United States Prevention, Pesticides EPA 738-R-99-007
Environmental Protection And Toxic Substances November 1999
Agency (7508C)
vvEPA Reregistration
Eligibility Decision (RED)
3-Trifluoro-Methyl-4-Nitro-Phenol
and Niclosamide
19nnDMa" code 3201
1200 Pennsylvania Avenue NW
Washington DC 20460
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United States
Environmental Protection
Agency
Prevention, Pesticides
And Toxic Substances
(7508C)
EPA-738-F99-012
November, 1999
R.E.D. FACTS
TFM
Pesticide
Reregistration
Use Profile
All pesticides sold or distributed in the United States must be registered
by EPA, based on scientific studies showing that they can be used without
posing unreasonable risks to people or the environment. Because of advances
in scientific knowledge, the law requires that pesticides which were first
registered before November 1, 1984, be reregistered to ensure that they meet
today's more stringent standards.
In evaluating pesticides for reregistration, EPA obtains and reviews a
complete set of studies from pesticide producers, describing the human health
and environmental effects of each pesticide. To implement provisions of the
Food Quality Protection Act of 1996, EPA considers the special sensitivity of
infants and children to pesticides, as well as aggregate exposure of the public
to pesticide residues from all sources, and the cumulative effects of pesticides
and other compounds with common mechanisms of toxicity. The Agency
develops any mitigation measures or regulatory controls needed to effectively
reduce each pesticide's risks. EPA then reregisters pesticides that meet the
safety standard of the FQPA and can be used without posing unreasonable
risks to human health or the environment.
When a pesticide is eligible for reregistration, EPA explains the basis for
its decision in a Reregistration Eligibility Decision (RED) document. The
decisions for TFM and Niclosamide were combined into one publication
because the use patterns are very similar and the compounds are often used
together This fact sheet summarizes the information in the RED document for
reregistration case 3082, 3-trifluoromethyl-4-nitrophenol (TFM, Lamprecid®).
TFM is a lampricide used to control sea lamprey larvae in tributaries to
the Great Lakes, the Finger Lakes and Lake Champlain.
Formulations include a liquid concentrate and a solid bar. The liquid
formulation is applied by metered pump from the back of a boat or by
backpack sprayer. The solid bar is placed in the water and allowed to dissolve
slowly.
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Regulatory TFM was first registered as a pesticide in the U.S. in 1964 by the U.S.
History Department of Agriculture (USDA), the Agency's predecessor for pesticide
regulation under FIFRA. Currently, two TFM products are registered with
EPA.
Human Health
Assessment
Toxicity
In animal studies with rats, TFM has an acute oral LD50 value of 141
mg/kg (Toxicity Category n). The acute dermal toxicity is minimal, as
indicated by a LDJO > 2000 mg/kg (Toxicity Category BO). It produced slight
skin irritation (Toxicity Category IV) and caused eye irritation which was
cleared within seven days after application (Toxicity Category HI). TFM is not
a skin sensitizer. The acute inhalation data are not available, but based on the
low vapor pressure of TFM, inhalation is not expected to be a major pathway of
exposure.
TFM showed no evidence of causing developmental toxicity,
carcinogenicity, mutagenicity or of increased tumor incidence.
Dietary Exposure
People are unlikely to be exposed to residues of TFM through the diet
due to: the low amount of compound used, the United States Fish and Wildlife
Service restrictions against removing irrigation and drinking water from
streams during treatment, and the rapid dissipation of residues in fish and water.
Tolerances have not have been established and are not required for TFM.
Occupational and Residential Exposure
Based on current use patterns, handlers (mixers, loaders, and applicators)
may be exposed to TFM during and after normal use of the liquid concentrate
formulation. Dermal exposure was considered to be the most relevant route of
exposure.
Human Risk Assessment
The use of TFM is not expected to pose risk to the general population
since exposure from food, water, and other non-occupational contact is
negligible.
Risk to TFM handlers is not of concern since margins of exposure are at
acceptable levels when the protective clothing required by current labeling was
included in the calculations. PPE requirements are complimented by routine
industrial hygiene and medical monitoring programs for workers who handle
and apply TFM.
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FQPA Considerations
There are no dietary exposures for TFM; therefore FQPA does not affect
these regulatory decisions.
Environmental TFM is applied to freshwater tributaries and is therefore expected to have
Assessment ^tt'e impact on terrestrial plants and animals. Applications are designed to have
minimal effects on fish, but other aquatic animals are expected to be impacted.
Environmental Fate
• TFM is chemically and biologically very stable.
• There is conflicting evidence on whether TFM photodegrades in water.
• TFM remains toxic for long periods (>80 days) in aqueous systems; however,
toxicity decreases in sediment-water systems over time.
• TFM was converted to reduced-TFM with a half-life of less than one week under
both aerobic and anaerobic aquatic metabolism conditions, but this conversion
was reversible.
• The tendency for TFM to bind to sediments is not strong, readily reversed,-and is
pH dependent with binding decreasing as pH increases.
• Based on rainbow trout studies, TFM is not expected to accumulate in fish.
• In the environment, the sorption and degradation of TFM by sediments is
expected to occur primarily in the lakes and not in the tributary streams. TFM is
expected to remain in solution in the lake system and persist for long periods of
time.
Ecological Effects
• Avian acute-nontoxic (>5, 000 ppm)
• Mammalian acute-moderately toxic (>14I to 160 mg/kg)
• Mammalian chronic ( >5,000 mg/kg)
• Fish (freshwater acute)- slightly to highly toxic ( 0.60 to 37 mg/L )
• Invertebrates (freshwater) acute- slightly to moderately toxic (3.8 to 22.3 mg/L)
• Aquatic plants- toxic (1.2 to > 15 mg/L)
Environmental Risk Characterization
TFM is both chemically and biologically stable and is expected to remain
toxic for long periods of time. However, mitigation of its effects at the treatment
site is likely to occur as a result of the flushing action of the stream/river
Predicted treatment concentrations for specific locations, based on
physico-chemical data or in-stream toxicity tests, are intended to result in a
concentration greater than the LC^ 9 for sea lamprey while being substantially less
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than the LC2S for brown trout. This improves treatment effectiveness for sea
lampreys, yet minimizes the effect on nontarget species. At the predicted treatment
levels, acute high risk, acute restricted use, and endangered species levels of
concern are exceeded for aquatic animals. Although TFM is likely to have an
immediate effect on the aquatic community, the data suggest that most organisms
recover quickly and the treatment area community structure returns to pre-
treatment conditions within weeks or months. This recovery is site specific and may
take much longer in certain environments. Certain species may be significantly
impacted, most notably the indigenous lamprey species that may populate treatment
areas. In general, however, native lamprey species have tended to populate the
upper reaches of tributary streams, whereas the sea lamprey is more likely to inhabit
lower reaches of the stream. Thus, nontarget species that may have been affected
in the treatment area are repopulated through downstream migration from untreated
areas. Furthermore, retreatment of the stream will not occur for at least 3 to 5
years. Additionally, a genuine effort is made to document where sensitive
populations reside, and steps are undertaken to avoid treatments at concentrations
known to be toxic to these organisms. The long-term effects remain uncertain to
more sensitive species, such as indigenous lampreys, and to aquatic communities
downstream from the treatment sites where chronic effects may be more likely.
Risk Mitigation The use practices of TFM have been refined over the past several years in
order to lower the impacts of these applications on non-target organisms and to
lower occupational and non-occupational exposure to people. TFM is a Restricted
Use Pesticide and its labels refer users to the US Fish and Wildlife Service's Manual
for Pesticide Applications. Additional mitigation required by the Agency includes
minor clarifications of label language. Aerial applications were prohibited on some
of the current labels and will be prohibited on all new labels in order to lessen
chances of nontarget human and other terrestrial animal exposures to these
restricted use compounds.
Additional Data EPA is requiring the following additional generic study for TFM to confirm
Required 'ts regulatory assessments and conclusions:
Photodegradation in Water Guideline # 835-2240 (161-2)
The Agency also is requiring product-specific data including product
chemistry and acute toxicity studies, revised Confidential Statements of Formula
(CSFs), and revised labeling for reregistration.
Product Labeling All TFM end-use products must comply with EPA's current pesticide
Changes Required Proa
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Reouldtory The use of currently registered products containing TFM in accordance
Conclusion ^^ approved labeling will not pose unreasonable risks or adverse effects to
humans or the environment. Therefore, all uses of these products are eligible for
reregistration.
TFM products will be reregistered once the required product-specific data,
revised Confidential Statements of Formula, and revised labeling are received and
accepted by EPA.
For Mor6 EPA is requesting public comments on the Reregistration Eligibility Decision
Information (RED) document for TFM during a 60-day time period, as announced in a Notice
of Availability published in the Federal Register. The document is entitled
Rereeistration Eligibility Decision: 3-Trifluoro-Methvl-4-Nitro-Phenol CASE 3082
and Niclosamide CASE 2455. To obtain a copy of the RED document or to submit
written comments, please contact the Pesticide Docket, Public Information and
Records Integrity Branch, Information Resources and Services Division (7502C),
Office of Pesticide Programs (OPP), US EPA, Washington, DC 20460, telephone
703-305-5805.
Electronic copies of the RED and this fact sheet are available on the Internet.
See http://www.epa.gov/REDs.
Printed copies of the RED and fact sheet can be obtained from EPA's National
Service Center for Environmental Publications (EPA/NSCEP), PO Box 42419,
Cincinnati, OH 45242-2419, telephone 1-800-490-9198; fax 5 13-489-8695.
Following the comment period, the TFM RED document also will be available
from the National Technical Information Service (NTIS), 5285 Port Royal Road,
Springfield, VA 22161, telephone 1-800-553-6847, or 703-605-6000.
For more information about EPA's pesticide reregistration program, the TFM
RED, or reregistration of individual products containing TFM, please contact the
Special Review and Reregistration Division (7508C), OPP, US EPA, Washington,
DC 20460, telephone 703-308-8000.
For information about the health effects of pesticides, or for assistance in
recognizing and managing pesticide poisoning symptoms, please contact the
National Pesticide Telecommunications Network (NPTN). Call toll-free 1-800-
858-7378, from 6:30 am to 4:30 pm Pacific Time, or 9:30 am to 7:30 pm Eastern
Standard Time, seven days a week. Their internet address is ace.orst.edu/info/nptn.
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United States
Environmental Protection
Agency
Prevention, Pesticides
And Toxic Substances
(75Q8CJ
EPA-738-F99-013
November, 1999
R.E.D. FACTS
Niclosamide
Pesticide
Reregistration
Use Profile
All pesticides sold or distributed in the United States must be registered
by EPA, based on scientific studies showing that they can be used without
posing unreasonable risks to people or the environment. Because of advances
in scientific knowledge, the law requires that pesticides which were first
registered before November 1, 1984, be reregistered to ensure that they meet
today's more stringent standards.
In evaluating pesticides for reregistration, EPA obtains and reviews a
complete set of studies from pesticide producers, describing the human health
and environmental effects of each pesticide. To implement provisions of the
Food Quality Protection Act of 1996, EPA considers the special sensitivity of
infants and children to pesticides, as well as aggregate exposure of the public
to pesticide residues from all sources, and the cumulative effects of pesticides
and other compounds with common mechanisms of toxicity. The Agency
develops any mitigation measures or regulatory controls needed to effectively
reduce each pesticide's risks. EPA then reregisters pesticides that meet the
safety standard of the FQPA and can be used without posing unreasonable
risks to human health or the environment.
When a pesticide is eligible for reregistration, EPA explains the basis for
its decision in a Reregistration Eligibility Decision (RED) document. The
decisions for Niclosamide and TFM were combined into one publication
because the use patterns are very similar and the compounds are often used
together. This fact sheet summarizes the information in the RED document for
reregistration case 2455, 2-amino ethanol salt of 2'.,5l-dichloro-4'-nitro
salicylanilide (Niclosamide).
Niclosamide is used as (1) a lampricide to control sea lamprey larvae in
tributaries to the Great Lakes, the Finger Lakes and Lake Champlain and (2) a
molluscicide to control freshwater snails which carry the vectors for diseases
which affect fish and humans. Less than 400 pounds of active ingredient
niclosamide is used each year in lamprey and freshwater snail treatments.
Niclosamide has been used as a human and veterinary drug for treatment of
parasites.
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Formulations include a 70% wettable powder (WP) and two granular
formulations. The WP is applied by metered pump from the back of a boat or
by backpack sprayer. The 3.2% granular product is applied with a backpack
blower device that spreads the granules over a wide surface area.
Regulatory
History
Human Health
Assessment
Niclosamide was first registered as a pesticide in the U.S. in 1964 by the
U.S. Department of Agriculture (USDA), the Agency's predecessor for
pesticide regulation under FIFRA. Currently, five niclosamide products are
registered with EPA: a 70% WP for sea lamprey control, two Special Local
Needs labels with the 70% WP, one 3.2% granular formulation, and one 5%
granular formulation. The registrant has requested voluntary cancellation of
the 5% granular product.
Toxicity
Niclosamide has acute oral LDSO values of > 1000 mg/kg (Toxicity
Category HI). The acute dermal toxicity is minimal, as indicated by a LDSO >
2000 mg/kg (Toxicity Category ffl). It produced slight skin irritation (Toxicity
Category IV) and caused eye irritation (unclassified Toxicity Category based
on short time interval of eye examination). It was a moderate skin sensitizer.
The acute inhalation data are not available.
Niclosamide showed no evidence of causing developmental toxicity,
mutagenicity or carcinogenicity.
Dietary Exposure
People are unlikely to be exposed to residues of niclosamide through the
diet due to: the low amount of compound used, the United States Fish and
Wildlife Service restrictions against removing irrigation and drinking water
from streams during treatment, and the rapid dissipation of residues in fish and
water. The Special Local Needs Labels for the use in ornamental fish ponds are
also not likely to result in any dietary exposure. Tolerances have not have been
established and are not required for niclosamide.
Occupational and Residential Exposure
Occupational and residential risk assessments were not conducted for
niclosamide based on the low volume used. Protective measures currently on
niclosamide labels were considered adequate for the products being
reregistered. All products are Restricted Use Pesticides and all labels require
double layers of clothing and respirators. Industrial hygiene and medical
monitoring programs are required routinely for all handlers of products
containing niclosamide.
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Human Risk Assessment
Risk assessments were not conducted for niclosamide based on the
extremely low volume and infrequency of use. Niclosamide use is closely
regulated by the US Fish and Wildlife Service and by the states which issued
Special Local Need labels.
Environmental Niclosamide is applied to freshwater tributaries and is therefore expected to
Assessment ^ave ^tt'e imPact °n terrestrial plants and animals. Applications are designed to have
minimal effects on fish, but other aquatic animals are expected to be impacted.
Environmental Fate
• In addition to dilution and dispersion, sorption to sediments and suspended
particulates and possibly photodegradation (in clear shallow waters), are the major
routes of dissipation of niclosamide. Neither hydrolysis nor volatilization from soil
or water surfaces should be major fate processes for this compound.
• In most aquatic environments, niclosamide will adsorb to suspended solids and
sediment and this binding is reversible.
• It is unclear what role, if any, aerobic and anaerobic microbial degradation plays in
the dissipation of niclosamide in the aquatic environment.
• Accumulation in fish is not expected.
Ecological Effects
• Avian acute- moderately toxic (LDSO 60 mg/kg)
• Avian subacute dietary- practically nontoxic (LCSO > 5,419 mg/kg dietQ
• Mammalian acute- practically nontoxic (LD50 > 1,000 mg/kg)
• Fish (freshwater acute)- highly toxic to very highly toxic (LC50 0.03 - 0.23 mg/L)
• Invertebrates acute- slightly to very highly toxic (ECSO 0.034-50 mg/L)
• Invertebrates chronic- (NOAEC 0.03 mg/L; LOEC 0.05 mg/L)
• Aquatic plants- toxic (0.04 to > 1,450 mg/L)
Environmental Risk Characterization
The effects of niclosamide at the treatment site are likely to be mitigated by
photodegradation and the flushing action of the stream/river.
At the predicted treatment levels, acute high risk, acute restricted use, and
endangered species levels of concern are exceeded for aquatic animals. Although
niclosamide is likely to have an immediate effect on the aquatic community, the data
suggest that most organisms recover quickly and the treatment area community
structure returns to pre-treatment conditions within weeks or months. This recovery
is site specific and may take much longer in certain environments. Certain species
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Risk Mitigation
may be significantly impacted, most notably the indigenous lamprey species. In
general, however, native lamprey species have tended to populate the upper reaches
of tributary streams, whereas the sea lamprey is more likely to inhabit lower reaches
of the stream. Thus, nontarget species that may have been affected in the treatment
area are repopulated through downstream migration from untreated areas.
Furthermore, retreatment of the stream will not occur for at least 3 to 5 years.
Additionally, a genuine effort is made to document where sensitive populations
reside, and steps are undertaken to avoid treatments at concentrations known to be
toxic to these organisms. The long-term effects remain uncertain to more sensitive
species, such as indigenous lampreys, and to aquatic communities downstream from
the treatment sites where chronic effects may be more likely.
The use practices of niclosamide have been refined over the past several years
in order to lower the impacts of these applications on non-target organisms and to
lower occupational and non-occupational exposure to people. Niclosamide is a
Restricted Use Pesticide and the labels refer users to the US Fish and Wildlife
Service's Manual for Pesticide Applications. Additional mitigation required by the
Agency includes minor clarifications of label language. Aerial applications were
prohibited on some of the current labels and will be prohibited on all new labels in
order to lessen chances of nontarget human and other terrestrial animal exposures to
these restricted use compounds.
Additional Data EPA is requiring the following additional generic studies for niclosamide to
Required confirm its regulatory assessments and conclusions:
Photodegradation in Water Guideline # 83 5-2240 (161-2)
Aerobic Aquatic Metabolism Guideline # 835-4300 (162-4)
Anaerobic Aquatic Metabolism Guideline #835-4400 (162-3)
The Agency also is requiring product-specific data including product
chemistry and acute toxicity studies, revised Confidential Statements of Formula
(CSFs), and revised labeling for reregistration.
Product Labeling All niclosamide end-use products must comply with EPA's current pesticide
Changes Required Pr°duct labeling requirements. For a comprehensive list of labeling requirements,
please see attached labeling table from the Niclosamide RED document.
Reg U latory The use of currently registered products containing niclosamide in
Conclusion accordance with approved labeling for sea lamprey control or in ornamental fish
aquaculture will not pose unreasonable risks or adverse effects to humans or the
environment. Therefore, uses of several niclosamide products are eligible for
reregistration.
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The registrant has requested cancellation of the 5% granular product used to
kill snails which carry the vector for Swimmer's Itch.
The use of the 70% WP as a molluscicide in Puerto Rico against snails which
carry the vector for Schistosomiasis is considered to be ineligible pending additional
use information and exposure data.
Niclosamide products will be reregistered for all other uses once the required
product-specific data, revised Confidential Statements of Formula, and revised
labeling are received and accepted by EPA.
For More EPA is requesting public comments on the Reregistration Eligibility Decision (RED)
information document for niclosamide during a 60-day time period, as announced in a Notice of
Availability published in the Federal Register. The document is entitled
Reregistration Eligibility Decision: 3-Trifluoro-Methyl-4-Nitro-Phenol CASE 3082
and Niclosamide CASE 2455. To obtain a copy of this RED document or to submit
written comments, please contact the Pesticide Docket, Public Information and
Records Integrity Branch, Information Resources and Services Division (7502C),
Office of Pesticide Programs (OPP), US EPA, Washington, DC 20460, telephone
703-305-5805.
Electronic copies of the RED and this fact sheet are available on the Internet. See
http ://www. epa.gov/REDs.
Printed copies of the RED and fact sheet can be obtained from EPA's National
Service Center for Environmental Publications (EPA/NSCEP), PO Box 42419,
Cincinnati, OH 45242-2419, telephone 1-800-490-9198; fax 513-489-8695.
Following the comment period, the niclosamide RED document also will be
available from the National Technical Information Service (NTIS), 5285 Port Royal
Road, Springfield, VA 22161, telephone 1-800-553-6847, or 703-605-6000.
For more information about EPA's pesticide reregistration program, the
niclosamide RED, or reregistration of individual products containing niclosamide,
please contact the Special Review and Reregistration Division (7508C), OPP, US
EPA, Washington, DC 20460, telephone 703-308-8000.
For information about the health effects of pesticides, or for assistance in
recognizing and managing pesticide poisoning symptoms, please contact the National
Pesticide Telecommunications Network (NPTN). Call toll-free 1-800-858-7378,
from 6:30 am to 4:30 pm Pacific Time, or 9:30 am to 7:30 pm Eastern Standard
Time, seven days a week. Their internet address is ace.orst.edu/info/nptn.
-------
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
OFFICE OF
PREVENTION, PESTICIDES
AND TOXIC SUBSTANCES
CERTIFIED MAIL
NOV 171999
Dear Registrant:
I am pleased to announce that the Environmental Protection Agency has completed its
reregistration eligibility review and decisions on the pesticide chemical case for the active ingredients
TFM and Niclosamide. The enclosed Reregistration Eligibility Decisions (REDs), which were approved
on September 30,1999, contain the Agency's evaluation of the data base of these chemicals, its
conclusions of the potential human health and environmental risks of the current product uses, and its
decisions and conditions under which these uses and products will be eligible for reregisttation. The
RED bcludes the data and labeling requirements for products for reregistration. It may also include
requirements for additional data (generic) on the active ingredients to confirm the risk assessments.
To assist you with a proper response, read the enclosed document entitled "Summary of
Instructions for Responding to the RED." This summary also refers to other enclosed documents which
include further instructions. You must follow all instructions and submit complete and timely responses.
The first set of required responses is due 90 days from the receipt of this letter. The second
set of required responses is due 8 months from the date of this letter. Complete and timely
responses will avoid the Agency taking the enforcement action of suspension against your products.
