP No. D347515, P. Savoia, 09/18/2008).

For this current registration action, new data characterizing the magnitude of the residue in plants were 

appropriately provided by the registrant to support the additional crop uses which are being proposed. 

There were no new toxicological studies, public health, residential, or occupational data provided in 

the Syngenta submission. Therefore, the presentation of the toxicity database, points of departure, and 

hazard characterization presented in section 4.0, while more streamlined, are substantively the same as 

those appearing in recent previous assessments. The assessment of residential exposures and risks are 

similarly based upon the relevant information provided in the August 2005 tolerance reassessment (DP 

No. D316891, D. Locke, 08/29/2005). 

To establish permanent tolerances for residues of fluazifop-P-butyl on banana, citrus, grape, and sugar 

beet RACs as well as an imported potatoes, this memorandum updates the prior risk assessments 

noted. It provides residue chemistry, dietary exposure, aggregate risk assessment, and occupational 

risk assessment updates to reflect the new crop uses which are being proposed. In doing so, all 

information and/or conclusions contained in the August 2005 and September 2008 HED human health 

risk assessments will therefore remain unchanged unless otherwise noted in this memorandum. 

3.0 Summary of Proposed Uses

The expanded use of fluazifop-P-butyl will utilize the Fusilade® DX Herbicide for multiple foliar or 

vineyard/orchard floor applications at maximum seasonal rates of 1.125 lb ai/A for bananas, grapes, 

and citrus and 0.75 lb ai/A for sugar beets. This product can be applied with an adjuvant using ground 

or aerial equipment at PHIs which range from 0 days on treatments made to bananas up to 90 days for 

sugar beet applications. For the new use requested on potatoes, the VENTURE L product will be 

utilized as a single foliar spray not to exceed the maximum labeled rate of 250 g ai/ha timed at a PHI 

of 45 or 90 days. In using this product, spray mist and drift is to be avoided with applications never to 

be made by aircraft or within 15 m of fish bearing waters. A detailed summary of the proposed new 

uses on bananas, grapes, citrus, potatoes and sugar beets is presented below in Table 1 for review. 
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Table 1. Summary of Directions for Use of Fluazifop-P-butyl.

Applic. Timing, Type, 

and Equip. 

Formulation

[EPA Reg. No.]

Maximum 

Applic. Rate 

(lb ai/A)

Max. No. 

Applic. per 

Season

Max. Seasonal 

Applic. Rate

(lb ai/A)

PHI

(days)

Use Directions and 

Limitations

Banana

Ground and Aerial.

Fusilade® DX 

Herbicide,

2 lb/gal EC

[100-1070]

0.375 3 1.125 0

A minimum 30-day RTI is 

specified.

Citrus

Ground and Aerial.

Fusilade® DX 

Herbicide,

2 lb/gal EC

[100-1070]

0.375 3 1.125 14 A minimum 21-day RTI is 

specified.

Grape

Ground and Aerial.

Fusilade® DX 

Herbicide,

2 lb/gal EC

[100-1070]

0.375 3 1.125 50 A minimum 14-day RTI is 

specified.

Sugar Beet

Ground and Aerial.

Fusilade® DX 

Herbicide,

2 lb/gal EC

[100-1070]

0.375 2 0.75 90 A minimum 14-day RTI is 

specified.

Potato

Post-emergence

Ground.

Venture L® 

Herbicide,

125 g ai/L EC

[Canadian Reg. 

No.: 21209]

0.275 1 0.275 45 or 90

May be mixed with Lexone 

or sencore formulations for 

early post emergent 

application.

The general label use directions of the Fusilade® DX Herbicide specify that: (1) adjuvants (crop oil 

concentrate, non-ionic surfactant, or other approved adjuvants) plus liquid nitrogen fertilizer may be 

used on soybeans; (2) ground and aerial applications are to be made in a minimum of 5 gal/A; (3) for 

chemigation (sprinkler irrigation), adjuvants are not to be used in the manner described for use in 

conventional applications or applied with a system connected to a public water system; and (4) the 

restricted-entry interval is 12 hours. Rotational grass crops such as corn, sorghum and cereals are not 

to be planted within 60 days of last application.

For the VENTURE L product, general label use directions specify that it will be less effective when 

weeds are not growing rapidly because of stress from lack of moisture, excessive moisture, flooding, 

low temperature and/or very low humidity. Treatments should be applied to actively growing grass 

weeds that have 3 to 5 fully developed leaves for best results. Spray mist and drift is to be avoided 

with applications never to be made by aircraft or within 15 m of fish bearing waters. The use of 

adjuvants (crop oil concentrate, non-ionic surfactant, or other approved adjuvants) plus liquid nitrogen 

fertilizer may be used on specified crops such as soybeans and potatoes. 

4.0 Hazard Characterization and FQPA Considerations

The 2005 risk assessment contained a thorough description of toxicology profile for fluazifop-P-butyl 

(DP No. D316891, D. Locke, 08/29/2005). The data base is adequate for FQPA assessment, endpoint 

selection, and dose-response evaluation for fluazifop-P-butyl and the fluazifop mixed isomers. 
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4.1 Toxicology Studies Available for Analysis

The toxicity database on fluazifop-butyl is essentially complete with sufficient toxicity data on 

fluazifop-P-butyl to show similar responses in animal toxicity studies. The toxicity database is 

adequate for FQPA assessment, endpoint selection and dose-response evaluation of both products. 

Fluazifop-P-butyl has low volatility, is not an eye or skin irritant in acute or 21-day dermal studies, 

and is not a skin sensitizer. Fluazifop-P-butyl is likely to show similar toxicity by the inhalation route 

and the oral route, because it is metabolized by blood to the acid form and excreted as the acid form. 

The use pattern and exposure pattern for the residential handler show high MOEs, well above the level 

of concern using endpoints based on oral exposure. The data are relatively consistent among the rat 

with fluazifop-butyl and fluazifop-P-butyl, dog with fluazifop-butyl, and the hamster with fluazifop-Pbutyl, probably with some within-animal variation, although all endpoints were not evaluated with all 

species with fluazifop-P-butyl and its mixed isomers. 

Data from the following studies were used to evaluate the hazard potential of fluazifop-P-butyl:

Acute: Oral, Dermal, Inhalation, Eye and skin irritation, Dermal sensitization with 

fluazifop-butyl and fluazifop-P-butyl

Subchronic: Oral rat with fluazifop-butyl and fluazifop-P-butyl, Oral dog with fluazifopbutyl, Dermal 21-day rabbit with fluazifop-butyl, Inhalation - no studies 

available.

Chronic: Chronic/Cancer rat with fluazifop-butyl, Cancer hamster with fluazifop-P-butyl, 

Oral dog with fluazifop-butyl

Developmental: Two in the Sprague Dawley rat with fluazifop-butyl and three in the Wistar rat 

with fluazifop-P-butyl. One in the NZW Rabbit with fluazifop-butyl and one in 

the NZW rabbit with fluazifop-P-butyl.

Reproduction: Two-generation in rats with fluazifop-butyl

Metabolism: Rat, human and dog with fluazifop-butyl and comparative in the rat with 

fluazifop-butyl and fluazifop-P-butyl, and hamsters with fluazifop-P-butyl.

Dermal Penetration: Human study (ethics of study cleared)

Literature Studies: Literature studies regarding information for which similar, but more detailed, 

reports were submitted to the Agency.
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4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)

Fluazifop-butyl is a herbicide with mixed isomeric [RS] content, while fluazifop-P-butyl is the 

purified [R] enantiomer, the only herbicide supported for re-registration. Metabolism studies have 

been conducted in the rat with fluazifop-butyl, and absorption, excretion and confirmatory metabolism 

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 converted to the [R] enantiomer in the 

blood, yielding similar toxicities within animal variation. In characterizing this herbicide active 

ingredient, fluazifop-P-butyl is the purified (R) enantiomer of the mixed isomeric (RS) fluazifop-butyl 

product. Fluazifop-butyl (PC code 122805) has since been cancelled resulting in only fluazifop-Pbutyl (PC code 122809) currently being supported for re-registration. In vivo, the S-isomer quickly 

converts to the R-isomer. A 50:50 mixture of the two isomers quickly converts to 97% R-isomer in 

vivo. Given this distinction, the toxicological data-base on fluazifop-butyl is complete with sufficient 

data available showing equivalence of fluazifop-butyl (FB, PC code 122805) for fluazifop-P-butyl

(FPB, PC code 122809) in animal toxicity. The toxicity data-base is therefore adequate to carry out 

FQPA assessment, endpoint selection, and dose-response evaluation for both chemicals. Peroxisome 

proliferation was shown in rat and mouse, and to a lesser extent in the hamster, in vivo, and human 

liver cells, in vitro. 

Oral dog and female rat studies show similar results. 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 

excretion to the female, but excretion is slower because fluazifop is excreted in the bile, resulting in a 

higher % in the feces of males rats. The greater toxicity in male rats may be due to the longer 

retention time. In rats, the blood half-lives after intravenous administration ranged from 2.7-43 hours 

for 1 mg/kg and 1000 mg/kg doses, respectively. Based on radioactivity recovered in the urine after 1 

mg/kg oral dosing in rats, absorption was extensive in females (75-89%), but was less so in males (49-

51%). Furthermore, excretion in the urine was rapid in females, 66-83% dose within 1 day post-dose. 

Conversely, excretion was slower in males, largely taking place over a 3 day period post-dose in urine 

(41-43% dose) and feces (26-27% dose). Over the 7 day post-dose period in rats, relatively little of 

the dose was excreted in the feces of females (3-11%), while 35% dose was excreted in the feces of 

males. Residual fluazifop acid appears to be retained in the body fat (<1% to 8% in the rat) and 

speculated to be esterified to mono- or di-glycerides. This small amount of residual material, if 

released, was too low to be accurately detectable in the urine. This residual material is relatively 

immobile and may be toxicologically insignificant, since multiple dosing studies show that fluazifopbutyl does not accumulate in the body and is not a carcinogen. In hamsters dosed orally, 72-82% of the 

administered radioactivity was excreted by males and 82-88% by females within 12 hours of dosing. 

Over the 72-hour collection period, the majority of the radiolabel was excreted in the urine (70-83% 

for males; 76-93% for females) and feces (11-24% for males; 10-16% for females), irrespective of 

dose. The hamsters had low levels of radiolabel in the tissues and carcasses (0.18-0.43% of the given 

dose). 
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In a metabolism study (MRID# 00131464)(Fluazifop-butyl, 99.6% a.i, Y00083/012/003) were 

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 fluazifopbutyl is rapidly absorbed, 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 lacked the delayed excretion 

characteristic of male rats possibly being due to biliary 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. In toxicity studies in rats, toxicity in males was always 

more severe than in females. Only hydrolyzed fluazifop-butyl or the free acid was detectable in 

plasma and the free acid and its conjugate were detected in urine. The excretion of the test material 

was complete within 7 days, with plasma levels being undetectable within 72-144 hours (3-6 days) and 

with urine levels being undetectable at 96-144 hours (4-6 days). Total recoveries of fluazifop as the 

conjugate and the free acid in the urine from each of the 3 men were 80%, 93% and 92% (Mean 

88.3%) of the dose and 1-4%, 6% and 23% as a conjugate, respectively. The ethics of this human 

study was cleared in the memo “Ethics Review of Fluazifop-Butyl Absorption, Distribution and 

Metabolism Study” (K Sherman, August 13, 2010).

4.2.1 Dermal Absorption

In a dermal absorption and pharmacokinetic study in humans (MRID# 46082918, ethics of study

cleared, Lowe MF, Carley JM, June 10, 2006), six men/dose (age 18-45; weight 60-90 kg) were 

exposed dermally with 2 mg or 200 mg of 0.05% or a 5.0% (w/v) solution of fluazifop-butyl in a 

formulation. The washes, T-shirts, plasma and urine samples were analyzed for fluazifop-butyl or 

fluazifop acid.

Most 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). Recovery of test material was good, 

a mean of 93.4% ± a standard deviation of 13% at the 2 mg dose and mean of 83.2% ± a standard 

deviation of 21% at the 200 mg dose. Peak plasma levels were shown to occur 24 to 31 hours after 

application in these men. The one half-life for excretion was about 18 hours. In the 2005 risk 

assessment, HED (D316891) modified the study author’s percentage absorption via scaling the 

amount recovered material to 100%, yielding absorption factors of 8.6% and 1.9% at the 2 mg dose 

and 200 mg dose, respectively.
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4.3 Toxicological Effects

Fluazifop-P-butyl herbicidal specificity is by inhibiting acetyl CoA carboxylase (a key enzyme in 

plant fatty acid synthesis and required for maintaining membranes in functioning condition). 

Fluazifop-P-butyl has low volatility proving no indication of being an eye or skin irritant in acute or 

21-day dermal studies, and is not a skin sensitizer. Fluazifop-P-butyl shows similar toxicity by both 

the inhalation and oral routes because of its metabolization by blood into the acid form and excretion 

in this manner. The liver and kidney have demonstrated to be 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 the rat with fluazifop-butyl and 

fluazifop-P-butyl, dog with fluazifop-butyl, and hamster with fluazifop-P-butyl. Although all 

endpoints were not tested in all species using both compounds, some disparities may be evident 

probably within animal variation. In general, there were no carcinogenicity concerns in any

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 prolifieration more closely resembled what 

was found for human liver cells. There were no mutagenicity concerns evident for fluazifop-butyl or 

fluazifop-P-butyl. 

The current risk assessment is based on the most sensitive endpoints (decreased testes and epididymal 

weights in male rats and decreased pituitary and uterine weights in females) in the most sensitive 

species. The reproduction study male/female NOAELs are 0.74 and 0.88 mg/kg/day while the 

LOAELs are 5.8 and 7.1 mg/kg/day, respectively.

A rat developmental study exhibiting diaphragmatic hernia effects was used as the basis to select the 

acute dietary endpoint for females 13-49 years of age. In contrast, there was no appropriate endpoint 

which correlated to a single dose identifiable for the general U.S. population. The short-term 

incidental oral endpoint was selected based upon a maternal body weight gain decrement exhibited in 

the developmental toxicity studies performed on rats. The chronic dietary (all populations), 

intermediate-term dermal and inhalation, as well as the intermediate-term incidental oral endpoints, 

were selected from the 2-generation reproduction study in rats. This study 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 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. 

In summarizing the available toxicity data on fluazifop-P-butyl, the established toxicity endpoints for 

risk assessment are presented below in Appendix A2 for review (DP No. D316891, D. Locke, 

08/29/2005). There were no concerns for neurotoxicity resulting from fluazifop-P-butyl which were 

evident at relevant exposure levels. There was also no evidence of clinical signs which would indicate 

neurotoxicity or neuropathology in the available studies, however, the Revised Part 158 Data 

Requirements list the acute and 90-day neurotoxicity studies as mandatory. Marginal increases in 

brain weights at termination were observed in a sub-chronic toxicity study in rats, and in a 

carcinogenicity study performed on hamsters, but only at higher doses. 
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For fluazifop, there were some indications of potential immunotoxicity in the form of thymic 

involution, altered spleen weights, lymphadenopathy and bone marrow myelogram changes in dogs 

treated orally (capsule) with 25 mg/kg/day (mid-dose) and 125 mg/kg/day (high-dose) fluazifop for 55 

weeks. However, these effects are not of concern because: (1) thymic involution was of slight severity

in only 1 female treated with the mid-dose. In addition, the response was equivocal in the males as 

there was no dose-response relationship (incidence and severity) and controls also exhibited thymic 

involution. One control dog had severe thymic involution. Also, the colony of dogs used in the study

had excessive health problems that may have impacted normal immune status; (2) the statistical and 

biological significance of the alterations in spleen weights could not be assessed because of the large 

variation of the weights in control dogs. Also, the alterations were inconsistent between dogs that died 

(these dogs displayed increased adrenal weights) and dogs that survived (these dogs displayed 

decreased adrenal weights); (3) lymphadenopathy was observed only at the high dose (125 mg/kg/day) 

and the response is questionable since the colony of dogs used in the study had excessive health 

problems that included lymphadenopathy; (4) the bone marrow myelogram changes were discounted 

by an HED Peer Review Committee which determined that the changes were small and variable and 

not dose related. In addition, the colony of dogs used in the study exhibited health problems that may

have impacted the normal immune system; and (5) none of the potential immunological signs in the 

dog were seen in a chronic study of the rat, the most sensitive species. HED considered the results of 

the chronic dog study to be unreliable due to fact that the animals were unhealthy, so that apparent 

immunotoxic effects were observed in some untreated control animals. Moreover, no immunotoxic 

effects were observed in the sub-chronic dog study; a study where healthy animals were used. HED 

therefore believes that the available data do not warrant an additional 10X be applied to the 

uncertainty factor used for estimating risk at this time. An immunotoxicity study (870.7800) must be 

performed on fluazifop-P-butyl, under 40 CFR Part 158, so that its immunotoxic potential can be fully

evaluated.

4.4 FQPA Safety Factor

No increased offspring sensitivity over parent was seen the rabbit pre-natal developmental studies or 

the 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 in five developmental studies 

was selected based delayed ossification and fetal weight decrement at much lower doses (100 fold 

lower). 

There is an adequate toxicity database for fluazifop-P-butyl and exposure data are complete or are 

estimated based on data that reasonably account for potential exposures. There is no evidence of 

susceptibility following in utero and/or post-natal exposure in the 2-generation rat reproduction study

(parental NOAEL=0.74 mg/kg/day and offspring NOAEL=7.1 mg/kg/day). There are no residual 

uncertainties pertaining to pre- and post-natal toxicity and no developmental neurotoxicity or 

immunotoxicity concerns were revealed in past studies. The chronic dietary (food and drinking water) 

exposure assessments are conservative. The dietary and residential assessments are based on reliable 

data and will not underestimate exposure/risk. Based on these data and conclusions, the FQPA Safety 

Factor can be reduced to 1X.

90-Day dermal and inhalation toxicity studies are also required to confirm the PODs selected for 

assessing dermal and inhalation exposures based on route-to-route extrapolations from oral studies. 

Fluazifop-P-butyl is expected to show similar toxicity by the inhalation and oral routes because of its 
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metabolism by blood into the acid form and excretion in this manner. The NOAEL from the available 

28-day dermal study is considerably higher (100 mg/kg/day). 

Although a point of departure from an oral study was used to assess residential handler inhalation risks 

for fluazifop-P-butyl, EPA does not believe this aggregate risk assessment is under-protective of adult 

handlers. Handler MOEs based on the extrapolated endpoint are quite high (14,000 to 1.1 million), 

and the contribution of residential exposure to aggregate risk is small. Therefore, even if an inhalation 

study were to provide a lower point of departure than the oral study, it’s not expected to have a 

significant impact on aggregate risk.

4.4.1 Completeness of the Toxicology Database

The toxicity database for fluazifop-P-butyl is complete except for acute and sub-chronic neurotoxicity

studies and immunotoxicity testing. Recent changes to 40 CFR §158 make these studies (OPPTS 

Guideline 870.7800) required for pesticide registration. A 90-day dermal study and 90-day inhalation 

study have also been requested for purposes of further evaluation and confirmation of the oral PODs 

route-to-route extrapolations used for these potential exposure routes. Fluazifop-P-butyl is likely to 

show similar toxicity by both the inhalation and oral routes because of its metabolization by blood into 

the acid form and excretion in this manner. The short-term dermal and short-term inhalation endpoints 

utilized the developmental toxicity study data with a NOAEL of 2.0 mg/kg/day, since it was more 

protective than the 28-day dermal study endpoint of 100 mg/kg/day. Although neurotoxicity studies 

have not yet been submitted, there is no evidence of neurotoxicity in any study in the toxicity database 

for fluazifop-P-butyl. In the absence of specific immunotoxicity studies, EPA has evaluated the 

available fluazifop-P-butyl toxicity database to determine whether an additional database uncertainty

factor is needed to account for potential immunotoxicity. No evidence of immunotoxicity was found in 

the most sensitive species, as described previously. The complete description for the lack of 

immunotoxicity testing not warranting a 10X FQPA factor is described in the memo “Fluazifop-PButyl. Rationale for Reducing the 10X Safety Factor to 1X for Lack of an Immunotoxicity Study. 

Addendum to Fluazifop-P-Butyl Risk Assessment for Dry Beans, Peanuts, and Soybeans [D347515, P. 

Savoia et al., 19-SEP-2008], J. Liccione, January 23, 2009, DP Barcode: 359779.

Due to the lack of evidence of neurotoxicity and immunotoxicity for fluazifop-P-butyl, EPA does not 

believe that conducting immunotoxicity and acute and sub-chronic neurotoxicity testing will result in a 

NOAEL less than that to derive the current cRfD of 0.0074 mg/kg bw/day. Likewise, the oral POD 

selected for residential dermal and inhalation routes of exposure (Developmental NOAEL=2.0 

mg/kg/day) is believed to be protective. Residential MOEs are large (14,000) and fluazifop-p-butyl is 

expected to show similar toxicity by both the inhalation and oral routes because of its metabolization 

by blood into the acid form and excretion in this manner. Consequently, the EPA believes the existing 

data are sufficient for endpoint selection for exposure/risk assessment scenarios and for evaluation of 

the requirements under the FQPA, and an additional database uncertainty factor does not need to be 

applied.

In the case of fluazifop-p-butyl, the 2008 risk assessment included a table that listed decreased spleen 

weights in male rats in the two-generation reproduction rat study as one of the effects observed at the 

LOAEL for several endpoints. However, upon closer examination of the effects seen, HED has 

determined that the spleen weight effect should not be cited as a toxicological effect at the study 

LOAEL for the following reasons: 1) the apparent spleen effect was marginal, only observed in one 

generation of male rats, and relatively independent of dose, 2) the apparent spleen effect was not 
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observed in the chronic carcinogenicity rat study, and 3) histological examination of the spleen tissue 

did not indicate that any changes were occurring on a cellular level. Based on these detailed 

considerations, HED now concludes that it is inappropriate to list spleen weight as a toxicological 

effect at the LOAEL of the two-generation rat reproduction study.

