  

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

  OFFICE OF CHEMICAL SAFETY AND

                                                                        
                      POLLUTION PREVENTION

DATE:		June 7, 2010	

MEMORANDUM

	SUBJECT:	Indaziflam:  Occupational and Residential Exposure Assessment
for the First Food Use of the Herbicide on Citrus Fruit, Stone Fruit,
Pome Fruit, Grapes, Tree Nuts, Pistachios and Olives.

PC Code: 080818	DP Number: D376907

Decision No.:  416570	Registration Nos.: 264-xxxx (Indaziflam 200 SC
Herbicide and Indaziflam 500 SC Herbicide)

Petition Nos: 9F7589, 9E7588	Regulatory Action:  Section 3 Registration

Assessment Type: Occupational/Residential	Case No.: NA

TXR No.:  NA	CAS Number:   950782-86-2

MRID:  NA	40 CFR: NA

			

				

FROM:		Margarita Collantes, Biologist

		Risk Assessment Branch (RAB) II

		Health Effects Division (7509P)

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

		Risk Assessment Branch (RAB) II 

		Health Effects Division (7509P)

TO:		Erik Kraft/James Tompkins, RM Team 25 

		Herbicide Branch

		Registration Division (7505P)

ACTION REQUESTED:

The Registration Division (RD) requested that the Health Effects
Division (HED) conduct an exposure and risk assessment for proposed uses
of the active ingredient indaziflam to control annual grasses and
broadleaf weeds in citrus fruit, stone fruit, pome fruit, grapes, tree
nuts, pistachios and olives.  Occupational handler and postapplication
exposure assessments were conducted for the proposed indaziflam uses. 
Residential use patterns are not expected for the proposed uses but have
been assessed in a previous memorandum.  

TABLE OF CONTENTS

  TOC \o "1-3" \h \z \u    HYPERLINK \l "_Toc260396302"  1.0	EXECUTIVE
SUMMARY	  PAGEREF _Toc260396302 \h  3  

  HYPERLINK \l "_Toc260396303"  2.0.	HAZARD CHARACTERIZATION	  PAGEREF
_Toc260396303 \h  4  

  HYPERLINK \l "_Toc260396304"  2.1	Hazard Profile	  PAGEREF
_Toc260396304 \h  4  

  HYPERLINK \l "_Toc260396305"  2.2	FQPA and Uncertainty Factor
Considerations	  PAGEREF _Toc260396305 \h  5  

  HYPERLINK \l "_Toc260396306"  3.0	PROPOSED USE PATTERNS	  PAGEREF
_Toc260396306 \h  7  

  HYPERLINK \l "_Toc260396307"  4.0	RESIDENTIAL (NON-OCCUPATIONAL)
EXPOSURE	  PAGEREF _Toc260396307 \h  7  

  HYPERLINK \l "_Toc260396308"  5.0	 OCCUPATIONAL EXPOSURE	  PAGEREF
_Toc260396308 \h  9  

  HYPERLINK \l "_Toc260396309"  5.1	Occupational Handlers	10 

  HYPERLINK \l "_Toc260396318"  5.2	Occupational Postapplication
Exposure	  PAGEREF _Toc260396318 \h  13  

  HYPERLINK \l "_Toc260396319"  5.2.1	Postapplication Inhalation
Exposure	  PAGEREF _Toc260396319 \h  13  

  HYPERLINK \l "_Toc260396320"  5.2.2	Postapplication Dermal Exposure	 
PAGEREF _Toc260396320 \h  14  

 

1.0	EXECUTIVE SUMMARY TC \1 " 1.0	Executive Summary  

Indaziflam
([1,3,5-triazine-2,4-diamine,N-[(1R,2S)-2,3-dihydro-2,6-dimethyl-1H-inde
n-1-yl]-6-(1-fluoroethyl)]) is a selective, pre-emergent and
post-emergent alkylazine herbicide that controls weeds by inhibiting
cellulose biosynthesis in plants. The proposed end-use products
evaluated in this assessment include Indaziflam 200 SC Herbicide and
Indaziflam 500 SC Herbicide, both formulated as suspension concentrates
containing 19.05% and 45.05% indaziflam as the active ingredient,
respectively. These products are used as a pre-emergent herbicide for
weed control in citrus fruit that have been established for at least one
year after transplanting, and in stone fruit, pome fruit, grapes, tree
nuts, pistachios and olives that have been established for at least
three years after transplanting.  Proposed uses are anticipated to
result in short- and intermediate-term durations of exposure.