If you have questions on the product specific data requirements or wish to meet with the
Agency, please contact the Special Review and Reregistration Division representative Linda Propst at
(703) 308-8165. Address any questions on required generic data to the Special Review and
Reregistration Division representative Laura Parsons at (703) 305-5776.
Sincerely yeujs,
sis A. Rogsi, Director/
Special Review and
Reregistration Division
Enclosures
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SUMMARY OF INSTRUCTIONS FOR RESPONDING TO
THE REREGISTRATION ELIGIBILITY DECISION (RED)
1. DATA CALL-IN (PCn OR "90-DAY RESPONSE"-If generic data are required for
reregistration, a DCI letter will be enclosed describing such data. If product specific data are required,
a DCI letter will be enclosed listing such requirements. If both generic and product specific data are
required, a combined Generic and Product Specific DCI letter will be enclosed describing such data.
However, if you are an end-use product registrant only and have been granted a generic data exemption
(GDE) by EPA, you are being sent only the product specific response forms (2 forms) with the RED.
Registrants responsible for generic data are being sent response forms for both generic and product
specific data requirements (4 forms). You must submit the appropriate response forms (following
the instructions provided) within 90 days of the receipt of this RED/DCI letter; otherwise, your
product may be suspended.
2. TIME EXTENSIONS AND DATA WAIVER REOUESTS-No time extension requests will be
granted for the 90-day response. Time extension requests may be submitted only with respect to actual
data submissions. Requests for time extensions for product specific data should be submitted in the 90-
day response. Requests for data waivers must be submitted as part of the 90-day response. All data
waiver and time extension requests must be accompanied by a full justificatioa All waivers and time
extensions must be granted by EPA in order to go into effect.
3. APPLICATION FOR REREGISTRATION OR "8-MONTH RESPONSE"-You must
submit the following items for each product within eight months of the date of this letter (RED
issuance date).
a. Application for Reregistratipn (EPA Form 8570-1). Use only an original application
form. Mark it "Application for Reregistratioa" Send your Application for Reregistration (along with the
other forms listed in b-e below) to the address listed in item 5.
b. Five copies of draft labeling which complies with the RED and current regulations and
requirements. Only make labeling changes which are required by the RED and current regulations (40
CFR 156.10) and policies. Submit any other amendments (such as formulation changes, or labeling
changes not related to reregistration) separately. You may, but are not required to, delete uses which
the RED says are ineligible for reregistration. For further labeling guidance, refer to the labeling section
of the EPA publication "General Information on Applying for Registration in the U.S., Second Edition,
August 1992" (available from the National Technical Information Service, publication #PB92-221811;
telephone number 703-605-6000).
c. Generic or Product Specific Data. Submit all data in a format which complies with PR
Notice 86-5, and/or submit citations of data already submitted and give the EPA identifier (MRID)
numbers. Before citing these studies, you must make sure that they meet the Agency's acceptance
criteria (attached to the DCI).
d- Two copies of the Confidential Statement of Formula (CSFl for each basic and each
alternate formulation. The labeling and CSF which you submit for each product must comply with P.R.
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Notice 91-2 by declaring the active ingredient as the nominal concentration. You have two options
for submitting a CSF: (1) accept the standard certified limits (see 40 CFR §158.175) or (2) provide
certified limits that are supported by the analysis of five batches. If you choose the second option, you
must submit or cite the data for the five batches along with a certification statement as described in 40
CFR §158.175(e). A copy of the CSF is enclosed; follow the instructions on its back.
e. Certification With Respect to Data Compensation Requirements. Complete and sign
EPA form 8570-31 for each product.
4. COMMENTS IN RESPONS E TO FEDERAL REGISTER NQTICE-Comments pertaining
to the content of the RED may be submitted to the address shown in the Federal Register Notice which
announces the availability of this RED.
5. WHERE TO SEND PRODUCT SPECIFIC PCI RESPONSES q»0-DAY) AND
APPLICATIONS FOR REREGISTRAT1ON rS-MONTH RESPONSES!
Bv U.S. Mail:
Document Processing Desk (RED-SRRD-PRB)
Office of Pesticide Programs (7504C)
EPA, 401 M St. S.W.
Washington, D.C. 20460-0001
By express:
Document Processing Desk (RED-SRRD-PRB)
Office of Pesticide Programs (7504C)
Room 266A, Crystal Mall 2
1921 Jefferson Davis Hwy.
Arlington, VA 22202
6. ERA'S RE VIEWS-EPA will screen all submissions for completeness; those which are not
complete will be returned with a request for corrections. EPA will try to respond to data waiver and
time extension requests within 60 days. EPA will also try to respond to all 8-month submissions with a
final reregistration determination within 14 months after the RED has been issued
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REREGISTRATION ELIGIBILITY DECISION
3-Trifluoro-Methyl-4-Nitro-PhenoI
CASE 3082
and
Niclosamide
CASE 2455
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TABLE OF CONTENTS
EXECUTIVE SUMMARY v
I. INTRODUCTION I
II. CASE OVERVIEW 1
A. Chemical Overview 1
B. Use Profile 2
C. Estimated Usage of Pesticide 4
D. Data Requirements 5
E. Regulatory History 5
III. SCIENCE ASSESSMENT 7
A. Physical Chemistry Assessment for TFM 7
B. Human Health Assessment for TFM 7
1. Toxicology Assessment 7
a. Acute Toxicity 7
b. Subchronic Toxicity 8
c. Developmental Toxicity 9
d Mutagenicity 10
2. Dose Response Assessment II
a. Dermal and Inhalation Exposure (any time period) 11
b. Cancer Classification 12
3. Exposure Assessment 12
a. Dietary Exposure 12
b. Occupational/Residential Exposure 12
4. Risk Characterization and Occupational Exposure 12
C. Physical Chemistry Assessment for Niclosamide 14
D. Human Health Assessment for Niclosamide 14
1. Toxicology Assessment 14
a. Acute Toxicity 14
b. Subchronic Toxicity 15
c. Chronic Toxicity/Carcinogenicity 17
d. Developmental Toxicity 18
e. Mutagenicity 19
E. Dose Response Assessment 20
1. Exposure Assessment 20
a. Dietary Exposure From Food and from Drinking Water 20
b. Occupational/Residential Exposure 20
2. Risk Characterization 21
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a. Dietary Risk including Drinking Water Risk 21
b. Occupational/ResidentialRisk 21
F. Environmental Assessment for TFM 21
I. Ecological Toxicity Data 21
a. Summary 21
b. Toxicity to Terrestrial Animals 22
(1) Avian Acute Oral, Subacute Dietary and Chronic 22
(2) Mammals, Acute and Chronic 22
(3) Insects 22
c. Toxicity to Freshwater Aquatic Organism 22
(1) Freshwater Fish, Acute and Chronic 22
(2) Freshwater Invertebrates, Acute and Chronic 23
(3) Toxicity to Estuarine/Marine Organisms 24
d. Toxicity to plants 24
2. TFM Environmental Fate and Transport 24
a. TFM Degradation 25
b. TFM Metabolism 26
c. TFM Mobility 27
d. TFM Accumulation 28
3. TFM Aquatic Exposure Assessment 28
G. Environmental Assessment for Niclosamide 28
1. Ecological Exposure and Risk Characterization for Niclosamide .... 28
a. Summary 28
b. Toxicity to Terrestrial Animals 29
(1) Avian Acute Oral, Subacute Dietary and Chronic 29
(2) Mammals, Acute and Chronic 29
(3) Insects 29
c. Toxicity to Aquatic Animals 29
(1) Freshwater Fish, Acute and Chronic 29
(2) Freshwater Invertebrates, Acute, Chronic 30
(3) Toxicity to Estuarine and Marine Organisms 30
d. Toxicity to Aquatic Plants 30
2. Niclosamide Environmental Fate and Transport 31
a. Niclosamide Chemical Degradation 31
b. Niclosamide Mobility 32
c. NicllosamideBioaccumulation 33
d. Niclosamide Field Studies 33
3. Niclosamide Aquatic Exposure Assessment 34
H. Environmental Exposure and Risk Characterization for TFM
and Niclosamide 34
a. Risk presumptions 34
b. Environmental Risk Assessment 35
c. Exposure and Risk to Non-target Terrestrial Organisms 36
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d. Exposure and Risk to Non-Target Freshwater Aquatic
Organisms 36
(1) Acute Fish 36
(2) Chronic Fish 37
(3) Acute Aquatic Invertebrates 38
e. Plants 38
f. Endangered Species 39
I. Environmental Risk Characterization 39
1. Terrestrial 42
2. Aquatic 42
3. Uncertainties 46
IV. RISK MANAGEMENT AND REREGISTRATION DECISION 47
A. Determination of Eligibility 47
B. Determination of Ebgibility Decision 47
1. Eligibility Decision 47
2. Eligible and Ineligible Uses 48
C. Regulatory Position 48
1. Food Quality Protection Act Findings 50
a. Determination of Safety for U.S. Population 50
b. Endocrine Disruptor Effects 50
2. Tolerance Reassessment 50
3. Benefits from Use of TFM/Niclosamide 50
4. Human Health Risk Mitigation 51
5. Ecological Risk Mitigation 52
6. Labeling Rationale 53
V. ACTIONS REQUIRED OF REGISTRANTS 55
A. Manufacturing-Use Products 55
B. End-Use Products 56
1. Additional Product-Specific Data Requirements 56
2. Labeling Requirements for End-Use Products 57
C. Required Labeling Changes Table Summary 57
D. Existing Stocks 65
VL APPENDICES 67
A. TABLE OF USE PATTERNS ELIGIBLE FOR
REREGISTRATION 69
B. TABLE OF GENERIC DATA REQUIREMENTS AND
STUDIES USED TO MAKE THE REREGISTRATION
DECISION 75
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C CITATIONS CONSIDERED TO BE PART OF THE
DATA BASE SUPPORTING THE REREGISTRATION
DECISION (BIBLIOGRAPHY) 85
D. COMBINED GENERIC AND PRODUCT SPECIFIC
DATA CALL-IN 99
1. Chemical Status Sheets 123
2. Combined Generic and Product Specific DCI Response
Forms (Insert A) Plus Instructions 127
3. Generic and Product Specific Requirements Status and
Registrants' Response Forms (Insert B) and Instructions ... 137
4. EPA's Batching of TFM and Niclosamide Products for
Meeting Acute Toxicity Data Requirements for
Reregistration 155
5. List of All Registrants Sent This Data Call-in Notice 161
E. LIST OF AVAILABLE RELATED DOCUMENTS AND
ELECTRONICALLY AVAILABLE FORMS 163
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TFM AND NICLOSAMIDE REREGISTRATION ELIGIBILITY DECISION TEAM
Office of Pesticide Programs:
Biological and Economic Analysis
Arnold Aspelin
Richard Peacock
William Gross
Timothy Kiely
Environmental Fate and Effects Assessment
Thomas Steeger
Dana Spatz
Health Effects Risk Assessment
William Hazel
Whang Phang
Virginia Dobozy
Jeffery Dawson
Registration Support
Daniel Peacock
Risk Management
Laura Parsons
Mark Wilhite
LUIS Representative for TFM
LUIS Representative for Niclosamide
Herbicide and Insecticide Branch
Economic Analysis Branch
Environmental Risk Branch IV
Environmental Risk Branch IV
Reregistration Branch 1
Reregistration Branch 1
Reregistration Branch 1
Reregistration Branch 1
Rodenticide and Insecticide Branch
Reregistration Branch I
Reregistration Branch I
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GLOSSARY OF TERMS AND ABBREVIATIONS
ADI Acceptable Daily intake. A now defiinct term for reference dose (RfD).
A E Acid Equivalent
a.i. Active Ingredient
ARC Anticipated Residue Contribution
CAS . Chemical Abstracts Service
CI Cation
CNS Central Nervous System
CSF Confidential Statement of Formula
DFR Dislodgeable Foliar Residue
ORES Dietary Risk Evaluation System
DWEL Drinking Water Equivalent Level (DWEL) The DWEL represents a medium specific (i.e. drinking water)
lifetime exposure at which adverse, non carcinogenic health effects are not anticipated to occur.
EEC Estimated Environmental Concentration. The estimated pesticide concentration in an environment, such
as a terrestrial ecosystem.
EP End-Use Product
EPA U.S. Environmental Protection Agency
FAQ/WHO Food and Agriculture Organization/World Health Organization
FDA Food and Drug Administration
FIFRA Federal Insecticide, Fungicide, and Rodenticide Act
FFDCA Federal Food, Drug, and Cosmetic Act
FQPA Food Quality Protection Act
FOB Functional Observation Battery
GLC Gas Liquid Chromatography
GM Geometric Mean
GRAS Generally Recognized as Sale as Designated by FDA
HA Health Advisory (HA). The HA values are used as informal guidance to municipalities and other
organizations when emergency spills or contamination situations occur.
HOT Highest Dose Tested
LC5n Median Lethal Concentration. A statistically derived concentration of a substance that can be expected
to cause death in 50% of test animals. It is usually expressed as the weight of substance per weight or
volume of water, air or feed, e.g., mg/l, mg/kg or ppm.
LDSO Median Lethal Dose. A statistically derived single dose that can be expected to cause death in 50% of
the test animals when administered by the route indicated (oral, dermal, inhalation). It is expressed as
a weight of substance per unit weight of animal, e.g.. mg/kg.
LDlo Lethal Dose-low. Lowest Dose at which lethality occurs.
LEL Lowest Effect Level
LOC Level of Concern
LOD Limit of Detection
LOEL Lowest Observed Effect Level
LOAEL Lowest Observed Adverse Effect Level
LUIS Label User Information System
MATC Maximum Acceptable Toxicant Concentration
MCLG MaximumContaminant Level Goal (MCLG) The MCLG is used by the Agency to regulate contaminants
in drinking water under the Safe Drinking Water Act.
Hg/g Micrograms Per <3ram
;.-g/L Micrograms per liter
mg/L Milligrams Per Liter
MO E Margin of Exposure
M P Manufacturing-Use Product
111
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MPI Maximum Permissible intake
MRiD Master Record Identification (number). EPA's system of recording and tracking studies submitted.
N/A Not Applicable
NOEC No Observable Effect Concentration
NPDES National Pollutant Discharge Elimination System
NOEL No Observed Effect Level
NOAEL No Observed Adverse Effect Level
OP Organophosphate
OPP Office of Pesticide Programs
Pa pascal, the pressure exerted by a force of one newton acting on an area of one square meter.
PAD1 Provisional Acceptable Daily Intake
PAG Pesticide Assessment Guideline
PAM Pesticide Analytical Method
PHED Pesticide Handler's Exposure Data
PHI Preharvest Interval
ppb Parts Per Billion
PPE Personal Protective Equipment
ppm Parts Per Million
PRN Pesticide Registration Notice
Q', The Carcinogenic Potential of a Compound, Quantified by the EPA's Cancer Risk Model
RBC Red Blood Cell
RED Reregistration Eligibility Decision
RE) Restricted Entry Interval
RfD Reference Dose
RS Registration Standard
RUP Restricted Use Pesticide
SLN Special Local Need (Registrations Under Section 24 © of F1FRA)
TC Toxic Concentration. The concentration at which a substance produces a toxic effect.
TD Toxic Dose. The dose at which a substance produces a toxic effect.
TEP Typical End-Use Product
TGA1 Technical Grade Active ingredient
TLC Thin Layer Chromatography
TMRC Theoretical Maximum Residue Contribution
torr A unit of pressure needed to support a column of mercury 1 mm high under standard conditions.
WP Wettable Powder
WPS Worker Prelection Standard
IV
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EXECUTIVE SUMMARY
EPA has completed its reregistration eligibility decisions forthe pesticides trifluoro-4-nitro-m-
cresol (TFM; Case 3082) and niclosamide (Case 2455) and determined that all lampricide uses, when
labeled and used as specified in this document, are eligible for reregistration. There are two Special Local
Needs labels for niclosamide which are eligible for reregistration assuming monitoring programs similar to
those conducted by the U.S. Fish and Wildlife Service (USFWS) are instituted for these uses. The public
health mollusicide use of niclosamide against snails that carry vectors for swimmer's itch has been voluntarily
canceled by the registrant The public health use for use of niclosamide against snails that carry vectors for
schistosomiasis is ineligible for reregistration at this time. These reregistration eligibility decisions include a
comprehensive reassessment of the required target data base supporting the use patterns of currently
registered products.
This document contains the reregistration eligibility decisions for two compounds which are
used alone or in combination against the same pest TFM is the main chemical used to kill sea lamprey larvae
in tributaries to the Great Lakes, the Finger Lakes, and Lake Champlain. Niclosamide is used to kill sea
lamprey larvae in combination with TFM; granular niclosamide is also used in situations where TFM would
not be appropriate, such as very deep waters, where it is cost prohibitive to treat the entire water column.
Tributaries are screened for larvae which are ready to transform to the adult stage and when populations are
high enough, the stream is treated Streams harboring sea lamprey larvae are treated once every three to five
years. Additionally, niclosamide is used as a mollusicide to kill freshwater snails which are vectors for human
and fish disease agents.
There are no tolerances for TFM and niclosamide because the Agency considers the uses
of these compounds to be non-food. Based on current use pattens and exposure profiles, residues in and
on food and/or feed or in drinking water are not expected to occur. Therefore, a dietary risk assessment is
not required.
Human risks from exposures to TFM and niclosamide do not exceed levels of concern for
the currently registered uses. The USFWS exerts tight control over the use of these compounds including:
(I) public notification prior to treating Great Lake tributaries to eliminate exposure to riparian water users
including fishermen, boaters, and swimmers; (ii) dissemination of information describing the treatment
programs and the associated application locations, dates, and duration; (iii) constant monitoring of the treated
stream for TFM and niclosamide concentrations during treatment; (iv) if requested by a given state,
concentrations at public water utility intakes are monitored and notification of state and local officials is made
regarding monitoring results to permit implementation of activated charcoal use, if necessary; and (v)
prohibition of irrigation during treatment
There are ecological concerns with the use of these compounds since impacts are expected
to non-target aquatic organism populations: however, the benefits of controlling the populations of the
introduced sea lamprey are expected to outweigh the risks to aquatic organisms. Most nontarget species
are tar less sensitive to the lampricides than are sea lampreys, and only a few are as sensitive. Pretreatment
assessments that determine abundance and distribution of sea lamprey larvae are used to identify specific
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streams and stream reaches that require latnpricide treatment Sensitive nontarget species in the streams are
identified prior to treatment, and measures are taken to protect them during applications of lampricides.
Threatened or endangered species are identified through consultation with state and federal agencies.
Procedures then are modified or developed, and employed to protect these species. Prior to treatment,
toxicity tests and in-stream studies sissess the effects of treatment on sensitive species or species of concern,
and the results indicate if a modification of treatment procedures is required to assure the safety of nontarget
organisms.
The USFWS which holds the registrations for these compounds has refined the use practices
over the past several years in order to lower the impacts of these applications on non-target organisms and
to lower occupational and non-occupational exposure to people. Additional mitigation required by the
Agency includes minor clarification;) of label language. Aerial applications were prohibited on some of the
current labels and will be prohibited on all new labels in order to lessen chances of nontarget human and other
terrestrial animal exposures to these restricted use compounds.
Some additional daia are required to understand the photodegradation potential of TFM and
niclosamide in water, and the aerobic and anaerobic aquatic behavior of niclosamide. The following data
requirements are being held in reserve pending the results of an ongoing monitoring study the USFWS is
currently conducting: the potential chronic effects of TFM and TFM/'niclosamide mixture on fish and aquatic
invertebrates, and the chronic sediment toxicity of niclosamide.
Before reregistering the products containing TFM and niclosamide, the Agency is requiring that
product specific data, revised Confidential Statements of Formula (CSF), and revised labeling be submitted
within eight months of the issuance of this document These data include product chemistry and acute toxicity
testing for each registration. After reviewing these data and any revised labels and finding them acceptable
in accordance with Section 3(c)(5) of FIFRA, the Agency will reregister a product Those products which
contain other active ingredients will be eligible for reregistration only when the other active ingredients are
determined to be eligible for reregistration.
VI
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I.
INTRODUCTION
In 1988, the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA) was amended to
accelerate the reregistration of products with active ingredients registered prior to November 1, 1984.
The amended Act provides a schedule for the reregistration process to be completed in nine years.
There are five phases to the reregistration process. The first four phases of the process focus on
identification of data requirements to support the reregistration of an active ingredient and the
development and the submission of data to fulfill the requirements. The fifth phase is a review by the
U.S. Environmental Protection Agency (referred to as "The Agency") of all data submitted to support
reregistration.
FIFRA Section 4{g)(2XA) states that in Phase 5 "the Administrator shall determine whether
pesticides containing such active ingredients are eligible for reregistration" before calling in data on
products, and either reregistering products or taking "other appropriate regulatory action." Thus,
reregistration involves a thorough review of the scientific data base underlying a pesticide's registration.
The purpose of the Agency's review is to reassess the potential hazards arising from the currently
registered uses of the pesticide; to determine the need for additional data on health and environmental
effects; and to evaluate whether the pesticide meets the "no unreasonable adverse effects" criterion of
FIFRA.
This document presents the Agencys decision regarding the reregjstiation eligibility of the
registered uses of TFM and niclosamide. The document consists of six sections. Section I is the
introduction. Section H describes TFM and niclosamide, their uses, data requirements, and regulatory
history. Section in discusses the human health and environmental assessment based on the data available
to the Agency. The human health assessment for TFM is discussed first, followed by the human health
assessment for niclosamide. Next the environmental fate and ecotoxicity assessment of TFM is followed
by this assessment for niclosamide. The final topic of Section III is a combined exposure and risk
characterization of the two chemicals. Section IV presents the reregistration decision for TFM and
niclosamide. Section V discusses the reregistration requirements for TFM and niciosamide. Finally,
Section VI contains the Appendices which support this Reregistration Eligibility Decision. Additional
details concerning the Agency's review of applicable data are available on request.
