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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460 

OFFICE OF CHEMICAL SAFETY AND

 POLLUTION PREVENTION

MEMORANDUM

DATE: July 26, 2010

SUBJECT: Isoxaben: Occupational and Residential Exposure Assessment for the First Food 

Use on Tree Nuts and Grapes and Non-bearing Fruit and Nut Trees and Vines. 

PC Code: 125851 DP Barcode Nos.

D374750 (62719-LIN)

D368834 (62719-ARE)

Decision Nos.:

379577 (62719-LIN)

417487 (62719-ARE)

Registration Nos.

EPA File Symbol: 62719-LIN

(FN-3133 Specialty Herbicide)

EPA File Symbol: 62719-ARE 

(AmoreTM DF Herbicide)

Petition No.: 7F7222 Reg. Action: Section 3

Assessment Type: Occupational 

and Residential

Case No.: 7219

TXR No.: NA CAS No.: 82558-50-7

MRID No.: NA 40 CFR §: 180.xxx (to be determined)

FROM: Suku Oonnithan, Biologist

Risk Assessment Branch II

Health Effects Division (7509P)

THROUGH: Richard A. Loranger, Ph.D., Senior Scientist 

Risk Assessment Branch II

Health Effects Division (7509P)

TO: Kathryn Montague 

Herbicide Branch 

Registration Division (7505P) 

I. ACTION REQUESTED

Perform an occupational and residential exposure (ORE) assessment for the first food use of 

isoxaben herbicide in bearing tree nuts and grapes and non-bearing fruit and nut trees and grape 

vines.
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TABLE OF CONTENTS

I. ACTION REQUESTED............................................................................................................. 1

II. EXECUTIVE SUMMARY....................................................................................................... 3

III. BACKGROUND ..................................................................................................................... 6

IV. USE PATTERN OF ISOXABEN ........................................................................................... 6

V. HAZARD CHARACTERIZATION......................................................................................... 7

VI. RESIDENTIAL AND NON-OCCUPATIONAL EXPOSURES............................................ 9

1. Residential Handler Exposure and Risk ............................................................................... 10

2. Residential Postapplication Exposures and Risks............................................................... 111

VII. OCCUPATIONAL EXPOSURE ....................................................................................... 133

1. Exposure Scenarios, Inputs And Assumptions................................................................... 133

2. Occupational Exposures and Risks.................................................................................... 144

VIII. OCCUPATIONAL POSTAPPLICATION EXPOSURE................................................. 155

IX. SPRAY DRIFT...................................................................................................................... 16

X. REVIEW OF HUMAN RESEARCH................................................................................... 166

XI. CONCLUSIONS ................................................................................................................. 166

XII. REFERENCES..................................................................................................................... 17
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II. EXECUTIVE SUMMARY 

INTRODUCTION: Dow AgroSciences has submitted applications to register two new end-use 

product (EP) formulations of isoxaben, FN-3133 Specialty Herbicide (EPA File Symbol: 62719-

LIN) for use on bearing and non-bearing nut trees and grapes and AmoreTM DF Herbicide (EPA 

File Symbol: 62719-ARE) for use on non-bearing tree nuts and grape vines. For isoxaben, this is 

the first food use registration. 

PROPOSED USE PATTERN: The FN-3133 Specialty Herbicide is being proposed for broadleaf 

weed control in bearing tree nuts and grapes and non-bearing fruit and nut trees and grapes. The 

AmoreTM DF Herbicide label is proposed for broadleaf weed control in non-bearing tree nuts and 

non-bearing vineyards. Both formulations have application rates of 0.5-1.0 lb ai/A using lowpressure ground equipment as 1-2 broadcast sprays per crop year in a minimum spray volume of 

10 gal/A. The maximum single and yearly application rates are 1.0 lb ai/A. The preharvest 

intervals (PHIs) are 60 and 165 days for tree nuts and grapes, respectively.

HAZARD CHARACTERIZATION: Technical isoxaben has low acute oral, dermal, and inhalation 

toxicities (Toxicity Categories III-IV). It is not a skin irritant (Category IV), but, causes minor 

irritation to the eye (Category III). Isoxaben is not a skin sensitizer.

No treatment related effects were reported in a 21-day repeated dose dermal toxicity study in the 

rabbit. This is consistent with the relatively low dermal absorption (≤11% of administered dose) 

observed in a dermal penetration study in the monkey, and the low toxicity observed in 

subchronic oral studies in the rat, mouse and dog. Due to the absence of relevant toxic effects, 

no appropriate endpoints were identified for short-term incidental oral and dermal risk 

assessments. An intermediate-term dermal endpoint also was not selected. For intermediateterm incidental oral and inhalation exposures, a no observed adverse effect level (NOAEL) of 

200 mg/kg/day was selected from a reproductive toxicity study in rat based on decreased body 

weight gain in F1 female animals at the lowest observed effect level (LOAEL) of 625 or 1000 

mg/kg/day (from co-critical studies). There was no evidence of neurotoxicity or 

immunotoxicity. There are low concerns for increased susceptibility of offspring and effects on 

offspring viability in the reproductive study, and there was no evidence of susceptibility in 

developmental toxicity studies in two species. Therefore, the 10x FQPA Safety Factor was 

reduced to 1x. The combined uncertainty factor (UF) of 100 is based on 10X factors for both 

interspecies extrapolation and intraspecies variability, serving as the basis for the level of 

concern (LOC), which is a margin of exposure (MOE) of 100 for residential and occupational 

risks. Isoxaben was classified as having “suggestive evidence of carcinogenic potential" based 

on increased hepatocellular adenoma incidence in male and female mice. Because there were no 

treatment-related increases in tumors in the rat and low concerns for genotoxicity, quantification 

of cancer risk using a cancer potency factor is not required.

