BIOPESTICIDES REGISTRATION ACTION DOCUMENT
Indole
PC Code 025000
U.S. Environmental Protection Agency
Office of Pesticide Programs
Biopesticides and Pollution Prevention Division
(Last updated May 28, 2009)
This document is for informational purposes only and is representative of the Agency's justification in registering
products containing this active ingredient. This is not a legal document.
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Biopesticides Registration Action Document
TABLE OF CONTENTS
BIOPESTICIDES REGISTRATION ACTION DOCUMENT TEAM 4
I. EXECUTIVE SUMMARY: 5
II. ACTIVE INGREDIENT OVERVIEW 6
III. REGULATORY BACKGROUND 6
A. CLASSIFICATION 6
B. FOOD CLEARANCES/TOLERANCES 7
IV. RISK ASSESSMENT 7
A. ACTIVE INGREDIENT CHARACTERIZATION 7
B. HUMAN HEALTH ASSESSMENT 7
3. DRINKING WATER EXPOSURE AND RISK CHARACTERIZATION 9
4. OCCUPATIONAL, RESIDENTIAL, SCHOOL AND DAY CARE EXPOSURE AND
RISK CHARACTERIZATION 9
5. RISK CHARACTERIZATION 9
C. ENVIRONMENTAL ASSESSMENT 10
1. ECOLOGICAL HAZARDS 10
2. ENVIRONMENTAL FATE AND GROUND WATER DATA 10
3. ECOLOGICAL EXPOSURE AND RISK CHARACTERIZATION 10
4. ENDANGERED SPECIES ASSESSMENT 10
D. PRODUCT PERFORMANCE DATA (EFFICACY) 10
V. RISK MANAGEMENT DECISION 11
A. DETERMINATION OF ELIGIBILITY FOR REGISTRATION 11
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B. REGULATORY DECISION 11
1. CONDITIONAL/UNCONDITIONAL REGISTRATION 11
C. ENVIRONMENTAL JUSTICE 11
VI. ACTIONS REQUIRED BY REGISTRANTS 11
A. REPORTING OF ADVERSE EFFECTS 12
B. REPORTING OF HYPERSENSITIVITY INCIDENTS 12
VII. APPENDIX A. DATA REQUIREMENTS (40 CFR PART 158-SUBPART U) 13
VIM. APPENDIX B 15
IX. APPENDIX C 15
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BIOPESTICIDES REGISTRATION ACTION DOCUMENT TEAM
Office of Pesticide Programs:
Biopesticides and Pollution Prevention Division
Biochemical Pesticides Branch (BPB)
Chief
Linda A. Hollis, M.S.
Health Effects/Nontarget Organisms
Clara Fuentes, PhD
Regulatory Action Leader
John Fournier, M.S.
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I. EXECUTIVE SUMMARY:
Indole, a new active ingredient, is a naturally-occurring, aromatic substance that is responsible
for the fecal odors associated with human waste. As all animal waste contains indole, as do
some plants and other naturally-occurring substances, it is ubiquitous in the environment. At
high concentrations, it gives off the odor of feces but at lower concentrations, it smells flowery.
For this reason, it is a common ingredient in perfumes and synthetically-produced essential oils,
such as jasmine oil. Indole is also a major constituent of coal tar, the main industrial source, but
was first isolated from indigo for use as a dyestuff.
In its pure form, indole is irritating to the eyes and skin and it may be fatal if swallowed or
contacted by the skin. According to the Material Data Safety Sheet (MSDS) for indole, the acute
oral LD50 is lOOOmg/kg. The concentrated vapor of indole is irritating to the throat and lungs.
The proposed use pattern, as a component of a fly attractant, however, utilizes only minute
quantities of indole that are much lower in concentration than many naturally-occurring essential
oils or human feces. In the proposed product, Bull Run Fly Attractant, indole is enclosed with
other active ingredients in a water-soluble, vapor-barrier pouch that will be placed in a fly trap so
there is little to no anticipated exposure. At the proposed concentration of 0.2%, even at the
maximum use rate, total usage of indole would not exceed 6.7 grams per acre.