II. CASE OVERVIEW
A. Chemical Overview
The following active ingredients are covered by this Reregistration Eligibility Decision:
Common Name:
Chemical Name:
Chemical Family:
CAS Registry Number:
Lampricid®, TFM
3-Tnfluoromethyl-4-nitrophenol (IUPAC)
a,a,a-trifluoro-4-nitro-m-cresol, sodium salt (CAS)
phenol
88-30-2
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OPP Chemical Code: 036201
Empirical Formula:
Basic Manufacturer: Clariant International (Germany)
H & S Chemical Company,
packed for USFWS (USA) and Fisheries and Oceans
Canada, Ottawa, Ontario (Canada).
Common Name:
Chemical Name:
Bayluscide, niclosamide
5-chloro-N-(2-chloro-4-nitrophenyl)-2-
hydroxybenzamide (IUPAC)
2-amtno ethanol salt of 2',5'-dichloro-4'-nitro
salicylanilide (CAS)
Chemical Family: halogenated mononitrobenzamide
CAS Registry Number: 1420-04-8
OPP Chemical Code: 077401
Empirical Formula: CuHgCy^O,
Basic Manufacturer: Bayer, Specialty Products, Inc.
packed for USFWS (USA) and Fisheries and Oceans
Canada, Ottawa, Ontario (Canada).
B. Use Profile
TFM and Niclosamide:
Type of Pesticide:
Use Sites:
Target Pests:
Formulation Types:
TFM:
Niclosamide
lampricides
tributaries to the Great Lakes, the Finger Lakes and Lake
Champlain
Larval stage of the Sea Lamprey (Peiromyzon marinus)
Liquid concentrate (38%), Bar (solid)
70% Wettable Powder, Granular (3.2% and 5%)
Niclosamide
Type of Pesticide:
Use Sites:
Mollusicide for use against fresh water snails
Special Local Needs labels: Commercial ponds for
growing ornamental fish in FL and AR
Public Health Uses: Swimmer's Itch in MI, MN and WI,
Schistosomiasis in Puerto Rico
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Formulation Types:
70% Wettable Powder in FL, AR, and Puerto Rico
5% Granular in MI, MN, and WI
Method and Rates of Application:
TFM is the primary chemical used to control sea lamprey; niclosamide is used with TFM under
circumstances when TFM alone would pose too much risk to non-target organisms or would be cost
prohibitive. Niclosamide alone is also used as a survey tool for determining lamprey larval populations
and under certain conditions alone to treat deep, turoid waters. Specific application instructions and
formulas for application rates are included in the Manual for Application of Lampricides in the U.S.
Fish and Wildlife Service Sea Lamprey (Petromyzon Marinus) Control Program including
Standard Operating Procedures (1993). The different application methods complement each other to
achieve effective control. There are various non-chemical means of control, such as weirs, traps, and a
sterile male release program in place, but these non-chemical methods arc not adequate to control
lamprey populations without the use of TFM and niclosamide.
The liquid sodium salt formulation of TFM accounts for the majority of the applications. Most of
these liquid TFM applications are made with a direct-siphoning meter pump system in which the liquid
formulation is withdrawn from 5-gallon containers and routed directly into the treated stream. A rapid
calculation for larger bodies of water is 1 ppm TFM in 1 acre-foot of water requires 0.75 gallons of TFM
per surface area treated. Liquid TFM is also applied to many stagnant bodies of water that are
connected to or isolated from the main river during treatment by backpack sprayer or by boat.
The TFM bar formulation is sometimes applied to small springs and tributaries to give a
controlled release of TFM over a period of time. The rate of release depends on water velocity and
temperature. Each bar is used to treat 0.25 ft3 per second of discharge at 1 ppm for 8 hours at 18 >C or
0.8 ppm for 10 hours at 12°C. For best results, the USFWS manual recommends that TFM bars should
be suspended at least one inch above the stream bottom to permit movement of water on all sides and
should be placed where current velocity is < 0.5 feet per second
The wettable powder (WP) formulation of niclosamide is generally used to make a liquid slurry
which is not to exceed 20 pounds of the 70 WP (14 Ib ai) in 100 gallons of water. Additionally, the
concentration in the treated stream should not exceed 2 percent of the corresponding TFM
concentration. The slurries are prepared in an open system and since niclosamide is not readily soluble in
water, the slurry is constantly agitated and is delivered to the water surface by a peristaltic pump.
Applications of the granular 3.2% niclosamide formulation are used as a survey tool to "detect
and collect sea lamprey larvae in deep and turbid waters where electrofishing is ineffective." Applications
are made using a gasoline powered backpack blower device that spreads the granules over a wide area.
This formulation can also be used in specific treatment areas where the water depth makes the use of
TFM cost prohibitive.
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Decisions regarding application rates and times are based on both abiotic and biotic factors
including pH, stream discharge, time of day, temperature, total alkalinity, in-field bioassays, and lamprey
population assessment data. Spreadsheet-based models incorporating the aforementioned factors have
been developed to assist in determining application rates; the inter-relationship of the model input
parameters is based on historical data collected from previous applications to specific streams and, as
such, these predictive models are stream specific. Predicted treatment concentrations based on physico-
chemical data are then modified based on in-field flow-through bioassays used to establish the site-
specific LC99.9 for sea lamprey larvae and the LC25 for brown trout, hi Lake Superior and upper Lake
Michigan, streams tend to have soft water with pH less than 8.2 and thus require lower application rates
and are less likely to be candidates for niclosamide treatment In the lower tier of the Great Lake,
tributaries harboring lamprey may exhibit hardnesses exceeding 200 ppm with a pH range 8.1 - 8.7.
These streams tend to have greater diurnal pH fluctuations and may require that lampricide applications
be adjusted to reflect changing pH.
The manual states that while water concentrations of TFM are not to exceed 12 ppm, typical
target concentrations are generally 1 to 6 ppm. Niclosamide target concentrations in hard water streams
have ranged from 25 to 35 ppb; however, treatment concentrations are not allowed to exceed 50 ppb
(personal communication, Dorance Brege, U.S. Fish and Wildlife Service Treatment Supervisor 1999).
The wettable powder formulation of niclosamide is also labeled for use in ornamental fish ponds
in Florida and Arkansas. The product is applied to the bottom of drained ponds which are filled
immediately. The filled ponds are then allowed to sit undisturbed for at least four days before ornamental
fish are added (personal communication Craig Watson, Director, Tropical Aquaculture Laboratory,
August, 1999).
The Fish and Wildlife Service has made some aerial applications of Bayluscide 3.2% granular
formulation to the SL Mary's River in the US and Canada. The application is being made with a
helicopter and the rate is similar to the granular application from a boat. This one-time aerial application
is to treat 1562 surface acres of the St. Mary's River in Michigan over a three year period from 1998-
2000. It is not physically or economically feasible to treat the St Mary's River by boat since the time
period when Bayluscide application can be made is very short in order to protect spawning fish and
nesting osprey.
C Estimated Usage of Pesticide
According to the U.S. Fish and Wildlife Service (Johnson and Weisser 1996), of the 5,339
streams tributary to the Great Lakes, only 309 in the US are known to be or have been infested with sea
lampreys; there are 130 infested streams in Canada. Of the US streams, about 300 (<6%) have been
treated since the chemical control of sea lampreys began in the 1960's. Currently, 166 streams (<3% of
the total number of tributaries) are treated on a 3 - 5 year cycle. In a normal treatment year, 30 to 40
U.S. tributaries receive applications of lampricides. An average of approximately 80,000 pounds of
TFM active ingredient and approximately 300 pounds of niclosamide active ingredient were applied in the
Great Lakes from 1993 to 1997.
-------
Specific use data were received from the USFWS for the years 1993 through 1997. Tables 1
and 2 summarize the use of both compounds during these years.
Table 1: Summary of TFM use by the USFWS in the Great Lakes Region (1993-1997)
Lake
1993
1994
1995
1996
1997
pounds active ingredient used
Superior
Michigan
Huron
Erie
Ontario
Total
6717
18150
40371
0
9438
74676
19991
31219
26953
9561
7026
94750
15997
25507
24065
414
10307
76290
12083
29811
14605
5981
11001
73481
18768
22959
27926
2815
6442
78910
Table 2: Summary of Niclosamide use by the USFWS in the Great Lakes Region (1993-1997)
Lake | 1993
1994
1995
1996
1997
pounds active ingredient used
Superior
Michigan
Huron
Erie
Ontario
Total
0
I)
74
0
-.
81
53
251
33
0
16
353
114
53
198
0
0
365
18
207
16
0
33
274
197
103
89
0
21
410
D. Data Requirements
The Agency required the registrants to submit studies as specified in 40 CFR Section 158, Data
from these studies are sufficient to characterize the risks associated with the uses described in this
document. Appendix B includes all data requirements identified by the Agency for currently registered
uses needed to support reregistration.
E. Regulatory History
The sea lamprey (Petromyzon marinas) is a primitive eel-like fish distinguished from other fishes
by its lack of paired fins and jaws. Sea lampreys are closely related to the hagfish, and are generally
found as adults in saltwater. Most of the life of a sea lamprey is spent as a larva burrowed in the
sediment of fresh water streams. In this Hie stage, the animal is not harmful to other fish and feeds by
-------
filtering food from stream water. Sea lampreys may remain in the larval stage from 3 to more than 17
years before transfonning into the parasitic (predatory) stage. Parasitic stage lampreys feed by attaching
to fish and rasping deep wounds from which they suck blood, body fluids, and pieces of flesh. The
results of such attacks are often fatal for the host fish.
Sea lampreys were introduced to the Great Lakes when the Welland Canal around Niagara Falls
was constructed in 1829; by the late 1940's, lampreys had severely impacted the commercial and sport
fisheries in the Great Lakes. Early attempts to control sea lampreys began in 1953 with the installation of
mechanical traps in spawning streams, but these measures were largely unsuccessful. No effective control
was accomplished until the advent of a chemical control program with TFM (Lamprecid®) and
niclosamide (Bayluscide) in the late 1950's. According to the USFWS "the successful chemical control of
sea lampreys has allowed reestablishment of a robust sport and commercial fishery in the Great Lakes."
These compounds have been used since that time to manage the sea lamprey populations in the Great
Lakes, the Finger Lakes, and Lake Champlain. The use of these chemicals is managed by the Great
Lakes Fisheries Commission and its agents. The Commission was established by the Convention on
Great Lakes Fisheries Between the United States of America and Canada to enhance and protect
fisheries in the Great Lakes.
hi 1964, the U.S. Department of Agriculture (USDA), the Agency's predecessor for pesticide
regulation under FIFRA, registered its first product with TFM, a liquid formulation for control of sea
lamprey larvae. In the same year, USDA first registered a product containing niclosamide, a wettable
powder formulation for control of sea lamprey larvae and snails. In 1967, USDA registered two
manufacturing-use products containing niclosamide. In 1968, USDA registered its first granular
niclosamide products for sea lamprey larvae and snail control. In 1984, the EPA registered a new form
of TFM, a bar formulation, for sea lamprey control.
Currently the Agency has two registered TFM products, a liquid and bar formulation, for sea
lamprey larvae. It has also currently registered seven niclosamide products, five federal (Section 3 under
FIFRA) and two Special Local Need (Section 24c under FIFRA) products.
TFM (Lamprecid®) is an aquatic non-food outdoor use chemical. The lampricides (TFM and
niclosamide) Phase 4 review dated 03/21/92 summarized regulatory conclusions on the available residue
chemistry data and specified that additional data were required for reregistration purposes. Additional
submissions of data have been received since the Phase 4 Review was issued. There are currently no
tolerances for TFM or niclosamide residues in/on food/feed commodities. The Agency has determined
that the TFM residues hi fish are parent TFM and the TFM-glucuronide conjugate.
-------
m. SCIENCE ASSESSMENT
A. Physical Chemistry Assessment for TFM
TFM (Lamprecid®) is chemically a,a,a-trifluoro-4-nitro-m-cresol. Pure TFM is a yellow to
orange crystalline solid, with a melting point of 76° C and ionization constant of 4.4 x 10"7. The TGAI is
a dark red-brown liquid with a boiling point of 135-138° C, a density of 1.463 g/mL. and a vapor
pressure of 22 mm Hg at 25° C. TFM is soluble in water (0.498 g/100 g water at 25° C), and highly
soluble in most organic solvents. Aqueous solutions of TFM are acidic with tree phenol (pK = 6.07) and
form phenolate salts in alkali conditions.
B. Human Health Assessment for TFM
1. Toxicology Assessment
a. Acute Toxicity
The data on acute mammalian toxicity are summarized in Table 3. TFM has acute oral LD50 values of
141 and 160 mg/kg for males and females, respectively (Toxicity Category II). The acute dermal toxicity
is minimal, as indicated by a LD50 > 2000 mg/kg (Toxicity Category HI). It produced slight skin irritation
(Toxicity Category W) and caused eye irritation which was cleared within seven days after application
(Toxicity Category HI). It was not a dermal sensitizer. The acute inhalation data arc not available.
-------
Table 3. Summary of the Results of Acute Toxicity Studies on Technical Grade TFM1
GUIDE-
LINE #
8J-1
81-2
81-3
81-4
81-5
81-6
STUDY TYPE
Acute oral-rat
Acute dermal-rabbit
Acute inhalation
Primary eye irritation -
rabbits
Primary dermal irritation
- rabbits
Dermal sensilizalion
MRID#
40999204
41898102
'W99205
^•1898103
40999207
41898104
40999206
41898105
41898106
RESULTS
UD50= 160 mg/kg (M)
[A,, = 141 mg/kg (F);
LDM > 2000 mg/kg;
Eye irritant (corneal opacity, conjurtctival
redness, chemosis, & discharge; all clear by
day 7 after treatment)
Slight erythema seen on the treatment site.
Not a dermal scnsitizer
TOXICITY
CATEGORY
11
111
Not available
111
IV
1. The acute toxicity endpoints, listed above, are for informational purposes only. The data supporting these
endpoints may or may not meet current acceptability criteria. The acceptability status of these data may be reassessed
during product reregistration.
b.
Subchronic Toxicitv
The results did not show significant toxicity in two 90-day feeding studies in rats and in a 6-month
feeding study in dogs.
In a 90-day feeding study in rats (MRID 00112726), groups of weanling SD rats (10/sex/group)
were fed diets containing TFM (82 4%) at concentrations of 500,900,1620,2916, or 5248 ppm for
90 day. The control groups (20/sex) received the untreated diet The results showed that body weight,
food consumption, food efficiency, and hematological parameters were similar to those of the controls.
Observation data did not indicate any clinical signs in the treated rats. For clinical chemistry, there was a
decrease in aspartate aminotransferase (SGOT or AST) in both treated males and females of all groups.
However, this change did not show a dose-related effect, and was not considered biologically significant.
All other clinical parameters were similar to those of die controls. Organ weights, gross pathology, and
histological data did not show a treatment-related effect The NOAEL for this study was 5248 ppm (525
mg/kg/day, based on 1 ppm=0.1 mg/kg for young rats) which was the highest dose tested. No LOAEL
was established
In a second 90-day feeding study in rats (MRID 00112727), groups of weanling SD rats
(10/sex/group) were fed diets containing TFM (90%) at concentrations of 500,900, 1620, 2916, or
5248 ppm for 90 days. The control groups (20/sex) received the untreated diet The results showed that
body weights of the 2916 and 5248 ppm groups were consistently decreased (10-13%) in males from
week 3 to the end of the study. The decrease was statistically significant. Food consumption, and
-------
hematological parameters were similar to those of the controls. Clinical signs were not seen in the treated
or control rats. There was a decrease in the aspartate aminotransferase (SGOT) activity in both males
and females at 5248 ppm on the 21 day examination period, but by 90 day examination period the
SGOT values of 5248 ppm animals were similar to those of the controls. The alkaline phosphatase level
was slightly increased in both males and females of 5248 ppm groups, but no statistical significance was
found. At sacrifice, liver weights of the 2916 and 5248 ppm females were slightly increased. No gross
pathology and histological changes were observed. The LOAEL of this study was 2916 ppm (292
mg/kg/day, based on 1 ppm=0.1 mg/kg/day) based on decreased in body weights; the NOAEL was
1620 ppm (162 mg/kg/day).
A 90-day feeding study in dogs is not available, but there is a 6-month feeding study in dogs. In
the 6-month feeding study in dogs (MRID 00112725), groups of beagle dogs (4/sex/dose; 8-10 weeks
old) received TFM (85.6%) in fhe diet at concentrations of 300,1250, or 5000 ppm for 6 months. The
controls (4/sex) received 2% com oil by weight The results showed that a decrease in body weights was
seen in both males (12-15%) and females (8-16%) of the 5000 ppm level beginning at 10 weeks. The
body weight gains in these dogs were also decreased. Food consumption and food efficiency in 5000
ppm males and females also decreased, but not markedly. Clinical signs, hematology, clinical chemistry,
and urinalysis values were similar between the control and the treated animals. No treatment-related
changes in organ weight were seen in any treatment groups. Treatment-related gross and histological
changes were not found in TFM treated dogs. Under the conditions of this study, the LOAEL was 5000
ppm (125 mg/kg/day; based on 1 ppm =0.025 mg/kg/'day) based on decreases in body weights and
body weight gains; the NOAEL was 1250 ppm (31.25 mg/kg/day).
c. Developmental Toxicity
In a developmental toxicity study (MRID 00131201), pregnant COBS® CD* (SD) Br rats
(25/group) received TFM (85.9% a.i.) by gavage at doses of 0 (corn oil vehicle), 25, 125, or 250
mg/kg/day on gestation days (GD) 6-15, inclusive. It was not specified whether doses were adjusted for
percent active ingredient. On GD 20, all dams were sacrificed and all fetuses were examined for external
malformations/variations. Approximately one-half of each litter was placed hi Bourn's fixative for
subsequent visceral examination and the remainder stained for skeletal examrnation.
All animals in the control, low-, and mid-dose groups survived until scheduled sacrifice. Two
high-dose dams died during the treatment interval, one on GD 6 and the other on GD 12 and the study
author stated that the deaths were treatment related. The only other clinical sign of toxicity was salivation
which was observed in 0/25, 0/25, 2/25, and 22/25 (p < 0.01) animals in the 0,25, 125, and 250
mg/kg/day groups, respectively. There were no significant differences in maternal body weights between
the treated and control groups at any time during gestation. Food consumption was not measured.
Therefore, the maternal toxicity LOAEL is 250 mg/kg/'day based on salivation and mortality. The
corresponding maternal toxicity NOAEL is 125 mg/kg/day.
No treatment-related effects were observed for gravid uterine weights, number of fetuses/litter,
pre- and postimplantation loss, numbers of corpora lutea/dam, number of implantations/dam.
-------
lesorptions/'dam, fetal body weights, or fetal sex ratios. No statistically significant differences in the
incidence rates of any external, visceral, or skeletal malformations/variations were observed in the treated
litters as compared to the controls. Therefore, the NOAEL for developmental toxicity is 250 mg/kg/day
(highest dose tested).
d Muitagenicity
The available mutagenicity studies showed that TFM did not induce mutation in Ames assays
(MRID 42551801). TFM was shown to be negative in a mouse micronucleus assay (in vivo) (MRID
42187101) and in an unscheduled DNA synthesis assay with primary rat hepatocytes (MRID
40999202). However, TFM produced chromosomal aberrations in an in-vitro cytogenetic assay in
CHO cells, in the presence and absence of metabolic activation (MRID 40999201).
In an Ames assay (MRID 42551801), TFM (40.24%) was tested on Salmonella strains TA98,
TA100, TA1535, TAI537, andTAI638. The doses used were 75,100,200,300, or 400 ug/plate b
the presence and absence of the metabolic activatioa The positive controls were 4-nitroquinoline-N-
oxide, benzo(a)pyiiene and N-methyl-N-nitro-N-nitro$o-2-amino fluorene. TFM was shown to be
negative for mutagenicity under the conditions of this test.
In amouse micronucleus assay (MRID 42187101), groups of mice (5/sex/dose) received a single
administration of TFM by gavage at doses of 80,400, or 800 mg/kg. A negative control group (com oil),
a positive control group (cyclophos-phamide, 80 mg/kg), and a secondary dose group (10
mice/sexXTFM at 800 mg/kg) were included in mis study. At 800 mg/kg of TFM, there were deaths
within the first 24 hours after dosing. The results showed that under the conditions of this study, TFM did
not induce a significant increase in the incidence of micronucleated marrow polychromatic erythrocytes.
Therefore, TFM is considered as negative in the in vivo mouse micronucleus assay.
In an unscheduled DNA synthesis assay (MRID 40999202), freshly prepared rat hepatocytes
were exposed to TFM (=86%) at final concentrations of 0.025,0.05,0.101,0.252,0.504,1.01,2.52,
or 5.04 fj.g/m\. Concentrations > 10.09 ,wg/ml were not listed because there was complete cytotoxicity
and some precipitation. At 5.04 ^g/iaL, 5% of the cells died. Under the conditions of this study, TFM
was negative for mutagenicity.
In an in vitro cytogenetic assay (MRID 40999201), cultured CHO cells were exposed to TFM
(86%) at concentrations of 49.6, 99.2, 149, or 198 Mg/ml for 17.25 hrs. in absence of die S9 metabolic
activation. In the presence of the S9 activation, the CHO cells were exposed to TFM at concentrations
of 115,384, 769, 1150, or 1540 ^g/ml for 2 hrs. After exposure to TFM, the treated cells were washed
with buffered saline, and complete McCoy's a medium containing 0.1 ^g/ml Colcemid was added to the
washed cells. The cells were then incubated for 2.5 hrs (without S9) or 7.5 hrs (with S9). The
metaphase cells were then harvested, and slides prepared for analysis. The results showed that, without
S9 activation, TFM at concentrations of 149 and 198 ,ug/ml induced chromosomal aberrations, consisting
mainly of simple chromatid breaks. In the presence of S9 activation, 1150 and 1540 ug/ml of TFM
10
-------
caused a statistically significant and dose-related increase in chromosomal aberrations, consisting of
simple chromatid and chromosome breaks.