RESIDENTIAL AND NON-OCCUPATIONAL EXPOSURES: No new residential uses for isoxaben were 

included with the proposed new product applications. However, several EPs have been 

registered for weed control on residential lawns and recreational turf areas. For assessing 

residential handler exposures, two representative products, an emulsifiable concentrate (EC) and

a granule, were selected based on maximum single application rates on residential lawns and turf 
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areas. Both the EC and granular products could be applied by homeowners twice a year with the 

maximum rate per application being 0.49 and 1.0 lb ai/A, respectively. The intervals between 

treatments are 56-60 days resulting in residential applicators being subjected to short-term 

exposures. The short-term dermal risks to homeowners were not estimated due to the lack of an 

endpoint. The short-term inhalation MOEs ranged from 2.9E+06 to 2.8E+07 with an LOC of 

100, indicating the risks are not of concern for residential handlers when using the EC and/or 

granule formulations of isoxaben on home lawns.

RESIDENTIAL POSTAPPLICATION EXPOSURES: There is a potential for postapplication dermal, 

inhalation and oral (children only) exposures of isoxaben to adults and children when they work 

and/or play on treated lawn areas. The short-term dermal and incidental oral (children) 

exposures were not estimated due to the lack of respective endpoints. The short-term inhalation 

exposure is expected to be negligible because of soil directed applications of EC and granules 

and because of the label recommendation for incorporation by irrigation or rain soon after 

application. 

However, there is a potential for intermediate-term oral exposure to children through soil 

ingestion due to the second application of isoxaben granules at 56 days after the first treatment,

and because of the potential for higher persistence of isoxaben in soil. Usually HED does not

assess such intermediate-term postapplication exposures under residential conditions, except on a 

case-by-case basis. Due to the persistence of isoxaben in the soil, HED decided to assess 

children's’ exposure from ingesting soil when turf is treated with isoxaben at the maximum 

yearly rate. The residential-use product selected for this assessment was Isoxaben 75 DF where

maximum single and yearly application rates are 1.0 and 3.0 lb ai/A. HED assumed that 

incidental ingestion of soil represents the worst case for oral postapplication exposure, since no

other oral scenarios would be expected to have an equivalent duration of exposure to residues as 

high as those possible in soil. The MOE associated with soil ingestion is 1,300,000 with an LOC 

of 100, and therefore is not of concern. This scenario is expected to be protective of all other 

postapplication risks for children in residential settings.

OCCUPATIONAL EXPOSURE: The proposed use of FN-3133 Specialty Herbicide and AmoreTM 

DF in orchards of bearing tree nuts, grapes and non-bearing fruit and nut trees is expected to 

result in short- and intermediate-term occupational exposures to mixers, loaders, and applicators. 

There are no chemical- specific data available for estimating occupational handler exposure. 

Therefore, Health Effects Division (HED) used surrogate unit exposures from the Pesticide 

Handlers Exposure Database (PHED) to estimate occupational exposures. Short-and 

intermediate-term dermal risks were not estimated due to the absence of respective endpoints. 

Short- and intermediate-term inhalation MOEs for applicators were ≥ 2,700 with an LOC of 100 

and are not of concern. 

OCCUPATIONAL POSTAPPLICATION EXPOSURE: Only one application of isoxaben is allowed 

per season at the maximum rate per application (two at lower rates) on tree nuts, grapes and 

non-bearing fruit and nut trees. Postapplication workers who enter treated fields after the 

restricted entry interval (REI) of 12 hours are subjected to only short-term dermal and inhalation 

exposures and such risks to workers are not of concern because of the soil-directed application 

method proposed for applying isoxaben formulations, thereby minimizing inhalation exposure, 
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and due to the lack of a dermal endpoint. The labels also recommend incorporation of the spray

by rainfall or irrigation for maximum efficacy as a preemergence herbicide, thereby further 

minimizing postapplication exposure.

CONCLUSIONS: The potential risks to occupational workers who apply FN-3133 Specialty

Herbicide and AmoreTM DF Herbicide formulations of isoxaben to bearing tree nuts and grapes 

and nonbearing fruit and nut tress and grape vines are below HED's level of concern. Potential 

risks to homeowners from applying isoxaben formulations registered for residential use on 

home lawns and to adults and children from postapplication exposures are also not of concern. 

Therefore, pending the results of an aggregate human health risk assessment, HED has no 

objection to registering the proposed new formulations of isoxaben for the proposed uses, which 

include the first food use for isoxaben.
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III. BACKGROUND

Dow AgroSciences has applied to register a new end-use product FN-3133 Specialty Herbicide 

(EPA File Symbol. 62719-LIN) containing isoxaben (75%) for use on bearing tree nuts and 

grapes and non-bearing fruit and nut trees and grape vines. For isoxaben, this is the first food 

use registration. Another new product, AmoreTM DF Herbicide (EPA File Symbol: 62719-ARE) 

containing isoxaben (75%) and penoxsulam (3.12%) is proposed for use on non-bearing tree nuts 

and non-bearing vines. This assessment addresses only isoxaben and its occupational and 

residential exposures. For penoxsulam, tolerances have been established (40 CFR §180.605) for 

residues in almond, grape, pistachio and rice and the occupational and residential exposures were 

reviewed in conjunction with the aggregate risk assessment for penoxsulam. 