Guideline toxicity and non-target organism studies were not submitted in support of the
registrant's application. In lieu of studies, the registrant requested data waivers from the
requirements for all guideline studies and submitted a compendium of information in support of
the data waivers. The registrant also provided adequate justification for waiving data
requirements based on the proposed use pattern, which would result in no exposure to the active
ingredient. Therefore, the Agency believes that this product containing indole can be used
without causing unreasonable adverse effects to humans or the environment.
Based on data and acceptable waivers submitted by the registrant, there is no reason to believe
that any non-target organisms, including honeybees and other beneficial insects, would be
attracted to or adversely affected by the use of indole in a fly trap. Data submitted by the
registrant indicated that only insects classified as "filth flies" were attracted to the fly trap.
Due to the negligible risk concerns when used as an attractant and the resulting lack of exposure,
indole meets the criteria as specified in §3(c)(5) of the Federal Insecticide, Fungicide and
Rodenticide Act (FIFRA), as amended, and is thus eligible for unconditional registration. It was
determined that the data/information submitted adequately satisfy current guideline requirements
per 40 CFR Subpart U §158.2000.
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II. ACTIVE INGREDIENT OVERVIEW
Common Name: Indole
Chemical Names: Indole
Trade & Other Names: 1-Azaindene
1-Benzazole
1 -Benzo(b)pyrrole,
2,3-Benzopyrole
2,3-Benzopyrrole
Indol
Ketole
CAS Registry Number: 120-72-9
OPP Chemical Code: 025000
Type of Pesticide: Biochemical pesticide, attractant
Application rates and methods vary depending on the product. For specific information
regarding the product(s) refer to Appendix B.
III. REGULATORY BACKGROUND
On April 4, 2008, the Agency received an application from Bull Run Scientific, VBT to register
indole as an active ingredient in an end-use product (EP) containing 0.2% indole. A notice of
receipt of the application for registration for trimethylamine as a new active ingredient was
published in the Federal Register on March 11, 2009, with a 30 day comment period. No
comments were received as a result of this publication.
A. Classification
On September 1, 1993, the Biochemical Classification Committee determined that indole can be
classified as a biochemical pesticide due to its non-toxic mode of action, natural occurrence in
the environment, and history of exposure to humans and the environment demonstrating minimal
toxicity at low concentrations. In a concentrated form, indole can be both toxic and a sensory
irritant. Used in Biochemical pesticides at low concentrations as an attractant, however, it
demonstrates minimal toxicity.
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B. Food Clearances/Tolerances
Currently, this active ingredient is not registered for use on food or feed commodities. A
tolerance or exemption from the requirement of a tolerance is not relevant.
IV. RISK ASSESSMENT
A. Active Ingredient Characterization
The new active ingredient, indole, will be formulated as an EP for use as an attractant for filth
flies. The technical grade active ingredient (TGAI) is a flaky white solid. It has the odor of
feces at high concentrations but, at lower concentrations, has a flowery scent. In its pure form,
indole is toxic with an LDso of lOOOmg/kg.
The mode of action of indole is to produce odors that attract filth flies seeking a food source or
medium in which to deposit their eggs. As part of a water-soluble attractant insert in a
disposable or re-useable trap, it draws filth flies into the apparatus where they are trapped.
The product chemistry data submitted by the registrant, including manufacturing process,
discussion of formation of impurities, analysis of samples, and certified ingredients limits
satisfied the requirement for product identity. Refer to Table 1 in Appendix A for a summary of
product chemistry data requirements. Refer to Table 2 in Appendix A for the summary of
physical and chemical characteristics for indole.
All product chemistry data requirements for registration of indole have been satisfied.
B. Human Health Assessment
1. Toxicology
For acute toxicity data requirements, toxicity categories are assigned based on the hazard(s)
identified from studies and/or information on file with the Agency. The active ingredient is
classified into Toxicity Category I, II, III or IV where Toxicity Category I indicates the highest
toxicity and Toxicity Category IV indicates the lowest toxicity. For more information, refer to
40CFR§ 156.62.