The Assessment team concluded that the toxicology database for fluazifop-butyl and fluazifop-P-butyl 

is complete for FQPA evaluation and that the current NOAEL of 0.74 mg/kg/day is sufficiently

protective, since no immunotoxicity nor neurotoxicity were observed in previous studies. Acceptable 

developmental toxicity studies in rats and rabbits on fluazifop-butyl and fluazifop-P-butyl are 

available in addition to an acceptable 2-generation reproduction study in rats. Studies on fluazifopbutyl may be used to support fluazifop-P-butyl due to equivalency in toxicity. A more comprehensive 

description of these data needs is listed in Appendix A3.

4.4.2 Evidence of Neurotoxicity

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. Marginal increases in brain weights at 

termination were seen in a sub-chronic toxicity study in a rats and a carcinogenicity study in hamsters, 

but only at high doses. A developmental neurotoxicity study is not required at this time.

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

There is no concern for increased susceptibility to offspring following pre- and postnatal exposure to 

rats or in utero exposure in rabbits.

There is no indication of developmental neurotoxicity resulting from exposure to fluazifop-P-butyl 

with the current data sets, so this study will not be requested at this time. Evidence that supports not 

requiring a DNT study include there was 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 

developmental neurotoxicity resulting from exposure to fluazifop-butyl or fluazifop-P-butyl. The 

toxicology database is adequate for hazard characterization and endpoint selection. Therefore, no 

database uncertainty factors are needed for any database deficiencies.

The data base 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 New Zealand rabbits; and 1 with 

fluazifop-P-butyl in New Zealand rabbits. These studies 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). 
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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 developmental 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# 46082913, 46082903), and 

statistically significant increased incidence of fetuses and litters with interparietals, occipitals and 

parietals partially ossified, calcaneum not ossified and increased manus and pes scores at 5.0 

mg/kg/day (MRID# 46082903 and 46158401). The NOAEL of 1.0 mg/kg/day in the 160 litter per 

group 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 dose group failed to 

elicit a dose dependant 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# 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.

The maternal toxicity NOAEL/LOAEL of 100/300 mg/kg/day was based a combination of factors. 

There was a clear effect on maternal weight 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 maternal 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 Wistar rat developmental toxicity studies to remove this 

ambiguity in maternal toxicity.

While there was quantitative evidence of increased susceptibility in the fetuses of rats exposed in utero 

to fluazifop-butyl and fluazifop-P-butyl, the 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 is considered to be more serious in nature; 

there were considerable variations in the incidences among the five studies; the NOAELs/LOAELs for 

this effect were well defined and consistent across these studies; and a developmental endpoint of 

concern (diaphragmatic hernia) is used for assessing acute dietary risk. Also, in a two-generation 

reproduction toxicity study in rats, there was no evidence (quantitative or qualitative) of increased 

susceptibility following in utero exposures to rabbits or following pre-and/or post-natal toxicity. 

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

4.4.4 Residual Uncertainty in the Exposure Database

There are no residual uncertainties in the exposure database. Since the dietary and non-dietary

exposure estimates were based on several conservative assumptions, HED does not believe that the 

exposure estimates are underestimated.
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The acute and chronic dietary assessments are conservative evaluations. The acute 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 more refined 

anlysis was performed for the chronic assessment, using percent crop treated, average field trial 

residue levels and default processing factors. 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 underestimate risk from exposure to fluazifop-P-butyl.

4.4.4.1 HED’s Levels of Concern (LOC)

Summary of HED’s LOCs for risk assessment. MOEs that are less than the LOCs are of concern.

Route

 

Duration

Short-Term

(1-30 Days)

Intermediate-Term

(1 - 6 Months)

Long-Term

(> 6 Months)

Occupational (Worker) Exposure

Dermal 100 100 100

Inhalation 100 100 100

Residential (Non-Dietary) Exposure

Oral 100 100 N/A

Dermal (All Populations) 100 100 100

Inhalation (All Populations) 100 100 100

For Occupational exposure: This is based on the conventional uncertainty factor of 100X (10X for interspecies extrapolation and 10X for intra-species 

variation).

For Residential exposure: This is based on the conventional uncertainty factor of 100X (1X for FQPA, 10X for interspecies extrapolation and 10X for 

intra-species variation).

4.5 Toxicity Endpoint and Point of Departure Selections

The details for selecting toxicity endpoints and points of departure for various exposure scenarios are 

presented in the appendix A2. 

An acute dietary endpoint for females 13-49 years of age was selected from a developmental toxicity 

study in rats, based on diaphragmatic hernia. No appropriate endpoint attributable to a single dose was 

identified for the general U.S. population. The short-term incidental oral endpoint was selected from 

the developmental toxicity studies in rats and is based on maternal body weight gain decrement. The 

chronic dietary (all populations), intermediate-term dermal and inhalation, and intermediate-term 

incidental oral endpoints were selected from the 2-generation reproduction study in rats based on 

decreased testes and epididymal weights in males, and decreased uterine and pituitary weights in 

females. The short-term dermal and inhalation endpoints used in the assessment were selected from 

the developmental toxicity studies in rats based on decreased fetal weights, hydroureter and delayed 

ossification. Though this endpoint was selected by the Hazard Identification Risk Assessment 

Committee specifically for females 13-49 years of age, and a separate, higher, dose/endpoint was 

selected for all other population subgroups from the developmental toxicity studies in rats, based on 
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maternal weight gain decrement, the fluazifop-P-butyl assessment team chose to use the femalespecific endpoint for all population subgroups for initial screening. By using the lower dose/endpoint 

approach for all population subgroups, the risk assessment is protective of the toxic effects seen at 

higher doses. This approach is particularly appropriate as a screening level assessment to determine if 

there are any potential risks of concern. Oral NOAELs were selected for dermal and inhalation 

endpoints. Dermal absorption factors, calculated from a dermal absorption and pharmacokinetic study

in humans, of 1.9% for high exposures and 8.6% for low exposures were used for oral-dermal routeto-route extrapolation, and 100% absorption was used for inhalation exposure. 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-butyl and fluazifop-P-butyl.

4.5.1 Dose-Response Assessment

The decreased testes weight and decreased epididymal weight in PO and F1 adult rats showed a 

marginally adequate dose response. The statistically significant decrease in both organs could 

potentially have resulted from a decreased sperm count. The cancer study in hamsters showed a good 

dose-response in testes weight decrement. Since the statistically significant effects were seen in the 

male P0 and F1 parents and in the hamster study, the effects were considered treatment related. The 

testicular endpoint from the reproduction study was selected for the chronic RfD, intermediate-term 

oral incidental exposure, intermediate and long-term dermal and inhalation exposure. Other studies 

showed testes weight decrement and epididymal effects at higher dose levels, but there were only

equivocal histological effects shown. Although extensive short-term studies on the testes weight 

decrement and epididymal effects were conducted, all failed to show that the effect was incidental or 

find an explanation for the effect. However, the more sensitive studies on sperm parameters, such as 

sperm motility and sperm count, were not among the extra studies conducted. An acceptable negative 

study of sufficient duration on sperm parameters would add confidence to the possibility that the testes 

and epididymal weight decrement seen in the rat reproduction study were incidental and not 

reproducible. 

The uterine weight decrement seen in the reproduction study showed a good dose-response and was 

supported by a dose-response in the pituitary weight decrement at the same doses. In addition, in the 

hamster, hyperplasia in the ovary was seen at high dose levels. One of the sub-chronic studies in the 

rat with fluazifop-P-butyl showed testicular weight decrement, while the other one with fluazifopbutyl did not at approximately the same doses as in the reproduction study (at the highest dose tested 

in the sub-chronic study with fluazifop-butyl absolute testes weights were increased 30%). The reason 

is unknown, but may be due to animal variation or other unknown factors such as edema. 

The testes and epididymal weight decrement and uterine and ovarian effects suggest possible 

endocrine related effects. However, negative in vitro studies suggest estrogen and androgen hormones 

were not involved. Agonistic and antagonistic studies with fluazifop-butyl, fluazifop-P-butyl and the 

fluazifop acid metabolite were conducted in yeast cells containing human estrogen and androgen 

receptors. No receptor activity was found with any of the test materials over a sufficiently wide 

concentration range. 
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The acute RfD and short-term incidental oral, and short-term dermal and inhalation exposure 

endpoints were selected from the developmental data base which includes 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 New Zealand rabbits; and 1 with fluazifop-P-butyl in New Zealand rabbits. There 

was evidence (quantitative) of increased susceptibility in the fetuses of two strains of rats exposed in 

utero to fluazifop-butyl. Diaphragmatic hernia was seen at the highest dose tested in the Sprague 

Dawley rat and other developmental toxicity, characterized as delays in skeletal ossifications, were 

seen in the absence of maternal toxicity relatively consistently in all five rat studies. However, the 

concern is low for the increased susceptibility seen in the rats based on the endpoint of concern 

(delayed ossifications). This developmental delay occurred at a lower dose level than the 

malformations. The delayed ossification in a given parameter showed considerable variation in the 

incidence among the five studies requiring a weight of evidence to determine the appropriate 

NOAEL/LOAEL among the five rat studies. There was no evidence (quantitative or qualitative) of 

increased susceptibility following in utero exposures to rabbits.

The dose-related liver and kidney toxicity shown in the older sub-chronic and chronic studies was 

expressed as exacerbation of age related kidney toxicity. Tests show that this toxicity was in the 

presence of peroxisome proliferation. However, the extensive and age related nephropathy in control 

groups complicate this conclusion with regard to the kidney. A possible treatment related slight 

increase in chronic nephropathy was noted only at the highest dose tested in the more recent study of 

reproduction in the rat. 

The uncertainty factors used with all endpoints were 10X for inter-species extrapolation and 10X for 

intra-species variation for a total of 100X.

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

As per FQPA, 1996, when there are potential residential exposures to the pesticide, aggregate risk 

assessment must consider exposures from three major routes: oral, dermal and inhalation. The 

fluazifop-P-butyl team chose to aggregate high-end exposures using conservative endpoints for a 

screening level assessment. If the resulting assessment showed risks of concern, further refinements 

would have been incorporated into the assessment but, it was not necessary. 

4.5.3 Cancer Classification and Risk Assessment Recommendation

The assessment team, in accordance with the 1999 Draft Carcinogen Risk Assessment Guideline 

(April, 1999) classified fluazifop-butyl and fluazifop-P-butyl as “Not likely to be carcinogenic in 

humans,” based on the lack of evidence of carcinogenicity in rats and hamsters. Progressive chronic 

nephropathy was observed in both rats and hamsters, but there was no statistically significant 

incidence of malignant and/or benign tumors seen at any dose in either study.

A carcinogenicity study in mice was not conducted. Peroxisome proliferation in the mouse was at 

levels much higher than in the hamster at comparable dose levels. Therefore, a carcinogenicity study 

in hamsters was conducted instead. The hamster was chosen because peroxisome proliferation in vivo 

and in vitro was more comparable to that found in human cell culture.
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The assessment team concluded that there is not a concern for mutagenicity resulting from exposure to 

fluazifop-P-butyl. The database for mutagenicity is considered adequate based on pre-1991 

guidelines. No mutagenic potential was seen in adequately conducted pre-1991 guideline 

mutagenicity studies (in vivo and in vitro) on fluazifop-P-butyl or fluazifop-butyl. A structural 

analogue {haloxyfop-methyl [methyl 2-[4-[[3-chloro-5-(trifluromethyl)-2-pyridinyl] 

oxy]phenoxy]propinonate]} of fluazifop-P-butyl also showed no mutagenic potential.

4.5.3.1 Carcinogenic Potential in Rats

In a combined chronic/carcinogenicity study (MRID# 41563703) PP009 (fluazifop-butyl, 94.8% a.i., 

batch/lot # 14, Reference C4915, CTL Y00082/001/005)] was administered to [(60 Wistar 

rats/sex/group in the diet at dose levels of 0, 2, 10, 80 or 250 ppm (equivalent to 0, 0.10, 0.51, 4.15 or 

12.29 mg/kg bw/day for males and 0.127, 0.65, 5.20 or 16.0 for females) for 106 or 107 days, 

respectively. Additional groups of 10 rats/sex/group were administered the test material in an 

analogous manner for 52 weeks prior to an interim sacrifice. 

Clinical signs were characteristic of rats, except respiratory distress, nasal and ocular discharge were 

seen among some males at 80 and among some males and females at 250 ppm from week 29 to 55. 

These signs were accompanied by body weight loss and death in the seriously affected males at 80 and 

250 ppm and in the seriously affected females at 250 ppm. 

Body weight gain of males and females, not dying, were increased significantly up to week 28 at 80 

(14% in males and 19% in females) and 250 ppm (10% in males and 20% in females) and in males 

week 29-44 at 250 ppm (26%), thereafter body weight gain was nominally increased in males at 10, 80 

and 250 ppm and nominally increased in females from week 29-108 at 2, 10, 80 and 250 ppm. There 

was an overall nominal body weight gain increase in males and females at the three top dose levels for 

the 106 weeks of the study. However, male (-79 g to -123 g versus -101 in control males) and female 

(-9 g to -24 g versus -24g in control females) rats lost body weight between week 81-85 and at the end 

of the study. No differences from control were seen in food consumption, food efficiency, water 

consumption or urinalysis among the groups. 

There appeared to be a dose related increased mortality among males at 80 and 250 ppm (33% at 80 

ppm and 34% at 250 ppm versus 14% in control) and among females (21% at 250 ppm versus 4% in 

control) during the first 52 weeks of the study. Overall mortality at cumulative termination appeared 

to be increased in males at 80 and 250 ppm (88%-86% versus 68% in control) and in females at 250 

ppm (65% versus 45% in controls). The report stated that the death occurring up to week 52 was 

caused by respiratory problems exacerbated by test material related nephropathy (all grades) in nearly

100% of the affected males dying at 80 and 250 ppm and 87% of the affected females dying at 250 

ppm. No dose-related mortality was seen from week 52 to termination.

Dose-related nephropathology, slight, moderate and marked, but not otherwise specified was seen in 

the animals dying or killed in extremis during the first 52 weeks of the study. This nephropathy was 

seen in control, 2, 10, 80 and 250 ppm group animals; 9/10, 9/9, 6/6, 22/23, and 24/24, respectively in 

males and 0/3, 0/1, 1/6, 1/ 2 and 13/15, respectively in females dying or killed in extremis. Treatment 

may have exacerbated the nephropathy. In animals sacrificed at termination, geriatric nephropathy

was seen in nearly all surviving animals [23/24 (96%) HDT versus 30/31 (97%) in control males] and 

[20/24 (83%) HDT versus 19/24 (79%) control females]. Gastrointestinal tract lesions appeared to be 

increased slightly at 250 ppm in males and females. 
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At ophthalmological examination, increased keratitis was seen in males (5/20) at 250 ppm. Since this 

observation was not seen in females and did not appear to be dose related at lower dose levels, the 

study authors questioned the toxicological significance of the finding. 

Hematological parameters showed slight changes in males at 80 and 250 ppm. Decreased hematocrit 

(6-8%), hemoglobin concentration (3-4%) and erythrocyte count (6-8%) were slightly but statistically

significant at week 12 and 25 and nominally decreased at week 78 at 80 ppm and 250 ppm. 

Hemosiderosis was found only in the spleens of one female each in control, 2, 80 and 250 ppm groups. 

Blood chemistries showed increased cholesterol (about 85% to 107%) at various times of analyses up 

to 78 weeks in males and females, but not after 100 weeks in females at 250 ppm; males showed a 

nominal decrease in cholesterol after 100 weeks at the same dose. Albumin showed statistically

significantly decreases of about 24% in males and females at 250 ppm. Bone smears on males and 

female rats were similar to controls at week 52 or 106, but many smears in all groups could not be 

evaluated.

Decreased absolute (16%) and relative (17%) liver weights were statistically significant in males at 

250 ppm at terminal sacrifice, and increased absolute (40%) and relative (37%) ovarian weights were 

significant at termination at 250 ppm; animals with ovarian cysts and masses were excluded from 

these calculations. Testes and seminal vesicle weight did not differ from control weight at terminal 

sacrifice, but were nominally decreased at 250 ppm. At the 52 week interim sacrifice, absolute and 

relative kidney (Abs. 29%) and thyroid (Abs. 33%) weights were significantly increased in males, but

not in females at 250 ppm. Absolute (31%) and relative (24%) testes weight showed a treatment 

related decrease at 250 ppm at the 52 week sacrifice. Ovarian weights were nominally increased at 

250 ppm and 52 weeks. Ovaries, possibly enlarged by cysts, appeared to have an increased incidence 

in the 250 ppm group than in control. 

The LOAEL in males is 80 ppm (4.15 mg/kg/day) based on increased mortality and nephropathy from 

start to week 52 of the study. The NOAEL is 10 ppm (0.51 mg/kg/day in males). The LOAEL in 

females is 250 ppm (16.0 mg/kg/day) based on increased morality and nephropathy during the first 52 

weeks of the study and increased ovarian weight and ovarian cysts at termination. The NOAEL was 

80 ppm (5.2 mg/kg/day) for females.

At the doses tested, there was no treatment related increase in tumor incidence when compared to 

controls. The only statistically significant neoplasia seen in the study was an increase in male adrenal 

phaeochromocytomas at 80 ppm, but not at 250 ppm. The incidence of adrenal phaeochromocytoma 

bearing males (left or right adrenal was calculated from the individual animal data) in control, 2, 10, 

80 or 250 ppm were, respectively, 5/70, 3/70, 2/70, 11*/70 and 7/70 for males that died or were 

sacrificed. [* Significant at p < 0.019 by a Peto analysis, when the 80 ppm group was compared with 

control] None of these adrenal tumors were seen at the interim sacrifice. This 

chronic/carcinogenicity study in the rat is ACCEPTABLE (GUIDELINE) and satisfies the guideline 

requirement for a chronic/carcinogenicity study OPPTS 870.4300); OECD 453] in the rat. This study

was upgraded from supplementary (TXR#009746) to acceptable by a 3/12/1996 peer review 

committee (TXR# 011840). The confusion in TXR# 009746 over which enantiomer was studied is 

corrected from [R] in TXR# 009746 to [RS]. The test material studied was PP009, the [RS] racemic 

mixture. The conclusions take precedence over previous conclusions. 
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4.5.3.2 Carcinogenicity Study in Hamsters

In a carcinogenicity study (MRID# 45345401, 46082905) [fluazifop-P-butyl, 91.6% a.i., batch/lot# 

P23] was administered to 63 Golden Syrian hamsters/sex/dose in the diet at dose levels of 0, 0, 200, 

750 or 3000 ppm (mean of measured test material consumption equivalent to 0, 0, 12.5, 47.4 or 193.6 

mg/kg bw/day for males and 0, 0, 12.1, 45.5 or 181.4 mg/kgbw/day for females, page 25 of 45345401) 

for 80 weeks. Of these animals, 12/sex/group were designated for interim sacrifice on week 53. Two 

control groups were included.

There were no significant definitive body weight changes or meaningful food consumption or food 

efficiency differences from control in males or females during the study. There was an increased 

frequency of a clinical observation at 3000 ppm (“thin”) (13 versus 5 in control). Survival was 

unchanged statistically, but females showed a slight nominal decrease at 3000 ppm (70.6% versus 

78.5% in pooled control). 

Probably no biologically-significant hematological effects were seen in the study. Statistically

significant decreases in white cell count in interim sacrificed males (22%-23%) at 750 ppm and 3000 

ppm and in terminal females (17%) at 3000 ppm were observed. The remaining statistically 

significant hematological changes at 3000 ppm were minor and probably not biologically significant. 

No clinical chemistry analysis was conducted. 

Testes weights were decreased at 750 and 3000 ppm and liver and kidney weights were increased in 

males and females at 3000 ppm. In males, absolute and adjusted testes weights were decreased in a 

dose related manner and statistically significantly reduced (p < 0.01) at 750 (abs 8% and adj 10%) and 

3000 ppm (abs 20% and adj 19%). In males, adjusted liver weight was statistically significantly 

elevated at 750 (5%) and 3000 ppm (7%), but the absolute weight was not elevated at any dose level. 

In males and females, a kidney weight (males 11% and females 9%) and adjusted kidney weights 

(males 11% and females 9%) were statistically significantly elevated in the 3000 ppm group, only. In 

females absolute liver weight was statistically significantly elevated at all dose levels (9%-38%), but 

adjusted liver weights (34%) were significantly elevated only at 3000 ppm. Slight absolute and 

adjusted brain weight increases (2.5% and 1.6%) respectively in males and females at 3000 ppm are of 

unknown biological significance. 

Non-neoplastic microscopic histological findings were increased in the epididymis, testes, eyes, livers 

and gall bladder in males and in females, ovarian stroma cell/sex cord hyperplasia was increased at 

750 and 3000 ppm. In males dose related incidences were seen at 750 ppm of reduced spermatozoa in 

epididymis (24% versus 8% in pooled controls), increased incidences of testicular tubule degeneration 

(37% versus 7% in pooled controls), increased incidences of eye cataract changes (31% in males at 

750 ppm versus 16% in pooled controls), increased incidences of male liver mononuclear cell 

infiltration (35% versus 20% in pooled controls) and increased incidences of gall bladder stones (73% 

versus 31% in pooled controls) in males and in females at 3000 ppm (41% versus 13% in pooled 

controls). The incidence of chronic nephropathy was nominally increased in males and females at all 

dose levels. In females dose-related increased incidences were seen at 750 ppm in ovarian stroma/sex 

cord hyperplasia (14%versus 6% in pooled controls).
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The LOAEL for systemic effects is 750 ppm (equivalent to 47.4 mg/kg/day in males and 45.5 

mg/kg/day in females) based on increased incidence of males with reduced sperm, testicular 

degeneration, eye cataract changes, liver inflammation and gall stones and in females increased 

incidences of ovarian stroma cell/sex cord hyperplasia. The NOAEL is 200 ppm (equivalent to 12.5 

mg/kg/day in males and 12.1 mg/kg/day in females. 

No dose-related tumors were seen in males. Benign ovarian stroma cell/sex cord tumors were 

statistically significantly elevated at the 3000 ppm 5/51 (9.8%) versus 3/103 (2.9%) in pooled controls. 