Isoxaben is a benzamide herbicide with broad spectrum preemergence activity against broadleaf 

weeds. It is currently registered for use on ornamentals, home lawns, turf, and Christmas tree 

and conifer plantations. The registered formulations include dry flowable (DF), ready-to-use 

(RTU), emulsifiable concentrate (EC) and granule mixed with fertilizers. Both FN-3133 

Specialty Herbicide and AmoreTM DF are dry flowable formulations.

IV. USE PATTERN OF ISOXABEN

Both products are being registered for control of certain broadleaf weeds in bearing and/or nonbearing fruit and nut tree orchards and grapes. The proposed use pattern for isoxaben is provided 

in the following table (Table 1).

Table 1. Proposed Use Patterns of FN-3133 (File Symbol: 62719-LIN) and AmoreTM DF (File Symbol: 

62719-ARE) Formulations of Isoxaben. 

EPA File Symbol & 

Active Ingredients 

Use 

sites

Application 

equipment

Application 

rates

No. appls./ 

season & 

interval 1 Comments

62719-LIN 

(FN-3133)

Isoxaben 75%

(DF Formulation)

Bearing tree nuts, 

grapes and nonbearing fruit and 

nut trees and nonbearing grape vines

Low pressure 

ground sprayers, 

spray volume 

≥ 10 gal/A

Single = 0.66-1.33 

lb product/A 

Max. single rate = 

1.0 lb ai/A)

Max. seasonal rate 

= 1.0 lb ai/A

1-2 per 

crop year, 

(harvest to 

harvest)

PHI = 60 days 

for tree nuts 

and 165 days 

for grapes

62719-ARE 

(AmoreTM DF)

Isoxaben = 75.0% plus 

Penoxsulam = 3.12% 

(DF formulation) 

Non-bearing tree 

nuts and nonbearing grape vines

Single = 1.0-1.33 

lbs product/A 

Max. single rate 

=1.0 lb ai/A)

Max. seasonal rate 

= 1.0 lb ai/A

1 per 

season

NA 

Abbreviations used: DF = dry flowable, NA = not applicable and PHI = preharvest interval. 

1. No spray interval was given in the submitted draft label. 

The FN-3133 Specialty Herbicide is proposed for preemergence control of broadleaf weeds in 

tree nuts, grapes, and non-bearing fruit and nut trees and non-bearing grape vines. The nonbearing trees are those that will not bear fruit for at least one year after treatment. 
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Labels of both products recommend use of ground application equipment including ground boom 

and low pressure handwand to spray the base of trees and vines to avoid crop injury. Activation 

of the applied spray by rain or irrigation for optimum weed control is recommended. Tank 

mixes with both formulations are allowed; however, chemigation or application by any type of 

irrigation system is prohibited. 

The submitted draft labels of both products have CAUTION as Signal Word. The personal 

protective equipment (PPE) statement on FN-3133 Specialty Herbicide includes long sleeved 

shirt, long pants, shoes plus socks and chemical resistant gloves; for AmoreTM DF, the PPE 

statement includes only long sleeved shirt, long pants and shoes plus socks. Both product labels 

have 12 hour restricted entry intervals (REIs) per the worker protection standard (WPS). 

V. HAZARD CHARACTERIZATION

Technical isoxaben has low to moderate acute toxicities by oral, dermal, and inhalation routes 

(Toxicity Categories III-IV). It is not a skin irritant (Category IV) or a dermal sensitizer and 

causes only minor transient irritation to the eye (Category III). The acute toxicity profile of 

isoxaben is summarized in Table 2.

Table 2. Acute Toxicity Profile – Isoxaben

Guideline No. Study Type Results Toxicity Category

870.1100 Acute oral – rat LD50 > 10,000 mg/kg (both sexes) IV

870.1200 Acute dermal - rabbit LD50 > 2000 mg/kg (both sexes) III

870.1300 Acute inhalation - rat LC50 > 1.99 mg/L (both sexes) III

870.2400 Acute eye irritation - rabbit Irritation to the cornea and iris 

cleared within 24 hrs

III

870.2500 Acute dermal irritation - rabbit Non-irritating IV

870.2600 Skin sensitization - guinea pig Not a sensitizer (Buehler method) N/A

The primary target organs for the toxicity of isoxaben are the liver and kidney. No treatment 

related effects were reported in a 21-day repeated dose dermal toxicity study in the rabbit. This 

is consistent with relatively low dermal absorption (≤11% of administered dose) observed in a 

dermal penetration study in the monkey and the low toxicity observed in sub-chronic oral studies 

in the rat, mouse and dog. No appropriate points of departure (PODs) or endpoints were selected 

for short-term incidental oral and short-and intermediate-term dermal exposure routes due to the 

absence of adverse effects. For the intermediate-term incidental oral and short- and 

intermediate-term inhalation exposures, a NOAEL of 200 mg/kg/day was selected from the rat 

reproductive toxicity study based on decreased body weight gain in F1 females observed at the 

LOAEL of 625 or 1000 mg/kg/day (co-critical studies). There was no evidence of neurotoxicity

or immunotoxicity. There are low concerns for increased quantitative susceptibility of offspring 

and effects on offspring viability in the reproductive toxicity study, and there was no evidence of 

susceptibility in developmental toxicity studies in two species. Therefore, the 10x FQPA Safety

Factor was reduced to 1x. A combined UF of 100 is based on 10X factors for both interspecies 
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extrapolation and intraspecies variability, serving as the basis for the level of concern (LOC), 

which is a margin of exposure (MOE) of 100 for residential and occupational risks. HED notes 

that a 60 kg body weight was assumed for residential and occupational handlers in order to be 

protective of the offspring effects seen in the reproduction toxicity study.