Adequate mammalian toxicology data/information is available to support registration of indole.
All toxicology data requirements for indole have been satisfied.
a. Acute Toxicity
Acute toxicity testing is required to 1) determine systemic toxicity from acute exposure via the
dermal, inhalation and oral routes, 2) determine irritant effects from exposure to the eyes and 3)
determine the potential for skin sensitization (allergic contact dermatitis). All required
toxicology data for indole are waived. No additional toxicological data are needed. The
decision to waive these data is based on: 1) the product is naturally occurring, 2) possesses a
non-toxic mode of action, 3) will not accumulate in the environment, and 4) due to the design of
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the trap, there is no anticipated exposure to the attractant pouch ingredients. For more
information regarding the acute toxicity data requirements, refer to Table 3 in Appendix A.
b. Subchronic Toxicity
Subchronic data is required to determine a no-observed-effect-level (NOEL) and toxic effects (if
any) associated with repeated or continuous exposure to a test substance for a period of 90 days.
The request submitted by the registrant to waive Subchronic mammalian toxicity data was
determined to be acceptable. For more information regarding the Subchronic data requirements,
refer to Table 3 in Appendix A.
c. Developmental Toxicity and Mutagenicity
The Agency waived data requirements for developmental toxicity and mutagenicity of indole
based on 1) its natural occurrence in the environment, 2) little to no potential for exposure to
humans based on the EP attractant packet and fly trap designs and 3) the fact that it will not
accumulate in the environment. For more information regarding these data requirements, refer to
Table 3 in Appendix A.
e. Effects on the Endocrine System
EPA is required under the Federal Food, Drug, and Cosmetics Act (FFDCA), as amended by the
Food Quality Protection Act (FQPA), to develop a screening program to determine whether
certain substances (including all pesticide active and other ingredients) "may have an effect in
humans that is similar to an effect produced by a naturally-occurring estrogen, or other such
endocrine effects as the Administrator may designate." Following the recommendations of its
Endocrine Disrupter Screening and Testing Advisory Committee (EDSTAC), EPA determined
that there was scientific basis for including, as part of the program, the androgen and thyroid
hormone systems, in addition to the estrogen hormone system. EPA also adopted EDSTAC's
recommendation that the program include evaluations of potential effects in wildlife. For
pesticide chemicals, the Agency will use FIFRA and, to the extent that effects in wildlife may
help determine whether a substance may have an effect in humans, FFDCA authority to require
the wildlife evaluations. As the science develops and resources allow, screening of additional
hormone systems may be added to the Endocrine Disrupter Screening Program (EDSP).
The Agency is not requiring information on the endocrine effects of indole at this time. The
Agency has considered, among other relevant factors, available information concerning whether
the active ingredient may have an effect on humans similar to an effect produced by naturally-
occurring estrogen or other endocrine effects. There is no known metabolite that acts as an
endocrine disrupter produced by this active ingredient. Based on the low potential exposure level
associated with the proposed use, the Agency expects no incremental adverse effects to the
endocrine or immune systems.
2. Dose Response Assessment
No toxicological endpoints were identified; therefore, a dose response assessment was not
required.
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3. Drinking Water Exposure and Risk Characterization
Based on the proposed use pattern, no significant exposure is expected from use of indole in the
environment when used according to label instructions.
4. Occupational, Residential, School and Day Care Exposure and Risk Characterization
a. Occupational Exposure and Risk Characterization
Occupational exposures are not a concern based on the use pattern, low to no potential for
exposure due to trap design, and because indole is naturally occurring in the environment and
possesses a non-toxic mode of action when used as an attractant at a low concentration. The
application method of indole inside a water-soluble pouch that is placed within a trap poses no
significant concern for dermal, eye, and inhalation exposures. Based on little or no potential for
exposure and the small percentage of indole in the attractant pouch, worker exposure data on
indole are not required. Based on the nature, use pattern, non-toxic mode of action, and relative
safety of indole in this product, including the battery of information from the open scientific
literature, the toxicity category for the fly attractant has been characterized as IV and the product
label will bear the signal word "Caution." No reentry interval is required in conjunction with the
use of the EP.
b. Residential, School and Day Care Exposure and Risk Characterization
The end use product containing indole is intended for use in a residential or agricultural setting.
