Document ID: EPA-HQ-OPP-2007-0504-0011
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2010-09-15T04:00Z

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 

(Amore™ 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.

 

TABLE OF CONTENTS

  TOC \o "1-2" \u  I.  ACTION REQUESTED	  PAGEREF _Toc267296565 \h  1 

II.  EXECUTIVE SUMMARY	  PAGEREF _Toc267296566 \h  3 

III.  BACKGROUND	  PAGEREF _Toc267296567 \h  6 

IV.  USE PATTERN OF ISOXABEN	  PAGEREF _Toc267296568 \h  6 

V.  HAZARD CHARACTERIZATION	  PAGEREF _Toc267296569 \h  7 

VI.  RESIDENTIAL AND NON-OCCUPATIONAL EXPOSURES	  PAGEREF _Toc267296570
\h  9 

1. Residential Handler Exposure and Risk	  PAGEREF _Toc267296571 \h  10 

2. Residential Postapplication Exposures and Risks	  PAGEREF
_Toc267296572 \h  1 1

VII.  OCCUPATIONAL EXPOSURE	  PAGEREF _Toc267296573 \h  1 3

1. Exposure Scenarios, Inputs And Assumptions	  PAGEREF _Toc267296574 \h
 1 3

2.  Occupational Exposures and Risks	  PAGEREF _Toc267296575 \h  1 4

VIII.  OCCUPATIONAL POSTAPPLICATION EXPOSURE	  PAGEREF _Toc267296576 \h 
1 5

IX.  SPRAY DRIFT	  PAGEREF _Toc267296577 \h  16 

X.  REVIEW OF HUMAN RESEARCH	  PAGEREF _Toc267296578 \h  1 6

XI.  CONCLUSIONS	  PAGEREF _Toc267296579 \h  1 6

XII.  REFERENCES	  PAGEREF _Toc267296580 \h  17 

 

II.  EXECUTIVE SUMMARY 

e™ 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 Amore™ 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 low-pressure 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
intermediate-term 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 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.

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, 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 Amore™ 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.

III.  BACKGROUND

Amore™ 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 Amore™ 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 non-bearing 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
Amore™ 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%

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 

(Amore™ DF)  

Isoxaben = 75.0% plus                Penoxsulam = 3.12%  (DF
formulation) 	Non-bearing tree nuts and non-bearing 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 non-bearing trees are those that
will not bear fruit for at least one year after treatment. 

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 Amore™ 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 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 intermediate-term 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 (co-critical 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, Short- and 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.

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 (co-critical 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 treatment-related 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).

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 

 ≥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
Fertilizer-Contains 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 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.                 MOE 5

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 non-bearing 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.  

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-to-mouth 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. 

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 Amore™ 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:

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.

and Amore™ DF Herbicide in orchards of bearing and non-bearing fruit
and nut trees and grape vines.

Table 6.  Short- and Intermediate-term Exposures Resulting from the Use
of FN-3133 Specialty Herbicide and Amore™ 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 low-pressure
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 short-term durations. 
However, postapplication dermal risk for workers is not of concern
because of the absence of a short-term dermal endpoint. 

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ency 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 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 Amore™ DF
Herbicide) to bearing tree nuts and grapes and non-bearing fruit and nut
trees and grapes are below HED's LOC.

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.

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(sment for the Isoxaben Proposed 

New Use on Bearing Nut Trees and Vineyards.

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