Isoxaben was classified as having “suggestive evidence of carcinogenic potential" based on 

increased hepatocellular adenoma incidence in male and female mice. Because there were no 

treatment-related increases in tumors in the rat and low concerns for genotoxicity, quantification 

of cancer risk with a cancer potency factor is not required.

Based on the available toxicity data and HED’s current practices, the short- and intermediateterm inhalation risks for isoxaben were assessed using an oral toxicity study. However, HED is 

in the process of re-examining policies and procedures for conducting inhalation risk 

assessments, including route to route extrapolation of toxicity data. If any new policies or 

procedures are developed, HED may revisit the need for an inhalation toxicity study for 

isoxaben. Endpoints and doses selected for the occupational and residential risk assessment of 

isoxaben are summarized in Table 3. A detailed discussion of isoxaben's hazard assessment is 

available in the latest risk assessment (D. McNeilly, D376428, 2010). 

Table 3. Toxicological Doses and Endpoints of Isoxaben Selected for Occupational and Residential Risk 

Assessments. 

Exposure 

Scenario 1

Point of 

Departure

Uncertainty 

& FQPA 

Safety Factors

Level of 

Concern Study and Toxicological Effects

Acute dietary, 

General 

population, 

including children

An appropriate endpoint to assess exposure for this route and duration was not identified.

Incidental oral,

Short-term

An appropriate endpoint to assess exposure for this route and duration was not identified.

Incidental oral, 

Interm.-term 

NOAEL=200

mg/kg/day 

UFA =10x 

UFH =10x 

FQPA SF = 1x 

Residential 

LOC for 

MOE = 100

Reproductive toxicity in the rat (oral).

Offspring LOAEL = 1,000 mg/kg/day, 

based on decreased body weight gain in 

F1 females on Day 70.

One year dietary study in the rat (cocritical supporting study).

LOAEL = 625 mg/kg/day based on 

decreased body weight gain in females 

during the first six months with a 

NOAEL of 62.5 mg/kg/day.

Dermal, Shortand Interm.-term

An appropriate endpoint to assess exposure for this route and duration was not identified.

Inhalation, 

Short-term 

NOAEL=200

mg/kg/day 

Inhalation 

absorption 

rate = 100% 

UFA =10x 

UFH =10x 

FQPA SF = 1x 

Residential/

Occupational 

LOC for 

MOE = 100

Reproductive toxicity in the rat (oral).

Offspring LOAEL = 1,000 mg/kg/day, 

based on decreased F2 pup weights, 

gestation survival and live pups/litter and 

increased incidence of malformations.
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Table 3. Toxicological Doses and Endpoints of Isoxaben Selected for Occupational and Residential Risk 

Assessments. 

Exposure 

Scenario 1

Point of 

Departure

Uncertainty 

& FQPA 

Safety Factors

Level of 

Concern Study and Toxicological Effects

Inhalation, 

Interm.-term

NOAEL=200

mg/kg/day 

Inhalation 

absorption 

rate = 100% 

UFA =10x 

UFH =10x 

FQPA SF = 1x 

Residential 

LOC for 

MOE = 100

Occupational 

LOC for 

MOE = 100

Reproductive toxicity in the rat (oral).

Offspring LOAEL = 1,000 mg/kg/day, 

based on decreased F2 pup weights, 

gestation survival and live pups/litter and 

increased incidence of malformations.

One year dietary study in the rat (cocritical supporting study).

LOAEL = 625 mg/kg/day based on 

decreased body weight gain in females 

during the first six months with a 

NOAEL of 62.5 mg/kg/day.

Cancer (oral, 

dermal, 

inhalation)

Classified as having “suggestive evidence of carcinogenic potential” based on increased 

incidence of hepatocellular adenomas in male and female mice. A quantitative cancer risk 

assessment with a cancer potency factor is not required because there were no treatmentrelated increases in tumors in the rat and low concerns for genotoxicity.

Abbreviations used: FQPA SF = Food Quality Protection Act Safety Factor, LOAEL = lowest observed adverse 

effect level, NOAEL = no observed adverse effect level, LOC = level of concern, MOE = margin of exposure, UFA

= extrapolation from animal to human, and UFH = potential variation in sensitivity among human population. 

1. Short-term is 1-30 days and intermediate-term is 1-6 months duration. 

VI. RESIDENTIAL AND NON-OCCUPATIONAL EXPOSURES

There are several registered liquid and solid end-use product formulations available for weed 

control on home lawns, recreational turf areas and ornamental plantings. Some products are 

labeled for use by homeowners and others are for use by professional applicators. No new 

residential uses for isoxaben are being requested with this application. 

Even though isoxaben is already registered for weed control in residential areas, quantitative 

homeowner (handler) and postapplication exposure assessments were not previously conducted

due to the lack of short-term incidental oral, dermal and inhalation endpoints needed to estimate 

these risks. Based on the current hazard characterization and in order to complete an aggregate 

risk assessment in conjunction with the proposed first food use of isoxaben, residential exposures 

were estimated, taking into consideration all end-use products registered for residential uses. 

For assessing residential handler exposure, two representative product formulations having the 

highest single application rates were selected. They are an EC (Lawn 3iP Herbicide Concentrate, 

Reg. No. 72155-87) and a granule (T&O Fertilizer-Contains Gallery plus Team, EPA Reg. No. 

62719-280). The liquid and granule have maximum single application rates of 0.49 and 1.0 lb 

ai/A, respectively. The granule product is packaged and marketed individually as homeowner

and commercial products and both labels have almost identical use patterns (Table 4).
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Table 4. Use Pattern of Isoxaben End-use Products Selected for Residential Handler and Postapplication 

Exposure Assessments.