However, when the incidences of malignant and benign tumors were combined, no significant 

differences were seen at any dose. It was concluded that fluazifop-butyl, [R] isomer is not 

carcinogenic at the dose levels studied. Dosing was adequate in males and females as indicated by

the kidney weight increase and histological findings in eyes [cataracts], liver [inflammation], gall 

bladder [gall stones], the testes [tubular degeneration] and epididymis [reduced spermatozoa] of males, 

and in females by the ovarian findings [hyperplasia and adenomas], gall bladder [gall stones] and the 

severity of progressive chronic nephropathy at 3000 ppm (HDT). The carcinogenicity study 

[MRID#46082901, but not 45345401] in the hamster is ACCEPTABLE (guideline) and does satisfy 

the guideline requirement for a carcinogenicity study [OPPTS 870.4200; OECD 451] in hamsters.

4.5.3.3 Classification of Carcinogenic Potential

The assessment team, in accordance with the 1999 Draft Carcinogen Risk Assessment Guideline 

(April, 1999) classified fluazifop-butyl and fluazifop-P-butyl as “Not likely to be carcinogenic in 

humans,” based on the lack of evidence of carcinogenicity in rats and hamsters.

4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk Assessment

Table 1a Summary of Toxicological Doses and Endpoints for Fluazifop-P-butyl+

Exposure

Scenario

Dose Used in Risk 

Assessment, UF

FQPA SF and Level 

of Concern for Risk 

Assessment Study and Toxicological Effects

Acute Dietary*

(Females 13-49 years 

of age)

NOAEL = 50

mg/kg/day

UF = 100

Acute RfD = 0.50 

mg/kg/day

FQPA SF = 1X

aPAD = 

0.50 mg/kg/day

Developmental Toxicity in Rats

Developmental LOAEL = 200 mg/kg/day based on 

diaphragmatic hernia.

Acute Dietary

(General population 

including infants and 

children)

An appropriate endpoint attributable to a single dose was not identified in the available studies including the 

developmental toxicity studies.

Chronic Dietary

(All populations)

NOAEL= 0.74

mg/kg/day

UF = 100

Chronic RfD = 

0.0074 mg/kg/day

FQPA SF = 1X

cPAD =

0.0074 mg/kg/day

Two-Generation Reproduction in Rats

LOAEL = 5.8 mg/kg/day in males and 7.1 in females 

based on decreased testes & epididymal weights in 

males, and uterine & pituitary weights in females.

Short-Term Incidental 

Oral (1-30 days)

Maternal 

NOAEL = 100 

mg/kg/day

Residential LOC for MOE 

= 100

Occupational = N/A

Developmental Toxicity in Rats

Maternal LOAEL = 300 mg/kg/day based on 

maternal body weight gain decrement during GD 

7-16.

Intermediate-Term 

Incidental Oral (1-6 

months)

Parental/Systemic 

NOAEL = 0.74 

mg/kg/day

Residential LOC for MOE 

= 100

Occupational = N/A

Two-Generation Reproduction in Rats

LOAEL = 5.8 mg/kg/day in males and 7.1 in females 

based on decreased testes & epididymal weights in 

males, and uterine & pituitary weights in females.
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Table 1a Summary of Toxicological Doses and Endpoints for Fluazifop-P-butyl+

Exposure

Scenario

Dose Used in Risk 

Assessment, UF

FQPA SF and Level 

of Concern for Risk 

Assessment Study and Toxicological Effects

Short-Term Dermal (1 

to 30 days)

Developmental NOAEL 

= 2.0 mg/kg/day

Residential LOC for MOE 

= 100

Occupational LOC for 

MOE = 100

Developmental Toxicity in Rats

LOAEL = 5.0 mg/kg/day based on fetal weight 

decrement, hydroureter, and delayed ossification.

Intermediate- & LongTerm Dermal (1 to >6 

months)a

Parental/Systemic 

NOAEL = 0.74 

mg/kg/day

Residential LOC for MOE 

= 100

Occupational LOC for 

MOE = 100

Two-Generation Reproduction in Rats

LOAEL = 5.8 mg/kg/day in males and 7.1 in females 

based on decreased testes & epididymal weights in 

males, and uterine & pituitary weights in females.

Short-Term Inhalation 

(1 to 30 days) b

Developmental NOAEL 

= 2.0 mg/kg/day

Residential LOC for MOE 

= 100

Occupational LOC for 

MOE = 100

Developmental Toxicity in Rats

LOAEL = 5.0 mg/kg/day based on fetal weight 

decrement, hydroureter, and delayed ossification.

Intermediate- & LongTerm Inhalation (1 to 

>6 months)b

Parental/Systemic 

NOAEL = 0.74 

mg/kg/day

Residential LOC for MOE 

= 100

Occupational LOC for 

MOE = 100

Two-Generation Reproduction in Rats

LOAEL = 5.8 mg/kg/day in males and 7.1 in females 

based on decreased testes & epididymal weights in 

males, and uterine & pituitary weights in females.

Cancer (oral, dermal, 

inhalation)

Not likely to be carcinogenic to humans.

* Selected by the Assessment team for Females 13-49 years of age. + Table taken from DP Barcode: 359779, J Liccione, Jan. 23, 2009

a

Use either 9% (low exposure scenario) or 2% (high exposure scenario) for route-to-route extrapolations 

b

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

UF = uncertainty factor, FQPA SF = FQPA safety factor, NOAEL = no observed adverse effect level, LOAEL = lowest observed adverse 

effect level, PAD = population adjusted dose (a = acute, c = chronic) RfD = reference dose, MOE = margin of exposure, LOC = level of concern, 

NA = Not Applicable 

4.6 Endocrine Disruption

In the available studies on fluazifop–P-butyl, there was no estrogen, androgen and/or thyroid mediated 

toxicity shown. No androgen/estrogen agonist or antagonist activity was detected for fluazifop-Pbutyl or its acid metabolite. Fluazifop-P-butyl is not among the group of 58 pesticide active 

ingredients on the initial list to be screened under the Endocrine Disruption Screening Program. 

As required under FFDCA section 408(p), EPA has developed the Endocrine Disruptor Screening 

Program (EDSP) to determine whether certain substances (including pesticide active and other 

ingredients) may have an effect in humans or wildlife similar to an effect produced by a “naturally 

occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP 

employs a two-tiered approach to making the statutorily required determinations. Tier 1 consists of a 

battery of 11 screening assays to identify the potential of a chemical substance to interact with the 

estrogen, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 

screening and are found to have the potential to interact with E, A, or T hormonal systems will 

proceed to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests are 

necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine 

related effects caused by the substance, and establish a dose-response relationship between the dose 

and the E, A, or T effect.
Fluazifop-P-Butyl Human Health Risk Assessment to Support New Uses DP No.: 385178

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Between October 2009 and February 2010, EPA has issued test orders/data call-ins for the first group 

of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. This list of 

chemicals was selected based on the potential for human exposure through pathways such as food and 

water, residential activity, and certain post-application agricultural scenarios. This list should not be 

construed as a list of known or likely endocrine disruptors.

For further information on the status of the EDSP, the policies and procedures, the list of 67 

chemicals, the test guidelines and the Tier 1 screening battery, please visit the website: 

http://www.epa.gov/endo/.

5.0 Metabolism 

5.1 Nature of the Residue – Plants

N

F3C

O

O

H

CH3

O

O

C4H9(n)

Fluazifop-P-butyl 

The Fluazifop-P-Butyl Residue Chapter of the TRED (DP No. 319907, S. L. Kinard, 08/17/2005) 

concluded that the nature of the residue in soybeans is adequately understood. No new plant 

metabolism studies for the proposed new use crops were submitted as part of the current petition. The 

MARC has determined that for tolerance expression, parent and fluazifop-acid (free and conjugated) 

are the residues of concern since they are adequate to determine misuse. The MARC also concluded 

that the residues of concern in plants for risk assessment are parent, fluazifop-acid (free and 

conjugated), 5-trifluoromethyl-2-pyridone, and 2-(4-hydroxyphenoxy) propionic acid (free and 

conjugated). 

5.2 Nature of the Residue - Animals

The MARC has concluded that for tolerance expression and risk assessment, parent and fluazifop-acid 

(free and conjugated) are the residues of concern since they are adequate to determine misuse.

5.3 Meat, Milk, Poultry, and Eggs

In evaluating the data provided to support this petition, the establishment of tolerance limits will be 

recommended for several RACs commonly recognized for use as livestock feedstuffs. This would 

include establishing tolerance limits for sugar beet tops, citrus dried pulp and potatoes as requested in 

part with this action. Although in the assessment of prior actions sugar beet tops would have 

comprised a large portion of the beef and dairy cattle diet, it is no longer a factor for consideration in 

the calculation of dietary burden. For the citrus dried pulp commodity, the tolerance of this livestock 

feed is being tentatively set following the concentration factor of 4x determined from the processing 

data that were provided. In comparing the resulting limit of 0.40 ppm for this commodity to the 2.5 

ppm residue level of the soybean roughage now being fed, a net increase in the contribution of dietary

burden to livestock will not result. In regard to potato RACs, this use will be only established as an 

import tolerance which will not result in making this commodity a contributor to the dietary burden of 

cattle. 
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Given these circumstances, it will not be necessary to provide a re-calculation of dietary burden in 

support of this action. The prior calculations tentatively depicting the secondary transfer of fluazifopP-butyl residues to meat, milk, poultry, and eggs made for the uses established on dry beans and 

peanuts remain current (DP No. D348246, D. Soderberg, 09/16/2008).

5.4 Analytical Methods

There are adequate residue analytical methods listed in PAM II for tolerance enforcement and data 

collection. For the enforcement of tolerances for fluazifop-P-butyl residues of concern, a High 

Performance Liquid Chromatography/Ultra-Violet Spectrometry (HPLC/UV) method is available for 

crop commodities. In conjunction, HPLC/UV and Gas Chromatography/Mass Spectrometry (GC/MS) 

methods are available for milk and animal commodities. The stated quantitation limits are 0.02-0.05 

ppm for crop commodities, 0.01 ppm for milk, and 0.02 ppm for animal tissues. In addition, the FDA 

PESTDATA database dated 11/01 (PAM Volume I, Appendix I) indicates that fluazifop-butyl (only)

is completely recovered using Multiresidue Methods Sections 302 (Luke Method; Protocol D) and 303 

(Mills, Onley, and Gaither Method; Protocol E, nonfatty food). It is important to note that none of 

these methods can distinguish the optical isomers of fluazifop-butyl or fluazifop.

To support PP#9F7624, the banana, citrus, grape, and sugar beet field trial samples were analyzed for 

residues of total fluazifop (fluazifop-P-butyl, fluazifop free and conjugated) using either a GC/MS or 

Fluorine-19 Nuclear Magnetic Resonance (19F NMR) protocol. These procedures provide a total 

determination by hydrolyzing the fluazifop ester or acid conjugates and then derivatizing them to form 

the fluazifop methyl ester for quantitation with residues being reported as fluazifop. For PP#9E7561, 

the potato field trial samples were analyzed for residues of total fluazifop using a High Performance 

Liquid Chromatography/Mass Spectrometry/Mass Spectrometry (HPLC/MS/MS) protocol. This 

procedure is a common moiety method which works by hydrolyzing the fluazifop ester or acid 

conjugates so that a total determination can be made. In all, these protocols are adequate for data 

collection based upon acceptable method validation and concurrent method recoveries. 

5.5 Storage Stability Update

Storage stability data have been reviewed in conjunction with earlier actions undertaken for fluazifopP-butyl which indicate that its residues are stable in a number of crop commodities. As such, its 

stability has been investigated in a wide variety of frozen crop commodities and documented in 

several prior reports generated by Syngenta. These reports demonstrate that residues of fluazifop are 

stable in/on soybeans, sugar beets, green beans, strawberries, oilseed rape, coffee, cauliflower, onions, 

potatoes, peanuts, macadamia nuts, tomatoes, endive, and celery for durations of 3 to 28 months (DP

No. D348246, D. Soderberg, 09/16/2008). Given the results obtained from these prior studies, these

data are adequate in directly supporting or can be translated to corroborate the sample storage intervals 

incurred in these field trials. Although no data were provided to substantiate the holding times that 

were incurred for many of the processed commodities tested, none are needed since these analyses 

were made within thirty (30) days of production. As such, there are adequate data to support all of the 

sample storage conditions and durations that were incurred for all of the RACs tested in part for these 

petition requests (PP#9F7624 & PP#9E7561). However, no data were provided to substantiate the 

holding times that were incurred for any of the potato processed commodities which were analyzed. 

Data are available which demonstrate fluazifop-P-butyl is stable in a wide variety of frozen crop 

commodities including potatoes. As such, HED expects fluazifop to be stable in the frozen potato 

processed commodities noted but data should be provided to confirm its stability in these fractions. 
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5.6 Magnitude of Residue in Food Update

The data described below are from the HED residue chemistry chapter made for PP#9F7624 which 

requests to allow new uses of fluazifop-P-butyl to be made on bananas, citrus, grapes, and sugar beets 

(DP No. D380017, P. Savoia, 08/31/2010). In addition, data are also presented from the 

accompanying HED residue chemistry chapter made for PP#9E7651 which proposes the establishment 

of an import tolerance for fluazifop-P-butyl on potatoes (DP No. D372408, P. Savoia, 08/31/2010). 

These results are adequate to support each of the proposed new crop uses put forward in these petition 

requests.

Banana results

To determine the magnitude of fluazifop-P-butyl residue, five (5) field trials were conducted in/on 

bagged and unbagged bananas in the United States during the 1999 growing season. The trials were 

conducted in Zone 3 (1 trial in Florida) and Zone 13 (4 trials in Hawaii). For each trial, three 

applications of the 2 lb/gal EC formulation of fluazifop-P-butyl were made at a target rate of 0.375 lbs 

fluazifop-p-butyl/acre for a total seasonal rate of 1.125 lb a.i./acre. All applications were made in 

spray volumes of 17 to 29 gal/A (GPA) using ground-based equipment. An adjuvant was added to the 

spray mixture for all applications (non-ionic surfactant or crop oil concentrate). Each test site 

consisted of a control and treated plot for both bagged and unbagged bananas. Applications were 

made by broadcast spray to the soil at 60, 30, and 0 days prior to normal harvest. Banana whole fruit 

samples were collected at the normal harvest which was immediately following the last application 

(PHI of 0 days). 

The banana field trial results demonstrate the application of the fluazifop-P-butyl herbicide made at 

the 1x maximum directed labeled use rate. It was appropriately carried out in line with the 

requirements set forth in the OPPTS 860.1500 Residue Chemistry Test Guidelines for bananas. 

Following three applications of fluazifop-p-butyl at a seasonal target application rate of 1.125 lbs ai/A, 

residue levels (reported as total fluazifop) were below the LOQ (0.01 ppm) in all bagged and 

unbagged samples of whole bananas (PHI of 0 days). Based on concurrent recoveries, an acceptable 

method was used for the quantitation of total fluazifop in/on unbagged and bagged bananas. Adequate 

stability data available for other similar crops can be translated to substantiate the storage conditions 

and durations that were incurred in this study. These data which were reported are adequate to support 

the proposed seasonal use pattern on bananas (MRID No. 47874601, P. Savoia, 08/31/2010). 
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Citrus results

To determine the magnitude of fluazifop-P-butyl residue in/on citrus RACs, twenty-three (23) field 

trial studies were provided by the registrant in support of this petition request. In accordance, MRID 

No. 41373705 contains 15 field trials and MRID No. 47874602 provides an additional 8 more to 

satisfy the data requirement for a total of 23 studies in all. For the data submission which contained

the 15 field trials, these studies were conducted in the United States during the 1986 growing season. 

It is comprised of 5 trials made for oranges (zone 3; Florida) along with 5 trials each carried out for 

grapefruits and lemons (2 trials in zone 3; Florida, 1 trial zone 6; Texas & 2 trials in zone 10; 

California & Arizona). The treated test plots in this study received 2 to 3 applications of the 2 lb/gal 

EC formulation of fluazifop-P-butyl made at 21 day RTIs for a total seasonal rate of 1.5 lb ai/acre to 

2.25 lb ai/acre. In regard to the data submission containing the 8 field trials that were made, these 

studies were conducted in the United States during the 2000 growing season. It consisted of 7 trials 

made for oranges (3 trials in zone 3; Florida, 1 trial in zone 6; Texas & 3 trials in zone 10; California 

& Arizona) along with 1 trial carried out on grapefruit (1 trial in zone 3; Florida). The treated test 

plots in this study each received 3 applications of the 2 lb/gal EC formulation of fluazifop-P-butyl at 

19-21 day RTIs for a total seasonal rate of 1.125 lb ai/acre.

The number and locations of the field trials were made in accordance with OPPTS Guideline 860.1500 

for oranges, grapefruit, and lemons. The trials generally reflect the proposed maximum seasonal use 

pattern, although the trials made in 1986 (MRID No. 41373705) were performed at a 1.3x and 2x 

greater rate. For the data submission which contained the 15 field trials carried out in 1986, an 19F 

NMR instrumental technique was used to carry out these analyses. Following the treatment program 

made at a seasonal target application rate of 1.5 lbs ai/A to 2.25 lb ai/A, residue levels (reported as 

total fluazifop) were below the LOQ (0.03 ppm) in oranges, grapefruit and lemon (PHI 14 days). In 

regard to the data submission containing the 8 field trials that were made, a GC/MS instrumental 

technique was used to carry out these analyses. For this treatment program of 3 applications made at a 

seasonal targeted rate of 1.125 lbs ai/A, residue levels (reported as total fluazifop) were below the 

LOQ (0.01 ppm) in oranges and grapefruit (PHI of 12 to 14 days). Based on concurrent recoveries of 

fortified oranges, grapefruit, and lemons, the methods used for these analyses were adequate for data 

collection. Adequate stability data available for other similar crops can be translated to substantiate 

the storage conditions and durations that were incurred in this study. These data which were reported 

are adequate to support the proposed seasonal use pattern on citrus commodities (MRID No. 

47874602, P. Savoia, 08/31/2010).

Grape results

To determine the magnitude of fluazifop-P-butyl residue in/on grapes, twelve (12) were conducted in 

the United States during the 2000 growing season. For this study, the trials were carried out in zone 1 

(2 trials; New York), zone 10 (8 trials: California), and zone 11 (2 trials; Oregon & Washington). 

Separate untreated control and treated test plots were established at each trial site. At each test 

location, three broadcast spray applications of the 2 lb/gal EC formulation of fluazifop-P-butyl were 

made to the vineyard floor beneath the grape vines at a target application rate of 0.375 lb 

ai/A/application, for a total target seasonal rate of 1.125 lb ai/A. Applications were made 12 to 15

days apart in spray volumes of 10 to 30 gal/A at 9 trial sites and 8 to 10 gal/A at 3 trial sites. 

Adjuvants (non-ionic surfactant or crop oil concentrate) were used at all the sites and the grapes 

subsequently harvested at a PHI of 49-50 days. 
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The grape field trial results demonstrate the application of the fluazifop-P-butyl herbicide made at the 

1x maximum directed labeled use rate. It was appropriately carried out in line with the requirements 

set forth in the OPPTS 860.1500 Residue Chemistry Test Guidelines for grapes. Following the last of 

three vineyard floor applications made with the 2 lb/gal EC formulation at a total rate of 1.11 to 1.16 

lb ai/A/season, residue levels (reported as total fluazifop) were <LOQ (0.01 ppm) in/on grapes (PHI of 

49 to 50 days). Based upon acceptable method validation and concurrent method recoveries, the

protocol used for these analyses was adequate for data collection. Adequate stability data available for 

other similar crops can be translated to substantiate the storage conditions and durations that were 

incurred in this study. These data which were reported are adequate to support the proposed seasonal 

use pattern on grape commodities (MRID No. 47874604, P. Savoia, 08/31/2010).

Sugar beet results

To determine the magnitude of fluazifop-P-butyl residue in/on sugar beets, twelve (12) field trials 

were conducted in the United States during the 2000 growing season. For this study, trials were 

carried out in zones 5 (2 trials; Minnesota, 2 trials; North Dakota & 1 trial; Wisconsin), 7 (1 trial: 

Nebraska), 8 (1 trial; Kansas), 9 (1 trial; Montana), 10 (2 trials; California), and 11 (2 trials; Idaho & 

Washington). Separate untreated control and treated test plots were established at each trial site. At 

each test location, two foliar broadcast spray applications of the 2 lb/gal EC formulation of fluazifopP-butyl were made to sugar beets at a target application rate of 0.375 lb ai/A/application, for a total 

target seasonal rate of 0.75 lb ai/A. Applications were made at 12- to 14-day retreatment intervals in 

spray volumes of 10 to 30 gal/A at 9 trial sites and 8 to 10 gal/A at the other 3 trial sites. Adjuvants 

(non-ionic surfactant or crop oil concentrate) were used at all sites and the sugar beets subsequently

harvested at a PHI of 89 to 90 days. 

The sugar beet field trial results demonstrate the application of the fluazifop-P-butyl herbicide made at 

the 1x maximum directed labeled use rate. It was appropriately carried out in line with the 

requirements set forth in the OPPTS 860.1500 Residue Chemistry Test Guidelines for sugar beets. For 

the application program tested, samples were harvested 89 to 90 days after the last of two broadcast 

foliar applications made with the 2 lb/gal EC formulation at total rates of 0.747-0.764 lb ai/A/season. 

In accordance, maximum residues of total fluazifop were found to be 1.45 ppm in/on sugar beet tops 

and at 0.23 ppm for the roots. Based upon acceptable method validation and concurrent method 

recoveries, the protocol used for these analyses was adequate for data collection. Adequate stability

data are available for this RAC to substantiate the storage conditions and durations that were incurred 

for this study. These data which were reported are adequate to support the proposed seasonal use 

pattern on sugar beet commodities (MRID No. 47874603, P. Savoia, 08/31/2010).
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Potato results

To establish a new import tolerance for the residues of fluazifop-P-butyl in/on potatoes, field trial 

studies were conducted within the various geographic/climatological production regions of Canada. In

accordance, MRID No. 47920402 contains 13 field trials and MRID No. 47920403 provides an 

additional 3 more to satisfy the Canadian requirement for a total of 16 studies in all. For the data 

submission which contained the 13 field trials, these studies were carried out in Canadian growing 

zones 1, 1A, 5, 5B, 7A, 12 and 14 during the 2008 growing season. As such, two trials were held at 

New Glasgow, Elm Creek, and Malden along with single ones made at Albany, Branchton, St. Marcsur-Richeilieu, Taber, Abbotsford, Minto, and Innisfall. In regard to the data submission containing 

the 3 field trials that were made, these studies were held at Hunter River (2 trials) and Portage la 

Prairie (1 trial) in Canada during the 2007 growing season. Each trial site was managed according to 

the practices routinely followed by Canadian commercial producers for cultivating potatoes. Test 

plots were sufficiently large enough to provide a 1 Kg sample of mature potato tubers to be collected 

from at least six (6) different plants. At each study location, market quality potato samples were 

cultivated using both untreated control and treated test plots. Each treated test plot received a single 

application of the VENTURE L end-use product applied at the maximum labeled rate of 250 g ai/ha so 

that late seasonal treatments made at a PHI of 45 days could be evaluated. 