Again, because indole is naturally occurring, possesses a non-toxic mode of action, and the trap
design will result in low potential for exposure, the Agency is not concerned about the potential
exposure to children.
5. Risk Characterization
The Agency considered human exposure to indole in light of the relevant safety factors in
FIFRA. A determination has been made that no unreasonable adverse effects to the U.S.
population in general, and to infants and children in particular, will result from the use of indole
when label instructions are followed.
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C. ENVIRONMENTAL ASSESSMENT
1. Ecological Hazards
Based on the natural occurrence of indole as a component of animal feces and the fact that indole
is not expected to cause adverse effects on non-target organisms, adequate rationales for waiving
non-target toxicology data were submitted to support registration of indole. All non-target
toxicology data requirements for indole have been satisfied.
For more information regarding the non-target toxicity data requirements, refer to Table 4 in
Appendix A.
2. Environmental Fate and Ground Water Data
The need for environmental fate and groundwater data was not triggered because results of the
acute toxicity studies did not trigger any additional Tier I studies.
3. Ecological Exposure and Risk Characterization
The end use product, Bull Run Fly Attractant, is intended for residential or agricultural use.
When used according to the proposed label directions, no direct exposures are expected for non-
target organisms. Moreover, the active ingredient is naturally occurring, has a non-toxic mode
of action when used at a low concentration as an attractant, is a natural component of feces, and
is not expected to accumulate in the environment. Given these characteristics of indole, non-
target exposure and ecological effects studies were waived for the use of indole in the fly trap.
4. Endangered Species Assessment
Adverse effects on threatened and endangered species are not expected based on available
information about the use pattern of the product, product performance data, and habitat of
Diptera species currently listed as threatened or endangered.
D. PRODUCT PERFORMANCE DATA (EFFICACY)
Submission of product performance data (OPPTS 810.3000) is listed as a requirement for all
pesticide products. Customarily, the Agency requires efficacy data to be submitted for review
only in connection with the registration of products directly pertaining to the mitigation of
disease bearing human health organisms and certain designated quarantine pests, i.e., ticks,
mosquitoes, fleas, Mediterranean fruit flies, gypsy moths, Japanese beetles, etc. For a list of
organisms considered by the Agency as "public health pests", please refer to Pesticide
Registration Notice 2002-1 (http://www.epa.gov/PR Notices/pr2002-l .pdf).
Based on the data submitted by the registrant, the Agency determined that product performance
data were acceptable.
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V. Risk Management Decision
A. Determination of Eligibility for Registration
Section 3(c)(5) of FIFRA provides for the registration of new active ingredients if it is
determined that (A) its composition is such as to warrant the proposed claims for it; (B) its
labeling and other materials required to be submitted comply with the requirements of FIFRA;
(C) it will perform its intended function without unreasonable adverse effects on the
environment; and (D) when used in accordance with widespread and commonly recognized
practice it will not generally cause unreasonable adverse effects on the environment.
The four criteria of the Eligibility Determination for Pesticidal Active Ingredients are satisfied
by the science assessments supporting products containing indole. Such products are not
expected to cause unreasonable adverse effects, and are likely to provide protection as claimed
when used according to label instructions. Therefore, indole is eligible for registration for the
labeled uses.
B. Regulatory Decision
The data submitted fulfill the requirements of registration for use as an ingredient in a water-
soluble, vapor-barrier fly attractant packet inside an insect trap. Refer to Appendix B for
product-specific information.
1. Conditional/Unconditional Registration
All data requirements are fulfilled and EPA has determined that unconditional registration of
indole is appropriate.
C. Environmental Justice
EPA seeks to achieve environmental justice - the fair treatment and meaningful involvement of
all people, regardless of race, color, national origin, or income - in the development,
implementation, and enforcement of environmental laws, regulations, and policies. At this time
EPA does not believe that use of pesticide products containing indole will cause harm or a
disproportionate impact on at-risk communities.