Proposed Use Profile

For all crops, indaziflam may be applied to the soil as a uniform
broadcast or band application using ground application equipment only
(i.e., groundboom and handgun).  Chemigation and aerial applications are
prohibited. The maximum single application rate is 0.085 lb ai/A and the
maximum annual application rate is 0.13 lb ai/A.  The minimum
retreatment interval is 30 days (except 90 days in Florida and Georgia).
 The pre-harvest interval is 7 days for citrus and 14 days for the other
crops.   

Hazard Characterization

Indaziflam shows low acute toxicity by all routes of exposure (Toxicity
Category III, oral and dermal and Category IV, inhalation) and is not an
ocular or dermal irritant or a dermal sensitizer.  

The point of departure (PoD) selected for regulation of oral, dermal and
inhalation risk at all durations is the no observed adverse effect level
(NOAEL) of 7.5 mg/kg/day, based on brain, spinal cord and sciatic nerve
degenerative lesions observed at the lowest observed adverse effect
level (LOAEL) of 15 mg/kg/day from a subchronic oral (gavage) dog study.
 Since the dermal PoD was selected from an oral study a 7.3% dermal
absorption factor was used to estimate dermal exposure.  Since the
dermal and inhalation PoDs were the same, margins of exposure (MOEs)
were combined to provide a total margin of exposure for handler exposure
scenarios.

Indaziflam is classified as “Not likely to be carcinogenic to
humans.”

FQPA and Uncertainty Factors

HED recommends reduction of the FQPA safety factor to 1X.  HED has
retained the traditional uncertainty factors of 10X for inter-species
extrapolation and 10X for intra-species variability.  Therefore, HED’s
level of concern (LOC) for residential and occupational handler and
postapplication risk is equal to a Margin of Exposure (MOE) of 100. 
Scenarios resulting in MOEs greater than or equal to 100 do not exceed
HED’s level of concern.

Residential Exposure:

A residential assessment for use of indaziflam on turf was previously
conducted and resulted in no risks of concern.  No new residential uses
are being requested at this time.  The previous residential assessment
resulted in handler and postapplication MOEs ranging from 2,800 to
2,100,000.

Occupational Handler Exposure:

No chemical specific data were available to assess potential exposure to
pesticide handlers.  The estimates of exposure to pesticide handlers are
based upon surrogate study data available in the PHED (v. 1.1, 1998) and
from the Outdoor Residential Exposure Task Force (ORETF: MRID 44972201).
  Short- and intermediate-term exposure and risks resulted in total MOEs
ranging from 360 to 43,000 and; therefore, do not exceed HED’s level
of concern.   

Occupational Postapplication Exposure

Based on the Agency's current practices, a quantitative postapplication
inhalation exposure assessment was not performed for the proposed uses
of indaziflam, primarily because it has a very low vapor pressure, it is
applied at relatively low application rates (maximum rate is 0.085 lbs
ai/A), and it is not projected to be applied via typically high
inhalation exposure application equipment (e.g., airblast or aerial
equipment). The proposed uses for indaziflam are ground-directed uses
where no crop foliage is treated.  Currently, HED has no data to assess
postapplication dermal exposures to treated soil by occupational
workers.  In general, such exposures are considered to be negligible.
Therefore, for the proposed soil-directed uses, postapplication
exposures and risks to occupational workers were not quantitatively
assessed, but are not considered to be of concern.  