The potato field trial results demonstrate the application of the fluazifop-P-butyl herbicide made at the 

1x maximum directed labeled use rate. The number and location of field trials were sufficient in scope

since they were undertaken in line with the requirements set forth in the PMRA Regulatory Directive 

to evaluate this use. Following a single treatment of the VENTURE L EC formulation of fluazifop 

made at the maximum seasonal rate of 250 g ai/ha, total residue levels were observed ranging at levels 

between <0.0033 - 0.61 ppm (PHI of 45 days ± 1 day). The treatment regimen also appropriately 

included two (2) residue decline studies made at the New Glasgow and Elm Creek sites with samples 

collected at -7, 0, +7, +14 and +21 days of normal commercial harvest. The results generated in the 

two decline studies illustrate demonstrate that concentrations of fluazifop will in fact decrease as 

greater PHIs for treatment are followed. Based upon acceptable method validation and concurrent 

method recoveries, the protocol used for these analyses was adequate for data collection. Adequate 

stability data are available to show that fluazifop residues are stable in frozen potatoes stored at -18°C 

for 18 months which substantiate the storage conditions and durations that were incurred in these 

studies. These data which were reported are adequate to support the proposed seasonal use pattern on 

sugar beet commodities (MRID Nos. 47920402 & 47920403, P. Savoia, 08/31/2010).

5.7 Processing Factors

The data described below are from the HED residue chemistry chapter made for PP#9F7624 which 

requests to allow new uses of fluazifop-P-butyl to be made on bananas, citrus, grapes, and sugar beets 

(DP No. D380017, P. Savoia, 08/31/2010). In addition, data are also presented from the 

accompanying HED residue chemistry chapter made for PP#9E7651 which proposes the establishment 

of an import tolerance for fluazifop-P-butyl on potatoes (DP No. D372408, P. Savoia, 08/31/2010). 

These results are adequate to determine residue concentration factors for processed fractions to 

support the new crop uses put forward in these petition requests.
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Citrus processed commodity results

To determine residue concentration factors in citrus processed fractions, a single trial on oranges was 

conducted in Florida during the 1986 growing season using the 2 lb/gal EC formulation of fluazifop-Pbutyl. For this test program, three applications were made at the nominal rate of 3.75 lb 

ai/A/application, for a total seasonal rate of 11.25 lb ai/A (10x the maximum proposed seasonal rate 

for citrus). Applications were made at 21 day intervals using ground equipment, with the spray

directed to the ground beneath and around the trees. Samples of oranges were harvested 14 days after 

the last application and processed into chopped peel, dried pulp, molasses, juice, and oil.

Total fluazifop residues were <LOQ (0.03 ppm) in/on the whole oranges treated with fluazifop-P-butyl 

at a total of 11.25 lb ai/A. Following processing of the whole oranges, total fluazifop residues were 

1.7 ppm in chopped peel, 2.6 ppm in dried pulp, 0.09 ppm in molasses and oil, and <LOQ (0.03 ppm) 

in juice. Based on these data, processing factors would be 87x in dried pulp, 3x in oil, and <1x in 

juice. However, the Petitioner states that processing factor in dried pulp in unreasonable considering 

that oranges contain about 86% water. Therefore, the Petitioner calculated processing factors by 

assuming that the residue in the whole oranges was 0.65 ppm, as calculated from the total residue 

found in the processed commodities and the weight of the starting oranges. The resulting reported 

processing factors were 4x for dried pulp, 2.6x for peel, 1.7x for molasses, and 0.14x for oil.

EPA previously concluded that proposed tolerances in citrus fruit and dried citrus cannot be 

determined (DEB No. 6343, M. J. Bradley, 08/15/1990). Rather then attempting to upgrade these 

results, it would be prudent for the petitioner to provide a new study given the age of this data 

submission. To satisfy the establishment of tolerances for the citrus processed commodities, the 

theoretical concentration factors are therefore used for setting the pertinent limits on juice (2x) and oil 

(1000x). These factors along with the citrus HAFT of 0.03 ppm, determine that an appropriate 

fluazifop-P-butyl tolerance for citrus juice would be 0.06 ppm and 30.0 ppm for the oil fraction. In 

regard to citrus dried pulp, there is no theoretical concentration factor determined for this processed 

commodity. However, in a recent action made for chlorantraniliprole, a snap-shot of 27 pesticides 

having citrus dried pulp limits was made to determine a practical maximum concentration factor for 

this processed commodity (DP No. D361791, D. Rate, 01/08/2010). This determination found that 

concentration factors range between 2-13x for the citrus dried pulp tolerances which were examined. 

Therefore, using the maximum concentration factor of 13x for fluazifop, a resulting tolerance of 0.40 

ppm should be set for the citrus dried pulp processed commodity (D385205, P. Savoia, 01/04/11) 

Grape processed commodity results

To determine residue concentration factors in grape processed fractions, a single field trial was 

conducted during the 2000 growing season in Zone 10 (1 trial in CA). Separate untreated control and 

treated test plots were established at the trial site. Three broadcast spray applications of the 2 lb/gal 

EC formulation of fluazifop-P-butyl were made to the vineyard floor beneath the grape vines to 

conduct this trial. Treatments were made at a target application rate of 1.875 lb ai/A/application, with 

a 14-day retreatment interval (RTI), for a total target seasonal rate of 5.63 lb ai/A (5x the maximum 

application rate). Grapes were harvested 50 days after final treatment. The grape RACs were 

processed into grape juice and raisins.
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Total fluazifop residues were found to be <LOQ (0.01 ppm) in/on the grape RAC harvested 50 days 

after the last of three treatments made at a 5x seasonal application rate (5.64 lb ai/A/season). Total 

fluazifop residues were also found to be <LOQ (0.01 ppm) in/on the grape juice and raisin processed 

grape fractions. As such, the observed processing factors for grape juice and raisins are less than the 

theoretical concentration factor of 4.7x for raisins (based on the loss of water on processing grapes 

into raisins; OPPTS 860.1520, Table 1) and 1.2x for grape juice (based on separation of components; 

OPPTS 860.1520, Table 3). These data indicate that total fluazifop residues do not appear to 

concentrate in raisins or grape juice. These data are adequate for determining residue concentration 

factors for the grape processed commodities (MRID No. 47874605, P. Savoia, 08/31/2010). 

Sugar beet processed commodity results 

To determine residue concentration factors in sugar beet processed fractions, a single field trial was 

conducted during the 2000 growing season in Zone 11 (1 trial in WA). Separate untreated control and 

treated test plots were established at the trial site. Two foliar broadcast spray applications using the 2 

lb/gal EC formulation of fluazifop-P-butyl were made to sugar beets to conduct this trial. Treatments 

were made at a target application rate of 1.875 lb ai/A/application, with a 14-day RTI, for a total target 

seasonal rate of 3.75 lb ai/A (5x the maximum application rate). Sugar beets were harvested 90 days 

after final treatment. The sugar beet RAC was processed into refined sugar, dry pulp and molasses.

Average total fluazifop residues were found to be 0.86 ppm in/on the sugar beet RAC (root) harvested 

90 days after the last of two broadcast foliar treatments made at a 5x seasonal application rate (3.79 lb 

ai/A/season). In processed sugar beet fractions, average total fluazifop residues were found to be 0.31 

ppm in refined sugar, 3.35 ppm in the dry pulp, and 12 ppm in molasses. A comparison of the 

residues in the RAC with those in each processed fraction resulted in concentration factors of 0.36x 

for refined sugar, 3.9x for dry pulp, and 14x for molasses. These concentration factors are consistent 

with the theoretical concentration factor of 12.5x for sugar (based on separation of components; 

OPPTS 860.1520, Table 3) and the maximum observed concentration factor of 20x (OPPTS 860.1520, 

Table 4) for dry pulp and molasses. These data indicate that total fluazifop residues do not appear to 

concentrate in sugar beet refined sugar, but may concentrate in sugar beet dried pulp and sugar beet 

molasses (MRID No. 47874606, P. Savoia, 08/31/2010).

Potato processed commodity results

To determine residue concentration factors in potato processed fractions, ZENECA AGRO based in 

Frankfurt held six (6) field trials at separate sites within Germany to cultivate potatoes during the 1993 

growing season. No details concerning the varieties of potatoes that were grown, the use of any 

maintenance pesticides and fertilizers, soil chemistry, weather data, or the use of supplemental 

irrigation was provided. The data submission only noted that each test location received an 

application of the Fusilade end-use product formulation of fluazifop-P-butyl applied at a late seasonal 

Pre-Harvest Interval (PHI) of six weeks. These treatments were made at the targeted amount of 375 g 

ai/ha in order to provide each test plot with a total seasonal application that was equivalent to 1.5x the 

maximum labeled use rate. For this program, the field samples from the two trials observed with the 

highest residues of total fluazifop were processed into potato peels, cooked potatoes, chips and dried 

flakes for testing. 
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The results in this data submission provide a determination of residue concentration factors for 

fluazifop-P-butyl in potato processed commodities. It was appropriately carried out in line with the 

recommendations set forth in the OPPTS 860.1520 Residue Chemistry Test Guidelines for evaluating 

the concentration of residues in processed commodities. Processing of the potato RAC bearing 

quantifiable residues of fluazifop resulted in no concentration of residues in the peel (1.1x processing 

factor). However, total fluazifop residues were found to concentrate in potato chips and dried flakes at 

a processing factor of 3.3x, and 6.4x, respectively. These results indicate that total fluazifop residues 

do not appear to concentrate in the potato peels, but may do so in the chips and granules/flakes 

processed fractions. In all, these data are adequate for determining residue concentration factors for 

potato processed commodities (MRID No. 47920405, P. Savoia, 08/31/2010). 

5.8 Rotational Crops

For these actions (PP#9F7624 & PP#9E7651), no new rotational crop data are required. 

5.9 Proposed and Recommended Tolerances

In a meeting on March 3, 2004, the MARC concluded that for tolerance expression, parent and 

fluazifop-acid (free and conjugated) are the residues of concern since they are adequate to determine 

misuse (DP No. D298939, S. L. Kinard, 06/22/2004). An acceptable soybean metabolism study is 

available along with new studies made to a root crop and leafy vegetable which are currently

undergoing Agency review. In accordance, tolerances are established under 40 CFR §180.411(a)(1) 

and (c)(1) for residues of fluazifop-butyl, including free and conjugated fluazifop, expressed as 

fluazifop. For fluazifop-P-butyl, including free and conjugated fluazifop (R isomer), tolerances are 

likewise established under 40 CFR §180.411(a)(2) and (c)(2) with residues expressed as fluazifop. Its 

registered uses include dry beans, carrot, cotton, endive (escarole), macadamia nut, onion, peanut, 

pecan, soybean, spinach, stone fruit, and sweet potato. It also carries tolerances with regional 

registrations on asparagus, coffee, pepper, and rhubarb along with being registered for use on lawns as 

a weed control application.

For PP#9F7624, field trials on bananas, citrus, grapes, and sugar beets along with corresponding 

studies made on the relevant processed commodities were submitted to support this action. In 

evaluating the field trials provided by the registrant, these studies were found to be adequate in 

satisfying these residue chemistry data requirements. In regard to the banana, grape, and citrus RACs, 

residues levels in all of the treated samples analyzed were found to be below the LOQ of the test 

method. As such, the proposed tolerance of 0.01 ppm specified by the registrant for bananas and 

grapes is acceptable. Following this approach a revised tolerance of 0.03 ppm for citrus based upon 

the corresponding LOQ of the test method is therefore recommended instead of the 0.05 ppm level 

proposed by the registrant. Total fluazifop residues in/on sugar beet RACs were found to be readily

quantifiable at levels greater then the LOQ of the test method. The residue data for sugar beets were 

entered into the Agency’s tolerance spreadsheet as specified by the Guidance for Setting Pesticide 

Tolerances Based on Field Trial Data SOP to determine an appropriate tolerance level (Appendix I). 

The spreadsheet provides a best estimate of a tolerance at 0.25 ppm for sugar beet roots. In regard to 

sugar beet tops, no tolerance will be required for this commodity since it is no longer considered to be 

a significant food or feed item.
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In evaluating of the corresponding processing study data that were provided, it can be concluded that 

no additional tolerances are needed for grape juice and raisins as well as sugar beet refined sugar. 

However, residues of fluazifop were found to concentrate in sugar beet dry pulp (3.9x) and sugar beet 

molasses (14x). Based on the sugar beet root HAFT of 0.22 ppm and the processing factors calculated 

for dried pulp and molasses, expected residues in these fractions are 0.86 ppm and 3.1 ppm, 

respectively. As a result, the tolerances of 1.0 ppm in dried pulp and 3.5 ppm for molasses proposed 

by the registrant are adequate for these sugar beet processed commodities. 

For the citrus processed commodities, the petitioner has also proposed tolerances of 0.40 ppm in dried 

pulp along with 0.05 ppm in juice and oil. However, EPA previously concluded that proposed 

tolerances in citrus fruit and dried citrus cannot be determined (DEB No. 6343, M. J. Bradley, 

08/15/1990). Rather then attempting to upgrade these results, it would be prudent for the petitioner to 

provide a new study given the age of this data submission. To satisfy the establishment of tolerances 

for the citrus processed commodities, the theoretical concentration factors are therefore used for 

setting the pertinent limits on juice (2x) and oil (1000x). These factors along with the citrus HAFT of 

0.03 ppm, determine that an appropriate fluazifop-P-butyl tolerance for citrus juice would be 0.06 ppm 

and 30.0 ppm for the oil fraction. In regard to citrus dried pulp, there is no theoretical concentration 

factor determined for this processed commodity. Using the maximum concentration factor of 13x 

calculated in the recent chlorantraniliprole action along with the citrus HAFT of 0.03 ppm, setting a 

fluazifop-P-butyl tolerance of 0.40 for dried pulp would be relevant for this fraction.

For PP#9E7651, field trials on potatoes along with a corresponding study made on its pertinent 

processed commodities were submitted to support this action. In evaluating the field trials provided 

by the registrant, these studies were found to be adequate in satisfying these residue chemistry data 

requirements. Total fluazifop residues in/on the potato RAC were found to be readily quantifiable at 

levels greater then the LOQ of the test method. In accordance, the Agency’s Guidance for Setting 

Pesticide Tolerances Based on Field Trial Data was utilized for determining appropriate tolerance 

levels for potato tubers. Based on these calculations, the proposed potato tolerance of 0.25 in roots is 

adequate and a limit of 1.0 ppm for tops is recommended. In regard to the corresponding processing 

study data that were provided, it can be concluded that no additional tolerances are needed for the 

peel. However, residues of fluazifop were found to concentrate in potato chips (3.3x) and dried flakes 

(6.4x). Based on the potato HAFT of 0.55 ppm and the processing factors calculated for chips and 

dried flakes, expected residues in these fractions are 1.82 ppm and 3.52 ppm, respectively. As a result, 

the tolerances of 2.0 ppm in chips and 4.0 ppm for dried flakes are recommended for these potato 

processed commodities.

The available residue data provided for fluazifop-P-butyl are adequate to support the establishment of 

permanent tolerances on bananas, citrus, grapes, and sugar beets along with an import limit on 

potatoes. There are no Codex, Canadian or Mexican established Maximum Residue Limits (MRLs) 

for residues of fluazifop-P-butyl in/on bananas, citrus, grapes, sugar beets, and potatoes. However, 

PP#9E7651 is being put forward as a request for the establishment of import tolerances on potato 

commodities which will be cultivated in Canada. As noted, there are no established MRLs for 

residues of fluazifop-P-butyl in/on potatoes in Canada but the promulgation of regulatory levels by

PMRA are in the process of being finalized. As a result, international harmonization with Canada is a

consideration for this data evaluation concerning the establishment of import tolerances on potato

commodities. In all, the proposed tolerances should therefore be revised to reflect the recommended 

tolerance levels and correct commodity definitions specified below in Table 2.
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Table 2. Tolerance Summary for Fluazifop-P-butyl.

Commodity Established

Tolerance 

(ppm)

Proposed

Tolerance 

(ppm)

Recommend

ed Tolerance 

(ppm)

Comments; Correct Commodity 

Definition

Tolerances Proposed for 40 CFR §180.411(a)(1)

Bananas -- 0.01 0.01

Citrus -- 0.05 0.03 Fruit, citrus, group 10

Citrus, oil -- 0.05 30.0

Citrus, dried pulp -- 0.40 0.40

Citrus, juice -- 0.05 0.06

Grape -- 0.01 0.01

Beet, sugar, root -- 0.25 0.25

Beet, sugar, top -- 1.5 None Removed from Table 1 Feedstuffs, 

June 2008

Beet, sugar, dried pulp -- 1.0 1.0

Beet, sugar, molasses -- 3.5 3.5

Potato, tubers -- 1.1 1.0 Potato

Potato, chips -- 3.0 2.0

Potato, granules/flakes -- 5.0 4.0

Note; the establishment of a tolerance on banana includes the plantain raw agricultural commodity.

6.0 Exposure Characterization/Assessment Section Update 

6.1 Dietary Exposure/Pathway

6.1.1 Acute and Chronic Dietary Exposure and Risk Update 

Revised acute and chronic dietary exposure assessments using the version 2.03 Dietary Exposure 

Evaluation Model (DEEM-FCIDTM) were conducted for fluazifop-P-butyl (DP No. D379452, S. 

Tadayon, 08/09/2010). This modeling effort uses food consumption data from the U.S. Department of 

Agriculture’s Continuing Surveys of Food Intakes by Individuals (CSFII) from 1994-1996 and 1998 to 

calculate dietary risk. These analyses were performed to support the Section 3 registration of 

fluazifop-P-butyl on bananas, citrus, grapes and grape processed commodities, as well as sugar beets. 

Also included in this determination are all uses relevant to the establishment of an import tolerance 

made for fluazifop-P-butyl on potatoes. These new crop uses were incorporated into the residue data 

of file inputs for all other registered commodities to render a current evaluation of dietary exposure. 

The resulting acute and chronic risk assessments which include both food and water are conservative 

evaluations. For the acute dietary exposure assessment, tolerance level residues with a ratio 

adjustment to account for additional metabolites of concern were used with the assumption that 100% 

of all crops are treated. Where applicable, DEEM 7.81 processing factors were utilized for the 

applicable commodities to reflect the possible altering of residue levels through the manufacture of 

other food forms such as meal and flour. For all other commodities, the default adjustment factor of 

1.0 was used to weight the processing effects of alternate food forms. 
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In contrast, percent crop treated estimates determined by BEAD along with the average residue levels 

observed in the applicable field trial studies with ratio adjustment was used to carry out the refined 

chronic analysis. Default processing factors along with the measured potato processing factors were 

used to weight the effects of alternate food forms for chronic assessment. For both determinations, 

drinking water estimates were incorporated directly into these analyses using the EECs generated by

EFED to complete the combined dietary exposure assessments.

 

Results of Acute and Chronic Dietary Exposure Analysis

Acute and chronic dietary risk analyses were made with the DEEM-FCIDTM model to form a careful

evaluation of exposure for fluazifop-P-butyl. The acute dietary assessment focuses on the population 

subgroup, females 13-49 years of age. This is the only population subgroup for which an appropriate 

toxic endpoint attributable to a single dose was identified. For this population subgroup, female 13-49 

years of age, acute dietary risk was estimated to be only 13 % of the aPAD with an exposure of 0.0641 

mg/Kg/day. No acute dietary endpoint attributable to a single dose was identified for general 

population including infants and children. This assessment concludes that for all supported registered 

commodities and new uses, the acute food plus water dietary risk estimates are below the Agency’s 

level of concern (<100 % aPAD).

In conjunction, the refined chronic analysis performed concludes that for all commodities, the 

resulting food plus water dietary risk is below the Agency’s level of concern (<100 %cPAD) for the 

U.S. population (12% cPAD with an exposure of 0.009 mg/kg/day) and all population subgroups. The 

most highly exposed population subgroup in the chronic dietary exposure analysis performed was for 

children 1-2 years of age (40% cPAD with an exposure of 0.003 mg/kg/day). An overview 

summarizing the results of the acute and chronic dietary assessments with the population subgroup 

having the highest exposure being noted in bold is presented below in Table 3. 

Table 3. Summary of Acute & Chronic Dietary Exposure for Fluazifop-P-butyl

1

Population Subgroup

Acute Dietary2 (95th Percentile) Chronic Dietary3

Dietary Exposure 

(mg/kg/day) % aRfD Dietary Exposure(mg/kg/day) % cRfD

General U.S. Population N/A4 N/A 0.0009 12

All Infants 0.0015 20

Children 1-2 years old 0.003 40

Children 3-5 years old 0.0022 30

Children 6-12 years old 0.0014 19

Youth 13-19 years old 0.0008 11

Adults 20-49 years old 0.007 8.9

Adults 50+ years old 0.0006 8.7

Females 13-49 years old 0.0641 13 0.0006 8.6

1

Fluazifop-P-butyl is not a likely human carcinogen based on lack of evidence of carcinogenicity in rats and mice; therefore, a 

 dietary cancer exposure and risk analysis was not conducted.

2 Acute dietary analysis derived from a 0.50 mg/kg/day aRfD.

3 Chronic dietary analysis derived from a 0.0074 mg/kg/day cRfD.

4 N/A – None Applicable.
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7.0 Water Exposure Risk/Pathway

To address the proposed new crop uses for this action (PP#9F7624), the potential human exposure to 

fluazifop-P-butyl in drinking water was subsequently re-evaluated (DP Nos. D371093 & D371094, W. 