EPA 

Reg. No.1

Application 

Equipment Appl. rates

No. appls./ 

season & 

interval 2 Comments

Lawn 3iP 

Herbicide 

Conc., Reg. 

No. 72155-87

(EC, Isoxaben 

= 2.63%)

Homeowner/Commercial Label

After mixing with water

- pump style hand held sprayer

- concentrate plus water hose-end

sprayer

Without mixing with water

- dial-style hose-end sprayer

- single-rate or dual- rate hose-end 

sprayer

Rate/appl.= 1.6-3.2 

fl. oz. /500 sq. ft 

Max/appl.= 0.49 lb 

ai/A

Max/year = 0.98 lb 

ai/A

2/year 

60 days

NA

T&O Fertilizer,

EPA Reg. No. 

62719-280

(Granule) 

Isoxaben = 

0.38%) 

Homeowner/Commercial Label

- drop or rotary-type granule spreader 

Rate/appl.= 174-265

lbs/A

Max/appl.= 1.0 lb 

ai/A 

Max/year = 2.0 lb 

ai/A 

2-7/year

56 days 

Sprinkler 

irrigation or 

rainfall within a 

few hours is 

recommended 

Isoxaben 75DF 

Specialty

Herbicide

EPA Reg. No. 

34704-917, DF

Isoxaben=75%

Commercial Label 

- herbicide sprayer 

- spray volume ≥10 gal/A 

Rate/appl.= 0.66-

1.33 lbs/A 

Max/appl.= 1.0 lb 

ai/A

Max/year = 4 lbs/A 

(3.0 lb ai/A)

3 or more

60 days 

Sprinkler 

irrigation or 

rainfall after 

application is 

recommended

Abbreviations used: DF = dry flowable, EC = emulsifiable concentrate, NA = not applicable

1. Lawn 3iP Herbicide Concentrate/Ready-to-Spray (Reg. No. 72155-87) is an EC containing isoxaben (2.63%), 

2,4-D dimethylamine salt (4.73%), dicamba (0.52%) and mecoprop-p potassium salt (1.1%). T&O FertilizerContains Gallery plus Team (EPA Reg. No. 62719-280) is a granule + fertilizer containing isoxaben (0.38%), 

trifluralin (0.39%) and benefin (0.76%). 

2. Repeat applications may represent rates that are lower than the maximum single rate/A. 

1. Residential Handler Exposure and Risk

The use patterns used for a quantitative assessment of homeowner exposures are from EC and 

granule products (Table 4).

Potential Exposure Scenarios: The following scenarios were assessed:

1. mixing/loading/applying EC using a hose-end sprayer

2. mixing/loading/applying EC using a hand-held pump sprayer

3. loading/applying granules using a granular push-type spreader

Application Rate and Exposure Durations: For residential handler exposure assessment, HED 

uses maximum single application rates and frequency of treatments for determining short- and

intermediate-term exposures. The EC product label recommends two applications per year for

weed control on home lawns at a single maximum rate of 0.49 lb ai/A. The minimum interval 

between treatments is 60 days. Therefore, homeowners are exposed to only short-term dermal 

and inhalation risks. The granule product label recommends repeat applications at an interval of 

56 days on cool season grass and 70 days on warm season grass at a single maximum single rate 
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of 0.99 lb ai/A, resulting in short-term exposures. There are some distributor products sold in 

Florida (both homeowner and commercial labels) that recommend up to 7 applications per year 

on Bermuda grass with a maximum rate of 2 lb ai/A/year. These repeated applications are 

assumed to be made at an average rate of 0.3 lb ai/A/application taking into account an annual 

limit of 2.0 lb ai/A. Despite the potential for repeated applications, HED continues to consider 

residential handler exposures to be short-term in duration based on the minimum 56 day

retreatment interval.

Exposure and Risk to Residential Handlers: No chemical specific exposure data have been 

submitted by the registrant to estimate the inhalation unit exposures for residential handlers. 

Therefore, surrogate unit exposures from the Outdoor Residential Exposure Task Force database 

(ORETF) were selected. Short-term dermal risks were not estimated due to the lack of a dermal 

endpoint. The short-term inhalation MOEs ranged from 2.9E+06 to 2.8E+07 (LOC=100) and 

are not of concern (Table 5).

Table 5. Exposures and Risks for Residential Handlers Applying Liquid and Granule Formulations of 

Isoxaben on Residential Lawns. 1

Exposure 

Scenarios

Max. Single 

Appl. rate, 

lb ai/Acre 2

Area 

treated 

Acres/day 3

Inhal. UE 

mg/lb ai 

(ORETF)

Inhal. dose 

mg/kg/day 4

Short-term Inhal. 

MOE5

M/L/A, liquid,

hose-end sprayer 0.49 0.5 0.017 6.94E-05 2.9E+06

M/L/A, liquid,

hand-held sprayer 0.49 0.5 0.0038 1.55E-05 1.3E+07

L/A, granules,

push-type spreader 0.99 0.5 0.00088 7.2E-06 2.8E+07

Abbreviations used: A= applicator, L= loader, ORETF = Outdoor Residential Exposure Task Force, and UE= unit 

exposure. 

1. Short-term dermal exposures were not estimated due to the absence of a dermal endpoint. 

2. The maximum single application rate is from Table 5.

3. The area treated is assumed to be 0.5 A for hose-end and hand-held sprayers (based on a standard rate of 10 gal 

of spray/A) and 0.5 acres for granules. 