Restricted Entry Interval

The restricted entry interval (REI) is based on the acute toxicity of
indaziflam technical material.  Active ingredients classified as
category III or IV for acute dermal toxicity, eye irritation potential,
and skin irritation potential are assigned a default REI of 12 hours
under the Worker Protection Standard for Agricultural Pesticides.  Based
on the acute toxicity profile of indaziflam, the 12-hour REI which
appears on the proposed labels is adequate.

Review of Human Research

This risk assessment relies in part on data from studies in which adult
human subjects were intentionally exposed to a pesticide or other
chemical.  These studies, which comprise the Pesticide Handlers Exposure
Database (PHED), and the Outdoor Residential Exposure Task Force (ORETF)
Database, have been determined to require a review of their ethical
conduct, have received that review, and have been determined to be
ethically conducted.

2.0.	HAZARD CHARACTERIZATION TC \2 " 2.0	HAZARD CHARACTERIZATION  

2.1	Hazard Profile TC \2 " 2.1	Hazard Profile  

Indaziflam shows low acute toxicity by all routes of exposure (Toxicity
Category III, oral and dermal and Category IV, inhalation) and is not an
ocular or dermal irritant or a dermal sensitizer.  The database for
acute toxicity for indaziflam is complete and is summarized below in
Table 2.1a.   

The short- and intermediate-term incidental dermal and inhalation no
observed adverse effect level (NOAEL) of 7.5 mg/kg/day is based on
brain, spinal cord and sciatic nerve degenerative lesions observed at
the LOAEL of 15 mg/kg/day from a subchronic oral (gavage) dog study. 
Since the dermal PoD was selected from an oral study, a 7.3% dermal
absorption factor was used to estimate human dermal absorption.  Since
no inhalation absorption data are available, toxicity by the inhalation
route is considered to be equivalent to the estimated toxicity by the
oral route of exposure (i.e., 100% inhalation absorption is assumed). 
The dermal and inhalation PoDs were the same; therefore, margins of
exposure (MOEs) were combined to provide a total margin of exposure for
handler exposure scenarios.

The selected PoD (neurotoxicity) is the most sensitive NOAEL available
from a study of appropriate exposure duration (90-days) for short- and
intermediate-term exposure.  The subchronic oral dog study was selected
over other studies because the dog was the most sensitive species for
neurotoxicity and the subchronic study had the overall lowest NOAEL. 
Although a 28-day dermal toxicity study in the rat showed no effects at
the limit dose (including neuropathology), it was not selected as a PoD
for the dermal exposure scenario due to the significantly greater
sensitivity for neurotoxicity seen in the dog relative to the rat. 
Neurotoxic effects in the dog were identified at doses that were 10-20
times lower than in the rat.  The PoD is nonetheless considered
conservative because the effects in the dog were observed following
gavage dosing, in contrast to a relatively slower dermal absorption rate
expected for occupational  exposure.  

Indaziflam is classified as “Not likely to be carcinogenic to
humans.”  

A summary of the toxicological doses and PoDs for occupational exposure
scenarios is provided in Table 2.1b.  

2.2	FQPA and Uncertainty Factor Considerations

HED recommends reduction of the FQPA safety factor to 1X.  The toxicity
database for indaziflam is complete, including the required studies that
characterize potential susceptibility of infants and children. There was
no evidence of increased quantitative or qualitative pre- and/or
postnatal susceptibility; developmental effects in the rat were observed
only at high doses in the presence of maternal/parental toxicity. 
Although indaziflam causes neurotoxicity, the effects are well
characterized and served as the basis for endpoint selection. 
Therefore, the risk assessment is protective of potential neurotoxicity
and other effects which occurred at higher doses.  

HED has retained the traditional uncertainty factors of 10X for
inter-species extrapolation and 10X for intra-species variability. 
Therefore, HED’s level of concern (LOC) for residential and
occupational handler and postapplication exposure is an MOE of 100. 
Therefore, scenarios resulting in MOEs greater than or equal to 100 do
not exceed HED’s level of concern.