J Shaughnessy, 05/25/2010). This modeling was updated to reflect updated application rates based on 

acid equivalents, applications with two and four total applications, and half-lives calculated using the 

linear/natural log equation. It was carried out by EFED to support risk assessment efforts for the 

Section 3 registration of fluazifop-p-butyl for use on bananas, citrus, grapes, and sugar beets.

Ground water EECs were modeled using Tier I SCIGROW (version 2.3, dated July 29, 2003) and 

surface water EECs with Tier II PRZM (Pesticide Root Zone Model; vers. 3.12.2, May 12, 2005) and 

EXAMS (EXposure Analysis Modeling System; Vers. 2.98.04.06). The resulting EECs represent 

exposure to fluazifop-acid, with assumptions that fluazifop-acid may be present in the R or S form or 

as a mixture of the enantiomers. Fluazifop-butyl (PC Code 122805) was detected in both surface 

water and ground water samples at low concentrations in Spain (<0.2 μg/L) indicating that exposure to 

fluazifop-butyl in drinking water is possible. However, based on the metabolism studies fluazifopacid is still expected to be the primary component present in drinking water (Martinez et al. 2000). 

Fluazifop-acid was not detected in a non-targeted ground water monitoring study (MRID No.

40439401).

The results of this updated modeling analyses performed by EFED is presented below in Table 4 for 

review. The results of current assessment are higher than 2008 assessment (DP No. D347521, K. 

White, 08/04/2008). For aerial applications the highest surface water EECs reported for peak, 1 in 10 

year average, and the 30 year average as estimated by PRZM/EXAMS for all crop use scenarios were 

33.4, 6.6 ppb, and 4.4 ppb, respectively. For ground applications the highest EECs for peak, 1 in 10 

year average, and the 30 year average were 32.1 ppb, 5.8 ppb, and 3.1 ppb, respectively. SCI-GROW 

estimated the concentration of fluazifop-acid in shallow ground water sources to be 1.56 ppb. The 

difference between the 2008 and current assessment results can be attributed to a proposed increase in 

the maximum number of allowable applications (i.e., 3 vs. 2), and differences in crop use scenarios 

used in the two assessments.
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Table 4. Summary of the highest predicted surface and ground water concentrations for the 

drinking water assessment for the use of fluazifop-p-butyl on bananas, plantains, citrus, grapes, 

and sugar beets.

Use

Estimated Drinking Water Concentration of Fluazifop-Acid (g/L)

Acute or 

Peak

1 in 10 year Average 

(Noncancer Chronic)

30 year Average (Cancer 

Chronic) 

Aerial Applications Surface Water

Bananas & Plantains 33.4 6.2 3.2

Citrus 28.5 5.4 3.7

Grapes 19.8 6.6 4.4

Sugar Beets 13.0 4.8 3.3

Ground Applications Surface Water

Bananas & Plantains 32.1 5.8 2.7

Citrus 27.3 5.1 2.8

Grapes 16.6 5.3 3.1

Sugar Beets 10.6 3.9 2.3

Ground Water

All Uses 1.56 1.56 1.56

The resulting modeling estimates indicate that the most significant levels of fluazifop-P-butyl would 

likely be found in surface water resulting from applications made to bananas and plantains. These 

new EECs were then appropriately used to complete this updated risk assessment. 

8.0 Residential Exposure Risk Characterization 

Non-dietary, non-occupational exposure was addressed in the HED tolerance reassessment made for 

the fluazifop-P-butyl herbicide in August 2005 (DP No. D316891, D. Locke, 08/29/2005). Upon 

completion of this human health risk assessment, no new information on residential exposure has been 

submitted. For this action, the existing residential application of fluazifop-P-butyl will not be 

impacted because the proposed new uses will only augment commercial agricultural practices. 

Sections of the prior residential analyses made for fluazifop-P-butyl are therefore repeated to allow for 

the transparent calculation of aggregate risk required to support the proposed new uses. 

Non-Occupational (Residential) Handler Exposure and Risks

Fluazifop-P-butyl is a registered herbicide for residential use on turfgrass and broadleaf ornamentals 

for the post-emergent control of weed grasses. It is used in this manner as a total grass weed control in 

a number of outdoor environments such as on lawns, walks, driveways, and ornamental planting beds. 

Homeowners that apply fluazifop-P-butyl products may therefore become exposed for short-term 

durations via the dermal and inhalation routes. There are several residential handler exposure 

scenarios given the types of equipment and techniques for applying fluazifop-P-butyl based upon 

anticipated use patterns and current labeling instructions. The exposure scenarios developed for 

residential handlers of fluazifop-P-butyl are as follows: 
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1. Liquid Concentrate: Low Pressure Handwand.

2. Liquid Concentrate: Hose-end Sprayer.

3. Liquid Concentrate: Watering Can.

4. Ready-to-Use (RTU) Formulations: Sprinkling Application.

5. Ready-to-Use (RTU) Formulations: Trigger-pump Sprayer.

The results for residential handlers of fluazifop-P-butyl were found to yield MOEs above 100 which 

indicate no risks are of concern. The results from these exposure and risk calculations are presented 

below in Table 5 which are taken from the HED August 2005 tolerance reassessment.

Table 5. Summary of Residential Handler Risks from Fluazifop-P-butyl.

Exposure 

Scenario

Target Appl. 

Ratea

Area 

Treated 

Dailyb

Dermal 

Unit 

Exposure 

(mg/lb ai)

Inhalation 

Unit 

Exposure 

(g/lb ai)

Dermal 

Dose 

(mg/Kg/day)

Inhalation 

Dose 

(mg/Kg/day)

MOE (HED’s level 

of concern = 100)

DerdInhl.

e

Der 

+ 

Inhl.

Mixer/Loader/Applicator

Mixing/Loading

/Applying 

Liquid Conc. 

with Low Press. 

Handwand (1)

Walks, 

drives, 

patios & 

fences

0.0056 

lb 

ai/gal

5 gallons 56 3.8 0.0024 0.0000018 850 1.1 x 

106

850

Mixing/Loading

/Applying 

Liquid Conc. 

with Hose-end 

Sprayer (2)

Walks, 

drives, 

patios, 

fences & 

lawns

0.98 lb 

ai/acre

0.5 acre 11 17 0.0081 0.00014 250 1400

0

240

Mixing/Loading

/Applying 

Liquid Conc. 

with Watering 

Can (3)

Walks, 

drives, 

patios & 

fences

0.0056 

lb 

ai/gal

5 gallons 11 17 0.00046 0.0000079 430

0

2500

00

4300

Loading/

Applying RTU

Liquid with 

Watering Can 

(4)

In/around 

ornamental 

plants & 

ground 

cover

0.04 lb 

ai/gal

1 gallon 11 17 0.00066 0.000011 300

0

1800

00

3000

Loading/

Applying RTU 

Liquid with 

Trigger Pump 

Sprayer (5)

In/around 

ornamental 

plants & 

ground 

cover

0.04 lb 

ai/gal

1 gallon 13.5 123 0.00081 0.000082 250

0

2400

0

2200

a

 Application rates are the maximum application rates determined from EPA registered labels for fluazifop-P-butyl. 

b

 Amount handled per day values are EPA estimates. Attire is short-sleeve shirt, short pants, and no gloves and no respirator. 

c

 Dermal MOE = NOAEL (2 mg/kg/day) / dermal daily dose (mg/kg/day), where dermal dose = daily unit exposure (mg/lb ai) x 

application rate amount handled per day / body weight (60 kg female adult). 

d

Inhalation MOE = NOAEL (2 mg/kg/day) / inhalation daily dose (mg/kg/day), where inhalation dose = daily unit exposure (μg/lb ai) x 

application rate x amount handled per day x conversion factor (1 mg/1,000 g)/body weight (60 Kg adult female). 

Residential Post-Application Exposure and Risks

Fluazifop-P-butyl can be used in a number of residential areas which may be frequented by the general 

population such as on home lawns. This provides the potential for dermal (adults and children) and 

incidental oral exposure (children) following residential applications of fluazifop-P-butyl. For these 

purposes, exposure and risk estimates were derived using the HED Standard Operating Procedures for 

Residential Exposure Assessments (draft December 18, 1997). In accordance, the following 

fluazifop-P-butyl post-application risk scenarios were assessed for children:

1. Residential Turf (High Contact Activities).

2. Hand to Mouth Activity on Turf.
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3. Object to Mouth Activity on Turf.

4. Incidental Soil Ingestion.

The results for residential post-application exposures were found to yield MOEs above 100 which 

indicate that no risks are of concern. The results from these exposure and risk calculations are 

presented below in Table 6 which are taken from the HED August 2005 tolerance reassessment.

Table 6. Fluazifop-P-butyl Post-Application Risk Estimates for Children.

Exposure Scenario Route of 

Exposure

Application Rate (lb 

ai/acre)

MOE on Day 0 

(HED’s level of 

concern = 100)

Residential Turf (High 

Contact Activities) Dermal 

0.98 (lawn renovation) 260 

0.09 (established turf) 2,900 

0.075 (turf) 170,000 

Hand to Mouth Activity on 

Turf Oral 

0.98 (lawn renovation) 6,800 

0.09 (established turf) 74,000 

0.075 (turf) 89,000 

Object to Mouth Activity on 

Turf Oral 

0.98 (lawn renovation) 27,000 

0.09 (established turf) 300,000 

0.075 (turf) 360,000 

Incidental Soil Ingestion Oral 

0.98 (lawn renovation) 2,000,000 

0.09 (established turf) 22,000,000 

0.075 (turf) 26,000,000 

Fluazifop-P-butyl Post-Application Risk Estimates for Adults.

High Contact Lawn 

Activities Dermal 0.98 (lawn renovation) 380

0.09 (established turf) 4,200

0.075 (turf) 5,000

Mowing Turf Dermal 0.09 (established turf) 26,000

0.075 (turf) 32,000

Golf Course Dermal 0.09 (established turf) 13,000

0.075 (turf) 16,000

Spray Drift

Spray drift is always a potential source of exposure to residents who may be nearby to spraying 

operations. This is particularly the case with aerial application, but could also be a potential source of 

exposure from ground application methods to a lesser extent. Labeling instructions for fluazifop-Pbutyl specify that it is registered for use on several major agricultural crops, including cotton, 

soybeans, fruit/nut trees, and vegetable crops. As such, it may be applied with aircraft, ground-boom, 

or air-blast equipment. As indicated in this assessment, fluazifop-P-butyl can be directly applied to 

residential turf, which will not result in exposures of concern. Based on this assessment, HED 

believes that it is unlikely that there is a higher potential for risk from exposure to spray drift from 

agricultural uses of this active ingredient.
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9.0 Aggregate Risk Assessment and Risk Characterization Updates

In compliance with FQPA, HED must consider and aggregate (add) the risks whenever there are 

potential residential exposures to a pesticide active ingredient. In doing so, the pesticide risks from the 

three (3) major potential sources of exposure (food, drinking water & residential use) are evaluated 

collectively. This assessment is made by adding together the exposures from these relevant sources 

and comparing them to quantitative estimates of hazard (NOAEL, PAD, etc.), or the risks themselves 

can be aggregated. When aggregating exposures and risks from various sources, HED will routinely

consider both the route and duration of exposure.

For the proposed new uses put forward in these petitions (PP#9F7624 & PP#9E7651), there are 

potential exposures to fluazifop-P-butyl which can occur through food, drinking water, and residential 

uses (turf & ornamental application). For the most part, identical hazards were identified via the oral, 

dermal, and inhalation routes over the short- and intermediate-time durations. Short-term residential 

exposures are anticipated but intermediate- and long-term residential exposures are not. Therefore, 

this aggregate risk assessment will consider potential short-term residential exposures plus those 

averaged for food and drinking water estimated with DEEM-FCIDTM modeling described beforehand. 

Estimated drinking water concentrations provided by EFED were directly incorporated into the 

assessment. 

Acute and Chronic Aggregate Risk Assessments (Food & Drinking Water)

For a detailed discussion of the acute and chronic aggregate risk assessments of food and drinking 

water exposure, refer to Section 6.1.1 in this memorandum for the analyses made with DEEM-FCIDTM 

modeling. These assessments concluded that for all supported registered commodities and new uses, 

the food plus water dietary risk estimates for acute and chronic exposure are both below the Agency’s 

level of concern (<100 % of the aPAD & cPAD).

Short-Term Aggregate Risk Assessments

Short-term aggregate risk assessments are made to estimate the potential effects from exposures which 

can occur from 1 to 30 days in duration. For fluazifop-P-butyl, there are a number of short-term 

exposure scenarios which could be aggregated. In doing so, only the most likely occurrences were 

combined so that a conservative (high-end) determination would be made. For adults, HED combined 

the average chronic food and drinking water exposures with handler (dermal and inhalation) and 

postapplication exposures on treated turf (dermal). For children, HED combined the average chronic 

food and drinking water exposures with postapplication dermal and incidental oral (hand-to-mouth, 

object-to-mouth, soil ingestion) from contact with treated turf. The results from this assessment are 

presented below in Table 7 for review. These results indicate that short-term aggregate risks are not of 

concern for fluazifop-P-butyl.

Table 7. Short-Term Aggregate Risk 

Population Short-Term Scenario1 Aggregate MOE (food 

and residential)7

HED’s 

Aggregate 

LOC2

MOE 

food + 

water3

MOE 

incidental

oral4

MOE 

dermal5 MOE inhalation6

Gen. U.S. Population 100 110,000 NA 150 14,000 150

Adult Female 100 170,000 NA 150 14,000 150

Child 100 33,000 5,500 260 NA 250

1 

Level of Concern (LOC) along with the Margin of Exposure (MOE) for incidental oral, dermal, and inhalation see DP No. D316891, D. Locke, 

08/29/2005. MOE for food + water see Table 3 of this memorandum.
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2 

Level of Concern (LOC) is 100 based on 10X for inter-species extrapolation and 10X for intra-species variation. 

3

 MOE food + water = [(short-term oral NOAEL 100 mg/kg/day)/(chronic dietary exposure)] 

Chronic dietary exposure: General U.S. Pop.= 0.002309 mg/kg/day; Females 13-49 yrs = 0.001823 mg/kg/day; Children 1-2 yrs. = 0.005994 

mg/kg/day.

4

 MOE incidental oral = [(short-term incidental oral NOAEL 100 mg/kg/day)/(child residential exposure)] Child residential exposure: Hand-to-mouth = 

0.015 mg/kg/day; Object-to-mouth = 0.0037 mg/kg/day; Incidental soil ingestion = 0.000049 mg/kg/day. 

5

 MOE dermal = [(short-term dermal NOAEL 2 mg/kg/day)/(high-end dermal residential exposure)] Dermal exposure: Adults = handler 0.0081 

mg/kg/day + postapp 0.0053 mg/kg/day; Child = 0.0076 mg/kg/day. 

6

 MOE inhalation = [(inhalation NOAEL 2 mg/kg/day)/(high-end inhalation residential exposure)] Inhalation exposure: Adult = handler 0.00014 

mg/kg/day.

7

Aggregate MOE (food + water + residential) = 1÷[ [(1÷MOE food + water) + (1÷MOE incidental oral) + (1÷MOEdermal) + (1÷MOE inhalation)]].

Intermediate-Term Aggregate Risk Assessments

All residential/recreational exposures are anticipated to be short-term in duration (DP No. D316891, 

D. Locke, 08/29/2005).

Long-Term Aggregate Risk Assessments

Long-term aggregate risks are captured under the chronic dietary risk assessment previously

discussed. As stated above, no long-term residential exposures are anticipated for fluazifop-P-butyl.

 

10.0 Occupational Exposure/Pathway 

The new crop uses which are proposed will be made with the Fusilade® DX Herbicide (EPA Reg. No. 

100-1070) EC formulation containing 24.5% fluazifop-P-butyl ai (equivalent to 2 lb ai/gal). Its 

expanded use will employ multiple foliar or vineyard/orchard floor applications at maximum seasonal 

rates of 1.125 lb ai/A for bananas, grapes, and citrus and 0.75 lb ai/A for sugar beets. Applications are 

to be made with an adjuvant using ground or aerial equipment at Pre-Harvest Intervals (PHIs) which 

range from 0 days on treatments made to bananas up to 90 days for sugar beets. In accordance, 

occupational handlers and post-application workers can become exposed to fluazifop-P-butyl at shortor intermediate-term durations through its use. 

For the new crop uses being proposed in this action, the expanded use of fluazifop-P-butyl will 

support commercial agricultural efforts in controlling grass weeds through limited foliar application. 

Occupational exposures/risks were not addressed in the prior HED human health risk assessment to 

support tolerance reassessment (DP No. D316891, D. Locke, 08/29/2005). An evaluation of the 

occupational exposure/risk pathway was performed herein to ensure worker protection safeguards (DP 

No. D379451, S. Tadayon, 06/23/2010). 

10.1 Handler Exposure and Risk

For the new crop uses being proposed, agricultural workers may likely become exposed to fluazifopP-butyl through a number of different application activities. There is a potential for exposure to 

fluazifop-P-butyl during mixing, loading, and application activities. As such, a short-/intermediateterm risk assessment to evaluate exposure using the applicable endpoints selected by the HIARC 

(06/15/2004) was performed. In doing so, the following worker scenarios were identified for the uses 

being proposed:

Mixer/Loader: 

1. Mixing/Loading Liquid Concentrates for Aerial Applications (PHED) 

2. Mixing Loading Liquid Concentrates for Chemigation Applications (PHED) 

3. Mixing Loading Liquid Concentrates for Groundboom Applications (PHED) 
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Applicators

1. Applying Sprays via Aerial Equipment (PHED) 

2. Applying Sprays via Groundboom Equipment (PHED) 

Mixer/Loader/Applicator

1. Mixing/Loading/Applying with Handgun Sprayer (ORETF data)

Flaggers

1. Flagging for Aerial Spray Applications (PHED) 

To estimate risks from occupational exposures associated with these new uses, HED used dermal 

absorption data from a study involving human volunteers (Woolen, BH, 1991, "Fluazifop-butyl -

Dermal Absorption and Pharmacokinetics in man following single dose of 2 mg and 200 mg"). This 

study has had the appropriate ethical review and been deemed acceptable for use in human health risk 

assessment (Lowe, MF, June 10, 2006, Initial Ethics Review of a Human Study of Dermal Absorption 

and Pharmacokinetics of Fluazifop-Butyl"). This study provides two estimates of dermal absorption 

for fluazifop-butyl, 2% and 9 %. The study indicates that the rate of absorption of fluazifop-butyl 

through the skin is dependent on the level of exposure or dose applied to the skin. Specifically, low 

levels of exposure result in higher rates of absorption (9%), and high levels of exposure result in lower 

rates of absorption (2%). HED's HIARC determined that the data were acceptable and both factors 

could be used for risk assessment (Report of the Hazard Identification Assessment Review Committee 

for Fluazifop-P-butyl, D. Anderson, 05/20/2004). 

HED's TOX SAC met on 08/28/2008 to reconsider the use of both factors in risk assessment. The 

TOX SAC reconfirmed the appropriateness of the use of both factors for risk assessment because there 

is high confidence in the data as they come from a study using humans. In addition, the TOX SAC 

concurred that the use of the 9% dermal absorption factor across all scenarios is conservative given the 

results of the dermal absorption study in humans, which indicates that as exposures to fluazifop-butyl 

on the skin increase, the skin becomes saturated and the percentage of dermal absorption decreases. 

More specifically, a high dose results in a chemical build up on the skin. This chemical build up acts 

as a shield and therefore prevents further absorption of the chemical. As a result, there is a lowering 

of the dermal absorption factor (2%) at higher doses. Conversely, a scenario in which there is a low 

daily dose allows the chemical to absorb into the skin without the shielding effect from chemical build 

up. As a result, a higher dermal absorption factor (9%) is observed at low daily doses.

Following this approach, a range of risk estimates (MOEs) for occupational exposures associated with 

the new uses, one set of MOEs based on 9% dermal absorption and a second set of MOEs based on 

2% dermal absorption were determined. The TOX SAC considered this a unique circumstance in 

which available human data could be used to provide a range of risk estimates. In this manner, the use 

of 2% absorption is considered a refinement. The non-cancer risk or margin of exposure (MOE) for 

all time durations was calculated as follows: 

 

MOE = NOAEL (mg/Kg/day) 

Dermal or Inhalation Daily Dose (mg/Kg/day) 

 
Fluazifop-P-Butyl Human Health Risk Assessment to Support New Uses DP No.: 385178

Page 48 of 78

The levels of concern for occupational workers are MOEs of 100 for dermal and inhalation risk.