2. Dose Response Assessment
TFM has been classified as a low-volume and nonfood use chemical based on the quantity used,
the method of application, and the rapid dissipation of any possible residues in fish and water. Therefore,
the acute and chronic dietary toxicity endpoints and a dietary risk assessment are not required for TFM.
Based on the use and possible exposure scenarios, the relevant exposure is short-term
occupational dermal exposure. No residential exposure is expected because TFM is applied in a very
limited use area and extensive public notification is required by the USFWS to eliminate exposure to
riparian water users including fishermen, boaters and swimmers. Inhalation toxicity endpoints for risk
assessment were not selected because significant inhalation exposure is not expected; also TFM is a
viscous dark liquid and certain formulations are in the form of solid bars.
Table 4. Summary of the Results of Subchronic Toxicity Studies on TFM
GUIDE-
LINES
82-la
82- la
82-lb
83-3
84-2
STUDY TYPE
feeding studies
developmental
mutagenicity
MKlDNo.
00112726
rats
OOII2727
rats
001 12725
dogs
00131201
rats
42551801
42187101
40999202
40999201
RESULTS
no treatment related effects
decreased body weights
decreased body weights
and body weight gains
maternal salivation and
mortality
litter no treatment related
effects
ENDPOIMT
NOAEL - 5249 ppm (525 mg/kg/day)
LOAEL not established
NOAEL = 1620 ppm (162 mg/kg/day)
LOAEL - 291 6 ppm (292 mg/lcg/day)
NOAEL - 1 250 ppm (31 mg/kg/day)
LOAEL = 5000 ppm (125 ing/kg/day)
NOAEL = 125 mg/kg/day
LOAEL - 250 mg/kg/day
NOAEL = 250 mg/kg/day
LOAEL not established
negative (Ames assay)
negative (mouse micro-nucleus assay)
negative (UDS assay)
positive (in vitro cytogenetic assay)
a. Dermal and Inhalation Exposure (any time period)
A short-term dermal endpoint of 125 mg/kg/day was chosen based on a rat developmental
toxicity study. The toxic effect was not developmental in nature with salivation and mortality as the effect
in the dams. This is the most pertinent toxicity study to use for a dermal endpoint, and although no males
11
-------
were evaluated, the endpoint has been applied to account for exposures to the general population
including both males and females.
Although an inhalation toxicity endpoint was not selected, exposures contributed by the inhalation
route were combined with the dermal exposures as a conservative measure.
b.
Cancer Classification
There is an acceptable chrccic feeding study in hamsters, and the results do not indicate that
TFM induced an increase in any tumor incidence (MRID 00081184). A chronic feeding study in rats was
also conducted in 1975 (MRID 00059379). but the results are not conclusive regarding whether TFM
induced an increase in any specific tumor incidence. It should be noted that the chronic toxicity studies
were conducted in the i 970's prior to implementation of the EPA Guidelines (1982) for toxicity testing.
Because TFM is a nonfood use, the Agency does not require a cancer study.
3. Exposure Assessment
a- Dietary Exposure From Food and Drinking Water
TFM has been classified as a low-volume and nonfood use chemical based on the quantity used,
the method of application, the USFWS restrictions against irrigation and drinking water removal from
streams during treatment, and the rapid dissipation of any possible residues in fish and water. Therefore,
the dietary exposure is expected to be minimal and a dietary risk assessment is not required for TFM.
b. Occupational/Residential Exposure
Based on the use and possible exposure scenarios, the relevant exposure is occupational dermal
and inhalation exposure. No residential exposure is expected because TFM is applied in a very limited
use area and extensive public notification is required by the Fish and Wildlife Service to eliminate
exposure to riparian water users including fishermen, boaters, and swimmers.
4. Risk Characterization and Occupational Exposure
The USFWS program for the chemical control of sea lampreys using TFM and niclosamide is
presented in the Manual for Application of Lampricides in the U.S. Fish and Wildlife Service Sea
Lamprey Control Program including Standard Operating Procedures (1993). This manual focuses
on minimizing occupational and general public exposures by specifying the manner in which applications
are made (i.e., techniques and equipment), the level of risk mitigation for those occupationally exposed,
and die approaches commonly used to reduce risks to the general public resulting from the use of treated
waterways (e.g., swimming, fishing, or boating) or through drinking water exposures are mandated. This
program served as the basis for the exposure/risk assessment completed for TFM and niclosamide.
12
-------
Several issues pertain to the quality of the assessment and should be considered when interpreting
the results of the occupational handler risk assessment. These include:
No chemical-specific exposure data were submitted As a result, all handler analyses were
completed using surrogate data from the Pesticide Handlers Exposure Database (PHED).
The backpack handler assessment was completed using "low quality" PHED data, due to the
lack of a more acceptable data set
Use information provided for the years 1993 through 1997 served as the basis for this
assessment.- Specifically, data from 1997 were selected as being representative of TFM and
niclosamide use patterns. The upper ranges of these application rates were accepted as
representing a reasonable limit to the daily use capacity (i.e., maximum amount in a single day that
can be applied). However, based on personal communication between J. Dawson (EPA) and
Terry Morse (USFWS) on 9/28/98, handling of the TFM necessary to treat larger rivers (e.g.
1500 to >3000 kg/stream) would actually be conducted by 3-5 workers over, perhaps, 3-5
days.
The use patterns, based on the USFWS manual, and current labeling indicate 4 major
occupational exposure scenarios for TFM based on the specified types of equipment and application
techniques that can potentially be used to make applications. These scenarios include:
(1 a) niixmg/loading/application of liquid TFM via direct metering pump from 6 gallon end-use product
drums (low chemical use treatment events);
(1 b) mking/loading/application of liquid TFM via direct metering pump from drum filled by open pour
of 6 gallon end-use product drums (larger chemical use treatment events);
(2) mixing/loading/application of liquid TFM using backpack sprayers for supplementary still water
applications; and
(3) applicator (i.e., placement) of TFM bars.
Even though 4 exposure scenarios were identified for the use of TFM. exposures/risks were only
calculated for scenarios Ib and 2 because these scenarios present the highest exposures for TFM.
Risks associated with two occupational TFM scenarios were calculated using the variables
associated with 41 actual USFWS treatments of Great Lakes tributaries conducted in 1997. Exposure
estimates were based on PHED data, assumed 100% dermal and inhalation absorption, and assumed a
70-kg body weight. A margin of exposure (MOE) of 100 or greater is considered to not be of concern.
MOEs for mixer/Ioader/applicators applying TFM via metering pumps and wearing maximum PPE as per
the USFWS Manual were 100-14,186 for 38 of the 41 stream applications. In the remaining three
streams, MOEs were 66, 68, and 96 for high treatment volumes of greater than 2100 kg/treatment/day.
This assessment assumes that the treatment amount was handled per day by one mixer/loader/applicator
and so the values are thought to be conservative because the USFWS lias informed the Agency that
larger applications are actually made by a crew of 3-5 handlers over a period of 3-5 days.
13
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MOEs were calculated for the backpack sprayer scenarios assuming that 1% of the treatment
amount for the 41 stream treatments from 1997 was applied via a backpack sprayer. MOEs were 106-
15,571 for 39 stream scenarios; the other two treatments resulted in MOEs of 73 and 75. Again, this
assessment assumes that the treatment amount was handled per day by one rnixer/loader/applicator and
so the values are thought to be conservative because the USFWS has informed the Agency that larger
applications are actually made by a crew of 3-5 handlers over a period of 3-5 days. In the case of the
backpack spray scenario, The USFWS provided additional information that details how much TFM was
applied by backpack spray in 1997. The amount applied in four treatments ranged from 3.1 to 55.2
kg/treatment which would result in MOE's of 45 to 807 if these applications were made by one
mixer/loader/applicator in one day. Again, since these were also assumed to be 3-5 handlers over a
period of 3-5 day. the Agency has no concern for those fairly infrequent scenarios where large
treatments result in apparent MOEs below 100.
C Physical Chemistry Assessment for Niclosamide
Niclosamide is a yellow crystalline solid; pure niclosamide (ethanolamine salt) decomposes at
208° C, has a bulk density of 1.59 g/cm3 at 22° C, and a vapor pressure of 9.9 x 10'9 mm Hg at 25"C.
Niclosamide is practically insoluble in water (1.05 x 10~5 g/100 mL).
D. Human Health Assessment for Niclosamide
1. Toxicology Assessment
a. Acute Toxicity
The following table summarizes the available acute toxicity data for niclosamide.
14
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Table 5: Acute Toxicity of Niclosamide.
Guideline #
81-1
81-2
81-4
81-5
81-6
Study Type
Acute Oral - rat
Acute Dermal -
rabbit
Primary Eye
Irritation
Primary Skin
Irritation
Dermal
Sensitization
MRlDs*
42552301*
42552301*
42552305*
42552305
42552306
Results and Toxicity Cateeorv
Single dose 1 000 mg/kg; no mortality or clinical signs
LD50>1000mg/kg.
Toxicity Category in females III or higher; could not be
determined in males.
No mortality or clinical signs; LD50>2000mgAcg.
Toxicity Category 111 for females; could not be determined for
males.
Evidence of eye irritation (iritis, cornea! opacity, chemosis,
redness) at 72 hours.
Toxicity category not assigned because eyes were not
examined beyond 72 hours.
Toxicity Category IV based on no irritation in animals %vith
unabraded skin.
Moderate dermal scnsitizer.
* Submitted studies were not acceptable to fulfill guidelines, but provided some useful information for risk assessment.
b. Subchronic ToxJcity
The available subchronic studies are summarized below.
Subchronic toxicity in rats
In a subchronic toxicity study (MRID 42552307), Bayer 73 (niclosamide) (purity not given;
batch 8059410, formula 11089) was administered to 20 Sprague-Dawley rats/sex/dose in the diet at
dose levels of 0, 300, 1250, or 5000 ppm (0, 30, 125 and 500 mg/kg/day, respectively), for 90 days.
There were no treatment-related deaths. Clinical signs were not provided, but were reportedly
similar in control and treated groups. The weekly and terminal body weights of treated rats were < 7.4%
lower than that of controls (p & 0.05) for terminal body weight in both sexes given 5000 ppm and in
males given 1250 ppm and overall body weight gains were <. 8.6% lower than of controls, but these small
decreases were not toxicologically significant. There were no treatment-related effects on food
consumption or food utilization efficiency. Urinalysis, clinical chemistry and hematology analysis revealed
no notable differences from the controls, although most clinical chemistry and some hematology
parameters required by EPA Guidelines were not assayed. The small but statistically significant
alterations (<. 9.9%, p < 0.05 or 0.01) in the absolute and/or relative weights of the liver, kidneys, heart,
spleen, and gonads in one or both sexes lacked histopathological correlates, were often unrelated to
dose, and were not toxicologically significant. There were no treatment-related gross or microscopic
lesions.
15
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Under the conditions of this study, a LOAEL cannot be established for either male or female rats
because there were no treatment-related findings. The NOAEL is 2 5000 ppm (500 mg/kg/day).
This subchronic toxicity (Guideline 82-la) study is classified as unacceptable and not
upgradeable because the animals were not adequately dosed; the maximum dose was well below the limit
intake of 1000 mg/kg/day. Additionally, numerous parameters required by die Agency study guidelines
(e.g. compound analysis in the diet, clinical chemistry) were not measured.
SubchroTiic toxicity in dogs
In a subchronic toxicity study (MRID 42552309), Bayer 73 (niclosamide) (70% wettable
powder, batch 0053050) was administered for 180 days to 3 beagle dogs/sex/dose in the diet at dose
levels of 0, 62.5,250, or 1000 ppm (0, 1.56,6.25, or 25 mg/kg/day, respectively). No statistical
analysis was performed on the study results.
No animals died or exhibited any toxic signs during the study. The biweekly body weights and
daily food consumption of treated and control dogs were similar. Body weight gains were not clearly
treatment-related in either sex, and were within approximately 8% of controls at 1000 ppm for die major
part of the study (weeks Vz-24 for males and V^-20 for females). There were no treatment-related erTects
on any clinical chemistry, hematology, or urinalysis parameters, and the rates of bromsulfophthalein and
phenol-sulfonephthalein clearance were similar in treated and control groups. The bone marrow
myeloid/erythroid ratio of high-dose males and females was much lower than that of controls (4.3/1 in
controls vs. 1.0/1 for males and 2.0/1 for females), suggestive of lowered WBC production or elevated
erythrocyte production, but neither possibility was substantiated by the hematology results.
Microscopic lesions were seen primarily in the lungs, kidneys, and liver of both sexes, but these
lesions could not be definitively attributed to treatment because they were seen in both treated and control
dogs (incidence of 0/3 to 2/3 per dose). Additionally, none of the histology findings were correlated with
gross Lesions or alterations in clinical chemistry parameters.
Based on the lack of definitive treatment-related findings under the conditions of this study, a
LOAEL cannot be established for either male or female dogs. The NOAEL is z 1000 ppm (highest dose
tested; calculated as 25 mg/kg/day.
This subchronic toxicity (Guideline 82-lb) study is classified as unacceptable and not
upgradeable because the animals were not adequately dosed; the maximum dose was well below the limit
intake of 1000 mg/kg/day recommended by the guideline. Additionally, 4 dogs/sex should have been
used and data for a number of other parameters (e.g. compound analysis in the diet, some clinical
chemistry parameters) were not provided.
16
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icTt fa* hamsters
In a subchronic toxicity study (MRID 42552308), Bayer 73 (niclosamide) {purity not given;
batch 8059410, formula 11089) was administered to 20 Syrian hamsters/sex/dose in the diet at dose
levels of 0, 300, 1250, or 5000 ppm (0, 39, 177, and 726 mg/kg/day, respectively, calculated by the
reviewer) for 90 days,
No treatment-related clinical signs of toxicity were observed in the study, and there were no
treatment-related deaths. However, the treatments caused the hamsters in all dose groups, except for
low-dose females, to have significantly lower body weights compared to controls (P < 0.05) at the
termination of the experiment and probably much earlier. At the termination of the experiment, the
reductions in body weights compared to controls were 8,6%, 9.3%, and 14.3% in males fed 300 ppm,
1250 ppm, and 5000 ppm, respectively. In females, the reductions were 5.5% (not significant), 9.7%,
and 1 1.0%, at the same doses, respectively. The percent reductions in body weight gain over the 13
weeks were 12.0%, 12.0%, and 20.7% in males, and 8.2%, 14.3% and 17.3% in females at the
respective doses. Food consumption was decreased in the 5000 ppm group males and females at week 1
but was then relatively consistent across treated groups. If the reduced food consumption had been
caused by palatability alone, it is expected that the animals would adjust and consume equal or increased
amounts for the remainder of the study and that the body weights would rebound. However, there was
continued decreased body weights in the treated animals, especially the 5000 ppm group males and
females. Therefore, it is concluded that there was a treatment-related effect on body weight and body
weight gain. The effect is more pronounced in the 5000 ppm group males and somewhat in the 5000 ppm
group females. There was an associated decrease in the weights of certain organs and in the animals'
efficiency of food utilization. There were no treatment-related effects on hematology, clinical chemistry,
urinalyses, gross pathology, or histopathology.
The LOAEL is 5000 ppm (726 mg/kg/day) in males and females based on decreased body
weight and body weight gain. The NOAEL is 1250 ppm (177 mg/kg/day).
This subchronic study is classified as unacceptable/guideline but upgradeable to
acceptable/guideline upon furnishing missing information regarding compound purity. Numerous endpoints
were not tested for, including many clinical chemistry parameters and a few hematology parameters;
however the study can be used for regulatory purposes if the compound purity is supplied.
c. Chronic Toxiciry/Carcinogenicity
Chronic toxicity and carcinogenicity studies are not required for non-food use chemicals.
However, if available, the studies could substitute for missing subchronic studies. A chronic toxicity study
in rats (MRID 42698001C) has been submitted but it has been classified as unacceptable. The National
Cancer Institute conducted bioassays in rats and mice with niclosamide in 1978. Osborne-Mendel rats
and B6C3F1 mice were treated with clonitralid (synonym for niclosamide) in the diet at concentrations of
28,433 (« 1421 mg/kg/day) or 14,216 (*71 1 ppm) for rats, and 549 («78 mg/kg/day) or 274 ppm («39
mg/kg/day) for mice for 78 weeks. Because of inadequate survival among male mice, the results could
17
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not be considered conclusive in this sex. There was no evidence that clonitralid was carcinogenic to male
and female rats and female mice.
d Developmental Toxicity
The available study does not satisfy the developmental toxicity testing requirements.
Developmental toxicity in rabbits
In a developmental toxicity study (MRID 42552310), pregnant New Zealand white rabbits were
administered Bayer 73 (niclosamide, 70%, a.i.; Batch No. 0053050) by gavage at doses of 0.20,60.
and 180 mg/kg/day on gestation days (GD) 8-18, inclusive. Does were deemed pregnant if live fetuses
were observed at cesarean section (GD 29) resulting in only 10,10,10, and 7 animals used per group,
respectively. All fetuses were sexed, weighed, examined for external maltbnnations/variations. and X-
rayed for subsequent skeletal examination. One-half of the fetuses were preserved in Bouin's solution for
razor blade sectioning by the Wilson technique. The other half were preserved in formaldehyde and
subjected to gross necropsy.
No evidence of maternal toxicity was observed in this study. Mean fetal body weights of the
treated groups were 83-89% of the control group level, but there was a corresponding increase in the
number of fetuses/litter. Statistical analysis of fetal body weights did not account for litter size and fetal
body weights of the treated groups were within the expected range for the tabbit. Therefore, the
decrease in fetal body weights is no*, considered treatment-related. When the incidence rates of
peritoneal hemorrhage observed in fetuses during either Wilson's examination or gross necropsy are
combined, 0/10,4/10,5/10, and 4/7 litters in the 0, 20, 60, and 180 mg/kg/day groups, respectively,
contained affected fetuses. The incidence rate is statistically significant (p s 0.05) in all treated groups.
Lack of a clear dose-response in the number of litters affected, involvement of only one fetus in each
affected litter, and few numbers of litters evaluated, make peritoneal hemorrhage an equivocal treatment-
related effect.
Several major deficiencies in the conduct of this study make it inadequate for the evaluation of the
potential developmental toxicity of Bayer 73 in the rabbit. Therefore, LOAELs for maternal and
developmental toxicity could not be established
This Guideline 83-3b study is classified as unacceptable (not upgradable) and does not satisfy the
Agency guideline requirements for a developmental toxicity study in rabbits. This study is inadequate for
determining either a maternal or developmental toxicity LOAEL. All animals were not treated
concurrently, only females with live fetuses were included in the study, inappropriate statistical analyses
were used for fetal body weight data, the use of X-ray films is inadequate for fetal skeletal evaluation, and
the dosing solutions were nov analyzed for concentration, homogeneity, or stability.
18
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e.
Mutagenicity
Hie mutagenicity testing requirements have not been fully satisfied The Salmonella
typhimurium reverse mutation assay (Ames assay) has not been fulfilled
Chromosome Aberration in Bone Marrow Cells
In a mammalian cell cytogenetics assay (chromosome aberration in bone marrow cells) (MRID
43677902), male and female Crl:CD(ICR) BR mice, 15/sex/group, were exposed to niclosamide
(98.9%) at doses of either 1250,2500 or 5000 mg/kg by a single gavage administration. At 6, 18, or 30
hours after test substance administration, 5/sex/group were sacrificed at each period Bone marrow cells
were harvested immediately after sacrifice. The vehicle control was com oil. The positive control, which
was cyclophosphamide, was adequate. There is no evidence of chromosome aberrations in bone
marrow cells induced over background
This study is classified as acceptable/guideline. It satisfies the requirement for FTPRA Test
Guideline 84-2 for in vivo cytogenetic mutagenicity data.
Mammalian Forward Gene Mutation Assay
In a mammalian cell gene mutation assay (thymidine kinase locus) (MRID 43677901), L5178Y
mouse lymphoma cells cultured in vitro were exposed to niclosamide (98.9%) in dimethylsulfoxide at
concentrations of 2.50 to 80.0 ug/ml in the presence and absence of mammalian metabolic activation.
Without S9 activation, trial 1 was aborted due to excessive cytotoxicity. In trial 2, doses of 30 to
80 ug/ml were excessively cytotoxic; the remaining six doses of 2.50 to 25.0 ug/ml produced no increase
in the number of mutant colonies. Survival (relative growth) was relatively constant at 15.5 to 19.9% over
the six doses.
With S9 activation, trials 1 and 3 were aborted due to excessive cytotoxicity. In trial 2, at doses
of 1.25 to 40 ug/ml, severe cytotoxicity was observed at > 3.75 ug/ml. At 1.25,2.5 and 3.75 ug/ml,
there was no increase in mutant colonies. In trial 4, at doses of 2.5 to 40.0 ug/ml, there was no increase in
mutation frequency. There was a dose-related increase in relative growth (9.0% at 40.0 ug/ml to 76% at
2,5 ug/ml). There was no increase in the mutant frequency with niclosamide at cytotoxic doses (25.0
ug/ml -S9; 40 ug/ml +S9). The positive controls induced the appropriate response.
This study is classified as acceptable/guideline. It satisfies the requirement for FIFRA Test
Guideline 84-2 for in vitro mutagenicity (mammalian forward gene mutation) data.
19
U.S. EPA Headquarters Library
Mail code 3201
1200 Pennsylvania Avenue NW
Washington DC 20460
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E. Dose Response Assessment
a. Dietary
Niclosamide is classified as a low-volume, and nonfood use chemical based on the quantity used,
the method of application, and the rapid dissipation of residues in fish and water. As a nonfood use
chemical, the acute and chronic dieiary endpoints for niclosamide are not necessary and a reference dose
is not required.
b. Short/Intermediate Term Occupational and Residential
No endpoints were established for niclosamide. Short and intermediate term exposures may
occur, but are not expected to be substantial based on the low volume used. Long term exposure and,
therefore, long-term risk is not expected
There are no residential uses.