For additional information regarding environmental justice issues, please visit EPA's website at:
http://www.epa.gov/compliance/environmentaljustice/index.html.
VI. ACTIONS REQUIRED BY REGISTRANTS
The Agency evaluated all of the data submitted in connection with the initial registration of
indole and determined that these data are sufficient to satisfy current registration data
requirements. No additional data are required to be submitted to the Agency at this time. For
new uses and/or changes to existing uses, additional data may be required.
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Not withstanding the information stated in the previous paragraph, it should be clearly
understood that certain, specific, data are required to be reported to the Agency as a requirement
for maintaining the Federal registration for a pesticide product. A brief summary of these types
of data are listed below.
A. Reporting of Adverse Effects
Reports of all incidents of adverse effects to the environment must be submitted to the Agency
under the provisions stated in FIFRA, Section 6(a)(2).
B. Reporting of Hypersensitivity Incidents
Additionally, all incidents of hypersensitivity (including both suspected and confirmed incidents)
must be reported to the Agency under the provisions of 40 CFR Part 158.2050(d).
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VII. Appendix A. Data Requirements (40 CFR Part 158-Subpart U)
*NOTE: MRID numbers listed in the following tables are representative of supporting data for
the original registration of the product containing this active ingredient. Subsequent to this
registration, there may be additional MRIDs that support registration of other products
containing this active ingredient.
TABLE 1. Product Chemistry Data Requirements for Indole (40 CFR § 158.2030)
OPPTS Guideline No.
830.1550
to
830.1670
830.1700
830.1750
830.1800
Study
Product identity;
Manufacturing process;
Discussion of formation of
unintentional ingredients
Analysis of samples
Certification of limits
Analytical method
Results
Submitted data satisfy the requirements
for product identity, manufacturing
process, and discussion of formation of
impurities.
Submitted data satisfy the requirements
for analysis of samples.
Limits listed in the CSF are adequate /
acceptable.
Acceptable.
MRID
473969-16
473969-16
473969-16
473969-16
TABLE 2. Physical and Chemical Properties of Indole (40 CFR § 158.2030)
OPPTS Guideline No.
830.6302
830.6303
830.6304
830.6313
830.6315
830.6317
830.6319
830.6320
830.7000
830.7050
830.7100
830.7200
830.7220
830.7300
830.7520
830.7550
830.7560
830.7570
830.7840
830.7950
Property
Color
Physical State
Odor
Stability to Normal and Elevated
Temperatures, Metals and Metal Ions
Flammability
Storage Stability
Miscibility
Corrosion Characteristics
pH
UV/Visible Light Absorption
Viscosity
Melting Point/Range
Boiling Point/Range
Density
Particle Size, Fiber Length and
Diameter Distribution
Partition Coefficient (n-
Octanol/Water)
Water Solubility
Vapor Pressure
Description of Result
White
Solid at room temperature
Fecal odor at high
concentration, flowery odor at
low concentration
Stable for 12 months when
stored in original package,
tightly sealed in cool, dry
location.
Not required for EP
Stable for 12 months
Not required for EP
Not required for EP
5.9
Not required for EP
Not applicable
52.5°C
254°C
1.22 g/cm3
Not required for EP
LogKow = 2.14
3560 mg/L at 25°C
0.0122 mm Hg at 25°C
MRID
473969-17
473969-17
473969-17
473969-17
N/A
473969-17
N/A
N/A
473969-18
N/A
N/A
473969-17
473969-17
473969-17
N/A
473969-17
473969-17
473969-17
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Table 3. Human Toxicology Data Requirements for Indole (40 CFR § 158.2050)
Study/OPPTS Guideline No.