The adverse effects seen in both the dermal and inhalation studies were similar; therefore, the

MOEs were combined to identify a total risk. All short/intermediate-term MOEs calculated for the 

mixer/loader are greater than 100 at the engineering control level. These MOEs do not exceed HED’s 

level of concern. In characterizing these risks, the dermal toxicity study associates a 9% dermal 

absorption factor with a dermal dose of 0.02 mg/Kg/day, and a 2% dermal absorption factor with a 

dermal dose of 2.6 mg/Kg/day. As a result, occupational exposures for the new uses of fluazifop-Pbutyl were found to range from a high of 0.07 mg/Kg/day to a low of 0.006 mg/Kg/day. To illustrate 

these findings, the results of occupation handler risk assessment are presented below in Tables 8 and 9 

for review. This analysis has determined that exposures greater thean 0.1 mg/Kg/day represent high 

doses and the use of the 2% dermal absorption factor would be most appropriate for these exposure 

scenarios (high pressure handwand). Alternately, exposures less than 0.1 mg/Kg/day represent low 

doses and application of the 9% dermal adsorption factor for these scenarios (all other scenarios) 

would be more appropriate.
Fluazifop-P-Butyl Human Health Risk Assessment to Support New Uses DP No.: 385178

Page 49 of 78

Table 8. Short-Term Fluazifop-P-butyl Occupational Handler Risks

Exposure Scenario Crop or Target Application 

Ratea(lb ai/A)

Area 

Treated 

Dailyb(A/gal)

Dermal 

Dose 

(mg/Kg/day)

Dermal

Absorption

Factor

Total MOEc

Baseline+ 

Gloved Eng Conte

Mixer/Loader

Mixing/Loading Liquid for 

Aerial and Applications Potato, sugar beet 0.375 350 4.53E-03 9% 280 NA

Mixing/Loading Liquid for 

chemigation Applications Potato, sugar beet 0.375 350 4.53E-03 9% 280 NA

Mixing/Loading Liquid for 

Groundboom Applications 

Potato, sugar beet, citrus, 

grape, banana, plantains 0.375 80 1.04E-03 9% 1223 NA

Applicator

Applying Sprays via Aerial 

Equipment Potato, sugar beet 0.375 350 9.84E-04 9% No Data 1765

Applying Sprays via 

Groundboom Equipment 

Potato, sugar beet, citrus, 

grape, banana, plantains 0.375 80 6.30E-04 9% 2000 NA

Mixer/Loader/Applicator

Handgun Sprayer (ORETF)

Citrus, grape, banana, 

plantains 0.375 25 6.33E-03 9% 303 NA

Flagger

Flagging for Aerial Spray 

Applications Potato, sugar beet 0.375 350 2.17E-03 9% 682 NA

NA Not assessed since an acceptable risk is achieved

a Application rates are the maximum application rates determined from proposed labels for fluazifop- P- butyl

b Amount handled per day values are HED estimates of acres treated per day based on Exposure SAC SOP #9 “Standard Values for Daily Acres Treated in Agriculture,” industry sources, and 

HED estimates.

c Short-term Inhalation and dermal MOE = NOAEL (2.mg/kg/day) / inhalation or dermal daily dose (mg/kg/day), where ;

Dermal dose = daily unit exposure (μg/lb ai) x application rate x amount handled per day x 9% dermal absorption factor (since all the dermal dose values were less then 0.1 mg/Kg/day a value 

of 9% dermal absorption factor was used)/body weight (60 Kg).

Inhalation dose = daily unit exposure (μg/lb ai) x application rate x amount handled per day x conversion factor (1 mg/1,000 μg/body weight (60 Kg).

Total MOE = NOAEL / (Dermal dose + Inhalation Dose)

d PPE- long pants, long sleeved shirt shoes and glove .

e Engineering Controls is closed mixing/loading system, enclosed cab, or enclosed cockpit.
Fluazifop-P-Butyl Human Health Risk Assessment to Support New Uses DP No.: 385178

Page 50 of 78

Table 9. Intermediate-Term Fluazifop-P-butyl Occupational Handler Risks

Exposure Scenario Crop or Target

Application 

Ratea

lb ai/A

Area 

Treated 

Dailyb

(A/gal)

Dermal

Dose 

(mg/Kg/day)

Dermal

Absorption 

Factor

Total MOEc

Baseline+

Gloved

Eng 

Conte

Mixer/Loader

Mixing/Loading Liquid for 

Aerial and Applications Potato, sugar beet 0.375 350 3.88E-03 9% 114 NA

Mixing/Loading Liquid for 

Chemigation Applications Potato, sugar beet 0.375 350 3.88E-03 9% 114 NA

Mixing/Loading Liquids for 

Groundboom Applications 

Potato, sugar beet, citrus, 

grape, banana, plantains 0.375 80 8.87E-04 9% 198 NA

Applicator

Applying Sprays via Aerial 

Equipment Potato, sugar beet 0.375 350 8.44E-04 9% No Data 746

Applying Sprays via 

Groundboom Equipment 

Potato, sugar beet, citrus, 

grape, banana, plantains 0.375 80 5.40E-04 9% 813 NA

Mixer/Loader/Applicator

Handgun Sprayer (ORETF)

Citrus, grape, banana, 

plantains 0.375 25 5.42E-03 9% 130 NA

Flagger

Flagging for Aerial Sprays 

Applications Potato, sugar beet 0.375 350 1.86E-03 9% 282 NA

NA Not assessed since an acceptable risk is achieved

a Application rates are the maximum application rates determined from proposed labels for fluazifop- p- butyl

b Amount handled per day values are HED estimates of acres treated per day based on Exposure SAC SOP #9 “Standard Values for Daily Acres Treated in Agriculture,” , and HED estimates.

c Intermediate-term inhalation and dermal MOE = NOAEL (0.74mg/Kg/day) / inhalation or dermal daily dose (mg/Kg/day), where;

Dermal dose = daily unit exposure (μg/lb ai) x application rate x amount handled per day x 9% dermal absorption factor (since all the dermal dose values were less then 0.1 mg/Kg/day a value 

of 9% dermal absorption factor was used)/body weight (70 Kg).

Inhalation dose = daily unit exposure (μg/lb ai) x application rate x amount handled per day x conversion factor (1mg/1,000 μg /body weight (70 Kg). 

Total MOE = NOAEL / (Dermal dose + Inhalation Dose)

d Baseline attire is single layer and no gloves/no respirator.

e Engineering Controls is closed mixing/loading system, enclosed cab, or enclosed cockpit.
Fluazifop-P-Butyl Human Health Risk Assessment to Support New Uses DP No.: 385178

Page 51 of 78

10.2 Occupational Post-Application Exposure and Risks

Most of the proposed new uses of fluazifop-P-butyl are ground-directed applications where no crop 

foliage is treated. Currently, HED has no TCs or other data to assess post-application dermal 

exposures to soil by occupational workers. For citrus, grapes, bananas, and plantains, the fluazifopP-butyl label prohibits spraying on the foliage. Consequently, for these proposed soil-directed uses, 

post-application exposures and risks to occupational workers were not quantitatively assessed. 

Alternately, for potatoes and sugar beets, the fluazifop-P-butyl label allows for spraying on the 

foliage to occur. Therefore, for these proposed uses, post-application exposures and risks to 

occupational workers were quantitatively assessed. 

HED’s post-application exposure estimates are based on a surrogate approach due to the lack of 

chemical-specific data for fluazifop-P-butyl. The maximum application rate is used in this 

assessment, while assumptions regarding Dislodgeable Foliar Residues (DFR) and workday duration 

are believed to be average values. Twenty percent of the residues are assumed available for transfer. 

Dissipation of foliar residues is assumed to occur at the rate of 10% of the application rate per day. 

The workday duration is assumed to be 8 hours. These risk estimates are characterized as central to 

high-end.

Most post-application activities will involve frequent contacts made with the foliage of treated crops 

requiring the consideration of dermal exposure when evaluating re-entry risks. For any given 

activity, the extent of exposure will depend on the amount of residue on the foliage, the intensity of 

the contact made with the foliage, and the duration of contact. Dermal absorption factors of 2% and 

9% were determined for fluazifop-P-butyl depending on low versus high exposures, respectively. 

Re-entry intervals have been assessed using both values. HED believes that prior dermal absorption 

studies demonstrate saturation if the mass per unit area exceeds a certain level. Given this, use of the 

9% factor in combination with high levels of exposure would result in providing a conservative 

estimate of risk. 

The determination of both short- and intermediate-term dermal MOEs for post-application exposure 

were found to range from 100 to 8900. In reaching or exceeding the LOC of 100, the resulting 

MOEs indicate these risks are not of concern. The results of this post-application assessment 

indicate that MOEs are greater than 100 for short- and intermediate-term scouting activities at day 0

when the 2% dermal absorption factor is used. Nevertheless, the MOEs are ≥ 100 for short- and 

intermediate-term scouting activities with REIs of 3 and 10 days, respectively, when a conservative 

dermal absorption factor of 9% is assumed. A summary of the Post-application Exposure and Risk 

Assessment made herein is presented below in Table 10 for review.
Fluazifop-P-Butyl Human Health Risk Assessment to Support New Uses DP No.: 385178

Page 52 of 78

Table 10. Fluazifop-P-butyl Exposure and Risk Assessment for Occupational Post-Application Activities.

Crops1

Applicati

on Rate

(lb ai/A)

Dislodgeable 

Foliar Residue

(ug/cm2)

2

Dermal Transfer 

Coefficient3(cm2/hr)

Short-Term (2%DAF)

4

Intermediate-Term4

(2%DAF)

MOE REI 

(days)

MOE REI (days)

Potato, 

sugar beet

0.375 0.84 (day 0)

0.61 (day 3)

0.29 (day 10)

High end activities Scouting 

2500

360 0 155 0

Low end activities 

(Irrigation) 100

8900 0 3800 0

Dermal Transfer 

Coefficient (cm2/hr)

Short-Term (9% DAF) Intermediate-Term 

(9%DAF)

MOE REI 

(days)

MOE REI (days)

High end activities Scouting 

2500 110 3 100 10

Low end activities 

(Irrigation) 100

1985 0 875 0

1. Crop types are taken from the HED Science Advisory Council (SAC) for Exposure Policy 003.1 (August 2000).

2. Dislodgeable Foliar Residue Postapplication day (ug/cm2) = Application rate (lb ai/A) x Fraction of ai Retained on the Foliage x (1- Fraction 

of Residue that Dissipates Daily)

postapplication day x 4.54E+8 ug/lb x 4.7E-9 A/cm2

3. Transfer coefficients are taken from the HED Science Advisory Council (SAC) for Exposure Policy 003.1 (August 2000), which

include data supplied by the Agricultural Reentry Task Force.

4. For short- and intermediate-term dermal risk assessment, the dermal absorption factor of 2% and 9% were applied because the 

endpoint chosen for this risk assessment was derived from an oral toxicity study.
Fluazifop-P-Butyl Human Health Risk Assessment to Support New Uses DP No.: 385178

Page 53 of 78

11.0 Data Needs and Label Requirements

11.1 Toxicology

See Appendix A.5 for list of studies and rational for requirements.

11.2 Residue Chemistry

860.1200 Directions for Use

The submitted bridging study data made for the Venture L and Fusilade Maxx EC formulations 

show that when they are applied to potatoes at 1x the maximum seasonal rate, the resulting 

residues will be similar. If the registrant so chooses, a revised section B could be submitted which 

includes this use for both product formulations. 

860.1380 Storage Stability

Adequate storage stability data are available to support sample storage conditions that were 

incurred for the potato RAC, but none have been provided for the processed commodities. This is 

required since the processed commodities do not appear to have been analyzed within thirty (30) 

days of production.

860.1520 Processed Food and Feed

The submitted citrus processing study is not acceptable having been previously concluded by the 

Agency to be inadequate (DEB No. 6343, M. J. Bradley, 08/15/1990). Rather then attempting to 

upgrade these results, it would be prudent for the petitioner to provide a new study given the age of 

this data submission.

860.1550 Proposed Tolerances

The proposed tolerances should be revised to reflect the recommended tolerance levels and correct 

commodity definitions as specified in Table 2 of this memorandum. 

11.3 Occupational and Residential Exposure

None

12.0 References

DP No.: D347515

Subject: Fluazifop-P-Butyl. Amended Human Health Risk Assessment to Support Use on 

Dry Beans, Peanuts, and the Post-Bloom Application to Soybeans.

From: P. Savoia

To: J. Miller & J. Stone

Dated: 09/19/2008

MRID Nos.: 47285501-47285505
Fluazifop-P-Butyl Human Health Risk Assessment to Support New Uses DP No.: 385178

Page 54 of 78

DP No.: D319907

Subject: Fluazifop-P-butyl. REVISED TRED – Report on FQPA Tolerance Reassessment 

Progress and Interim Risk Management Decisions. Residue Chemistry

Considerations. Case No. 2285.

From: S. L. Kinard

To: D. Locke

Dated: 08/17/2005

MRID Nos.: 00093840-1, 00093843, 00093845, 00137763, 00144014, 00151494, 00157191, 

001517193, 40140401, 40241901, 40341601, 40361104, 40361108, 40361111, 

40693108, 40725701, 40831303-5, 40831307, 40831309-10, 41018001, 41373703.

DP No.: D298939

Subject: Fluazifop-P-butyl. Report of the Metabolism Assessment Review Committee. 

From: S. L. Kinard

To: Y. Donovan

Dated: 03/17/2004

MRID No.: None

DP No.: D291905

Subject: Fluazifop-P-butyl: Revised Residential Exposure Assessment and 

Recommendations for the Tolerance Reassessment Eligibility Decision (TRED) 

Document. 

From: M. Collantes

To: D. Locke

Dated: 08/10/2004

MRID No.: None

DP No.: D379452

Subject: Fluazifop-P-butyl Acute and Chronic Aggregate Dietary (Food and Drinking 

Water) Exposure and Risk assessment for the Section 3 Registration Action to add 

uses on Banana, Plantains, Citrus, Grapes, Potato and Sugar beet. 

From: S. Tadayon

To: P. Savoia

Dated: 08/09/2010

MRID No.: None

DP Nos.: D371093 and D371904

Subject: Drinking Water Assessment for the Section 3 registration of Fluazifop-P-butyl for 

New Use on Bananas, Plantains, Citrus, Grapes, and Sugar Beets

From: Wm. J. Shaughnessy

To: J. Miller and M. Walsh

Dated: 05/25/2010

MRID No.: None
Fluazifop-P-Butyl Human Health Risk Assessment to Support New Uses DP No.: 385178

Page 55 of 78

DP No.: D379451

Subject: Occupational Risk Assessment to Support Request for a Section 3 registration of 

New Uses of Fluazifop-P-butyl

From: S. Tadayon

To: P. Savoia

Dated: 06/23/2010

MRID No.: None

DP No.: D316891

Subject: Fluazifop-P-butyl. REVISED HED Chapter of the Tolerance Reassessment 

Eligibility Document (TRED). PC Code: 122809, Case #2285, DP No. D316891.

From: D. Locke

To: L. Wormell

Dated: 08/17/2005

MRID No.: None

DP No.: D348246

Subject: Fluazifop-P-Butyl. Section 3 Registration Request to Add New Uses on Beans 

(Dry), Peanuts and Soybeans. Summary of Analytical Chemistry and Residue Data.

From: D. Soderberg

To: J. Miller

Dated: 09/16/2008

MRID Nos.: 47285501-05; 46412503

DP No.: D385205

Subject: Fluazifop-P-Butyl. Amended Section 3 Registration Request to Add New Uses on 

Bananas, Citrus, Grapes, and Sugar beets. Summary of Analytical Chemistry and 

Residue Data. 

From: P. Savoia

To: K. Montague and M. Walsh

Dated: 01/04/2011

MRID Nos.: 47874601-47874606

DP No.: D372408

Subject: Fluazifop-P-Butyl. Request for the Registration of a Reduced Pre-Harvest Interval 

for Application of the Venture L End-Use Product on Potatoes. Summary of 

Analytical Chemistry and Residue Data.

From: P. Savoia

To: K. Montague and M. Walsh

Date: 08/31/2010

MRID Nos.: 47920401-47920401
Fluazifop-P-Butyl Human Health Risk Assessment to Support New Uses DP No.: 385178

Page 56 of 78

MRID No.: 47874601. Kleinschmidt M., M.M. Miller. (2000) Fluazifop-P-Butyl – Residue 

Levels in Banana from Trials Carried Out in the United States During 1999 (Final 

Report). Report Number RR 00-43B. Study Number FLUA-99-MR-01. 

Unpublished study prepared by Syngenta Crop Protection, Inc. 79 pages.

MRID No.: 47874602. Stewart, ER. (2001) Fluazifop-P-butyl – Residue Levels on Citrus from 

Trials Conducted in the United States During 2000 (Final Report). Report Number 

RR 00-63B. Study Number FLUA-00-MR-03. Unpublished study prepared by

Syngenta Crop Protection, Inc. 126 pages. 

MRID No.: 47874604. Stewart, E. (2001) Fluazifop-P-Butyl - Residue Levels on Grapes from 

Trials Conducted in the United States During 2000 (Final Report). Report Number 

RR 00-062B. Study Number FLUA-00MR-02. Unpublished study prepared by

Syngenta Crop Protection, Inc. 158 pages.

MRID No.: 47874603. Stewart, E. (2001) Fluazifop-P-Butyl - Residue Levels on Sugar Beets 

from Trials Conducted in the United States During 2000 (Final Report). Report 

Number RR 00-066B. Study Number FLUA-00-MR-06. Unpublished study

prepared by Syngenta Crop Protection, Inc. 177 pages.

MRID No.: 47920402 Sagan, K. (2009) Fluazifop EC (A12791B) – Residue Levels on 

Potatoes from Trials Conducted in Canada During 2008; Final Report. Laboratory

Project ID Report Number: CER02608/08. Task Number: TK0021556. 

Unpublished study prepared by ALS Laboratory Group Canada, Atlantic Agri 

Tech., Inc., ICMS, Inc., and Syngenta Crop Protection, Inc. 194 pages.

MRID No.: 47920403 Sagan, K. (2008) Fluazifop EC (A12791B) – Residue Levels on 

Potatoes from Trials Conducted in Canada During 2007; Final Report. Laboratory

Project ID Report Number: CER02606/07. Task Number: TK0021557. 

Unpublished study prepared by ALS Laboratory Group Canada, Atlantic Agri 

Tech., Inc., ICMS, Inc., and Syngenta Crop Protection, Inc. 118 pages.

DP No.: None

Subject: PP#0F3842/FAP#0H5596. Fluazifop-P-butyl on Citrus. Evaluation of Analytical 

Methods and Residue Data. MRID Nos. 41373701-06. DEB No. 6343. HED 

Project No. 0-0683.

From: M. J. Bradley

To: J. Miller

Dated: 08/15/1990

MRID Nos.: 41373701 - 41373706.
Fluazifop-P-Butyl Human Health Risk Assessment to Support New Uses DP No.: 385178

Page 57 of 78

DP No.: D361791

Subject: Chlorantraniliprole. Amended Section 3 Registration Request for Uses on Various 

Field, Vegetable, and Fruit Crops and Discussion of Future Registration and 

Tolerance Requests. Summary of Analytical Chemistry and Residue Data.

From: D. Rate

To: V. Eagle and K. Davis

Dated: 01/08/2010

MRID Nos.: 47588201-11 and 47588214-29

MRID No.: 47874605. Stewart, E. (2001) Fluazifop-P-Butyl - Residue Levels on Grape Juice 

and Raisins from a Trial Conducted in the United States in 2000 (Final Report). 

Report Number RR 00-067B. Study Number FLUA-00-PR-01. Unpublished study

prepared by Syngenta Crop Protection, Inc. 124 pages.

MRID No.: 47874606. Stewart, E. (2001) Fluazifop-P-Butyl - Residue Levels on Sugar beet

Sugar (Refined), Dry Pulp and Molasses from a Trial Conducted in the United 

States During 2000 (Final Report). Report Number RR 00-070B. Study Number 

FLUA-00-PR-04. Unpublished study prepared by Syngenta Crop Protection, Inc. 

134 pages.

MRID No.: 47920405 Sagan, K. (1994) Determination of Residues of Total-Fluazifop 

(Fluazifop-P-Butyl + Fluazifop-P) in Potatoes and their Processed Products Federal 

Republic of Germany 1993. Laboratory Project ID Report Number: ICI-9301. 

Study Number: Az. 13430/93. Task Number: TK0022593. Unpublished study

prepared by Dr. Specht & Partner Chemische Laboratorien GMBH, and Syngenta 

Crop Protection, Inc. 66 pages.

Fluazifop, a grass-selective herbicide which inhibits acetyl-CoA carboxylase in sensitive plant 

species. Walker KA, Ridley SM, Lewis T, Harwood JL., Biochem J. 1988 Aug 15;254(1):307-10.

Initial Ethics Review of a Human Study of Dermal Absorption and Pharmacokinetics of FluazifopButyl (MRID 46082918). Lowe MF, Carley JM, June 10, 2006

Ethics Review of Fluazifop-Butyl Absorption, Distribution, and Metabolism Study (MRID 

00131464). Sherman K, August 13, 2010

Fluazifop-P-Butyl. Rationale for Reducing the 10X Safety Factor to 1X for Lack of an 

Immunotoxicity Study. Addendum to Fluazifop-P-Butyl Risk Assessment for Dry Beans, Peanuts, 

and Soybeans [D347515, P. Savoia et al., 19-SEP-2008], J. Liccione, January 23, 2009 DP 

Barcode: 359779

Appendix A Toxicology Data Requirements and Profile

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.500) for food and non-food use for fluazifop-P-butyl are in Table 

A1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols 

were used.
Fluazifop-P-Butyl Human Health Risk Assessment to Support New Uses DP No.: 385178

Page 58 of 78

 Table A1: Toxicology Data Requirements 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 Sub-chronic (rodent).....................................

870.3150 Oral Sub-chronic (nonrodent)...............................

870.3200 21-Day Dermal .....................................................

870.3250 90-Day Dermal .....................................................

870.3465 90-Day/28-Day Inhalation....................................

yes

yes

yes

R

R

yes

yes

yes 

no

no

870.3700aDevelopmental Toxicity (rodent) .........................

870.3700bDevelopmental Toxicity (nonrodent) ...................

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

yes

yes

yes

yes

yes

yes 

870.4100aChronic Toxicity (rodent).....................................

870.4100bChronic Toxicity (nonrodent)...............................

870.4200aOncogenicity (rat).................................................

870.4200b Oncogenicity (mouse) 

.................................................. 

870.4200bOncogenicity (hamster) ........................................

870.4300 Chronic/Oncogenicity 

(rat)...........................................

yes

yes

yes

yes

no

yes

yes a

yes 

yes 

no b

yes 

yes

870.5100 Mutagenicity—Gene Mutation - bacterial............

870.5300 Mutagenicity—Gene Mutation - mammalian.......

870.5375 Mutagenicity—Structural Chromosomal 

Aberrations...........................................................

870.5395 Mutagenicity—Other Genotoxic Effects..............

yes

yes

yes

yes

yes

yes

yes

yes

870.6100aAcute Delayed Neurotox. (hen)............................

870.6100b90-Day Neurotoxicity (hen)..................................

870.6200aAcute Neurotox. Screening Battery (rat)..............

870.6200b90-Day Neuro. Screening Battery (rat).................