1. Exposure Assessment
a. Dietary Exposure From Food and from Drinking Water
Niclosamide is classified as a low-volume and nonfood use chemical based on the quantity used,
the method of application, the USFWS restrictions against irrigation and drinking water removal from
streams during treatment, and the rapid dissipation of any possible residues in fish and water. Therefore,
the dietary exposure is expected to be minimal and a dietary risk assessment is not required for
niclosamide.
b. Occupational/Residential Exposure
It is anticipated that regardless of whether niclosamide is used to control sea lampreys or fresh
water snails, the application methods: and exposure issues are similar for handlers. As a result, the
USFWS sea lamprey control program manual was used as a basis for the niclosamide and TFM
exposure/risk assessment The specifics of this manual and available labeling should be the basis for any
niclosamide and TFM use. Postapplication scenarios to swimmers, boaters and fisherman should result in
minimal exposure from the lampricide use of niclosamide based on the USFWS program.
There are currently two Special Local Needs labels for use of niclosamide in commercial
aquaculture for the production of ornamental fish in Florida and Arkansas. The water from this treatment
is not released and the fish are not used as a food source. There should be limited occupational and no
residential exposure from these uses.
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2. Risk Characterization
a. Dietary Risk including Drinking Water Risk
There is no reasonable expectation of humans being exposed to niclosamide residues in die diet
via water, fish, irrigated crops, and livestock for the following reasons: (I) the low use volume (300 Ib
ai/yr); (ii) the inirequency of use (every 3-5 yr if a given stream harbors lamprey); (iii) die very tight
control USFWS has over the use of niclosamide including 24-hr irrigation and potable water intake
restrictions, other label restrictions, door-to-door as well as broadcast riparian user notification and
enforcement particularly for sport fishermen, etc.; (iv) the fact that die treated water moves as a slug
down the treated stream resulting in only a 1-3 day exposure interval every 3-5 years; (v) what is, in
effect, infinite dilution as treated stream water enters the Great Lakes, where virtually all of the
commercial fishing occurs; (vi) the rapid and complete dissipation of niclosamide residues from treated
streams; (vii) the very low level of bioconcentration as well as the rapid and complete depuration of
niclosamide residues from exposed fish; and (viii) based on reasons given above, residues of niclosamide
in irrigated crops and livestock are not expected.
b. Occupational/Residential Risk
It has been determined that there is a potential for exposure from handling niclosamide-contaming
products during the application process (i.e., mixer/loaders and mixer/loader/applicators) as well as from
various post-application activities such as recreational boating and swimming. The two potential
niclosamide exposure scenarios are: (I) mdxmg/loading/appHcation of niclosamide wettable powder slurry
and (ii) loading/application of niclosamide granules using powered backpack blowers for population
survey applications. However, based on the extremely low usage (300 Ib ai/yr), the infrequency of use,
and the risk mitigation measures already implemented by USFWS, occupational exposure and risk
assessments have not been conducted for niclosamide.
F. Environmental Assessment for TFM
1. Ecological Toxicity Data
a. Summary
The information in this assessment is based on a combination of both open literature and studies
specifically conducted to meet EPA data requirements. While all of the data included in this assessment
were considered scientifically sound, open literature studies were not subject to the rigorous standards
currently required under Good Laboratory Practice (GLP) protocols. Given the range of protocols over
which ecotoxicity data were collected, there is some uncertainty over how the toxicity of TFM may have
been effected had the studies been conducted under GLP standards. Based on ecological effects data,
the toxicity potential of TFM can be characterized as follows:
21
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Avian acute-nontoxic (>5,000 ppm)
• Mammalian acute-moderately toxic (>141 to 160 mg/kg)
Mammalian chronic ( >5,000 mg/kg)
Fish (freshwater acute)- slightly to highly toxic (0.60 to 37 mg/L)
Invertebrates (freshwater) acute- slightly to moderately toxic (3.8 to 22.3 mg/L)
Aquatic plants- toxic (1.2 to > 15 mg/L)
Mammals were the only animal group for which chronic toxicity data were available and for this group
there were no chronic effects noted.
Environmental factors influenced die toxicity of TFM. hi general TFM was more toxic as water
temperature increased and pH and water hardness decreased When TFM is used in combination with
niclosamide. the toxicity potential of the combined lampricides was additive.
b. Toxicity to Terrestrial Animals
(1) Avian Acute Oral, Subacute Dietary and Chronic
The acute oral toxicity data suggest that TFM analytical and formulated grade material is
moderately to slightly toxic (LD50 250-546 mg/kg) to avian species and practically non-toxic (LC50 >
5,000 ppm) on a subacute dietary basis (MRJD 00022923; Ace # 160000), Avian chronic reproduction
studies are not required
(2) Mammals, Acute and Chronic
TFM has acute oral LD50 values of 141 and 160 mg/kg for males and females, respectively
(MRID 40999204 and 41898102).
(3) Insects
A honey bee acute contact study using the TGA1 is not required for TFM because its use, i. e.,
streams and rivers, will not result in honey bee exposure.
c. Toxicity to Freshwater Aquatic Organism
(1) Freshwater Fish, Acute and Chronic
Acute toxicity of TFM ranges from being slightly toxic to highly toxic for freshwater fish species.
The most sensitive species tested was the channel catfish. Ictaluruspunctaius (96 hour LC50 = 0.60
mg/L in soft, reconstituted well water, pH 7.2 to 7.6), while the least sensitive species tested was die
bhregill sunfish, Lepomis macrochirus (96 hour LC50 = 37 mg/L in hard well water, pH 8.3 to 8.5).
22
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In a study comparing the toxicity of TFM to native species of lampreys with sea lampreys, the
toxicity of TFM to lamprey larvae was highest in the sea lamprey, intetmediate in the northern brook
lamprey (Icthymyzonfossor), and lowest in the American brook lamprey (Lamptera appendix) (King
et at 1985).
Because TFM is also used in combination with niclosamide, toxicity tests for the combination of
these two chemicals were conducted by Bills and Marking (1976). Of die fish tested, channel catfish was
again die most sensitive species to TFM alone (LC50 = 0.75 mg/L) and to the combination of the two
chemicals (LCSO = 0.615 mg/L). M general, the data show that the combination of TFM and niclosamide
was at most additive under various test conditions.
Although fish life cycle data are not available for TFM, there arc acute data available for various
developmental stages offish. All the early developmental stages of walleye (Stizostedion vitreum) from
gametes to sac fry were more resistant to TFM than were similar developmental stages of sea lamprey
larvae. Olson and Marking (1973) examined the toxicity of TFM to six developmental stages of the
rainbow trout and found that sac fry were the most sensitive life stage studied Exposure to TFM during
sea lamprey embryonic development increased the frequency of abnormalities that lead to increased
mortalities (Piavis and Howell 1975;NRCC 1985).
TFM treatments have been associated with induction of hepatic mixed function oxyganase activity
and altered levels of circulating steroids in fish and induced hepatic vitellogenesis in primary cultures of
rainbow trout hepatocytes (Hewitt et al. 1997). As such, TFM acts as an estradiol agonist and has a
demonstrated endocrine disrupting effect. Since the data on various developmental stages represented
disjointed acute studies, chronic toxicity data on fish were not available and as such, a fish full life cycle
study of both technical grade TFM and TFM/niclosamide mixture is required to address this deficiency.
Abundance of sea lamprey peaked in several Great Lakes before chemical control began. The
sex ratio in these peak populations were predominately males (68-71%). Following a decade of
lampricide treatments, populations of sea lampreys showed marked declines and the sex ratios in these
populations shifted toward a predominance of females accounting for 72% of the population (Henrich, et
al, 1979). This publication by Henrich concludes that lampricides reduced the populations of sea
lampreys in the Great Lakes and contributed to the sequential shifting of the sex composition from a
predominance of males to a predominance of females. There are no data to support that the endocrine
mediated effect associated with TFM is related to the observed sex-ratio shifts among TFM-treated
populations of sea lamprey.
(2) Freshwater Invertebrates, Acute and Chronic
In acute toxicity tests, TFM was moderately to slightly toxic to aquatic invertebrates (24 hour
LC50 range: 3.8 to 22.3 mg/L). When TFM is used in combination with niclosamide (98:2 by weight),
LC50 values for die mixture ranged from 1.5 mg/L (moderately toxic) to greater than 100.0 mg/L
(practically non-toxic). The most tolerant species tested were crayfish, dragonflies, snipeflies, and
23
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dobsonflies. The most sensitive species were snails and aquatic earthwoims. These data indicate that the
mixture of TFM and niclosamide enhanced the toxicity of TFM to some aquatic invertebrates.
There are no chronic toxicity data available for aquatic invertebrates. An aquatic invertebrate life
cycle study (72^4) of both technical grade TFM and TFM/'niclosamide mixture is required to address this
deficiency.
(3) Toxicity to Estuarine/Marine Organisms
Because the use of TFM is unlikely to directly enter into estuarine/marine environments, toxicity
testing for these species is not required,
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There is conflicting evidence on whether TFM photodegrades in water.
TFM remains toxic for long periods (>80 days) in aqueous systems; however, toxicity decreases
in sediment-water systems over time, hi sediment-water systems, irreversible sorption of
reduced-TFM [R-TFM; 4-amino-3-(trifluoromethyl)phenol] to sediments was reported. R-TFM
is capable of binding to other organic components of the sediment through the ammo group or be
polymerized to longer chain compounds.
TFM was converted to reduced-TFM with a half-life of less than one week under both aerobic
and anaerobic aquatic metabolism conditions. It must be stressed that when reduced-TFM is
reported as a reaction product, degradation has not occurred. TFM has just undergone a
chemical reduction and under appropriate conditions, reduced-TFM may be re-oxidized to TFM.
The tendency for TFM to bind to sediments is not strong, readily reversed, and is very pH
dependent. Binding tends to decrease as pH increases.
Based on studies with the rainbow trout, TFM is not expected to accumulate in fish.
• In the environment, the soiption and degradation of TFM by sediments is expected to occur
primarily in the lakes and not in the tributary streams. TFM is expected to remain in solution in '
the lake system and persist for long periods of time.
TFM (C7H4F3NO3; M.W. 207.11) is chemically and biologically very stable. An examination of
its structure, i.e., aromatic, fluoro-containing, m-substituted phenol, shows that the compound possesses
many of the chemical features known to impart persistence to organic compounds. Its pK, is 6.07 and
the effect of pH on the toxicity appears to follow closely to the concentration of the lipid-soluble, free
phenol form of TFM. This pH sensitivity is used to maximize effectiveness. As pH increases, toxicity.
bioaccumulation, and adsorption to sediment decrease. Aqueous solubility of the sodium salt is 5 g/L.
a. TFM Degradation
In an acceptable Hydrolysis guideline study, Reynolds (1997, MRID 44429501) found that "C-
TFM was stable in sterile buffered aqueous solutions at pH's 5, 7, and 9 at 25°C in the dark for 30 days.
No degradation products were identified, hi bioassay experiments, Thingvold (1975) found that the
toxicity of TFM was not altered over die course of 5 to 8 weeks by buffering aqueous solutions at pH
values of 6.5, 7.7, 8.5, or 9.5. Carey and Fox (1981) demonstrated in distilled water systems buffered at
pH 5, 6, 7, 8, or 9 that TFM was stable in the dark controls of a photodegradation study. The hydrolysis
study requirement is fulfilled.
Photolysis may be an important route of degradation in the environment, however there is
conflicting evidence on this, in the Carey and Fox study, the authors found that TFM photodegraded in
unbuffered distilled water under natural sunlight with a half-life of 3.3 days. The principle identified
25
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photoproduct was 2,5-dihydroxybenzoic acid. There was no build-up of photoproducts and by the end
of the experiment (11 days), most of the TFM degradation products were unextractable. These authors
believe that under appropriate weather conditions, the photodegradation half-life in a shallow stream
would be on the order of several days. Contrary to this, Thingvold (1975) found that solutions of TFM
were very stable in the presence of sunlight thus indicating that photodecomposition is an unlikely
dissipator of TFM from the Great Lakes environment This contradiction leads to some uncertainty as to
whether photolysis plays a role in the dissipation of TFM. Based on this uncertainty, an additional
aqueous photolysis study is required
b.
TFM Metabolism
In a study designed to evaluate the degradation of TFM where aquatic sediments are not an
influential factor, Thingvold (1981) found no evidence of microbial degradation of TFM over test periods
of up to 80 days. Thingvold demonstrated, using bioassay experiments, that TFM remains toxic for long
periods in aqueous systems; however, toxichy decreases in sediment-water systems, hi sediment-water
systems, irreversible sorption to sediments was reported. It is likely mat the bound residue was not TFM,
but the reduced form of TFM (4-ammo-3-(trifluoromethyl)phenol. Thingvold (1975) found no evidence
that indicated that TFM degrades in the presence or absence of auxiliary carbon sources, or under
aerobic or anaerobic conditions, in sediment-fee aqueous systems. Carey, Fox and Schleen (1988)
report that with the exception of reduction of the nitre group to an ammo group under anaerobic
conditions, TFM is chemically and biologically very stable. However, these authors believe that this
reduction is not likely to be an important route of environmental degradation since TFM is almost
completely ionized at the pH of most natural waters and does not partition strongly to sediment where
anaerobic conditions exist. In addition, it must be noted that when reduced TFM is reported as a
reaction product, degradation has not occurred. TFM has merely been reduced and under appropriate
conditions, reduced-TFM may be re-oxidized to TFM (Carey and Fox, 1981).
hi an acceptable anaerobic aquatic metabolism guideline study, Fathulla (1996, MRID
43887601) found that KC-TFM applied to a loamy sand sediment/water system degraded rapidly in the
dark under anaerobic conditions with a half-life of 2.1 days. The major degradate was 4-amino-3-
(trifluoromethyl)phenol. reduced TFM (R-TFM), which comprised 38.2% at approximately 4 hours, and
increased to a maximum of 9-4.1% of the applied radioactivity on day 14 of anaerobicity and then
decreased to 26.6% on day 178 and finally disappeared by day 273. 14CO2 was the only volatile
component found in the traps, reaching 7.7% of applied on day 273. Radioactivity recovered in the
water layer ranged from 71.7 to 87.7% of applied on days 0 through 92. After day 92, the majority of
the radioactivity partitioned to the sediment (41-49% of this radioactivity was bound). pH ranged from
5.43 (day 3) to 8.34 (day 273). Under aerobic conditions, Fathulla (1995, MRID 43781801)
demonstrated in an acceptable aerobic aquatic metabolism study that 14C-TFM applied to a loamy sand
sediment/water system degraded rapidly in the dark under aerobic conditions with a half-life of 5.4 days.
The major degradate was reduced TFM, which comprised 38.4% at approximately 7 days, 30.2% on
day 15,1.2% on day 21 and 0.7% on day 30. I4C02 was the only volatile component found in the traps,
reaching 7.8% of applied on day 30. The pH ranged from 7.51 (day 1) to 8.83 (day 30). Radioactivity
recovered in the water layer ranged from 91.6 to 30.2% of applied on days 0 through 30. On day 30,
26
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the majority of the radioactivity partitioned to the sediment (45% of this radioactivity was bound). Based
on these data, the anaerobic aquatic metabolism and aerobic aquatic metabolism study requirements are
fulfilled
c. TFM Mobility
Dawson (1986) studied the adsorption of TFM by bottom sediments (Table 6), and found that
increases in pH lead to decreases in K^, while increases in organic carbon result in increases in Kj.
Overall, the mobility of TFM, as determined by Dawson is medium to very high. The table below
provides the results at 20°C for systems at pH 6 and 8. Based on these data, the leaching and
absorption/desorption study requirement is fulfilled.
Table 6: Absorption (Kd) of Trifluoromethyl nitrophenol (TFM) by four different bottom sediments at pH 6 and 8
(Dawson 1986).
sediment
Cedar River
Ford River
Tahquamenon River
Arkansas River
soil type
sandy loam
loamy sand
sand
loam
sand/si!t/clay
64/32/4
84/14/2 •
96/1/2
44/46/10
organic
matter
9.0
5.0
0.9
2.5
CEC
meq/lOOg
13.2
4.6
1.1
62
K,
pU6
11.7
6.65
l.tl
5.66
Ka
pH8
2.01
1.46
0.157
0.749
Carey, Fox, and Schleen (1988) also noted that the tendency for TFM to bind to sediments is not
strong, readily reversed, and is very pH dependent Un-ionized TFM (acidic solution) is more readily
absorbed than ionized forms (basic solutions) (Dawson et al. 1986). On the other hand, Thingvold
(1975) claims that TFM is sorbed by sediments in a rapid and irreversible manner, so much so that it is
difficult to extract with organic solvents. Thingvold believes the binding may involve the NO2 group
converting to the NH2 form. This then would mean that rather than TFM binding, it is reduced-TFM that
is bound. R-TFM is capable of binding to other organic components of the sediment through 1he amino
group, or being polymerized to longer chain compounds, which would explain the difficulty in extracting
TFM from the sediment.
In the environment, the sorption and degradation of TFM by sediments is expected to occur
primarily in the lakes and not in the tributary streams. Most of the TFM will be quickly flushed into the
lakes. The amount removed by sorption to the stream sediments is unknown, but is likely to be minimal.
In the lake environment, degradation of TFM must occur in a primarily sediment-free system, given the
high ratio of water to sediment and the lack of sediments containing appreciable amounts of organic
material (Thingvold, 1975). As such, TFM is expected to remain in solution in the lake system and
persist for long periods of time at low concentrations.
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d. TFM Accumulation
The amount of TFM uptake by fish has been correlated to pH and total hardness of the water.
Ten times as much TFM was found in fish residing in soft-acid water as compared to hard-alkaline water
(Thingvold, 1975). According to Thingvold, TFM is not readily metabolized by aquatic organisms and is
generally excreted in an unaltered form. In an acceptable fish accumulation study conducting according to
Subdivision N guidelines (MRJD 44666501), TFM residues accumulated in rainbow trout that were
exposed to nonradiolabeled plus uniformly phenyl ring-labeled [14C]TFM, at a nominal concentration of
62.0 ugfL, under flow-through aquarium conditions at a pH of 7.8. Maximum bioconcentration factors,
based on total radioactivity, were 5C.3X for viscera, 1.3X for fillet, and 8.4X for whole body tissues.
The maximum mean concentrations of [14C]residues were 3.0 ± 0.9-1.7 ppm for the viscera tissue, 0.08
± 0.03 ppm for the fillet tissue and 0.5 ± 0.1 -0.2 ppm for the whole fish tissue. Accumulation plateaus
were generally reached by 3 days in the viscera, fillet, and whole fish tissues. Parent compound was
present at 1.4 ± 0.05 ppm in the viscera, and 0.006 ± 0.006 ppm in the fillet tissues. The major
metabolite TFM-glucuronide was present at 0.9 ± 0.2 ppm in the viscera, and 0.036 ± 0.003 ppm in the
fillet tissue samples. Two unidentified metabolites (Unknowns 1 and 3) were present at 0.7 ± 0.03 ppm
and 0.09 ± 0.01 ppm, respectively, in the viscera; an unidentified minor metabolite (Unknown 2) was
present at 0.034 ppm (1 of 4 replicates). Depuration was rapid, with >98.7% of total accumulated
[l4C]residues eliminated by days 4,1.5, and 11, respectively, from the viscera, fillet, and whole body
tissue samples. Based on these data, the accumulation in fish study requirement is fulfilled
3. TFM Aquatic Exposure Assessment
Since TFM is added directly to water, the estimated environmental concentrations (EECs) used
in this evaluation were based on projected treatment concentrations. Application rates for TFM are
based on pH, alkalinity, temperature, stream/river discharge rates, and bioassay data. Spreadsheet-
based models incorporating the aforementioned factors have been developed to assist in determining
applications rates and were used in predicting exposure concentrations used in the present risk
assessment.
G. Environmental Assessment for Niclosamide
1. Ecological Exposure and Risk Characterization for Niclosamide
a. Summary
The information in this assessment is based on a combination of both open literature and studies
specifically conducted to meet EPA data requirements. While all of the data included in this assessment
were considered scientifically sound, open literature studies were not subject to die rigorous standards
currently required under Good Laboratory Practice (GLP) protocols. Given the range of protocols over
which the ecotoxicity data were collected there is some uncertainty over how the toxicity results may
have been impacted by this lack of GLP standards. Based on ecological effects data, the toxicity
potential of niclosamide can be characterized as follows:
28
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Avian acute- moderately toxic (LD50 60 rng/kg)
Avian subacute dietary- practically nontoxic (LC50 > 5,419 mg/kg dietQ
• Mammalian acute- practically nontoxic (LD50 >1,000 mg/kg)
Fish (freshwater acute)- highly toxic to very highly toxic (LC50 0.03 - 0.23 mg/L)
Invertebrates (freshwater) acute- slightly to very highly toxic (EC50 0.034 - > 50 mg/L)
Invertebrates (freshwater) chronic- (NOAEC 0.03 mg/L; LOEC 0.05 mg/L)
Aquatic plants-toxic (0.04 to > 1,450 mg/L)
Environmental factors influenced the toxicity of niclosamide. In general niclosamide was more toxic as
pH and water hardness decreased When niclosamide is used in combination with TFM, the toxicity
potential of the combined lampricides was additive.
b. Toxicity to Terrestrial Animals
(1) Avian Acute Oral, Subacute Dietary and Chronic
The acute oral toxicity data suggest that niclosamide ranges in toxicity from being moderately
toxic to practically nontoxic (LD50 60 to > 2,000 mg/kg) to avian species (MRIDs 43677701,
43677702, and 44180301) and practically non-toxic (LC50 > 5,419 ppm) on a subacute dietary basis
(MRJDs 44180302 and 44180303). Avian chronic reproduction studies are not required. The guideline
requirements for acute studies have been fulfilled,
(2) Mammals, Acute and Chronic
Niclosamide was practically nontoxic to small mammals on an acute oral basis (LD50 > 1,000
mg/kg) (MRID 4255223-01). No chronic toxicity data were available.