4. Inhalation dose (mg/kg/day) = (application rate * area treated/day * inhalation unit exposure * inhalation 

absorption rate) / body wt. (60 kg).

5. Inhalation MOE = Short-term Inhalation NOAEL (200 mg/kg/day) / inhalation dose.

2. Residential Postapplication Exposures and Risks

For evaluating the residential postapplication exposure of isoxaben, EC, granule and solid 

formulations were considered (Table 4). Since the Isoxaben 75 DF Specialty Herbicide, EPA 

Reg. No. 34704-917, had the highest application rate/year, it was assumed that the estimated 

risks would be protective of those associated with other formulations and application rates. This

solid formulation is labeled for use by professional applicators on established turf, landscape, 

container and field grown ornamentals, non-cropland, non-bearing fruit and nut trees and nonbearing vineyards. It has a maximum single application rate of 1.0 lb ai/A (similar to EC and 

granule), with a yearly rate of 3.0 lb ai/A. 
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Dermal Exposures to Children, Youth and Adults: Dermal endpoints were not selected for 

isoxaben, for any duration of exposure, due to the lack of toxic effects via the dermal route; 

therefore, there is no risk of concern associated with dermal postapplication exposure.

Short-Term Incidental Oral Exposures to Children from Hand-to-Mouth and Object-to-Mouth 

Events: It is likely that children playing in treated turf areas would ingest residues of isoxaben 

from hand-to-mouth and objects-to-mouth events. However, there is no endpoint applicable to 

short-term oral exposure, and therefore, there are no risks of concern associated with hand-tomouth and object-to-mouth exposure.

Episodic Oral Exposures to Children from Ingestion of Granules: Ingestion of isoxaben granules 

following application of T&O Fertilizer-Contains Gallery plus Team to turf is considered to be 

an episodic event for children playing on treated lawns. The granules are not likely to be present 

on treated turf for up to 30 days (i.e., short-term durations) due to the label recommendation for 

irrigation/watering within hours of application. Further, in the absence of an acute dietary

endpoint attributable to a single exposure, episodic ingestion of granules was not assessed. 

Bystander Inhalation Exposure: Based on the Agency's current practices, residential 

postapplication inhalation risk to children is not assessed; however, bystander exposure could 

occur for children playing in areas adjacent to pesticide applications. For adult bystanders, 

postapplication inhalation exposure is expected to be negligible because (i) technical isoxaben 

has low inhalation toxicity (Category III); (ii) label recommended incorporation by rainfall or 

irrigation after application; (iii) isoxaben has low volatility (vapor pressure 1.3E-8 Pa at 25 ̊ C, 

McNeilly 2010); and (iv) products are not applied using airblast or aerial equipment that would 

result in significant inhalation exposure. However, volatilization of pesticides may be a potential 

source of postapplication inhalation exposure to individuals nearby to pesticide applications. 

The Agency sought expert advice and input on issues related to volatilization of pesticides from 

its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in 

December 2009. The Agency received the SAP’s final report on March 2, 2010 

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

process of evaluating the SAP report and may, as appropriate, develop policies and procedures to 

identify the need for and, subsequently, the way to incorporate postapplication inhalation 

exposure into the Agency's risk assessments. If new policies or procedures are put into place, the 

Agency may revisit the need for a quantitative postapplication inhalation exposure assessment 

for isoxaben.

Intermediate-term Incidental Oral Exposure to Children resulting from Soil Ingestion: HED 

does not typically consider soil ingestion to occur over intermediate-term durations, i.e., from 1-

6 months, largely due to use pattern and the fact that residues are removed by precipitation or 

through microbial degradation in soil. In the case of isoxaben, HED estimated incidental oral 

exposure from ingestion of soil because the use pattern calls for repeat applications, and because 

the environmental fate data indicated that isoxaben is persistent in the soil, with a half life of 

≥150 days (C. Peck., D341497, 3/18/2010). Because of the likely persistence of isoxaben in 

soil, HED conducted a conservative assessment of potential intermediate-term oral risk from soil 

ingestion by using an yearly application rate of 3.0 lb ai/A from Isoxaben 75 DF instead of the 

maximum single rate of 1.0 lb ai/A. 
Page 13 of 17

To address the persistence of isoxaben in the soil, HED assumed that exposure resulting from 

incidental oral ingestion of soil (intermediate-term) at an exaggerated rate of 3.0 lb ai/A/year

would be a conservative estimate that would address the likely potential build up of isoxaben in 

the soil. The exposure and risk from incidental oral ingestion of soil was calculated using the 

following formula:

ADD = (SR * IgR2 * CF4) / BW where, SR = AR * F3 * CF1 * CF2 * CF3

MOE = NOAEL / ADD

SR = 3.0 lb ai/A * 100%/cm * 4.54E+08 μg/lb * 2.47E-08 A/cm2 * 0.67 cm3 /g soil = 22.54 μg ai/g

ADD = [22.54 μg ai/g * 100 mg/day * 0.000001 g/μg] / 15 kg = 1.50E-04 mg/kg/day

MOE = 200 mg/kg/day / 1.50E-04 mg kg/day = 1.30E+06

where, 

ADD = Average daily dose (mg/kg/day)

AR = Application rate (3.0 lb ai/A/year) 

BW = Body weight of child (15 kg)

CF1 = Conversion factor for μ/lb (4.54E+08)

CF2 = Conversion factor for A/cm2 (2.47E-08)

CF3 = conversion factor for volume to weight (0.67 cm3/g soil) 

CF4 = conversion factor for g/μg (0.000001)

F3 = Percent of ai available in uppermost cm of soil (100% assumed)

IgR2 = Ingestion rate of soil (100 mg/day)

MOE = NOAEL (intermediate-term, mg/kg/day) / ADD (mg/kg/day)

NOAEL (intermediate.-term) = 200 mg/kg/day

SR = Soil residue at intermediate-term (μg ai/g soil) 

t = postapplication day on which exposure is assessed (intermediate-term) 

It is emphasized here that the application rate of 3.0 lb ai/A/year used for estimating the 

intermediate-term exposure is an exaggerated rate when compared with the single application 

rate of 1.0 lb ai/A of granule and DF formulations. At the intermediate-term exposure duration, 

the risk was found to be not of concern to children who may ingest soil treated with isoxaben 

(MOE = 1.30E+06, LOC =100).

