Page 1 of 14

 

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.
Page 2 of 14

TABLE OF CONTENTS

1.0 EXECUTIVE SUMMARY ................................................................................................. 3

2.0. HAZARD CHARACTERIZATION ................................................................................... 4

2.1 Hazard Profile .................................................................................................................. 4

2.2 FQPA and Uncertainty Factor Considerations................................................................. 5

3.0 PROPOSED USE PATTERNS ........................................................................................... 7

4.0 RESIDENTIAL (NON-OCCUPATIONAL) EXPOSURE................................................. 7

5.0 OCCUPATIONAL EXPOSURE........................................................................................ 9

5.1 Occupational Handlers................................................................................................... 10

5.2 Occupational Postapplication Exposure......................................................................... 13

5.2.1 Postapplication Inhalation Exposure....................................................................... 13

5.2.2 Postapplication Dermal Exposure........................................................................... 14
Page 3 of 14

1.0 EXECUTIVE SUMMARY

Indaziflam ([1,3,5-triazine-2,4-diamine,N-[(1R,2S)-2,3-dihydro-2,6-dimethyl-1H-inden-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.
Page 4 of 14

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 grounddirected 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

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 
Page 5 of 14

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.
Page 6 of 14

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 

IntermediateTerm (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 ShortTerm (1 to 30 

days) and 

Intermediateterm (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, LongTerm (>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 

IntermediateTerm (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 
Page 7 of 14

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 nondietary ingestion exposures were assessed for children (i.e. soil ingestion, and hand-/object-tomouth). 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 
Page 8 of 14

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 intermediateterm 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. 
Page 9 of 14

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

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

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

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

4. 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.

 

5.0 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).
Page 10 of 14

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: 

1) mixing/loading liquids for groundboom applications (PHED);

2) applying sprays using groundboom equipment (PHED); and

3) 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 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 intermediateterm 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. 
Page 11 of 14

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 intermediateterm 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
Page 12 of 14

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:

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

Handlers Exposure and Risk:

Summaries of the risks for occupational handlers are included in Table 5.1. The results of the 

occupational handler exposure and risk assessment indicate that short- and intermediate-term 

dermal, inhalation and total MOEs were greater than the level of concern (MOEs ≥ 100) at the 

baseline clothing level (i.e. single layer clothing and no respirator), when baseline data are 

available. There are no baseline dermal data to assess the mixing/loading/applying handgun 

scenario. 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. When baseline 

attire plus chemical-resistant gloves are used for this scenario, short- and intermediate-term 

dermal and total MOEs were greater than the level of concern (MOEs ≥ 100). 
Page 13 of 14

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 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.
Page 14 of 14

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. 

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.