Table 2.1a	Acute Toxicity Profile - Indaziflam

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

870.1100	Acute oral - rat	47443281	LD50 > 2000 mg/kg (both sexes)	III

870.1200	Acute dermal - rabbit	47443282	LD50 > 2000 mg/kg (both sexes)
III

870.1300	Acute inhalation - rat	47443283	LC50 > 2.3 mg/L (both sexes)	IV

870.2400	Acute eye irritation - rabbit	47443284	Non-irritant	IV

870.2500	Acute dermal irritation - rabbit	47443285	Non-irritant	IV

870.2600	Skin sensitization - guinea pig	47443286	Not a sensitizer
(Buehler method)	N/A



Table 2.1b Summary of Toxicological Doses and Points of Departure for
Indaziflam for Use in Occupational and Residential Risk Assessments

Exposure/

Scenario	Point of Departure (PoD)	Uncertainty Factors	Level of Concern
for Risk Assessment	Study and Toxicological Effects

Incidental Oral Short-Term (1 to 30 days) and Intermediate-Term (1 to 6
months)	NOAEL = 7.5 mg/kg/day	UFA=10X

UFH=10X

FQPA SF = 1X (residential)	Occupational & Residential LOC = MOE = 100
Subchronic oral (gavage) in the dog

LOAEL = 15 mg/kg/day, based on axonal degenerative microscopic findings
in the brain, spinal cord and sciatic nerve.

Dermal Short-Term (1 to 30 days) and Intermediate-term (1 to 6 months)
NOAEL = 7.5 mg/kg/day

DAF = 7.3%	UFA=10X

UFH=10X FQPA SF = 1X (residential)	Occupational & Residential LOC MOE =
100	Subchronic oral (gavage) in the dog

LOAEL = 15 mg/kg/day, based on axonal degenerative microscopic findings
in the brain, spinal cord and sciatic nerve.

Dermal, Long-Term (>6 months)	Not required for this assessment (exposure
is seasonal; long-term occupational exposure scenarios are not
anticipated).

Inhalation Short-Term (1 to 30 days) and Intermediate-Term (1 to 6
months)	NOAEL= 7.5 mg/kg/day.  Inhalation absorption assumed to be 100%
(default) relative to oral.	UFA=10X

UFH=10X

FQPA SF = 1X (residential)	Occupational & Residential LOC = MOE = 100
Subchronic oral (gavage) in the dog

LOAEL = 15 mg/kg/day, based on axonal degenerative microscopic findings
in the brain, spinal cord and sciatic nerve.

Inhalation Long-Term (> 6 months)	Not required for this assessment
(exposure is seasonal; long-term occupational exposure scenarios are not
anticipated).

Cancer (oral, dermal, inhalation)	Classification:  “Not likely to be
Carcinogenic to Humans” 

Point of Departure (PoD) = A data point or an estimated point that is
derived from observed dose-response data and used to mark the beginning
of extrapolation to determine risk associated with lower environmentally
relevant human exposures.  NOAEL = no observed adverse effect level. 
LOAEL = lowest observed adverse effect level.  UF = uncertainty factor. 
UFA = extrapolation from animal to human (interspecies).  UFH =
potential variation in sensitivity among members of the human population
(intraspecies).  MOE = margin of exposure.  LOC = level of concern.  N/A
= not applicable.

3.0	PROPOSED USE PATTERNS

Table 3 provides a summary of the proposed uses of indaziflam.  The
proposed product label involved in this assessment directs handlers to
wear long sleeved shirt and long pants, shoes plus socks, and chemical
resistant gloves. 

Table 3: Proposed Uses of Indaziflam

Product	Use Site	Target of Application	Treatment Type	Application Method
Maximum Application Rate	Comments

Indaziflam 200 SC Herbicide 

(5.0 to 6.5 fl oz product/A)

1.67 lbs a.i./gal

and 

Indaziflam 500 SC Herbicide (2.0 to 2.6 fl oz product/A)

4.16 lbs a.i./gal

(EPA Reg. 264-xxxx)

	Citrus Fruit, Stone Fruit, Pome Fruit, Grapes, Trees Nuts, Pistachios,
Olives	Soil (preemergence control of annual grasses and broadleaf weeds)
Broadcast and band application	Groundboom, handgun	0.085 lb ai/A per
application	Only apply to citrus trees that have been established for at
least one year after transplanting.