VII. OCCUPATIONAL EXPOSURE

1. Exposure Scenarios, Inputs and Assumptions

Both isoxaben products (FN-3133 Specialty Herbicide and AmoreTM DF) are DF formulations 

and have identical application rates and methods. Therefore, both products have similar exposure 

scenarios as shown below:

1. mixing and loading of DF formulation for ground boom spray

2. applying the diluted spray using tractor mounted ground boom spray equipment 

3. mixing, loading and applying DF formulation using a tractor mounted low-pressure handwand

sprayer to treat areas not covered by boom sprayer.

The inputs and assumptions used for estimating the exposures to handlers are the following:
Page 14 of 17

1. Application rate: The maximum single application rate for isoxaben is 1.0 lb ai/A for bearing 

or non-bearing trees and grape vines.

2. Unit exposures: No chemical specific exposure data are available to estimate inhalation unit 

exposures for handlers. Therefore, surrogate unit exposures were selected from PHED, based on 

the formulation type, application equipment and PPE. In PHED, there are no inhalation unit 

exposures for a M/L/A scenario for a solid DF formulation using a low-pressure handwand 

sprayer. Therefore, unit exposures for the wettable powder (WP) formulation were used. Since 

the WP is dustier than the DF, the resulting exposure estimates are expected to be conservative 

for assessing exposure from the DF formulation.

3. Area treated/8-hr day: ExpoSAC Policy No. 9 estimates that 40-200 acres can be treated/day

with a tractor mounted ground boom sprayer depending upon the crop treated. For this

assessment, 80 A/day was selected for the orchard setting based on treatment of orchard trees 

planted in rows. Areas not covered with a ground-boom sprayer (corners and edges of orchards)

or spot treatments may be made using a tractor mounted low-pressure handwand sprayer. It is 

assumed that a handler (M/L/A) can mix, load and apply 40 gal/day (ExpoSAC Policy No. 9); at 

the label recommended spray volume of 10 gal/A, HED estimates 4 acres/day could be treated 

for the tractor mounted low-pressure handwand scenario. 

4. Personal Protective Equipment (PPE): Baseline PPE (long sleeved shirt, long pants and shoes 

with socks) was used as a starting point to calculate handler exposures. For the present 

assessment additional protection (e.g., respirators; engineering controls (enclosed cab and 

cockpit, closed systems)) was not needed to obtain an MOE that is higher than the LOC.

5. Duration of exposure: The label allows only 1 application of FN-3133 at the maximum single 

rate of 1.0 lb ai/A (harvest to harvest) on tree nuts, grape, and non-bearing fruit tree and 

grapevine orchards, resulting in short-term exposure to occupational handlers. However, it is 

possible that contract applicators may use FN-3133 Herbicide on several fields, with sequential 

applications lasting longer than a month during the weed growing season, resulting in 

intermediate-term exposure to handlers.

6. Body weight of handlers and postapplication workers: A bodyweight of 60 kg was used for 

handlers because the toxicity endpoints selected for assessing inhalation risks are based on 

offspring effects in the reproductive toxicity study.

2. Occupational Exposures and Risks

Table 6 summarizes the exposures and risks associated with the use of FN-3133 Specialty

Herbicide and AmoreTM DF Herbicide in orchards of bearing and non-bearing fruit and nut trees 

and grape vines.
Page 15 of 17

Table 6. Short- and Intermediate-term Exposures Resulting from the Use of FN-3133 Specialty Herbicide and 

AmoreTM DF Herbicide in Orchards of Bearing and Non-bearing Fruit and Nut Trees and Grape Vines 1.

Exposure Scenario Appl. rate

Area 

treated

(A/day)

PPE & 

Eng.

Control 2

Inhal. unit 

exposure 

(mg/lb ai) 3

Inhalation, Short– and 

Intermediate-term 

Exposure 

mg/kg/day 4 MOE 5

1. Mixing/loading DF 

for ground boom 

spray (open mixing)

1.0 lb al/A

80 Baseline 0.00077 0.00103 190,000

2. Applying spray 

using ground boom

Baseline & 

open cab. 0.00074 0.00099 200,000

3. Mixing, loading, 

and applying using a 

tractor powered lowpressure hand wand

4

Baseline 1.1 0.07333 2,700

1. MOE = Margin of exposure and PPE = Personal protective equipment. The inputs used for calculations are

explained under Exposure Scenarios, Inputs and Assumptions.

2. Baseline PPE includes long sleeved shirt, long pants and shoes with socks. Engineering controls include open cab

(tractor) for applicators. 

3. Lacking unit exposures in PHED for a DF formulation, unit exposures for mixing, loading and applying a 

wettable powder formulation with a low-pressure handwand were used as surrogate.

4. Inhalation exposure = [Inhalation unit exposure (mg/lb ai) * appl. rate (lb ai/A) * area treated/day (acres) * 

inhalation absorption 100 %] / body wt (60 kg).