(3)
Insects
A honey bee acute contact study using the TGAI is not required for niclosamide because its use
(aquatic sites) will not result in honey bee exposure.
c. Toxicity to Aquatic Animals
(1) Freshwater Fish, Acute and Chronic
The data indicate that the acute toxicity of niclosamide ranges from being highly toxic to very
highly toxic for freshwater fish species. The most sensitive species tested were the rainbow trout,
Onchorhynchus mykiss (LC50 = 0.03 mg/L), sea lamprey, Petromyzon marinus, (LC50 = 0.049 mg/L)
and the bluegfll sunfish, Lepomis marcrochirus, (LC50 = 0.049 mg/L). The freshwater fish acute toxicity
requirement has been fulfilled (MRID 43679302, 44206101).
29
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Because niclosamide is also used in combination with TFM, toxicity tests for the combination of
these two chemicals are used to assess risk. Results of tests specifically conducted to address this issue
show that the channe] catfish was ths most sensitive species to TFM (LC50 = 0.75 mg/L), niclosamide
(LC50 = 0.0125 mg/L) and to the combination of these chemicals (LC50 = 0.615 mg/L). Based on die
results of this study the authors concluded that the mixture of TFM:niclosamide was at most additive
under various test conditions (Bills and Marking 1976).
No data were provided on the chronic toxicity of niclosamide to fish. Thus, die guideline studies
for the fish early life stage and fish full life cycle are not fulfilled and represent data gaps.
(2) Freshwater Invertebrates, Acute, Chronic
hi acute toxicity tests, niclosamide was slightly to very highly toxic to aquatic invertebrates (ECSO
range: 0.034 to > 50 mg/L). The acute freshwater invertebrate study requirement has been fulfilled
(MRID 44174804).
When TFM is used in combination with niclosamide (98:2 by weight), LC50 values for the mixture
ranged from 1.5 mg/L (moderately toxic) to greater than 100.0 mg/L (practically non-toxic) among
freshwater invertebrates. The most tolerant species tested were crayfish, dragonflies, snipeflies, and
dobsonfiies. The most sensitive species were ttnbellarians, snails, and aquatic earthworms and appeared
to affect organisms inhabiting sediments. These data indicate that the mixture of TFM and niclosamide
are additive for the toxicity of TFM to aquatic invertebrates.
Given niclosamide's potential to adsorb to sediments, the use of formulations specifically designed
to slowly release the chemical at the water-sediment interface, and the acute toxicity of niclosamide to
aquatic invertebrates, acute and chronic data on sediment toxicity testing using chironomids is necessary
since these organisms would be highly exposed.
(3) Toxicity to Estuarine and Marine Organisms
Because the use of niclosamide is unlikely to directly enter into estuarine/marine environments,
toxicity testing for these species is not required
d. Toxicity to Aquatic Plants
Niclosamide inhibited the growth of aquatic plants; diatoms suffered 50% growth inhibition at
concentrations less than 130 ppb. Green algae exhibited a considerable range in sensitivity to the effects
of niclosamide; EC50 values ranged from 0.41 to 1,450 ppm. The studies submitted for review did not
comply with recommended guidelines, and were classified as supplemental.
30
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2. Niclosamide Environmental Fate and Transport
The information in this assessment is based primarily on open literature studies submitted by the
registrant to fulfill EPA data requirements. Unless otherwise noted, the data cited here are not from
studies conducted according to Subdivision N guidelines, but nonetheless are considered scientifically
valid and may be used in assessing the fate and transport of niclosamide in the environment Because the
open literature studies were not conducted according to the rigorous standards required under
Subdivision N, there is some degree of uncertainty associated with die data, particularly if one is
comparing the results of these studies to studies for other chemicals conducted according to Subdivision
N guidance.
There are insufficient data available to adequately assess the environmental fate of niclosamide.
* In addition to dilution and dispersion, sorption to sediments and suspended particulates and
possibly photodegradation (in clear shallow waters), are the major routes of dissipation of
niclosamide. Neither hydrolysis nor volatilization from soil or water surfaces should be major fate
processes for this compound.
• In most aquatic environments, niclosamide will adsorb to suspended solids and sediment Though
niclosamide does tend to bind to sediments, the binding is by no means irreversible, thus non-
target species and benthic organisms, in particular, will be exposed to niclosamide for extended
periods of time.
• It is unclear what role, if any, aerobic and anaerobic microbial degradation plays in the dissipation
of niclosamide in the aquatic environment
• In the lake environment, degradation of niclosamide would be expected to occur in a primarily
sediment-free system, given the high ratio of water to sediment As such, niclosamide is expected
to remain in solution in the lake system and persist for long periods of time.
• Based on the bioconcentration factors and the rapid rate of depuration, accumulation in fish is not
expected.
a. Niclosamide Chemical Degradation
Niclosamide does not appear to undergo hydrolytic degradation, however it does photodegrade
in water. In a supplemental study that addressed both the hydrolysis and aqueous photolysis data
requirements (MRJDD 42552313), [14C]niclosamide did not degrade either in buffered solutions adjusted
to pH 5.0,6.9, or 8.7; or in pond water (pH 7.0-7.8) incubated in the dark for up to 56 days.
Niclosamide ranged from 93 to 99% of the total radioactivity from each TLC plate in the study. Under
photolytic conditions, niclosamide degraded with a half-life of 3.3 days in a pH 6.9 buffered solution that
was irradiated by long-wave UV light for up to 14 days. A new photodegradation in water study is
needed because, among other deficiencies, degradates were not identified, material balances were not
31
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reported, and the output of the light source may not have been comparable with natural sunlight
Therefore, there is a high degree of uncertainty surrounding the photolysis half-life. However, based on
this supplemental study and the UV/visible spectrum of niclosamide (max. 330 nm), it does appear that
niclosamide is susceptible to photoclegradation in water, and this will be a significant route of dissipation
only in clear and shallow water bodies.
b. Niclosamide Mobility
In an acceptable batch equilibrium study (Dawson et al., 1986) (MRID 42552315,42552316),
it was found that the mobility of niclosamide was dependent on the pH of the system. Mobility appeared
to increase at higher pH's. It should be noted that niclosamide reportedly precipitates from aqueous
solutions when the pH is less than 6.5.
Table 7: Average dissociation constants (Kd) for niclosamide at differing pH and sediment type.
sediment
Tahquamenon River sand
Ford River loamy sand
Arkansas loam
Cedar River sandy loam
% organic
matter
0.9
5.0
2.5
9.0
pH&5 pH7.0 pH8LO PH9jO
average KH
17
60
199
316
14
79
129
85
5
41
39
69
1
12
15
7
Under acidic and neutral conditions, niclosamide was not mobile. At pH 8, niclosamide was
moderately mobile in the sand sediment, but not mobile in the other three sediments. In alkaline (pH 9)
conditions, niclosamide was very mobile in the sand and moderately to slightly mobile in the loamy sand,
loam, and sandy loam sediments. In most aquatic environments, niclosamide will adsorb to suspended
solids and sediment.
A supplemental mobility study identified the major route of dissipation for niclosamide from the
water column, excluding dilution or dispersion, is adsorption to the sediment (MRID 42552317).
Niclosamide concentrations decreased in the water column at a raster rate in beakers with lake water and
sediment exposed to sunlight than in beakers without sediment exposed to sunlight There was no
difference in disappearance rates of niclosamide between light and dark beakers without sediment,
indicating that photolysis may not play a major role in the dissipation of niclosamide. After 96 hours,
71% of the niclosamide was still present in beakers with sediment exposed to sunlight, versus 107% in
light exposed beakers without sediment and 110% in dark beakers without sediment. In a test that
eliminated microbial and photolytic processes, niclosamide concentrations decreased faster in sterile dark
test tubes with sediment than in sterile dark test tubes without sediment This study also found no
difference in disappearance rates of niclosamide among non-sterile light test tubes with sediment, sterile
light test tubes with sediment and sterile dark test tubes with sediment In the presence of sediment, the
half-life of niclosamide in the water column was less than 10 days.
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In the lake environment, degradation of niclosamide must occur in a primarily sediment-free
system, given the high ratio of water to sediment As such, niclosamide is expected to remain in solution
in the lake system and persist for long periods of time.
Volatilization from dry and moist soil surfaces, or from water surfaces should not be a major fate
process for this compound The measured vapor pressure is 9.9 x 10* mm Hg at 25°C and the
estimated Henry's Law constant is 6.5 x 10~10 atm-mVmole.
No data have been provided concerning the mobility of niclosamide degradates. However,
previous information suggested that aminoniclosamide binds to sediment as well. Since aminoniclosanjide
is said to be 80-fold less toxic than parent niclosamide, confirmatory mobility data on this degradate is not
required.
c.
Niclosamide Bioaccumulation
In a supplemental study (MRID 44128201), bioconcentration factors were determined to be 49x
for edible tissue, 215x for whole fish, and 916x for viscera in rainbow trout The concentration of
radioactive residues in the fish increased very rapidly to a plateau during the first three days of exposure.
Depuration was rapid and fairly complete by day 10 of the elimination period. There is some degree of
uncertainty surrounding the results of this study since neither the radioactivity in the water, nor the
accumulated radioactivity in the fish tissues was identified, but was assumed to be parent niclosamide.
There is reason for concern that photodegradates may have been present in die test tank, particularly
since it appears that niclosamide may be susceptible to photolysis and that a small amount of acetone, a
photosensitizer, was used as a co-solvent. However, given the stability of niclosamide to hydrolysis at the
pH values in the study, and the flow-through design of the experiment, significant degradation of
niclosamide in the exposure tank would not be expected
d.
Niclosamide Field Studies
A monitoring study (MRID 42552317) was conducted in Seneca Lake, New York to describe
the distribution, dispersion, and dissipation of niclosamide in the water column after an application and to
assess its bioaccumulation by, and toxicity to, two species of caged, non-target fish.
Granular Bayer 73 was applied at a nominal rate of 110 kg/ha (2300 ug/L, assuming dissolution
into the bottom 10 cm of water). Niclosamide concentrations in the lake water samples ranged from <10
to 573 ug/L. Concentrations were generally lowest at the surface and highest at the bottom (0.1 m).
Although there is an expectation that niclosamide is released from granules into the bottom 5 cm of the
water column, it was found throughout the water column; a result of either mixing or premature release.
Concentrations greater than 40 ug/L were measured at all depths and stations within the treatment area.
After 48 hours, all concentrations were below 30 ug/L. Concentrations were below the detection limit
(10 ug/L) by 96 hours after application.
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Niclosamide residues in fish muscle tissue were consistent with water concentration and
distribution patterns. Residues ranged from 0 to 858 ng/g and were highest in fish from the bottom depth
at all stations. Residues increased until 14-24 hours after application and then declined.
The selective toxicity of granular niclosamide is based on the assumption that dissolution takes
place at the sediment-water interface, implying that non-target fish could escape lethal concentrations
whereas sea lamprey larvae, which live in the substrate and are relatively weak swimmers, would be
killed. However, the results of mis investigation show that both lampreys and non-target fish will be
exposed to niclosamide throughout the water column.
3. Niclosamide Aquatic Exposure Assessment
Since niclosamide is added directly to water, the estimated environmental concentrations (EECs)
used in this evaluation were based on projected treatment concentrations derived from when niclosamide
is applied with TFM. Application rates for the TFM/niclosamide mixture are based on pH, temperature,
stream/river discharge rates and bioassay data. Treatment levels of niclosamide have historically ranged
between 25 to 35 ppb (personal communication, Terry Bills, Fishery Biologist, U. S. Geological Survey
Biological Resource Division 1999); (his range of treatment levels was used in the aquatic risk
assessment.
H. Environmental Exposure and Risk Characterization for TFM and Niclosamide
a. Risk presumptions
Risk characterization integrates the results of the exposure and ecotoxicity data to evaluate the
likelihood of adverse ecological effects. The means of this integration is called the quotient method Risk
quotients (R.Q.) are calculated by dividing exposure estimates by acute and chronic ecotoxiciry values.
RQ= EXPOSURE/TOXiaTY
RQ values are then compared to OPPs levels of concern (LOCs). These LOCs are used by
OPP to analyze potential risk to nontarget organisms and the need to consider regulatory action. The
criteria indicate that a pesticide used as directed has the potential to cause adverse effects on nontarget
organisms. LOCs currently address the following risk presumption categories: (1) acute high —
potential for acute risk is high; regulatory action may be warranted in addition to restricted use
classification, (2) acute restricted use - the potential for acute risk is high, but may be mitigated
through restricted use classification, (3) acute endangered species - endangered species may be
adversely affected, and (4) chronic risk - the potential for chronic risk is high regulatory action may be
warranted. Currently, the Agency does not perform assessments for chronic risk to plants, acute or
chronic risks to nontarget insects, or chronic risk from granular/bait formulations to birds or mammals.
The ecotoxicity test values (measurement endpoints) used in the acute and chronic risk quotients
are derived from required studies. Examples of ecotoxicity values derived from short-term laboratory
34
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studies that assess acute effects are: (1) LC50 (fish and birds), (2) LD50 (birds and mammals), (3) EC50
(aquatic plants and aquatic invertebrates) and (4) EC25 (terrestrial plants). Examples of toxicity test
effect levels derived from the results of long-term laboratory studies that assess chronic effects are: (1)
LOAEC (birds, fish, and aquatic invertebrates), (2) NOAEC (birds, fish and aquatic invertebrates), and
(3) MATC (fish and aquatic invertebrates). For birds and mammals, the NOAEC generally is used as
the ecotoxicity test value in assessing chronic effects, although other values may be used when justified.
Generally, the MATC (defined as the geometric mean of the NOAEC and LOAEC) is used as the
ecotoxicity test value in assessing chronic effects to fish and aquatic invertebrates. However, the
NOAEC is used if the measurement end point is production of offspring or survival.
Risk presumptions and the corresponding RQ values and LOCs, are tabulated below.
Table 8: Risk Presumptions for Terrestrial and Aquatic Animals
Risk Presumption
RQ | LOG
Birds and Mammals
Acute High Risk
Acute Restricted
Use
Acute Endangered
Species
Chronic Risk
EEC'/LC50 or LDSO/sqft2 or LDSO/day3
EEC/LC50 or LD50/sqft or LDSO/day
(or LD50 < 50 mg/kg)
EEC/LC50 or LD50/sqft or LDSO/day
EEC'NOAEC
0.5
02
0.1
1
LOG
Aquatic Animals
EEC/LC50orEC50
EEC/LC50orEC50
EEC/LC50orEC50
EEC/MATC or NOAEC
0.5
0.1
0.05
1
1 abbreviation for Estimated Environmental Concentration (ppm) on avian/mammalian food items
2 (rag/ft J)/(LD50 x wt. of bird)
3 (mg of toxicant consumed day) (LDSOx wt. of bird)
Table 9. Risk Presumptions for Plants
Risk Presumption
Acute High Risk
Acute Endangered Species
Terrestrial and Semi-Aquatic Plants
RQ
EEC'/EC25
EEOEC05 or NOAEC
LOG
1
1
Aquatic Plants
RQ
EEC^/ECSO
EEC/EC05 or NOAEC
LOC
1
1
= !bsai/A
2 EEC = (ppb/ppm) in water
b.
Environmental Risk Assessment
In order to evaluate the potential risk to aquatic and terrestrial organisms from the use of TFM
and niclosamide, risk quotients (RQ) are calculated from the ratio of estimated environmental
concentrations (EECs) to ecotoxicity values; all calculated values can be found in an appendix to the
Environmental Fate and Effects Division Niclosamide Risk Assessment (July, 1999). For Ibis analysis,
avian EECs were based on the maximum application rate reported, i.e., 12 ppm of TFM. Aquatic EECs
were based on actual predicted application rates for TFM. Since much of the TFM toxicity data were
35
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collected using pH range 7.2-7.6, the predicted concentrations of TFM in the water, based on model
outputs, ranged from 0.7-2.2 ppm (personal communication, Donance Brege, U. S. Geological Survey
Biological Resource Division 1999). These rates are based on pH, alkalinity, temperature, stream/river
discharge rates and bioassay data that have been incorporated into a spread-sheet format by the U. S.
Fish and Wildlife Service. Based on application rates and past use history it has been determined that
typical EECs from die use of nicloscimide will range from 25 to 35 ppm. All risk quotient calculations for
niclosamide will be based on these EECs. RQ values are then compared to levels of concern (LOG)
criteria that are used by the Office of Pesticide Programs in the determination of potential risk to
nontarget organisms and the resulting need for possible regulatory action.
c. Exposure and Risk to Non-target Terrestrial Organisms
TFM and niclosamide are only registered for use on aquatic sites; therefore, the typical terrestrial
analysis of risk, based on exposure;; developed by Hoerger and Kenega (1972) and as modified by
Fletcher et al. (1994) is not applicable for establishing the risk of TFM to non-target terrestrial species.
However, because numerous avian, i.e., waterfowl and shorebirds, and mammalian species (muskrats,
beavers, raccoons and numerous other small mammals) typically utilize aquatic environments as nesting
and/or feeding habitats and may be exposed to TFM and or niclosamide via contaminated water, it is
appropriate to use the aquatic EECs for conducting the risk assessment to terrestrial species.
Calculated acute RQ values show that there is virtually no acute risk to birds or mammals from
the use of TFM or niclosamide (RQ < 0.1). RQ values for chronic exposure were not calculated; no
chronic concerns are expected.
d. Exposure and Risk to Non-Target Freshwater Aquatic Organisms.
(1) Acute Fish
For TFM, RQ values based on 1,24, and 96-hr LCso values and predicted treatment levels of
2.2 ppm and 0.7 ppm exceeded acute high risk levels of concern. Based on 1-hr LC50 values and an
exposure level of 0.7 to 2.2 ppm, acute high risk LOCs were exceeded for 33% of the species tested.
Using 24-hr LC50 values and an exposure level of 0.7 ppm, acute high risk LOCs were exceeded for
17% of the species tested.
TFM RQ values for the various developmental stages of fish were calculated for predicted
treatment concentrations of 0.7 ppm and 2.2 ppm. Acute high risk LOCs are exceeded for 17% of the
developmental stages at treatment concentrations of 0.7 ppm and all of the developmental stages at a
treatment concentration of 2.2 ppm Green eggs and eyed eggs were the most sensitive developmental
stages based on RQ.
TFM RQ values were examined over a range of pH (6.5 - 9.5) for rainbow trout, and were
based on predicted treatment concentrations for each of the pH levels. Predicted treatment
concentrations ranged from a low of 0.2 ppm at pH 6.5 to a high of 9 ppm at pH 9.5. RQ values were
36
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relatively consistent (range 0.16 to 0.39) for minimum target concentrations and underscore how
treatment levels are adjusted relative to pH to reflect changes in toxicity. At maximum projected
treatment concentrations (range 0.6 - 9 ppm), RQ values range from 0.36 to 1.2; acute high risk,
restricted use and endangered species LOCs are exceeded at pH values less than 8.1. At minimum
predicted application rates ranging from 0.2 to 1.6 ppm, restricted use and endangered species LOCs
are exceeded for rainbow trout at all pH levels.
For niclosamide, RQ values based on 96-hr LC50 values and predicted treatment levels of 25
ppb and 35 ppb exceeded acute high risk levels of concern. Acute high risk LOCs were exceeded for
sea lamprey and rainbow trout at a treatment level of 25 ppb; at 35 ppb, acute high risk LOCs were
exceeded for the majority (60%) of the species tested. The following table summarizes risk quotients for
freshwater fish tested.
Table 10: Summary of risk quotients to fresh water fish species based on predicted treatment levels of
niclosamide at 25 and 35 ppb.
Species
Flow-through or Static
Rainbow trout
Bluegiil sunfish
Sea lamprey .
Carp (Cyprinus carpio)
Green sunfish (Lepomis cyanellus)
EEC
(ppm)
0.025
0.025
0.025
0.025
0.025
96-hour
LC»(iMMi)
0.03
0.094
0.049
0.120
0.170
RQ
0.83"
0.27**
0.5*
0.21"
0.15"
EEC
(ppm)
0.035
0.035
0.035
0.035
. 0.035
RQ
13"
0.37"
0.71*
029"
0.50*
' Acute high risk, acute restricted use and endangered species LOCs exceeded.
Acute restricted use and endangered species LOCs exceeded.
""Endangered species LOCs exceeded
Niclosamide RQ values were examined over a range of pH (6.5 - 9.5) for rainbow trout and
were based on treatment concentrations of 25 and 35 ppb. The data indicate that as water becomes
more acidic, the risk to fish increases by roughly a factor of 10.
RQ values for the mixture of TFM/niclosamide (98:2 by weight), based on predicted treatment
concentration of 0.7 ppm and 2.2 ppm and niclosamide of 25 to 35 ppb indicate that acute high risk
LOCs are exceeded. It should be noted however, that niclosamide is typically added to TFM to reduce
the amount of TFM needed. Thus, predicted TFM treatment concentrations of 0.7 to 2.2 ppm for water
with pH 7.2 to 7.6 would be considered high.
(2)
Chronic Fish
No chronic toxicity data for TFM or niclosamide were available for fish. Since little is known
about the persistence of these compounds, it is not possible to predict the likelihood offish being
exposed to toxic levels. Given the dilution potential with die volume of water in the lakes, there is little
37
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concern about toxic levels in the Great Lakes themselves. However, due to the uncertainty regarding
persistence, there may be chronic concerns for organisms downstream from the application site prior to
dilution in die lake.
(3) Acute Aquatic Invertebrates
Aquatic acute high risk, acute restricted use, and endangered species LOCs are exceeded for
aquatic invertebrates at the typical use rates of TFM. Acute restricted use and endangered species
LOCs are exceeded for 67% of the ;iquatic invertebrates at the predicted minimum concentration in
water pH 12 - 7.6. At the maximum predicted treatment concentration, acute restricted use and
endangered species LOCs are exceeded for 83% of the aquatic invertebrates tested.