Only apply to all other labeled tree and vine crops that have been
established for at least three years after transplanting.

Retreatment Interval: 30 days (except 90 days in   FL and   GA)

Preharvest Interval: 7 days for citrus, 14 days for other crops 

Maximum annual application rate is 0.13 lb ai/A.

Do not apply by chemigation or air.



4.0	RESIDENTIAL (NON-OCCUPATIONAL) EXPOSURE

A residential assessment for use of indaziflam on turf was previously
conducted in D372538 (M. Collantes; 4/21/10).   No new residential uses
are being requested at this time.   Handler MOEs were significantly
greater than 100 (ranging from 3,000 to 510,000) and are not of concern.
 

Dermal postapplication exposures were assessed for adults and children. 
Additionally, oral non-dietary ingestion exposures were assessed for
children (i.e. soil ingestion, and hand-/object-to-mouth).  The
postapplication scenarios resulting from commercial and residential
applications were assessed using the HED Draft Standard Operating
Procedures (SOP’s) for Residential Exposure Assessments, 2000.   All
adult and children residential lawn and golf dermal scenarios resulted
in MOEs greater than the level of concern (ranging from 2,800 to 90,000)
for short-term exposure and are not of concern to HED.      

Since the short- and intermediate-term dermal endpoints are the same,
only short-term dermal exposures were assessed for adults and children. 
HED estimates short-term dermal postapplication exposure based on day-0
residues.  Using day-0 residues to assess intermediate-term exposure
does not take into account dissipation of residues over time and thus
results in a conservative estimation.  Therefore, the short-term dermal
postapplication exposure assessment represents the worst case scenario
and is protective of intermediate-term dermal exposure.

All short-term hand-to-mouth (HTM), object-to-mouth (OTM) and soil
ingestion scenarios resulted in MOEs ranging from 5,300 to 2,100,000;
therefore, these exposures pose no risk of concern to HED.

Based on the Agency's current practices, a quantitative postapplication
inhalation exposure assessment was not performed for the proposed uses
of indaziflam at this time primarily because it has a very low vapor
pressure (vapor pressure less than 5 x 10-10 mmHg at 25ºC), it is
applied at low application rates (maximum rate is 0.085 lbs ai/A), and
it is not projected to be applied via typically high inhalation exposure
application equipment (e.g., airblast or aerial equipment).  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
indaziflam.

4.1	Spray Drift

Spray drift is a potential source of exposure for residents living in
close proximity to spraying operations.  This situation is particularly
the case with aerial application.  However, to a lesser extent, spray
drift resulting from the ground application of indaziflam could also be
a potential source of exposure.  The Agency has been working with the
Spray Drift Task Force (a membership of US pesticide registrants), EPA
Regional Offices, State Lead Agencies for pesticide regulation, and
other parties to develop the best spray drift management practices.  The
Agency is now requiring interim mitigation measures for aerial
applications that must be placed on product labels/labeling.  The Agency
has completed its evaluation of the new database submitted by the Spray
Drift Task Force, 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 airblast, 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, and risks associated with pesticide application.  

Spray drift is always a potential source of exposure to residents nearby
to spraying operations.  It is noted that the 0.094 lb ai/acre
application rate for turf was modeled to estimate postapplication
residential exposure of children (ages 1 to 6 years of age).  As this
rate is equal to or higher than many of the commercial application
rates, this scenario is protective of any exposure of children via spray
drift from commercial indaziflam applications.      