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

R

R

yes

yes

R

yes c

yes c

no

no

no

870.7485 General Metabolism .............................................

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

yes

no

yes

yes

870.7800 

Immunotoxicity.............................................................

 yes no

a Guideline 870.4300 satisfies this requirement. b

The study in the hamster satisfies this 

requirement. c Required for organophosphates only. 

d Reserved. R: Required
Fluazifop-P-Butyl Human Health Risk Assessment to Support New Uses DP No.: 385178

Page 59 of 78

A.2 Toxicity Profiles

Table A.2.1 Acute Studies with Fluazifop-P-butyl (PC 122809)

Guideline No./ Study Type MRID No. Results Toxicity 

Category

870.1100 Acute oral 

toxicity/rats

(PP005; 93.7% & 86.3% )

00162440

(1984)

LD50 = 3680 mg/kg for males 

rats

LD50 = 2451 mg/kg for female 

rats

III

III

870.1200 Acute dermal 

toxicity/rabbits 

(PP005; 93.7% & 86.3%)

00162440

(1984)

LD50 > 2000 mg/kg or >1.73 

mL/kg

III

870.1300 Acute inhalation 1

toxicity/rats 

(PP005; 24.6%) CTL/P/3331

41917904

(1991)

LC50 > 1.7 mg/L III

870.2400 Acute eye 

irritation/rabbit 

(PP005; 86.3%) CTL/P/856

00162441

(1983)

Mild irritation, cleared within 3 

days

IV

870.2500 Acute dermal 

irritation/rabbit 

(PP005; 86.3%) CTL/P/856

00162441

(1983)

Slight irritation, cleared within 

72 hours

IV

870.2600 Skin 

sensitization/GP (PP005; 

99.6%) 80/ILK026/349

00162441

(1983)

Not a skin sensitizer
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Table A.2.2 Subchronic, Chronic, Developmental, Reproductive and Other Toxicity Profile on 

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 were also seen. 

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. 

870.3150

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. 

870.3200

21/28-Day dermal 

toxicity (rabbit) 

with FB

00093819 (1980)

Acceptable/guideline

0, 100, 500, 2000 

mg/kg/day

NOAEL = 100 mg/kg/day

LOAEL = 500 mg/kg/day based on death in 1 male 

and at 2000 mg/kg/day, death 4 males and 5 females, 

possibly due to kidney failure.

870.3700a

Prenatal 

developmental in 

(Sprague Dawley 

rats) with FB

0008857, 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.

Malformations NOAEL = 50 mg/kg/day

LOAEL = 200 mg/kg/day based on diaphragmatic 

hernia.
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Table A.2.2 Subchronic, Chronic, Developmental, Reproductive and Other Toxicity Profile on 

Fluazifop- butyl [FB] and Fluazifop-P-butyl [FPB].

Guideline No./ 

Study Type

MRID No. (year)/ 

Classification /Doses

Results

870.3700a 

Developmental 

toxicity (Sprague 

Dawley rat) with 

FB

00088858, 92067048, 

92967020 (1981)

Acceptable/guideline

0, 1.0, 5.0, 10, 200 

mg/kg/day with FB

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.

Malformations NOAEL= 10 mg/kg/day

LOAEL=200 mg/kg/day based on increased incidence 

of diaphragmatic hernia. 

870.3700a 

Developmental 

toxicity (Wistar 

rats) with FPB 

46158401 (1991) 

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 arches and centrum in fetuses 

and litters and delayed ossification in the manus and 

pes.

870.3700a 

Developmental 

Toxicity (Wistar 

rats) with FPB

46082903 (1989)

Acceptable/guideline

0, 2, 5 or 100 

mg/kg/day 

Maternal NOAEL=100 mg/kg/day

LOAEL= None based no maternal toxicity.

Developmental NOAEL=2.0 mg/kg/day

LOAEL=5.0 mg/kg/day based on based on dose 

related delayed ossification in skull bones [occipital 

and parietal] in fetuses and litters.

870.3700a 

Developmental 

Toxicity (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 unossifided in fetuses and litters.

The overall conclusions based on a weight of evidence on the five studies of developmental toxicity in 

the rat were a NOAEL/LOAEL = 2.0/5.0 mg/kg/day based on fetal weight decrement and delayed 

ossification. 
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Table A.2.2 Subchronic, Chronic, Developmental, Reproductive and Other Toxicity Profile on 

Fluazifop- butyl [FB] and Fluazifop-P-butyl [FPB].

Guideline No./ 

Study Type

MRID No. (year)/ 

Classification /Doses

Results

870.3700b 

Developmental 

toxicity (NZW 

rabbit) with FB

00088856, 92067049, 

92067021 (1981)

Acceptable/guideline

0, 10, 30, 90 mg/kg/day 

Maternal NOAEL=30 mg/kg/day

LOAEL=90 mg/kg/day based on abortions.

Developmental NOAEL=30 mg/kg/day

LOAEL=90 mg/kg/day based on nominal increases in 

delayed ossification, total litter loss, abortions, small 

fetuses, cloudy eyes all above mean or range of 

historical controls

870.3700b 

Developmental 

toxicity (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 13th rib and delayed ossification in sternebrae 2.

870.3800

Reproduction and 

fertility effects

(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 0.74/0.88mg/kg/day

LOAEL = M/F 5.8/7.1 mg/kg/day based on decreased 

abs. & rel testes & epididymal weight and in females 

decreased pituitary & uterine weights. Sperm counts 

not available.

Conclusions on the 2-generation study on reproduction in the Sprague Dawley rat: The cause of the 

dose related testes wt decrease in the P0 and F1 generations has not been demonstrated, but no sperm 

counts, morphology, motility have been conducted to date. Extensive short term studies on testes 

weight, testes histopathology, and endocrine effects (MRID# 46082911, 46082916, 46082917, 

46082920 & 46082920, see table 4.1d) failed to find the reason for the testes weight decrement in the 

rat and hamster. However, since the most sensitive tests for effects on sperm were not conducted 

(sperm count, motility and morphology as indicated in the 1996 guidelines), it is concluded that testes 

weight decrement from possible decrements in sperm seen in the rat reproduction and the chronic study 

in hamsters have not been adequately eliminated. The histology on the testes does not support an 

effect, but histology is insufficiently sensitive to detect a slight effect. 

870.4100a

Chronic toxicity

(rats)

870.4300 satisfies the 

requirement
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Table A.2.2 Subchronic, Chronic, Developmental, Reproductive and Other Toxicity Profile on 

Fluazifop- butyl [FB] and Fluazifop-P-butyl [FPB].

Guideline No./ 

Study Type

MRID No. (year)/ 

Classification /Doses

Results

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

(hamster) with FPB

4534501, 46082905 

(2001)

Acceptable/guideline

0, 0, 200, 750, 3000 

ppm 

M: 0, 0, 12.5, 47.4, 

193.6 mg/kg/day F: 0, 

0, 12.1, 45.5, 181.4 

mg/kg/day

NOAEL =M/F 12.5/12.1 mg/kg/day

LOAEL = 47.5/45.5 mg/kg/day based on based on 

increased incidence of males with reduced sperm, 

testicular degeneration, eye cataract changes, liver 

inflamation and gall stones and in females, increased 

incidence of ovarian stroma cell/sex chord 

hyperplasia.

No evidence of carcinogenicity

870.4300

Chronic/Carcinoge

nicity

(rat) with FB

41563703 (1985)

Acceptable/guideline

0, 2, 10, 80, 250 ppm

M: 0, 0.10, 0.51, 4.15,

12.3 mg/kg/day

F: 0, 0.13, 0.65, 5.2, 

16.0 mg/kg/day 

NOAEL =M/F 0.51/5.2 mg/kg/day

LOAEL =M/F 4.15/16.0 mg/kg/day based on 

increased mortality & nephropathy exacerbated by 

respiratory stress, and in females possible increased 

basal and/or follicular/luteal cysts.

No evidence of carcinogenicity

870.6100a Acute 

neurotoxicity in 

hens with FB

00093818 (1981)

Acceptable/guideline

0, 3750, 7500 or 15000 

or 15000 mg/kg 

Fluazifop-butyl exposed hens showed no evidence of 

delayed neurotoxicity.

870.7485

Metabolism and 

pharmacokinetics

(rats) with FB

00093822 through 

00093828 (1981) 

Acceptable/guideline

1 mg/kg and 1000 

mg/kg 

Fluazifop-butyl is rapidly hydrolyzed to fluazifop acid 

by blood enzymes and excreted as the acid and its 

conjugates in the urine of males and females. Due to 

biliary excretion parent compound, fluazifop acid and 

its conjugates are excreted in the feces of males at 

much higher proportions than in feces of the female. 

Excretion was complete in 7 days, with the exception 

of small amounts in the fat in some rats. 

870.7600

Dermal penetration

(human)

46082918 A human study/NG satisfies guideline 870.7600.

Ethics of study cleared.
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Table A.2.2 Subchronic, Chronic, Developmental, Reproductive and Other Toxicity Profile on 

Fluazifop- butyl [FB] and Fluazifop-P-butyl [FPB].

Guideline No./ 

Study Type

MRID No. (year)/ 

Classification /Doses

Results

NG Comparative 

metabolism with 

FB and FPB in rats

00162445, 0012446 

(1983) Acceptable/NG 

1 mg/kg 

FB is hydrolyzed and the [S] enantiomer is converted 

to the [R] enantiomer. Whether fluazifop-butyl [RS] 

(50:50) or fluazifop-P-butyl [S] (90:10) is 

administered, within a hour the blood contained a 

mixture composed of fluazifop acid in a ratio of [R]

95% and [S] 3%. The two products behaved similarly 

and reached the same equilibrium within experimental 

error. 

NG Plasma level 

time course with 

FB and FPB in rats

46082910 (1998)

Acceptable/NG

200 mg/kg

The time course of plasma levels and elimination of 

the acid metabolite were similar for both fluazifopbutyl and fluazifop-P-butyl. Plasma levels of the acid 

from both isomers were much higher in males than in 

females. The data support previous studies. 

NG Absorption and 

excretion study in 

hamsters with FPB 

46082923 (2002)

Acceptable/NG

0, 200, 750, 3000 ppm

The study was conducted in two phases, Phase 1-

single dose followed by 3 days of unlabeled test 

material and Phase 2 - 24 hour feeding of labeled test 

material followed by 3 day of unlabeled test material. 

Data were consistent with excretion data from other 

species. The system appeared saturated, since the 

ratio of the 3000/200 ppm dose levels was much 

lower than the ratio of respective plasma levels, 

especially for males. 

NG Absorption, 

excretion and 

tissue retention in 

mice with FB 

46082925 (1992)

Acceptable/NG

1 and 150 mg/kg

Male mice excreted proportionally more in feces and 

less in urine than females. Although males excreted 

more than females in the feces and females excreted 

more than males in the urine, the difference between 

males and female mice was smaller than with male 

and female rats. The study showed individual 

variability in excretion, similar to that found in the 

rats and dogs, although analytical deviation may have 

explained part of the variation. 

NG Absorption and 

excretion in dogs 

with FB

0093829 (1981) 

Acceptable/NG

1 mg/kg

One dog showed delayed absorption. Excretion rate 

similar to females rats. No evidence of biliary 

excretion. 

NG Peroxisome

proliferation in 

mice, rats, 

hamsters and 

humans with FPB

46082919 (1988)

Acceptable/NG

0, 80, 250, 1000 or 

2000 ppm 

In vivo and in vitro peroxisome proliferation was 

studied in the mouse, rat and hamster and in vitro 

human hepatocytes. Proliferation in hepatocytes from 

the greatest to the smallest was: mice > rats > 

hamster >> human. No increase in cell replication 

was seen at any dose. 
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Table A.2.2 Subchronic, Chronic, Developmental, Reproductive and Other Toxicity Profile on 

Fluazifop- butyl [FB] and Fluazifop-P-butyl [FPB].

Guideline No./ 

Study Type

MRID No. (year)/ 

Classification /Doses

Results

NG 

Androgen/estrogen 

activity with FPB 

& acid; FB & acid 

metabolite

46082916 (2001)

Acceptable/NG

No agonist or antagonist activity was detected for 

FPB or FB or their acid metabolites. Using 

recombinant yeast strains expressing human androgen 

receptor or estrogen receptor, the intrinsic androgenic, 

anti-androgenic, estrogenic, anti-estrogenic activity of 

FPB, FB and their respective acid metabolites have 

been assessed by absorbance in a transcription assay. 

Positive antagonists were hydrotamoxifen and 

flutamide, which induced appropriate antagonic 

activity. Agonistic activity assessed by comparison to 

17β-estradiol and dihydrotestosterone; antagonic 

activity was assessed by inhibition of 17βestradiol and 

dihydrotestosterone activity. No agonist or antagonic 

activity was found within 7 orders of magnitude 

(oom) greater than the conc. of estradiol transcription, 

4 oom greater for inhibition of estradiol transcription 

and 6 oom for agonistic activity of 

dihydrotestosterone and up to 156 μM antagonist 

activity by a dose related decrease in 

dihydrotestosterone-mediated androgenic activity.

NG Dermal 

absorption in 

humans with FB

46082918

Acceptable/NG

2 mg & 200 mg/person

Dermal absorption was 8.6% at 2 mg/person and 

1.9% at 200 mg/person, Ethics of study cleared
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Table A2.3: Mutagenicity Data Summaries on Fluazifop-butyl (FB) and fluazifop-P-butyl (FPB) 

Adequacy of data base for Mutagenicity: No mutagenic potential was seen in adequately conducted 

pre-1991 guideline mutagenicity studies (in vivo and in vitro) on fluazifop-P-butyl [FPB] or fluazifopbutyl [FB]. A structural analogue {haloxyfop-methyl [methyl 2-[4-[[3-chloro-5-(trifluromethyl)-2-

pyridinyl] oxy]phenoxy]propinonate]} of fluazifop-P-butyl showed no mutagenic potential. 

1. Gene Mutation

Guideline 870.5100, 

Ames/Salmonella 

typhimurium, reverse 

mutation

MRID#00162443

Acceptable 

Test material [FB]

In a reverse gene mutation assay in bacteria (MRID#00162443, 

92067023), histidine deficient strains TA98, TA100, TA1535, 

TA1537, TA1538 of S. typhimurium were exposed to fluazifop-butyl 

(96.8% a.i., batch/lot# P25) 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. 

 

Guideline 870.5100, 

Ames/Salmonella 

typhimurium, reverse 

mutation

MRID#00162442

Acceptable 

Test material [FPB]

In a reverse gene mutation assay in bacteria (MRID#00162442, 

92067013), histidine deficient strains TA98, TA100, TA1535, 

TA1537, TA1538 of S. typhimurium were exposed to fluazifop-butyl 

(93.6% a.i., batch/lot# P8) 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 5000μg/plate). 

Guideline 870.5300, Mouse 

lymphoma cell test 

Acceptable 

Test material [FB]

In a mammalian cell gene mutation assay (MRID# 00116678), 

heterozygous TK+/- P 388 mouse lymphoma cells cultured in vitro

were exposed to fluazifop-butyl, (99.6% a.i., batch/lot # 

ADGM/1021/79) at concentrations of 0, 0.25, 2.5, 25, 250 or 2500 

μg/mL in the presence and absence of mammalian metabolic 

activation, S9, for 30 minutes. 

 Negative with and without S9 up to cytotoxic doses.

Guideline 870.5300, Mouse 

lymphoma L5178Y TK+ 

test

Acceptable

Test material [FPB]

In a mammalian cell gene mutation assay (MRID#46082906), mouse 

lymphoma L5178Y TK+ cells in vitro were exposed 4 hr to fluazifopP-butyl at 0, 100, 200, 500, 700, 1000 or 1500 μg/mL with and without 

S9 activation. In second assay the cells were exposed to 0, 100, 200, 

500, 700 or 1000 μg/mL with and without S9 activation. 

Test was negative with and without S9 activation up to and 

including excessive precipitation. 

2. Cytogenetics
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Table A2.3: Mutagenicity Data Summaries on Fluazifop-butyl (FB) and fluazifop-P-butyl (FPB) 

Guideline 870.5375; In vitro

chromosomal aberrations in 

human blood lymphocytes. 

(1985)

Acceptable

Test material: [FPB]

In independently performed mammalian cell cytogenetic assays 

(chromosome aberration) (MRID#41555202), lymphocyte cultures 

prepared from human peripheral blood were exposed to fluazifop-pbutyl (R-enantiomer, 93.8% a.i.; CTL reference # Y02746/001/008) in 

dimethyl sulfoxide for 4 hours at concentrations of 0, 1, 10, 100, 500, 

or 1000 μg/mL both in the presence and absence of S9-activation. 

Cells were harvested at 27 hours after initiation of treatment.

 The was no evidence of chromosome aberration induced over 

background in the presence or absence of S9-activation at toxic doses.

Guideline 870.5385, In vivo

rat mammalian cytogenetics; 

bone marrow chromosomal 

aberrations (1980)

Acceptable 

Test material: [FB]

In independent bone marrow chromosome aberration assays 

(MRID#00088861), 10 male CD rats/dose were treated via oral gavage 

(10 mL/kg) either once (acute) or daily for 5 consecutive days (subacute) with fluazifop-butyl (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. Bone marrow cells were harvested at 6 or 24 hours after 

treatment in the acute study, and at 6 hours after treatment in the subacute study. 

 There was no evidence of chromosome aberration induced over 

background at toxic doses.

Guideline 870.5450, Mouse 

Dominant lethal test (1980)

Unacceptable: Top dose not 

sufficiently toxic

Test material: [FB]

In a dominant lethal assay (MRID#00088862) [PP009, fluazifop-butyl 

(97.0% a.i., batch/lot # 310M)] was administered to 25 CD-1 male 

mice/group by corn oil gavage (10 mL /kg) at dose levels of 0, 28.7, 

91.8 or 287 mg/kg/day 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. The investigators reported that fluazifop-butyl 

does not cause dominant lethal effects in CD-1 mice up to and 

including 287 mg/kg/day for 5 days. No toxicity demonstrated.

3. Other Genotoxicity

Guideline 870.5395; In vivo

mouse micronucleus test 

(1983)

Acceptable 

Test material: [FB] and 

[FPB]

Acceptable

In an in vivo mammalian cell mouse micronucleus assay (MRID# 

0016244,92068014), C57BL/6J mice were administered FB or FPB at 

doses of 250 or 400 mg/kg and bone marrow removed after 24, 48 or 

72 hours to determine the frequency of MPCEP. FB and FPB were 

tested up to 80% and 50% of the LD50 in mice.

 There were 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.
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Page 68 of 78

A.3 Hazard Identification and Endpoint Selection

A.3.1 Acute Reference Dose (aRfD) - Females age 13-49

In a developmental toxicity study (MRID# 00088857), fluazifop-butyl was administered to 22 

female CD Sprague Dawley strain rats/group in a corn oil (2 ml/kg) gavage at dose levels of 0, 10, 

50 or 200 mg/kg bw/day from days 6 through 20 of gestation. Diaphragmatic hernia was seen in 1 

fetus at 10 mg/kg/day, none at 50 mg/kg/day and in 3 fetuses at 200 mg/kg/day. No diaphragmatic 

hernia was seen in 2970 historical control fetuses. In a subsequent study (discussed below) with a 

larger number of litters (160 litter/group) diaphragmatic hernias were seen in 3 of 1113 control 

fetuses, 1 of 1081 fetuses at 1 mg/kg/day, 3 of 1073 fetuses at 5 mg/kg/day, 2 of 1064 fetuses at 

10 mg/kg/day and in 59 of 1064 fetuses (and 45/159 litters)at 200 mg/kg/day. Since this anomaly

was seen at a higher incidence (3 fetuses) in the controls in this study and was not replicated at the 

same dose in the second study, the single incidence of diaphragmatic hernia at 10 mg/kg/day was 

considered to be an aberration and not attributable to treatment.

In an another developmental toxicity study (MRID# 00088858) fluazifop-butyl was administered 

to 159 or 160 female CD Sprague Dawley strain rats/group in a corn oil (2 ml/kg) gavage at dose 

levels of 0, 1.0, 5.0, 10 or 200 mg/kg bw/day from day 6 through 20 of gestation. There was an 

increased incidence of diaphragmatic hernia were seen in fetuses (5% versus 0.13% in control) and 

litters (43.4% versus 1.9%) at 200 mg/kg/day.

Dose and Endpoint for Establishing aRfD: NOAEL is 50 mg/kg/day based on the increased 

incidence of diaphragmatic hernia at 200 mg/kg/day. 

Uncertainty Factor (UF): 100. This includes 10X for inter-species extrapolation and 10X for intraspecies variation.

Comments about Study/Endpoint/Uncertainty Factor: The NOAEL selected is based on the 

combined results of the two studies. In the two studies conducted in the same strain of rats with an 

identical dosing regimen, diaphragmatic hernias were seen at 200 mg/kg/day in both studies; none 

were seen at 50 mg/kg/day in the second study (MRID# 00088858); and a single incidence was 

seen at 10 mg/kg/day in the first study (MRID# 00088857). The single incidence in the first study

was not considered to be treatment-related since the incidence was lower than that seen in the 

control fetuses in the second study and was not replicated at the same dose in the later study. 

Therefore, based on the combined doses tested, 0, 1, 5, 10, 50, or 200 mg/kg/day, for this effect, 

the NOAEL is 50 mg/kg/day and the LOAEL is 200 mg/kg/day. These values differ from the 

study NOAEL/LOAEL. This particular developmental effect is presumed to occur after a single 

exposure and thus is appropriate for this population subgroup (Females 13-49).

A.3.2 Acute Reference Dose (aRfD) - General Population

An appropriate endpoint attributable to a single dose was not available in the database including 

the developmental toxicity studies.

Acute RfD (Female 13- 49) = 50 mg/kg (NOAEL)/100 (UF) = 0.50 mg/kg
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Page 69 of 78

A.3.3 Chronic Reference Dose (cRfD) 

See Section 4.2.4 for a descriptive summary of the Two-Generation Reproduction Study in rats 

(MRID# 00008859, 92067022 & 92067050).

Dose and Endpoint for Establishing cRfD: NOAEL is 0.74 mg/kg/day based on decreases in 

absolute and relative testes and epididymal weights in males at 5.8 mg/kg/day (LOAEL). 

Uncertainty Factor(s): 100X (10X for inter species extrapolation and 10X for intra species 

variation.