For niclosamide, acute high risk LOCs are exceeded for aquatic earthworms and flatworms.
Aquatic acute high risk, acute restricted use, and endangered species LOCs are exceeded for aquatic
invertebrates at the typical use rates of niclosamide.
Aquatic invertebrate RQ values for the mixture of TFM and niclosamide at the minimum
predicted concentration of 0.7 ppm TFM, range from 0.03 to 0.46, while RQ values for the maximum
predicted treatment concentration of 2.2 ppm TFM range from 0.08 to 1.47. Acute restricted use and
endangered species LOCs are exceeded for aquatic invertebrates at minimum predicted treatment
concentrations for waters of pH 7.2 - 7.6. The data indicate that of the species tested, flatworms are at
the greatest risk from the use of mixture of TFM and niclosamide to control the sea lamprey. Data
suggest that aquatic invertebrates feeding on bottom sediments are more likely to be at risk to
TFM/niclosamide treatments and exposures may be a result of ingestion of TFM/niclosamide bound to
detritus.
The TFM/niclosamide mixture results in higher toxicity to aquatic invertebrates; however, the
increase in toxicity is not proportional to that of the lamprey. In other words, lampreys undergo a marked
increase in toxicity to the TFM'niciosamide compared to the relatively small increase in sensitivity
exhibited by aquatic invertebrates. This differential toxicity between sea lamprey larvae and nontarget
aquatic invertebrates as a result of using the TFM/niclosamide mix is exploited to enhance mortality of sea
lamprey larvae while reducing effects on nontargets (pers. comm. Terry Bills, Fishery Biologist, U.S.
Geological Survey 1999).
e.
Plants
For TFM, the RQ values for aquatic plants, at the minimum treatment level of 0.7 ppm, range
from <0.2 to 0.58, while the RQ values for the maximum treatment level of 22 ppm range from < 0.15 to
1.83. Acute high risk and endangered species LOCs are exceeded for aquatic plants at the typical use
rates of TFM.
38
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No acute levels of concern were exceeded for the aquatic plant species tested with niclosamide.
At the typical maximum treatment rate of 35 ppb for niclosamide, green algae were the most sensitive
with an RQ of 0.85.
f. Endangered Species
Freshwater fish and aquatic invertebrate endangered species LOCs are exceeded for TFM and
niclosamide and aquatic plant endangered species LOCs are exceeded for TFM. The Agency has
developed the Endangered Species Protection Program to identify pesticides whose use may cause
adverse impacts on endangered and threatened species, and to implement mitigation measures that will
eliminate the adverse impacts. At present, (he program is being implemented on an interim basis as
described in a Federal Register notice (54 FR 27984-28008, July 3,1989), and is providing information
to pesticide users to help them protect endangered species on a voluntary basis. As currently planned,
the final program will call for label modifications referring to required limitations on pesticide uses,
typically as depicted in county-specific bulletins or by other site-specific mechanisms as specified by state
partners. A final program, which may be altered from the interim program, will be described in a future
Federal Register notice.
The U.S. Fish and Wildlife Service's lamprey control program routinely engages in Section 7
consultations when endangered/threatened species are suspected to be present in treatment areas. In
studies conducted on lake sturgeon (Acipenser fulvescens), concentrations of TFM approximately 1.3
times the LC99 9 of sea lamprey larvae were not lethal to juvenile lake sturgeons (Johnson et al. 1999). If
endangered or threatened species were known to inhabit projected treatment sites, treatment
concentrations of the lampricides would be adjusted to minimize impact to these species. Adjustments
would include the use of TFM/niclosamide mix to broaden the differential toxicity of these compounds,
and thus increase toxicity to sea lamprey larvae while holding the toxicity to nontarget species relatively
constant (personal communication, Terry Bills, Fishery Biologist, U.S. Geological Survey Biological
Resource Division 1999; Bills et al. 1985). According to the U.S. Fish and Wildlife Service (personal
communication, Terry Morse, Treatment Supervisor, U.S. Fish and Wildlife Service 1999), if treatment
concentrations could not be adjusted to minimize impact to sensitive nontarget species, then the identified
habitats would not be subjected to lampricide use.
I.
Environmental Risk Characterization for TFM and Niclosamide
TFM is both chemically and biologically stable and without evidence to the contrary is expected
to remain toxic for long periods of time. However, mitigation of its effects at the treatment site is likely to
occur as a result of die flushing action of the stream/river. TFM is a phenolic compound and behaves as
a weak acid; its neutral form (free phenol) is more likely to cross cell lipid membranes, and thus its uptake
and toxicity are strongly dependent on pH (Bills et al. 1988); however, at the pH of most natural
streams/rivers, the majority of the compound will be in the ionized form. Un-ionized TFM was more
readily adsorbed than the ionized (phenolate) form; however, the adsorption process was readily
reversible.
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Decisions regarding application rates and times are based on both abiotic and biotic factors
including pH, stream discharge, time of day, temperature, in-field bioassays and population assessment
data. Spreadsheet-based flow models have been developed to assist in determining application rates,
flowtimes, and dilution factors. Models are developed only for streams with complex treatment
scenarios, including marked diurnal fluctuations in pH or physical/chemical changes. These models permit
greater latitude in explaining possible effects of input factors on treatment concentrations and start times of
applications. Predicted treatment concentrations for specific locations, based on physico-chemical data
or in-stream toxicity tests, are intended to result in a concentration greater than the LC99 9 for sea lamprey
while being substantially less than the LC^ for brown trout This improves treatment effectiveness for sea
lampreys, yet minimizes the effect on nontarget species. Predicted treatment concentrations based on
physico-chemical data may be modified on the basis of data produced by on-site flow-through toxicity
tests. In Lake Superior and upper Lake Michigan, streams tend to have soft water with pH less than 8.2
and thus require lower application rates, i.e., less than 6 ppm. In the lower tier of the Great Lake,
tributaries harboring lamprey may exhibit hardnesses exceeding 200 ppm with a pH range 8.1 - 8.7.
Care must be taken in selecting application rates for streams with large diurnal pH fluctuations. Typically,
initial target concentrations remain primarily based on the lower observed pH values because of the
increased toxicity potential of TFM at lower pH. TFM target concentrations in hard water streams may
range from 1 to 6 ppm. While application rates as high as 12 ppm have been reported, the cost
effectiveness of TFM at this concentration would be better offset by applying TFM/niclosamide mix
(99:1) and as such, applications of TFM at greater than 9 ppm would rarely occur (personal
communication, Dorance Brege, U.S. Fish and Wildlife Service Treatment Supervisor 1999).
Estimated environmental TFM concentrations used in this evaluation (range 0.7 - 2.2 ppm) are
projected treatment concentrations derived from a nomograph developed by U.S. Fish and Wildlife
Service reflecting toxicity over ranges in both pH and alkalinity that were representative of the conditions
under which most of the toxicity data were reported, i.e., pH range 7.2 - 7.6 and water hardness 44
mg/L as CaCO3. Estimated environmental concentrations of niclosamide used in this evaluation (25 to 35
ppb) were based on typical concentrations reported by the Fish and Wildlife Service. At the predicted
treatment levels, acute high risk, acute restricted use, and endangered species LOCs are exceeded for
aquatic animals. Use of the TFM/riiclosamide mixture results in larger exceedences of the LOCs;
however, the mixture tends to exhibit a marked increase in toxicity to sea lamprey larvae while nontarget
organisms exhibit only a moderate increase. Although TFM is likely to have an immediate effect on the
aquatic community, the data suggest mat most organisms recover quickly and the treatment area
community structure returns to pie-treatment conditions within approximately 6 months (Kolton et
al.,1986). Additionally, a genuine effort is made to document where sensitive populations reside and
steps are undertaken to avoid treatments at concentrations known to be toxic to these organisms. The
long-term effects to more sensitive species, such as indigenous lampreys, and to aquatic communities
downstream from die treatment sites where chronic effects may be more likely, remain uncertain.
Because of the nature of the use of TFM and niclosamide, i.e., applied to flowing water, it is
difficult to characterize the magnitude of the ecological effects associated with use of the chemical.
Aquatic organisms in the treatment area are expected to be impacted to some extent during the proposed
12-hr treatments. Impacts to aquatic communities in terms of food-web structure are unknown. The two
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Special Local Needs labels for niclosamide are for application to ponds in which ornamental fish are
grown; these fish ponds are contained, an NPDES permit is required for water release and there should
be very low exposure to nontargets from this use. Therefore, the risks associated with this use of
niclosamide are expected to be neglible.
In the environment, the sorption and degradation of TFM by sediments is expected to occur
primarily in the lakes and not in the tributary streams. Most of the TFM will be quickly flushed into the
lakes. The amount removed by sorption to the stream sediments is unknown, but is likely to be minimal.
hi the lake environment, degradation of TFM and niclosamide must occur in a primarily sediment-free
system, given the high ratio of water to sediment and the lack of sediments containing appreciable
amounts of organic material (Thingvold, 1975). As such, TFM is expected to remain in solution in the
lake system and persist for long periods of time at Jow concentrations.
In addition to dilution and dispersion, sorption to sediments and suspended particulates and
possibly photodegradation (in clear shallow waters), are the major routes of dissipation of niclosamide.
Neither hydrolysis nor volatilization from soil or water surfaces should be major fate processes for this
compound, hi most aquatic environments, niclosamide will adsorb to suspended solids and sediment
Though niclosamide does tend to bind to sediments, the binding is by no means irreversible, thus non-
target species and benthic organisms in particular, will be exposed to niclosamide for extended periods of
time. It is unclear what role, if any, aerobic and anaerobic microbial degradation plays in the dissipation
of niclosamide in die aquatic environment
Although TFM and niclosamide are not expected to bioaccumulate in aquatic organisms, two
potential exposure scenarios exist Aquatic animals may be directly exposed to lampricide in the water as
the chemical block moves through during roughly a 24-hr period. Additionally, predatory animals may be
exposed through the consumption of prey incapacitated by lampricide treatments. However, in a study of
the lampricide niclosamide, it was estimated that the common tern (Sterna hirundo), a shore bird which
is a state-listed endangered species in Michigan, would have to consume roughly 16.8 times its body
weight in contaminated sea lamprey larvae to approach toxic levels (Hubert et ai 1999).
While TFM and niclosamide treatments will likely impact stream/river community structure in the
short term, data suggest that most organisms recover quickly and the treatment area community structure
returns to pre-treatment conditions within approximately 6 months (Kolton et al.,1986). This recovery is
site specific and may take much longer in certain environments and certain species may be significantly
impacted, most notably the indigenous lamprey species that may populate treatment areas, hi general,
however, native lamprey species have tended to populate the upper reaches of tributary streams'whereas
the sea lamprey is more likely to inhabit lower reaches of the stream. Thus, nontarget species that may
have been affected in the treatment area are repopulated through downstream migration from untreated
areas. Furthermore, retreatment of the stream will not occur for at least 3 to 5 years.
It is believed that, given the current application rates, the effects of TFM and niclosamide are
mitigated solely by the flushing action of the stream through the treatment site. Effects on the aquatic
environment downstream from the treatment site are unknown and would depend heavily on the
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stream/river discharge rate, water temperature, pH and alkalinity and the proximity of sensitive nontarget
organisms. While treatment areas have demonstrated a capacity to recover, the downstream acute and
chronic effects, where TFM is most likely to be deposited, remain uncertain.
Exposure to TFM during embryonic development increased the frequency of abnormalities mat
lead to increased mortalities and stream treatments with lampricides have resulted in a shift in sex ratios
among lampreys over a 16-yr period. TFM treatments have been associated with induction of hepatic
mixed function oxyganase activity and altered levels of circulating steroids in fish and induced hepatic
vitellogenesis in primary cultures of rainbow trout hepatocytes. As such, TFM acts as an estradiol agonist
and has a demonstrated endocrine disrupting effect. The potential for TFM to result in endocrine
disrupting effects on fish populations in treatment areas has been considered remote based on the fact that
streams are treated at most once every 3 to 5 years, exposure duration is less than 24 hours and TFM
has not been demonstrated to persist in treatment areas (Hewitt et al. 1998). However, the duration of
exposure to fish downstream of the application site has not been adequately characterized and thus the
potential for an endocrine disrupting effect cannot be dismissed.
1.
Terrestrial
TFM and niclosamide are only registered for use on aquatic sites. However, because numerous
avian, (waterfowl and shorebirds) and mammalian species (muskrats, beavers, raccoons and numerous
other small mammals) typically utilize aquatic environments as nesting and/or feeding habitats, and may
be exposed to TFM and niclosamide via contaminated water, there is some potential for exposure to
terrestrial species. Additionally, the; aerial application of the niclosamide 3.2% granular formulation may
serve as a route of exposure to nontarget terrestrial organisms.
Based on the available toxicity data mere is very little risk from either acute oral, acute dermal or
subacute dietary exposure to mammals or birds. Acute RQs for both birds and mammals (< 0.01) show
that mere is minimal risk from the concentrations likely even at a maximum treatment concentrations. In
addition, during the nearly forty years of TFM use to control the sea lamprey, mere are no actual field
reports documenting any acute mortality to avian or mammalian species.
There are no available chronic toxicity data for TFM or niclosamide for avian species. However,
because of the very low levels of exposure and the relatively short time that terrestrial species will be
exposed, chronic risk to terrestrial species is expected to be very low.
2. Aquatic
TFM and niclosamide are applied directly to water and maintained at a desired concentration for
a specified period of time, i.e., generally 12 hours. A number of environmental factors influence the
toxicity of TFM; these factors include stream/river discharge rate, pH, and temperature. Of all of the
water quality parameters investigated, pH had the greatest influence on the toxicity of TFM to aquatic
organisms as pH affects the availability and uptake of TFM by aquatic organisms. In general, the lower
the pH, die greater the uptake and thus, the greater the toxicity.
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TFM ranged in toxicity fiom slightly to highly toxic to freshwater fish. Based on 1 -hr LC50
values, acute high risk, acute restricted use and endangered species LOCs were exceeded for 33% of the
species tested while acute restricted use and endangered species LOCs were exceeded for all of the
species at predicted maximum treatment concentrations of 2.2 ppm. At the minimum predicted treatment
concentration of 0.7 ppm and based on 96-hr LC50 values, acute high risk, acute restricted use and
endangered species LOCs were exceeded for all of the species tested.
Studies described in NRCC (1985) have suggested that native lamprey (Ichthyomyzon spp. and
Lampetra spp.) are less sensitive (9-hr LC99 9 2.0 and 2.5 mg/L), than the sea lamprey (9-hr LC99 91.4
mg/L) and that this differential sensitivity may lessen the impact to native species.
TFM was slightly to moderately toxic to freshwater invertebrates; acute restricted use and
endangered species LOCs are exceeded for 67% of the aquatic invertebrates at the predicted minimum
concentration of 0.7 ppm in water pH 7.2 - 7.6. At the maximum treatment concentration of 2.2 ppm
for these waters, acute restricted use and endangered species LOCs were exceeded for 83% of the
aquatic invertebrates tested. Tricopterans appeared to be particularly sensitive to the effects of TFM.
Their sensitivity to die lampricide is consistent with the observation that bottom dwelling organisms that
feed on detritus may have increased exposure to the lampricide by ingestion of TFM-bound sediments
(pers. comm. Terry Bills, Fishery Biologist, U.S. Geological Survey Biological Resource Division 1999).
Since 1981, the U.S. Fish and Wildlife Service has examined the effect of lampricide applications on
more than 200 aquatic macroinvertebrates. Based on the data, it is estimated that greater than 95% of
the nontarget macroinvertebraes survive exposure to lampricide applications. Recovery of the 6 sensitive
nontarget organisms that were identified (Hexagenia, Litobranchia, Chimarra, Dolophilodes,
Glossosoma, and Simuljum) often begins within days or weeks after exposure, and the short- and long-
term diversity and health of the aquatic communities remains stable. The most apparent effect of TFM
based on field observations was an immediate reduction in macroinvertebrate density that was attributed
to increased downstream drift and mortality of sensitive organisms (NRCC 1985). Particulate feeding
macroinvertebrates were the most sensitive to the effects of TFM and may reflect increased uptake of
TFM by ingestion of TFM bound to paniculate matter.
The effects of niclosamide on non-target aquatic invertebrates from sea lamprey control
operations have been reported (Gilderhus, 1979). Although niclosamide treatment reduced the total
number of aquatic invertebrates by 56% in the first 7 days after treatment, this effect was transitory.
TFM was toxic to aquatic plants and resulted in the inhibition of growth; at concentrations of
greater than 35 ppm, TFM was herbicidal. Acute high risk and endangered species LOCs were
exceeded in 20% of the plants evaluated at 2.2 ppm TFM. There are limited data on the effects of
niclosamide on aquatic plants.
Since 1994, a broad range of nontarget mortality has been reported following application of both
TFM and niclosamide (document reference numbers 1008982-001 and 1008983). Nontarget mortality
affected 32 species offish, 4 species of amphibians, and 4 groups of invertebrates (Table 11) during
application of lampricides in tributaries of the Great Lakes, Lake Champlain, and Finger Lakes during
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1994 - 1998. The most notable fish kills have occurred following the aerial application of the 5%
granular formulation of niclosamide and resulted in approximately 169,000 fish killed. During September
1994, application of niclosamide to the Ausable River system, a tributary of Lake Champlain, killed
approximately 33,000 indigenous American brook lamprey (Lampetra appendix) and silver lamprey
(Ichthyomyzon unicuspis) combined. As recently as May 1999, nontarget fish mortality (log perch;
Percina caprodes) was reported following TFM applications and resulted from a downward shift in pH
in poorly buffered (low alkalinity) waters that increased the toxicity of TFM. These data indicate that
despite efforts to minimize impact to nontarget species, there are occasional situations where nontarget
mortality occurs. The incident reports on Lake Champlain suggest that nontarget mortality was enhanced
following aerial application of the 5% granular formulation of niclosamide. The magnitude of nontarget
mortality following this application verifies EPA's concern that aerial application of niclosamide is the least
controlled application method and as such is the most susceptible to nontarget mortality.
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Table 11: List of nontarget species or taxa experiencing mortality during application of lampricide in streams and
deltas of streams tributary to the Great Lakes, Lake Champlain and the Finger Lakes of the U. S. during 1994-
1998.
Invertebrates
annelids
Hexagenia
Phylum Annelida (segmented
worms: earthworms, aquatic
worms, and leeches)
Hexagenia spp.
burrowing mayflies
Mayflies
Family Ephemeridae
(burrowing mayflies)
Order Ephemeroptera
(mayflies)
Amphibians
frogs
Northern
two-lined salamander
Family Ranidae (frogs)
Eurycea hislineata
salamanders
red-spotted newt
Order Candata (salamanders)
Notrophtkaltnus viridescems
viridescens
Fishes
American brook lamprey
blacfcchin shiner
bluegill
bullheads
common shiner
emerald shiner
johnny darter
logperch
mimic shiner
Northern hog sucker
redhorses
silver iamprey
spottail shiner
suckers
tessellated darter
white sucker
Lampetra appendix
Notropis heterodon
Lepomis macrochirus
Ameiurus spp
Lusilus cornutus
Notropis alherinoides
Etheostoma nigrum
Percina caprodes
Notropis volucellus
Hypentelium nigricans
Moxostoma spp.
Ichthyomyzon unicuspis
Notropis hudsonius
Family Catastomidae
(suckers)
Etheostoma olmstedi
Catostomus commersoni
banded killifish
blacknose dace
brown bullhead
coiranon carp
creek chub
hornyhead chub
largemouth bass
longnose dace
minnows
perches
rock bass
smallmouth bass
stonecat
tadpole madtom
trout perch
fishes
Fundulus diaphanus
Rhinichthys atratulus
Ameiurus nebulosua
Cyprinus carpio
Semotilus atromaculatus
Nocomis biguttatus
Micropterus salmoides
jRhinichthys caiaractae
Family Cyprinidae (carps and
minnows)
Family Percidae (perches)
Ambloplites repestris
Micropterus dnlomieu
Noturusflavus
Noturus gyrinus
Per cops is omiscomaycus
Osteichthycs (bor ey fish)
Although adverse effects to certain species and/or taxa have been observed, the evidence
suggests that these effects are only transitory and do not threaten any populations of aquatic species.
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the treated areas usually occurs from untreated, upstream portions of the tributary although some
recolonization may also occur from sediments that were too deep to be exposed.
3.
Uncertainties
The environmental fate and ecological effects of TFM and niclosamide characterized in this
document are restricted to the specific treatment site and focus on the acute toxicity of the lampricides
given projected treatment levels selected to achieve a sea lamprey LC99 9 with little nontarget mortality.
Given the persistence of TFM and niclosamide, mitigation of their effects relies predominately on
the flushing action of the stream/river tributaries and eventual deposition and dilution in the Great Lakes.
Initial assessments of the ecological effects assumed that both TFM and niclosamide would not be
persistent in the treatment area and 'that the eventual dilution of both compounds in the Great Lakes
would render chronic-effect studies unnecessary. However, the Agency is uncertain to the degree to
which treatment site concentrations of TFM and niclosamide are rendered ineffective, meaning that the
potential for chronic effects is uncertain particularly in the mixing zones at the confluence of tributaries with
the Great Lakes. While the data suggest that treatment areas recover to pre-treatment community
structure, certain species are sensitive to the effects of TFM and niclosamide. Although the direct effects
of lampricide treatments have been partially characterized, the secondary effects on food chains and the
ability of nontarget species to feed during the recovery period is uncertain. Although the ecological data
gaps identified in this document may address uncertainties over potential chronic effects, the
environmental fate of TFM and niclosamide downstream of application sites, i.e., the stream/river deltas
is uncertain without monitoring studies to quantify TFM and niclosamide concentrations in the mixing
zones.
Also, chemical-specific uncertainties are that the potential effects of TFM as an endocrine
disrupter are difficult to characterize. Additionally, the newer formulations of niclosamide (3.2% granular)
that result in its slow release along the stream/river bottom pose an unknown risk in terms of both acute
and chronic toxicity to nontarget sediment-dwelling organisms.