5. MOE = Short- and intermediate-term NOAEL (200 mg/kg/day) /inhalation exposure (mg/kg/day)

Dermal exposure was not assessed due to the lack of dermal endpoints. The short- and 

intermediate-term inhalation MOEs for handlers ranged from 2,700 to 200,000 which are not of 

concern.

VIII. OCCUPATIONAL POSTAPPLICATION EXPOSURE

Workers entering treated areas to do crop related cultural practices such as irrigation, scouting, 

pruning, etc., may be exposed to isoxaben residues via dermal and inhalation routes for shortterm durations. However, postapplication dermal risk for workers is not of concern because of 

the absence of a short-term dermal endpoint. 

Based on the Agency's current practices, a quantitative occupational postapplication inhalation 

exposure assessment was not performed for isoxaben at this time. However, there are multiple 

potential sources of postapplication inhalation exposure to individuals performing 

postapplication activities in previously treated fields. These potential sources include 

volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides. 

The Agency sought expert advice and input on issues related to volatilization of pesticides from 

its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in 

December 2009. The Agency received the SAP’s final report on March 2, 2010 

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

process of evaluating the SAP report as well as available postapplication inhalation exposure 

data generated by the Agricultural Reentry Task Force and may, as appropriate, develop policies 

and procedures, to identify the need for and, subsequently, the way to incorporate occupational 

postapplication inhalation exposure into the Agency's risk assessments. If new policies or 
Page 16 of 17

procedures are put into place, the Agency may revisit the need for a quantitative occupational 

postapplication inhalation exposure assessment for isoxaben.

Restricted Entry Interval (REI): A 12-hour REI was set for isoxaben based on the acute 

toxicity properties of the technical material which is classified as Categories III (acute dermal,

inhalation and eye irritation) and IV (acute oral and skin irritation). Isoxaben is not a dermal 

sensitizer. The 12-hour REI is appropriate for isoxaben based on the WPS for agricultural 

pesticides.

IX. SPRAY DRIFT 

Spray drift is always a potential source of exposure to residents near to pesticide spraying 

operations. This is particularly the case with aerial applications, but, to a lesser extent, could 

also be a potential source of exposure from the ground application methods employed for 

isoxaben. The Agency has been working with the Spray Drift Task Force, EPA Regional Offices 

and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift 

management practices. On a chemical by chemical basis, the Agency is now requiring for aerial 

applications, interim mitigation measures that must be placed on product labels. The Agency has 

completed its evaluation of the new database submitted by the Spray Drift Task Force, a 

membership of U.S. pesticide registrants, and is developing a policy on how to appropriately 

apply the data and the AgDrift computer model to its risk assessments for pesticides applied by

air, orchard air blast and ground hydraulic methods. After the policy is in place, the Agency may

impose further refinements in spray drift management practices to reduce off-target drift with 

specific products with significant risks associated with drift.

X. REVIEW OF HUMAN RESEARCH

This risk assessment relies in part on data from studies in which adult human subjects were 

intentionally exposed to determine their dermal and inhalation exposures. Many such studies, 

involving exposure to many different pesticides, comprise generic pesticide exposure databases, 

such as Pesticide Handlers Exposure Database (PHED), the Outdoor Residential Exposure Task

Force (ORETF) database and the Agricultural Reentry Task Force (ARTF) database. EPA has 

reviewed all the studies in these multi-pesticide generic exposure databases, and on the basis of 

available evidence has found them to have been neither fundamentally unethical nor significantly

deficient relative to standards of ethical research conduct prevailing when they were conducted. 

There is no regulatory barrier to continued reliance on these studies, and all applicable 

requirements of EPA's Rule for the Protection of Human Subjects for Research (40 CFR part 26) 

have been satisfied. 

XI. CONCLUSIONS

1. The potential risks to occupational handlers who apply DF formulations of isoxaben

(FN-3133 Specialty Herbicide and AmoreTM DF Herbicide) to bearing tree nuts and 

grapes and non-bearing fruit and nut trees and grapes are below HED's LOC.
Page 17 of 17

2. The registrant did not propose new residential uses for isoxaben with these submissions. 

However, there are existing uses for isoxaben in residential settings resulting in exposure 

to homeowners. Residential handler exposure was estimated for a granule formulation of 

isoxaben applied at 1.0 lb ai/A or an EC formulation applied at 0.5 lb ai/A on residential

turf grasses. Both these scenarios resulted in risks for residential handlers which are not 

of concern. 

3. The short-term postapplication risks to adults and children from dermal and incidental

oral exposures of isoxaben were not assessed due to the lack of respective endpoints. 

There is a potential for intermediate-term oral postapplication exposure to children 

through ingestion of soil while playing on treated lawns. HED conservatively estimated

the risk from soil ingestion due to the potential for isoxaben to persist in soil following 

application to turf. A conservative estimate of children’s exposure and risk from soil 

ingestion demonstrated that the risk is not of concern, with an MOE of 1.30E+06.

4. Pending the results of an aggregate human health risk assessment, HED has no objection 

to registering the proposed new uses, including the first food use for isoxaben. The 

submitted worker protection statements on both draft labels are adequate to protect 

occupational handlers and postapplication workers. 

XII. REFERENCES

McNeilly, D. D376428, 2010. Isoxaben. Human Health Risk Assessment for the First Food 

Uses of the Herbicide on Grapes, Tree Nuts and Pistachios.

Peck, C. D341497, 3/18/2010). Tier I Drinking Water Assessment for the Isoxaben Proposed 

New Use on Bearing Nut Trees and Vineyards.