Acute oral toxicity (rat)
(870.1100)
Acute dermal toxicity (rat)
(870.1200)
Acute inhalation toxicity (rat)
(870.1300)
Primary eye irritation (rabbit)
(870.2400)
Primary dermal irritation (rabbit)
(870.2500)
Dermal sensitization (guinea pig)
(870.2600)
Hypersensitivity incidents
(885.3400)
90-Day oral toxicity (870.3100)
90-Day dermal toxicity (870.3250)
90-Day inhalation toxicity
(870.3465)
Mutagenicity
(870.5100, 5300 and 5375)
Developmental toxicity (870.3700)
Results
Waiver requested*
Waiver requested*
Waiver requested*
Waiver requested*
Waiver requested*
Waiver requested*
Waiver requested*
Waived due to lack of exposure
Waived due to lack of exposure
Waived due to lack of exposure
Waived due to lack of exposure
Waived due to lack of exposure
Toxicity
Category /Description
Acceptable
Acceptable
Acceptable
Acceptable
Acceptable
Acceptable
Acceptable
N/A
N/A
N/A
N/A
N/A
MRID
473969-21
473969-21
473969-21
473969-21
473969-21
473969-21
473969-21
* Due to the fact that no significant human exposure is expected, the Agency did not require
human health data on the Technical Grade Active Ingredient (TGAI). This is due to the fact that the active
ingredient is enclosed in a water-soluble vapor barrier packet which is placed inside the fly trap, resulting in no
exposure to the product handler. The Agency did, however, require data for the EP.
TABLE 4. Non-Target Organism Toxicity Requirements for Indole (40 CFR § 158.2060)
Study/OPPTS Guideline No.
/MRID No.
Avian acute oral toxicity
Colinus virginianus
(850.2100)
Avian dietary toxicity
Colinus virginianus
(850.2200)
Avian dietary toxicity
Anas platyrhynchos
(850.2200)
Aquatic invertebrate acute toxicity
(Daphnia magna)
(850.1010)
Freshwater fish LC50
(Oncorhynchus mykiss)
(850.1075)
Non-target plant studies
(850.4000-4800, as applicable)
Non-target insect testing
(880.4350)
Results
Waived only for the proposed use pattern of
the EP contained within a water-soluble
vapor barrier packet inside the fly trap
Waived only for the proposed use pattern of
the EP contained within a water-soluble
vapor barrier packet inside the fly trap
Waived only for the proposed use pattern of
the EP contained within a water-soluble
vapor barrier packet inside the fly trap
Waived only for the proposed use pattern of
the EP contained within a water-soluble
vapor barrier packet inside the fly trap
Waived only for the proposed use pattern of
the EP contained within a water-soluble
vapor barrier packet inside the fly trap
Waived only for the proposed use pattern of
the EP contained within a water-soluble
vapor barrier packet inside the fly trap
The study, Product performance data
indicated no evidence that the product
attracts non-target insects.
Toxicity
Category /Description
Acceptable
Acceptable
Acceptable
Acceptable
Acceptable
Acceptable
Acceptable
MRID
473969-20
473969-20
473969-20
473969-20
473969-20
473969-20
473696-03
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VIII. Appendix B.
For product specific information, please refer to http://www.epa.gov/pesticides/pestlabels/
IX. Appendix C.
REFERENCES
MBPBWINv. 1.42: Indole
Mulla M.S., Hwang Yih-Shen, Loomis B.C., Axelrod H., 1978, Product of Putrefaction and Brewing
Odors that Attract Synanthropic Flies. Proceedings and Papers of the Forty-sixth Annual Conference of
the California Mosquito and vector Control Association, Inc., pp. 70-73.
Mulla, M.S., Hwang Yih-Shen, Axelrod H., 1977, Attractants for Synanthropic Flies: Chemical
Attractants for Domestic Flies. Journal of Economic Entomology Vol. 70, No. 5. pp. 644-648.
TOXNET, 2009. http://toxnet.nlm.nih.gov
United States National Library of Medicine, ChemiDplus Lite: Indole
http: //chem. sis .nlm .nih. gov/chemidplus/chemidlite .j sp
Wikipedia, 2009. http://en.wikipedia.org/wiki/Indole
WSKOWWIINv. 1.41: Indole
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