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IV. RISK MANAGEMENT AND REREGISTRATION DECISION
A. Determination of Eligibility
Section 4(g)(2)(A) of HFRA calls for the Agency to determine, after submission of relevant date
concerning an active ingredient, whether products containing die active ingredient are eligible for
reregistration. The Agency has previously identified and required the submission of the generic (i.e. active
ingredient specific) data required to support reregistration of products containing TFM and niclosamide
as active ingredients. The Agency has completed its review of these generic data, and has determined
that the data are sufficient to support reregistration of all products containing TFM and niclosamide.
Appendix B identifies the generic data requirements that the Agency reviewed as part of its determination
of reregistration eligibility of TFM and niclosamide, and lists the submitted studies that die Agency found
acceptable.
The data identified in Appendix B were sufficient to allow the Agency to assess the registered
uses of TFM and the lampricide uses of niclosamide, and to determine that TFM and niclosamide can be
used as low volume, restricted use compounds, as specified in mis document, without resulting in
unreasonable adverse effects to humans and the environment The Agency therefore finds that all
products containing TFM and niclosamide as the active ingredients are eligible for reregistration. The
reregistration of particular products is addressed for lampricide uses in Section V of this document.
The Agency made its reregistration eligibility determination based upon the data required for
reregisteation, the current guidelines for conducting acceptable studies to generate such data, published
scientific literature, and die data identified in Appendix B. Although the Agency has found that all uses of
TFM and niclosamide are eligible for reregistration, it should be understood that the Agency may take
appropriate regulatory action, and/or require the submission of additional data to support the registration
of products containing TFM and niclosamide, if new information comes to the Agency's attention or if the
data requirements for registration or (he guidelines for generating such data) change.
B. Determination of Eligibility Decision
1. Eligibility Decision
Based on the reviews of the generic data for the active ingredients TFM and niclosamide, the
Agency has sufficient information on the health effects of TFM and niclosamide and on its potential for
causing adverse effects in fish and wildlife and the environment Although the current database is limited,
this finding of sufficient information is based on the limited use pattern, stringent use restrictions mandated
by the USFWS and the PPE required on current labels. The Agency has determined mat TFM and
niclosamide products, labeled and used as specified in this Reregistration Eligibility Decision, will not pose
unreasonable risks of adverse effects to humans or the environment. Therefore, the Agency concludes
that products containing TFM and niclosamide for all uses are eligible for reregistration.
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2. Eligible and Ineligible Uses
The Agency has determined that all uses of TFM and niclosamide for control of Sea Lamprey are
eligible for reregistration under the conditions specified in this RED.
The niclosamide Special Local Needs labels for use in ornamental fish ponds should result in
minimum exposure to humans and non-target organisms and are eligible for reregistration under the
conditions specified in this RED assuming monitoring programs similar to those conducted by the U.S.
Fish and Wildlife Service (USFWS) are instituted for these uses. These monitoring programs include
medical monitoring for applicators, a routine industrial hygiene program, an incident reporting system, and
comprehensive use records.
The Agency has determined that the mollusicide use of niclosamide for human health purposes is
not eligible for reregistration due to lack of data on the use and potential non-occupational exposure of
humans to niclosamide. According; to the Public Health Service at the Centers for Disease Control and
Prevention, there are currently no public health uses for niclosamide in the United States. The currently
labeled public health use is the use of Bayluscide 70% Wettable Powder (EPA Registration Number
6704-87) in Puerto Rico against fresh water snails serving as the vector for schistosomiasis.
Niclosamide has not been used in Puerto Rico since 1980. This use is ineligible for reregistiation at mis
time. In order for this use to be eligible for reregistration, a minimum of use information, application
methods summary, and a 21-28 day dermal toxicity study (OPPTS 870.3200) are required.
The USFWS has submitted a voluntary cancellation letter for Bayluscide 5% Granular (EPA
Registration Number 6704-90) which was used to kill snails serving as the vector for swimmer's itch in
MI,WI,andMN.
C. Regulatory Position
The Agency recognizes the efforts of the USFWS and the Great Lakes Fisheries Commission to
lessen the risks posed by TFM and niclosamide, by the use of extensive monitoring, IPM measures,
public notification and worker training. In order to support these efforts EPA is requiring the following
clarification measures for TFM and niclosamide containing products.
• The manual for application must be cited on the label and must be available to all workers.
The required PPE must be clearly stated on the label.
• The label must prohibit aerial applications.
There are currently two Special Local Needs (SLN) labels issued for niclosamide; both labels are
for the Bayluscide 70% Wettable Powder formulation. These labels are for the use of Bayluscide in
ornamental fish ponds in Florida (SLN FL94000100) and Arkansas (SLN AR99000700). This use is
to kill fresh water snails which infect the fish. The empty pond is treated with Bayluscide at 1 Ib
formulated product per acre of surface area; the pond is then filled with water. Fish are usually added to
the pond in four to seven days. The labels require an NPDES permit for discharging the water from the
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pond, but in practical terms, the water is rarely released without treatment There have been no fish
toxicity incidents reported from this use.
The risk assessment calculations reported for risks to humans were made with the following
assumptions:
(1) The manual developed for the use of TFM and niclosamide by the USFWS will be
adopted by any user of these compounds (i.e., add it as a requirement on all labeling).
Manual for Application ofLampricides in the U.S. Fish and Wildlife Service Sea
Lamprey Control Program including Standard Operating Procedures (1993).
(2) The USFWS administers a comprehensive medical monitoring program for their
employees engaged in any activities involving the use of TFM and niclosamide.
(3) A routine industrial hygiene monitoring program is conducted to quantify exposures for
those occupationally exposed to TFM and niclosamide (in lieu of completing a
comprehensive pesticide guideline exposure study)
(4) The USFWS will maintain an incident reporting system.
(5) A record keeping system to document the use of TFM and niclosamide will also be
maintained by the USFWS. Such a system should be able to document chemical use,
locations, dates, site-specific data (e.g., water concentrations and amount used), efficacy,
incidents, and any postapplication follow-up required. This system could be used to
assess a relationship between the use of TFM and niclosamide and incidents and illnesses
should they occur.
The purpose of these monitoring and reporting systems is to verify that EPA's assumptions of low
exposure are correct and to ensure that potentially exposed populations are adequately protected.
The following is a summary of the Agency's regulatory position and rationale for managing risks
associated with the use of TFM/niclosamide. Where labeling revisions are imposed, specific language is
set forth in Section V of this document.
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1. Food Quality Protection Act Findings
a. Determination of Safety for U.S. Population
The Agency has determined that there is no reasonable expectation of humans being exposed to
TFM or niclosamide residues in the diet via water, fish, irrigated crops, and livestock due to the low use
volume, the infrequency of use and the tight control USFWS has over the use of TFM and niclosamide
including 24-hr irrigation and potable water intake restrictions. There are no established tolerances for
TFM or niclosamide.
There are no residential uses and residential exposure is expected to be neglible.
If the Agency determines, as a result of later implementation process of FQPA, mat any of die
determinations described in this RED are no longer appropriate, the Agency will consider itself tree to
pursue whatever action may be appropriate, including but not limited to, reconsideration of any portion of
this RED.
b. Endocrine Disrupter Effects
TFM treatments have been associated with induction of hepatic mixed function oxygenase
activity and altered levels of circulating steroids in fish and induced hepatic vitellogenesis in primary
cultures of rainbow trout hepatocytes (Hewitt et al. 1998). As such, TFM acts as an esteadiol agonist
and has a demonstrated endocrine disrupting effect.
EPA is required to develop a screening program to determine whether certain substances
(including all pesticides and inerts) "may have an effect in humans that is similar to an effect produced by a
naturally occurring estrogen, or such other endocrine effect..." The Agency is currently working with
interested stakeholders, including other government agencies, public interest groups, industry and
research scientists in developing a screening and testing program and a priority setting scheme to
implement this program. EPA may require further testing of TFM active ingredient and end use products
for endocrine disrupter effects when this program is in place.
2.
Tolerance Reassessment
TFM has been classified as a low-volume and nonfood use chemical based on the quantity used,
the method of application, and the rapid dissipation of any possible residues in fish and water. Therefore,
a dietary risk assessment is not required for TFM and there are no tolerances.
3.
Benefits from Use of TFM/Niclosamide
Although no formal benefits analysis was conducted for TFM and niclosamide, an informal
analysis was provided by the USFWS. Sea Lampreys were introduced to the Great Lakes when the
Welland Canal opened in 1829. These parasitic organisms are very destructive to commercial and sport
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fish species in the Great Lakes. A variety of IPM measures including traps, weirs and a sterilized male
program are in place to try to control the adult sea lamprey population; however, these measures are only
partially successful. The TFM/niclosamide treatment program managed by the Great Lakes Fisheries
Commission is necessary to protect commercial and sport fish populations in the Great Lakes.
4. Human Health Risk Mitigation
Worker Mitigation
Risk From Handler Exposure: Based on two worker exposure scenarios for.TFM, workers are
not at unreasonable risk from TFM use. The exposure assessments indicate that workers are primarily
at risk to dermal, rather than inhalation exposure. The exposure scenarios were calculated using
application information from 41 applications made in tributaries to the Great Lakes in 1997. The
backpack application scenarios were calculated assuming that 1% of the total applied could be applied
by backpack spray. The margins of exposure (MOE) were calculated taking into account the PPE
required in the Fish and Wildlife Services Manual for Pesticide Application which is a double layer of
clothing, rubber boots, chemical resistant gloves for TFM, and a respirator. However, respirators are
only required in poorly ventilated areas and are not required for general (open air) applications. MOEs
calculated with double layers of clothing, rubber boots and chemical resistant gloves, but with no
respirators are still above 100 except for three large application scenarios which have MOEs of 66,68,
and 96. These applications would not be made by one person during one day; therefore, the Agency has
determined that the MOEs for TFM are above the level of concerns and a respirator is not required for
workers handling or applying TFM.
The TFM and niclosamide labels must be updated to clarify the double layer clothing and to
ensure that me labels are consistent with the Manual for Lampricide Applications.
No risk assessment was conducted for niclosamide based on the low volume of use; therefore,
the Agency is recommending to retain the PPE and use restrictions which are currently on the niclosamide
labels.
Table 12 outlines the handler PPE required on the various TFM and niclosamide labels. No
engineering controls are required. Although EPA has no data to specifically assess the exposure
reduction to mixers/loaders afforded by a chemical-resistant apron, the Agency is persuaded that the
exposure reduction would be significant for this chemical. Available data indicate mat the preponderance
of non-hand exposure to mixers/loaders/applicators and other handlers is to the front torso. Therefore,
for mixers/loaders/applicators and other handlers the use of a chemical-resistant apron is probably
approximately equivalent to double-layer body protection.
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Table 12. Summary of Worker Protection Requirements for TFM and Niclosamide
Exposure Scenario
Mixing/Loading
Applying with metered pump.
Applying with backpack sprayer
PPE Required
TFM
face shield, double layer of clothing, rubber boots, and
chemical resistant gloves
face shield, double layer of clothing, rubber boots, and
chemical resistant gloves
face shield, double layer of clothing, rubber boots, and
chemical resistant gloves.
Niclosamide
Mixing/Loading/ Applying 70% Wettable Powder
Formulation
Mixing/Loading/Applying 3.2% Granular
applications
face shield, double layer of clothing, rubber boots, chemical
resistant gloves, NIOSH approved PF-10 respirator
face shield, double layer of clothing, rubber boots, chemical
resistant gloves, NIOSH approved PF-10 respirator.
Other Risks: No residential exposures or occupational post-application exposures are expected
from die approved registered uses of TFM and niclosamide given compliance with the USFWS
regulations.
5. Ecological Risk Mitigation
Mammalian and Avian Mitigation
Aerial applications are to be prohibited on all new labels in order to lessen chances of exposures
to nontarget terrestrial animals. Several of the fish kills reported to the Agency were the result of aerial
applications of the product which is being voluntarily canceled
There should be very limited exposure to terrestrial animals and, therefore, low risk to most birds
and mammals. The USFWS limits applications in order to avoid disturbing nesting osprey. No further
mitigation is necessary for terrestrial systems.
Aquatic Species Mitigation
Although application rates are carefully monitored and adjusted to minimize impact to nontarget
aquatic organisms, the analysis of the environmental fate and ecotoxicity indicates that current application
rates will impact non-target aquatic organisms. When the combination of TFM and niclosamide are
applied, the toxic effects of TFM are potentiated. The extent or degree of adverse effects in the
treatment area depends on stream/river discharge rate, pH, hardness and water temperature. Although
TFM is likely to have an immediate! effect on the aquatic community in the treatment area, the data
suggest that most organisms recover quickly and the treatment area community structure returns to pre-
-------
treatment conditions within approximately 6 months (Kolton et al.,1986). Additionally, a genuine effort is
made to document where sensitive populations reside and steps are undertaken to avoid treatments at
concentrations known to be toxic to these organisms. Some areas are not treated because of the
sensitive or endangered species concerns. The long-term effects to more sensitive species, e. g.,
indigenous lampreys, lake sturgeon and Mayflies, and to aquatic communities downstream from the
treatment sites where chronic effects are more likely, remain uncertain.
The goal of The Great Lakes Fishery Commission is to control the sea lamprey populations and
not to eradicate the sea lamprey. The Commission has targeted that the reliance on lampricides be
reduced by 50%. Through a combination of physical barriers, sterile male release and fine tuning of
lampncide applications, lampricide use has been reduced by 35% compared to levels used in the 1980's.
To further reduce chemical reliance while controUing the lamprey populations, the Commission has
recommended that additional research be conducted on the use of pheromones to serve as attractants to
traps and treatment areas, the use of TFM/niclosamide mix, and the use of lampricide formulations that
better direct treatments to habitats favored by larval sea lamprey.
6. Labeling Rationale
a. Occupational Risk Mitigation
The Worker Protection Standard (WPS)
At this time none of the registered uses of TFM and niclosamide are within the scope of the
Worker Protection Standard for Agricultural Pesticides (WPS).
(1) Personal Protective Equipment for Handlers (Mixers, Loaders,
Applicators, etc.)
For each end-use product, PPE requirements for pesticide handlers are set during reregistration
in one of two ways:
1. If EPA determines that no regulatory action must be taken as the result of the acute effects or other
adverse effects of an active ingredient, the PPE for pesticide handlers will be based on the acute toxicity
of the end-use product. For occupational-use products, PPE must be established using the process
described in PR Notice 93-7 or more recent EPA guidelines.
2. If EPA determines that regulatory action on an active ingredient must be taken as the result of very high
acute toxicity or certain other adverse effects, such as allergic effects or systemic effects (cancer,
developmental toxicity, reproductive effects, etc.):
• In the RED for that active ingredient, EPA may establish minimum or "baseline" handler
PPE requirements that pertain to all or most end-use products containing that active
ingredient.
53
-------
• These minimum PPE requirements must be compared with the PPE that would be
designated on the basis of the acute toxicity of the end-use product.
• The more stringent choice for each type of PPE (i.e., bodywear, hand protection,
footwear, eyewear, etc.) must be placed on the label of the end-use product.
The Agency concurs with fee PPE requirements for TFM and niclosamide which are currently
specified in the USFWS manual for application. For TFM, the requirements are two layers of doming,
rubber boots, and chemical resistant gloves. For niclosamide, the requirements are two layers of clothing,
rubber boots, chemical resistant gloves, a face shield and an approved organic vapor resistant respirator.
Although EPA has no data to specifically assess the exposure reduction to mixers/loaders afforded by a
chemical-resistant apron, the Agency is persuaded that the exposure reduction would be significant for
this chemical. Available data indicate that the preponderance of non-hand exposure to
mixers/loaders/applicators and other handlers is to the front torso. Therefore, for
mixers/loaders/applicators and other handlers the use of a chemical-resistant apron is probably
approximately equivalent to double-layer body protection.
b. Occupational-Use Products
NonWPS Uses: EPA's evaluation of the dermal and inhalation toxicity of TFM indicates that
significant toxicity from either route of exposure is unlikely with the PPE specified by the USFWS manual
for application of lampricides. Only very large applications (greater than 1500 kg/treatment) yielded
MOEs less than 100; and it is unlikely these large applications would be made by one applicator during
one day.
No toxicity endpoints were chosen for niclosamide based on the low volume of use; therefore, so
no worker risk assessment was done. The Agency concurs with the PPE currently required on fee
niclosamide labels.
4. Post-Application/Entry Restrictions
a. Occupational-Use Products
Restricted-Entry Interval: Due to the nature of the TFM and niclosamide use patterns, no
significant occupational postapplication exposure scenarios are thought to exist. There are no specified
worker re-entry intervals.
b. Other Labeling Requirements
The Agency is also requiring other use and safety information to be placed on the labeling of all
end-use products containing TFM/niclosamide. For the specific labeling statements, refer to Section V of
this document
54
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c. Endangered Species Statement
Currently, the Agency is developing a program ("The Endangered Species Protection Program")
to identify all pesticides whose use may cause adverse impacts on endangered and threatened species
and to implement mitigation measures that will eliminate the adverse impacts. The program would require
use restrictions to protect endangered and threatened species at the county level. Consultations with the
Fish and Wildlife Service may be necessary to assess risks to newly listed species or from proposed new
uses. In the future, the Agency plans to publish a description of the Endangered Species Program in the
Federal Register and have available voluntary county-specific bulletins. Because the Agency is taking this
approach for protecting endangered and threatened species, it is not imposing label modifications at this
time through the RED. Rather, any requirements for product use modifications will occur in the future
under the Endangered Species Protection Program.
V. ACTIONS REQUIRED OF REGISTRANTS
This section specifies the data requirements, responses and labeling changes necessary for the
reregistration of both manufacturing-use and end-use products.
A. Manufacturing-Use Products
1. Additional Generic Data Requirements
The generic data base supporting the reregistration of TFM and niclosamide for the eligible uses
has been reviewed and determined to be complete enough to make an assessment for the limited use
pattern and low volume usage of these restricted use compounds. The following data gaps remain and
these confirmatory data are still required:
Table 13: Data gaps for TFM and Niclosamide.
TFM
Niclosamide
New Guideline #
835-2240
835-2240
835^300
835-4400
Old Guideline*
161-2
161-2
162-4
162-3
Description
Photodegradation in water.
Photodegradation in water.
Aerobic aquatic metabolism
Anaerobic aquatic metabolism
The chronic ecotoxicity data requirements listed below are data gaps, but the requirements are
being held in reserve pending the results of a currently ongoing monitoring study which the USFWS is
conducting.
55
-------
Table 14: Data requirements held in reserve for TFM and Niclosamide.
TFM
Niclosamide
TFM/Niclosamide mixture
New Guideline #
850.1300
850.1. '500
850-1790
850.1500
850.1300
Old Guideline*
72-4b
72-5
—
72-5
72-4b
Description
Aquatic invertebrate life cycle
Fish full life cycle
Chronic sediment toxicity testing
Fish full life cycle
Aquatic invertebrate life cycle
Additionally, EPA may require further testing of this active ingredient and end use products for
endocrine disrupter effects when the endocrine disrupter test program is in place.
2. Labeling Requirements for Manufacturing-Use Products
To remain in compliance with FIFRA, manufacturing use product (MP) labeling must be revised
to comply with all current EPA regulations, PR Notices and applicable policies. The MP labeling must
bear the labeling contained in the table at the end of this section.
In addition, one of the following statements may be added to a label to allow reformulation of the
product for a specific use or ail additional uses supported by a formulator or user group.
"This product may be used to formulate products for specific use(s) not listed on the MP label if the
formulator, user group, or grower has complied with U.S. EPA submission requirements regarding
support of such use(s)."
"This product may be used to formulate products for any additional use(s) not listed on the MP label
if the formulator. user group, or grower has complied with U.S. EPA submission requirements
regarding support of such use(s)."
If included, mis statement should be placed in the Directions for Use section of the label.
B. End-Use Products
1. Additional Product-Specific Data Requirements
Section 4(gX2XB) of FIFRA calls for the Agency to obtain any needed product-specific data
regarding the pesticide after a deteimination of eligibility has been made. Registrants must review previous
data submissions to ensure that they meet current EPA acceptance criteria and if not, commit to conduct
new studies. If a registrant believes that previously submitted data meet current testing standards, then
study MRID numbers should be tiled according to the instructions in the Requirement Status and
Registrants Response Form provided for each product.
56
-------
2. Labeling Requirements for End-Use Products
Label changes are necessary to implement mitigation measures outlined in Section IV above.
Specific language to implement these changes is specified in the following table.
C. Required Labeling Changes Table Summary (Following Page)
57
-------
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Table 15: Summary of Required Labeling Changes for TFM
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water when cleaning equipment or disposing of equipment washwaters."
"Local, State, and Provincial Fish and Game Agencies must be contacted before product is
Municipalities that use streams requiring treatment as potable water sources must be notifl
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source of irrigation water must be notified of the impending treatment at least 24 hours prio
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D. Existing Stocks
Registrants may generally distribute and sell products bearing old labels/labeling for 26 months from
the date of the issuance of this Reregistration Eligibility Decision (RED). Persons other than the registrant
may generally distribute or sell such products for 50 months from the date of the issuance of this RED.
However, existing stocks time frames will be established case-by-case, depending on the number of products
involved, the number of label changes, and other factors. Refer to "Existing Stocks of Pesticide Products;
Statement of Policy"; Federal Register. Volume 56, No. 123, June 26,1991.
In accordance with the above policy, the Agency has determined mat registrants may distribute and
sell TFM and niclosamide products bearing old labels/labeling for 26 months from (he date of issuance of this
RED. Persons other than the registrant may distribute or sell such products for 50 months from the date of
the issuance of this RED. Registrants and persons other man registrants remain obligated to meet pre-existing
Agency imposed label changes and existing stocks requirements applicable to products they sell or distribute.
65
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66
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