 4.2	Combined Residential Exposure:

HED combines risk values resulting from separate exposure scenarios when
it is likely they can occur simultaneously based on the use-pattern and
the behavior associated with the exposed population.  HED evaluated the
following combined residential uses of indaziflam, 1.) adult dermal and
inhalation handler (lawns only) exposure, and 2.) child postapplication
dermal and oral exposures.  Since HED generally does not combine adult
handler and dermal postapplication exposure, such a combined
quantitative residential exposure estimate was not provided.  However,
combined residential scenario assessments for children which could occur
simultaneously were performed and did not result in risks of concern.  

Table 4.2:  Combined Residential Exposure and Risk 

Product	Use Site	Handler Total

MOE 1	Post-application Dermal MOE 2	Hand-to-Mouth MOE 3	Combined MOE 4

Adult 

Lawn 3FL Concentrate /Ready to spray

72155-IO	Lawns, hardscapes and ornamentals	

3,000	

4,700	

NA

	

NA

Child

Lawn 3 FL (72155-IO)	Lawns, hardscapes and ornamentals	

NA	

2,800	

5,300

	

1,800

See Table 4.1.2: Indaziflam Residential Handler Exposure and Risk (Hand
Held Pump); D372538; 4/21/10

See Table 4.2.2b Dermal Postapplication Exposure and Risk (DFR data);
D372538; 4/21/10

See Table 4.2.3 Hand-To-Mouth Exposure and Risk ; D372538; 4/21/10

Adult Combined MOE = NA = HED does not combine adult handler and
postapplication exposure

Child Combined MOE = NOAEL (7.5 mg/kg/day)/dermal postapplication dose
(0.00266) + HTM dose (0.00141)

HED did not combine risk resulting from adult homeowner handler,
postapplication and golfer exposure to treated turf because HED
considers the probability of co-occurrence for these scenarios to be
low.

                                                               

OCCUPATIONAL EXPOSURE 

The proposed uses of indaziflam are for control of annual grasses and
broadleaf weeds in citrus fruit, stone fruit, pome fruit, grapes, tree
nuts, pistachios and olives. This document assesses occupational
exposures and risks from the proposed uses of Indaziflam 200 SC
Herbicide (suspension concentrate, 19.05% ai, 1.67 lb ai/gal) and
Indaziflam 500 SC Herbicide (suspension concentrate, 45.05% ai, 4.16 lb
ai/gal).

5.1	Occupational Handlers

The quantitative exposure/risk assessment for occupational handlers is
based on the following exposure scenarios, which are considered to be
the most highly exposed scenarios by HED: 

mixing/loading liquids for groundboom applications (PHED);

applying sprays using groundboom equipment (PHED); and

mixing/loading/applying liquids with handgun sprayer (ORETF). 

Unit Exposures:

No chemical specific data were available to assess potential exposure to
pesticide handlers.  The estimates of exposure to pesticide handlers are
based upon surrogate study data available in the PHED (v. 1.1, 1998) and
from the Outdoor Residential Exposure Task Force (ORETF). The ORETF data
were designed to replace the present PHED data with higher-confidence,
higher quality data that contain more replicates than the PHED data for
those scenarios.  In this assessment, ORETF data were used to assess
mixing/loading/applying with handgun equipment (data from MRID   SEQ
CHAPTER \h \r 1 44972201).

Mitigation Approaches:

For pesticide handlers, it is HED standard practice to present estimates
of dermal and inhalation exposure for “baseline,” i.e., a single
layer of work clothing consisting of a long sleeved shirt, long pants,
shoes plus socks and no protective gloves and no respirator.  If further
exposure mitigation is needed to achieve an MOE greater than the LOC,
then personal protective equipment (such as chemical-resistant gloves,
double layer body protection and/or respirators) or engineering controls
may be considered.  The proposed product label involved in this
assessment directs handlers to wear long sleeved shirt and long pants,
shoes plus socks, and chemical resistant gloves. 

Exposure Duration:

Although, handler exposure is expected to be short- or intermediate-term
in duration based on information provided on proposed labels,
intermediate-term exposure is considered to be less likely.  In
addition, the short- and intermediate-term toxicological PoDs are the
same; therefore, the estimates of risk for short-term duration exposures
are protective of those for intermediate-term durations.  Long-term
exposures are not expected; therefore, a long-term assessment was not
conducted.  