Comments about Study/Endpoint/Uncertainty Factor: The study/dose/endpoint is appropriate for 

the route (oral) and duration (chronic) of concern. Although the endpoint of concern in based on 

male reproductive effects, decreases in pituitary and uterine weights were seen in females at a 

comparable NOAEL (0.88 mg/kg/day) and LOAEL (7.1 mg/kg/day). 

A.3.4 Incidental Oral Exposure (Short- and Intermediate-Term)

Short-Term Incidental Oral Exposure (1-30 days)

See Section 4.2.3 for a descriptive summary of the Developmental Toxicity Studies in rats 

(MRID# 46082913, 46158401, 46082903). A brief summary relevant to the endpoint selected is 

presented below.

In a developmental toxicity study (MRID# 46082913) fluazifop-P-butyl was administered to 

Aderly Park strain of Wistar rats by gavage at dose levels of 0, 2.0, 5.0 or 100 mg a.i./kgday from 

days 7 through 16 of gestation. No evidence of maternal toxicity was seen at any dose level. For 

maternal toxicity, the NOAEL is 100 mg/kg/day (HDT) and a LOAEL was not established.

In another developmental toxicity study (MRID# 46158401) fluazifop-P-butyl was administered to 

Alderly Park strain of Wistar rats by gavage at dose levels of 0, 0.5, 1.0, 20, or 300 mg/kg /day

from days 7 through 16 of gestation. Maternal toxicity at 300 mg/kg/day was indicated by a body 

weight gain decrement of 19% during the dosing period, GD 7-16. Food consumption was 

decreased statistically significantly at the same dose and food efficiency decreased 13%. For 

maternal toxicity, the NOAEL is 20 mg/kg/day and the LOAEL is 300 mg/kg/day based on 

decreases in body weight gain maternal animals.

In another developmental toxicity study (MRID# 46028903) fluazifop-P-butyl was administered to 

Alderly Park strain of Wistar rats by gavage at dose levels of 0, 2, 5 or 100 mg a.i./kgday from 

days 7 through 21 of gestation. No maternal toxicity was seen. For maternal toxicity, the NOAEL 

is 100 mg/kg/day (HDT) and a LOAEL is not established.

Chronic RfD = 0.74 mg/kg/day (NOAEL)/100 (UF) = 0.0074 mg/kg/day
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Dose and Endpoint for Risk Assessment: Maternal NOAEL of 100 mg/kg/day based on decreases 

in body weight gain in maternal animals during the dosing period (GD 7-16) at 300 mg/kg/day

(LOAEL).

Comments about Study/Endpoint: The maternal NOAEL is selected based on the combined results 

of the two studies with support from the third study. The first two studies were conducted in the 

same strain of rats (Wistar) with identical dosing regimen (dosing during GD 7-16) in the same 

laboratory. The lower NOAEL (20 mg/kg/day) in the second study (46158401) is an artifact of 

dose selection. Additionally, the NOAEL is supported by another study conducted in the same 

strain of rats with a slightly longer dosing period (GD 7-21) where no maternal toxicity was seen at 

100 mg/kg/day, the highest dose tested (MRID# 46082903). This dose/endpoint is appropriate for 

the population (infants and children) and duration (1-30 days) of concern.

Intermediate-Term Incidental Oral Exposure (1-6 months)

See Section 4.2.4 for a descriptive summary of the Two-Generation Reproduction Study in rats 

(MRID# 00008859, 92067022 & 92067050).

Dose and Endpoint for Establishing cRfD: NOAEL is 0.74 mg/kg/day based on decreases in 

absolute and relative testes and epididymal weights in males at 5.8 mg/kg/day (LOAEL). 

Comments about Study/Endpoint: The endpoint of concern was seen after approximately 13-16 

weeks of exposure and thus is appropriate for the duration (1-6 months) of concern. Although the 

endpoint of concern in based on male reproductive effects, decreases in pituitary and uterine 

weights were seen in females at a comparable NOAEL (0.88 mg/kg/day) and LOAEL (7.1 

mg/kg/day). This endpoint is appropriate for the population (infants and children) of concern.

A.3.5 Dermal Exposure (Short-, Intermediate- and Long-Term)

In a dermal absorption and pharmacokinetic study in humans (MRID# 46082918), six men (age 

18-45; weight 60-90 kg)/dose were dosed dermally with 2 mg or 200 mg of 0.05% or a 5.0% (w/v) 

solution of fluazifop-butyl in a formulation. Four ml of each solution was spread over 800 cm2of 

the backs of 6 men/dose level, allowed to dry and left un-occluded for 8 hours. Plasma and urine 

was collected in multiple samples over a 264 hour period. Plasma was collected hourly for 4 

hours, every 2 hours for 12 hours and every 24 hours to the end. Urines were collected every 4 

hours for 12 hours and then every 24 hours to the end. After 8 hours, the application site was 

washed with water using cotton swabs and 3% Teepol and covered with a T-shirt over the 

application site until morning. At 24 hours after application the site was again washed with a 3% 

solution of Teepol. The washes, T-shirts, plasma and urine samples were analyzed for fluazifopbutyl or fluazifop acid.
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Most of the applied dose appeared to be in the stratum corneum and easily removed. Recovery of 

test material was good, a mean of 93.4% ± a standard deviation of 13% at the 2 mg dose and mean 

of 83.2% ± a standard deviation of 21% at the 200 mg dose. Peak plasma levels were shown to 

occur 24 to 31 hours after application in these men. The one half-life for excretion was about 18 

hours. In arriving at these percentages of recovery, the study authors added a correction to the 

amount excreted in the urine (i.e. to the amount excreted up to 120 hours was added the amount 

excreted after 120 hours through a 2-compartment pharmacokinetic model). However, this latter 

correction was insignificantly small amounting about 0.008% of the 200 mg applied to the skin. 

HED modified the study author’s percentage absorption by scaling the recovered material to 

100%. The modified dermal absorption was calculated by two methods; (1) Unrecovered added to 

absorbed material, and (2) Scaling recovered material to100%. Method (1) yielded absorption 

factors of 18.4% and 14.6% at the 2 mg dose and 200 mg dose, respectively. Method (2) yielded 

absorption factors of 8.6% and 1.9% at the 2 mg dose and 200 mg dose, respectively. Method (2) 

appeared to be more reasonable because residual material (unrecovered) may have been relatively 

immobile. The unrecovered test material was speculated to be in the outer layers of the skin and 

appeared to be easily removed.

Short-Term Dermal Exposure (1-30 days)

See Sections 4.4.1 and 4.4.4 for a descriptive summary of the Developmental Toxicity Studies in 

rats (MRID# 00088858, 46082903, 46082913, 46158401). Though the Assessment team chose 

two short-term dermal endpoints, one for females of child-bearing age based on concerns for in 

utero effects, and another for all other population subgroups, for regulatory purposes, the dose and 

endpoint for the most sensitive population was used in the risk assessment for all population 

subgroups. Since females of child-bearing age cannot be excluded or treated separately from the 

general population should regulatory and/or mitigation measures be necessary, it is incumbent 

upon the Agency to address the potential risks of the most sensitive population as representative of 

the entire population.

The short-term dermal endpoint that the assessment team chose for the general population, 

including infants and children, was selected from 3 developmental toxicity studies in rats (MRID# 

46158401, 46082913 and 46082903). See a description under Section 4.4.4 Short-term Incidental 

Oral above. The dose/endpoint chosen is the maternal NOAEL of 100 mg/kg/day based on 

decreases in body weight gain in maternal animals during the dosing period (GD 7-16) at 300 

mg/kg/day (LOAEL). For the reasons stated above, the risk assessment was conducted using the 

short-term dermal endpoint selected for females 13-49 years of age.

Dose and Endpoint for Risk Assessment: Developmental NOAEL is 2.0 mg/kg/day based on fetal 

weight decrement, increased incidence of hydroureter and delayed ossification at 5.0 mg/kg/day

(LOAEL).

Comments about Study/Endpoint: The in utero effects are appropriate to assess dermal risks for 

the population subgroup, Females 13-49 from exposure to fluazifop-butyl. This endpoint was 

selected because of the developmental toxicity concerns seen consistently in rats and rabbits via 

the oral route. The team did not select the 21-day dermal toxicity study in rabbits due to the 

concern for developmental toxicity which is not evaluated in the dermal study. In addition, dermal 

study would not address the developmental concerns since the NOAEL (100 mg/kg/day) in that 
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study is considerably higher than the dermal equivalent dose (22 mg/kg/day) obtained using the 

oral dose (2.0 mg/kg/day) with a 9% dermal absorption factor (2.0  0.09 = 22). 

Since an oral NOAEL was selected, an appropriate dermal absorption factor (i.e., 2% or 9%, 

exposure depended) was used for route-to-route extrapolation. 

Intermediate and Long-Term Dermal Exposure (1-6 months & > 6 months)

See Section 4.2.4 for a descriptive summary of the Two-Generation Reproduction Study in rats 

(MRID# 00008859, 92067022 & 92067050).

Dose and Endpoint for Risk Assessment: NOAEL is 0.74 mg/kg/day based on decreases in 

absolute and relative testes and epididymal weights in males at 5.8 mg/kg/day (LOAEL). 

Comments about Study/Endpoint: The endpoint of concern was seen after approximately 13-16 

weeks of exposure and thus is appropriate for the duration (1-6 months) of concern. Although the 

endpoint of concern in based on male reproductive effects, decreases in pituitary and uterine 

weights were seen in females at a comparable NOAEL (0.88 mg/kg/day) and LOAEL (7.1 

mg/kg/day). These endpoints are appropriate for the general population including infants and 

children. Since an oral NOAEL was selected an appropriate dermal absorption factor (i.e., 2% or 

9%, exposure depended) was used for route-to-route extrapolation.

A.3.6 Inhalation Exposure (Short-, Intermediate- and Long-Term) 

Short-Term Inhalation Exposure (1-30 days)

See Sections 4.4.1 and 4.4.4 for a descriptive summary of the Developmental Toxicity Studies in 

rats (MRID# 00088858, 46082903, 46082913, 46158401). Again, though the Assessment team 

chose two short-term inhalation endpoints, one for females of child-bearing age based on concerns 

for in utero effects, and another for all other population subgroups, for regulatory purposes, the 

dose and endpoint for the most sensitive population was used in the risk assessment.

Dose and Endpoint for Risk Assessment: Developmental NOAEL is 2.0 mg/kg/day based on fetal 

weight decrement, increased incidence of hydroureter and delayed ossification at 5.0 mg/kg/day

(LOAEL)

Comments about Study/Endpoint: The in utero effects are appropriate to assess inhalation risks for 

the population subgroup, Females 13-49 years from exposure to fluazifop-P-butyl. This endpoint 

was selected because of the developmental toxicity concerns seen consistently in rats and rabbits 

via the oral route. The Assessment team noted the absence of a repeated exposure inhalation 

toxicity study. For route-to-route extrapolation, absorption via the inhalation route is assumed to 

be equivalent to oral absorption.

Intermediate- and Long-Term Inhalation Exposure (1-6 months & > 6 months)

See Section 4.2.4 for a descriptive summary of the Two-Generation Reproduction Study in rats 

(MRID# 00008859, 92067022 & 92067050).
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Dose and Endpoint for Risk Assessment: NOAEL is 0.74 mg/kg/day based on decreases in 

absolute and relative testes and epididymal weights in males at 5.8 mg/kg/day (LOAEL). 

Comments about Study/Endpoint: The endpoint of concern was seen after approximately 13-16 

weeks of exposure and thus is appropriate for the duration (1-6 months) of concern. Although the 

endpoint of concern is based on male reproductive effects, decreases in pituitary and uterine 

weights were seen in females at a comparable NOAEL (0.88 mg/kg/day) and LOAEL (7.1 

mg/kg/day). These endpoints are appropriate for the general population including infants and 

children. Again, the Assessment team noted the absence of a repeated exposure inhalation toxicity

study. For route-to-route extrapolation, absorption via the inhalation route is assumed to be 

equivalent to oral absorption.

A.4 Executive Summaries

A detailed summary of the various study executive summaries are listed in the document 

“Fluazifop-P-butyl: Revised HED Chapter of the Tolerance Reassessment Eligibility Document 

(TRED)” (August 29, 2005, PC Code: 122809, Case # 2285, DP Barcode: D316891).
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A.5 Toxicology Data Required as a Condition of Registration

Guideline Number: 870.3250

Study Title: 90-Day Dermal Toxicity 

Rationale for Requiring the Data

As well as food uses, fluazifop-P-butyl has non-food, commerical and residential uses, including 

roadsides, turf and shrub applications. The sub-chronic (90-day) dermal toxicity study is a new data 

requirement under 40 CFR Part 158 as a part of the data requirements for registration of a pesticide for 

non-food use.

The dermal toxicity Test Guidelines (OPPTS.870.3250) is intended to evaluate the toxic effects 

associated with continuous or repeated exposures to a test substance for a period of 90-days. 

The Agency requests a 90-day dermal toxicity study for non-food use pesticides because the dermal 

route will be the primary route of exposures for chemicals designated with this use pattern (i.e., nonfood). The Agency believes that this study is required because the longer term oral studies (i.e., chronic 

or carcinogenicity studies) which are required for food-use pesticides are usually not required for nonfood use pesticides. A 21/28 day dermal toxicity test is insufficient to identify potential hazards for 

non-food use pesticides because of the concern for the longer duration exposure associated with this 

use pattern. For example, professional applicators may be subjected to repeated exposure during the 3 

month period of peak summer usage. For this type of increased exposure, professional applicators may 

not be adequately protected using data from a 21/28-day study. Additionally, the 28-day dermal study 

revealed adverse responses such as an animal death at the study LOAEL, suggesting that further dermal 

testing is required to determine whether longer exposure may decrease the dermal LOAEL and 

NOAEL values. 

Practical Utility of the Data

How will the data be used? 

A route specific (i.e., dermal) study will provide critical scientific information needed to characterize 

potential hazard to the human population exposed to the pesticide by the dermal route. This study will 

provide a dose and a toxicological endpoint of concern for quantification of risks for dermal exposures. 

This study would eliminate the uncertainties associated with the use of an oral study with a default 

(100% oral equivalent) dermal absorption factor. 

In many cases, toxicity observed via the dermal route will be different than toxicity observed via oral 

exposure, due to absorption and distribution of the toxic agent after exposure or differences in 

metabolism (i.e., systemic versus local). This means that the route-to-route extrapolation (i.e., use of 

an oral dose/endpoint) in risk assessment could result in under or over estimation of risks from the 

dermal route. 

How could the data impact the Agency’s future decision-making?

If the dermal toxicity study indicates that the test material poses either a greater or lesser risk than that 

calculated using an oral dose, (as used in the interim decision), the risk assessment would be revised to 

reflect the magnitude of potential risk derived from the new data. Also, the requested data would allow 

the Agency to determine if the risks were over-estimated or under-estimated. If the risks were underestimated, additional risk mitigation measures could be required. If the risks were over-estimated, risk 

mitigation measures could be reduced.
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Guideline Number: 870.3465

Study Title: 90-Day/28-Day Inhalation Toxicity 

Rationale for Requiring the Data

Conducting the inhalation study for 90 days, is requested by the Agency because intermediate-term 

exposure to workers is expected based on fluazifop-P-butyl's use pattern. A longer-term inhalation study 

is required in situations in which a specific concern exists for increased hazard related to exposure via 

the inhalation route. The 28-day inhalation toxicity study evaluates the potential hazard of a pesticide 

chemical following repeated inhalation exposures. This study is important for pesticides such as 

fluazifop-P-butyl with use patterns in which there is potential for repeated human exposures (e.g., 

professional applicators, green house use, etc.) of periods of 28 days or more. The study design 

simulates one route of human exposure (inhalation) to a pesticide, the animals are exposed (nose/whole 

body) to aerosol concentrations of the test material for 6 hours/day, 5 days/week for 90/28 days. A 

detailed toxicological examination including the histopathology of the respiratory system is conducted. 

This route-specific study would provide data for hazard characterization, dose response assessment, and 

a dose and endpoint for assessing potential risks via the inhalation route. 

Practical Utility of the Data

How will the data be used? 

This study will identify hazard (i.e., provide a dose and endpoint) following repeated inhalation

exposures. The results will be used in risk assessments as appropriate.

How could the data impact the Agency’s decision-making? 

A sub-chronic inhalation study could provide scientific information to characterize potential hazard to 

the human respiratory system from pesticide exposure. In the case of fluazifop-P-butyl, there is no 

acceptable inhalation study available. A 90/28-day repeated exposure study that follows the Test 

Guidelines (870.3465) will characterize hazard and provide data for a more refined inhalation risk 

assessment. Exposure time may be reduced 28 days pending exposure patterns, plateauing of effects and 

considering the overall toxicity potential of fluazifop. 
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Guideline Number: 870.6200

Study Title: Neurotoxicity Battery (Acute and Sub-Chronic Studies)

Rationale for Requiring the Data

This is a new data requirement under 40 CFR Part 158 as a part of the data requirements for 

registration of a pesticide (food and non-food uses). 

The Neurotoxicity Screening Battery (OPPTS 870.6200) is designed to evaluate the potential adverse 

effects on the nervous system from exposure to pesticide chemicals. The Agency believes that the 

guideline studies are inadequate in their assessment of behavioral effects and do not use optimal 

methods to evaluate the potential toxicity to the nervous tissue structure and function. To detect and 

characterize these potential effects more fully, a battery of more sensitive testing is required. The 

objective of this neurotoxicity battery testing is to evaluate the incidence and severity of the functional 

and/or behavioral effects, the level of motor activity, and the histopathology of the nervous system. The 

acute neurotoxicity study is required to detect possible effects resulting from a single exposure. The 

sub-chronic neurotoxicity study is intended to detect possible effects resulting from repeated or longterm exposures.

Practical Utility of the Data

How will the data be used?

The acute and sub-chronic neurotoxicity studies could provide scientific information to characterize 

potential hazard to the human population on the nervous system from pesticide exposure. These studies 

can provide data on a wide range of functional tests for evaluating neurotoxicity including sensory 

effects, neuromuscular effects, learning and memory and histopathology of the nervous system For 

example, animal studies with organophosphorous chemicals have shown neurotoxicity to be the 

primary toxic endpoints (e.g., cholinesterase inhibition) of concern in rodents and non-rodents. These 

animal studies can be used to select endpoints and doses for use in risk assessment of all exposure 

scenarios and are considered a primary data source for reliable reference dose calculation. The Agency 

has established an oral reference dose (RfD) for assessing dietary risks for a number of chemicals (e.g., 

organophoshates and carbamates) where neurotoxicity was the most sensitive endpoint of concern.

How could the data impact the Agency's future decision-making?

If the acute or sub-chronic neurotoxicity studies show that fluazifop-P-butyl poses either a greater or a 

diminished risk than that given in the interim decision’s conclusion, the risk assessment for fluazifopP-butyl may need to be revised to reflect the magnitude of potential risk derived from the new data.

If the Agency does not have these data, a 10X database uncertainty factor may be applied when

conducting a risk assessment using the currently available studies.
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Guideline Number: 870.7800

Study Title: Immunotoxicity

Rationale for Requiring the Data

This is a new data requirement under 40 CFR Part 158 as a part of the data requirements for 

registration of a pesticide (food and non-food uses). 

The Immunotoxicity Test Guideline (OPPTS 870.7800) prescribes functional immunotoxicity

testing and is designed to evaluate the potential of a repeated chemical exposure to produce 

adverse effects (i.e. suppression) on the immune system. Immunosuppression is a deficit in the 

ability of the immune system to respond to a challenge of bacterial or viral infections such as 

tuberculosis (TB), Severe Acquired Respiratory Syndrome (SARS), or neoplasia. Because the 

immune system is highly complex, studies assessing functional immunotoxic endpoints are 

helpful in fully characterizing a pesticide’s potential immunotoxicity. These data will be used 

in combination with data from hematology, lymphoid organ weights, and histopathology in 

routine chronic or sub-chronic toxicity studies to characterize potential immunotoxic effects. 

Practical Utility of the Data

How will the data be used?

Immunotoxicity studies provide critical scientific information needed to characterize potential 

hazard to the human population on the immune system from pesticide exposure. Since 

epidemiologic data on the effects of chemical exposures on immune parameters are limited 

and are inadequate to characterize a pesticide’s potential immunotoxicity in humans, animal 

studies are used as the most sensitive endpoint for risk assessment. These animal studies can 

be used to select endpoints and doses for use in risk assessment of all exposure scenarios and 

are considered a primary data source for reliable reference dose calculation. For example, 

animal studies have demonstrated that immunotoxicity in rodents is one of the more sensitive 

manifestations of TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) among developmental, 

reproductive, and endocrinologic toxicities. Additionally, the EPA has established an oral 

reference dose (RfD) for tributyltin oxide (TBTO) based on observed immunotoxicity in 

animal studies (IRIS, 1997).

How could the data impact the Agency's future decision-making?

If the immunotoxicity study shows that the test material poses either a greater or a diminished 

risk than that given in the interim decision’s conclusion, the risk assessments for the test 

material may need to be revised to reflect the magnitude of potential risk derived from the new 

data.

If the Agency does not have this data, a 10X database uncertainty factor may be applied for 

conducting a risk assessment from the available studies.

Appendix B. Review of Human Research
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Past fluazifop-P-butyl risk assessments rely in part on data from studies in which adult human 

subjects were intentionally exposed to a pesticide to determine their dermal exposure and 

pharmacokinetics. Many such studies, involving exposure to many different pesticides, comprise 

generic pesticide exposure databases such as the Pesticide Handlers Exposure Database (PHED), 

the Agricultural Reentry Task Force (ARTF) Database, and the Outdoor Residential Exposure 

Task Force (ORETF) Database. EPA has reviewed all the studies supporting these multi-pesticide 

generic exposure databases, and has found no clear and convincing evidence that the conduct of 

any of them was either fundamentally unethical or significantly deficient relative to the ethical 

standards prevailing at the time the research was conducted. All applicable requirements of EPA’s 

Rule for the Protection of Human Subjects of Research (40 CFR Part 26) have been satisfied, and 

there is no regulatory barrier to continued reliance on these studies. The fluazifop-butyl human 

dermal study (MRID 46082918) utilized in this risk assessment was cleared for use 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.