	

Application Rate:

The proposed maximum application for all crops is 0.085 lb ai/A. 

Area Treated:

The area treated in a day is based on HED Exposure Science Advisory
Committee SOP No. 9.1 and professional judgment.  An area of 80 acres
per day was assumed for mixing/loading and applying using groundboom
equipment and an area of 25 acres per day was assumed for
mixing/loading/applying using handgun equipment mounted on motorized
vehicle. 

Body Weight:

The average adult body weight of 70 kg was used for estimating dermal
and inhalation dose, since the selected toxicological PoDs are not
sex-specific.

Absorption Factors:

Since the short- and intermediate-term dermal PoD was based on an oral
study, a dermal absorption factor of 7.3 percent was used to estimate
dermal exposure for short-and intermediate-term durations.  

Since no inhalation absorption data are available, toxicity by the
inhalation route is considered to be equivalent to the estimated
toxicity by the oral route of exposure (i.e., 100% inhalation absorption
is assumed). 

Equations and Calculations:

Daily handler exposures are estimated for each applicable handler task
with the application rate, the area treated in a day, and the applicable
dermal and inhalation unit exposure using the following formula:

Daily Exposure: Daily handler exposures are estimated for each
applicable handler task with the application rate, the amount of acres
treated in a day, and the applicable unit exposure using the following
formula:

Daily Exposure (mg ai/day) = Unit Exposure (µg ai/lb ai handled) *
Application Rate (lbs ai/A) * Daily Amount Handled (lbs/day) *
Conversion Factor (mg/1,000 µg)

	Where:  

		Daily Exposure =		Amount (mg ai/day) deposited on the surface of the
skin that is 

	available for dermal absorption or amount inhaled that is available for
inhalation absorption,

		Unit Exposure =		Unit exposure value (µg ai/day),

Application Rate=	Normalized application rate based on a logical unit
treatment, such as acres; maximum values are used (lb ai/A), and

Daily Amount Handled =	Normalized application area based on a logical
unit treatment such as acres (A/day). 

Daily Dose:  Daily dose (inhalation or dermal) was calculated by
normalizing the daily dermal or inhalation exposure value by body weight
and accounting for dermal and inhalation absorption. 

Average Daily Dose (mg/kg/day) = Daily Exposure (mg ai/day) x
{Absorption Factor (%/100)}

								              Body Weight (kg)

	Where:

		Average Daily Dose = 	Absorbed dose received from exposure to a
pesticide in a given 

	scenario	(mg pesticide active ingredient/kg body weight/day),

Daily Exposure =	Amount (mg ai/day) deposited on the surface of the skin
that is available for dermal absorption or amount inhaled that is
available for inhalation absorption,

Absorption Factor = 	A measure of the amount of chemical that crosses a
biological boundary such as 	the skin or lungs, and

Body Weight = 	Body weight determined to represent the population of
interest in a risk assessment.

Margin of Exposure (MOE): The daily dermal dose and daily inhalation
dose received by occupational handlers were compared to the appropriate
point of departure (i.e., NOAEL) to assess the risk to occupational
handlers for each exposure route. All MOE values were calculated
separately for dermal and inhalation exposure levels using the following
formula:

	MOE = 	  	NOAEL (mg/kg/day)

                                 Average Daily Dose (mg/kg/day)

	Where:

	MOE   =		Margin of exposure value used by HED to represent risk or how
close a 

			chemical exposure is to being a concern (unitless),

ADD =	Average daily dose (ADD) is absorbed dose received from exposure
to pesticide, and

		NOAEL	 =	Dose level in a toxicity study, where no observed adverse
effects occurred in the 				study.

Combined Risks:  Dermal and inhalation risks for short- and
intermediate-term exposures were combined in this assessment, since the
toxicological effects for the dermal and inhalations routes were the
same.  Dermal and inhalation risks were combined to determine a total
MOE using the following formula:

		  SEQ CHAPTER \h \r 1  Total MOE = 1/ ((1/ Dermal MOE) + (1/Inhalation
MOE))                      

Handlers Exposure and Risk:

e level of concern (MOEs ≥ 100).  

Table 5.1.  Occupational Handler Exposures and Risksa

Exposure Scenario	Crop or Target	App. Rateb 

(lb ai/A)	Area Treated Dailyc (acres)	Unit Exposured	Dosee

(µg/kg/day)	MOEf,g





Dermal (mg/lb ai)	Inhalation (mg/lb ai)	Dermal 	Inhalation 	Dermal 
Inhalation 	Total 

Mixer/Loader

Groundboom Equipment (PHED data)	Citrus Fruit, Pome Fruit, Stone Fruit,
Grapes, Tree Nuts, Pistachios, Olives	0.085	80	2.9	0.0012	0.021	0.000116
360	65,000	360

Applicator

Groundboom Equipment (PHED data)	Citrus Fruit, Pome Fruit, Stone Fruit,
Grapes, Tree Nuts, Pistachios, Olives	0.085	80	0.014	0.00074	0.000099
0.000072	76,000	100,000	43,000

Mixer/Loader/Applicator

Handgun Sprayer (ORETF data)	Citrus Fruit, Pome Fruit, Stone Fruit,
Grapes, Tree Nuts, Pistachios, Olives	0.085	25	0.45

(with gloves)	0.0018	0.001 

(with gloves)	0.000055	 7,500

(with gloves)	140,000	 7,100

(with gloves)

a.	Risks represent baseline attire (long-sleeve shirt, long pants, no
respirator), except where indicated (i.e. addition of chemical-resistant
gloves for the mixer/loader/applicator handgun scenario).

b.	Application rates = maximum application rates from labels.

c.	Amount handled per day values are HED estimates of acres treated per
day based on Exposure SAC SOP #9.1 “Standard Values for Daily Acres
Treated in Agriculture” and professional judgement.

d.  	Unit Exposures based on PHED Version 1.1 or ORETF data. 

e.	Dose (mg/kg/day) = Unit exposure (mg/lb ai) x App Rate (lb ai/acre) x
Area Treated (acres/day) x  % Absorption (7.3% dermal and 100%
inhalation) / Body weight (70 kg).  

f.	Dermal and Inhalation   SEQ CHAPTER \h \r 1 MOE = NOAEL (7.5
mg/kg/day) / Dose (mg/kg/day) 

g.	Total MOE = 1 / (1/ Dermal MOE) + (1/ Inhalation MOE).

5.2	Occupational Postapplication Exposure 

5.2.1	Postapplication Inhalation Exposure

Based on the Agency's current practices, a quantitative postapplication
inhalation exposure assessment was not performed for the proposed uses
of indaziflam at this time primarily because it has a very low vapor
pressure (vapor pressure less than 5 x 10-10 mmHg at 25ºC), it is
applied at low application rates (maximum rate is 0.085 lbs ai/A), and
it is not projected to be applied via typically high inhalation exposure
application equipment (e.g., airblast or aerial equipment).  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
indaziflam.

5.2.2	Postapplication Dermal Exposure

The proposed uses for indaziflam are ground-directed uses where no crop
foliage is treated.  Currently, HED has no data to assess
postapplication dermal exposures to treated soil by occupational
workers.  In general, such exposures are considered to be negligible.
Therefore, for the proposed soil-directed uses, postapplication
exposures and risks to occupational workers were not quantitatively
assessed, but are not considered to be of concern.  

	

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 technical material.  Active ingredients classified as category III or
IV for acute dermal toxicity, eye irritation potential, and skin
irritation potential are assigned a default REI of 12 hours under the
Worker Protection Standard for Agricultural Pesticides.  Based on the
acute toxicity profile of indaziflam, the 12-hour REI which appears on
the proposed labels is adequate.

Page   PAGE  1  of   NUMPAGES  14 

